university of groningen gestational diabetes mellitus ...€¦ · journal of diabetes....

University of Groningen

Gestational diabetes mellitus: diagnosis and outcomeKoning, Saakje Hillie

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.

Document VersionPublisher's PDF, also known as Version of record

Publication date:2017

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):Koning, S. H. (2017). Gestational diabetes mellitus: diagnosis and outcome: Need for a revision of theDutch perspective?. Rijksuniversiteit Groningen.

CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.

Download date: 27-03-2021

https://research.rug.nl/en/publications/gestational-diabetes-mellitus-diagnosis-and-outcome(7939314f-9fcb-4c68-ba21-5159a148b184).html

Gestational diabetes mellitus: diagnosis and outcome

Need for a revision of the Dutch perspective?

Saakje H. (Sarah) Koning

Gestational diabetes mellitus: diagnosis and outcomeNeed for a revision of the Dutch perspective?

Thesis, University of Groningen, the Netherlands

Lay-out: Ridderprint BV – www.ridderprint.nlPrinting: Ridderprint BV – www.ridderprint.nl

ISBN: 978-94-034-0158-4 (printed) 978-94-034-0157-7 (eBook)

Copyright © S.H. (Sarah) Koning 2017All rights reserved. No parts of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means without prior written permis-sion of the author.

The studies in this thesis have been supported with an unrestricted research grant of Novo Nordisk Nederland.Publication of this thesis was financially supported by: The Endocrinology Fund (as part of the Ubbo Emmius Fund), Graduate School of Medical Sciences/University Medical Center Groningen and University of Groningen.

Gestational diabetes mellitus: diagnosis and outcome

Need for a revision of the Dutch perspective?

Proefschrift

ter verkrijging van de graad van doctor aan deRijksuniversiteit Groningen

op gezag van derector magnificus prof. dr. E. Sterken

en volgens besluit van het College voor Promoties.

De openbare verdediging zal plaatsvinden op

maandag 27 november 2017 om 14.30 uur

door

Saakje Hillie Koning

geboren op 29 december 1989te Zuidhorn

PromotoresProf. dr. B.H.R. Wolffenbuttel Prof. dr. P.P. van den Berg

CopromotoresDr. H.L. Lutgers Dr. K. Hoogenberg

BeoordelingscommissieProf. dr. H.M. Boezen Prof. dr. G.H.A. Visser Prof. dr. C. Mathieu

ParanimfenDrs. E.G. Gruppen S. van Gosliga

CONTENTS

Chapter 1 Introduction and aim of the thesis 9Chapter 2 Gestational diabetes mellitus: current knowledge and unmet

needs21

Journal of Diabetes. 2016;8:770-781

PART A EVALUATION OF THE CURRENT NATIONAL DUTCH GUIDELINEChapter 3 Neonatal and obstetric outcomes in diet- and insulin-treated

women with gestational diabetes mellitus: a retrospective study

47

BMC Endocrine Disorders. 2016;16:52

Chapter 4 Risk stratification for healthcare planning in women with gestational diabetes mellitus

67

Netherlands Journal of Medicine. 2016;74:262-269

Chapter 5 Thyroid function and maternal and neonatal outcomes in women with gestational diabetes mellitus

83

Submitted

Chapter 6 Postpartum glucose follow-up and lifestyle management after gestational diabetes mellitus: general practitioner and patient perspectives

101

Journal of Diabetes & Metabolic Disorders. 2016;15:56

PART B EVALUATION OF NEW INTERNATIONAL DIAGNOSTIC CRITERIAChapter 7 New diagnostic criteria for gestational diabetes mellitus and

their impact on prevalence and pregnancy outcomes 121

Submitted

Chapter 8 Pregnancy outcomes in women with gestational diabetes mellitus diagnosed according to the WHO-2013 and WHO-1999 diagnostic criteria: a multicentre retrospective cohort study

145

Submitted

Chapter 9 Summary, general discussion, and future perspectives 161

Dutch summary 183Acknowledgements/Dankwoord 195About the author and list of publications 201

1 Introduction and aim of the thesis

Introduction

11

1GESTATIONAL DIABETES MELLITUS

Gestational diabetes mellitus (GDM) is one of the most common metabolic com-plications during pregnancy, and affects up to 14% of all pregnancies.1,2 The preva-lence of GDM is difficult to estimate as it largely depends on the population studied and the diagnostic criteria applied.1,2 Nationwide data on the prevalence of GDM in the Netherlands are scarce, but the estimated prevalence varies between 2-5%.3 Worldwide, the prevalence of GDM is still rising due to an increasing number of women with overweight and obesity during reproductive age and also the (recent) introduction of more stringent diagnostic criteria.2,4-6 Approximately 14% to 20% of women of reproductive age are obese in developed countries.7

GDM is characterized as a medical condition in pregnancy in which women without previously diagnosed diabetes mellitus (DM) exhibit high blood glucose levels (hyperglycaemia) during pregnancy, classically developing during the second or third trimester. For women diagnosed with GDM in the first trimester of preg-nancy, pre-existing DM or Maturity-Onset Diabetes of the Young (MODY) should be considered. In most of the women with GDM, blood glucose levels return to normal values after delivery.8

Physiology and pathophysiology In pregnancy maternal metabolic changes occur to ensure continuous supply of nutrients for foetal development and growth.9 Early pregnancy is characterized as an “anabolic state” and nutrients are stored in maternal tissue. In contrast, late pregnancy is more characterized as a “catabolic state”.10 During second and third trimester of pregnancy as the foetus starts to grow exponentially, its need for fuel (glucose) also rises exponentially. To facilitate glucose across the placenta there is an increase in maternal insulin resistance (decreased insulin sensitivity).10,11 This decrease in the insulin-mediated glucose disposal in peripheral muscle cells of the mother, accommodates the increased foetal glucose demands.11 The physiological factors partially responsible for the increase in insulin resistance are the combination of increased maternal adiposity and in the insulin-desensitizing effects of placental hormones, including human placental lactogen, progesterone, corticotrophin-releasing hormone, and estrogen.11,12,13 To maintain normal glucose control during pregnancy, the pancreatic β-cells of the mother have to increase insulin secretion to meet the increased insulin requirements.12,13

The development of GDM occurs when the woman’s pancreatic function fails to compensate for the increased resistance to insulin.12 Studies have suggested that a majority of the women with GDM already have pancreatic β-cell dysfunction and/or chronic insulin resistance before pregnancy.11,12,13

Chapter 1

12

PREGNANCY COMPLICATIONS

Comparable with pre-existent maternal DM in pregnancy, GDM is also associated with an increased risk of complications for both mother and child. These complica-tions are attributed to the effects of uncontrolled hyperglycaemia in the second and third trimester of pregnancy. It has been demonstrated that there is a graded linear association between maternal blood glucose concentrations and the risk of adverse pregnancy outcomes.14-16 Moreover, there is growing evidence of long-term health consequences for both mother and child.17-21

Short-term complicationsThe presence of GDM can adversely affect neonatal and maternal outcomes dur-ing pregnancy and childbirth. When GDM pregnancy remains untreated, the neo-nate is exposed to elevated blood glucose levels. Maternal insulin cannot cross the placental barrier, as a result the neonate increases its own insulin production, resulting in foetal hyperinsulinaemia.22 The combination of hyperinsulinaemia and hyperglycaemia will lead to excessive foetal growth (Fig. 1).22,23 Excessive foetal growth is also called “macrosomia”, and at delivery macrosomia is defined as a birth weight >4000 gram or “large for gestational age” (LGA), defined as a birth weight >90th percentile. Excessive foetal growth is one of the most common complications of GDM and can lead to an increased risk of birth injury (shoulder dystocia) and maternal morbidity from instrumental vaginal delivery or caesarean section.22,23

Other neonatal complications associated with GDM include neonatal hypogly-caemia, neonatal hyperbilirubinaemia (jaundice), preterm delivery, and admission to the neonatology department.15,24-26 Additionally, GDM increases the maternal risk of hypertensive disorders during pregnancy like pregnancy-induced hypertension and preeclampsia.15,25

FIGURE 1. Pathophysiology of foetal macrosomia in GDM (Pedersen’s hypothesis).

Introduction

13

1Long-term complicationsAlthough in most of the women with GDM blood glucose levels return to normal values after delivery, GDM is a strong predictor to develop future impaired glucose tolerance and type 2 DM (T2DM). Epidemiological studies have demonstrated that the risk of developing T2DM may be as high as 50% in the first 5-10 years postpar-tum.17,18 In addition, recent studies have suggested that women with a history of GDM also carry an increased risk for cardiovascular diseases.27-29

Several studies have indicated that children born to mothers with GDM also have an increased risk to develop obesity, metabolic syndrome, and T2DM.19-21 However, this topic is still contradictory and awaiting confirmation.30,31

DETECTION AND TREATMENT

Intervention studies have clearly shown that GDM is a treatable condition and that adequate glucose control during pregnancy can effectively decrease pregnancy complications such as excessive foetal growth, shoulder dystocia, caesarean deliv-ery, and hypertensive disorders.32,33 National and international guidelines recom-mend to screen for GDM. However, there is no worldwide uniformly accepted and implemented guideline for screening and diagnosis of GDM.34 In the Netherlands, the Dutch Society of Obstetrics and Gynaecology developed a guideline “Diabetes and Pregnancy” for the screening, diagnosis and treatment of GDM, which was implemented in 2010.35 This guideline focuses on active screening and treatment policy provided by “usual care”, where its diagnostic cut-off values are primarily based on the World Health Organization (WHO) criteria originating from 1999.36 The latter largely differ from recent updates in diagnostic criteria by the Interna-tional Association of Diabetes and Pregnancy Study Group (IADPSG) and WHO-2013 thresholds for diagnosis of GDM.37,38

Screening and diagnosis GDM is seldomly recognized because of hyperglycaemic symptoms and is mostly diagnosed by a screening oral glucose tolerance test (OGTT). According to the Dutch national guideline, screening for GDM is recommended in women with one or more risk factors for GDM or signs suggestive of GDM (e.g. foetal macrosomia and/or polyhydramnios). Risk factors related to GDM are: having a pre-gestational body mass index ≥30 kg/m2; having a previous infant weighing ≥4500 gram at birth or a birth weight >95th percentile; having a first degree relative with DM; having a his-tory of GDM, (unexplained) intrauterine foetal death or polycystic ovary syndrome; and belonging to an ethnic risk group (South-Asian i.e. Hindu, Afro-Caribbean,

Chapter 1

14

Middle-Eastern i.e. Moroccan and Egyptian). Pregnant women carrying at least one GDM risk factor should therefore be routinely screened with an OGTT between 24 and 28 weeks of gestation. Women with a history of GDM are screened between 16 and 18 weeks of gestation and between 24 to 28 weeks of gestation.35

The Dutch national guideline recommends the one-step screening strategy for GDM. The one-step screening strategy means the single use of a 75-g OGTT, whereby GDM is diagnosed on the basis of one abnormal value for either the fasting or the two-hour glucose levels. GDM is diagnosed when the fasting plasma glucose exceeds 7.0 mmol/l and/or 2-h glucose value ≥7.8 mmol/l after the 75-g glucose load.35 The values of the diagnostic criteria are based on the old WHO-1999 consen-sus and have until now not been updated to the newest IADPSG/WHO-2013 criteria (75-g OGTT; fasting plasma glucose ≥5.1 mmol/l; and/or 1-h glucose value ≥10.0 mmol/l; and/or 2-h glucose value ≥8.5 mmol/l).36-38

Treatment The main goal of treatment of GDM is to maintain adequate glucose levels dur-ing pregnancy. Lifestyle changes (healthy eating and exercise) are often sufficient to achieve adequate glucose control. Therefore, the first step of GDM treatment is nutritional advice by a dietician, which includes advice about carbohydrate distribution and carbohydrate intake. Moreover, women receive advice regarding self-monitoring of the blood glucose values by a diabetes specialist nurse. Treat-ment targets for GDM are a fasting plasma glucose level ≤5.3 mmol/l and/or one-hour postprandial plasma glucose level ≤7.8 mmol/l.35 When dietary advice fails to maintain glycaemic control, insulin therapy is the second step in GDM treatment. To date, the use of insulin therapy is the medication of choice in GDM as recom-mended in most international guidelines, although there is debate whether oral blood glucose-lowering agents may have a place in the treatment. In the United Kingdom, metformin has already been incorporated into the “National Institute for Health and Care Excellence” (NICE) guideline.39

Glucose testing after pregnancy is very important to reduce the rising T2DM pandemic. In the Netherlands, women are advised to visit the general practitioner (GP) at six weeks after delivery and subsequently once a year for the next five years for follow-up glucose testing.35,40 Moreover, the GP can motivate women to adopt and maintain a healthy lifestyle to prevent T2DM.

International guidelinesAlthough screening, diagnosis and treatment of GDM importantly reduce the risk connected to GDM, international guidelines on diagnostic cut-off values and treat-

Introduction

15

1ment vary and are predominantly the result of consensus instead of well-defined controlled outcome studies.

Chapter 2 provides a more extensive overview of the different diagnostic cri-teria and treatment modalities worldwide and the reasons for the discrepancies. In Chapter 2 we describe both the current knowledge regarding GDM and the unmet needs of this condition. We review the diagnostic criteria, different treat-ment regimens available (including diet, insulin therapy and the use of oral blood glucose-lowering agents), and the long-term consequences of GDM.

AIM AND OUTLINE OF THE THESIS

The Dutch Society of Obstetrics and Gynaecology guideline “Diabetes and Pregnan-cy” for the screening and treatment of GDM, was implemented in 2010 and largely follows the older WHO-1999 diagnostic criteria. However, new insights regarding hyperglycaemia during pregnancy have been reported and this has led to a national and international debate regarding the diagnosis and treatment of GDM encour-aged by the newer more stringent diagnostic criteria proposed by the IADPSG/WHO-2013. There is much uncertainty regarding the optimal glucose thresholds to define GDM.

Therefore, the aim of this thesis is to evaluate the current Dutch national guidelines for diagnosis and treatment of GDM i.e. what is the outcome of GDM pregnancies using this guideline? And what are consequences when the current diagnostic criteria of GDM are to be revised?

Outline of the thesisThis thesis comprises two parts. In the first part we evaluate the current Dutch national guidelines for diagnosis and treatment of GDM. In the second part we evaluate the pregnancy outcomes with respect to the new international diagnostic criteria for GDM compared with the current diagnostic thresholds.

In Chapter 2 an overview of the different diagnostic criteria and treatment mo-dalities worldwide is presented, and the unmet needs of this condition are outlined.

The first part consists of the Chapters 3, 4, 5 and 6 and describes the outcomes of the current Dutch national guidelines for GDM. In Chapter 3 we aimed to evalu-ate the neonatal and obstetric outcomes of pregnancies complicated by GDM after implementation of the 2010 Dutch Society of Obstetrics and Gynaecology “Diabetes and Pregnancy” guideline on screening and treatment. The pregnancy outcomes were compared between diet- and insulin treated women. In addition, we com-

Chapter 1

16

pared the GDM outcomes with the general obstetric population in the northern region of the Netherlands. We hypothesized that women treated with insulin are more likely to have adverse pregnancy outcomes and deliver children with a higher birth weight, due to a greater difficulty to maintain glycaemic control. In Chapter 4 we aimed to allow the recognition of a more “complex-care” group of insulin-treated women with GDM, but on the other hand a potential “low-risk” group of women treated with diet alone and likely to have good obstetric and/or neonatal outcomes. In Chapter 5 we aimed to investigate the potential effect of thyroid function (mea-sured in second trimester of pregnancy) on maternal and neonatal outcomes in women with GDM. We hypothesized that women with GDM and lower FT4 levels in the normal-range are more likely to have a higher weight gain during pregnancy and unfavourable pregnancy outcomes. In Chapter 6 we aimed to evaluate the adherence to follow-up six-weeks postpartum visit in secondary care after GDM and glucose testing longer than 12-14 months after delivery and the years thereafter in primary care. In addition, we also examined by questionnaire the lifestyle of the women with a history of GDM including physical activity and diet.

The second part consists of Chapters 7 and 8 and describes the pregnancy out-comes with respect to the new international diagnostic criteria for GDM compared with the current diagnostic thresholds. In Chapter 7 we aimed to investigate the possible impact on GDM prevalence and pregnancy outcomes of applying the new WHO-2013 criteria instead of the older WHO-1999 criteria. Pregnancy outcomes were compared between a normal glucose tolerance control-group and different GDM classification groups. In Chapter 8 we aimed to evaluate the maternal char-acteristics and pregnancy outcomes in two cohorts applying different diagnostic criteria for GDM i.e. WHO-2013 and WHO-1999. All women were treated according the Dutch national guideline. This study was in collaboration with Deventer Hospi-tal. This hospital already implemented the new IADPSG/WHO-2013 thresholds for diagnosis of GDM in 2012.

Finally, Chapter 9 provides a summary, general discussion, and future perspec-tives.

Introduction

17

1REFERENCES

1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37 (Suppl. 1):S81-90.

2. Farrar D. Hyperglycemia in pregnancy: Prevalence, impact, and management challenges. Int J Womens Health. 2016;8:519-27.

3. van Leeuwen M, Prins SM, de Valk HW, Evers IM, Visser GH, Mol BW. Gestational diabetes mellitus: Treatment reduces the risk of complications. Ned Tijdschr Geneeskd. 2011;155:A2291.

4. Hunt KJ, Schuller KL. The increasing prevalence of diabetes in pregnancy. Obstet Gynecol Clin North Am. 2007;34:173-99.

5. Ferrara A. Increasing prevalence of gestational diabetes mellitus: A public health perspective. Diabetes Care. 2007;30 (Suppl. 2):S141-6.

6. Moses RG, Morris GJ, Petocz P, San Gil F, Garg D. The impact of potential new diagnostic criteria on the prevalence of gestational diabetes mellitus in Australia. Med J Aust. 2011;194:338-40.

7. Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: A systematic analysis for the global burden of disease study 2013. Lancet. 2014;384:766-81.

8. American Diabetes Association. Classification and diagnosis of diabetes. Diabetes Care. 2015;38 (Suppl. 1):S8-16.

9. Butte NF. Carbohydrate and lipid metabolism in pregnancy: Normal compared with gestational diabetes mellitus. Am J Clin Nutr. 2000;71(5 Suppl.):1256S-61S.

10. Lain KY, Catalano PM. Metabolic changes in pregnancy. Clin Obstet Gynecol. 2007;50:938-48.

11. Barbour LA, McCurdy CE, Hernandez TL, Kirwan JP, Catalano PM, Friedman JE. Cellular mecha-nisms for insulin resistance in normal pregnancy and gestational diabetes. Diabetes Care. 2007;30 (Suppl. 2):S112-9.

12. Buchanan TA, Xiang A, Kjos SL, Watanabe R. What is gestational diabetes? Diabetes Care. 2007;30 (Suppl. 2):S105-11.

13. Buchanan TA, Xiang AH. Gestational diabetes mellitus. J Clin Invest. 2005;115:485-91.

14. Farrar D, Simmonds M, Bryant M, et al. Hyperglycaemia and risk of adverse perinatal outcomes: Systematic review and meta-analysis. BMJ. 2016;354:i4694.

15. Metzger BE, Lowe LP, Dyer AR, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358:1991-2002.

16. Farrar D, Fairley L, Santorelli G, et al. Association between hyperglycaemia and adverse perinatal outcomes in South Asian and white British women: Analysis of data from the born in Bradford cohort. Lancet Diabetes Endocrinol. 2015;3:795-804.

17. Bellamy L, Casas J, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: A systematic review and meta-analysis. Lancet. 2009;373:1773-9.

18. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: A systematic review. Diabetes Care. 2002;25:1862-8.

Chapter 1

18

19. Clausen TD, Mathiesen ER, Hansen T, et al. High prevalence of type 2 diabetes and pre-diabetes in adult offspring of women with gestational diabetes mellitus or type 1 diabetes: The role of intrauterine hyperglycemia. Diabetes Care. 2008;31:340-6.

20. Hillier TA, Pedula KL, Schmidt MM, Mullen JA, Charles M, Pettitt DJ. Childhood obesity and meta-bolic imprinting the ongoing effects of maternal hyperglycemia. Diabetes Care. 2007;30:2287-92.

21. Vohr BR, Boney CM. Gestational diabetes: The forerunner for the development of maternal and childhood obesity and metabolic syndrome? J Matern Fetal Neonatal Med. 2008;21:149-57.

22. Reece EA, Leguizamón G, Wiznitzer A. Gestational diabetes: The need for a common ground. Lancet. 2009;373:1789-97.

23. Kc K, Shakya S, Zhang H. Gestational diabetes mellitus and macrosomia: A literature review. Ann Nutr Metab. 2015;66:14-20.

24. Langer O, Yogev Y, Most O, Xenakis EMJ. Gestational diabetes: The consequences of not treating. Obstet Gynecol. 2005;192:989-97.

25. Sermer M, Naylor CD, Gare DJ, et al. Impact of increasing carbohydrate intolerance on maternal-fetal outcomes in 3637 women without gestational diabetes: The Toronto Tri-Hospital gestational diabetes project. Obstet Gynecol. 1995;173:146-56.

26. Yang X, Hsu-Hage B, Zhang H, Zhang C, Zhang Y, Zhang C. Women with impaired glucose tolerance during pregnancy have significantly poor pregnancy outcomes. Diabetes Care. 2002;25:1619-24.

27. Shah BR, Retnakaran R, Booth GL. Increased risk of cardiovascular disease in young women fol-lowing gestational diabetes mellitus. Diabetes Care. 2008;31:1668-9.

28. Retnakaran R, Shah BR. Mild glucose intolerance in pregnancy and risk of cardiovascular disease: A population-based cohort study. CMAJ. 2009;181:371-6.

29. Goueslard K, Cottenet J, Mariet A, et al. Early cardiovascular events in women with a history of gestational diabetes mellitus. Cardiovasc Diabetol. 2016;15:15.

30. Donovan LE, Cundy T. Does exposure to hyperglycaemia in utero increase the risk of obesity and diabetes in the offspring? A critical reappraisal. Diabet Med. 2015;32:295-304.

31. Kim SY, England JL, Sharma JA, Njoroge T. Gestational diabetes mellitus and risk of childhood overweight and obesity in offspring: A systematic review. Exp Diabetes Res. 2011;2011:541308.

32. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of treatment of gesta-tional diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352:2477-86.

33. Landon MB, Spong CY, Thom E, et al. A multicenter, randomized trial of treatment for mild gesta-tional diabetes. N Engl J Med. 2009;361:1339-48.

34. Buckley B, Harreiter J, Damm P, et al. Gestational diabetes mellitus in Europe: Prevalence, current screening practice and barriers to screening. A review. Diabet Med. 2012;29:844-54.

35. The Dutch Society of Obstetrics and Gynaecology. Diabetes mellitus and pregnancy. Clinical guideline version 2.0. 2010. Available from: http://www.nvog-documenten.nl/index.php?pagina=/richtlijn/item/pagina.php&richtlijn_id=863, accessed 2 June 2017.

36. World Health Organization (WHO). Definition and classification of diabetes mellitus and its com-plications. Report of a WHO consultation. Part 1: Diagnosis and classification of diabetes mellitus. Geneva, WHO, 1999. Department of Noncommunicable Disease Surveillance.

Introduction

19

1 37. International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger

BE, Gabbe SG, et al. International Association of Diabetes and Pregnancy Study Groups recom-mendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33:676-82.

38. World Health Organization (WHO). Diagnostic criteria and Classification of Hyperglycemia First detected in pregnancy. 2013. Available from: http://apps.who.int/iris/bitstream/10665/85975/1/WHO_NMH_MND_13.2_eng.pdf, accessed 2 June 2017.

39. National Institute for Health and Care Excellence. Diabetes in Pregnancy: Management of Diabe-tes and its Complications from Pre-conception to the postnatal period. Clinical Guideline NG3. 2015. Available from: https://www.nice.org.uk/guidance/ng3, accessed 2 June 2017.

40. Rutten GEH, de Grauw WJC, Nijpels G, et al. NHG standard diabetes mellitus type 2. Huisarts Wet. 2013;56:512-25.

2 Gestational diabetes mellitus: current knowledge and unmet needs

Koning SH, Hoogenberg K, Lutgers HL, van den Berg PP, Wolff enbuttel BHR

Journal of Diabetes. 2016;8:770-781.

Chapter 2

22

ABSTRACT

Gestational diabetes mellitus (GDM) is a global health concern, not only because its prevalence is high and on the increase, but also because of the potential implica-tions for the health of mothers and their offspring. Unfortunately, there is consid-erable controversy in the literature surrounding the diagnosis and treatment of GDM, as well as the possible long-term consequences for the offspring. As a result, worldwide there is a lack of uniformly accepted diagnostic criteria and the advice regarding the treatment of GDM, including diet, insulin therapy, and the use of oral blood glucose-lowering agents, is highly variable. In this review we provide an overview of the important issues in the field of GDM, including diagnostic criteria, different treatment regimens available, and the long-term consequences of GDM in the offspring.

GDM: current knowledge and unmet needs

23

2

INTRODUCTION

Historically, gestational diabetes mellitus (GDM) was defined as any degree of glucose intolerance with an onset or first recognition during pregnancy. Accord-ing to the American Diabetes Association (ADA),1 GDM is diabetes mellitus (DM) diagnosed in the second or third trimester of pregnancy that does not clearly meet the criteria of overt DM. For women diagnosed with GDM in the first trimester of pregnancy, pre-existing DM should be strongly considered.1 Gestational diabetes mellitus affects up to 14% of all pregnancies, depending on the diagnostic criteria used and the population studied.2 Given the fact that both obesity and DM are now worldwide epidemics, the prevalence of GDM is still increasing.2–4

Untreated GDM carries a risk for both the mother and child and is associated with serious short- and long-term consequences, including neonatal and obstetric complications during pregnancy and childbirth (e.g. macrosomia, birth injury, cesarean section) 5–7 and a predisposition to obesity and DM in the offspring in later life.8–10 Fortunately, studies have shown that many of these consequences can be reduced by early detection and intervention.11,12 However, worldwide there is still a lack of agreement on the best way to diagnose and treat GDM. Different diagnostic criteria are used, and many countries use their own recommendations. As a result, discussion remains on the efficiency, and safety, of treatment modalities for GDM, including the use of oral blood glucose-lowering agents, as well as the possible short- and long-term consequences for the offspring.

Herein we describe both the current knowledge regarding GDM and the unmet needs of this condition. We review the diagnostic criteria, different treatment regi-mens available, and the consequences of GDM in the offspring.

DIAGNOSTIC CRITERIA

The original diagnostic criteria for GDM were established in 1964 by O’Sullivan and Mahan.13 Their criteria were based on a 3-h 100-g oral glucose tolerance test (OGTT) and were chosen to identify women at high risk for development of diabetes after pregnancy.13 In 1979–80, the 2-h 75-g OGTT was introduced as diagnostic test for non-pregnant diabetic individuals, and the World Health Organization (WHO) advised that this be used to diagnose diabetes in pregnant women, with cut-off values for the diagnosis of GDM being fasting plasma glucose (FPG) ≥7.8 mmol/L and 2-h glucose levels ≥11.1 mmol/L.14,15 In 1997, the ADA proposed to lower the FPG from 7.8 to 7.0 mmol/L for non-pregnant diabetic individuals.16 Two years later, the WHO 1999 report on the definition, screening, and diagnosis of GDM was the

Chapter 2

24


25

2

first step to creating a universal guideline for GDM.17 In that report, the same fasting glucose values for pregnant women were recommended as proposed by the ADA.17 These diagnostic criteria were not specifically intended to identify increased risk of adverse neonatal and maternal outcomes.18

For decades, the degree of hyperglycemia that was associated with increased risk of adverse neonatal and maternal outcomes remained uncertain. In 2008, the multinational prospective observational Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study reported on the associations between FPG and 1- and 2-h plasma glucose values during an OGTT and the risk of adverse neonatal and maternal outcomes.19 More than 25 000 non-diabetic women with singleton preg-nancies underwent a 75-g OGTT at 24–32 weeks gestation. The study demonstrated a continuous association of maternal glucose levels with increased rates of both the predefined primary adverse pregnancy outcomes (i.e. birth weight >90th per-centile and cord blood serum C-peptide levels >90th percentile) and the secondary outcomes (i.e. premature delivery, shoulder dystocia or birth injury, intensive neo-natal care, hyperbilirubinemia, and pre-eclampsia).19 As a result of these findings and those from earlier observational studies,5,20–23 the diagnostic criteria of GDM were reconsidered worldwide, and guidelines were adapted to include these more stringent criteria. In 2010, the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) published new criteria for the diagnosis of GDM, which recommended the following 75-g OGTT glycemic thresholds: fasting value ≥5.1 mmol/L (92 mg/dL); 1-h value ≥10.0 mmol/L (180 mg/dL); and 2-h value ≥8.5 mmol/L (153 mg/dL).18 These values were chosen because they predict an increased risk of adverse pregnancy outcomes (defined as a 75% higher chance of adverse outcomes vs normal glucose values). For the other adverse outcomes of the HAPO study, no threshold risk could be identified.18

The IADPSG criteria were adopted by the ADA in 201024 and by the WHO in 2013.14 However, the ADA did not follow the one-step diagnostic approach recom-mended by the IADPSG and left the door open for the two-step screening strategy based on the National Institutes of Health (NIH) consensus conference report.24,25 The IADPSG’s one-step screening strategy involves the use of a 75-g OGTT, whereby GDM is diagnosed on the basis of one abnormal value for either the fasting or the 2-h glucose level. The two-step screening strategy makes use of a non-fasting 50-g glucose challenge test, whereby an abnormal test result (i.e. 1-h value ≥7.8 mmol/L) is followed by a 100-g OGTT. Gestational diabetes mellitus is then diagnosed on the basis of two abnormal values in this 100-g OGTT for the fasting, 1-, 2-, or 3-h glucose levels, using either the Carpenter and Coustan criteria26 or the National Diabetes and Data Group criteria (Table 1).27

Chapter 2

24


25

2

TAB

LE 1

. O

verv

iew

of t

he c

urre

ntly

use

d di

agno

stic

crit

eria

for g

esta

tiona

l dia

bete

s m

ellit

us w

orld

wid

e.

WH

O19

9917

WH

O 2

013,

14

IAD

PSG

201

018A

DA

201

5A,2

4N

ICE

2015

98A

DIP

S112

Carp

ente

r and

Co

usta

n26N

DD

G27

Glu

cose

leve

ls (m

mol

/L [m

g/dL

])

Fast

ing

≥7.0

(≥12

8)≥5

.1 (≥

92)

≥5.1

(≥92

)≥5

.3 (≥

95)

≥5.6

(≥10

0)≥5

.1 (≥

92)

≥5.3

(≥95

)≥5

.8 (≥

105)

OG

TT

1-h

2-

h

3-h

–≥7

.8 (≥

140)

–

≥1

0.0

(≥18

0)≥8

.5 (≥

153)

–

≥1

0.0

(≥18

0)≥8

.5 (≥

153)

–

≥1

0.0

(≥18

0)≥8

.6 (≥

155)

≥7.8

(≥14

0)

–≥7

.8 (≥

140)

–

≥1

0.0

(≥18

0)≥8

.5 (≥

153)

≥1

0.0

(≥18

0)≥8

.6 (≥

155)

≥7.8

(≥14

0)

≥1

0.6

(≥19

0)≥9

.2 (≥

165)

≥8.0

(≥14

5)

Tota

l no.

ab

norm

al

valu

es

≥1B

≥1B

≥1B

≥2C

≥1B

≥1B

≥2C

≥2C

Abbr

evia

tions

: WH

O, W

orld

Hea

lth O

rgan

izat

ion;

NIC

E, N

atio

nal I

nstit

ute

for H

ealth

and

Car

e Ex

celle

nce;

AD

IPS,

Aus

tral

asia

n D

iabe

tes i

n Pr

egna

ncy

Soci

ety.

A The

Am

eric

an D

iabe

tes A

ssoc

iatio

n (A

DA)

201

5 re

com

men

datio

ns le

ave

the

optio

n op

en to

use

eith

er th

e on

e-st

ep In

tern

atio

nal A

ssoc

iatio

n of

the

Dia

bete

s and

Pre

gnan

cy

Stud

y G

roup

s (IA

DPS

G) r

ecom

men

datio

n or

the

two-

step

str

ateg

y, w

ith th

e op

tion

in th

e tw

o-st

ep s

trat

egy

of u

sing

eith

er th

e Ca

rpen

ter a

nd C

oust

an c

riter

ia o

r the

Nat

iona

l D

iabe

tes a

nd D

ata

Gro

up (N

DD

G) c

riter

ia.

B O

n a

75-g

ora

l glu

cose

tole

ranc

e te

st (O

GTT

).C

On

a 10

0-g

OG

TT.

Chapter 2

26

Worldwide, there is a lack of uniformly accepted diagnostic criteria. The differ-ent criteria used by different expert groups are summarized in Table 1. The main discrepancies in these guidelines relate to the use of FPG values that are higher than those of the IADPSG criteria. However, studies have shown that global adoption of the IADPSG criteria would lead to an increase in the prevalence of GDM, which would result in a higher burden to obstetric healthcare and higher costs.28–30 Other critics of such a proposed change state that there is only limited evidence for the benefit of treatment of GDM diagnosed according to thresholds proposed by the IADPSG criteria (mild GDM), that the OGTT has poor reproducibility, and that data are lacking on the cost-effectiveness of GDM treatment when diagnosed according to the IADPSG criteria.31,32

The differences between the various guidelines in terms of cut-off levels indicate the need for large cost-benefit studies of the treatment of GDM diagnosed accord-ing to the IADPSG criteria. Such studies may help overcome reluctance for a broad implementation of strict diagnostic criteria. Because the main reason for this reluc-tance currently appears to be economic healthcare concerns regarding the burden of obstetric care, such studies will at least provide us with international consensus.

TREATMENT

Two randomized controlled trials (RCTs) have investigated the benefits of screen-ing and treatment of GDM in terms of pregnancy complications.11,12 The first was conducted in 2005 by the Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Trial Group.12 That study randomly assigned 1000 women with GDM between 24 and 34 weeks gestation to receive either dietary advice, self-mon-itoring of blood glucose (SMBG), and insulin therapy (intervention group) or routine care (control group). Women in the routine care (control) group replicated clinical care in which screening for GDM was not available. The study showed that treat-ment of GDM reduced the frequency of serious perinatal complications (defined as perinatal death, shoulder dystocia, bone fracture, and nerve palsy) and improved the mother’s health-related quality of life.12 However, the women in the intervention group were more likely to have labor induced than women in the routine group, and more of the neonates in the intervention group were admitted to the neonatal nursery.12

The second RCT was conducted in 2009 by Landon et al.11 and included 958 mild GDM pregnancies (defined as a fasting glucose <5.3 mmol/L) between 24 and 31 weeks gestation. The women were assigned to usual prenatal care (control group) or dietary advice, SMBG, and insulin therapy (intervention group). The study showed


27

2

that although treatment of mild GDM did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications, it did reduce the risk of fetal overgrowth, shoulder dystocia, cesarean delivery, and pregnancy hypertensive complications.11

Following on from these findings, several systematic reviews and meta-analyses summarized the evidence of the benefits of treatment for women with GDM.33–37 These reviews included mainly the aforementioned trials, but also additional studies that compared intensive treatment, including diet modification, glucose monitor-ing, and/or insulin, or any therapeutic intervention of GDM with usual obstetric care in women with GDM. These reviews demonstrated not only that treatment of GDM is effective, but that it also lowers the risk of pre-eclampsia and several neonatal complications, including macrosomia, shoulder dystocia, and neonates born large for gestational age (LGA).33–37

DietGlobally, the primary approach for GDM is dietary advice in combination with SMBG. It is estimated that dietary advice helps 70%–85% of women with GDM to obtain optimal glycemic control.38 Remarkably, there are no specific guidelines for diet or exercise in GDM. Nevertheless, there is consensus that the goal of dietary advice should be to fulfill nutrient intake for normal neonatal growth and to achieve optimal glycemic control, without inducing weight loss or excessive weight gain.39 Optimal glycemic control can be achieved by following a diet that includes carbo-hydrate distribution and a reduction in rapidly digested sugars.

Increasing attention is being paid to the effect of different types of dietary intervention on pregnancy outcomes in women with GDM. Such specific dietary ap-proaches include low-glycemic index (GI), energy restriction, and low-carbohydrate (LC) diets. A Cochrane systematic review on the effects of different types of dietary intervention in GDM found no effect for any specific type of dietary intervention in terms of reducing the following outcomes: instrumental deliveries, LGA neonates, or neonates with a birth weight >4000 g.40 However, this finding is in contrast with that of a more recent systematic review on the type of dietary interventions on maternal and neonatal outcomes in women with GDM.41 That review included nine RCTs that had studied different types of dietary advice. The authors performed three meta-analyses according to the three types of dietary intervention: low-GI diets (defined as GI <55); total energy restriction diets (defined as 1600–1800 kcal or ~33% reduction in caloric intake); and LC diets (<45% of energy supply com-ing from carbohydrates). When the dietary interventions were compared with the control diets, only a low-GI diet was associated with beneficial outcomes, such as less frequent insulin use and lower neonatal weight. The study suggested that a

Chapter 2

28

low-GI diet reduces the use of insulin because of its ability to reduce postprandial glucose excursions.41

Apart from these meta-analyses on dietary interventions, the role of LC diets in GDM has gained considerable attention. Low-carbohydrate diets are currently popular in the general population and are widely used to treat obesity.42 Evidence has shown that LC diets are also effective in the treatment of diabetes, particularly if the condition is complicated by insulin resistance.43,44 Consequently, more atten-tion is being paid to the use of an LC diet in GDM. However, evidence is lacking on both the short- and long-term effects of an LC diet in GDM, in terms of both blood glucose values and safety.

According to the National Academy of Medicine, the minimum daily carbohy-drate intake should be >130 g for the general population and >175 g for pregnant women.45 The additional 45 g/day carbohydrates are indicated for neonatal brain development and functioning. A carbohydrate intake <175 g can have negative consequences for the neonate.46 Furthermore, to compensate for the reduced car-bohydrate intake, the intake of other sources of nutrients, such as protein and fat, increases. Because of an LC diet’s restricted food choices, there is an increased risk of nutritional deficiencies. Therefore, such diets may theoretically limit the consump-tion of dietary fiber, vitamins, calcium, potassium, magnesium, and iron.47

Two RCTs48,49 and one non-randomized trial50 that investigated the short-term effectiveness of an LC diet in GDM reported conflicting results. Two of the studies showed postprandial glucose values were lower in women on an LC diet (ranging from 40% to 45% in the intervention group) than in women on a high-carbohydrate diet (ranging from >45% to 65% in the control group).49,50 Although neither of these studies reported a reduction in fasting glucose values, in the study by Major et al.50 the women with the lowest carbohydrate intake (<42%) required less additional insulin therapy. However, in the RCT by Moreno-Castilla et al.,48 an LC diet (interven-tion 40% vs control 55%) did not significantly reduce the need for insulin therapy.

A recent prospective cohort study in women with a history of GDM51 investi-gated whether there was an association between an LC diet and the long-term risk of type 2 DM (T2DM). An LC diet with a high intake of protein and fat mainly from animal-based foods was associated with a higher risk of T2DM, whereas an LC diet with a high intake of protein and fat mainly from plant-based foods was not. These findings suggest that women with a history of GDM who follow an LC diet may reduce their future risk of T2DM by consuming plant- rather than animal-based sources of protein and fat.51

In summary, there is general agreement on limiting excessive carbohydrate intake and that carbohydrates should be distributed equally throughout the day. Although it is unknown whether carbohydrate restriction is beneficial in GDM,


29

2

some studies have shown beneficial effects on glucose control and also on the risk of developing T2DM after GDM.

Insulin Women who receive dietary advice but fail to maintain glycemic control within 1–2 weeks generally receive additional insulin therapy. Insulin therapy is the medication of choice in GDM and is recommended in almost all international guidelines. Insulin is safe in pregnancy because it virtually does not cross the placental barrier and it is not known to have any teratogenic effects. The most frequently used types of insulin are regular insulin (RI) and neutral protamine Hagedorn (NPH) insulin, which are both completely homogeneous with human insulin and therefore considered safe in pregnancy. A major drawback of RI is that its activity profile does not match that of physiological insulin. The onset of action of RI begins between 30 and 60 min after injection, reaching peak activity after 2–3 h and having an effective working duration lasting up to 8–10 h.52 Not only does it often peak too late to control post-prandial blood glucose values, but it also carries an increased risk of hypoglycemia. To overcome this, rapid-acting insulin analogs have been developed in which one of the amino acids is substituted to improve the pharmacokinetic profile. The ac-tion of rapid-acting insulin analogs (i.e. lispro, aspart, and glulisine) begins 5–15 min after injection, reaching peak activity between 30 and 90 min and having an effective working duration of 4–6 h.52 Rapid-acting insulin analogs can therefore help achieve good postprandial blood glucose values while minimizing the risk of hypoglycemia.52

Both insulin aspart and lispro have been shown to be effective in pre-existing DM but have not been studied extensively in GDM.53–55 To date, few studies have looked specifically at aspart and lispro in GDM.56–61 A review by Lambert and Holt62 on the use of insulin analogs in pregnancy showed that compared with RI, the use of aspart and lispro is associated with better maternal glycemic control and a simi-lar fetal outcome. No evidence of increased risk of congenital anomalies has been reported.63 Because insulin aspart and lispro are licensed for use during pregnancy in Europe, both insulin lispro and insulin aspart can be safely administered in preg-nancy.

The use of NPH and the long-acting basal insulin analogs has both advantages and disadvantages. A major drawback of NPH insulin is that both its duration of action and peak effect are intermediate. The action of NPH begins 2–4 h after injec-tion, its peak action effect is between 4 and 10 h, and its effective working duration is 12–18 h.52 Indeed, outside pregnancy, rates of nocturnal hypoglycemia are known to be higher for NPH insulin than for long-acting analogs.64 The onset of action for long-acting insulin analogs is 2–4 h after injection and their effective duration is

Chapter 2

30

16–20 h, with no peak effect.52 Insulin detemir has been approved by the US Food and Drug Administration (FDA) for use during pregnancy,65 and its use has shown no adverse pregnancy outcomes.66 The data on insulin glargine in pregnancy ap-pear to be insufficient because most of the studies that have included this drug are small and retrospective.62 Furthermore, insulin glargine has insulin-like growth factor (IGF)-1-binding properties, which could be a disadvantage in pregnancy. 63,67 However, as for RI, insulin glargine does not to cross the placental barrier.68 There is no evidence to support the use of insulin glargine in GDM.

Oral blood glucose-lowering agents In recent years, the use of oral blood glucose-lowering agents has gained consider-able interest as an alternative for insulin therapy during pregnancy. Oral agents are not only less expensive, but they are also more easy to use, making them more patient friendly than insulin therapy, which requires training in insulin injection technique and demands time of healthcare providers.69 It has been suggested that the oral blood glucose-lowering agents glyburide and metformin can be used in pregnancy.

Glyburide is a second-generation sulfonylurea (SU) that directly stimulates insulin secretion by binding to the SU receptor on the cell membrane of pancreatic β-cells. The major side effects of glyburide are an increased risk of maternal hypoglycemia and weight gain. There was a long-standing controversy as to whether glyburide can cross the placental barrier. In earlier studies glyburide, was not detected in the cord blood of the neonates,70,71 but this was rejected by a later study that reported detecting glyburide in the cord blood at concentrations around 70% of those in maternal blood.72

Metformin is a biguanide blood glucose-lowering agent that acts by reducing hepatic gluconeogenesis. In contrast with glyburide, metformin does not carry an increased risk of hypoglycemia and weight gain. Metformin is known to cross the placental barrier, with the fetus being exposed to levels of metformin similar to those in the mother.73

Short-term effects of glyburideThe first major RCT to compare glyburide and insulin in GDM was conducted by Langer et al. in 2000.71 In total, 404 women with GDM between 11 and 33 weeks gestation were randomly assigned to receive glyburide or insulin. The primary end-point was glycemic control and the secondary endpoints included perinatal com-plications. Glycemic control and perinatal outcomes were similar in both groups. There was less maternal hypoglycemia in the glyburide group (2% vs 20%). In 4%


31

2

of women in the glyburide group, this medication failed to produce good glycemic control, and these women needed additional insulin.71

Since the RCT by Langer et al., numerous trials and cohort studies have investi-gated the effects of glyburide in GDM. A recent and well-conducted meta-analysis by Balsells et al.74 summarized the short-term outcomes of RCTs that compared glyburide or metformin with insulin or with each other. The analysis included seven trials that compared glyburide with insulin and demonstrated that glyburide was associated with a higher birth weight, an almost threefold higher risk of macroso-mia, and a twofold higher risk of neonatal hypoglycemia.74 The findings of Balsells et al.74 are comparable with those of an earlier meta-analysis conducted by Zeng et al.75 However, this earlier study concluded that glyburide is as effective as insulin, while also reporting a higher risk of neonatal hypoglycemia, high birth weight, and macrosomia.75

Balsells et al.74 only included two studies that compared metformin with glybu-ride and found metformin to be associated with less maternal weight gain, lower birth weight, less macrosomia, and fewer LGA neonates. Metformin was associated with slightly higher fasting blood glucose levels and higher treatment failure com-pared with glyburide.74

In summary, the evidence available from clinical studies does not support the use of glyburide in GDM, especially if metformin or insulin is available.

Short-term effects of metforminSince 2007, evidence for the efficacy and safety of metformin use in pregnancy has been reinforced by the results of several RCTs and meta-analyses.74,76–80 In 2013, the first meta-analysis was conducted by Gui et al.76; this study included five RCTs81–85 that compared the effects of metformin with those of insulin therapy in terms of glycemic control and maternal and neonatal outcomes in GDM. Although Gui et al.76 reported no differences between metformin and insulin in terms of glycemic control and neonatal outcomes (birth weight, LGA neonates, hypoglycemia, shoulder dys-tocia, and cesarean delivery), rates of preterm birth were found to be increased for metformin. Conversely, compared with insulin therapy, metformin was associated with less maternal weight gain and lower rates of pregnancy-induced hypertension, the latter thought to be explained by insulin-mediated sodium retention.76

Recently, five other meta-analyses have been published comparing metformin and insulin therapy in GDM.74,77–80 The meta-analyses by Poolsup et al.,77 Balsells et al.,74 and Gui et al.76 included the same RCTs and found comparable results. The main difference between these meta-analyses was that Poolsup et al.77 and Balsells et al.74 included an additional RCT;86 they also did not address exactly the same outcomes: Poolsup et al.77 had no information on maternal weight gain and Balsells et al.74

Chapter 2

32

added additional outcomes, including severe neonatal hypoglycemia and maternal total weight gain. In this respect, Balsells et al.74 reported lower occurrence of severe neonatal hypoglycemia and a lower maternal total weight gain in the metformin group. The other three meta-analyses78–80 included the aforementioned RTCs as well as additional RCTs.87–89

On the basis of current evidence, it seems that metformin may have some ben-efits with short-term neonatal outcomes similar to those for insulin therapy. How-ever, the higher risk of preterm birth in metformin treatment is a point of concern that should be addressed in further studies.

Long-term effects of metforminUnfortunately, little is known about the long-term effects of metformin in GDM. To date, several studies have investigated the long-term effects of metformin use in pregnancy on the subsequent growth and development of the children.90–93 In 2011, the results of a 2-year follow-up study of offspring were reported by the Metformin in Gestational Diabetes (MiG) Trial. The aim of that study was to compare the results of metformin and insulin treatment in terms of body composition and measures of adiposity in the children of women who participated in the MiG trial.83,92 Children who were exposed to metformin in utero had larger subscapular and biceps skin folds than the offspring of mothers who received insulin. The study suggests that metformin use is associated with more fat being stored in subcutaneous sites and perhaps less accumulation of ectopic or visceral fat.92 The study found no differ-ence in total or percentage body fat between the children exposed to metformin or insulin.92 One other follow-up study found that children exposed to metformin were heavier at the age of 12 months and were both taller and heavier at 18 months.90 However, in the multivariate regression analysis, maternal body mass index (BMI) was the only risk factor predicting a child being overweight or obese at the age of 18 months. Compared with insulin exposure, the study found no adverse effects of prenatal metformin exposure on motor, linguistic, or social development of the offspring during the first 18 months of life.90

Another two follow-up studies of offspring and their mothers were from an RCT conducted in women with polycystic ovary syndrome who had been treated with metformin or placebo during pregnancy.91,93 The first study,93 with a 1-year follow-up, showed that women who received a placebo during their pregnancy had lost more weight and had a lower BMI 1 year after delivery than women who received metformin during their pregnancy. However, the women in the metformin group gained less weight during their pregnancy. The offspring exposed to metformin in utero had a higher body weight at 1 year of age than those exposed to placebo.93 In another study,91 the same authors performed a small follow-up study of the offspring


33

2

at the age of 8 years. At that age there were no differences in height, weight, body composition, and insulin resistance. However, the children exposed to metformin in utero had higher fasting glucose levels, higher systolic blood pressure, and lower low-density lipoprotein cholesterol.91

There appears to be an urgent need for longer follow-up studies assessing the true effect of metformin in a larger offspring cohort at least until adolescence or adulthood. Studies on the effects of metformin during pregnancy in humans have reported no harmful effects or teratogenicity.94,95 However, animal studies have shown that metformin may harm the male reproductive system. Tartarin et al.96 investigated both testicular development and function in the offspring of mice administered metformin during pregnancy. As well as analyzing embryonic mice testes in vivo, that study included human and mouse in vitro models. The results showed that, in vitro, metformin reduced testosterone secretion by decreased mRNA expression involved in steroid production. In vivo, the number of Sertoli cells was slightly reduced. The number of Leydig cells, which produce androgens, including testosterone was diminished in the fetal period. The study showed that metformin has detrimental effects on the developing fetal testis.96

Other studies on the possible endocrine-disrupting effects of metformin on male reproduction have been performed in adult male fish. Because metformin is a widely used medication in T2DM patients and is not metabolized by the human body, high amounts are commonly found in wastewater and surface water. The medication is apparently not fully removed by wastewater treatment processes and is thought to be affecting the health of fish populations. Recent studies have shown that metformin can cause intersex in fish and cause male fish to produce eggs.97 This environmental pollution clearly illustrates that more studies are needed to investigate the possible endocrine-disrupting effects of metformin on vertebrate development and male fertility.

Despite the fact that the use of metformin in GDM is questionable, especially because of the lack of long-term safety data in offspring, metformin has already been incorporated into at least two sets of guidelines. The National Institute for Heath and Care Excellence (NICE) guideline (UK) recommends the use of metformin or insulin if lifestyle interventions fail to control glycemic levels98; the American College of Obstetricians and Gynecologists guideline also recommends the use of metformin in GDM.99

Chapter 2

34

LONG-TERM EFFECTS OF GDM

In recent years there has been increasing concern that GDM may also be associated with long-term consequences for the mother and child. Metabolic changes in the mother during pregnancy can lead to structural and functional adaptations during the development of the fetus, with potential consequences for growth and metabo-lism in the child’s later life. This phenomenon is called fetal programming and was first introduced by Hales and Barker.100 These authors found that babies who grow less well due to starvation in utero were more likely to become overweight and develop T2DM and cardiovascular diseases in adulthood.100

To date, several studies have investigated the association between maternal diabetes and the consequences for offspring in later life. These studies have pre-dominantly shown that maternal diabetes is associated with obesity and T2DM in the offspring in later life.8,101–103 Animal models have also shown that intrauterine exposure to mild maternal DM during pregnancy is associated with T2DM, insulin resistance, and obesity in the offspring.104 However, in animal studies it is easier to study the precise effect of maternal glucose levels on fetal development than in human studies. It is also easier to control for the main confounders, such as genetic susceptibility and postnatal environmental influences.

Several systematic reviews have summarized evidence from studies on the long-term consequences for offspring of women with GDM. However, in terms of an association between GDM and overweight and obesity in the offspring, the results of the reviews were inconsistent.105,106 In a recent critical review by Donavan and Cundy,107 there was no robust evidence found that exposure to hyperglycemia in utero increases the risk of obesity and diabetes in the offspring. These authors sug-gested that the increased risk of obesity seen in the offspring of women with GDM may be explained by confounding factors, such as parental obesity (Fig. 1).

There is a need for more research into GDM, and especially for long-term stud-ies into the programming and development of offspring who have been exposed prenatally to mild or moderate hyperglycemia that include adequate controls for confounding factors.

Even though in most women with GDM glucose values normalize after delivery, it is well known that women with a history of GDM are at increased risk for impaired glucose tolerance and for developing T2DM postpartum.108–110 Studies have shown that the risk of developing T2DM may be as high as 50% in the 5–10 years after GDM.108,109 Therefore, it is important that we recognize persistent glucose intoler-ance and diagnose T2DM as early as possible in these women in order to start early interventions and to prevent long-term DM complications. Prevention strategies,


35

2

such as lifestyle interventions, could have a considerable positive public health impact.111

FIGURE 1. Fetal programming in gestational diabetes mellitus. Abbreviations: GDM, gestational diabetes mellitus; T2DM, type 2 diabetes mellitus.

FUTURE DIRECTIONS AND CHALLENGES

There is clearly a need for more GDM research. Gestational diabetes mellitus is a global health problem, not only because its prevalence is high and on the increase, but also because of the potential implications for the health of mothers and their offspring. There is a clear need for a set of globally uniform guidelines on the diag-nosis of and treatment strategy for GDM. Currently, guidelines differ with regard to diagnostic cut-off criteria, most likely prompted by the fear of the costs and healthcare efforts that would be attached to any strengthening of diagnostic crite-ria. Endeavors to adopt the criteria proposed by IADPSG will warrant large cohort studies in GDM in order to provide both medical and economic justifications for such a change.

The treatment of GDM is also accompanied by both certainties and caveats. There is no specific guideline on dietary treatment and studies are scarce, although there is general consensus that excessive carbohydrate intake should limited and distributed over meals to lower glycemic excursions. However, it is unknown wheth-er carbohydrate restriction is actually beneficial in GDM, as has been indicated by a number of studies on this topic. Although these studies showed promising results on glycemic control and the reduced risk of later developing T2DM, there is a clear need for further investigating the benefits and perils of carbohydrate restriction in GDM both during pregnancy and afterwards.

Chapter 2

36

With the exception of specific issues related to the use of insulin in GDM, drug treatment remains contentious and the advice provided in guidelines is highly variable. In terms of the use of oral blood glucose-lowering agents, the risk of neo-natal hypoglycemia and increased neonatal birth weights does not support use of glyburide in GDM. The use of metformin seems promising and has already been incorporated into several guidelines. The uncertainties related to metformin use are a possible risk of premature delivery and concerns of the long-term safety regarding male fertility, and there is a particular need for studies regarding fetal programming and development in the offspring.

Acknowledgements

The author’s work reported herein was supported by an unrestricted research grant from Novo Nordisk Netherlands.

Disclosure

The authors have nothing to declare.


37

2

REFERENCES



3. Ferrara A. Increasing prevalence of gestational diabetes mellitus a public health perspective. Diabetes Care. 2007;30:S141-6.

4. Dabelea D, Snell-Bergeon JK, Hartsfield CL, Bischoff KJ, Hamman RF, McDuffie RS. Increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth cohort. Kaiser Perman-ente of Colorado GDM Screening Program. Diabetes Care. 2005;28:579-84.

5. Sermer M, Naylor CD, Gare DJ, et al. Impact of increasing carbohydrate intolerance on maternal-fetal outcomes in 3637 women without gestational diabetes: The Toronto Tri-Hospital Gestational Diabetes Project. Am J Obstet Gynecol. 1995;173:146-56.

6. Langer O, Yogev Y, Most O, Xenakis EM. Gestational diabetes: The consequences of not treating. Am J Obstet Gynecol. 2005;192:989-97.



9. Hillier TA, Pedula KL, Schmidt MM, Mullen JA, Charles M-A, Pettitt DJ. Childhood obesity and meta-bolic imprinting the ongoing effects of maternal hyperglycemia. Diabetes Care. 2007;30:2287-92.

10. Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers: Relationship to fetal hyperinsulinism. Diabetes Care. 1995;18:611-7.



13. O’Sullivan JB, Mahan CM. Criteria for the oral glucose tolerance test in pregnancy. Diabetes. 1964;13:278-85.

14. World Health Organization (WHO). Diagnostic Criteria and Classification of Hyperglycemia First Detected in Pregnancy. 2013. Available from: http://apps.who.int/iris/bitstream/10665/85975/1/WHO_NMH_MND_13.2_eng.pdf, accessed 22 September 2015.

15. World Health Organization (WHO). WHO Expert Committee on Diabetes Mellitus. Second Report. Geneva, WHO, 1980.

16. Gabir MM, Hanson RL, Dabelea D, et al. The 1997 American Diabetes Association and 1999 World Health Organization criteria for hyperglycemia in the diagnosis and prediction of diabetes. Dia-betes Care. 2000;23:1108-12.

17. World Health Organization (WHO). Definition and Classification of Diabetes Mellitus and its Complications. Report of a WHO Consultation. Part 1: Diagnosis and Classification of Diabetes Mellitus. Geneva, WHO, 1999. Department of Noncommunicable Disease Surveillance.

Chapter 2

38

18. International Association of Diabetes and Pregnancy Study Groups Consensus Panel. Interna-tional Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33:676-82.

19. HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358:1991-2002.

20. Jensen DM, Korsholm L, Ovesen P, Beck-Nielsen H, Mølsted-Pedersen L, Damm P. Adverse pregnancy outcome in women with mild glucose intolerance: Is there a clinically meaningful threshold value for glucose? Acta Obstet Gynecol Scand. 2008;87:59-62.

21. Pettitt DJ, Knowler WC, Baird HR, Bennett PH. Gestational diabetes: Infant and maternal complica-tions of pregnancy in relation to third-trimester glucose tolerance in the Pima Indians. Diabetes Care. 1980;3:458-64.

22. Jensen DM, Damm P, Sørensen B, et al. Clinical impact of mild carbohydrate intolerance in pregnancy: A study of 2904 nondiabetic Danish women with risk factors for gestational diabetes mellitus. Am J Obstet Gynecol. 2001;185:413-9.

23. Ferrara A, Weiss N, Hedderson M, et al. Pregnancy plasma glucose levels exceeding the American Diabetes Association thresholds, but below the National Diabetes Data Group thresholds for gestational diabetes mellitus, are related to the risk of neonatal macrosomia, hypoglycaemia and hyperbilirubinaemia. Diabetologia. 2007;50:298-306.


25. Vandorsten J, Dodson W, Espeland M, et al. NIH consensus development conference: Diagnosing gestational diabetes mellitus. NIH Consens State Sci Statements. 2012;29:1-31.

26. Carpenter MW, Coustan DR. Criteria for screening tests for gestational diabetes mellitus. Am J Obstet Gynecol. 1982;144:768-73.

27. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other catego-ries of glucose intolerance. Diabetes. 1979;28:1039-57.

28. Cundy T, Ackermann E, Ryan EA. Gestational diabetes: New criteria may triple the prevalence but effect on outcomes is unclear. BMJ. 2014;11:348-g1567.


30. O’Sullivan E, Avalos G, O’Reilly M, et al. Atlantic Diabetes in Pregnancy (DIP): The prevalence and outcomes of gestational diabetes mellitus using new diagnostic criteria. Diabetologia. 2011;54:1670-5.

31. Harlass FE, Brady K, Read JA. Reproducibility of the oral glucose tolerance test in pregnancy. Am J Obstet Gynecol .1991;164:564-8.

32. Visser GH, de Valk HW. Is the evidence strong enough to change the diagnostic criteria for gesta-tional diabetes now? Am J Obstet Gynecol. 2013;208:260-4.

33. Hartling L, Dryden DM, Guthrie A, Muise M, Vandermeer B, Donovan L. Benefits and harms of treating gestational diabetes mellitus: A systematic review and meta-analysis for the US Preven-tive Services Task Force and the National Institutes of Health Office of Medical Applications of Research. Ann Intern Med. 2013;159:123-9.


39

2

34. Falavigna M, Schmidt MI, Trujillo J, et al. Effectiveness of gestational diabetes treatment: A sys-tematic review with quality of evidence assessment. Diabetes Res Clin Pract. 2012;98:396-405.

35. Poolsup N, Suksomboon N, Amin M. Effect of treatment of gestational diabetes mellitus: A sys-tematic review and meta-analysis. PloS one. 2014;9:e92485.

36. Alwan N, Tuffnell DJ, West J. Treatments for gestational diabetes. Cochrane Databese Syst Rev. 2009;3:CD003395.

37. Horvath K, Koch K, Jeitler K, et al. Effects of treatment in women with gestational diabetes mel-litus: Systematic review and meta-analysis. BMJ. 2010;340:c1395.

38. American Diabetes Association. Management of diabetes in pregnancy. Diabetes Care. 2015;38 (Suppl.):S77-9.

39. Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth Interna-tional Workshop Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007;30; S251-60.

40. Han S, Crowther CA, Middleton P, Heatley E. Different types of dietary advice for women with gestational diabetes mellitus. Cochrane Databese Syst Rev. 2013;3:CD009275.

41. Viana LV, Gross JL, Azevedo MJ. Dietary intervention in patients with gestational diabetes melli-tus: A systematic review and meta-analysis of randomized clinical trials on maternal and newborn outcomes. Diabetes Care. 2014;37:3345-55.

42. Hession M, Rolland C, Kulkarni U, Wise A, Broom J. Systematic review of randomized controlled trials of low‐carbohydrate vs. low-fat/low-calorie diets in the management of obesity and its comorbidities. Obes Rev. 2009;10:36-50.

43. Yancy Jr WS, Foy M, Chalecki AM, Vernon MC, Westman EC. A low-carbohydrate, ketogenic diet to treat type 2 diabetes. Nutr Metab (Lond). 2005;2:34.

44. Nielsen JV, Joensson EA. Low-carbohydrate diet in type 2 diabetes: Stable improvement of body-weight and glycemic control during 44 months follow-up. Nutr Metab (Lond). 2008;5:14.

45. Trumbo P, Schlicker S, Yates AA, Poos M. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids. J Am Diet Assoc. 2002;102:1621-30.

46. Uplinger N. The controversy continues: Nutritional management of the pregnancy complicated by diabetes. Curr Diab Rep. 2009;9:291-5.

47. Adam-Perrot A, Clifton P, Brouns F. Low-carbohydrate diets: Nutritional and physiological aspects. Obes Rev. 2006;7:49-58.

48. Moreno-Castilla C, Hernandez M, Bergua M, et al. Low-carbohydrate diet for the treatment of gestational diabetes mellitus: A randomized controlled trial. Diabetes Care. 2013;36:2233-8.

49. Cypryk K, Kamińska P, Kosiński M, Pertyńska-Marczewska M, Lewiński A. A comparison of the ef-fectiveness, tolerability and safety of high and low carbohydrate diets in women with gestational diabetes. Endokrynol Pol. 2007;58:313-20.

50. Major CA, Henry MJ, de Veciana M, Morgan MA. The effects of carbohydrate restriction in patients with diet-controlled gestational diabetes. Obstet Gynecol. 1998;91:600-4.

51. Bao W, Li S, Chavarro JE, et al. Low-carbohydrate-diet scores and long-term risk of type 2 diabetes among women with a history of gestational diabetes: A prospective cohort study. Diabetes Care. 2016;39:43-9.

52. Hirsch IB. Insulin analogues. N Engl J Med. 2005;352:174-83.

Chapter 2

40

53. Hod M, Damm P, Kaaja R et al. Fetal and perinatal outcomes in type 1 diabetes pregnancy: A randomized study comparing insulin aspart with human insulin in 322 subjects. Am J Obstet Gynecol. 2008;198:186.e1-7.

54. Mathiesen ER, Kinsley B, Amiel SA, et al. Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: A randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care. 2007;30:771-6.

55. Blanco CG, Ballesteros AC, Saladich IG, Pla RC. Glycemic control and pregnancy outcomes in women with type 1 diabetes mellitus using lispro versus regular insulin: A systematic review and meta-analysis. Diabetes Technol Ther. 2011;13:907-11.

56. Pettitt DJ, Ospina P, Kolaczynski JW, Jovanovic L. Comparison of an insulin analog, insulin as-part, and regular human insulin with no insulin in gestational diabetes mellitus. Diabetes Care. 2003;26:183-6.

57. Pettitt D, Ospina P, Howard C, Zisser H, Jovanovic L. Efficacy, safety and lack of immunogenicity of insulin aspart compared with regular human insulin for women with gestational diabetes mel-litus. Diabet Med. 2007;24:1129-35.

58. Di Cianni G, Volpe L, Ghio A, et al. Maternal metabolic control and perinatal outcome in women with gestational diabetes mellitus treated with lispro or aspart insulin: Comparison with regular insulin. Diabetes Care. 2007;30:e11.

59. Bhattacharyya A, Brown S, Hughes S, Vice P. Insulin lispro and regular insulin in pregnancy. QJM. 2001;94:255-60.

60. Mecacci F, Carignani L, Cioni R, et al. Maternal metabolic control and perinatal outcome in women with gestational diabetes treated with regular or lispro insulin: Comparison with non-diabetic pregnant women. Eur J Obstet Gynecol Reprod Biol. 2003;111:19-24.

61. Jovanovic L, Ilic S, Pettitt DJ, et al. Metabolic and immunologic effects of insulin lispro in gesta-tional diabetes. Diabetes Care. 1999;22:1422-7.

62. Lambert K, Holt R. The use of insulin analogues in pregnancy. Diabetes Obes Metab. 2013;15:888-900.

63. Jong J, Garne E, Wender-Ozegowska E, Morgan M, Jong-van den Berg LT, Wang H. Insulin ana-logues in pregnancy and specific congenital anomalies: A literature review. Diabetes Metab Res Rev. 2016;32:366-75.

64. Horvath K, Jeitler K, Berghold A, et al. Long‐acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Databese Syst Rev. 2007;2:CD005613.

65. Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy: An Endocrine Society clinical prac-tice guideline. J Clin Endocrinol Metab. 2013;98:4227-49.

66. Lv S, Wang J, Xu Y. Safety of insulin analogs during pregnancy: A meta-analysis. Arch Gynecol Obstet. 2015; 292:749-56.

67. Woolderink JM, van Loon AJ, Storms F, de Heide L, Hoogenberg K. Use of insulin glargine during pregnancy in seven type 1 diabetic women. Diabetes Care. 2005;28:2594-5.

68. Kovo M, Golan A, Wainstein J, Matas Z, Haroutiunian S, Hoffman A. Placental transfer of the insulin analog glargine in the ex vivo perfused placental cotyledon model. Endocr Res. 2011;36:19-24.

69. Norman RJ, Wang JX, Hague W. Should we continue or stop insulin sensitizing drugs during pregnancy? Curr Opin Obstet Gynecol. 2004;16:245-50.


41

2

70. Elliott BD, Schenker S, Langer O, Johnson R, Prihoda T. Comparative placental transport of oral hypoglycemic agents in humans: A model of human placental drug transfer. Am J Obstet Gynecol. 1994;171:653-60.

71. Langer O, Conway DL, Berkus MD, Xenakis EM-J, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000;343:1134-8.

72. Hebert M, Ma X, Naraharisetti S, et al. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther. 2009;85:607-14.

73. Vanky E, Zahlsen K, Spigset O, Carlsen SM. Placental passage of metformin in women with poly-cystic ovary syndrome. Fertil Steril. 2005;83:1575-8.

74. Balsells M, García-Patterson A, Solà I, Roqué M, Gich I, Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: A systematic review and meta-analysis. BMJ. 2015;350:h102.

75. Zeng Y-C, Li M-J, Chen Y, et al. The use of glyburide in the management of gestational diabetes mellitus: A meta-analysis. Adv Med Sci. 2014;59:95-101.

76. Gui J, Liu Q, Feng L. Metformin vs insulin in the management of gestational diabetes: A meta-analysis. PLoS One. 2013;8:e64585.

77. Poolsup N, Suksomboon N, Amin M. Efficacy and safety of oral antidiabetic drugs in comparison to insulin in treating gestational diabetes mellitus: A meta-analysis. PLoS One. 2014;9:e109985.

78. Su D, Wang X. Metformin vs insulin in the management of gestational diabetes: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2014;104:353-7.

79. Kitwitee P, Limwattananon S, Limwattananon C et al. Metformin for the treatment of gestational diabetes: An updated meta-analysis. Diabetes Res Clin Pract. 2015;109:521-32.

80. Zhao L, Sheng X, Zhou S, et al. Metformin versus insulin for gestational diabetes mellitus: A meta‐analysis. Br J Clin Pharmacol. 2015;80:1224-34.

81. Moore LE, Briery CM, Clokey D, et al. Metformin and insulin in the management of gestational diabetes mellitus: Preliminary results of a comparison. J Reprod Med. 2007;52:1011-5.

82. Ijäs H, Vääräsmäki M, Morin-Papunen L, et al. Metformin should be considered in the treatment of gestational diabetes: A prospective randomised study. BJOG. 2011;118:880-5.

83. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus insulin for the treatment of gestational diabetes. N Eng J Med. 2008;358:2003-15.

84. Niromanesh S, Alavi A, Sharbaf FR, Amjadi N, Moosavi S, Akbari S. Metformin compared with insulin in the management of gestational diabetes mellitus: A randomized clinical trial. Diabetes Res Clin Pract. 2012;98:422-9.

85. Tertti K, Ekblad U, Koskinen P, Vahlberg T, Rönnemaa T. Metformin vs. insulin in gestational diabe-tes. A randomized study characterizing metformin patients needing additional insulin. Diabetes Obes Metab. 2013;15:246-51.

86. Spaulonci CP, Bernardes LS, Trindade TC, Zugaib M, Francisco RPV. Randomized trial of metformin vs insulin in the management of gestational diabetes. Am J Obstet Gynecol. 2013;209:34.e1-7.

87. Hasan JA, Karim N, Sheikh Z. Metformin prevents macrosomia and neonatal morbidity in gesta-tional diabetes. Pak J Med Sci. 2012;28:384-9.

Chapter 2

42

88. Mesdaghinia E, Samimi M, Homaei Z, Saberi F, Moosavi SGA, Yaribakht M. Comparison of newborn outcomes in women with gestational diabetes mellitus treated with metformin or insulin: A randomised blinded trial. Int J Prev Med. 2013;4:327-33.

89. Hague W, Davoren P, Oliver J, Rowan J. Contraindications to use of metformin: Metformin may be useful in gestational diabetes. BMJ. 2003;326:762-3.

90. Ijäs H, Vääräsmäki M, Saarela T, Keravuo R, Raudaskoski T. A follow-up of a randomised study of metformin and insulin in gestational diabetes mellitus: Growth and development of the children at the age of 18 months. BJOG. 2015;122:994-1000.

91. Rø TB, Ludvigsen HV, Carlsen SM, Vanky E. Growth, body composition and metabolic profile of 8-year-old children exposed to metformin in utero. Scand J Clin Lab Invest. 2012;72:570-5.

92. Rowan JA, Rush EC, Obolonkin V, Battin M, Wouldes T, Hague WM. Metformin in gestational diabetes: The offspring follow-up (MiG TOFU): body composition at 2 years of age. Diabetes Care. 2011;34:2279-84.

93. Carlsen SM, Martinussen MP, Vanky E. Metformin’s effect on first-year weight gain: A follow-up study. Pediatrics. 2012;130:e1222-6.

94. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod. 2002;17:2858-64.

95. Lautatzis M-E, Goulis DG, Vrontakis M. Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: A systematic review. Metabolism. 2013;62:1522-34.

96. Tartarin P, Moison D, Guibert E, et al. Metformin exposure affects human and mouse fetal testicu-lar cells. Hum Reprod. 2012;27:3304-14.

97. Niemuth NJ, Klaper RD. Emerging wastewater contaminant metformin causes intersex and reduced fecundity in fish. Chemosphere. 2015;135:38-45.

98. National Institute for Health and Care Excellence (NICE). Diabetes in Pregnancy: Management of Diabetes and its Complications from Pre-conception to the Postnatal Period. Clinical Guideline NG3. 2015. Available from: http://www.nice.org.uk/guidance/ng3/resources/diabetes-in-preg-nancy-management-of-diabetes-and-its-complications-from-preconception-to-the-postnatal-period-51038446021, accessed 22 September 2015.

99. Brown HL. ACOG guidelines at a glance: Gestational diabetes mellitus. Obstet Gynecol. 2013;122:406-16.

100. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: The thrifty phenotype hypothesis. Diabetologia. 1992;35:595-601.

101. Dabelea D, Crume T. Maternal environment and the transgenerational cycle of obesity and diabe-tes. Diabetes. 2011;60:1849-55.

102. Reece EA. The fetal and maternal consequences of gestational diabetes mellitus. J Matern Fetal Neonatal Med. 2010;23:199-203.

103. Fetita L-S, Sobngwi E, Serradas P, Calvo F, Gautier J-F. Consequences of fetal exposure to maternal diabetes in offspring. J Clin Endocrinol Metab. 2006;91:3718-24.

104. Aerts L, Van Assche FA. Animal evidence for the transgenerational development of diabetes mel-litus. Int J Biochem Cell Biol. 2006;38:894-903.


43

2

105. Kim SY, England JL, Sharma JA, Njoroge T. Gestational diabetes mellitus and risk of childhood overweight and obesity in offspring: A systematic review. Exp Diab Res. 2011;2011:541308.

106. Philipps L, Santhakumaran S, Gale C, et al. The diabetic pregnancy and offspring BMI in childhood: A systematic review and meta-analysis. Diabetologia. 2011;54:1957-66.

107. Donovan L, Cundy T. Does exposure to hyperglycaemia in utero increase the risk of obesity and diabetes in the offspring? A critical reappraisal. Diabet Med. 2015;32:295-304.

108. Bellamy L, Casas J-P, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: A systematic review and meta-analysis. Lancet. 2009;373:1773-9.


110. Ben‐Haroush A, Yogev Y, Hod M. Epidemiology of gestational diabetes mellitus and its association with Type 2 diabetes. Diabet Med. 2004;21:103-13.

111. Cheung NW, Byth K. Population health significance of gestational diabetes. Diabetes Care. 2003;26:2005-9.

112. Nankervis A, McIntyre HD, Moses R, et al. ADIPS consensus guidelines for the testing and diagnosis of gestational diabetes mellitus in Australia. 2012. Australasian diabetes in preg-nancy society. Available from: http://adips.org/downloads/ADIPSConsensusGuidelinesGDM-03.05.13VersionACCEPTEDFINAL.pdf, accessed 10 May 2016.

A Evaluation of the current national Dutch guideline

3 Neonatal and obstetric outcomes in diet- and insulin-treated women with gestational diabetes mellitus: a retrospective study

Koning SH, Hoogenberg K, Scheuneman KA, Baas MG, Korteweg FJ, Sollie KM, Schering BJ, van Loon AJ, Wolff enbuttel BHR, van den Berg PP, Lutgers HL

BMC Endocrine Disorders. 2016;16:52.

Chapter 3

48

ABSTRACT

Background: To evaluate the neonatal and obstetric outcomes of pregnancies com-plicated by gestational diabetes mellitus (GDM). Screening and treatment – diet-only versus additional insulin therapy – were based on the 2010 national Dutch guidelines.

Methods: Retrospective study of the electronic medical files of 820 singleton GDM pregnancies treated between January 2011 and September 2014 in a university and non-university hospital. Pregnancy outcomes were compared between regular care treatment regimens –diet-only versus additional insulin therapy- and pregnancy outcomes of the northern region of the Netherlands served as a reference popula-tion.

Results: A total of 460 women (56%) met glycaemic control on diet-only and 360 women (44%) required additional insulin therapy. Between the groups, there were no differences in perinatal complications (mortality, birth trauma, hyperbilirubi-naemia, hypoglycaemia), small for gestational age, large for gestational age (LGA), neonate weighing >4200 g, neonate weighing ≥4500 g, Apgar score <7 at 5 min, re-spiratory support, preterm delivery, and admission to the neonatology department. Neonates born in the insulin-group had a lower birth weight compared with the diet-group (3364 vs. 3467 g, p=0.005) and a lower gestational age at birth (p=0.001). However, birth weight was not different between the groups when expressed in percentiles, adjusted for gestational age, gender, parity, and ethnicity. The occur-rence of preeclampsia and gestational hypertension was comparable between the groups. In the insulin-group, labour was more often induced and more planned caesarean sections were performed (p=0.001). Compared with the general obstetric population, the percentage of LGA neonates was higher in the GDM population (11.0% vs. 19.9%, p=<0.001).

Conclusions: Neonatal and obstetric outcomes were comparable either with diet-only or additional insulin therapy. However, compared with the general obstetric population, the incidence of LGA neonates was significantly increased in this GDM cohort.

Pregnancy outcomes in GDM

49

3

BACKGROUND

Gestational diabetes mellitus (GDM) is a rising health problem worldwide and af-fects up to 14% of all pregnancies, depending on the diagnostic criteria used and the population studied.1,2 GDM increases the risk of short-term and long-term ad-verse health outcomes for both mother and child, including neonatal and obstetric complications during childbirth and obesity and diabetes in later life.3-7

Landmark studies have consistently shown that strict glycaemic control throughout pregnancy can effectively improve adverse health outcomes for mother and child.8-10 Based on their results, new criteria for screening and treatment of GDM have been adopted in national and international guidelines. In the Netherlands, the Dutch Society of Obstetrics and Gynaecology guideline “Diabetes and Pregnancy” was revised in 2010.11 This guideline for the screening and treatment of GDM was largely based on the British National Institute for Health and Care Excellence (NICE) 2008 guidelines and the World Health Organization’s (WHO) diagnostic criteria (1999) for GDM, recommending to screen for GDM in high-risk women using the 2-h 75-g oral glucose tolerance test (OGTT).12,13 This new guideline focused on a more active screening and treatment policy provided by “usual care” in the preced-ing years.

To date, the consequences of the guidelines on pregnancy treatment and outcomes have not been evaluated extensively. Moreover, as described in system-atic reviews, most of the earlier studies only compared intensive treatment or any therapeutic intervention for GDM with usual obstetric care and made no distinction in pregnancy outcomes for diet-only treatment compared with insulin-treated women.14-18

Hence, in this retrospective observational study we evaluated the neonatal and obstetric outcomes of pregnancies complicated by GDM. Screening and treatment – diet-only versus additional insulin therapy – were based on the 2010 national Dutch guidelines. We also compared these GDM outcomes with the general obstet-ric population in the northern region of the Netherlands.

METHODS

Study design and populationThis retrospective observational cohort study of women with GDM was conducted in two hospitals in the north of the Netherlands, University Medical Center Gronin-gen and non-university Martini Hospital Groningen. Those centers adopted a joint protocol on screening and treatment of GDM in January 2011 after revision of the

Chapter 3

50

Dutch guideline in 2010.11 The electronic medical fi les of all women with a diagnosis of GDM, who visited the outpatient clinic of both hospitals between January 2011 and September 2014, were eligible for inclusion in the study.

Pregnant women were tested for GDM if they had risk factors for GDM according to the Dutch guideline or signs suggestive of GDM (like foetal macrosomia and/or polyhydramnios).These GDM risk factors were: previous GDM, pre-gestational body mass index (BMI) ≥30 kg/m2, previous infant weighing ≥4500 g at birth, fi rst-degree relative with type 2 diabetes, ethnic origin (South-Asian, Hindu, Afro-Caribbean, Middle-Eastern, Morocco, and Egypt), history of intrauterine foetal death, and his-tory of polycystic ovary syndrome. Pregnant women with GDM risk factors were routinely screened for GDM at 24-28 weeks of gestation by their midwife’s offi ce care, or by their gynaecologist in secondary care. Women with previous GDM were screened at 16-18 weeks of gestation and when the results were negative, this was repeated in week 24-28 of gestation.

A 75-g OGTT was used for the screening of GDM. GDM was diagnosed when fasting plasma glucose was ≥7.0 mmol/l and/or 2-h value ≥7.8 mmol/l after the 75-g glucose load, according to the diagnostic criteria of the WHO (1999).12 In addition, GDM was diagnosed without an OGTT if fasting glucose was >7.0 mmol/l or a ran-dom glucose was >11.1 mmol/l.

In total 839 women were diagnosed with GDM and referred to the diabetes out-patient clinic for treatment. For the present analysis, women with twin pregnancy (n=15) or missing pregnancy outcomes (n=4) were excluded (Fig. 1). This study is conducted in accordance with the guidelines of the Declaration of Helsinki and Good Clinical Practice. The study has been exempted for approval according to the Medical Research Involving Human Subjects Act.19 This report is based on patient data acquired during care-as-usual, the data has been analyzed retrospectively and all the requirements for patient anonymity are in agreement to the regulations of the ethics committee of both hospitals for publication of patient data. According to this and the Dutch law Medical Research with Human Subjects, no approval from an ethics committee is necessary.

GDM management The fi rst step in the management of women with GDM was dietary advice by a dietician, which included advice about carbohydrate intake and carbohydrate distribution. Women were also instructed to measure fasting and 1-h postprandial blood glucose levels every day. Blood glucose levels were reviewed after 1-2 weeks. Women with fasting blood glucose level >5.3 mmol/l and/or post prandial blood glucose level >7.8 mmol/l received additional insulin therapy to obtain blood glucose values below these treatment goals. Insulin was commenced when two


51

3

blood glucose results at the same moment of the day were elevated despite dietary intervention. Insulin treatment regimens were: long-acting insulin only, prandial short-acting insulin or a combination of both (basal-bolus regimen), depending on

FIGURE 1. Flow-chart of the study design.Abbreviations: GDM, Gestational Diabetes Mellitus; NPH, Neutral Protamine Hagedorn; SMBG, Self-Monitoring Blood Glucose.

Chapter 3

52

the individual glycaemic profile. In both centres short-acting insulin analogues and Neutral Protamine Hagedorn (NPH) insulin were used in GDM treatment.

Women were intensively followed with regular e-mail and/or telephone contact, at least weekly, in order to assist them to achieve and maintain the glycaemic tar-gets. Every 3-4 weeks or on request if indicated, women visited the diabetes and obstetric outpatient clinics. If applicable based on self-monitoring of the blood glucose values, diet was adjusted and insulin dose increased to maintain blood glucose levels within the target range.

Foetal growth was evaluated by ultrasonography, performed every four weeks by trained obstetricians. In both centres labour was induced at or around 38 weeks in women on insulin therapy with taking blood glucose control as well as foetal growth into consideration. Labour was also induced for non-GDM related maternal or foetal indications, for instance gestational hypertension or preeclampsia. The diet- and insulin-treated women were both followed to the date of delivery and were discussed every 3 weeks in a multidisciplinary consultation in the University Medical Center Groningen. In the Martini Hospital multidisciplinary consultation occurred immediately after the outpatient clinic visit.

Clinical data collection All data were collected from electronic medical- and birth records. Ethnicity was labeled in five categories: Caucasian, Asian (Indian or South-East Asian), African-American, Mediterranean (Hispanic, Middle-Eastern, North-African or South-Amer-ican), and unknown. Chronic hypertension was defined as a systolic blood pressure (SBP) ≥140 mmHg, a diastolic blood pressure (DBP) ≥90 mmHg on two occasions at least 4 h apart or the use of blood-pressure lowering drugs, before pregnancy. Family history of diabetes was defined as having a first degree relative who had type 2 diabetes. HbA1c values were measured by standardized HPLC method on a Tosoh G8 system (Tosoh, Tokyo, Japan), considering 22-42 mmol/mol (4.2-6.0%) as normal. The HbA1c values were measured at the time of GDM diagnosis within 1 week after the OGTT.

Neonatal outcomesNeonatal outcomes were a composite outcome of perinatal complications (still birth/neonatal death, birth trauma (shoulder dystocia, fracture of humerus or clavicle, brachial plexus injury), neonatal hypoglycaemia and neonatal hyperbiliru-binaemia), gestational age at birth, birth weight, neonate weighing >4000-4499 g, neonate weighing >4200 g, neonate weighing ≥4500 g, large for gestational age (LGA) (defined as birth weight above the 90th percentile, adjusted for gestational age, gender, parity, and ethnicity),20 small for gestational age (SGA) (defined as birth


53

3

weight below the 10th percentile, adjusted for gestational age, gender, parity, and ethnicity),20 Apgar score <7 at 5 min, need for respiratory support, preterm delivery (defined as delivery before 37 completed weeks of gestation), and admission to the neonatology department.

The presence of neonatal hypoglycaemia (occurring >2 h after birth) was defined as a blood glucose level <2.6 mmol/l or treatment with a glucose infusion.11 Neonatal hyperbilirubinaemia was recorded when the infant was treated with phototherapy after birth or admission at the neonatology department for this reason. Respiratory support was defined as the need for supplemental oxygen or continuous positive airway pressure after birth.

Obstetric outcomesThe obstetric outcomes were: induction of labour, delivery type (spontaneous, instrumental (forceps or vacuum extraction), planned caesarean section and sec-ondary caesarean section), gestational hypertension, and preeclampsia.

Gestational hypertension was defined as a SBP ≥140 mmHg and/or a DBP ≥90 mmHg, with no evidence of pre-existing hypertension and the absence of protein-uria. Preeclampsia was defined as a combination of gestational hypertension and proteinuria (≥300 mg/24-h) and included eclampsia and “Hemolysis Elevated Liver enzymes and Low Platelets” (HELLP)-syndrome.

For comparison, the general obstetric population in the northern region of the Netherlands and their registered neonatal and obstetric outcomes during the period 2011-2013 served as a reference population screened with the same guide-lines, these data were provided from the Dutch Perinatal Registry and the Municipal Health Service Groningen. Data of the general obstetric population were available for the following outcomes: still birth/neonatal death, neonate weighing >4000-4499 g, neonate weighing ≥4500 g, LGA, SGA, and Apgar score <7 at 5 min.

Statistical analysesContinuous data are presented as mean ± standard deviation (SD) or as median and inter quartile range [IQR] in case of skewed distribution. Categorical data are presented as number and percentage. Differences between the groups were tested using Student’s unpaired t-test for continuous data or Mann-Whitney U Test in case of skewed distribution. For categorical data Chi-square or Fisher’s exact test were used.

All P-values are two-tailed, and P-values <0.05 were considered statistically significant. All analyses were conducted with the use of the statistical package IBM SPSS (version 22.0. Armonk, NY: IBM Corp).

Chapter 3

54

TABLE 1. Clinical characteristics according to the treatment groups of 820 women with gestational dia-betes mellitus.

Characteristics Overall

Treatment groups

P-value*Diet Insulin

N (%) 820 460 (56.1) 360 (43.9)

Age (years) 32.0 ± 5.1 31.6 ± 4.9 32.6 ± 5.2 0.010

Ethnicity, n (%) Caucasian Asian African-American Mediterranean Unknown

658 (80.2)55 (6.7)35 (4.3)57 (7.0)15 (1.8)

377 (82.0)35 (7.6)18 (3.9)22 (4.8)8 (1.7)

281 (78.1)20 (5.6)17 (4.7)35 (9.7)7 (1.9)

NS

Family history of DM, n (%) 326 (39.8) 156 (33.9) 170 (47.2) <0.001

History of PCOS, n (%) 40 (4.9) 24 (5.2) 16 (4.4) NS

Previous GDM, n (%) 86 (10.5) 25 (5.4) 61 (16.9) <0.001

Previous infant weighing ≥4500 g at birth, n (%) 90 (11.0) 35 (7.6) 55 (15.3) <0.001

History of IUFD, n (%) 16 (2.0) 5 (1.1) 11 (3.1) 0.043

History of spontaneous abortion, n (%) 223 (27.2) 113 (24.6) 110 (30.6) NS

Chronic hypertension, n (%) 37 (4.5) 15 (3.3) 22 (6.1) NS

Smoking during pregnancy, n (%) 81 (9.9) 42 (9.1) 39 (10.8) NS

Multigravida, n (%) 564 (68.8) 285 (62.0) 279 (77.5) <0.001

Parity, n (%) 0 1-2 >2

333 (40.6)436 (53.2)

51 (6.2)

223 (48.5)216 (47.0)

21 (4.6)

110 (30.6)220 (61.1)

30 (8.3)

<0.001

Pre-gestational BMI, n (%)b

<25 kg/m2

25-29.9 kg/m2

≥30 kg/m2

260 (32.7)231 (29.1)304 (38.2)

173 (38.7)126 (28.2)148 (33.1)

87 (25.0)105 (30.2)156 (44.8)

<0.001

Pre-gestational BMI (kg/m2) 27.7 [24.0-31.9] 26.9 [23.3-31.4] 29.2 [25.0-33.4] <0.001

Weight gain mother (kg)a 8.0 [4.0-12.0] 9.0 [5.0-13.0] 7.0 [3.0-11.0] <0.001

Indication for OGTT, n (%)c

Risk factors Signs

523 (66.2)267 (33.8)

275 (62.4)166 (37.6)

248 (71.1)101 (28.9)

0.010

Fasting glucose level (mmol/l) 5.0 [4.6-5.5] 4.8 [4.5-5.2] 5.3 [4.9-5.9] <0.001

2-h glucose level after a 75-g OGTT (mmol/l) 8.6 [8.1-9.4] 8.5 [8.0-9.1] 8.8 [8.2-9.7] <0.001

Abnormal value only on fasting glucose level, n (%) 8 (1.0) 3 (0.7) 5 (1.5) NS

Abnormal value only on 2-h glucose level, n (%) 746 (91.0) 440 (95.7) 306 (85) 0.003

Gestational age at time of OGTT (wks) 27.9 [25.9-30.7] 28.4 [26.7-32.3] 27.1 [24.4-29.3] <0.001

HbA1c d

mmol/mol

% 37 [34-40]

5.5 [5.3-5.8]37 [34-39]

5.5 [5.3-5.7]38 [36-42]

5.6 [5.4-6.0]

<0.001

Abbreviations: BMI, Body Mass Index; DM, Diabetes Mellitus; GDM, Gestational Diabetes Mellitus; IUFD, Intra-uterine Foetal Death; PCOS, Polycystic Ovary Syndrome; OGTT, Oral Glucose Tolerance Test; HbA1c, Haemoglo-bin A1c; wks, weeks; g, gram; NS, not significant.Data are expressed as mean ± SD, median [IQR], or proportion n (%).* P-values were based on Student’s unpaired t-test (non-skewed continuous variables), Mann-Whitney U Test (skewed continuous variables) or Chi-square test (categorical variables).


55

3RESULTS

The maternal characteristics are summarized in Table 1. Of the 820 women with GDM, 460 women (56.1%) met the glycaemic goals on diet-only and 360 women (43.9%) required additional insulin therapy. Of the women who required additional insulin therapy, 143 women (40%) received trice daily pre-prandial short-acting in-sulin, 165 women (46%) received basal-bolus insulin therapy and 39 women (11%) received long-acting insulin therapy to achieve the glycaemic targets (n=13 missing data on type of insulin). The median insulin dose was 22 U/day; IQR 12-42 U/day. All women were monitored and treated similarly and achieved good glycaemic control. To establish glycaemic control third trimester HbA1c values were evaluated (week 32-36 of gestation). For a small sample of women (n=212) the HbA1c values were also measured in third trimester of their pregnancy. The median Hb1Ac values were higher in the insulin-group (n=125; median 5.7% (39 mmol/mol), IQR 5.4-6.0% (36-42 mmol/mol)) compared with the diet-group (n=87; median 5.5% (37 mmol/mol), IQR 5.3-5.6% (34-38 mmol/mol)). The women in the insulin-group were slightly older and were more often overweight (BMI ≥25 kg/m2). In addition, multiparity was higher in the insulin-group and a higher proportion had a previous GDM, previ-ous infant weighing ≥4500 g at birth, and a family history of diabetes. The median fasting glucose level and 2-h glucose level after a 75-g OGTT were higher in the insulin-group compared with the diet-group. In the whole cohort, GDM diagnosis was based only on the fasting glucose in 1% during the OGTT, and 91% tested posi-tive only on the 2-h value. In total 9685 women (with a mean maternal age of 30.9 ± 4.9) and 9854 neonates of the northern region of the Netherlands served as a reference population.

Neonatal outcomesTable 2 shows the neonatal outcomes. Between the treatment groups, there were no significant differences in neonatal outcomes with respect to the perinatal complica-tions (p=0.221). Although the frequency of neonatal hypoglycaemia and neonatal hyperbilirubinaemia tended to be higher in the insulin-group, these differences were not statistically significant. For the variable neonatal hypoglycaemia, neonates born <37 weeks of gestation with neonatal hypoglycaemia were excluded (n=7).

a Weight gain from pre-pregnancy weight to first visit.b N=795 due to missing data on weight or height.c N=790 due to missing data on indication of OGTT.d N=643 due to missing data. The HbA1c values were measured at the time of GDM diagnosis within 1 week after the OGTT.

Chapter 3

56

TABLE 2. Neonatal outcomes according to gestational diabetes mellitus treatment groups.

Outcome variable Overall

Treatment groups

P-value*

Generalobstetric

population P-value**Diet Insulin

N (%) 820 460 (56.1) 360 (43.9) 9854a

Perinatal complications, n (%)b 75 (9.1) 36 (7.8) 39 (10.8) NS

Still birth/neonatal death, n (%)c 2 (0.2) 0 (0.0) 2 (0.6) NS 89 (0.9) 0.048

Birth trauma, n (%) 30 (3.7) 19 (4.1) 11 (3.1) NS

Hypoglycaemia, n (%)d 28 (3.4) 12 (2.6) 16 (4.5) NS

Hyperbilirubinaemia, n (%) 15 (1.8) 5 (1.1) 10 (2.8) NS

Birth weight (g)e 3422 ± 522 3467 ± 522 3364 ± 517 0.005

Infants >4000-4499 g, n (%) 96 (11.7) 63 (14.0) 32 (8.8) 0.009 1207 (12.2) 0.350

Infants >4200 g, n (%) 40 (4.9) 25 (5.4) 15 (4.2) NS

Infants ≥4500 g, n (%) 10 (1.2) 8 (1.7) 2 (0.6) NS 218 (2.2) 0.059

Birth weight percentiles, n (%)f

<10th percentile 10- 20th percentile 20- 50th percentile 50- 90th percentile 90- 95th percentile >95th percentile

27 (3.3)44 (5.4)

202 (24.6)384 (48.6)

67 (8.2)96 (11.7)

19 (4.1)20 (4.3)

109 (23.7)214 (46.5)46 (10.0)52 (11.3)

8 (2.2)24 (6.7)

93 (25.8)170 (47.2)

21 (5.8)44 (12.2)

NS

Large for gestational age, n (%)g 163 (19.9) 98 (21.3) 65 (18.1) NS 1082 (11.0) <0.001

Small for gestational age, n (%)h 27 (3.3) 19 (4.1) 8 (2.2) NS 788 (8.0) <0.001

Gestational age at birth (wks) 38.3[38.0-39.0]

38.6[38.0-39.6]

38.1[38.0-38.4]

<0.001

Apgar <7 at 5 min, n (%) 27 (3.3) 17 (3.7) 10 (2.8) NS 192 (2.0) 0.009

Respiratory support, n (%) 26 (3.2) 16 (3.5) 10 (2.8) NS

Preterm delivery, n (%) <28 wks 28-32 wks 32-37 wks

3 (0.4)5 (0.6)

44 (5.4)

1 (0.2)2 (0.4)

25 (5.4)

2 (0.6)3 (0.8)

19 (5.3)

NS

Admission neonatology, n (%) 121 (14.8) 61 (13.3) 60 (16.7) NS

Abbreviations: g, grams; wks, weeks; NS, not significant.Data are expressed as mean ± SD, median [IQR], or proportion n (%).* P-values were based on Student’s unpaired t-test (non-skewed continuous variables), Mann-Whitney U Test (skewed continuous variables) or Chi-square test (categorical variables).** P-values for the GDM population (overall) and general obstetric population were based on Chi-square test.a In total n=9685 mothers with a mean age of 30.9 ± 4.9. Not all of the neonatal and obstetric outcomes in the general population were well reported and this has resulted in lack of information for some neonatal outcomes.b Perinatal complications included the following: still birth/neonatal death, birth trauma (shoulder dystocia, fracture of humerus or clavicle), hypoglycaemia, and hyperbilirubinaemia.c One still birth was associated with gestational diabetes and the other still birth was associated with a congeni-tal heart defect.d Hypoglycaemia was defined as neonates without prematurity (born <37 weeks of gestation). There were n=7 neonates with hypoglycaemia and prematurity excluded.e Mean birth weight was calculated after exclusion of neonates with extreme prematurity (born <28 weeks of gestation). There were n=3 neonates with extreme prematurity (178 days, 185 days, and 195 days).f Birth weights in percentiles were adjusted for gestational age, gender, parity, and ethnicity.


57

3Neonates born to women in the insulin-group had a significantly lower birth weight (3364 vs. 3467 g, p=0.005) and a lower gestational age at birth (38.1 vs. 38.6 weeks, p=0.001) compared with neonates born to women in the diet-group. Moreover, the frequency of neonates weighing >4000-4499 g were higher in the diet-group compared with the insulin group (14.0% vs. 8.8% p=0.009). However, birth weight was not different between the groups when expressed in percentiles (p=>0.05), adjusted for gestational age, parity, ethnicity, and gender. For the variable birth weight, neonates with extreme prematurity (born <28 weeks) were excluded (n=3), to remove the potential bias for extreme low birth weight. There were no significant differences between the two groups with respect to LGA, SGA, neonate weighing >4200 g, neonate weighing ≥4500 g, Apgar score <7 at 5 min, need for respiratory support, preterm delivery, and admission to the neonatology department.

In comparison, the percentage of LGA neonates with a birth weight >90th per-centile was significantly higher in the GDM population (19.9%) compared to the general obstetric reference population (11.0%) (p=<0.001). Further, the percentage of SGA neonates with a birth weight <10th percentile was significantly lower in the GDM population (3.3%) compared to the general obstetric reference population (8.0%) (p=<0.001). Apgar score <7 at 5 min was significantly lower in the general obstetric reference population (2.0%) compared with the GDM population (3.3%) (p=0.009). There were no differences between the GDM population and the general obstetric reference population with respect to infants weighing >4000-4499 g and infants weighing ≥4500 g.

Obstetric outcomesThe obstetric outcomes are shown in Table 3. Labour was induced more frequently in the insulin-group. However, insulin therapy was one of the indications to induce labour in both hospitals at or around 38 weeks. There were significantly more planned caesarean sections in the insulin-group compared with the diet-group (p=0.001) while secondary caesarean sections were comparable (p=0.335). There were more instrumental vaginal deliveries in the diet-group (p=0.052). There were no differences in occurrence of preeclampsia and gestational hypertension between the two groups.

g Large for gestational age was defined as a birth weight above the 90th percentile, adjusted for gestational age, gender, parity, and ethnicity.h Small for gestational age was defined as birth weight below the 10th percentile, adjusted for gestational age, gender, parity, and ethnicity.

Chapter 3

58

TABLE 3. Obstetric outcomes according to gestational diabetes mellitus treatment groups.

Outcome variable Overall

Treatment groups

P-value*Diet Insulin

N (%) 820 460 (56.1) 360 (43.9)

Induction of labour, n (%) 533 (65.0) 271 (58.9) 262 (72.8) NAa

Delivery type, n (%) Spontaneous Instrumentalb

Caesarean section Planned caesarean section

561 (68.4)67 (8.2)

99 (12.1)93 (11.3)

317 (68.9)46 (10.0)60 (13.0)37 (8.0)

244 (67.8)21 (5.8)

39 (10.8)56 (15.6)

NSNSNS

0.001

Preeclampsia, n (%)c 28 (3.4) 16 (3.5) 12 (3.3) NS

Gestational hypertension, n (%) 75 (9.1) 43 (9.3) 32 (8.9) NS

Abbreviations: NS, not significant; NA, not applicable.Data are expressed as proportion n (%).* P-values were based on Chi-square test for categorical variables.a Not applicable, insulin therapy is one of the indications to induce labour in GDM pregnancy at or around 38 weeks of gestation.b Instrumental is defined as forceps and vacuum extraction.c Preeclampsia included eclampsia (n=1) and Hemolysis Elevated Liver enzymes and Low Platelets (HELLP) syn-drome (n=1).

DISCUSSION

In this retrospective observational cohort study of 820 singleton GDM pregnan-cies treated according the revised national guideline on systematic screening and treatment of GDM, we found a higher incidence of LGA neonates of approximately 20% compared with 11% in the general obstetric population in the northern region of the Netherlands. However, there were no major differences in neonatal and obstetric outcomes between women treated with diet-only and those who needed additional insulin therapy.

A recent large population-based study investigated the pregnancy outcomes complicated by pre-existing diabetes and GDM in Alberta, Canada.21 Compared with our GDM population we found comparable results for the following adverse pregnancy outcomes, preeclampsia, stillbirth, admission to the neonatology de-partment, and Apgar score below 7 at 5 min. In the Canadian study there was a much higher proportion of caesarean sections performed in the GDM pregnancies compared with our study (36.9 % vs. 12.1%). Furthermore, the percentage LGA in-fants was lower in the Canadian GDM population (15.3% vs. 19.9%) and they found a higher percentage of SGA ( 9.4% vs. 3.3%) infants compared with our study.21

Five systematic reviews have summarized the studies specifically on the ef-fect of treatment of GDM on pregnancy outcomes.14-18 They included studies that compared intensive treatment – including diet modification, glucose monitoring


59

3

and/or insulin – or any therapeutic intervention of GDM with usual obstetric care in GDM women. It was shown that intensive treatment of GDM reduced the risk of preeclampsia, shoulder dystocia, and macrosomia. In line with our findings, these reviews reported a low incidence of serious adverse outcomes, like mortality and birth trauma.

In contrast with the landmark trials on treatment of GDM, the number of LGA neonates in our study was relatively high.8,9 In the Australian Carbohydrate Intoler-ance Study (ACHOIS) the prevalence of LGA neonates was 13% in the treatment group and in the study by Landon et al. it was 7.1%.8,9 This discrepancy in the preva-lence of LGA neonates can be possibly explained by the differences in diagnostic criteria for GDM. Especially, the study by Landon et al., included women with milder glucose intolerance using the following cut-off values: fasting value <5.3 mmol/l; 1-h value ≥10.0 mmol/l; 2-h value ≥8.6 mmol/l; and 3-h value ≥7.8 mmol/l after a 100-g OGTT.8 Compared with our study, they included women who had slightly lower fast-ing glucose value but higher post GTT value. Furthermore, different definitions for LGA were used between the studies. In the Landon study the percentage neonates with a birth weight >4000 g was almost similar with the percentage observed in our GDM population. However, in the Landon study there was a small difference between the proportion neonates with a birth weight >4000 g and the proportion LGA neonates, as they did not correct for gender, ethnicity and parity.8 In our study LGA was defined as a birth weight above the 90th percentile, specifically adjusted for gender, parity and ethnicity.20 Therefore, we found a larger difference between neonates weighing >4000 g and LGA neonates.

In 2010 the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) and in 2013 the WHO adopted new diagnostic criteria for GDM.22,23 The WHO 2013/IADPSG diagnostic criteria for GDM recommends the following 75-g OGTT glycaemic thresholds: fasting value ≥5.1 mmol/l; 1-h ≥10.0 mmol/l; and a 2-h value ≥8.5 mmol/l.22,23 In our study the WHO 199912 diagnostic criteria for GDM were used, with a much higher fasting glucose threshold. However, the screening and diagnostic criteria for GDM are inconsistent across Europe.24 The recently revised British NICE guideline 2015 recommends the following alternative 75-g OGTT glycaemic thresholds: fasting value ≥5.6 mmol/l; 2-h value ≥7.8 mmol/l.25 The 2-h glucose level of the NICE guideline corresponds with our guideline for the diagnosis of GDM, only the NICE guideline proposed a lower fasting glucose value. The NICE guideline proposed these thresholds, because of the treatment costs and the lim-ited evidence for treating at lower diagnostic thresholds.25 Nevertheless, a recent study comparing the outcomes among the IADPSG criteria and NICE 2015 criteria, demonstrated that women who test positive for GDM according to the IADPSG criteria but negative for the NICE 2015 criteria, had the highest risk of having infants

Chapter 3

60

with LGA. In other words, the IADPSG criteria identified women at risk of LGA who may benefit from treatment, but these women were unidentified and not treated with the WHO 199912 guideline and NICE 201525 guideline.26 A similar problem of too high cut-off value for fasting blood glucose may hamper the Dutch guideline.

A reduction in the proportion of LGA neonates is an important treatment target in GDM, since LGA neonates apart from the risk of obstetrical complications are possible more likely to develop obesity and diabetes in early adulthood and later life.3,4 The more stringent IADPSG glycaemic thresholds may contribute as they have been shown to accurately identify women at risk of delivery LGA neonates.22,26 The timing of the diagnosis and intervention of GDM is another factor of concern. GDM screening is advised between 24-28 weeks of gestation. In our study the median gestational age at GDM diagnosis ranged from 26 to 31 weeks, in a considerable proportion of women, intervention was started late in pregnancy. The OGTT could be scheduled more strictly at week 24 or even before week 24. One recent study27 has shown that despite early testing and treatment, early GDM diagnosis (<24 weeks) in high-risk women was associated with adverse pregnancy outcomes, including LGA neonates. The study indicates that early identification in high-risk GDM women is important to improve the pregnancy outcomes.27 However, screening for GDM before 24 weeks of gestation would increase the amount of false negative OGTT’s.

The neonates born in the diet-group and insulin-group were more likely to be LGA compared with the general obstetric population in the northern region of the Netherlands. It has been shown that LGA is not always a consequence of hyper-glycaemia, other risk factors such as pre-pregnancy overweight/obesity, maternal weight gain during pregnancy, and maternal age increases the risk of having a LGA neonate.28-31 The women in this GDM cohort were older compared with the general obstetric population and the percentage of pre-pregnancy overweight women in our present cohort was high, almost 70%, but not higher than the Landon study.8 However, a recent meta-analysis has shown that lifestyle intervention in obese pregnant women reduces maternal weight gain, but without differences in LGA or macrosomia.32

The main strength of this study is that it evaluated the results of the implemen-tation of the in 2010 introduced guideline in a large GDM population. It further focuses on outcomes in diet-only and insulin-treated women. Therefore the study is indicative for routine clinical practice and makes the results more applicable to real-life clinical care. An additional strength is the comparison with data from the general obstetric population in the same region of the Netherlands. A theoretical limitation of this study is the retrospective design. This may have resulted in lack of information from variables in existing medical and birth records, however most of the medical and birth records in our study were complete. A further limitation


61

3

is that our national guideline uses the “old” WHO 1999 diagnostic criteria for GDM which differ greatly from the new WHO 2013 criteria.12,23 On the other hand, for the treatment of GDM we use the new stringent international glucose targets to obtain glycaemic control in GDM pregnancies. At last, not all the neonatal and obstetric outcomes in the general population are available from public dataset with sufficient detail and this has resulted in lack of information for some neonatal and obstetric outcomes.

Our current GDM guideline on systematic screening and stringent treatment of GDM was successful in achieving a low incidence of birth complications compa-rable to the literature, but the percentage of LGA neonates was significantly higher in GDM compared to other international GDM studies, and to the general obstetric population. This has practical implications for the Dutch clinical guideline for GDM that is not optimal at this moment for reducing LGA neonates. Adopting stricter diagnostic criteria should be considered in the next revision of the Dutch guideline, the current criteria is likely not stringent enough. There is more evidence from other countries that the more stringent criteria is associated with significant improve-ments in pregnancy outcomes, including lowering the frequency of LGA neonates.33 Furthermore, we agree with Benhalima et al. who ultimately recommend the use of the same diagnostic criteria for GDM across Europe.24

CONCLUSIONS

In summary, in this GDM population screened and treated according to the 2010 national guideline, we found an elevated percentage of LGA neonates compared with the general obstetric reference population. Although the incidence of severe pregnancy outcomes was low. We found no major differences in neonatal and ob-stetric outcomes between GDM women treated with diet-only or additional insulin. Despite the progress in screening and treatment of GDM, we suggest an adjustment of the diagnostic criteria is needed to further improve GDM outcomes, especially to reduce the risk of LGA neonates for obesity and diabetes later in life.

Abbreviations

ACHOIS: Australian Carbohydrate Intolerance Study; BMI: Body Mass Index; DBP: Diastolic blood pres-sure; GDM: Gestational diabetes mellitus; HELLP: Hemolysis Elevated Liver enzymes and Low Platelets; IADPSG: International Association of the Diabetes and Pregnancy Study Groups; IQR: Inter quartile range; LGA: Large for gestational age; NICE: National Institute for Health and Care Excellence; NPH: Neutral Prot-amine Hagedorn; OGTT: Oral glucose tolerance test; SBP: Systolic blood pressure; SD: standard deviation; SGA: Small for gestational age; WHO: World Health Organization.

Chapter 3

62

Acknowledgements

The authors wish to thank the endocrinologists, gynaecologists, diabetes specialist nurses, and dieti-cians of the University Medical Center and Martini Hospital Groningen. Special thanks are expressed to epidemiologist H. Groen, the Dutch Perinatal Registry and the Municipal Health Service Groningen for providing the reference population in the Northern region of the Netherlands.

Funding

Novo Nordisk Netherlands provided an unrestricted research grant.

Availability of data and materials

The dataset contains clinical data, which because of the Dutch law for Personal Data Protection and patient confidentiality cannot be shared publicly. Data are available upon request to prof. Wolffenbuttel. Patients did not sign informed consent to release their data on an individual basis on the internet. For this reason, a research proposal should be filled upon contacting prof. Wolffenbuttel ([email protected]).

Authors’ contributions

Conceived and designed the study: SHK, BHRW, HLL, KH, PPB. Collecting the data: KAS, BJS, MGB, SHK. Wrote the manuscript: SHK. Intellectual contributions to the manuscript, helped drafting the manuscript and have read and approved the final version: KH, KAS, MGB, FJK, KMS, BJS, AJL, BHRW, PPB, HLL. All authors read and approved the final manuscript.

Authors’ information

SHK, PhD-student, University Medical Center Groningen, Department Endocrinology.

BHRW, Professor Endocrinology and Metabolism, University Medical Center Groningen, Department Endocrinology.

PPB, Professor Obstetrics and Gynaecology, University Medical Center Groningen, Department Gynae-cology and Obstetrics.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

This study is conducted in accordance with the guidelines of the Declaration of Helsinki and Good Clinical Practice. The study has been exempted for approval according to the Medical Research Involving Human Subjects Act.19 This report is based on patient data acquired during care-as-usual, the data has been analyzed retrospectively and all the requirements for patient anonymity are in agreement to the regulations of the ethical committee of both hospitals for publication of patient data. According to this


63

3

and the Dutch law Medical Research with Human Subjects, no approval from an ethics committee is necessary.

Chapter 3

64

REFERENCES



3. Hillier TA, Pedula KL, Schmidt MM, Mullen JA, Charles MA, Pettitt DJ. Childhood obesity and metabolic imprinting: the ongoing effects of maternal hyperglycemia. Diabetes Care. 2007;30:2287-92.

4. Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers. Relationship to fetal hyperinsulinism. Diabetes Care. 1995;18:611-7.

5. Sermer M, Naylor CD, Gare DJ, et al. Impact of increasing carbohydrate intolerance on maternal-fetal out-comes in 3637 women without gestational diabetes: The Toronto Tri-Hospital Gestational Diabetes Project. Obstet Gynecol. 1995;173:146-56.


7. Langer O, Yogev Y, Most O, Xenakis EM. Gestational diabetes: The consequences of not treating. Obstet Gynecol. 2005;192:989-97.

8. Landon MB, Spong CY, Thom E, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009;361:1339-48.

9. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352:2477-86.


11. The Dutch Society of Obstetrics and Gynaecology. Diabetes mellitus and Pregnancy. Clinical guideline version 2.0. 2010. Available from: http://www.nvog-documenten.nl/richtlijn/item/pagina.php?richtlijn_id=863, accessed 22 September 2015.

12. World Health Organization (WHO). Definition and Classification of Diabetes mellitus and its Complications. Report of a WHO consultation. Part 1: Diagnosis and Classification of Diabetes Mellitus. Geneva, WHO, 1999. Department of Noncommunicable Disease Surveillance.

13. National Institute for Health and Clinical Excellence (NICE). Diabetes in pregnancy: management of diabetes and its complications from pre-conception to the postnatal period. London, NICE, 2008. National Collaborating Centre for Women’s and Children’s Health.

14. Hartling L, Dryden DM, Guthrie A, Muise M, Vandermeer B, Donovan L. Benefits and harms of treating gestational diabetes mellitus: A systematic review and meta-analysis for the US Preventive Services Task Force and the National Institutes of Health Office of Medical Applications of Research. Ann Intern Med. 2013;159:123-9.

15. Falavigna M, Schmidt MI, Trujillo J, et al. Effectiveness of gestational diabetes treatment: a systematic review with quality of evidence assessment. Diabetes Res Clin Pract. 2012;98:396-405.

16. Poolsup N, Suksomboon N, Amin M. Effect of treatment of gestational diabetes mellitus: A systematic review and meta-analysis. PLoS One. 2014;9:e92485.

17. Alwan N, Tuffnell DJ, West J. Treatments for gestational diabetes. Cochrane Database Syst Rev. 2009;3:CD003395.


65

3

18. Horvath K, Koch K, Jeitler K, et al. Effects of treatment in women with gestational diabetes mellitus: system-atic review and meta-analysis. BMJ. 2010;340:c1395.

19. University Medical Center Groningen. Researchcode University Medical Center Groningen. 2013. Available from: https://www.umcg.nl/SiteCollectionDocuments/English/Researchcode/UMCG-Researchcode,%20basic%20principles%202013.pdf, accessed 16 March 2016.

20. Visser GH, Eilers PH, Elferink-Stinkens PM, Merkus HM, Wit JM. New Dutch reference curves for birthweight by gestational age. Early Hum Dev. 2009;85:737-44.

21. Lai FY, Johnson JA, Dover D, Kaul P. Outcomes of singleton and twin pregnancies complicated by pre‐exist-ing diabetes and gestational diabetes: A population‐based study in Alberta, Canada, 2005–11. J Diabetes. 2016;8:45-55.

22. International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International As-sociation of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33:676-82.

23. World Health Organization (WHO). Diagnostic criteria and Classification of Hyperglycemia First De-tected in Pregnancy. 2013. Available from: http://apps.who.int/iris/bitstream/10665/85975/1/WHO_NMH_MND_13.2_eng.pdf, accessed 16 March 2016.

24. Benhalima K, Mathieu C, Damm P, et al. A proposal for the use of uniform diagnostic criteria for gestational diabetes in Europe: an opinion paper by the European Board & College of Obstetrics and Gynaecology (EBCOG). Diabetologia. 2015;58:1422-9.

25. National Institute for Health and Clinical Excellence (NICE). Diabetes in pregnancy: Management of Diabetes and its Complications from Pre-conception to the Postnatal period. Clinical guideline NG3. 2015. Available from: http://www.nice.org.uk/guidance/ng3/resources/diabetes-in-pregnancy-management-of-diabetes-and-its-complications-from-preconception-to-the-postnatal-period-51038446021, accessed 16 March 2016.

26. Meek CL, Lewis HB, Patient C, Murphy HR, Simmons D. Diagnosis of gestational diabetes mellitus: Falling through the net. Diabetologia. 2015;58:2003-12.

27. Sweeting AN, Ross GP, Hyett J et al. Gestational diabetes mellitus in early pregnancy: Evidence for poor pregnancy outcomes despite treatment. Diabetes Care. 2016;39:75-81.

28. Black MH, Sacks DA, Xiang AH, Lawrence JM. The relative contribution of prepregnancy overweight and obesity, gestational weight gain, and IADPSG-defined gestational diabetes mellitus to fetal overgrowth. Diabetes Care. 2013;36:56-62.

29. Barnes R, Edghill N, Mackenzie J, et al. Predictors of large and small for gestational age birthweight in offspring of women with gestational diabetes mellitus. Diabet Med. 2013;30:1040-6.

30. Catalano PM, McIntyre HD, Cruickshank JK, et al. The hyperglycemia and adverse pregnancy outcome study: associations of GDM and obesity with pregnancy outcomes. Diabetes Care. 2012;35:780-6.

31. Wahabi HA, Fayed AA, Alzeidan RA, Mandil AA. The independent effects of maternal obesity and gesta-tional diabetes on the pregnancy outcomes. BMC Endocr Disord. 2014;14:1.

32. Oteng-Ntim E, Varma R, Croker H, Poston L, Doyle P. Lifestyle interventions for overweight and obese preg-nant women to improve pregnancy outcome: Systematic review and meta-analysis. BMC Med. 2012;10:1.

33. Duran A, Saenz S, Torrejon MJ, et al. Introduction of IADPSG criteria for the screening and diagnosis of gestational diabetes mellitus results in improved pregnancy outcomes at a lower cost in a large cohort of pregnant women: the St Carlos Gestational Diabetes study. Diabetes Care. 2014;37:2442-50.

4 Risk stratifi cation for healthcare planning in women with gestational diabetes mellitus

Koning SH, Scheuneman KA, Lutgers HL, Korteweg FJ, van den Berg G, Sollie KM, Roos A, van Loon AJ, Links TP, van Tol KM, Hoogenberg K, van den Berg PP*, Wolff enbuttel BHR*

* Contributed equally

Netherlands Journal of Medicine. 2016;74:262-269.

Chapter 4

68

ABSTRACT

Background: To identify relevant factors predicting the need for insulin therapy in women with gestational diabetes mellitus (GDM) and secondly to determine a potential “low-risk” diet-treated group who are likely to have good pregnancy outcomes.

Methods: A retrospective analysis between 2011-2014. Multivariable backward stepwise logistic regression was used to identify the predictors of the need for insulin therapy. To identify a “low-risk” diet-treated group, the group was stratified according to pregnancy complications. Diet-treated women with indications for induction in secondary care were excluded.

Results: A total of 820 GDM women were included, 360 (44%) women required additional insulin therapy. The factors predicting the need for insulin therapy were: previous GDM, family history of diabetes, a previous infant weighing ≥4500 gram, Middle-East/North-African descent, multiparity, pre-gestational BMI ≥30 kg/m2, and an increased fasting glucose level ≥5.5 mmol/l (OR 6.03;CI 3.56-10.22) and two-hour glucose level ≥9.4 mmol/l after a 75-gram oral glucose tolerance test at GDM diagnosis. In total 125 (54%) women treated with diet-only had pregnancy complications. Primiparity and higher weight gain during pregnancy were the best predictors for complications (predictive probability 0.586 and 0.603).

Conclusion: In this GDM population we found various relevant factors predicting the need for insulin therapy. A fasting glucose level ≥5.5 mmol/l at GDM diagnosis was by far the strongest predictor. Women with GDM who had good glycaemic control on diet-only with a higher parity and less weight gain had a lower risk for pregnancy complications.

Risk stratification in women with GDM

69

4

INTRODUCTION

Gestational diabetes mellitus (GDM) is one of the most common metabolic complica-tions during pregnancy and occurs in 1-14% of all pregnancies, depending on the population demographics and the diagnostic criteria used.1 Given that obesity is a worldwide epidemic and the recent more stringent guidelines for screening and diag-nosis, the prevalence of GDM is still increasing which burdens obstetric care systems.2-7

GDM is associated with an elevated risk of adverse obstetric and neonatal out-comes during pregnancy.8-11 However, studies demonstrated that GDM is a treatable condition and controlling blood glucose levels throughout pregnancy can reduce the risk of complications.12-13 Dietary advice is the first step and cornerstone in GDM treatment. When diet fails, insulin therapy is the second step in treatment, accord-ing to almost all international guidelines.14

In our country, we have a special obstetric care system which is divided between primary and secondary care. The primary care is organised by independently prac-tising midwives and general practitioners (GP’s) who take care of normal pregnancy and childbirth, and secondary care is organised by in-hospital obstetricians and specialised clinical midwives caring for pathological pregnancy and childbirth or pregnancies accompanied by comorbidity.15

Since GDM pregnancies are at increased risk for adverse obstetric and neonatal outcomes, women with GDM are referred to hospitals for obstetric care and are advised to give birth in a hospital with good neonatal facilities. This is especially ap-plicable for women with GDM who are treated with additional insulin therapy and who are considered to present a more severe GDM group due to a greater difficulty to maintain glycaemic control.16

However, there may be “low-risk” women with GDM who do not need obstetric care in secondary care but can maintain care from their midwives or GP’s. Women with GDM treated with diet only might be the potential “low-risk” group who could be treated in a low-risk setting and even qualify for delivery at home. Such a policy demands the correct identification of women with GDM with a high-risk of adverse pregnancy outcomes.

In an earlier paper, we reported the neonatal and obstetric outcomes of preg-nancies complicated with GDM after implementation of the 2010 Dutch Society of Obstetrics and Gynaecology GDM guideline on screening and treatment – diet only versus additional insulin therapy – and we compared these outcomes with the gen-eral obstetric population in the northern region of the Netherlands.17 In the present study we aim to identify relevant factors predicting the need for insulin therapy in women with GDM and secondly to determine a potential “low-risk” diet-treated group likely to have good obstetric and/or neonatal outcomes.

Chapter 4

70

MATERIALS AND METHODS

Study population and designThe study population consisted of all women with singleton pregnancies who were diagnosed with GDM according to the Dutch national guidelines in the University Medical Center Groningen and in the Martini Hospital Groningen, between January 2011 and September 2014. As previously reported,17 pregnant women were recom-mended to undergo a 75-gram oral glucose tolerance test (OGTT) at week 24-28 of gestation if they had one or more risk factors for GDM according to the Dutch national guideline: previous GDM, first degree relative with type 2 diabetes mellitus (DM), a previous neonate weighing ≥4500 gram, pre-pregnancy body mass index (BMI) ≥30 kg/m2, some ethnic risk groups (South-Asian, Hindu, African-Caribbean, Middle Eastern, Morocco and Egypt), history of intrauterine foetal death (IUFD), and history of polycystic ovary syndrome (PCOS). Also women with signs suggestive of GDM (e.g. polyhydramnios and/or foetal macrosomia) were screened.14 Women with previous GDM were screened at week 16-18 of gestation and when the test was negative, it was repeated at week 24-28 of gestation. GDM was diagnosed if the fasting plasma glucose was ≥7.0 mmol/l and/or the two-hour plasma glucose ≥7.8 mmol/l. In addition, GDM was diagnosed if fasting glucose was >7.0 mmol/l or random glucose was >11.1 mmol/l.14,18 The guideline uses these diagnostic criteria, based on the criteria of the World Health Organization (WHO) 1999.18

Women with a twin pregnancy (n=15) and women with missing data on neonatal complications (n=4) were excluded. Women with pre-existing diabetes were not included in the study. This study has been exempted for approval according to the Medical Research Involving Human Subjects Act. This report is based on patient data acquired during care as usual, the data were analysed retrospectively and all the requirements for patient anonymity are in agreement with the regulations of the ethics committee of both hospitals. According to this and the Dutch law on Medical Research with Human Subjects, no approval from an ethics committee is necessary.

GDM treatment regimensAll women diagnosed with GDM received dietary advice by a trained dietician, which included education about carbohydrate intake and carbohydrate distribution. The women also received instructions regarding self-monitoring of blood glucose levels by a diabetes specialist nurse and were instructed to measure fasting and one-hour postprandial blood glucose levels every day for one week. After 1-2 weeks the blood glucoses values were evaluated at the diabetes outpatient clinic. If the fast-ing plasma glucose level was >5.3 mmol/l and/or postprandial plasma glucose level >7.8 mmol/l additional insulin therapy was started. Insulin was commenced with


71

4

two elevated blood glucose levels on two successive days and no expected ben-efits of further dietary intervention. There were three options for insulin therapy: once daily long-acting, prandial ultrashort-acting insulin or a combination of both (basal-bolus regimen), depending on the specific glycaemic profile. In both centres short-acting insulin analogues and NPH insulin were used in GDM treatment.

MeasuresAll data were assessed from medical and birth records. Ethnicity was classified into four categories: Caucasian, African-American, Middle-Eastern/North-African descents, and Asian (Indian or South-East Asian). Family history of diabetes was defined as having a first-degree relative with type 2 DM. Weight gain was calculated from pre-pregnancy weight to the first visit. HbA1c values were measured by stan-dardised HPLC method on a Tosoh G8 system (Tosoh, Tokyo, Japan), considering 22-42 mmol/mol (4.2-6.0%) as normal. The HbA1c values were measured at the time of GDM diagnosis within one week after the OGTT.

Neonatal complications included: a composite outcome of perinatal compli-cations (still-birth/neonatal death, birth trauma (shoulder dystocia, fracture of humerus or clavicle), hyperbilirubinaemia and neonatal hypoglycaemia), large for gestational age (defined as birth weight above the 90th percentile, adjusted for age, gender, parity, and ethnicity),19 small for gestational age (defined as birth weight below the 10th percentile, adjusted for age, gender, parity, and ethnicity),19 preterm delivery (defined as delivery <37 weeks), Apgar score <7 at 5 minutes, and admis-sion to the neonatology department. The presence of neonatal hypoglycaemia was defined as a blood glucose level <2.6 mmol/l or treatment with a glucose infusion. Obstetric complications included: instrumental delivery (forceps or vacuum extrac-tion), planned caesarean section and secondary caesarean section.

Statistical analysesMaternal characteristics are presented according to the GDM treatment regimens. Continuous data are presented as mean with standard deviation or as median and inter quartile range [IQR] in case of skewed distribution. Categorical data are pre-sented as number and percentage. For continuous data, the differences between the groups were tested using Student’s unpaired t-test or the Mann-Whitney U test in case of skewed distribution. Categorical variables were compared using Chi-square test and Fisher’s exact test.

To examine the potential predictors of need for insulin therapy in GDM, analyses were performed using logistic regression models to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs). Factors considered in the model were: maternal age, smoking during pregnancy, parity, ethnicity, history of PCOS, history of IUFD, pre-

Chapter 4

72

gestational BMI, previous GDM, previous neonate weighing ≥4500 gram, first-degree relative with diabetes, chronic hypertension, HbA1c, fasting glucose level at time of GDM diagnosis (quartiles), and two-hour glucose level after a 75-gram OGTT at time of GDM diagnosis (quartiles). First univariable logistic regression was performed and significant factors (two-sided P-value <0.10) were included in a multivariable backward stepwise logistic regression model to determine the final model. In the final prediction model a two-sided P-value <0.10 was considered statistical significant.

To determine a potential “low-risk” diet-treated group, women with other indica-tions for induction in secondary-care – according to the “List of Obstetric Indications” used by midwives in the Netherlands20 – were excluded. The diet group was stratified in a group without and with obstetric and/or neonatal complications as defined above. Comparison between the risk groups was applied using Mann-Whitney U test or Chi-square test. Receiver operating characteristics curves analysis was used to evaluate the predicted probability. All P-values were two-sided and P <0.05 was

TABLE 1. Comparison of the characteristics between GDM women treated with diet only and the women who required additional insulin therapy.

CharacteristicsOveralln=820

Diet groupn=460

Insulin groupn=360 P-value*

Age (years) 32.0 ± 5.1 31.6 ± 4.9 32.6 ± 5.2 0.010

Family history of diabetes, n (%) 326 (39.8) 156 (33.9) 170 (47.2) <0.001

Previous gestational diabetes mellitus, n (%) 86 (10.5) 25 (5.4) 61 (16.9) <0.001

Previous infant weighing ≥4500 g, n (%) 90 (11.0) 35 (7.6) 55 (15.3) <0.001

History of IUFD, n (%) 16 (2.0) 5 (1.1) 11 (3.1) 0.043

Parity, n (%) 0 1-2 >2

333 (40.6)436 (53.2)

51 (6.2)

223 (48.5)216 (47.0)

21 (4.6)

110 (30.6)220 (61.1)

30 (8.3)

<0.001

Pre-gestational BMI (kg/m2) 27.7[24.0-31.9]

26.9[23.3-31.4]

29.2[25.0-33.4]

<0.001

Weight gain mother (kg)† 8.0 [4.0-12.0] 9.0 [5.0-13.0] 7.0 [3.0-11.0] <0.001

Fasting glucose level (mmol/l) 5.0 [4.6-5.5] 4.8 [4.5-5.2] 5.3 [4.9 5.9] <0.001

2-hour glucose level (mmol/l) 8.6 [8.1-9.4] 8.5 [8.0-9.1] 8.8 [8.2-9.7] <0.001

HbA1c‡

mmol/mol %

37 [34-40]5.5 [5.3-5.8]

37 [34-39]5.5 [5.3-5.7]

38 [36-42]5.6 [5.4-6.0]

<0.001

Abbreviations: IUFD, intrauterine foetal death; BMI, body mass index.Data are expressed as mean ± SD, median [IQR], or proportion n (%).Data with respect to family history of diabetes, pre-gestational body mass index, weight gain mother, and HbA1c are missing in 24 (2.9%), 25 (3.0%), 225 (27.4%), 177 (21.6%) of the women, respectively. * P-values were based on Student’s unpaired t-test (non-skewed continuous variables), Mann-Whitney U Test (skewed continuous variables) or Chi-square test (categorical variables).† Weight gain from pre-pregnancy weight to first visit.‡ The HbA1c values were measured at the time of GDM diagnosis within 1 week after.


73

4

considered statistical significant. All statistical analyses were performed with the use of the statistical package IBM SPSS Statistics (version 22.0. Armonk, NY: IBM Corp).

RESULTS

Maternal characteristicsThe most important characteristics of the study population are summarized in Table 1. A total of 820 GDM women were referred for treatment, 460 women (56%) were able to maintain adequate glycaemic control with dietary advice only, while 360 (44%) required additional insulin therapy. Of the women who required insulin therapy, 143 women (40%) received trice daily pre-prandial ultrashort-acting insulin, 165 women

TABLE 2. Multivariable logistic regression analyses of predictors for additional insulin therapy.

Predictors OR 95% CI P-value*

Previous gestational diabetes 2.05 1.13-3.70 0.018

Family history of diabetes 1.90 1.36-2.66 <0.001

Previous infant weighing ≥4500 gram 1.68 0.98-2.89 0.061

Parity 0 1-2 >2

1.00 (Ref.)1.832.06

1.27-2.660.94-4.52

0.0010.070

Ethnicity Caucasian African-American Middle-East/North-African Asian

1.00 (Ref.)0.982.450.98

0.39-2.471.29-4.650.48-1.99

0.9730.0060.944

Pre-gestational body mass index (kg/m2) <25 25-30 ≥30

1.00 (Ref.)1.371.63

0.90-2.091.08-2.45

0.1410.020

Fasting glucose level (mmol/l)**

<4.6 4.6-5.0 5.0-5.5 ≥5.5

1.00 (Ref.)1.472.546.03

0.90-2.411.02-2.67

3.56-10.22

0.1210.001

<0.001

2-hour glucose level after a 75-gram OGTT (mmol/l)**

<8.1 8.1-8.6 8.6-9.4 ≥9.4

1.00 (Ref.)1.131.651.93

0.71-1.811.02-2.671.20-3.11

0.6090.0400.007

Abbreviations: OGTT, oral glucose tolerance test; OR, odds ratio.ORs, 95% confidence intervals and P-values were derived from logistic regression models (backward- stepwise method).* P-value <0.10 was considered statistical significant.** The fasting glucose level and two-hour glucose at time of GDM diagnosis.

Chapter 4

74

(46%) received basal-bolus insulin therapy, and 39 women (11%) received once long-acting insulin (for 13 women type of insulin was not recorded) at the end of their pregnancy. The median insulin dose was 22 U/day; IQR 12-42 U/day.

The women in the insulin group were older, were more often multiparous, and had a higher pre-gestational BMI. No differences in earlier diagnosis of PCOS, hypertension, history of spontaneous abortion, smoking during pregnancy, and ethnicity were observed between the groups. The frequency rates of previous GDM, a previous neonate weighing ≥4500 gram at birth, and first degree relative with diabetes were higher in the insulin group. The median fasting glucose level and two-hour glucose level after a 75-gram OGTT at time of GDM diagnosis were higher in the insulin group compared with the diet group.

Predictors of need for insulin therapyTable 2 shows the significant predictors of need for insulin therapy. Previous GDM, family history of diabetes, a previous infant weighing ≥4500 gram, Middle-Eastern/North-African descent, multiparity, pre-gestational BMI ≥30 kg/m2, and an increased fasting glucose level and two-hour glucose after a 75-gram OGTT at GDM diagnosis were significant predictors of need for insulin therapy, with a fasting glucose level ≥5.5 mmol/l having the highest OR 6.03; CI 3.56-10.22.

TABLE 3. Indications for the diet group for surveillance of pregnancy and delivery in secondary care.

Indication* n=229**

Pre-existing diseasesMorbus CrohnHyperthyroidism with medicationChronic hypertension†

Asthma with medication

21

154

Obstetric historyIUFD/perinatal deathPreterm birth <33 weeksCaesarean sectionPre-eclampsia‡

93

186

Complications during pregnancyPregnancy-induced hypertensionPre-eclampsiaPolyhydramnios/foetal macrosomiaPost-term pregnancy¶

4316

1658

Abbreviations: IUFD, intrauterine foetal death.* Indications are based on the List of Obstetric Indications used by midwives in the Netherlands. ** Some women had more than one indication for treatment in secondary care.† Chronic hypertension was defined as a pre-gestational systolic blood pressure (SBP) ≥140 mmHg and/or a dia-stolic blood pressure (DBP) ≥90 mmHg on two occasions or the use of blood-pressure lowering drugs.‡ Pre-eclampsia was defined as a combination of gestational hypertension and proteinuria (≥300 mg/24-h) and included eclampsia and haemolysis elevated liver enzymes and low platelets (HELLP) syndrome.¶ Post-term pregnancy was defined as being pregnant for 42 weeks.


75

4

Stratification diet-treated group Of the 460 diet-treated women, 229 women (49.8%) were excluded because of other indications for induction. Table 3 gives an overview of these indications. Table 4 shows GDM pregnancies without (106 women (45.9%)) and with (125 women (54.1%)) obstetric and/or neonatal complications. Primiparity and higher weight gain during pregnancy were the best predictors for complications (predictive prob-ability 0.586 and 0.603) respectively.

TABLE 4. Identification of a low-risk group of diet-treated women with gestational diabetes according to obstetric and/or neonatal complications.

CharacteristicsOveralln=231

Low-risk group

P-value*No complications

n=106Complications**

n=125

Age (years) 31.4 ± 4.9 31.2 ± 4.7 31.7 ± 5.2 0.501

Parity, n (%) 0 1-2 >2

109 (47.2)109 (47.2)

13 (5.6)

39 (36.8)60 (56.6)

7 (6.6)

70 (56.0)49 (39.2)

6 (4.8)

0.014

Total risk factors for gestational diabetes, n (%)§

0 1-2 >2

9 (4.1)194 (89.0)

15 (6.9)

7 (6.9)83 (81.4)12 (11.8)

2 (1.7)111 (95.7)

3 (2.6)

0.003

Pre-gestational BMI (kg/m2) 28.0 [23.0-31.9] 27.6 [22.7-31.1] 28.5 [23.5-32.6] 0.290

Weight gain mother (kg)† 8.0 [4.0-11.0] 7.0 [3.0-10.0] 9.0 [4.9-12.3] 0.019

Fasting glucose level (mmol/l) 4.8 [4.5-5.2] 4.8 [4.5-5.2] 4.7 [4.5-5.2] 0.670

2-hour glucose level after 75-g OGTT (mmol/l) 8.5 [8.0-9.1] 8.4 [8.0-9.0] 8.5 [8.1-9.2] 0.381

HbA1c mmol/mol %

37 [34-40]5.5 [5.3-5.7]

35 [33-37]5.4 [5.2-5.6]

37 [34-40]5.5 [5.3-5.7]

0.158

Abbreviations: BMI, body mass index; OGTT, Oral Glucose Tolerance Test. Data are expressed as mean ± SD, median [IQR] or proportion n (%).Data with respect to total risks factors for gestational diabetes (GDM), pre-gestational BMI, weight gain mother, and HbA1c are missing in 13 (5.6%), 9 (3,9%), 56 (24.2%), 55 (23.8%) of the women, respectively.*P-values were based on Student’s unpaired t-test (non-skewed continuous variables), Mann-Whitney U Test (skewed continuous variables) or Chi-square test (categorical variables).**Complications during pregnancy, including: perinatal complications (perinatal mortality, birth trauma, hyper-bilirubinaemia and neonatal hypoglycaemia), large for gestational age (birth weight above the 90th percentile), small for gestational age (birth weight below the 10th percentile), Apgar score <7 after 5 minutes, preterm deliv-ery <37 weeks, admission to neonatology, instrumental delivery, and (elective) caesarean section.§Risk factors for GDM were: a previous GDM, first degree relative with type 2 diabetes mellitus, a previous neonate weighing ≥4500 gram, pre-pregnancy BMI ≥30 kg/m2, some ethnic risk groups (South-Asian, Hindu, African-Caribbean, Middle Eastern, Morocco and Egypt), history of intrauterine foetal death, and history of polycystic ovary syndrome.†Weight gain from pre-pregnancy weight to first visit.

Chapter 4

76

DISCUSSION

In this study we identified the following risk factors in GDM that predicted the need for additional insulin therapy: previous GDM, family history of diabetes, a previous infant weighing ≥4500 gram, Middle-Eastern/North-African descent, multiparity, pre-gestational BMI ≥30 kg/m2, and a markedly increased fasting and two-hour glucose level after a 75-gram OGTT at time of GDM diagnosis. A fasting glucose level ≥5.5 mmol/l at time of GDM diagnosis was the strongest predictor of need for insulin therapy.

Moreover, the study showed that diet-treated primiparous women with GDM had more obstetric and/or neonatal complications compared with multiparous. Also, a higher weight gain in diet-treated women with GDM was associated with more pregnancy complications.

Predictors of need for insulin therapyWomen who receive dietary advice but fail to maintain glycaemic control within 1-2 weeks generally receive additional insulin therapy. In several studies insulin therapy was required in ~20-30% of the women with GDM.12,13,21,22 In our study a higher percentage (44%) of women with GDM required additional insulin therapy. This is in line with two other studies which reported that 51-53% needed insulin therapy.23,24 Possible explanations for the wide range in percentages for insulin need between studies are: differences in the study population, dietary compliance, criteria for diagnosis of GDM, and criteria to start insulin therapy.

A number of previous studies have addressed the possible predictors of the need for insulin therapy in women with GDM. In analogy to our study, three compa-rable studies with regard to sample size and ethnicity showed that elevated fasting plasma glucose at time of GDM diagnosis was a potent predictor for additional insu-lin therapy.23-25 One study25 showed in a large cohort of 2365 women with GDM that women requiring insulin therapy were more likely to have a fasting blood glucose of >5.3 mmol/l (>95 mg/dl) before a 100-gram OGTT. Moreover, the study found that multiparity, obesity, history of GDM, diagnosis, a three-hour glucose tolerance test >7.8 mmol/l (>140 mg/dl), and HbA1c of ≥6.0% at GDM diagnosis were additional predictors of need for insulin therapy. In a second study,23 BMI, gestational age when GDM was diagnosed, and fasting and two-hour glucose levels after a 75-gram OGTT were independent predictors of insulin therapy among 612 women with GDM. For each increase of 0.5 mmol/l to the level of the fasting glucose, they reported an OR for insulin therapy of 2.75. The last study24 identified a number of significant predic-tors for insulin including measures of glycaemia – fasting glucose level – diagnosis,


77

4

and family history of GDM among 3009 women with GDM. However, they found a low predictive power for the risk factors.

Although the aforementioned studies used different glucose targets and screen-ing strategies, comparable results regarding fasting glucose levels were observed. Similar to our study, these studies used “old” diagnostic criteria, before the imple-mentation of the more stringent criteria of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) in 2010.23,24 The fasting glucose level – at time of GDM diagnosis – found in our study (≥5.5 mmol/l) is comparable with the national recommended fasting glucose target for start of insulin treatment (≥5.3 mmol/l), but much lower than the fasting glucose level used to diagnose GDM (≥7.0 mmol/l) according to our current national guideline. The fasting glucose level is more comparable with the new diagnostic criteria adopted by the IADPSG and the WHO 2013 (fasting glucose ≥5.1 mmol/l; one-hour ≥10.0 mmol/l; and a two-hour value ≥8.5 mmol/l).26,27 Revision of the diagnostic criteria of our national guideline seems justified, to overcome the discrepancy between the diagnostic cut-off and treatment target values of fasting glucose in GDM.

The fasting glucose level was a more potent predictor of the need for insulin therapy than the two-hour glucose level at time of the OGTT. The finding that a fasting glucose level is a strong predictor for insulin therapy may be explained by the pathophysiology of GDM and type 2 DM. In GDM, fasting glucose levels may remain normal, when insulin resistance is initially compensated by increased insulin production and therefore the abnormality might only be seen in the postprandial blood glucose values.28 However, it has been demonstrated that GDM women not only have defects in insulin sensitivity but also in insulin secretion.28 Studies also suggest that the fasting glucose level on diagnostic OGTT is more associated with a defect in basal insulin secretion; this might be a plausible explanation why the fast-ing glucose level is a strong predictor for the need of insulin.29,30 Finally, it has been shown that elevated glucose levels during pregnancy also predict the development of type 2 DM after pregnancy.31 So it may be that women with more pronounced increased fasting plasma glucose are already in an advanced stage to develop type 2 DM.

Stratification diet-treated groupAfter the findings on the benefits of GDM treatment, worldwide revisions of the guidelines for screening and diagnosis of GDM were performed.9,12,13 Lowering the diagnostic threshold strongly increases the number of women referred for treat-ment, which imposes a large burden on obstetric healthcare worldwide due to higher costs.5-7

Chapter 4

78

This study allowed the recognition of a more complex-care group of insulin-treated women with GDM, but on the other hand a potential “low-risk” group of women who can be treated with diet alone, and who could possibly be referred back to primary care. Only primiparity and weight gain during pregnancy were risk factors to develop obstetric and/or neonatal complications in the diet group, but these risk factors had a very low predictive probability. The rather large proportion of 54% of the diet-treated women who suffered pregnancy-related complications could not validly be identified beforehand. Therefore, it is not possible to identify a circumscribed “low-risk” diet-treated group from our data based on pregnancy outcomes. As some authors suggest that diet-treated women – who are likely to maintain good glycaemic control throughout pregnancy with diet-only – can be referred back to midwives in primary care,23,32 there remains uncertainty regarding the possible development of pregnancy-related complications. To be able to refer women back to primary care, a healthcare system with optimal interaction and communication between primary and secondary care is required. However, such shared-care models require further evaluation for GDM care. There is more need for prospective studies investigating the safety of treating diet-only women with GDM in primary care.

The strengths of the study are the large cohort of women with GDM and the large database with the collection of commonly used measures. A limitation of the study is the retrospective nature of the analyses and the fact that this GDM cohort is based on the “old” WHO 1999 diagnostic criteria for GDM in our national guideline, which differ greatly from the new WHO 2013 criteria, while for treatment of GDM we use the new stringent international glucose targets in GDM pregnancies. This dis-crepancy clearly needs reconsideration of the current Dutch guideline on diagnosis and treatment of GDM.

In summary, in this GDM population we found various relevant factors predict-ing the need for additional insulin therapy in GDM. Especially, a fasting glucose level ≥5.5 mmol/l at GDM diagnosis was the strongest predictor of need for insulin therapy. These predictors might be helpful to recognise a complex-care group of insulin-treated women within the GDM population. Women with GDM who had good glycaemic control on diet only with a higher parity and less weight gain, had a lower risk for obstetric and/or neonatal complications. However, from our data a risk-stratification approach for the diet group based on neonatal and obstetric complications alone did not have predictive utility.


79

4

Acknowledgements

The authors wish to thank the diabetes specialist nurses, and dieticians of the University Medical Center and Martini Hospital Groningen. Further we want to thank: B.J. Schering and M.G. Baas for assistance with the data collection.

Disclosures

Grant support: Novo Nordisk Netherlands provided an unrestricted research grant.

The authors declare no conflicts of interest.

Bibliography

1. EASD: European Association for the study of Diabetes; 51st annual meeting: September 17 2015; Stockholm, Sweden. Title: Predictors of need for insulin therapy in gestational diabetes mellitus.

2. JNVE: The Young Dutch Society for Endocrinology; JNVE meeting; October 30; Holiday Inn Hotel, Leiden, The Netherlands. Title: Predictors of need for insulin therapy in gestational diabetes mellitus.

Chapter 4

80

REFERENCES


2. Ferrara A. Increasing prevalence of gestational diabetes mellitus a public health perspective. Diabetes Care. 2007;30 (Suppl. 2):S141-6.


4. Dabelea D, Snell-Bergeon JK, Hartsfield CL, Bischoff KJ, Hamman RF, McDuffie RS. Increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth Cohort Kaiser Perman-ente of Colorado GDM Screening Program. Diabetes Care. 2005;28:579-84.

5. O’Sullivan E, Avalos G, O’Reilly M, Dennedy M, Gaffney G, Dunne F. Atlantic Diabetes in Pregnancy (DIP): the prevalence and outcomes of gestational diabetes mellitus using new diagnostic crite-ria. Diabetologia. 2011;54:1670-5.


7. Cundy T, Ackermann E, Ryan EA. Gestational diabetes: new criteria may triple the prevalence but effect on outcomes is unclear. BMJ. 2014; 11:348-g1567.

8. Langer O, Yogev Y, Most O, Xenakis EM. Gestational diabetes: The consequences of not treating. Am J Obstet Gynecol. 2005;192:989-97.


10. Sermer M, Naylor CD, Gare DJ, et al. Impact of increasing carbohydrate intolerance on maternal-fetal outcomes in 3637 women without gestational diabetes: The Toronto Tri-Hospital Gestational Diabetes Project. Am J Obstet Gynecol. 1995;173:146-56.




14. The Dutch Society of Obstetrics and Gynaecology. Diabetes Mellitus and Pregnancy. Clinical guide-line version 2.0. 2010. Available from: http://www.nvog-documenten.nl/index.php?pagina=/richtlijn/item/pagina.php&richtlijn_id=863, accessed 10 December 2015.

15. Amelink‐Verburg MP, Buitendijk SE. Pregnancy and labour in the Dutch maternity care system: what is normal? The role division between midwives and obstetricians. J Midwifery Women’s Health. 2010;55:216-25.

16. Russell C, Dodds L, Armson B, Kephart G, Joseph K. Diabetes mellitus following gestational diabe-tes: role of subsequent pregnancy. BJOG. 2008;115:253-60.

17. Scheuneman KA, Koning SH, Hoogenberg K, et al. Predictors of need for insulin therapy in gesta-tional diabetes mellitus. Diabetologia. 2015;58 (Suppl. 1):S73.


81

4

18. World Health Organization (WHO). Definition and Classification of Diabetes Mellitus and its Complications. Report of a WHO consultation. Part 1: Diagnosis and Classification of Diabetes Mellitus.Geneva, WHO, 1999. Department of Noncommunicable Disease Surveillance.


20. The Dutch Society of Obstetrics and Gynaecology. Obstetric indication list. Available from: http://www.knov.nl/fms/file/knov.nl/knov_downloads/2119/file/5 Herziene richtlijn_VIL_2014_-_4_onderwerpen.pdf?download_category=richtlijnen-praktijkkaarten, accessed 10 December 2015.

21. Benhalima K, Robyns K, Van Crombrugge P, et al. Differences in pregnancy outcomes and char-acteristics between insulin-and diet-treated women with gestational diabetes. BMC Pregnancy Childbirth. 2015;15:1.

22. Kosman MW, Eskes SA, van Selst J, et al. Perinatal outcomes in gestational diabetes in relation to ethnicity in the Netherlands. Neth J Med. 2016;74:22-9.

23. Wong VW, Jalaludin B. Gestational diabetes mellitus: who requires insulin therapy? Aust N Z J Obstet Gynaecol. 2011;51:432-6.

24. Pertot T, Molyneaux L, Tan K, Ross GP, Yue DK, Wong J. Can common clinical parameters be used to identify patients who will need insulin treatment in gestational diabetes mellitus? Diabetes Care. 2011;34:2214-6.

25. González-Quintero VH, Istwan NB, Rhea DJ, et al. Antenatal factors predicting subsequent need for insulin treatment in women with gestational diabetes. J Women’s Health. 2008;17:1183-7.


27. World Health Organization (WHO). Diagnostic Criteria and Classification of Hyperglycemia First Detected in Pregnancy. 2013. Available from: http://apps.who.int/iris/bitstream/10665/85975/1/WHO_NMH_MND_13.2_eng.pdf, accessed 22 September 2015.

28. Buchanan TA. Pancreatic B-cell defects in gestational diabetes: implications for the pathogenesis and prevention of type 2 diabetes. J Clin Endocrinol Metab. 2001;86:989-93.

29. Akinci B, Celtik A, Yener S, Yesil S. Is fasting glucose level during oral glucose tolerance test an indicator of the insulin need in gestational diabetes? Diabetes Res Clin Prac. 2008;82:219-25.

30. Bakiner O, Bozkirli E, Ozsahin K, Sariturk C, Ertorer E. Risk factors that can predict antenatal insulin need in gestational diabetes. J Clin Med Res. 2013;5:381-8.

31. Kim C, Newton KM, Knopp RH. Gestational Diabetes and the Incidence of Type 2 Diabetes A systematic review. Diabetes Care. 2002;25:1862-8.

32. Flack JR, Ross GP, Ho S, McElduff A. Recommended changes to diagnostic criteria for gestational diabetes: impact on workload. Aust N Z J Obst Gynaecol. 2010;50:439-43.

5 Thyroid function and maternal and neonatal outcomes in women with gestational diabetes mellitus

Koning SH, Hoogenberg K, van den Berg PP, Lutgers HL, Wolff enbuttel BHR

Submitted

Chapter 5

84

ABSTRACT

Objective: The purpose of this study is to evaluate the potential effect of thyroid hormone level on maternal and neonatal outcomes in euthyroid women with ges-tational diabetes mellitus (GDM).

Subjects and Methods: Women with singleton pregnancies diagnosed with GDM between January 2011 and January 2016 and with available FT4 and TSH measures, were included. Maternal and neonatal outcomes were compared between quartiles of FT4 and TSH levels, measured between 24-29 weeks of gestation.

Results: In total, 222 women could be evaluated. There were no significant differ-ences with respect to almost all pregnancy outcomes between the quartiles of FT4 and TSH. Neonates born to mothers in the lowest FT4 quartile were more often admitted to the neonatology department and preterm delivery tended to be more frequent in the lowest FT4 quartile (p-trend=0.022). Other neonatal outcomes were not different. Pre-gestational body mass index (BMI) was highest in the lowest FT4 quartile (p=0.024). There was a trend across the quartiles for weight gain which again was highest in the first FT4 quartiles (p-trend=0.016). Between the quartiles of TSH, large-for-gestational-age neonates and macrosomia were more frequent in the third TSH quartile. Small-for-gestational-age neonates were more frequent in the lowest TSH quartiles. Pre-gestational BMI was highest in the fourth TSH quartile and weight gain highest in the third and fourth TSH quartiles.

Conclusions: This study showed no major unfavourable neonatal outcomes be-tween FT4 and TSH levels in women with GDM. However, this study showed that pre-gestational BMI and weight gain during pregnancy were higher in women with low FT4 levels.

Thyroid function and pregnancy outcomes in GDM

85

5

INTRODUCTION

Maternal thyroid hormones are essential during pregnancy, especially for foetal development and achieving good pregnancy outcomes.1 Overt thyroid dysfunc-tion is a risk for both the mother and child and is associated with serious adverse pregnancy complications, including spontaneous abortion, pregnancy-induced hypertension (PIH), low birth weight, and premature delivery.2 Therefore, correct identification of thyroid dysfunction is important to reduce the risk of pregnancy complications.2

In normal pregnancy changes occur in the function of the maternal thyroid due to the influence of the pregnancy hormones estrogen and human chorionic gonad-otropin (HCG).2,3 Estrogen increases thyroxin binding globulin (TBG) concentrations almost two-fold by increasing TBG production and TBG sialylation which decreases its clearance.2,3 To maintain adequate free thyroid hormone concentrations, the thyroid gland must produce 50% more thyroid hormone. Further, HCG is peaking in the first trimester and has weak thyroid-stimulating activity as it cross-reacts with the TSH receptor. The net effect is a slight increase in free thyroxine (FT4) and free triiodothyronine (FT3) concentrations and an appropriate reduction in serum thy-roid stimulating hormone (TSH) concentrations.2 This transient, usually subclinical, hyperthyroxinaemia is considered a normal physiologic finding. Later in pregnancy, as HCG secretion declines, serum FT4 and FT3 concentrations decline and serum TSH concentrations rise slightly to or within the normal range.

Many studies have investigated the association between overt thyroid dysfunc-tion and pregnancy complications. However, in recent years, studies have investi-gated the effects of variation in first or second trimester maternal thyroid function on pregnancy outcomes. These studies have shown that both low FT4 and high FT4 levels within the normal range are associated with unfavourable pregnancy out-comes.4-8 Specifically, low-normal FT4 levels have been associated with premature delivery6,7 and impaired child neurocognitive development4 and high-normal FT4 levels with lower birth weight8 and an increased risk of hypertensive disorders, including PIH and preeclampsia.5

Diabetes in pregnancy is also associated with an increased risk of adverse pregnancy outcomes.9 It has been demonstrated that in both type 1 and type 2 diabetes (DM) patients thyroid dysfunction is more prevalent compared with the normal population,10 and several studies have also shown associations between thyroid dysfunction and gestational diabetes mellitus (GDM).11-13 Recently, studies have reported associations between low FT4 levels during the second and third trimesters and development of GDM.14-18 A reciprocal relationship between FT4 and maternal weight has very recently been reported.16 However, there is little evidence

Chapter 5

86

about the effect of thyroid function on pregnancy outcomes in euthyroid women with GDM.

Therefore, in the present study we assessed the potential effect of thyroid func-tion tests TSH and FT4 on maternal and neonatal outcomes in women with GDM. We hypothesized that women with lower FT4 levels are more likely to have a higher weight gain (as weight by itself has been recognized with lower FT4 during preg-nancy) and possibly unfavourable pregnancy outcomes.

SUBJECTS AND METHODS

Study populationIn this study women with singleton pregnancies and diagnosed in the University Medical Center Groningen with GDM according to the Dutch national guidelines between January 2011 and January 2016, were included. In these women serum TSH and FT4 levels were assessed routinely at the first visit after being diagnosed with GDM. Women with pre-existing DM and women with known thyroid disease or thyroid medication usage were not included, as were women with a twin pregnancy (n=7) and women with missing data on pregnancy outcomes (n=2) or thyroid func-tion (n=14). The study has been conducted in accordance with the guideline of the Declaration of Helsinki and Good Clinical Practice. The study has been exempted for approval according to the Medical research involving Human Subjects Act.19 This report is based on patient data acquired during care-as-usual, the data has been analysed retrospectively and all the requirements for patient anonymity are in agreement with the regulations of the ethics committee. According to this and the Dutch law on Medical research with Human Subjects, no approval from an ethics committee is necessary.

Gestational diabetes mellitusAs previously described,20,21 women were screened for GDM between 24-28 weeks of gestation with a 75-g oral glucose tolerance test (OGTT) when they had one or more GDM risk factors according the Dutch national guideline.22 Screening was also performed in women with signs suggestive of GDM (e.g. polyhydramnios or foetal macrosomia). Abnormal blood glucose values were defined according to the diag-nostic criteria established by the World Health Organization 1999: a fasting plasma glucose ≥7.0 mmol/l and/or a 2-h value ≥7.8 mmol/l.23 Details regarding dietary and – if needed – insulin therapy and follow-up have been described previously.21


87

5

Thyroid functionThyroid function (TSH and FT4 levels) was measured at or around the first visit at the diabetes outpatient clinic at time of GDM diagnosis, between 24-29 weeks of gestation. Serum FT4 and TSH levels were analysed using an electrochemilumines-cence immunoassay on the Roche Modular E170 Analyzer using kits provided by the manufacturer (Roche, Switzerland). Normal values outside pregnancy for FT4 are 11-20 pmol/L, for TSH 0.4-4.5 mU/L.

Outcome measuresMaternal characteristics were recorded and all the data were obtained from review of the electronic medical and birth records. Ethnicity was divided into: Caucasian, African-American, Middle-Eastern/North-African descent, Asian (Indian or South-East Asian), and other. Weight gain was defined as the difference in weight between pre-pregnancy weight and weight at the first visit at the diabetes outpatient clinic. Pre-existing hypertension was defined as a systolic blood pressure (SBP) ≥140 mmHg, a diastolic blood pressure (DBP) ≥90 mmHg or the use of blood-pressure lowering drugs, before pregnancy or before 20 weeks of gestation.24

Neonatal and maternal outcomesNeonatal outcomes included gestational age at birth, birth weight, expected birth weight at 40 weeks of gestation, large for gestational age (LGA) (birth weight above the 90th percentile, corrected for gestational age, gender, parity, and ethnicity),25 small for gestational age (SGA) (birth weight below the 10th percentile, corrected for gestational age, gender, parity, and ethnicity),25 macrosomia (birth weight >4000 grams), still birth/neonatal death, birth trauma (shoulder dystocia, fracture of hu-merus or clavicle), Apgar score below 7 after 5 minutes, preterm delivery (delivery before 37 weeks of gestation), and admission to the neonatology department. Expected birth weight at 40 weeks was estimated with the Dutch reference curves for birth weight by gestational age, corrected for gender, parity and ethnicity.25 The calculated birth percentiles and birth weight were compared with the birth percentiles at 40 weeks of gestation. The percentage change between birth weight and the expected birth weight at 40 weeks for the individual percentile was added to the actual birth weight.

The maternal characteristics and outcomes included fasting glucose level, 2-h glucose level after a 75-g oral glucose load, HbA1c, pre-gestational body mass index (BMI), weight gain during pregnancy, insulin use, and several obstetric outcomes: mode of delivery (spontaneous, instrumental (forceps or vacuum extraction), cae-sarean section (planned or secondary)), PIH, and preeclampsia. PIH was defined as a SBP ≥140 mmHg and/or DBP ≥90 mmHg on two occasions at least four hour apart in

Chapter 5

88

the second half of pregnancy in previously normotensive women, with the absence of proteinuria.24 Preeclampsia was defined as a combination of PIH and proteinuria (≥300 mg/24-h).24

Statistical analysesContinuous variables are given as mean and standard deviation (SD) or as median and inter quartile range (IQR) in case of skewed distribution. Categorical variables are given as frequencies and percentages.

Neonatal and maternal outcomes were calculated across quartiles of serum FT4 and TSH levels. Differences between the quartiles were tested by analysis of variance (ANOVA) for normally distributed continuous variables, Kruskal-Wallis for non-normally distributed continuous variables, or Chi-square test or Fisher’s exact test for categorical variables. In addition, P for trend (tests of trend across quartiles) was calculated by treating FT4 and TSH levels as continuous linear term to use all the intra-categorical information that otherwise is ignored by mere categorical comparisons.26

All P-values were two-tailed, and P-values <0.05 were considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics (version 22.0. Armonk, NY: IBM Corp).

RESULTS

The maternal characteristics of the study population are presented in Table 1. A total of 222 women with GDM and completed thyroid function measures were included in the study. The mean maternal age was 32.5 ± 5.3 years, and the median pre-gestational BMI was 27.7 (IQR 24.1-32.0) kg/m2. The median weight gain dur-ing pregnancy was 8.0 (IQR 4.1-11.0) kg. The majority of the women was Caucasian (71%) and multiparous (56%).

The median gestational age at time of the OGTT was 26.9 (IQR 25.4-27.6) weeks. The median fasting and 2-h glucose were 5.0 (IQR 4.6-5.4) mmol/l and 8.6 (IQR 8.1-9.2) mmol/l, respectively. The median gestational age at time of the thyroid function test was 27.6 (IQR 26.3-28.8) weeks. Median TSH level and FT4 levels were 1.5 (IQR 1.02-2.02) mU/L and 11.4 (IQR 10.3-12.3) pmol/L, respectively.


89

5

TABLE 1. Maternal characteristics of the study population.

Characteristics N=222

Age (years) 32.5 ± 5.3

Ethnicity, n (%) Caucasian African- American Middle-East/North-African Asian Other

157 (70.7)7 (3.2)

18 (8.1)28 (12.6)12 (5.5)

Parity, n (%) 0 1-2 >2

98 (44.1)109 (49.1)

15 (6.8)

Pre-gestational BMI (kg/m2) 27.7 [24.1-32.0]

Weight gain during pregnancy (kg) 8.0 [4.1-11.0]

Smoking during pregnancy, n (%) 23 (10.4)

First degree relative with DM, n (%) 110 (49.5)

History of GDM, n (%) 21 (9.5)

Previous infant weighing ≥4500 g at birth, n (%) 15 (6.8)

Pre-existing hypertension, n (%) 10 (4.5)

Gestational age at time of OGTT (wks) 26.9 [25.4-27.6]

Fasting glucose level (mmol/l) 5.0 [4.6-5.4]

2-h glucose level after a 75-g OGTT (mmol/l) 8.6 [8.1-9.2]

Gestational age at time of thyroid function test (wks) 27.6 [26.3-28.8]

TSH level (mU/L) 1.5 [1.02-2.02]

FT4 level (pmol/L) 11.4 [10.3-12.3]

Abbreviations: BMI, body mass index; DM, diabetes mellitus; GDM, gestational diabetes mellitus; OGTT, oral glu-cose tolerance test; TSH, thyroid stimulating hormone; FT4, free thyroxine.Data are expressed as mean ± SD, median [IQR], or proportion n (%).Data with respect to pre-gestational BMI, weight gain during pregnancy, family history of DM, are missing in 3 (1.4%), 14 (6.3%), 8 (3.6%) of the women, respectively.

Neonatal and maternal outcomes

FT4 quartilesNeonatal and maternal outcomes according to quartiles of second trimester serum FT4 levels are given in Table 2. Between the quartiles of FT4, there were no sig-nificant differences with respect to most of the neonatal outcomes. Admission to the neonatology department was higher in the first quartile and was statistically significant between the quartiles (p=0.036). Preterm delivery tended to be higher in the lower quartiles but this was not statistically significant between the groups. Even though, there were almost no statistical differences between the quartiles, there were statistical differences when we tested for a trend. FT4 quartiles were

Chapter 5

90


91

5

TAB

LE 2

. Pr

egna

ncy

outc

omes

acc

ordi

ng to

qua

rtile

s of

sec

ond

trim

este

r (24

-29

wee

ks o

f ges

tatio

n) F

T4 le

vels

in 2

22 w

omen

with

ges

tatio

nal d

iabe

tes

mel

litus

.

Qua

rtile

s of

FT4

(pm

ol/L

)

P-va

lue*

P-tr

end*

1 n=

51<1

0.3

2 n=

60≥1

0.3-

11.3

3 n=

52≥1

1.4-

12.2

4 n=

59≥1

2.3

Neo

nata

l out

com

es

Ges

tatio

nal a

ge a

t birt

h (w

ks)

38.3

[38.

1-39

.7]

38.4

[38.

0-40

.0]

38.4

[38.

0-39

.9]

39.0

[38.

1-40

.0]

0.31

10.

040

Birt

h w

eigh

t (g)

33

46 ±

556

3261

± 5

3633

96 ±

552

3320

± 5

390.

618

0.88

3

Expe

cted

birt

h w

eigh

t at 4

0 w

ks (g

) 36

32 ±

415

3532

± 4

2236

61 ±

423

3486

± 4

410.

105

0.17

2

Larg

e fo

r ges

tatio

nal a

ge, n

(%)

9 (1

7.6)

4 (6

.7)

9 (1

7.3)

6 (1

0.2)

0.21

60.

586

Mac

roso

mia

, n (%

)4

(7.8

)6

(10.

0)5

(9.6

)6

(10.

2)0.

976

0.72

0

Smal

l for

ges

tatio

nal a

ge, n

(%)

4 (7

.8)

6 (1

0.0)

1 (1

.9)

4 (6

.8)

0.38

80.

466

Still

birt

h/ne

onat

al d

eath

, n (%

)0

00

0N

AN

A

Birt

h tr

aum

a, n

(%)

00

2 (3

.8)

3 (5

.1)

0.15

10.

031

Apg

ar s

core

<7

afte

r 5 m

in, n

(%)

2 (3

.9)

2 (3

.3)

0 (0

.0)

3 (5

.2)

0.46

40.

919

Pret

erm

del

iver

y, n

(%)

6 (1

1.8)

4 (6

.7)

2 (3

.8)

1 (1

.7)

0.13

70.

022

Adm

issi

on to

the

neon

atol

ogy

depa

rtm

ent,

n (%

)13

(25.

5)6

(10.

0)4

(7.7

)7

(11.

9)0.

036

0.05

1

Mat

erna

l out

com

es

Fast

ing

gluc

ose

leve

l (m

mol

/l)5.

1 [4

.6-5

.5]

4.9

[4.6

-5.5

]5.

0 [4

.6-5

.5]

4.9

[4.6

-5.3

]0.

797

0.50

3

2-h

gluc

ose

leve

l aft

er a

75-

gram

OG

TT (m

mol

/l)8.

6 [8

.0-9

.4]

8.6

[8.1

-9.2

]8.

5 [8

.0-9

.1]

8.4

[8.1

-9.4

]0.

811

0.93

7

HbA

1c (%

)5.

6 [5

.4-5

.7]

5.6

[5.3

-5.8

]5.

5 [5

.3-5

.8]

5.4

[5.3

-5.6

]0.

285

0.09

5

Pre-

gest

atio

nal B

MI (

kg/m

2 )28

.9 [2

5.1-

32.3

]27

.6 [2

4.3-

30.2

]28

.2 [2

4.3-

34.0

]24

.9 [2

1.7-

30.5

]0.

024

0.12

0

Wei

ght g

ain

durin

g pr

egna

ncy

(kg)

9.0

[6.0

-12.

1]8.

0 [4

.8-1

2.0]

7.0

[4.0

-10.

5]7.

3 [2

.8-1

1.0]

0.16

70.

016

Insu

lin u

se, n

(%)

26 (5

1.0)

25 (4

1.7)

22 (4

2.3)

21 (3

5.6)

0.44

50.

132

Insu

lin d

ose,

U/d

ay20

.0 [1

2.0-

34.0

]14

.0 [7

.8-3

9.5]

25.5

[9.5

-38.

0]18

.0 [1

2.0-

22.0

]0.

744

0.43

4

Insu

lin d

ose,

U/k

g0.

2 [0

.1-0

.4]

0.1

[0.1

-0.3

]0.

3 [0

.1-0

.4]

0.2

[0.1

-0.3

]0.

692

0.93

7

Chapter 5

90


91

5

TAB

LE 2

. Pr

egna

ncy

outc

omes

acc

ordi

ng t

o qu

artil

es o

f sec

ond

trim

este

r (2

4-29

wee

ks o

f ges

tatio

n) F

T4 le

vels

in 2

22 w

omen

with

ges

tatio

nal d

iabe

tes

mel

litus

. (c

ontin

ued)

Qua

rtile

s of

FT4

(pm

ol/L

)

P-va

lue*

P-tr

end*

1 n=

51<1

0.3

2 n=

60≥1

0.3-

11.3

3 n=

52≥1

1.4-

12.2

4 n=

59≥1

2.3

Del

iver

y ty

pe, n

(%)

Sp

onta

neou

s

Inst

rum

enta

l

Caes

area

n se

ctio

n

Plan

ned

caes

area

n se

ctio

n

31 (6

0.8)

4 (7

.8)

9 (1

7.6)

7 (1

3.7)

47 (7

8.3)

2 (3

.3)

8 (1

3.3)

3 (5

.0)

34 (6

5.4)

6 (1

1.5)

6 (1

1.5)

6 (1

1.5)

42 (7

1.2)

7 (1

1.9)

7 (1

1.9)

3 (5

.1)

0.21

10.

232

0.78

70.

240

0.56

10.

187

0.37

10.

265

PIH

, n (%

)1

(2.0

)1

(1.7

)1

(1.9

)2

(3.4

)0.

922

0.59

3

Pree

clam

psia

, n (%

)2

(3.9

)2

(3.3

)1

(1.9

)2

(3.4

)0.

946

0.79

6

Abbr

evia

tions

: BM

I, bo

dy m

ass i

ndex

; FT4

, fre

e th

yorix

ine;

OG

TT, o

ral g

luco

se to

lera

nce

test

; PIH

, pre

gnan

cy- i

nduc

ed h

yper

tens

ion.

Dat

a ar

e ex

pres

sed

as m

ean

± SD

, med

ian

[IQR]

, or p

ropo

rtio

n n

(%).

Dat

a w

ith re

spec

t to

HbA

1c, p

re-g

esta

tiona

l BM

I, w

eigh

t gai

n du

ring

preg

nanc

y, in

sulin

dos

e U

/day

and

insu

lin d

ose

U/k

g ar

e m

issi

ng in

2 (0

.9%

), 3

(1.4

%),

14 (6

.3%

), 5

(5.3

%),

13 (1

3.9%

) of t

he w

omen

, res

pect

ivel

y.* P

-val

ues w

ere

base

d on

ana

lysi

s of v

aria

nce

(non

skew

ed c

ontin

uous

var

iabl

es),

Krus

kal-W

allis

(ske

wed

con

tinuo

us v

aria

bles

) or C

hi-s

quar

e te

st/F

ishe

r’s e

xact

test

(cat

egor

ical

va

riabl

es).

Test

acr

oss q

uart

iles (

P fo

r tre

nd) w

ere

base

d on

line

ar re

gres

sion

(con

tinue

s var

iabl

es) o

r Chi

-squ

are

(cat

egor

ical

var

iabl

es, l

inea

r-by

-line

ar a

ssoc

iatio

n)

Chapter 5

92


93

5

TAB

LE 3

. Pr

egna

ncy

outc

omes

acc

ordi

ng to

qua

rtile

s of

sec

ond

trim

este

r (24

-29

wee

ks o

f ges

tatio

n) T

SH le

vels

in 2

22 w

omen

with

ges

tatio

nal d

iabe

tes

mel

litus

.

Qua

rtile

s of

TSH

(mU

/L)

P-va

lue*

P-tr

end*

1 n=

54<1

.02

2 n=

56≥1

.02-

1.48

3 n=

57≥1

.49-

2.01

4 n=

55≥2

.02

Neo

nata

l out

com

es

Ges

tatio

nal a

ge a

t birt

h (w

ks)

38.1

[38.

0-39

.6]

39.1

[38.

1-40

.0]

38.4

[38.

1-40

.0]

38.4

[38.

0-40

.0]

0.26

70.

869

Birt

h w

eigh

t (g)

3263

± 4

7632

16 ±

585

3438

± 6

6233

91 ±

384

0.09

90.

570

Expe

cted

birt

h w

eigh

t at 4

0 w

ks (g

)35

34 ±

415

3411

± 4

8237

32 ±

411

3611

± 3

400.

001

0.40

0

Larg

e fo

r ges

tatio

nal a

ge, n

(%)

6 (1

1.1)

6 (1

0.7)

13 (2

2.8)

3 (5

.5)

0.04

20.

820

Mac

roso

mia

, n (%

)4

(7.4

)4

(7.1

)11

(19.

3)2

(3.6

)0.

026

0.94

9

Smal

l for

ges

tatio

nal a

ge, n

(%)

3 (5

.6)

9 (1

6.1)

1 (1

.8)

2 (3

.6)

0.01

20.

176

Still

birt

h/ne

onat

al d

eath

, n (%

)0

00

0N

AN

A

Birt

h tr

aum

a, n

(%)

01

(1.8

)2

(3.5

)2

(3.6

)0.

535

0.16

0

Apg

ar s

core

<7

afte

r 5 m

in, n

(%)

1 (1

.9)

2 (3

.6)

2 (3

.5)

2 (3

.7)

0.93

90.

608

Pret

erm

del

iver

y, n

(%)

3 (5

.6)

3 (5

.4)

5 (8

.8)

2 (3

.6)

0.70

40.

874

Adm

issi

on to

the

neon

atol

ogy

depa

rtm

ent,

n (%

)5

(9.3

)8

(14.

3)10

(17.

5)7

(12.

7)0.

640

0.51

0

Mat

erna

l out

com

es

Fast

ing

gluc

ose

leve

l (m

mol

/l)5.

0 [4

.6-5

.5]

5.0

[4.5

-5.3

]4.

9 [4

.6-5

.4]

5.0

[4.6

-5.5

]0.

768

0.74

6

2-h

gluc

ose

leve

l aft

er a

75-

gram

OG

TT (m

mol

/l)8.

7 [8

.1-9

.2]

8.6

[8.1

-9.1

]8.

5 [8

.0-9

.1]

8.6

[8.0

-9.4

]0.

947

0.76

4

HbA

1c (%

)5.

5 [5

.2-5

.8]

5.4

[5.3

-5.7

]5.

5 [5

.3-5

.8]

5.6

[5.4

-5.8

]0.

380

0.40

4

Pre-

gest

atio

nal B

MI (

kg/m

2 )25

.5 [2

1.9

-30.

5]28

.0 [2

2.4-

33.6

]27

.7 [2

4.4-

31.4

]29

.4 [2

5.0-

33.5

]0.

079

0.00

2

Wei

ght g

ain

durin

g pr

egna

ncy

(kg)

7.0

[5.0

-11.

0]6.

5 [2

.8-1

0.0]

10.0

[5.0

-12.

0]9.

0 [4

.3-1

2.3]

0.02

70.

385

Insu

lin u

se, n

(%)

28 (5

1.9)

17 (3

0.4)

28 (4

9.1)

21 (3

8.2)

0.08

00.

475

Insu

lin d

ose,

U/d

ay18

.0 [9

.3-2

6.0]

18.0

[10.

0-32

.5]

17.0

[7.5

-36.

5]24

.0 [1

2.3-

37.5

]0.

662

0.89

8

Insu

lin d

ose,

U/k

g0.

2 [0

.1-0

.4]

0.2

[0.1

-0.3

]0.

1 [0

.1-0

.3]

0.3

[0.1

-0.4

]0.

233

0.79

6

Chapter 5

92


93

5

TAB

LE 3

. Pr

egna

ncy

outc

omes

acc

ordi

ng to

qua

rtile

s of

sec

ond

trim

este

r (24

-29

wee

ks o

f ges

tatio

n) T

SH le

vels

in 2

22 w

omen

with

ges

tatio

nal d

iabe

tes

mel

litus

. (c

ontin

ued)

Qua

rtile

s of

TSH

(mU

/L)

P-va

lue*

P-tr

end*

1 n=

54<1

.02

2 n=

56≥1

.02-

1.48

3 n=

57≥1

.49-

2.01

4 n=

55≥2

.02

Del

iver

y ty

pe, n

(%)

Sp

onta

neou

s

Inst

rum

enta

l

Caes

area

n se

ctio

n

Plan

ned

caes

area

n se

ctio

n

44 (8

1.5)

5 (9

.3)

1 (1

.9)

4 (7

.4)

40 (7

1.4)

3 (5

.4)

8 (1

4.3)

5 (8

.9)

33 (5

7.9)

7 (1

2.3)

12 (2

1.1)

5 (8

.8)

37 (6

7.3)

4 (7

.3)

9 (1

6.4)

5 (9

.1)

0.05

80.

411

0.02

40.

989

0.04

40.

863

0.01

50.

774

PIH

, n (%

)2

(3.7

)2

(3.6

)0

(0.0

)1

(1.8

)0.

509

0.30

1

Pree

clam

psia

, n (%

)1

(1.9

)2

(3.6

)1

(1.8

)3

(5.5

)0.

648

0.40

0

Abbr

evia

tions

: BM

I, bo

dy m

ass i

ndex

; PIH

, pre

gnan

cy-in

duce

d hy

pert

ensi

on; O

GTT

, ora

l glu

cose

tole

ranc

e te

st; T

SH, t

hyro

id st

imul

atin

g ho

rmon

e.D

ata

are

expr

esse

d as

mea

n ±

SD, m

edia

n [IQ

R], o

r pro

port

ion

n (%

).D

ata

with

resp

ect t

o H

bA1c

, pre

-ges

tatio

nal B

MI,

wei

ght g

ain

durin

g pr

egna

ncy,

insu

lin d

ose

U/d

ay a

nd in

sulin

dos

e U

/kg

are

mis

sing

in 2

(0.9

%),

3 (1

.4%

), 14

(6.3

%),

5 (5

.3%

), 13

(13.

9%) o

f the

wom

en, r

espe

ctiv

ely.

* P-

valu

es w

ere

base

d on

ana

lysi

s of v

aria

nce

(non

skew

ed c

ontin

uous

var

iabl

es),

Krus

kal-W

allis

(ske

wed

con

tinuo

us v

aria

bles

) or C

hi-s

quar

e te

st/F

ishe

r’s e

xact

test

(cat

egor

ical

va

riabl

es).

Test

acr

oss q

uart

iles (

P fo

r tre

nd) w

ere

base

d on

line

ar re

gres

sion

(con

tinue

s var

iabl

es) o

r Chi

-squ

are

(cat

egor

ical

var

iabl

es, l

inea

r-by

-line

ar a

ssoc

iatio

n).

Chapter 5

94

negatively associated with gestational age at birth (p-trend=0.040) and preterm de-livery (p-trend=0.022) and positively associated with birth trauma (p-trend= 0.031).

For the maternal outcomes, both pre-gestational BMI and weight gain during pregnancy (p-trend=0.016) were highest in the lowest FT4 quartile. For the other maternal outcomes there were no statistical differences between the FT4 quartiles.

TSH quartilesNeonatal and maternal outcomes according to quartiles of second trimester serum TSH levels are given in Table 3. Neonates born from mothers with TSH levels in the third and fourth quartile were more likely to have a higher expected birth weight at 40 weeks (p=0.001). LGA neonates and macrosomia were more frequent in the third quartile. SGA neonates were more frequent in the lowest quartiles. There were no significant differences between the TSH quartiles with respect to gestational age at birth, birth weight, still birth/neonatal death, birth trauma, Apgar score <7 after 5 min, preterm delivery, and admission to the neonatology department.

For the maternal outcomes, pre-gestational BMI was highest in the fourth TSH quartile and weight gain during pregnancy was higher in the third and fourth quar-tiles. When we tested for a trend, there was a significant trend across the quartiles for pre-gestational BMI (p-trend= 0.002), spontaneous delivery (p-trend= 0.044), and caesarean section (p-trend= 0.021). There were no significant differences in ma-ternal outcomes for weight gain during pregnancy, instrumental delivery, planned caesarean section, gestational hypertension, and preeclampsia.

DISCUSSION

In this study in patients with singleton euthyroid GDM pregnancies, we showed no major differences in unfavourable neonatal outcomes across quartiles of FT4 and TSH levels within the normal range. However, women with low FT4 levels were more likely to have a higher pre-gestational BMI and showed a trend towards a higher weight gain during pregnancy. This last finding is in agreement with our hypothesis. Similarly, we observed that high TSH levels were also associated with a high pre-gestational BMI and larger weight gain during pregnancy.

Thyroid function and pregnancy outcomesOvert maternal thyroid dysfunction is associated with adverse outcomes occurring before, during and after pregnancy. Hyperthyroidism has been associated with an increased risk of spontaneous abortion, intrauterine growth retardation, low-birth-


95

5

weight infants and foetal death.2 In addition, hypothyroidism has been associated with PIH, placenta abruption, and low-birth-weight infants.2

Several studies have demonstrated that both low and high FT4 levels in first or second trimester within the normal range are associated with unfavourable pregnancy outcomes, e.g. preterm delivery, low-birth weight, and hypertensive disorders.5,7,8 In the present study we examined the combined effect of GDM and variation in normal thyroid function on pregnancy outcomes. Although there were almost no statistically significant differences found between thyroid function and pregnancy outcomes, there was a trend towards a higher frequency of preterm delivery in women with low FT4 and neonates born to mothers with the lowest FT4 levels were more often admitted to the neonatology department. This finding is in line with the finding of Korevaar et al.,7 who showed in a large cohort of 5971 pregnant women that low FT4 levels in first or second trimester of pregnancy are as-sociated with an increased risk of premature delivery, which is independent of TSH level.7 In the present study we found no associations between low FT4 and other neonatal and obstetric outcomes. Furthermore, we could not demonstrate associa-tions between high FT4 and low-birth-weight infants and hypertensive disorders. This may in part due to the low number of participants.

Thyroid function and maternal weight The present study showed that euthyroid women with GDM and with lower FT4 levels in second trimester of pregnancy were more likely to have a higher pre-gestational BMI and there was a trend towards a higher weight gain during pregnancy. A num-ber of previous studies have addressed the association between low FT4 throughout pregnancy and maternal weight or BMI.27-29 These studies demonstrated a reciprocal relationship between FT4 and maternal weight. Moreover, studies have also shown associations between low FT4 levels during the second and third trimesters and the incidence of GDM.14-18 A recent study investigated the association between FT4, maternal weight, and GDM in a large cohort of more than 9000 euthyroid women.16 This study demonstrated that high maternal weight was associated with both low FT4 and a higher GDM rate in second trimester of pregnancy.16 The reciprocal find-ing of maternal weight and FT4 is consistent with the findings of our study.

Haddow et al.,16 discussed the possible biologically explanation for these find-ings. Some studies showed a reciprocal relationship between maternal FT4 and BMI and a direct relationship between the FT3/FT4 ratio and BMI, which suggests an in-crease in peripheral deiodinase activity.28,29 Studies have also shown that the rate of peripheral transformations of T4 to T3 increased with excessive energy intake, sug-gesting that peripheral deiodinase activity is affected by energy intake.30 As a high BMI is associated with increased risk of GDM, increased caloric intake and higher

Chapter 5

96

weight connect with increased deiodinase activity on one hand and increased GDM incidence on the other.16

Comparable to the trend of FT4, the present study also showed that women with higher TSH were more likely to have a higher pre-gestational BMI and weight gain. The study by Han et al.,31 demonstrated in a large euthyroid pregnant population that TSH was significantly higher in overweight group compared with the normal weight group (2.11 mU/L vs. 1.86 mU/L).

Strengths and limitationsTo our knowledge this is the first study that investigated the combined effect of thyroid function and GDM on several maternal and neonatal outcomes, including maternal weight.

There are several potential limitations in this study that deserve attention. Due to the sample size there may not have been enough statistical power to find sig-nificant differences between the quartiles for relatively rare obstetric and neonatal outcomes, e.g. preeclampsia, stillbirth/neonatal death, birth trauma. Moreover, this was an observational retrospective study and this has resulted in missing obser-vations for some variables, e.g. HbA1c, pre-gestational BMI, weight gain during pregnancy and insulin dose.

CONCLUSIONS

In summary, this study showed no major differences between FT4 and TSH levels within the normal range and neonatal outcomes in women with GDM. However, women with the lowest FT4 levels and higher TSH levels had higher pre-gestational BMI and larger weight gain during pregnancy.

Acknowledgements

The authors wish to thank the endocrinologists and gynaecologists of the University Medical Center Groningen.


97

5

REFERENCES

1. LaFranchi SH, Haddow JE, Hollowell JG. Is thyroid inadequacy during gestation a risk factor for adverse pregnancy and developmental outcomes? Thyroid. 2005;15:60-71.

2. Fantz CR, Dagogo-Jack S, Ladenson JH, Gronowski AM. Thyroid function during pregnancy. Clin Chem. 1999;45:2250-8.

3. Glinoer D. What happens to the normal thyroid during pregnancy? Thyroid. 1999;9:631-5.

4. Korevaar TI, Muetzel R, Medici M, et al. Association of maternal thyroid function during early preg-nancy with offspring IQ and brain morphology in childhood: A population-based prospective cohort study. Lancet Diabetes Endocrinol. 2016;4:35-43.

5. Medici M, Korevaar TI, Schalekamp-Timmermans S, et al. Maternal early-pregnancy thyroid func-tion is associated with subsequent hypertensive disorders of pregnancy: The generation R study. J Clin Endocrinol Metab. 2014;99:E2591-8.

6. Korevaar TI, Chaker L, Medici M, et al. Maternal total T4 during the first half of pregnancy: Physi-ologic aspects and the risk of adverse outcomes in comparison with free T4. Clin Endocrinol (Oxf ). 2016;55:751-63.

7. Korevaar TI, Schalekamp-Timmermans S, de Rijke YB, et al. Hypothyroxinemia and TPO-antibody positivity are risk factors for premature delivery: The generation R study. J Clin Endocrinol Metab. 2013;98:4382-90.

8. Medici M, Timmermans S, Visser W, et al. Maternal thyroid hormone parameters during early pregnancy and birth weight: The generation R study. J Clin Endocrinol Metab. 2012;98:59-66.


10. Johnson JL. Diabetes control in thyroid disease. Diabetes Spectr. 2006;19:148-53.

11. Tudela CM, Casey BM, McIntire DD, Cunningham FG. Relationship of subclinical thyroid disease to the incidence of gestational diabetes. Obstet Gynecol. 2012;119:983-8.

12. Karakosta P, Alegakis D, Georgiou V, et al. Thyroid dysfunction and autoantibodies in early preg-nancy are associated with increased risk of gestational diabetes and adverse birth outcomes. J Clin Endocrinol Metab. 2012;97:4464-72.

13. Maleki N, Tavosi Z. Evaluation of thyroid dysfunction and autoimmunity in gestational diabetes mellitus and its relationship with postpartum thyroiditis. Diabet Med. 2015;32:206-12.

14. Oguz A, Tuzun D, Sahin M, et al. Frequency of isolated maternal hypothyroxinemia in women with gestational diabetes mellitus in a moderately iodine-deficient area. Gynecol Endocrinol. 2015;31:792-5.

15. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol. 2008;112:85-92.

16. Haddow JE, Craig WY, Neveux LM, et al. Free thyroxine during early pregnancy and risk for gesta-tional diabetes. PloS One. 2016;11:e0149065.

17. Velkoska Nakova V, Krstevska B, Dimitrovski C, Simeonova S, Hadzi-Lega M, Serafimoski V. Prevalence of thyroid dysfunction and autoimmunity in pregnant women with gestational and diabetes type 1. Prilozi. 2010;31:51-9.

Chapter 5

98

18. Yang S, Shi F, Leung PC, Huang H, Fan J. Low thyroid hormone in early pregnancy is associated with an increased risk of gestational diabetes mellitus. J Clin Endocrinol Metab. 2016;101:4237-43.

19. University Medical Center Groningen. Researchcode University Medical Center Groningen. 2013. Available from: https://www.umcg.nl/SiteCollectionDocuments/English/Researchcode/UMCG-Researchcode,%20basic%20principles%202013.pdf, assessed 24 March 2016.

20. Koning SH, Scheuneman KA, Lutgers HL, et al. Risk stratification for healthcare planning in women with gestational diabetes mellitus. Neth J Med. 2016;74:262-9.

21. Koning SH, Hoogenberg K, Scheuneman KA, et al. Neonatal and obstetric outcomes in diet- and insulin-treated women with gestational diabetes mellitus: A retrospective study. BMC Endocr Disord. 2016;16:52.

22. The Dutch Society of Obstetrics and Gynaecology. Diabetes mellitus and Pregnancy. Clinical guideline version 2.0. 2010. Available from: http://www.nvog-documenten.nl/richtlijn/item/pagina.php?richtlijn_id=863, accessed 24 March 2016.


24. Brown MA, Lindheimer MD, de Swiet M, Assche AV, Moutquin J. The classification and diagnosis of the hypertensive disorders of pregnancy: Statement from the international society for the study of hypertension in pregnancy (ISSHP). Hypertens pregnancy. 2001;20:ix-xiv.


26. Willet W. Issues in analysis and presentation of dietary data. In Nutritional Epidemiology, edn 3, pp. 305-333. Oxford University Press. New York, 2013.

27. Haddow JE, Craig WY, Palomaki GE, et al. Impact of adjusting for the reciprocal relationship between maternal weight and free thyroxine during early pregnancy. Thyroid. 2013;23:225-30.

28. Bassols J, Prats-Puig A, Soriano-Rodríguez P, et al. Lower free thyroxin associates with a less favorable metabolic phenotype in healthy pregnant women. Journal Clin Endocrinol Metab. 2011;96:3717-23.

29. Knight BA, Shields BM, Hattersley AT, Vaidya B. Maternal hypothyroxinaemia in pregnancy is asso-ciated with obesity and adverse maternal metabolic parameters. Eur J Endocrinol. 2016;174:51-7.

30. Danforth E,Jr, Horton ES, O’Connell M, et al. Dietary-induced alterations in thyroid hormone metabolism during overnutrition. J Clin Invest. 1979;64:1336-47.

31. Han C, Li C, Mao J, et al. High body mass index is an indicator of maternal hypothyroidism, hypo-thyroxinemia, and thyroid-peroxidase antibody positivity during early pregnancy. Biomed Res Int. 2015;2015:351831.

6 Postpartum glucose follow-up and lifestyle management after gestational diabetes mellitus: general practitioner and patient perspectives

Koning SH, Lutgers HL, Hoogenberg K, Trompert CA, van den Berg PP, Wolff enbuttel BHR

Journal of Diabetes & Metabolic Disorders. 2016;15:56.

Chapter 6

102

ABSTRACT

Background: Incidence of type 2 diabetes is high after gestational diabetes melli-tus (GDM). We aimed to evaluate the adherence to follow-up six-weeks postpartum visits in secondary care after GDM and glucose monitoring in primary care longer than 12-14 months after delivery and the years thereafter. In addition, we examined the women’s lifestyle after delivery.

Methods: A cross-sectional follow-up survey among women with a history of GDM and their general practitioners (GP). Rates of attendance at the six-weeks postpar-tum visit and glucose testing were obtained from hospital records, over the period 2011-2012. Rates of annual follow-up postpartum glucose testing were assessed by a survey among their GP’s. Lifestyle of the women on diet and exercise was assessed by questionnaire in 2015.

Results: In total 197 women were eligible for the study. Of these, 156 (79%) attended the six-weeks postpartum visit at the diabetes outpatient clinic and in 145 (93%) of these women glucose testing was performed. In total 77 (39%) women responded to the invitation to participate in this study and filled in the lifestyle questionnaire. About one third of the women met the recommendations for sufficient physical activity. A majority of them did not fulfil the Dutch guidelines on healthy diet – fruit intake 35.1%, vegetables intake 7.8%. Of the 74 invited GP’s, 61 responded (82%), only 12 (20%) reported that they had performed a follow-up glucose testing within >12-14 months postpartum. Of these women, five were tested only in the first year of follow-up, five also in the second year, and two were tested for three consecutive years.

Conclusions: Despite the high attendance rate of six-weeks postpartum visit and glucose testing, we observed low rates of longer-term follow-up regarding post-partum glucose testing. Moreover, we found a suboptimal adherence to healthy lifestyle for women with a history of GDM.

Postpartum glucose follow-up and lifestyle after GDM

103

6

BACKGROUND

Gestational diabetes mellitus (GDM) is historically defined as any degree of glucose intolerance with onset or first recognition during pregnancy.1 Although in most women with GDM glucose intolerance resolves after delivery, women with a history of GDM are at increased risk of developing impaired glucose tolerance and type 2 diabetes mellitus (DM). It has been estimated that the risk of type 2 DM may be as high as 50-70% in 5-10 years after delivery.2,3

Adequate lifestyle interventions may prevent or postpone the development of type 2 DM. In addition, early diagnosis and treatment of type 2 DM may contribute to the prevention of long-term DM complications, including cardiovascular- and renal diseases.4 Therefore, national and international guidelines recommend follow-up glucose testing in women with a history of GDM.5,6

In the Netherlands, the 2010 Dutch Society of Obstetrics and Gynaecology guideline “Diabetes and Pregnancy” recommends glucose testing six weeks after delivery and subsequently once a year for the next five years.5 Our department rou-tinely invited all patients to the Diabetes Centre to attend a six-weeks postpartum visit. Patients then are referred back to their general practitioner (GP), who has a central role in our health-care system and is therefore the most obvious caregiver to perform annual follow-up glucose testing and simultaneously to motivate women to adopt and maintain a healthy lifestyle to prevent type 2 DM.

It is however unclear how well the advices of this guideline are implemented. To improve early diagnosis of type 2 DM after GDM, we should first verify how many GP’s are aware that women with a history of GDM need annual follow-up glucose testing and take direct responsibility for follow-up glucose testing. For instance, do they have a system to track former GDM patients? In addition, it is important to know whether women with a history of GDM are aware of the recommended annual follow-up glucose testing, and take responsibility for visiting their GP once a year out of their own initiative and change their lifestyle. Successful monitoring depends on clear guidelines, good implementation in primary and secondary care, and education of self-management and adherence of the patient.

Hence, we evaluated the adherence-rate of the follow-up postpartum visit in secondary care after GDM and glucose testing longer than >12-14 months after de-livery and the years thereafter in primary care. We also examined by questionnaire the lifestyle of the women with a history of GDM including physical activity and diet.

Chapter 6

104

METHODS

Study participantsThis study is a cross-sectional follow-up survey of former women with GDM and their GP’s. All 215 women who were treated for GDM at the University Medical Cen-ter Groningen, with a first visit between January 2011 and December 2012, were eligible for participation.

All pregnant women had GDM screening at week 24-28 of gestation if they had one or more GDM risk factors.5 The World Health Organization 1999 criteria were used to diagnose GDM (fasting plasma glucose value ≥7.0 mmol/l and/or a two-hour value ≥7.8 mmol/l after a 75-g oral glucose tolerance test (OGTT)).7 In accordance with the standard of care, all women diagnosed with GDM were referred to the dietician for dietary counselling. If after 1-2 weeks the fasting plasma glucose was >5.3 mmol/l and/or postprandial plasma glucose level >7.8 mmol/l, insulin therapy was started. Routinely this is stopped after delivery.

Women were invited to visit the outpatient clinic six weeks after delivery. During this visit, laboratory testing for blood glucose values, HbA1c, lipid profile, and mi-croalbumuria was performed and all women received information about the future risk of developing type 2 DM. Glucose values were evaluated with results of a 75-g OGTT, HbA1c and/or self-monitoring of the blood glucose (SMBG) values. Women who were breastfeeding were recommended to perform additional glucose testing after cessation of breastfeeding. Targets for treatment were discussed, including weight reduction and information about healthy lifestyle, and they were verbally instructed to visit their GP at least annually for follow-up glucose testing. The GP received a discharge letter mentioning the increased risk for development of type 2 DM and a formal advise to invite their patient for –at least– annual follow-up glucose testing.

For the present study, all the women treated for GDM between January 2011 and December 2012 were invited, including women who did not visit the six-weeks postpartum glucose visit and/or women who did not test their glucose values at the six-weeks postpartum visit. Women were not invited to participate if they had a still birth (n=2). The GP was invited to fill in a questionnaire when their patient gave informed consent. The study was conducted in accordance with the guidelines of the Declaration of Helsinki and Good Clinical Practice, and approved by the Medical Ethical Review Committee of the University Medical Center Groningen.

Procedure and data collectionClinical and demographic data of all eligible women were obtained from the elec-tronic medical records, including: age at delivery, ethnicity, family history of DM,


105

6

previous GDM, previous infant weighing ≥4500 g at birth, pre-gestational body mass index (BMI), delivery of a large for gestational age (LGA) infant, requiring insulin during GDM pregnancy, gestational age at delivery, and data about the six-weeks postpartum visit and laboratory evaluation.

Family history of DM was defined as having a first degree relative with type 2 DM. LGA was defined as a birth weight above the 90th percentile, adjusted for gestational age, gender, parity, and ethnicity.8

Questionnaire women In August 2015, a letter was sent to all eligible women outlining the study goals and procedures, together with an informed consent form, a questionnaire, and a prepaid envelope. If needed seven weeks later a reminder was sent containing the same materials as the first invitation. The questionnaire comprised questions on educational level, breast feeding, and life style factors, including body weight, smoking, alcohol use, exercise, and diet.

Educational level was defined as low (primary education or intermediate vocational education), middle (higher secondary education), and high (higher vo-cational education and university). Duration of breastfeeding was labelled into four categories: 0 months, <3 months, 3 to <6 months, and ≥6 months.

Smoking status was defined as never smoker, ex-smoker or current smoker (1-6 or 6-20 cigarettes/day). Alcohol consumption was defined as ≤1 drinks/day (light drinker) and >1-2 drinks/day (moderate drinker). Weight loss and weight gain were defined as a difference in weight of ≥5 kg compared to pre-pregnancy weight.

Exercise behaviour was assessed using the validated Short Questionnaire to Asses Health enhancing physical activity (SQUASH) questionnaire.9 Women were asked to estimate commuting activities, leisure-time and sport-activities, household activities, and activities at work or school. According to the Dutch guidelines for healthy exercise, adults – 18 to 54 years – should have a moderate level of physical activity for at least half an hour, on at least five days a week.10

According to the “Dutch guidelines for a healthy diet 2006”11 we asked the women questions about their diet. These guidelines are translated by the Neth-erlands Nutrition Centre into the “Food Choice guidelines” and are formulated in terms of foods with two goals, to provide a nutritionally adequate diet containing all recommended macro- and micronutrients and to prevent chronic diseases.12 The guideline contains five basic food groups which deliver the essential micro-and macro nutrients. These basic food groups are divided into three subgroups: foods with a positive, neutral, and negative effect on health. The subgroup criteria to classify foods are based on four nutrients that increase the risk of chronic diseases: saturated fatty acids, trans unsaturated fatty acids, added sugar, sodium, and one

Chapter 6

106

nutrient that decrease the risk: dietary fiber.12 According to the basics foods groups and three subgroup criteria we asked women how much they eat of each basic food group and from which subgroup they mostly eat. For example: “How many parts of fruit do you eat per day?” “Which category is most consistent with your choice? A. Unprocessed fruit B. Pureed fruit or C. Fruit with added sugar/syrup”. The reported food choices were compared with the recommended amounts and the positive and neutral food groups were considered good.12 The women were also asked about their knowledge of the “Food Choice guidelines” and their eating moments (“How many times per week do you eat breakfast, lunch, or dinner?” “How many times do you eat or drink per day?”). The Dutch Health Council advices seven eat/drink mo-ments per day with a low intake of foods and drinks with easily fermentable sugars and drinks high in food acids (without the use of water, thee- and coffee (without sugar), or milk).11

Questionnaire general practitionersWomen were asked to give informed consent to send a questionnaire also to their GP. In November 2015, the eligible GP’s received a letter outlining the study, a ques-tionnaire, and a copy of the informed consent form of their patient. If needed seven weeks later a reminder was sent containing the same materials as the first invitation. The questionnaire included questions about the annual follow-up screening. The GP was asked if he/she sent an annual reminder to their patient and if the patient has visited the annual postpartum controls (if the answer was no, “can you give a reason why your patient did not visit the annual postpartum controls?” If the answer was yes, “How many times did your patient visit the annual postpartum testing?”, “Did you repeat life style advices during the postpartum testing?”, and “Did your patient develop type 2 DM?”).

Statistical analysesAll analyses were conducted using statistical package IBM SPSS Statistics (version 22.0. Armonk, NY: IBM Corp). Continuous data are given as mean ± standard devia-tion (SD) or as median and inter quartile range [IQR] in case of skewed distribution. Categorical data are given as number and percentage. Differences between the groups were tested using Student’s unpaired t-test for continuous data or Mann-Whitney U Test in case of skewed distribution. For categorical data Chi-square or Fisher’s exact test were used. All P-values are two-tailed, and P-values below 0.05 were considered statistically significant.


107

6

FIGURE 1. Flow-chart study population.Abbreviations: GDM, gestational diabetes mellitus; IUFD, intrauterine foetal death.

RESULTS

In total 213 women were invited to participate in the study, 16 women had moved (Fig. 1). The most important clinical and demographic characteristic of the 197 eligible women (77 responders (39%), 120 non-responders (61%)) are summarized in Table 1. The women who responded were more often Caucasian (87%), and they more frequently had a previous infant weighing ≥4500 g at birth (14%). The women in the non-responder group had a slightly higher pre-gestational BMI and were more often obese (≥30 kg/m2) compared with the responder group. There were no differences in maternal age, family history of GDM, previous GDM, insulin require-ments, LGA infant at delivery, and gestational age at delivery.

Chapter 6

108

TABLE 1. Pre-gestational and gestational characteristics of the eligible study participants (period 2011-2012) according to survey responders and non-responders.

Characteristics Total

Responder

P-value*Yes No

N (%) 197 77 (39.1) 120 (60.9)

Age at delivery (yrs) 32.2 ± 4.9 32.8 ± 5.0 31.9 ± 4.8 0.173

Family history of DM, n (%) 77 (41.8) 34 (47.2) 43 (38.4) 0.236

Previous GDM, n (%) 10 (5.1) 6 (7.8) 4 (3.3) 0.193

Previous infant weighing ≥ 4500 g at birth, n (%) 17 (8.6) 11 (14.3) 6 (5.0) 0.024

Pre-gestational BMI (kg/m2) 27.6 [24.1-31.2] 26.4 [22.9-30.6] 27.9 [24.3-32.0] 0.040

Pre-gestational BMI, n (%) <25 kg/m2

25-29.9 kg/m2

≥30 kg/m2

61 (32.4)61 (32.4)66 (35.1)

27 (37.5)25 (34.7)20 (27.8)

34 (29.3)36 (31.0)46 (39.7)

0.236

Requiring insulin during pregnancy, n (%) 90 (45.7) 32 (41.6) 58 (48.3) 0.352

Gestational age at delivery (wks) 38.3 [38.0-39.6] 38.4 [38.0-39.7] 38.1 [37.7-39.5] 0.070

LGA infant, n (%)‡ 41 (20.8) 16 (20.8) 25 (20.8) 0.993

Postpartum visit at the DM outpatient clinic, n (%) 156 (79.2) 71 (92.9) 85 (70.8) 0.001

Postpartum glucose testing, n (%) OGTT HbA1c**

SMBG No test

62 (42.8)122 (61.9)19 (13.1)11 (7.1)

31 (43.7)57 (74.0)8 (11.3)3 (4.2)

31(36.5)65 (53.3)11 (12.9)

8 (9.4)

0.558

Discharge letter sent to the GP, n (%) 171 (86.8) 68 (88.3) 103 (85.8) 0.616

Copy of the discharge letter sent to women, n (%) 22 (11.2) 12 (15.6) 10 (8.3) 0.115

Abbreviations: BMI, body mass index; DM, diabetes mellitus; GDM, gestational diabetes mellitus; LGA, large for gestational age; GP, general practitioner; OGTT, oral glucose tolerance test; SMBG, self-monitoring of the blood glucose. Data are expressed as mean ± SD, median [IQR], or proportion n (%).Data with respect to family history of diabetes and pre-gestational body mass index are missing, in 13 (6.6%) and 9 (4.6%) of the women, respectively. *P-values were based on Student’s unpaired t-test (non-skewed continuous variables), Mann-Whitney U Test (skewed continuous variables) or Chi-square test or Fisher’s exact test (categorical variables).‡Large for gestational age was defined as a birth weight above the 90th percentile, adjusted for gestational age, gender, parity, and ethnicity.**In 58 women who underwent a 75-g OGTT, Hb1Ac was also measured.

Of the 197 eligible women, 156 (79%) attended the six-weeks postpartum office visit at the diabetes outpatient clinic in secondary care. More women in the respond-er group attended this postpartum office visit compared with the non-responders group. In 145 (93%) women who attended the postpartum visit glucose testing was performed. In total 62 (43%) women underwent a postpartum 75-g OGTT. Based on the postpartum 75-g OGTT, nineteen women had impaired glucose tolerance (2-h value after 75-g OGTT between ≥7.8-11.0 mmol/l) and one woman was diagnosed with type 2 DM. In 122 (84%) women HbA1c was measured. In 58 women who


109

6

TABLE 2. Follow-up characteristics of the survey responders.

Follow-up characteristics N=77Postpartum (yrs) 3.5 ± 0.6

Age (yrs) 36.3 ± 5.0

Educational level, n (%) Low Middle High

7 (9.1)33 (42.9)37 (48.1)

Duration of breastfeeding, n (%) 0 month <3 months 3 to 6 months >6 months

24 (31.2)26 (33.8)11 (14.3)14 (18.2)

Current smoker, n (%) 17 (22.1)

Alcohol consumption, n (%) Non-drinker ≤1 drink/d >1-2 drinks/d

29 (37.8)46 (59.7)

2 (2.6)

WeightBMI (kg/m2) 26.5 [23.4-30.1]

BMI, n (%) <25 kg/m2

25-29.9 kg/m2

≥30 kg/m2

24 (31.2)29 (37.7)21 (27.3)

Weight gain, n (%)† 15 (19.5)

Weight loss, n (%)† 19 (24.7)

Physical ActivityKnowledge of Dutch recommendations on physical activity, n (%) 12 (15.6)

Active 30 min 5 days/week, n (%) 27 (35.1)

DietKnowledge of Dutch Food choice guidelines, n (%) Yes No, not exactly No, never heard of it

40 (51.9)31 (40.3)

6 (7.8)

Eating three meals p/d, n (%) 55 (71.4)

Max. two snacks p/d, n (%) 67 (87.0)

Fish two times p/wk, n (%) 15 (19.5)

Meeting the recommendations for basic food groups Fruit, n (%) Vegetables, n (%) Bread and grain products, n (%) Potatoes, rice, pasta, legumes, n (%) Milk (products), n (%) Cheese, n (%) Meat, fish, poultry, eggs, meat substitutes, n (%) Oils and soft margarines, n (%) Drinks, n (%)

27 (35.1)6 (7.8)1 (1.3)5 (6.5)

28 (36.4)43 (55.8)10 (13.0)25 (32.5)27 (35.1)

Abbreviations: BMI, body mass index.Data are expressed as mean ± SD, median [IQR], or proportion n (%).Data with respect to body mass index and breastfeeding are missing, in 3 (3.9%) and 2 (2.6%) of the women, respectively.†Weight loss since pregnancy was defined as ≥5 kg and weight gain as ≥5 kg.

Chapter 6

110

underwent a 75-g OGTT, HbA1c was also measured. In 19 (14%) women only SMBG was used to interpreted glucose status. HbA1c and SMBG were used for glucose status because of breastfeeding at time of the six-weeks postpartum visit (n=58), patient declined the OGTT (n=7), illness (n=2), or the reason was unknown (n=16). Almost 87% of the GP’s received a discharge letter, 22 (11%) women received a copy of this discharge letter.

Questionnaire women Table 2 summarizes the follow-up lifestyle characteristics of the 77 women who responded to the questionnaire. The mean follow-up time was 3.5 ± 0.6 years. The median BMI was 26.5 [IQR 23.4-30.1] kg/m2 and is comparable with their pre-gestational BMI of 26.4 [IQR 22.9-30.6] kg/m2. More women lost weight (25%) (≥5 kg) than gained weight (20%) (≥5 kg) compared with their pre-gestational weight. Knowledge of the national recommendations for healthy exercise and the Dutch Food Choice guidelines was limited.

TABLE 3. Annual glucose screening at the general practitioner.

GP responders N=61*

Annual postpartum control, n (%) N=12 (20.0)**

Received a discharge letter from secondary care, n 11

Patient in a re-call system, n 4

Total number of annual glucose screenings, n 1 year follow-up 2 years follow-up 3 years follow-up

5 5 2

Provided lifestyle advices, n 4

Total women diagnosed with type 2 diabetes, n 1

No annual postpartum control, n (%) N=49 (80.0)***

Received a discharge letter from secondary care, n 43

Patient in a re-call system, n 15

Reasons for not screening, n Patient declined testing GP did not know testing is needed Patient not in a call system GP did not see the patient, despite a reminder Patient had a second pregnancy within 1 year Patient had other GP at time of GDM pregnancy Controls at endocrinologist Reason unknown

1 4 1 4 2 4 5

28

Abbreviations: GP, general practitioner; GDM, gestational diabetes mellitus.Data are expressed as proportion, n (%).*Total general practitioners responded.**Total general practitioners responded and who screened their patient within 12-14 months after delivery.***Total general practitioners responded and who did not screened their patient within 12-14 months after delivery.


111

6

Questionnaire physician’sOutcomes of the annual follow-up glucose testing at the GP are summarized in Table 3. In total 74 GP’s were invited to participate in the study, and 61 GP’s (82%) responded. Of the 61 GP’s, 12 GP’s reported that they performed follow-up glucose testing within >12-14 months after delivery. Only two women were tested for three consecutive years. Reasons GP’s provided for not screening are also summarized in Table 3.

DISCUSSION

In this follow-up survey of women with a history of GDM and their GP, we found high rates of the six-weeks postpartum visit and glucose testing at the diabetes out-patient clinic. However, we found low rates of longer-term follow-up postpartum glucose testing in primary care.

Moreover, we found suboptimal performance of adherence to a healthy lifestyle for women with a history of GDM, particularly with respect to exercise and to a lesser extent regarding diet. Most of the GP’s also did not provide lifestyle advices at the annual follow-up glucose testing.

During the six-weeks postpartum office visit a noteworthy number of women tested with a 75-g OGTT were found to have impaired glucose tolerance and one woman was diagnosed to have type 2 DM. This finding indicates that a number of women are in an advanced stage of developing type 2 DM. Studies suggest that the association between GDM and type 2 DM can be explained by the fact that many of the risk factors for both disorders are the same, including high BMI, family history of diabetes, and ethnic origin.2,3 The prevalence of GDM is increasing worldwide and former GDM women are for several years at risk to develop type 2 DM. Therefore, the low long-term rates are a missed opportunity to postpone obesity and type 2 DM, disease which carry a high burden for the individual patient and for society.

There is limited published data on the long-term follow-up testing in primary care of women who have had GDM. Two recent studies,13,14 conducted in the United Kingdom, investigated the long-term follow-up testing of women with a history of GDM. The first study demonstrated that during a 5-year period around 20% of the 718 women with a history of GDM had long-term follow-up glucose testing and only three (0.4%) women were followed-up every year.14 Another study showed that of the 233 included women, 34% had glucose testing in the first year postpartum, 12% (16 of the 131) in the second year and 18% (8 of the 45) three years after deliv-ery.13 These findings are in line with the rates of long-term follow-up glucose testing found in our study.

Chapter 6

112

There are several potential explanations for the low long-term follow-up postpartum testing rates. This study indicates that follow-up of women with GDM is insufficiently incorporated in the primary care system. Possible reasons for this hampered follow-up system may include a lack of agreed protocols, insufficient or unclear communication by the treating physician in secondary care, and a lack of sufficient call- and tracking systems in Dutch family practices. Although the Dutch Society of Obstetrics and Gynaecology guideline 2010 “Diabetes and Pregnancy” recommends glucose testing six-weeks after delivery and subsequently once a year for the next 5 years, such follow-up glucose testing was added to GP guidelines only in 2013.15

There may be limited knowledge and reduced awareness of the importance of postpartum screening among GDM women. A number of GP’s reported that also the women declined testing and did not respond to a follow-up invitation despite sending a reminder. This is remarkable as during the six-week postpartum visit, all women have verbally received information about their future risk of type 2 DM and they were instructed to visit their GP at least annually for follow-up glucose testing. However, only a small number received a copy of the discharge letter sent to their GP, which summarized these verbal communications, and none have received addi-tional written information on the risk of development of type 2 DM and adoption of a healthy lifestyle. Studies have demonstrated that lifestyle modifications including weight loss, healthy diet, and moderate exercise can reduce the risk of developing type 2 DM in high risk subjects16,17 and also in women with a history of GDM.18-20 For this reason, during the six-weeks postpartum visit all women with a history of GDM received information about the benefits of weight management and moder-ate physical activity. In this study all women received a life-style questionnaire to examine the life-style of women with a history of GDM. The women who responded at the questionnaire were less often obese, had higher rates of a previous infant weighing ≥4500 g at birth, and more women attended the six-weeks postpartum visit and glucose testing compared with the non-responder group. These findings, may suggest that the responders group is more interested and aware about the importance of lifestyle changes compared with non-responder group. However, also in the responder group only one third of the women met the recommendations of physical activity and there were suboptimal levels of dietary intake, for instance a low intake of fruit and vegetables. Moreover, most of the women were overweight (BMI ≥25-29.9 kg/m2) or obese (BMI ≥30 kg/m2). A positive finding was the fact that more women lost weight than gained weight compared with their pre-pregnancy weight. A few studies have investigated the health status and lifestyle modifications in women with a history of GDM.21-27 In analogy to our study, these studies showed that diet and physical activity levels rarely met the recommendations.22,23,26,27


113

6

Even though most of the women were highly educated, we found a subopti-mal performance of adherence to a healthy lifestyle. There are several barriers for women with a history of GDM to adopt a healthy lifestyle including time, financial constraints, child care, lack of motivation, and lack of social support.28 These barriers are also found in women with the same age without a history of GDM.22

In the Dutch health-care system, the GP could be a good motivator for women to adopt a healthier lifestyle.29 However, the GP’s did not reinforce a healthier lifestyle as most of them did not provide such advices at the annual follow-up. This study and previous studies indicated that there is need for better lifestyle awareness and coaching in primary care, including advice about diet and physical activity. With our current health-care system we are missing opportunities to interfere in obesity and type 2 DM development. Successful monitoring depends on a good implementa-tion in secondary and primary care and education of self-management and adher-ence of the patient. There are several recommendations for the organization of care to expand and improve the long-term follow-up in former GDM women. First, the internist can improve care by sending a discharge letter to the GP and a copy of the letter to the patient, including written information (a brochure) about the future risk of type 2 DM. Secondly, the GP can denote a previous GDM patient carrying an increased cardiovascular risk and connect them to a tracking system in the GP practices and send postnatal reminders to women. A study in South Australia has shown that a GDM Recall Register for former GDM women – sending a reminder 15 months after the expected delivery date – is successful in recruiting women to remind them that they should continue to have their blood glucose checked over the long term.30 At last, another place for health promotion and raise further aware-ness could be the Early Childhood Centers. Women visit the Early Childhood Center regularly with their babies (0-4 years), and their nurses can help to recommend the mother to pursue follow-up care by their GP. Regional lifestyle programs/self-management programs can be offered by the Early Childhood Centers, for example in group classes.

Strengths and limitationsStrengths of the study are the evaluation of postpartum glucose visits in secondary care and additional the annual long-term postpartum glucose testing in primary care. To our knowledge this is the first study in the Netherlands which investigated the glucose screening of women with a history of GDM.

This study has several potential limitations. This study was conducted at only one institution with a relative small sample size. Therefore, the total number of women with a history of GDM who responded was too low to evaluate the type 2 DM incidence. Furthermore, we have no information about lifestyle factors of the

Chapter 6

114

women before their pregnancy. For this reason, we cannot determine to what extent the educational issues connected to GDM motivated patients to change lifestyle for example lose weight. Finally, in most of the guidelines an OGTT is recommended for blood glucose testing, because the OGTT has a high sensitivity compared with other screening methods. In our national guideline the OGTT is not the standard for blood glucose screening postpartum, because the OGTT screening method is time consuming and not patient-friendly.

CONCLUSIONS

In conclusion, this study demonstrated that in women with a history of GDM postpartum follow-up care was far from optimal and showed a striking discrepancy with current guidelines. Long-term postpartum follow-up clearly requires improve-ments in the Netherlands, to early diagnose pre-diabetes or type 2 DM and more importantly to pay attention to preventive strategies. The improvement of long-term follow-up testing could be realized by marking GDM patients and connect them to a yearly recall-system. Also a better communication between primary and secondary care is needed. Finally, awareness among women with a history of GDM will probably surface a healthier lifestyle and at least decrease the low rates at the postpartum visit in primary care. There is clearly more need for lifestyle coaching programs/self-management for women with a history of GDM to adopt a healthy lifestyle and make them aware about the risk of type 2 DM.

Abbreviations

BMI: Body Mass Index; DM: Diabetes mellitus; GDM: Gestational diabetes mellitus; GP: General practi-tioner; IQR: Inter quartile range; LGA: Large for gestational age; OGTT: Oral glucose tolerance test; SD: Standard deviation; SQUASH: Short questionnaire to assess health.

Acknowledgements

The authors wish to thank the women who responded and the general practitioners for participating in the study.

Funding

Novo Nordisk Netherlands provided an unrestricted research grant.

Availability of data and material

The dataset contains clinical data, which because the Dutch law for Personal Data Protection and patient confidentiality cannot be shared publicly. Data are available upon request to prof. Wolffenbuttel. Patients


115

6

did not sign informed consent to release their data on an individual basis on the internet. For this reason, a research proposal should be filled upon contacting prof. Wolffenbuttel ([email protected]).

Authors’ contributions

Conceived and designed the study: HLL, BHRW, SHK. Collecting the data and analysed the data: SHK. Wrote the manuscript: SHK. Intellectual contributions to the manuscript, helped drafting the manuscript and have read and approved the final version: BHRW, HLL, PPB, KH, CAT.

Competing interests

The authors declare that they have no competing interest.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Ethics approval was obtained from the Medical Ethics Review Committee of the University Medical Center Groningen. Written informed consent was obtained from all respondents.

Chapter 6

116

REFERENCES




4. Kim C, Tabaei BP, Burke R, et al. Missed opportunities for type 2 diabetes mellitus screening among women with a history of gestational diabetes mellitus. Am J Public Health. 2006;96:1643-8.

5. The Dutch Society of Obstetrics and Gynaecology. Diabetes mellitus and pregnancy. Clinical guideline version 2.0. 2010. Available from: http://www.nvog-documenten.nl/index.php?pagina=/richtlijn/item/pagina.php&richtlijn_id=863, accessed 22 September 2015.

6. American Diabetes Association. Management of diabetes in pregnancy. Diabetes Care. 2015;38 (Suppl.):S77-9.

7. World Health Organization (WHO). Definition and Classification of Diabetes Mellitus and its Complications. Report of a WHO Consultation. Part 1: Diagnosis and Classification of Diabetes Mellitus. Geneva, WHO, 1999. Department of Noncommunicable Disease Surveillance.


9. Wendel-Vos GW, Schuit AJ, Saris WH, Kromhout D. Reproducibility and relative validity of the short questionnaire to assess health-enhancing physical activity. J Clin Epidemiol. 2003;56:1163-9.

10. Kemper H, Ooijendijk W, Stiggelbout M. Consensus concerning the Dutch guidelines for healthy exercise. TSG Tijdschr Gezondheidswet. 2000;78:180-3.

11. Health council of the Netherlands. Guidelines of a healthy diet. The Hague, 2006. Health Council of the Netherlands.

12. Netherlands Nutrition Center. Guidelines food choice. Available from: http://www.voeding-scentrum.nl/Assets/Uploads/voedingscentrum/Documents/Professionals/Voedselvoorlicht-ing/01_Richtlijnen%20voedselkeuze%20Voedingscentrum.pdf, accessed 16 December 2014.

13. Adekojo O, Revell K, Preece H, Morris S, Coleman M, Holt R. Low uptake of postpartum screening for type 2 diabetes in women after a diagnosis of gestational diabetes. Diabet Med. 2016;33:1599-601.

14. McGovern A, Butler L, Jones S, et al. Diabetes screening after gestational diabetes in England: A quantitative retrospective cohort study. Br J Gen Pract. 2014;64:e17-23.

15. Rutten GEH, de Grauw WJC, Nijpels G, et al. NHG standard Diabetes mellitus type 2. Huisarts Wet. 2013;56:512-25.

16. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-50.

17. Eriksson K, Lindgärde F. Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise the 6-year Malmö feasibility study. Diabetologia. 1991;34:891-8.


117

6

18. Shek NWM, Ngai CSW, Lee CP, Chan JYC, Lao TTH. Lifestyle modifications in the development of diabetes mellitus and metabolic syndrome in Chinese women who had gestational diabetes mellitus: A randomized interventional trial. Arch Gynecol Obstet. 2014;289:319-27.

19. Tobias DK, Hu FB, Chavarro J, Rosner B, Mozaffarian D, Zhang C. Healthful dietary patterns and type 2 diabetes mellitus risk among women with a history of gestational diabetes mellitus. Arch Intern Med. 2012;172:1566-72.

20. Dornhorst A, Frost G. The potential for dietary intervention postpartum in women with gesta-tional diabetes. Diabetes Care. 1997;20:1635-7.

21. Stage E, Ronneby H, Damm P. Lifestyle change after gestational diabetes. Diabetes Res Clin Pract. 2004;63:67-72.

22. Kieffer EC, Sinco B, Kim C. Health behaviors among women of reproductive age with and without a history of gestational diabetes mellitus. Diabetes Care. 2006;29:1788-93.

23. Evans MK, Patrick LJ, Wellington CM. Health behaviours of postpartum women with a history of gestational diabetes. Can J of Diabetes. 2010;34:227-32.

24. Kim C, McEwen LN, Kieffer EC, Herman WH, Piette JD. Self-efficacy, social support, and associations with physical activity and body mass index among women with histories of gestational diabetes mellitus. Diabetes Educ. 2008;34:719-28.

25. Kim C, McEwen LN, Piette JD, Goewey J, Ferrara A, Walker EA. Risk perception for diabetes among women with histories of gestational diabetes mellitus. Diabetes Care. 2007;30:2281-6.

26. Persson M, Winkvist A, Mogren I. Lifestyle and health status in a sample of Swedish women four years after pregnancy: A comparison of women with a history of normal pregnancy and women with a history of gestational diabetes mellitus. BMC Pregnancy Childbirth. 2015;15:57.

27. Zehle K, Smith BJ, Chey T, McLean M, Bauman AE, Cheung NW. Psychosocial factors related to diet among women with recent gestational diabetes: Opportunities for intervention. Diabetes Educ. 2008;34:807-14.

28. Kaiser B, Razurel C. Determinants of postpartum physical activity, dietary habits and weight loss after gestational diabetes mellitus. J Nurs Manag. 2013;21:58-69.

29. Stuebe A, Ecker J, Bates DW, Zera C, Bentley-Lewis R, Seely E. Barriers to follow-up for women with a history of gestational diabetes. Am J Perinatol. 2010;27:705-10.

30. Chittleborough CR, Baldock KL, Taylor AW, et al. Long‐term follow‐up of women with gestational diabetes mellitus: The South Australian Gestational Diabetes Mellitus Recall Register. Aust N Z J Obstet Gynaecol. 2010;50:127-31.

B Evaluation of new international diagnostic criteria

7 New diagnostic criteria for gestational diabetes mellitus and their impact on prevalence and pregnancy outcomes

Koning SH, van Zanden JJ, Hoogenberg K, Lutgers HL, Klomp AW, Korteweg FJ, van Loon AJ, Wolff enbuttel BHR, van den Berg PP

Submitted

Chapter 7

122

ABSTRACT

Aims/hypothesis: Detection and management of gestational diabetes mellitus (GDM) are crucial to reduce the risk of pregnancy-related complications for both mother and child. The World Health Organization (WHO) adopted stricter GDM diagnostic criteria in 2013 to improve pregnancy outcomes. However, the evidence for these criteria is limited. Therefore, these new criteria have not yet been endorsed in the Netherlands. The aim of this study was to determine the impact of these cri-teria on GDM prevalence and pregnancy outcomes.

Methods: Data on screening were available from 10,642 women who underwent a 75-g OGTT due to risk factors or signs suggestive of GDM. Women were treated if diagnosed with GDM according to the WHO-1999 criteria. Data on pregnancy outcomes were obtained from extensive chart reviews in 4,431 women and were compared between women with normal glucose tolerance (NGT) and women diag-nosed according to the WHO-1999 and WHO-2013 criteria, respectively.

Results: When we compared the two sets of GDM diagnostic criteria in terms of GDM prevalence, we found that applying the new WHO-2013 criteria would have resulted in a higher number of diagnoses than applying the WHO-1999 criteria (31% versus 22%) in this population of women at higher risk for GDM. Compared with NGT women, women classified as having GDM based only on the WHO-2013 fasting glucose (FG) cut-off were more likely to have been obese and hypertensive before pregnancy, and to have had higher rates of gestational hypertension, planned caesarean section and induction of labour. In addition, their neonates were more likely to have had an Apgar score <7 at 5 min and to have been admitted to the neonatology department. The numbers of large-for-gestational-age (LGA) neonates were not significantly different between the two groups. Women potentially missed due to higher 2-h glucose cut-off (2HG) of the WHO-2013 criteria had similar preg-nancy outcomes to NGT women. These women were treated for GDM, all with diet, and 20.5% additionally with insulin.

Conclusions/interpretation: Applying the WHO-2013 criteria will have a major im-pact on the prevalence of GDM. Using the FG cut-off levels of the WHO-2013 criteria identifies a group of women with an increased risk of adverse outcomes compared with NGT women. However, adopting the WHO-2013 criteria with a higher 2HG cut-off excluded women where GDM-treatment seems to be effective.

Impact of new diagnostic criteria for GDM on prevalence and outcomes

123

7

BACKGROUND

Gestational diabetes mellitus (GDM) is a major health issue and is associated with an increased risk of pregnancy-related complications for both mother and child.1,2 International guidelines recommend active screening for GDM, since many of these risks can be reduced by detection and management of GDM.3,4 However, these guidelines lack uniformity in terms of their diagnostic cut-off values.

In 2010, the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) proposed more stringent thresholds for diagnosing GDM, which were based on the results of the international prospective Hyperglycemia and Ad-verse Pregnancy Outcomes (HAPO) study.5,6 The HAPO study demonstrated a linear association between fasting and post-load maternal glucose levels and the risk of adverse pregnancy outcomes such as increased birth weight, primary caesarean de-livery and neonatal hypoglycaemia.6 The IADPSG diagnostic criteria (fasting plasma glucose (FG) level ≥5.1 mmol/l and/or 1-h plasma glucose level ≥10.0 mmol/l and/or 2-h plasma glucose level (2HG) ≥8.5 mmol/l) have now been adopted by many guideline committees and expert groups, including the World Health Organization (WHO) who published their new guideline in 2013.5,7

However, evidence that applying the stricter criteria for GDM improves preg-nancy outcomes is limited. There is still uncertainty about the optimal glucose thresholds to define GDM, and international consensus has not yet been reached.8,9 Applying the new criteria causes more women to be diagnosed with GDM and the resulting cost increases and medicalization of pregnancy are causes for concern for healthcare managers and caregivers.10,11 Better appraisal of the value of these new glucose thresholds requires studies into clinical outcomes and cost-effectiveness analyses. In the Netherlands, the new WHO-2013 criteria have not yet been en-dorsed. In their 2010 guideline “Diabetes and Pregnancy”, the Dutch Society of Ob-stetrics and Gynaecology recommends using the WHO-1999 criteria for diagnosing GDM (FG ≥7.0 mmol/l and/or 2HG ≥7.8 mmol/l).12,13 When compared with the new WHO-2013 criteria, these criteria use a much higher cut-off value for FG and a lower cut-off value for 2HG.

The consequences of adopting the WHO-2013 thresholds need to be evaluated in order to answer crucial questions: Do women who are additionally diagnosed with GDM using the WHO-2013 FG criteria (FG ≥5.1- ≤6.9 mmol/l) indeed have un-favourable pregnancy outcomes? And what are the pregnancy outcomes of those women who will be missed due to the higher 2HG cut-off of the WHO-2013 criteria (i.e. women with 2HG ≥7.8- ≤8.4 mmol/l)?

Chapter 7

124

The aim of this study was therefore to evaluate the possible impact on GDM prevalence and pregnancy outcomes of applying the new WHO-2013 criteria in-stead of the older WHO-1999 criteria.

METHODS

Study design and populationThis study is a retrospective evaluation of data on GDM screening (in women with risk factors for GDM), pregnancy management and pregnancy outcomes collected between January 2011 and September 2016 in the Groningen area by Certe, a regional primary- and secondary healthcare laboratory in the north of the Nether-lands, and by the University Medical Center Groningen (UMCG), a tertiary referral centre.

As previously described,14,15 pregnant women between 24 and 28 weeks of gesta-tion were referred either by their midwife (in primary care) or by their gynaecologist (in secondary/tertiary care) for a 75-gram oral glucose tolerance test (OGTT) if they had one or more risk factors for GDM according to the Dutch national guideline.13 These risk factors were having a pre-pregnancy body mass index (BMI) ≥30 kg/m2; having a first-degree relative with diabetes mellitus; having a previous neonate weighing ≥4500 gram at birth or a birth weight >95th percentile; having a history of GDM, intrauterine foetal death or polycystic ovary syndrome; and belonging to an ethnic risk group (South-Asian i.e. Hindu, African-Caribbean, Middle Eastern i.e. Moroccan and Egyptian). Universal testing is not recommended in the Dutch national guideline.

Women with previous GDM were screened using a 75-g OGTT between 16 and 18 weeks of gestation, and if these results were normal the OGTT was repeated between 24 and 28 weeks of gestation. An OGTT was also recommended for women with signs suggestive of GDM (e.g. foetal macrosomia or polyhydramnios). Women were treated if diagnosed with GDM according to the WHO-1999 criteria: FG ≥7.0 mmol/l and/or 2HG value ≥7.8 mmol/l.12 All women were referred to a dietician for dietary counselling and received instructions for self-monitoring of blood glucose values by a diabetes specialist nurse. If, after 1-2 weeks, repeated measurements indicated FG >5.3 mmol/l and/or one-hour postprandial plasma glucose levels >7.8 mmol/l, insulin therapy was started.15

The study was conducted in accordance with the guidelines of the Declaration of Helsinki and Good Clinical Practice, and approved by the Medical Ethical Review Committee of the UMCG.


125

7

GDM classificationBased on their OGTT results, women were retrospectively classified into the follow-ing diagnostic groups:

1. Normal glucose tolerance (FG <5.1 mmol/l and 2HG <7.8 mmol/l), denoted as “NGT”;

2. GDM according to both WHO-1999 and WHO-2013 criteria (FG ≥5.1 mmol/l and/or 2HG ≥7.8 mmol/l), denoted as “both criteria GDM”;

3. GDM according to WHO-2013 criteria (FG ≥5.1 mmol/l and/or 2HG ≥8.5 mmol/l), denoted as “WHO-2013”;

4. GDM according to WHO-1999 criteria (FG ≥7.0 mmol/l and/or 2HG ≥7.8 mmol/l), denoted as “WHO-1999”;

We also identified two groups of women classified as follows: 5. GDM according to WHO-2013 FG cut-off criterion, but not WHO-1999 criteria (FG ≥5.1-≤6.9 mmol/l and 2HG <7.8 mmol/l), denoted as “WHO-2013 only FG”; 6. GDM according to WHO-1999 2HG cut-off criterion, but not WHO-2013 criteria (FG <5.1 mmol/l and 2HG ≥7.8-≤8.4 mmol/l), denoted as “WHO-1999 only 2HG”.

It should be noted that women in the NGT group were screened with an OGTT because they had risk factors for GDM or signs suggestive of GDM (e.g. foetal macrosomia or polyhydramnios). Approximately 85% of the women were tested based on predefined risk factors for GDM. Since the women in the NGT group are not representative of all non-GDM pregnancies, neonatal outcomes regarding birth weight in the general obstetric population in the northern region of the Nether-lands (period 2011-2013) were obtained from the Dutch Perinatal Registry and the Municipal Health Service Groningen. The nature of this dataset unfortunately does not allow to exclude those screened for GDM.

OutcomesData on maternal characteristics and pregnancy outcomes were retrospectively collected from medical and obstetric records at midwives offices in primary care and at two hospitals, the UMCG and the Martini Hospital Groningen. All data were incorporated in an anonymised database. Maternal outcomes of interest were gestational hypertension, preeclampsia, induction of labour, and mode of delivery (spontaneous vaginal delivery, instrumental delivery, emergency caesarean section (CS), and planned CS). Gestational hypertension was defined as a systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥90 mmHg, after 20 weeks of gestation in a previously normotensive woman. Preeclampsia was defined as

Chapter 7

126

gestational hypertension together with the presence of proteinuria (≥300 mg/24 hrs) and also included women who had eclampsia and HELLP syndrome.

Neonatal outcomes of interest were the following: stillbirth; gestational age at delivery; preterm delivery (delivery <37 weeks of gestation); birth weight; neonate born large for gestational age (LGA; birth weight >90th percentile corrected for gestational age, sex, parity, and ethnic background);16 neonate with macrosomia (birth weight >4000 gram); neonate born small for gestational age (SGA; birth weight <10th percentile corrected for gestational age, sex, parity, and ethnic back-ground);16 birth trauma (shoulder dystocia, fracture of humerus or clavicle, brachial plexus injury); Apgar score <7 at 5 min; hypoglycaemia (occurring >2 hrs after birth defined as a having a blood glucose level <2.6 mmol/l or requiring treatment with glucose infusion);13 hyperbilirubinaemia (defined as requiring treatment with pho-totherapy after birth); requirements for respiratory support (the need to intubate or apply continuous positive airway pressure); and admission to the neonatology department. The variables hypoglycaemia and hyperbilirubinaemia were only re-ported for the WHO-1999 group and WHO-1999 only 2HG, since only the women in these groups all delivered in secondary care.

Extrapolation models of data on birth weight and prevalence of LGA neonatesTreatment for GDM affects birth weight and the prevalence of LGA neonates. The positive effects of treatment are supported by previous studies that have shown that treating women who have mild GDM reduces birth weight by 100 to 140 grams.4,11 Based on our data, we developed extrapolation models to predict the influence of treatment (diet and/or additional insulin therapy) on birth weight and the likelihood of having an LGA neonate. We developed these extrapolation models for the follow-ing three GDM classification groups: WHO-1999 group, WHO-1999 only 2HG group and WHO-2013 only FG group. In our study, those women who were treated and responded well to dietary counseling were designated as the “diet-only” group, and those who remained significantly hyperglycaemic despite adequate diet and were therefore also prescribed insulin therapy were designated as the “insulin” group.

In Model 1, we hypothesized that neonates from mothers who had been treated for GDM and who had had more severe GDM (“WHO-1999” and “WHO-1999 only 2HG” groups) would have been an average of 100 grams heavier at birth in the diet-only group and 200 grams heavier in the insulin group if these women had not been treated. In Model 2, we applied a 200-gram birth weight difference in the diet-only group and a 400-gram difference in the insulin group if these women had not been treated. In Model 1, we also hypothesized that neonates from mothers who had not been treated for GDM and who had had milder GDM (“WHO-2013 only FG group”)


127

7

would have had a 50 gram lower birth weight if the mother had been treated with diet only and a 100 gram lower birth weight if they had been treated with insulin. In Model 2, the hypothesized differences were 100 grams on diet only and 200 grams on insulin. The extrapolated birth weights were used to calculate the percentages of LGA neonates in each group. A schematic explanation about the categories and models are given in suppl. Table 1.

Since the women in the “WHO-1999” and “WHO-1999 only 2HG groups” were treated with diet-only and/or were treated with insulin, resulting in normalization of their glycaemic profiles, these two groups cannot be directly compared with the women in the NGT group, who were not offered treatment. Nevertheless, for these two groups we tried to estimate the birth weight and prevalence of LGA that would have resulted had the women not been treated.

Statistical analysesContinuous data are presented as mean ± standard deviation (SD) in case of normal distribution, or as median and interquartile range (IQR) in case of skewed distri-bution. Categorical data are presented as numbers and percentages. Differences between groups were tested using the Student’s unpaired t-test for continuous data, or the Mann-Whitney U Test in case of skewed distribution. For categorical data, a Chi-square test or Fisher’s exact test was used.

To examine the associations between the GDM classification and pregnancy outcomes, analyses were performed using logistic regression models in which the ORs and 95% CIs for each criteria group were calculated using the NGT group as reference group. Results are presented as unadjusted models and multivariable-adjusted models, with the multivariable-adjusted models adjusted for maternal age, pre-pregnancy BMI, ethnicity, parity, and maternal smoking during pregnancy. The model analysing the association between GDM classification and LGA was adjusted for maternal age, pre-pregnancy BMI, and maternal smoking during pregnancy. All P-values are two-tailed, and P-values <0.05 were considered statistically significant. All analyses were conducted with the use of the statistical package SPSS (version 23.0; Armonk, NY: IBM Corp).

RESULTS

Prevalence and maternal characteristicsOGTT data were collected from 10,642 pregnant women with GDM risk factors or signs suggestive of GDM. The prevalence of GDM in the total cohort was 22% (n=2,341) when the WHO-1999 criteria were applied and 31% (n=3,299) when the

Chapter 7

128


129

7

WHO-2013 criteria were applied. In total 61% of women classified on the WHO-2013 criteria were diagnosed solely on the FG, while only 1% of those classified with WHO-1999 criteria were diagnosed solely on the FG.

The characteristics of the women in the different GDM classification groups are presented in Table 1. Characteristics and pregnancy outcomes were collected for 4,431 women who had singleton pregnancies. The fasting and two-hour post-load values of these 4,431 women were similar to the values obtained for the other 6,211 complete 75-gram OGTTs. Treatment for GDM was only given to women diagnosed according to the WHO-1999 criteria (FG ≥7.0 and/or 2HG ≥7.8 mmol/l), since a WHO-2013-based GDM classification was only assigned retrospectively to GDM-negative women diagnosed using WHO-1999 criteria. Compared with women in the NGT group, women classified as having GDM (using the WHO-2013 criteria, WHO-1999 criteria or both) were older, had a higher pre-pregnancy BMI, and were more likely to be multiparous and to have chronic hypertension.

A total of 667 women were retrospectively classified as having GDM based only on the FG cut-off of the WHO-2013 criteria (≥5.1-≤6.9 mmol/l). Compared with women in the NGT group, women in this group were older, had a higher pre-pregnancy BMI (29.1 [IQR 24.8-33.5] vs. 25.2 [IQR 22.0-30.4] kg/m2, p <0.001), were more likely to be obese (46.1% vs. 28.1%, p <0.001), to have smoked during pregnancy (13.2% vs. 10.5%, p=0.05) and to have chronic hypertension (3.3% vs. 1.2%, p <0.001).

A total of 234 women were retrospectively classified as having GDM based only on the 2HG cut-off of the WHO-1999 criteria (≥7.8-≤8.4 mmol/l). These women were all treated for GDM, 79.5% with diet-only and 20.5% with additional insulin therapy. Compared with women in the NGT, women in this group were older, had a slightly higher pre-pregnancy BMI (26.4 [IQR 23.3-30.4] vs. 25.2 [IQR 22.0-30.4] kg/m2, p=0.01), were more likely to be overweight (33.9% vs. 23.0%, p <0.001) and had higher rates of chronic hypertension (3.0% vs. 1.2%, p <0.001).

Pregnancy outcomesMaternal and neonatal outcomes according to the different GDM classification groups are given in Table 2 and Table 3. Compared with women in the NGT group, women classified as having GDM (using the WHO-2013 criteria, WHO-1999 criteria or both) were more likely to develop gestational hypertension or preeclampsia and to have had a planned CS delivery or induced labour.

Compared with women in the NGT group, women classified as having GDM based only on the FG cut-off of the WHO-2013 criteria were more likely to have gestational hypertension (7.8% vs. 4.9%, OR 1.65;CI 1.19-2.30), to have a planned CS (10.3% vs. 6.5%, OR 1.64;CI 1.23-2.20) and induced labour (34.8% vs. 28.0%, p <0.001). After multivariable adjustment, there were no significant differences for

Chapter 7

128


129

7

TAB

LE 1

. M

ater

nal c

hara

cter

istic

s ac

cord

ing

to th

e G

DM

cla

ssifi

catio

n gr

oups

.

Crit

eria

(m

mol

/l)

NG

TBo

th c

rite

ria

GD

MW

HO

-201

3W

HO

-199

9W

HO

-201

3 on

ly

FGW

HO

-199

9 on

ly

2HG

FG <

5.1

and

2HG

<7.

8FG

≥5.

1 or

2HG

≥7.

8FG

≥5.

1 an

d/or

2HG

≥8.

5FG

≥7.

0 an

d/or

2HG

≥7.

8FG

≥5.

1-≤6

.9 a

nd2H

G <

7.8

FG <

5.1

and

2HG

≥7.

8-≤8

.4

Char

acte

rist

ics

N

N44

3128

5115

8013

4691

366

723

4

Trea

ted

for G

DM

, n (%

)

Die

t

Addi

tiona

l ins

ulin

ther

apy

0 052

4 (3

3.2)

389

(24.

6)33

8 (2

5.1)

341

(25.

3)52

4 (5

7.4)

389

(42.

6)0 0

186

(79.

5)48

(20.

5)

Age

(yea

rs)

4431

30.7

± 4

.931

.9 ±

5.1

***

32.0

± 5

.2**

*32

.1 ±

5.1

***

31.6

± 5

.2**

*31

.6 ±

4.5

**

Pre-

preg

nanc

y BM

I (kg

/m2 )

4196

25.2

[22.

0-30

.4]

28.3

[24.

4-32

.5]**

*28

.7 [2

4.5-

32.9

]***

27.7

[24.

1-31

.8]**

*29

.1 [2

4.8-

33.5

]***

26.4

[23.

3-30

.4]**

Pre-

preg

nanc

y BM

I, n

(%)

<2

5 kg

/m2

25

-30

kg/m

2

≥3

0 kg

/m2

4196

1311

(48.

8)61

8 (2

3.0)

755

(28.

1)

***

452

(29.

9)

443

(29.

3)61

7 (4

0.8)

***

366

(28.

5)

365

(28.

4)55

1 (4

2.9)

***

285

(32.

0)

276

(30.

9)33

1 (3

7.1)

***

167

(26.

9)

167

(26.

9)28

6 (4

6.1)

***

86 (3

7.4)

78 (3

3.9)

66 (2

8.7)

Ethn

icity

, n (%

)

Cauc

asia

n

Asi

an

Afr

ican

-Am

eric

an

Med

iterr

anea

n

Oth

er

4431

2211

(77.

6)16

0 (5

.6)

150

(5.3

)20

7 (7

.3)

123

(4.3

)

1238

(78.

4)86

(5.4

)85

(5.4

)11

5 (7

.3)

56 (3

.5)

1060

(78.

8)62

(4.6

)78

(5.8

)95

(7.1

)51

(3.8

)

*

719

(78.

8)

65 (7

.1)

37 (4

.1)

68 (7

.4)

24 (2

.6)

*

519

(77.

8)

21 (3

.1)

48 (7

.2)

47 (7

.0)

32 (4

.8)

*

178

(76.

1)

24 (1

0.3)

7 (3

.0)

20 (8

.5)

5 (2

.1)

Nul

lipar

ous,

n (%

)44

3112

81 (4

4.9)

623

(39.

4)**

*52

3 (3

8.9)

***

373

(40.

9)*

250

(37.

5)**

*10

0 (4

2.7)

Chro

nic

hype

rten

sion

, n (%

)44

2734

(1.2

)59

(3.7

)***

52 (3

.9)**

*37

(4.1

)***

22 (3

.3)**

*7

(3.0

)*

Smok

ing

durin

g pr

egna

ncy,

n (%

)43

8129

6 (1

0.5)

188

(12.

0)16

5 (1

2.4)

101

(11.

1)87

(13.

2)*

23 (9

.8)

Abbr

evia

tions

: BM

I, bo

dy m

ass

inde

x; F

G, f

astin

g gl

ucos

e le

vel;

GD

M, g

esta

tiona

l dia

bete

s m

ellit

us; N

GT;

nor

mal

glu

cose

tole

ranc

e; W

HO

, Wor

ld H

ealth

Org

aniz

atio

n; 2

HG

, 2-

hour

glu

cose

leve

l. D

ata

are

expr

esse

d as

mea

n ±

SD, m

edia

n [IQ

R] o

r pro

port

ion

of n

(%).

P-va

lues

wer

e ba

sed

on S

tude

nt’s

unpa

ired

t-te

st (n

on-s

kew

ed c

ontin

uous

var

iabl

es),

Man

n-W

hitn

ey U

test

(ske

wed

con

tinuo

us v

aria

bles

), or

Chi

-squ

are

test

/Fis

her’s

exa

ct te

st.

* P<0.

05, **

P<0.

01, **

* P<0.

001

com

pare

d w

ith N

GT

grou

p.

Chapter 7

130


131

7

gestational hypertension (adjusted OR 1.38; CI 0.96-197) and planned CS (adjusted OR 1.36; CI 0.98-1.88) between this group and the NGT group.

Women with GDM classified as having GDM based only on the 2HG cut-off of the WHO-1999 criteria were more likely to have induced labour (62.8% vs. 28.0%, p <0.001) compared with women in the NGT group. There were no significant differ-ences in gestational hypertension, preeclampsia and mode of delivery between this group and the NGT group.

Neonates from mothers classified as having GDM (using the WHO-2013 criteria, WHO-1999 criteria or both) had a lower birth weight, a lower gestational age at delivery and were less likely to have macrosomia compared with those from moth-ers in the NGT group. However, the likelihood of these neonates being born LGA did not differ significantly from that of neonates in the NGT group. The likelihood of these neonates being born SGA was lower than that of neonates in the NGT group. Moreover, neonates from mothers classified as having GDM (using the WHO-2013 criteria, WHO-1999 criteria or both) were more likely to have been admitted to the neonatology department compared to those from mothers in the NGT group.

Compared with neonates from mothers in the NGT group, neonates from moth-ers classified as having GDM based only on the FG cut-off of the WHO-2013 criteria had no differences in terms of birth weight (3580 g vs. 3544 g), nor in their likeli-hood of having foetal macrosomia (22.2% vs. 20.9%, adjusted OR 1.07;CI 0.85-1.34) or being born LGA (21.0% vs. 18.0%, adjusted OR 1.22;CI 0.97-1.53). However, these neonates were more likely to have had an Apgar score <7 after 5 min (4.4% vs. 2.6%, P=0.015) and to have been admitted to the neonatology department (15.0% vs. 11.0%, p=0.004). None of the other neonatal outcomes showed significant differ-ences between these two groups.

Compared with neonates from mothers in the NGT group, neonates from moth-ers classified as having GDM based only on the 2HG cut-off of the WHO-1999 criteria had a lower birth weight (3437 g vs. 3544 g, p=0.01) and were less likely to have foetal macrosomia (12.8% vs. 20.9%, adjusted OR 0.57; CI 0.38-0.85). The likelihood of these neonates being born LGA was not significantly different from that in the NGT group (15.4% vs. 18.0%, adjusted OR 0.86; CI 0.59-1.24). However, 20.5% of the women in this group were treated with insulin therapy. None of the other neonatal outcomes showed significant differences between these two groups.

When we compared the percentage of LGA neonates in our data with those found in the general obstetric population in the north of the Netherlands (11%), we found that all GDM classification groups as well as the NGT group had a higher percentage of LGA neonates.

Chapter 7

130


131

7

TAB

LE 2

. Pr

egna

ncy

outc

omes

acc

ordi

ng to

the

GD

M c

lass

ifica

tion

grou

ps.

Gen

eral

ob

stet

ric

popu

lati

on

in th

e no

rth

of th

e N

ethe

rlan

dsCr

iter

ia

(mm

ol/l)

NG

TBo

th c

rite

ria

GD

MW

HO

-201

3W

HO

-199

9W

HO

-201

3 on

ly

FGW

HO

-199

9 on

ly

2HG

FG <

5.1

and

2HG

<7.

8FG

≥5.

1 or

2HG

≥7.

8FG

≥5.

1 an

d/or

2HG

≥8.

5FG

≥7.

0 an

d/or

2HG

≥7.

8FG

≥5.

1-≤6

.9 a

nd2H

G <

7.8

FG <

5.1

and

2HG

≥7.

8-≤8

.4

Preg

nanc

y ou

tcom

esN

N29

,562

4431

2851

1580

1346

913

667

234

Trea

ted

for G

DM

, n0

913

679

913

023

4

Mat

erna

l

Ges

tatio

nal h

yper

tens

ion,

n (%

)44

2713

9 (4

.9)

114

(7.2

)**98

(7.3

)**62

(6.8

)*52

(7.8

)**16

(6.9

)

Pree

clam

psia

, n (%

)44

2741

(1.4

)40

(2.5

)**35

(2.6

)**28

(3.1

)**12

(1.8

)5

(2.1

)

Indu

ctio

n of

labo

ur, n

(%)

4405

793

(28.

0)81

7 (5

1.9)

***

670

(50.

0)**

*58

7 (6

4.3)

***

230

(34.

8)**

147

(62.

8)**

*

Mod

e of

del

iver

y, n

(%)

Va

gina

l

Emer

genc

y CS

Pl

anne

d CS

In

stru

men

tal

4410

2051

(72.

3)32

7 (1

1.5)

185

(6.5

)27

2 (9

.6)

1069

(67.

9)**

205

(13.

0)17

1 (1

0.9)

***

130

(8.3

)

904

(67.

4)**

177

(13.

2)15

0 (1

1.2)

***

110

(8.2

)

618

(67.

7)**

116

(12.

7)10

3 (1

1.3)

***

76 (8

.3)

451

(68.

1)*

89 (1

3.4)

68 (1

0.3)

**

54 (8

.2)

165

(70.

5)28

(12.

0)21

(9.0

)20

(8.5

)

Ges

tatio

nal a

ge a

t del

iver

y (w

ks)

4431

39.7

[38.

7-40

.6]

38.6

[38.

0-39

.9]**

*38

.7 [3

8.0-

39.9

]***

38.3

[38.

0-39

.0]**

*39

.6 [3

8.3-

40.4

]***

38.6

[38.

1-39

.4]**

*

Neo

nata

l

Larg

e fo

r ges

tatio

nal a

ge, n

(%)

3246

(11.

0)44

3051

4 (1

8.0)

307

(19.

4)27

1 (2

0.1)

167

(18.

3)14

0 (2

1.0)

36 (1

5.4)

Mac

roso

mia

, n (%

)42

75 (1

4.5)

4431

595

(20.

9)25

6 (1

6.2)

***

226

(16.

8)**

108

(11.

8)**

*14

8 (2

2.2)

30 (1

2.8)

**

Smal

l for

ges

tatio

nal a

ge, n

(%)

2364

(8.0

)44

3019

5 (6

.8)

74 (4

.7)*

69 (5

.1)*

36 (3

.9)**

38 (5

.7)

5 (2

.1)**

Birt

h w

eigh

t (g)

4431

3544

± 5

7934

71 ±

578

***

3477

± 5

90**

3391

± 5

50**

*35

80 ±

596

3437

± 4

98**

Birt

h tr

aum

a, n

(%)

4420

64 (2

.3)

47 (3

.0)

43 (3

.2)

27 (3

.0)

20 (3

.0)

4 (1

.7)

Hyp

ogly

caem

ia, n

(%)a

4418

NA

NA

NA

38 (4

.2)**

*N

A4

(1.7

)

Hyp

erbi

lirub

inae

mia

, n (%

)a44

18N

AN

AN

A24

(2.6

)**N

A5

(2.1

)

Still

birt

h, n

(%)

4431

10 (0

.4)

6 (0

.4)

6 (0

.4)

2 (0

.2)

4 (0

.6)

0

Chapter 7

132


133

7

TAB

LE 2

. Pr

egna

ncy

outc

omes

acc

ordi

ng to

the

GD

M c

lass

ifica

tion

grou

ps. (

cont

inue

d)

Gen

eral

ob

stet

ric

popu

lati

on

in th

e no

rth

of th

e N

ethe

rlan

dsCr

iter

ia

(mm

ol/l)

NG

TBo

th c

rite

ria

GD

MW

HO

-201

3W

HO

-199

9W

HO

-201

3 on

ly

FGW

HO

-199

9 on

ly

2HG

FG <

5.1

and

2HG

<7.

8FG

≥5.

1 or

2HG

≥7.

8FG

≥5.

1 an

d/or

2HG

≥8.

5FG

≥7.

0 an

d/or

2HG

≥7.

8FG

≥5.

1-≤6

.9 a

nd2H

G <

7.8

FG <

5.1

and

2HG

≥7.

8-≤8

.4

Pret

erm

del

iver

y, n

(%)

4431

146

(5.1

)10

3 (6

.5)

92 (6

.8)*

57 (6

.2)

46 (6

.9)

11 (4

.7)

Resp

irato

ry s

uppo

rt, n

(%)

4418

116

(4.1

)61

(3.9

)51

(3.8

)34

(3.7

)27

(4.1

)10

(4.3

)

Apg

ar s

core

<7

at 5

min

, n (%

)44

1474

(2.6

)59

(3.7

)*57

(4.3

)**30

(3.3

)29

(4.4

)*2

(0.9

)

Adm

issi

on to

neo

nato

logy

, n (%

)44

2331

5 (1

1.1)

230

(14.

6)**

206

(15.

3)**

*13

0 (1

4.2)

*10

0 (1

5.0)

**24

(10.

3)

Abbr

evia

tions

: CS,

cae

sare

an se

ctio

n; F

G, f

astin

g gl

ucos

e; G

DM

, ges

tatio

nal d

iabe

tes m

ellit

us; N

GT,

nor

mal

glu

cose

tole

ranc

e; W

HO

, Wor

ld H

ealth

Org

aniz

atio

n; 2

HG

, 2-h

glu

-co

se.

Dat

a ar

e ex

pres

sed

as m

ean

± SD

, med

ian

[IQR]

or p

ropo

rtio

n of

n (%

). P-

valu

es w

ere

base

d on

Stu

dent

’s un

paire

d t-

test

(non

-ske

wed

con

tinuo

us v

aria

bles

), M

ann-

Whi

tney

U

test

(ske

wed

cont

inuo

us v

aria

bles

), or

Chi

-squ

are

test

/Fis

her’s

exa

ct te

st. * P<

0.05

, **P<

0.01

, *** P<

0.00

1 co

mpa

red

with

NG

T gr

oup.

a D

ata

wer

e co

llect

ed in

prim

ary

care

(mid

wiv

es) a

nd se

cond

ary

care

(hos

pita

l). In

prim

ary

care

neo

nata

l hyp

ogly

caem

ia a

nd h

yper

bilir

ubin

aem

ia w

ere

not r

epor

ted

and

mea

-su

red

in a

ll pr

egna

ncie

s. Th

eref

ore

we

only

repo

rted

the

perc

enta

ge fo

r the

WH

O-1

999

grou

p, a

ll th

ese

wom

en d

eliv

ered

in se

cond

ary

care

.

Chapter 7

132


133

7

TAB

LE 3

. O

dss

ratio

’s fo

r pre

gnan

cy o

utco

mes

acc

ordi

ng to

the

GD

M c

lass

ifica

tion

grou

ps.

Crit

eria

(m

mol

/l)

NG

TBo

th c

rite

ria

GD

MW

HO

-201

3W

HO

-199

9W

HO

-201

3 on

ly

FGW

HO

-199

9 on

ly

2HG

FG <

5.1

and

2HG

<7.

8FG

≥5.

1 or

2HG

≥7.

8FG

≥5.

1 an

d/or

2HG

≥8.

5FG

≥7.

0 an

d/or

2HG

≥7.

8FG

≥5.

1-≤6

.9 a

nd2H

G <

7.8

FG <

5.1

and

2HG

≥7.

8-≤8

.4

Preg

nanc

y ou

tcom

es

N28

5115

8013

4691

366

723

4

Trea

ted

for G

DM

, n0

913

679

913

023

4

Larg

e fo

r ges

tatio

nal a

ge N

o. o

f cas

es, n

(%)

Una

djus

ted

OR

Mul

tivar

iabl

e-ad

just

ed O

R a

514

(18.

0)1.

00 (R

ef)

1.00

(Ref

)

307

(19.

4)1.

10 (0

.94-

1.28

)1.

10 (0

.93-

1.30

)

271

(20.

1)1.

15 (0

.97-

1.35

)1.

14 (0

.96-

1.36

)

167

(18.

3)1.

02 (0

.84-

1.23

)1.

02 (0

.83-

1.25

)

140

(21.

0)1.

21 (0

.98-

1.49

)1.

22 (0

.97-

1.53

)

36 (1

5.4)

0.83

(0.5

7-1.

19)

0.86

(0.5

9-1.

24)

Mac

roso

mia

N

o. o

f cas

es, n

(%)

Una

djus

ted

OR

Mul

tivar

iabl

e-ad

just

ed O

R

595

(20.

9)1.

00 (R

ef)

1.00

(Ref

)

256

(16.

2)0.

73 (0

.62-

0.86

)***

0.71

(0.6

0-0.

85)**

*

226

(16.

8)0.

77 (0

.65-

0.91

)**

0.73

(0.6

1-0.

88)**

108

(11.

8)0.

51 (0

.41-

0.63

)***

0.50

(0.4

0-0.

63)**

*

148

(22.

2)1.

08 (0

.88-

1.33

) 1.

07 (0

.85-

1.34

)

30 (1

2.8)

0.56

(0.3

8-0.

83)**

0.57

(0.3

8-0.

85)**

Ges

tatio

nal h

yper

tens

ion

No.

of c

ases

, n (%

) U

nadj

uste

d O

R M

ultiv

aria

ble-

adju

sted

OR

139

(4.9

)1.

00 (R

ef)

1.00

(Ref

)

114

(7.2

)1.

52 (1

.18-

1.96

)**

1.35

(1.0

3-1.

77)*

98 (7

.3)

1.53

(1.1

7-2.

00)**

1.33

(1.0

0-1.

77)*

62 (6

.8)

1.42

(1.0

5-1.

94)*

1.29

(0.9

4-1.

79)

52 (7

.8)

1.65

(1.1

9-2.

30)**

1.38

(0.9

6-1.

97)

16 (6

.9)

1.44

(0.8

4-2.

46)

1.40

(0.8

1-2.

42)

Pree

clam

psia

No.

of c

ases

, n (%

) U

nadj

uste

d O

R M

ultiv

aria

ble-

adju

sted

OR

41 (1

.4)

1.00

(Ref

)1.

00 (R

ef)

40 (2

.5)

1.78

(1.1

5-2.

77)*

1.80

(1.1

2-2.

88)*

35 (2

.6)

1.83

(1.1

6-2.

89)**

1.82

(1.1

2-2.

97)*

28 (3

.1)

2.17

(1.3

3-3.

53)**

2.20

(1.3

1-3.

68)**

12 (1

.8)

1.26

(0.6

6-2.

41)

1.20

(0.6

0-2.

38)

5 (2

.1)

1.50

(0.5

9-3.

84)

1.59

(0.6

1-4.

12)

Plan

ned

CS N

o. o

f cas

es, n

(%)

Una

djus

ted

OR

Mul

tivar

iabl

e-ad

just

ed O

R

185

(6.5

)1.

00 (R

ef)

1.00

(Ref

)

171

(10.

9)1.

75 (1

.40-

2.17

)***

1.47

(1.1

6-1.

86)**

150

(11.

2)1.

80 (1

.44-

2.26

)***

1.52

(1.1

9-1.

94)**

103

(11.

3)1.

82 (1

.41-

2.35

)***

1.51

(1.1

5-1.

98)**

68 (1

0.3)

1.64

(1.2

3-2.

20)**

1.36

(0.9

8-1.

88)

21 (9

.0)

1.41

(0.8

8-2.

27)

1.32

(0.8

2-2.

16)

Abbr

evia

tions

: CS,

cae

sare

an se

ctio

n; F

G, f

astin

g gl

ucos

e; G

DM

, ges

tatio

nal d

iabe

tes m

ellit

us; N

GT,

nor

mal

glu

cose

tole

ranc

e; W

HO

, Wor

ld H

ealth

Org

aniz

atio

n; 2

HG

, 2-h

glu

-co

se.

OR,

95%

confi

denc

e in

terv

als,

and

P-va

lues

wer

e de

rived

from

logi

stic

regr

essi

on m

odel

s.* P<0.

05, **

P<0.

01, **

* P<0.

001c

ompa

red

with

NG

T gr

oup

(refe

renc

e po

pula

tion)

.M

ultiv

aria

ble

adju

stm

ent i

nclu

ded

mat

erna

l age

, pre

-ges

tatio

nal b

ody

mas

s ind

ex, e

thni

city

, par

ity a

nd m

ater

nal s

mok

ing.

a La

rge

for g

esta

tiona

l age

was

adj

uste

d fo

r mat

erna

l age

, pre

-ges

tatio

nal b

ody

mas

s ind

ex a

nd m

ater

nal s

mok

ing.

Chapter 7

134

Extrapolation of data on birth weight and prevalence of LGA neonatesFigure 1 and suppl. Table 2 illustrate the two models in which we predicted the possible influence of diet-only or diet plus insulin therapy on birth weight and prevalence of LGA neonates. In the WHO-1999 group, 57.4% of the women were treated with diet-only and 42.6% with additional insulin. In the group of women classified as having GDM based only on the 2HG cut-off of the WHO-1999 criteria, 79.5% of the women were treated with diet-only and 20.5% with additional insulin. Women classified as having GDM based only on the FG cut-off of the WHO-2013 criteria were not treated for GDM.

Both models predicted that non-treatment would significantly increase the percentage of LGA neonates in the WHO-1999 group. Model 1 predicted an increase from 19.5% to 27.9% for those women in the diet-only group, and from 16.7% to 29.6% for those in the insulin group. Model 2 predicted an increase from 19.5% to 35.7% in the diet-only group and from 16.7% to 48.3% in the insulin. For the group of women classified as having GDM based exclusively on the 2HG cut-off of the WHO-1999 criteria, non-treatment was also estimated to result in an increase in the percentage of LGA neonates. Overall, withholding treatment would double the percentage of LGA neonates. Moreover, Model 1 and Model 2 both estimated that for women with GDM based only on the FG cut-off of the WHO-2013, treatment would reduce the percentage of LGA neonates.

FIGURE 1. Prevalence of LGA-neonates and the estimated changes in LGA prevalence according to non-treatment and treatment.Abbreviations: WHO, World Health Organization; 2HG, 2-hour glucose level; FG fasting glucose level; LGA, large for gestational age. Data are expressed as proportion (%). Detailed explanation of the categories and models are given in Supplemental Table 1.


135

7

DISCUSSION

This large retrospective cohort study to evaluate the possible impact on GDM prevalence and pregnancy outcomes of applying the new WHO-2013 criteria dem-onstrates that GDM prevalence would increase from 22% to 31%, relative to the WHO-1999 criteria. We also show that applying these new criteria indeed identifies a new group of women (FG ≥5.1-≤6.9 mmol/l) who have unfavourable character-istics and more adverse pregnancy outcomes when compared either with women otherwise found to be normal glucose tolerance upon screening or with the general obstetric population. Our results show that women potentially missed due to the higher 2HG cut-off (2HG ≥7.8-≤8.4 mmol/l) of the WHO-2013 criteria have similar pregnancy outcomes to NGT women. Our results also indicate that neonates from mothers who are screened for GDM but are found to have normal glucose tolerance (NGT group) are more likely to be born large for gestational age or with macrosomia than those born to mothers in the general obstetric population in our region.

Strengths and limitationsA major strength of our study is the relatively large cohort of laboratory results of 75-gram OGTTs and the extensive and detailed information regarding pregnancy outcomes in a subset of 4,431 women with singleton pregnancies. All women with GDM were treated according to a detailed protocol in two large hospitals.14,15 Ma-ternal and pregnancy outcome data were collected manually from patient’s charts at their midwifes offices. This study also has limitations that should be noted. First, since universal screening for GDM is not currently recommended in the Nether-lands, only women with one or more risk factors for GDM or signs suggestive of GDM such as macrosomia were screened. The prevalence of GDM found in our study is therefore not a reflection of the general obstetric population, and repre-sents a selected group of women at higher risk of GDM. Universal testing is now recommended in several countries around the world. However, controversy in the literature on the best method of screening (universal or risk-based) remains.8 Sec-ondly, the WHO-2013 criteria also recommend that GDM diagnosis should include a one-hour plasma glucose level of ≥10.0 mmol/l following a 75-g OGTT. Since we did not have data for one-hour glucose levels, the prevalence of GDM reported here may be an underestimation. Thirdly, all women diagnosed according the WHO-1999 criteria were offered GDM treatment. Fourthly, we have compared outcomes with those in the general population in the north of the Netherlands between 2011 and 2013. Unfortunately data after 2013 have not yet been made available from public datasets. Also, this dataset does not indicate which women were tested with an OGTT. Finally, the models that we constructed to try and estimate the birth weight

Chapter 7

136

that would have resulted if women classified as having GDM based on the WHO-1999 criteria had not been treated cannot predict other pregnancy and neonatal outcomes. It therefore remains unclear whether these women could safely have been left untreated.

Prevalence and maternal characteristicsSeveral authors have expressed concerns about the adoption of the WHO-2013 cri-teria, as this will significantly increase the prevalence of GDM, and impose a higher burden on healthcare provided by obstetricians.10,11 Numerous studies have shown that implementing the new WHO-2013 criteria will result in a 2-3 fold increase in the prevalence of GDM.9,11,17 The increase from 22% to 31% observed in our cohort of women at higher risk of GDM was mainly the result of an increase in the number of women who would be diagnosed on the basis of an elevated FG level (between 5.1 and 7.0 mmol/l). Despite this net increase, at the same time a number of women would not be diagnosed due to the higher 2HG cut-off of the WHO-2013 criteria.

Our study clearly demonstrated that the lower FG cut-off of the WHO-2013 criteria (FG ≥5.1-≤6.9 mmol/l) identifies a group of women who are more likely than NGT women to be obese (BMI >30 kg/m2) and hypertensive. Moreover, the women classified as having GDM based only on the 2HG cut-off of the WHO-1999 criteria (2HG ≥7.8-8.4) were also more likely than NGT women to be overweight (BMI >25 kg/m2). It is known that impaired FG (IFG; FG ≥5.6-≤6.9 mmol/l) and/or impaired glucose tolerance (IGT; 2HG ≥7.8-≤11.0 mmol/l) are both predictors for the future development of type 2 diabetes mellitus (T2DM).18 IFG and IGT are associated with an unfavourable metabolic profile, including obesity and hypertension. Both groups successfully identify a group of high-risk women with an adverse metabolic profile.

Pregnancy outcomesAlthough uncertainty remains regarding the optimal glucose threshold used to de-fine GDM, hyperglycaemia during pregnancy is clearly associated with an increased risk of adverse pregnancy outcomes.6 Indeed, women in this study classified as hav-ing GDM by any criteria had higher rates of adverse maternal outcomes, including hypertensive disorders during pregnancy, planned CS and induced labour when compared with NGT women. Moreover, the neonates of mothers classified as having GDM by any criteria were likely to have been admitted to the neonatology department.

Concerns have been raised about the so-called medicalization of pregnancy should the new –more stringent – WHO-2013 criteria be used.10 Based on the WHO-1999 criteria currently applied in the Netherlands, these women are not diagnosed as having GDM and are therefore not treated with diet and/or insulin. However, our


137

7

findings suggest that despite not being diagnosed as having GDM, these women already have higher intervention rates. We demonstrated that, when compared with NGT women, the women classified as having GDM based only on the FG cut-off of the WHO-2013 criteria (≥5.1-≤6.9 mmol/l) had higher rates of gestational hypertension, planned CS and induced labour, and their neonates were more likely to have an Apgar score <7 at 5 min and to be admitted to the neonatology depart-ment compared with NGT women. These findings are consistent with those of other studies that found that women reclassified as having GDM based on the WHO-2013 criteria are at increased risk of adverse pregnancy outcomes, including gestational hypertension, caesarean section, neonatal intensive care admission, and LGA neo-nates.19-22

In terms of the likelihood of having an LGA neonate, we found no significant differences between the women classified as having GDM based on the FG cut-off of the WHO-2013 criteria and women in the NGT group. However, the percentage of women in this group having an LGA neonate was much higher than for the general obstetric population in the north of the Netherlands (21% versus 11%). Based on these findings, it seems that women classified with GDM based only on the FG cut-off of the WHO-2013 criteria should not be left untreated. The results of our model estimates indicate that treating these women with diet and/or insulin will reduce the percentage of LGA neonates by 2% to 8%. This prediction is supported by the results of a study by Landon et al., which suggests that early treatment in women with mild GDM reduces the percentage of women giving birth to LGA neonates by 7%.4

Our study has also shown that implementing the new WHO-2013 criteria with a higher 2HG cut-off may exclude a group of women who now benefit from treat-ment. The women classified as having GDM based only on the 2HG cut-off of the WHO-1999 criteria (≥7.8-≤8.4 mmol/l) had pregnancy outcomes similar to those of women in the NGT group. A notable finding was that they had the lowest rate of LGA neonates of all other diagnostic groups. The only obstetric parameter which differed with the NGT group was the rate of induced labour, but it has to be borne in mind that induction of labour at 38/39 weeks of gestation is more likely to be recommended in women being treated for GDM, especially those receiving insulin therapy.

All women classified as having GDM based on the WHO-1999 were actively treated with diet and/or insulin. These interventions normalized their glycaemic profile and the outcome findings for this group suggest that these interventions were indeed effective. Nevertheless, it is unclear whether these women can be safely left untreated after implementing the new WHO-2013 criteria. Indeed, our model estimates indicate that not treating these women with diet and/or insulin

Chapter 7

138

will increase the percentage of LGA neonates by 10% to 30%. These estimates are supported by a recent study by Farrar et al., who showed that even women with a two-hour post-load glucose level ≥7.5 mmol/l are at increased risk of adverse outcomes (i.e. birth weight >90th percentile, high infant adiposity, and caesarean section).23 These authors therefore recommend using a two-hour post-load glucose cut-off value even lower than that recommended by both WHO-1999 and WHO-2013 criteria.

A notable finding of our study is that the women in the NGT group who had undergone an OGTT for screening or diagnostic purposes and were subsequently found to be normal glucose tolerant – also had a rate of LGA neonates higher than that of the women receiving treatment after being diagnosed with GDM based on the 2HG cut-off of the WHO-1999 criteria (18.0% versus 15.4%). Although this finding was not statistically significant, it was a large difference compared with the incidence of LGA neonates in the general obstetric population (18% versus 11%). This coincidental finding shows that even women with a risk factor or signs sug-gestive of GDM and without a positive diagnosis of GDM are at increased risk of giving birth to an LGA neonate. This finding is agreement with a study by Meek et al., who demonstrated that women diagnosed and treated for GDM according to the National Institute for Health and Care Excellence (NICE) criteria in the United Kingdom had lower rates of LGA neonates than women negative for GDM according to both the NICE and IADPSG/WHO-2013 criteria.21 A possible explanation for this finding is that these women were screened too early in pregnancy and were there-fore not diagnosed with GDM at this screening test. Besides, studies have shown that the OGTT has a poor reproducibility, which means that some women who first test negative for GDM can test positive on a second test.24 We therefore agree with the suggestion made by Meek et al. that standard lifestyle interventions (including dietary advice) given to women with GDM might also benefit NGT women.

CONCLUSIONS

This large retrospective cohort study evaluated the possible impact on GDM preva-lence and pregnancy outcomes of applying the new WHO-2013 criteria, rather than the old WHO-1999 criteria. We demonstrated that the prevalence of GDM would increase markedly if the WHO-2013 criteria were implemented. Nevertheless, the FG cut-off of the WHO-2013 criteria (FG ≥5.1-≤6.9 mmol/l) identifies a group of women with an increased risk of pregnancy complications. We therefore recommend that to improve GDM outcomes the FG cut-off level in the Dutch national guideline needs to be adjusted. However, it is unclear from our data whether women with a 2HG level


139

7

between 7.8 and 8.5 mmol/l can be safely left untreated. Recent studies suggest that a post-load 2HG cut-off level of 7.5 mmol/l may be more appropriate. Future studies should evaluate whether a stricter post-GTT threshold further improves pregnancy outcomes. Such studies should also address pregnancy outcomes in women who are screened but found to be normal glucose tolerant.

Acknowledgements

The authors wish to thank the endocrinologists, gynaecologists, diabetes specialist nurses, and dieti-cians of the University Medical Center and Martini Hospital Groningen. Special thanks are expressed to the participating midwife practices: De Verloskundigenpraktijk van Groningen, Verloskundigenpraktijk Hoogezand, Verloskundigenpraktijk La Vie, Verloskundigenpraktijk New Life, Verloskundige Stadsprak-tijk, Verloskundigenpraktijk ‘t Stroomdal, Verloskundigenpraktijk Veendam. We would also like to thank H. Hepkema-Geerligs (customer relations manager Laboratory of Clinical Chemistry, Certe) and the students S. Klöppner and J. van Amstel for their contribution to the data collection. Finally, we thank epidemiologist H. Groen, the Dutch Perinatal Registry and the Municipal Health Service Groningen for providing the data on the reference population in the northern region of the Netherlands.

Chapter 7

140

REFERENCES

1. Langer O, Yogev Y, Most O, Xenakis EM. Gestational diabetes: The consequences of not treating. Obstet Gynecol. 2005;192:989-97.




5. International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger BE, Gabbe SG, et al. International Association of Diabetes and Pregnancy Study Groups recom-mendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33:676-82.


7. World Health Organization (WHO). Diagnostic criteria and Classification of Hyperglycemia First Detected in Pregnancy. 2013. Available from: http://apps.who.int/iris/bitstream/10665/85975/1/WHO_NMH_MND_13.2_eng.pdf, accessed 12 May 2017.

8. Benhalima K, Damm P, Van Assche A, et al. Screening for gestational diabetes in Europe: Where do we stand and how to move forward?: A scientific paper commissioned by the European board & college of obstetrics and gynaecology (EBCOG). Eur J Obstet Gynecol Reprod Biol. 2016;201:192-6.


10. Visser GHA, de Valk H,W. Is the evidence strong enough to change the diagnostic criteria for gestational diabetes now? Obstet Gynecol. 2013;208:260-4.

11. Cundy T, Ackermann E, Ryan EA. Gestational diabetes: New criteria may triple the prevalence but effect on outcomes is unclear. BMJ. 2014;11:348-g1567


13. The Dutch Society of Obstetrics and Gynaecology. Diabetes mellitus and Pregnancy. Clinical guideline version 2.0. 2010. Available from: http://www.nvog-documenten.nl/richtlijn/item/pagina.php?richtlijn_id=863, accessed 12 May 2017.





141

7

17. Agarwal MM. Gestational diabetes mellitus: An update on the current international diagnostic criteria. World J Diabetes. 2015;6:782-91.


19. Laafira A, White SW, Griffin CJ, Graham D. Impact of the new IADPSG gestational diabetes diagnos-tic criteria on pregnancy outcomes in western Australia. Aust N Z J Obstet Gynaecol. 2016;56:36-41.

20. Lapolla A, Dalfrà M, Ragazzi E, De Cata A, Fedele D. New international association of the diabetes and pregnancy study groups (IADPSG) recommendations for diagnosing gestational diabetes compared with former criteria: A retrospective study on pregnancy outcome. Diabet Med. 2011;28:1074-77.


22. O’Sullivan E, Avalos G, O’Reilly M, et al. Atlantic diabetes in pregnancy (DIP): The prevalence and outcomes of gestational diabetes mellitus using new diagnostic criteria. Diabetologia. 2011;54:1670-5.


24. Harlass FE, Brady K, Read JA. Reproducibility of the oral glucose tolerance test in pregnancy. Obstet Gynecol. 1991;164:564-8.

Chapter 7

142

SUPPLEMENTAL DATA

SUPPLEMENTAL TABLE 1. Explanation of the extrapolation models on birth weight and prevalence of LGA.

Criteria mmol/l

WHO-1999 WHO-1999 only 2HG WHO-2013 only FG

FG ≥7.0 and/or2HG ≥7.8

FG <5.1 and2HG ≥7.8-≤8.4

FG ≥5.1-≤6.9 and2HG <7.8

Treatment In the current national guideline women classified as having GDM according to the WHO-1999 criteria are treated for GDM with diet (“diet-only group“) or with diet + insulin when diet-only fails (“insulin group”).

In the current national guideline women classified as having GDM according the WHO-2013 only FG are not treated for GDM

This category indicated the birth weight and prevalence of LGA neonates observed in this group of women currently treated with diet-only or diet + insulin.

This category indicated the birth weight and prevalence of LGA neonates observed in this group of women currently not-treated.

Since these women were treated with diet-only and/or insulin these groups cannot be directly compared with women who were not offered treatment. Therefore, in model 1 and 2 we predicted the birth weight and prevalence of LGA neonates if their mothers had not been treated for GDM.

Since these women were not treated with diet-only and/or insulin this group cannot be directly compared with women who were offered treatment.Therefore, in model 1 and 2 we predicted the birth weight and prevalence of LGA neonates if their mothers had been treated for GDM.

Model 1a Hypothetical effect on birth weight: Hypothetical effect on birth weight:

Diet+ 100 gram

Diet + Insulin + 200 gram

Diet-50 gram

Diet + Insulin-100 gram

Model 2a Hypothetical effect on birth weight: Hypothetical effect on birth weight:

Diet+ 200 gram

Diet + Insulin+ 400 gram

Diet -100 gram

Diet + Insulin- 200 gram

Abbreviations: GDM, gestational diabetes mellitus; WHO, World Health Organization; 2HG, 2-hour glucose level; FG fasting glucose level; LGA, large for gestational age.

a The models were not corrected for a possible effect that a higher birth weight may lead to earlier start of deliv-ery. However, most of the women delivered between 38-39 weeks of gestation.


143

7

SUPP

LEM

ENTA

L TA

BLE

2.

Estim

ated

cha

nges

in b

irth

wei

ght a

nd L

GA

pre

vale

nce

acco

rdin

g to

non

-tre

atm

ent a

nd tr

eatm

ent.

Crit

eria

m

mol

/l

WH

O-1

999

WH

O-1

999

only

2H

GW

HO

-201

3 on

ly

FG

FG ≥

7.0

and/

or2H

G ≥

7.8

FG <

5.1

and

2HG

≥7.

8-≤8

.4FG

≥5.

1-≤6

.9 a

nd2H

G <

7.8

N91

323

466

7

N (%

)Tr

eatm

ent

Die

t52

4 (5

7.4)

Die

t + In

sulin

389

(42.

6)D

iet

186

(79.

5)D

iet +

Insu

lin48

(20.

5)no

t tre

ated

Birt

h w

eigh

t, gr

am34

38 ±

556

3328

± 5

3734

71 ±

524

3304

± 3

4935

80 ±

596

Larg

e fo

r ges

tatio

nal a

ge, n

(%)a

102

(19.

5)65

(16.

7)32

(17.

2)4

(8.3

)14

0 (2

1.0)

Ges

tatio

nal a

ge, w

ks38

.7 [3

8.1-

39.7

]38

.1 [3

8.0-

38.4

]38

.8 [3

8.1-

39.7

]38

.1 [3

8.0-

38.4

]39

.6 [3

8.3-

40.4

]

Mod

el 1

bN

o tr

eatm

ent

+ 10

0 gr

amN

o tr

eatm

ent

+ 20

0 gr

amN

o tr

eatm

ent

+ 10

0 gr

amN

o tr

eatm

ent

+ 20

0 gr

am T

reat

men

t die

t-5

0 gr

amTr

eatm

ent d

iet +

insu

lin- 1

00 g

ram

Birt

h w

eigh

t, gr

am35

38 ±

556

3528

± 5

3735

71 ±

524

3504

± 3

4935

30 ±

596

3480

± 5

96

Larg

e fo

r ges

tatio

nal a

ge, n

(%)a

146

(27.

9)11

5 (2

9.6)

51 (2

7.4)

9 (1

8.8)

127

(19.

0)11

5 (1

7.2)

Mod

el 2

bN

o tr

eatm

ent

+ 20

0 gr

amN

o tr

eatm

ent

+ 40

0 gr

amN

o tr

eatm

ent

+ 20

0 gr

amN

o tr

eatm

ent

+ 40

0 gr

am T

reat

men

t die

t-1

00 g

ram

Trea

tmen

t die

t + in

sulin

- 200

gra

m

Birt

h w

eigh

t, gr

am36

38 ±

556

3728

± 5

3736

71±

524

3704

± 3

4934

80 ±

596

3380

± 5

96

Larg

e fo

r ges

tatio

nal a

ge, n

(%)a

187

(35.

7)18

8 (4

8.3)

64 (3

4.4)

19 (3

9.6)

115

(17.

2)84

(12.

6)

Abbr

evia

tions

: WH

O, W

orld

Hea

lth O

rgan

izat

ion;

2H

G, 2

-hou

r glu

cose

leve

l; FG

fast

ing

gluc

ose

leve

l; LG

A, la

rge

for g

esta

tiona

l age

. D

ata

are

expr

esse

d as

mea

n ±

SD, m

edia

n [IQ

R] o

r pro

port

ion

of n

(%).

a Bi

rth

wei

ght >

90th

per

cent

ile, c

orre

cted

for g

esta

tiona

l age

, gen

der n

eona

te, p

arity

and

eth

nic

back

grou

nd.

b Det

aile

d ex

plan

atio

n of

the

cate

gorie

s and

mod

els a

re g

iven

in S

uppl

emen

tal T

able

1.

8 Pregnancy outcomes in women with gestational diabetes mellitus diagnosed according to the WHO-2013 and WHO-1999 diagnostic criteria: a multicentre retrospective cohort study

Goedegebure EAR*, Koning SH*, Hoogenberg K, Korteweg FJ, Lutgers HL, Diekman MJM, Stekkinger E, van den Berg PP, Zwart JJ

* Contributed equally

Submitted

CHAPTER 8

146

ABSTRACT

Background: The World Health Organization (WHO) adopted more stringent diag-nostic criteria for GDM in 2013, to improve pregnancy outcomes. However, there is no global consensus on these new diagnostic criteria, because of limited evidence. The objective of the study was to evaluate maternal characteristics and pregnancy outcomes in two cohorts in the Netherlands applying different diagnostic criteria for GDM i.e. WHO-2013 and WHO-1999.

Methods: A multicenter retrospective study involving singleton GDM pregnancies in two regions, between 2011 and 2016. Women were diagnosed according to the WHO-2013 criteria in the Deventer region (WHO-2013-cohort) and according to the WHO-1999 criteria in the Groningen region (WHO-1999-cohort). After GDM diag-nosis, all women were treated equally based on the national guideline. Maternal characteristics and pregnancy outcomes were compared between the two groups.

Results: In total 1386 women with GDM were included in the study. Women in the WHO-2013-cohort were older and had a higher pre-gestational body mass index. They were also diagnosed earlier (24.9 [IQR 23.3-29.0] versus 27.7 [IQR 25.9-30.7] weeks, p=<0.001) and less women were treated with additional insulin therapy (15.6% versus 43.4%, p=<0.001). Rate of spontaneous delivery was higher in the WHO-2013-cohort (73.1% versus 67.4%, p=0.032) and the percentage large-for-gestational-age (LGA) neonates (birth weight >90th percentile, corrected for sex, ethnicity, parity, and gestational age) was lower in this cohort (16.5% versus 18.5%, p=0.026). There were no differences between the cohorts regarding stillbirth, birth trauma, low Apgar score, and preeclampsia.

Conclusion: Using the new WHO-2013 criteria resulted in an earlier GDM diagnosis and lower prevalence of LGA neonates. Less women needed insulin treatment and more spontaneous deliveries occurred when compared to the cohort diagnosed with WHO-1999 criteria. No differences were found in adverse pregnancy outcomes.

Outcomes in GDM applying different diagnostic criteria

147

8

BACKGROUND

Gestational diabetes mellitus (GDM) is defined as glucose intolerance detected during pregnancy.1 The prevalence of GDM is increasing and affects between 1% and 14% of all pregnancies, caused by a global increase in the number of women with obesity around reproductive age and by more stringent diagnostic criteria for GDM.1-4 Untreated GDM is associated with an increased rate of neonatal and ob-stetric complications.5-7 Adverse pregnancy outcomes have been shown to improve with an early diagnosis and treatment of GDM.8,9

In 2008, the international prospective Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) study group demonstrated a continuous association between maternal hyperglycaemia and risk of adverse pregnancy outcomes, as birth weight greater than the 90th percentile, caesarean section, premature birth, birth injury, and preeclampsia.10 Based on these findings and earlier observational studies, the International Association of Diabetes and Pregnancy Study Group (IADPSG) pro-posed more stringent diagnostic thresholds for GDM.11 These new diagnostic criteria (fasting plasma glucose level ≥5.1 mmol/l; and/or 1-h plasma glucose level ≥10.0 mmol/l; and/or 2-h plasma glucose level ≥8.5 mmol/l) have been adopted by the American Diabetes Association in 2010, the World Health Organization (WHO) in 2013, and the International Federation of Gynaecology and Obstetrics in 2015.1,12,13

However, to date there is no global consensus on these new diagnostic criteria. A recent review on the current European situation showed a lack of consistency on GDM diagnosis.14 The apparent reluctance to adopt the IADPSG criteria may result from studies showing an increase in prevalence of GDM and thus a higher burden to obstetric healthcare providers,4,15 but most importantly from scepticism about the clinical benefit of lower diagnostic thresholds.15,16

Also in the Netherlands there is a debate regarding the diagnostic criteria for GDM. The Dutch Society of Obstetrics and Gynaecology guideline 2010 “Diabetes and Pregnancy’’ recommends screening for GDM in high-risk women using the 2-h 75-g oral glucose tolerance test (OGTT) using the WHO-1999 criteria, utilizing a fast-ing blood glucose ≥7.0 and 2-h blood glucose of ≥7.8 mmol/l.17,18 Notwithstanding that, a few hospitals in the Netherlands already implemented the new WHO-2013 thresholds for diagnosis of GDM.

In the current study, we evaluated maternal characteristics and obstetric and neonatal outcome in two cohorts in the Netherlands which applied different diag-nostic criteria for GDM i.e. WHO-2013 and WHO-1999.

CHAPTER 8

148

METHODS

Study PopulationA multicentre, retrospective cohort study was conducted involving three hospitals in the Netherlands (University Medical Center Groningen a tertiary care centre, Martini Hospital Groningen, and Deventer Hospital both secondary care centres). Both regions (Deventer region and Groningen region) are located in the relatively rural north-eastern part of the Netherlands. Part of the data of the Groningen region has been published previously.19,20 All pregnant women with diagnosis of GDM were eligible for inclusion in the study. Women with a twin pregnancy and women with pre-existing diabetes mellitus (DM) were excluded.

This study has been conducted in accordance with the guidelines of the Declara-tion of Helsinki and Good Clinical Practice. The patient data were retrospectively acquired from hospital records generated during care-as-usual. Statistical analysis was performed requiring patient anonymity in agreement with the ethics commit-tee regulations.21 According to the Dutch law on Medical Research with Human Subjects, this study has been exempted for approval by the local ethics committees.

Screening, diagnosis and treatment of GDM Criteria for screening and diagnosis of GDM are summarized in Figure 1.17,18

After GDM diagnosis, all women received dietary counselling and instructions for self-monitoring of the blood glucose levels (SMBG). According to the guideline, insulin therapy was started if the blood glucose levels were repeatedly above the treatment targets despite dietary treatment: fasting blood glucose level >5.3 mmol/l and/or either a 1-h postprandial blood glucose level >7.8 mmol/l, or 2-h postprandial blood glucose level >6.7 mmol/l. Options for insulin therapy regimens were: ultra-short-acting insulin, once daily long-acting insulin, or a combination of both (basal-bolus). Metformin was occasionally prescribed in obese women (body mass index (BMI) >30 kg/m2) in the Deventer hospital. Based on SMBG women were advised to adjust diet or increase insulin- or metformin dose to maintain blood glucose levels within the target range.

Women were seen at the obstetric outpatient clinic regularly and foetal growth was evaluated by ultrasonography at least every 4 weeks. Moreover, all patients were discussed every two to three weeks multidisciplinary. Labour was induced between 38 and 39 weeks of gestation in women on insulin therapy or earlier on indication. In women with a diet, labour was induced between 38 and 40 weeks taking glycaemic control, estimated foetal weight and non-GDM related risk factors into consideration.

Outcomes in GDM applying diff erent diagnostic criteria

149

8

FIGURE 1. Screening and diagnosis of gestational diabetes. Abbreviations: GDM, gestational diabetes mellitus; WHO, World Health Organization; OGTT, oral glucose toler-ance test; BMI, body mass index; DM; diabetes mellitus; IUFD, intra uterine foetal death; PCOS, polycystic ovary syndrome.

Outcomes and defi nitionsAll electronic medical- and birth records were retrospectively reviewed and data between 2011-2016 were included in an anonymised database. Maternal charac-teristics were age, ethnicity (Caucasian, Asian, African American, Mediterranean or unknown), parity, pre-gestational BMI, risk factors for GDM, hypertensive disorders, results of 75-gram OGTT, and treatment details. Chronic hypertension was defi ned as a systolic blood pressure (SBP) ≥140 mmHg and/or a diastolic blood pressure (DBP) ≥90 mmHg at booking before 20 weeks of gestation, or the use of blood-pressure lowering drugs before pregnancy.

Obstetric and neonatal outcomesObstetric outcomes collected were induction of labour, mode of delivery (spon-taneous vaginal delivery, assisted vaginal delivery (vacuum extraction or forceps), intrapartum caesarean delivery or planned caesarean delivery), gestational age at birth, pregnancy-induced hypertension (PIH) and preeclampsia. PIH was defi ned as a SBP ≥140 mmHg and/or a DBP ≥90 mmHg, after 20 weeks of gestation in a previ-ously normotensive woman. Preeclampsia was defi ned ad PIH plus the presence of proteinuria (≥300 mg/24-h) and also included women who had eclampsia and HELLP syndrome.

Neonatal outcomes were birth weight, large for gestational age (LGA; birth weight >90th percentile, corrected for sex, ethnicity, parity, and gestational age),22

CHAPTER 8

150

small for gestational age (SGA; birth weight <10th percentile, corrected for sex, eth-nicity, parity, and gestational age),22 preterm delivery (delivery before 37 weeks of gestation), 5 min Apgar score <7, need for respiratory support, still birth/neonatal death, birth trauma (shoulder dystocia, fracture of humerus or clavicle, brachial plexus injury), neonatal hypoglycaemia, neonatal hyperbilirubinaemia, and admis-sion to the neonatology department. Of note, neonates with extreme prematurity (delivery before 28 weeks of gestation, n=3) were excluded for the variable birth weight. Hyperbilirubinaemia was recorded if the neonate required treatment with phototherapy after birth. Neonatal hypoglycaemia (occurring >2-h after birth) was defined as a blood glucose level <2.6 mmol/l or treatment with glucose infusion.17 Neonates born before 32 weeks (n=2) of gestation with neonatal hypoglycaemia were excluded in this analysis as hypoglycaemia could well be caused by prema-turity. Respiratory support was defined as the need for continuous positive airway pressure after birth or intubation.

Statistical analysesStatistical analyses were carried out using statistical package IBM SPSS (version 23.0. Armonk, NY: IBM Corp). Continuous variables are presented as mean ± standard deviation (SD) or as median and inter quartile range (IQR) according to the normal distribution status. Categorical variables are presented as numbers and frequencies (%). Appropriate (non)parametric tests were used to compare differences between the groups for continuous variables (independent t-test or Mann-Whitney U-test in case of skewed distribution) and categorical variables (Chi-square or Fisher’s exact test). A P-value <0.05 was considered statistically significant.

RESULTS

Maternal characteristics are summarized in Table 1. A total of 1386 women with GDM were included in the study, 437 in the WHO-2013-cohort and 949 in the WHO-1999-cohort. In the WHO-2013-cohort, 49.4% of the women had GDM according to both the WHO-1999 criteria and WHO-2013 criteria. In the WHO-1999-cohort, 24.7% of the GDM women would not have had GDM according to the WHO-2013 criteria.

In total, 1341 women (96.4%) were diagnosed by OGTT and 45 (3.6%) women were already diagnosed in first trimester by a random or fasting glucose level. The median fasting glucose level was higher in the WHO-2013-cohort and the 2-h glucose level was lower, compared to the WHO-1999-cohort. GDM diagnosis was based on elevated fasting glucose level only in 40.2% in the WHO-2013-cohort, compared with 0.8% in the WHO-1999-cohort. GDM was diagnosed based on


151

8

elevated 2-h value in 10.9% in the WHO-2013-cohort and in 95.4% in the WHO-1999-cohort. Women in the WHO-2013-cohort were diagnosed earlier in pregnancy (24.9 [IQR 23.3-29.0] vs. 27.7 [IQR 25.9-30.7] weeks) and less women had their OGTT performed based on symptoms or signs in third trimester (15.1% vs. 28.5%) instead of screening based on predefined GDM risk-factors. Of the 270 women in the WHO-1999-cohort diagnosed with GDM based on signs suggestive of GDM, 127 (47.0%) retrospectively appeared to have risk factors for GDM. Of these, 12 women tested negative on a first OGTT in the 2nd trimester and 115 women were not screened. In the WHO-2013-cohort 15.6% of the women received insulin treatment compared with 43.4% in the WHO-1999-cohort. In the WHO-2013-cohort, 14 (3.2%) women were treated with metformin.

TABLE 1. Maternal characteristics of women diagnosed with gestational diabetes mellitus.

Characteristics

Cohort

P-value*WHO-2013 WHO-1999

N 437 949

Age (years) 34.7 ± 5.1 32.1 ± 5.1 <0.001

Ethnicity, n (%) Caucasian Asian African-American Mediterranean Unknown

357 (81.7)9 (2.1)2 (0.5)

64 (14.6)5 (1.1)

741 (78.1)72 (7.6)39 (4.1)69 (7.3)28 (3.0)

<0.001

Parity, n (%) 0 1-2 >2

158 (36.2)242 (55.5)

36 (8.3)

386 (40.7)499 (52.6)

64 (6.7)

0.232

First degree relative with DM, n (%) 82 (18.8) 376 (41.1) <0.001

History of PCOS, n (%) 10 (2.3) 50 (5.3) 0.011

History of GDM, n (%) 44 (10.1) 103 (10.9) 0.650

Previous infant weighing ≥4500 g at birth, n (%) 42 (9.6) 97 (10.2) 0.716

History of IUFD, n (%) 4 (0.9) 20 (2.1) 0.113

Pre-gestational BMI (kg/m2) 29.7 [26.0-34.4] 27.7 [24.2-31.8] <0.001

Pre-gestational BMI, n (%) <25 kg/m2

25-29.9 kg/m2

≥30 kg/m2

88 (20.8)129 (30.4)207 (48.8)

291 (31.5)288 (31.2)344 (37.3)

<0.001

Chronic hypertension, n (%) 8 (1.8) 43 (4.5) 0.013

Indication for OGTT, n (%) Screening based on risk factors Diagnostic test based on symptoms/signs Unknown

362 (82.8)66 (15.1)

9 (2.1)

650 (68.5)270 (28.5)

29 (3.1)

<0.001

Diagnosis based on OGTT, n (%) ‡ 422 (96.6) 919 (96.8) 0.791

Gestational age at time of OGTT (weeks) 24.9 [23.3-29.0] 27.7 [25.9-30.7] <0.001

CHAPTER 8

152

Obstetric and neonatal outcomeTable 2 summarizes the obstetric outcomes. In the WHO-2013-cohort there were more spontaneous deliveries (73.1% vs. 67.4%, p=0.032) and less planned caesar-ean deliveries. Median gestational age at birth was higher for women in the WHO-2013-cohort (39.0 vs. 38.3 weeks, p= <0.001). There were no differences between the groups with respect to assisted vaginal delivery, intrapartum caesarean delivery and induction of labour. Prevalence of PIH was higher in the WHO-2013-cohort, although no differences were seen between the two groups regarding incidence of preeclampsia.

Table 3 shows the neonatal outcomes. The percentage of LGA neonates (cor-rected for sex, ethnicity, parity, and gestational age) was significantly lower in the WHO-2013-cohort (16.5% vs. 18.5%, p=0.026) and birth weight was accordingly higher (3512 vs. 3399 g, p= <0.001). Neonatal hypoglycaemia was more often diag-nosed in offspring of the WHO-2013-cohort (9.6% vs. 4.2%, p= <0.001). There were no significant differences seen between the two groups with respect to neonatal hyperbilirubinaemia, preterm delivery, birth weight in categories, SGA, 5 min Apgar score <7, need for respiratory support, birth trauma, still birth/neonatal death, and admission to the neonatology department.

TABLE 1. Maternal characteristics of women diagnosed with gestational diabetes mellitus. (continued)

Characteristics

Cohort


Gestational age at time of OGTT screening only (weeks) 24.4 [22.6-26.9] 27.3 [25.1-28.7] <0.001

Gestational age at time of OGTT diagnostic 3rd trimester only (weeks)

33.1 [28.7-35.3] 30.4 [27.7-33.6] 0.001

75-g OGTT Fasting glucose level (mmol/l)

1-h glucose level (mmol/l) 2-h glucose level (mmol/l)

5.3 [5.1-5.6]9.6 [8.0-10.5]7.7 [6.6-9.0]

5.0 [4.6-5.5]-

8.6 [8.1-9.4]

<0.001 NA

<0.001

Diagnosis based on elevated fasting glucose level only, n (%) 170 (40.2) 8 (0.9) <0.001

Diagnosis based on elevated 2-h glucose level only, n (%) 46 (10.9) 877 (95.4) <0.001

Insulin treatment, n (%) 68 (15.6) 412 (43.4) <0.001

Metformin treatment, n (%) 14 (3.2) - NA

Abbreviations: WHO, World health Organization; BMI, Body Mass Index; DM, Diabetes Mellitus; IUFD, Intrauter-ine Foetal Death; PCOS, Polycystic Ovary Syndrome; OGTT, Oral Glucose Tolerance Test; NA, not applicable. Data are expressed as mean ± SD, median [IQR], or proportion of n (%). Data with respect to first degree relative with DM 35 (3.7%) (WHO-1999-cohort), BMI 13 (3.0%) (WHO-2013-cohort) and 26 (2.7%) (WHO-1999-cohort), gestational age at time of OGTT 15 (1.6%) (WHO-1999-cohort), are missing.* P-values were based on Student’s unpaired t-test (non-skewed continuous variables), Mann-Whitney U-Test (skewed continuous variables) or Chi-square test (categorical variables).‡ Total number of women diagnosed with a 75-gram OGTT. The other women (n=45) were diagnosed with a random or fasting glucose level in first trimester of their pregnancy.


153

8

TABLE 2. Obstetric outcomes of women diagnosed with gestational diabetes mellitus.

Outcome variable

Cohort


N 437 949

Induction of labour, n (%) 256 (59.3) 606 (63.9) 0.102

Delivery type, n (%) Spontaneous vaginal delivery Assisted vaginal delivery Intrapartum caesarean delivery Planned caesarean delivery

318 (73.1)35 (8.0)

48 (11.0)34 (7.8)

638 (67.4)79 (8.3)

121 (12.8)111 (11.7)

0.0320.7120.3650.029

Gestational age at birth (weeks) 39.0 [38.3-39.6] 38.3 [38.0-39.0] <0.001

Pregnancy-induced hypertension, n (%) 50 (11.5) 61 (6.4) 0.001

Preeclampsia‡, n (%) 12 (2.8) 30 (3.2) 0.683

Abbreviations: WHO, World health Organization.Data are expressed as median [IQR], or proportion of n (%). * P-values were based on Mann-Whitney U-Test (skewed continuous variables) or Chi-square test for categorical variables. ‡ Preeclampsia included also women who had eclampsia (n=3, WHO-1999-cohort).

TABLE 3. Neonatal outcomes of women diagnosed with gestational diabetes mellitus.

Outcome variable

Cohort


N 437 949

Preterm delivery, n (%) 27 (6.2) 60 (6.3) 0.797

Birth weight (g)** 3512 ± 459 3399 ± 532 <0.001

Birth weight, n (%) **

Infants <4000 g Infants 4000-4499 g Infants ≥4500 g

384 (87.9)42 (9.6)11 (2.5)

831 (87.8)104 (11.0)

11 (1.2)

0.136

Large for gestational age, n (%) ‡ 72 (16.5) 176 (18.5) 0.026

Small for gestational age, n (%) ‡ 14 (3.2) 37 (3.9) 0.538

5 min Apgar <7, n (%) 7 (1.6) 32 (3.4) 0.068

Respiratory support, n (%) 14 (3.2) 37 (3.9) 0.519

Birth trauma, n (%) 15 (3.4) 30 (3.2) 0.791

Hypoglycaemia, n (%) ¥ 42 (9.6) 40 (4.2) <0.001

Hyperbilirubinaemia, n (%) 4 (0.9) 24 (2.5) 0.062

Still birth/neonatal death, n (%) 1 (0.2) 2 (0.2) 1.000

Admission to the neonatology department, n (%) 54 (12.4) 139 (14.6) 0.272

Abbreviations: WHO, World health Organization. Data are expressed as mean ± SD, or proportion of n (%).* P-values were based on Student’s unpaired t-test (non-skewed continuous variables), or Chi-square test (cat-egorical variables). ** Neonates with extreme prematurity <28 weeks were excluded (n=3).‡ Corrected for sex, ethnicity, parity, and gestational age.¥ Neonates born before 32 weeks of gestation with hypoglycaemia were excluded (n=2).

CHAPTER 8

154

DISCUSSION

This multicentre, retrospective cohort study shows the pregnancy outcomes in two cohorts applying different diagnostic criteria for GDM i.e. WHO-2013 and WHO-1999. Women in the WHO-2013-cohort had a higher pre-gestational BMI and more often PIH. However, they were diagnosed earlier, less often needed insulin therapy, and had a higher percentage of spontaneous deliveries and a lower percentage of LGA neonates. No other differences in adverse obstetric and neonatal outcomes were seen between the two cohorts.

A number of previous international studies have addressed the effects of intro-duction of the WHO-2013 criteria on pregnancy outcomes.23-28 They retrospectively studied pregnancy outcomes in women previously classified as non-GDM with other diagnostic criteria and newly defined as GDM with the WHO- 2013 criteria.23-28 These studies suggested that women newly diagnosed with the WHO-2013 criteria if untreated were at increased risk for adverse pregnancy outcomes, including PIH, preeclampsia, neonatal intensive care admission, caesarean section, shoulder dystocia, macrosomia and LGA neonates, compared to non-GDM women.23-28 In contrast to the aforementioned studies, women in our study both diagnosed with WHO-2013 or WHO-1999 criteria were treated similarly according to our national guideline.

In analogy to our study, two comparable studies with regard to treatment and comparison of two diagnostic approaches (Carpenter-Coustan criteria compared with the WHO-2013 criteria) showed that the percentage of LGA neonates was lower in the WHO-2013-cohort.29,30 In addition, one study also showed a reduction in caesarean deliveries, PIH, and assisted delivery after implementation of the WHO-2013 criteria.30

The reduction of LGA neonates is an important treatment target in GDM, since LGA is associated with short- and long term complications for the neonate. There are several potential explanations for the lower rates of LGA neonates in the WHO-2013-cohort found in our study and others.29,30 Firstly, the WHO-2013 criteria included a new group of women: 40.2% of the women were only diagnosed based on the fasting glucose cut-off value compared to 0.8% in the WHO-1999-cohort. By applying the more strict WHO-2013 criteria, the prevalence of GDM increases, including presumably more mild cases of GDM, resulting in a lower percentage of LGA neonates. Several other studies have demonstrated that implementation of the WHO-2013 increases the prevalence of GDM.4,15 Moreover, a lower percentage of women in our WHO-2013-cohort (15.6%) required additional insulin therapy compared with the WHO-1999-cohort (43.4%).


155

8

Secondly, women in the WHO-2013-cohort were screened and diagnosed with GDM earlier (WHO-2013-cohort: median ~25 weeks, WHO-1999-cohort: median ~28 weeks), so that group had earlier dietary or insulin intervention. More women in the WHO-1999-cohort were diagnosed based on signs suggestive of GDM (e.g. polyhy-dramnios/foetal macrosomia). Therefore the WHO-1999-cohort may include women with a more advanced stage of GDM leading to higher rates of LGA. Nevertheless, approximately 50% of all women diagnosed with GDM based on signs suggestive of GDM, retrospectively had a risk factor for GDM that justified 2nd trimester screening in the first place. However, even when we only considered women who were diag-nosed based on 2nd trimester screening because of GDM risk factors, gestational age at diagnosis remained different between the groups. The earlier screening and diagnosis of GDM in the WHO-2013-cohort could have led to earlier treatment and therefore to a better outcome. Landon et al. also demonstrated that offering early treatment to women with modest degrees of hyperglycaemia in pregnancy results in reduction of foetal overgrowth.8

The only obstetric parameter which differed between the two cohorts was the higher incidence of planned caesarean section in the WHO-1999-cohort. This may be due to difference in clinical obstetric practice between both regions. But may also be due to differences related to GDM including more estimated macrosomia on ultrasound, worse glycaemic control indicated by significantly more insulin therapy

For the neonatal outcomes an increase in neonatal hypoglycaemia was seen in the WHO-2013-cohort. This can be explained by an active screening policy in all neonates in the hospital that used the WHO-2013 criteria unlike the “WHO-1999 hospitals”, that screened neonates by indication. This finding suggests that roughly 50% neonatal hypoglycaemia might be missed without active screening, poten-tially leading to long-term adverse outcomes. So, an active screening policy on neonatal hypoglycaemia can be recommended. Moreover, in the WHO-2013-cohort a higher percentage of women were diagnosed with PIH. In the WHO-1999-cohort more women were diagnosed with chronic hypertension in first trimester of their pregnancy. This finding suggests that the difference in PIH between the WHO-2013-cohort and WHO-1999-cohort also can be explained by an earlier diagnosis of chronic hypertension in first trimester in the WHO-1999 cohort.

This study gives no information on differences in incidence of GDM between the two diagnostic approaches. In the WHO-2013-cohort, 50.6% of the women were positive for GDM according the WHO-2013 criteria only and 49.4% had GDM accord-ing to both the WHO-2013 criteria and WHO-1999 criteria. Both cohorts were not totally equal in clinical characteristics: women in the WHO-2013-cohort were older and had a higher pre-gestational BMI compared with the WHO-1999-cohort. They were more often diagnosed on the fasting glucose level. These factors are associated

CHAPTER 8

156

with a less favourable metabolic profile. Although the WHO-2013-cohort seemingly consisted of a group of women with milder glucose intolerance, they appeared to have a more worse metabolic profile. It seems that the WHO-2013 criteria have a better ability to select women with a worse metabolic profile.

The main strength of this study is that it evaluates the pregnancy outcomes of women with GDM diagnosed by the old and new WHO-criteria in a real-life clini-cal setting. Moreover, after GDM diagnosis all women were treated equally based on the national guideline. Several potential limitations of this study should be noted. This study was conducted in three different hospitals in two regions of the Netherlands. It is possible that the study populations and obstetric management between the hospitals were slightly different. In addition, the study was limited by its retrospective study design. Therefore, data were missing for some variables in the electronic medical- and birth records and the sample size was limited to find significant differences between the groups for relatively rare pregnancy outcomes, such as birth trauma, still birth/neonatal death, and preeclampsia.

CONCLUSIONS

In summary, this study demonstrated that application of the WHO-2013 criteria was associated with a lower percentage of LGA neonates, a reduced need for insulin treatment and more spontaneous deliveries. Although an earlier diagnosis of GDM might contribute to these differences, milder GDM by selection is proposed to play a major role. No differences were found in adverse pregnancy outcomes between the two diagnostic approaches.

This study contributes to the current debate regarding the value of implementa-tion of new WHO-2013 diagnostic criteria for GDM but cannot provide a definitive answer. A population-based randomised study directly comparing the two diagnos-tic approaches might provide further guidance for the optimal screening strategy for GDM.


157

8

REFERENCES

1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37 (Supll. 1):S81-90.


3. Ferrara A. Increasing prevalence of gestational diabetes mellitus: A public health perspective. Diabetes Care. 2007;30 (Suppl. 2):S141-6.



6. Langer O, Yogev Y, Most O, Xenakis EMJ. Gestational diabetes: The consequences of not treating. Obstet Gynecol. 2005;192:989-97.

7. Sermer M, Naylor CD, Gare DJ, et al. Impact of increasing carbohydrate intolerance on maternal-fetal outcomes in 3637 women without gestational diabetes: The Toronto Tri-Hospital Gestational Diabetes Project. Obstet Gynecol. 1995;173:146-56.




11. International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger BE, Gabbe, SG, et al. International Association of Diabetes and Pregnancy Study Groups recom-mendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33:676-82.

12. World Health Organization (WHO). Diagnostic criteria and Classification of Hyperglycemia First Detected in Pregnancy. 2013. Available from: http://apps.who.int/iris/bitstream/10665/85975/1/WHO_NMH_MND_13.2_eng.pdf, accessed 2 June 2017.

13. Hod M, Kapur A, Sacks DA, et al. The international federation of gynecology and obstetrics (FIGO) initiative on gestational diabetes mellitus: A pragmatic guide for diagnosis, management, and care. Int J Gynaecol Obstet. 2015;131:S173-211.

14. Benhalima K, Damm P, Van Assche A, et al. Screening for gestational diabetes in Europe: Where do we stand and how to move forward?: A scientific paper commissioned by the European board & college of obstetrics and gynaecology (EBCOG). Eur J Obstet Gynecol Reprod Biol. 2016;201:192-6.


16. Visser GHA, de Valk H,W. Is the evidence strong enough to change the diagnostic criteria for gestational diabetes now? Obstet Gynecol. 2013;208:260-4.

CHAPTER 8

158

17. The Dutch Society of Obstetrics and Gynaecology. Diabetes mellitus and Pregnancy. Clinical guideline version 2.0. 2010. Available from: http://www.nvog-documenten.nl/richtlijn/item/pagina.php?richtlijn_id=863, accessed 2 June 2017.




21. University Medical Center Groningen. Researchcode University Medical Center Groningen. 2013. Available from: https://www.umcg.nl/SiteCollectionDocuments/English/Researchcode/UMCG-Researchcode,%20basic%20principles%202013.pdf, accessed 2 June 2017.


23. Laafira A, White SW, Griffin CJ, Graham D. Impact of the new IADPSG gestational diabetes diagnos-tic criteria on pregnancy outcomes in western Australia. Aust N Z J Obstet Gynaecol. 2016;56:36-41.

24. Benhalima K, Hanssens M, Devlieger R, Verhaeghe J, Mathieu C. Analysis of pregnancy outcomes using the new IADPSG recommendation compared with the Carpenter and Coustan criteria in an area with a low prevalence of gestational diabetes. Int J Endocrinol. 2013;2013:248121.


26. O’Sullivan E, Avalos G, O’Reilly M, et al. Atlantic diabetes in pregnancy (DIP): The prevalence and outcomes of gestational diabetes mellitus using new diagnostic criteria. Diabetologia. 2011;54:1670-5.

27. Lapolla A, Dalfrà M, Ragazzi E, De Cata A, Fedele D. New international association of the diabetes and pregnancy study groups (IADPSG) recommendations for diagnosing gestational diabetes compared with former criteria: A retrospective study on pregnancy outcome. Diabet Med. 2011;28:1074-7.

28. Ethridge JK,Jr, Catalano PM, Waters TP. Perinatal outcomes associated with the diagnosis of gestational diabetes made by the international association of the diabetes and pregnancy study groups criteria. Obstet Gynecol. 2014;124:571-8.

29. Hung T. The effects of implementing the international association of diabetes and pregnancy study groups criteria for diagnosing gestational diabetes on maternal and neonatal outcomes. PloS One. 2015;10:e0122261.

30. Duran A, Saenz S, Torrejon MJ, et al. Introduction of IADPSG criteria for the screening and diag-nosis of gestational diabetes mellitus results in improved pregnancy outcomes at a lower cost in a large cohort of pregnant women: The St. Carlos gestational diabetes study. Diabetes Care. 2014;37:2442-50.

9 Summary, general discussion, and future perspectives

Summary

163

9

SUMMARY

Gestational diabetes mellitusGestational diabetes mellitus (GDM) is defined as hyperglycaemia (high blood glucose levels) first detected during pregnancy. For women diagnosed with GDM in first trimester of pregnancy, pre-existing diabetes mellitus (DM) should be con-sidered.1 GDM affects up to 14% of all pregnancies and the prevalence is expected to keep increasing.2 Untreated GDM is associated with an elevated risk of neonatal and obstetric complications such as macrosomia (high birth weight), birth trauma, preeclampsia and caesarean section.3-5 Furthermore, GDM is associated with an in-creased risk of maternal type 2 diabetes mellitus (T2DM) and cardiovascular diseases after pregnancy and there is growing evidence for long-term health consequences for the child (obesity and/or T2DM).6-13 Intervention studies have demonstrated that early diagnosis and appropriate treatment of GDM can reduce the risk of pregnancy complications.14,15 However, worldwide there is no uniformly accepted guideline for GDM diagnosis and treatment.16

Dutch guideline for GDM screening and treatmentIn the Netherlands, the Dutch Society of Obstetrics and Gynaecology guideline “Dia-betes and Pregnancy” for the screening and treatment of GDM was implemented in 2010. Their guideline recommends to screen for GDM in high-risk women using a 75-g oral glucose tolerance test (OGTT). The World Health Organization (WHO) 1999 criteria are recommended for diagnosis of GDM (fasting plasma glucose (FG) ≥7.0 mmol/l and/or 2-h glucose value (2HG) ≥7.8 mmol/l).17,18

The main goal of GDM treatment is to achieve glycaemic control during preg-nancy. The first step in GDM treatment is dietary advice by a dietician. If dietary advice fails to maintain adequate glucose control during pregnancy, insulin therapy is the second step.18 After GDM pregnancy, the national guideline recommends glucose testing six weeks after delivery and subsequently once a year for the next five years in women with a history of GDM.18,19

International GDM guidelinesIn recent years, new findings are reported regarding maternal hyperglycaemia and the increased risk of pregnancy complications.3,5 This has led to a national and international debate regarding the diagnostic cut-off values of GDM. New more stringent diagnostic criteria for GDM are implemented by the International Association of Diabetes and Pregnancy Study Groups (IADPSG) in 2010, and these criteria have been endorsed by different expert groups including the WHO in 2013 (75-g OGTT; FG ≥5.1 mmol/l; and/or 1-h glucose value (1HG) ≥10.0 mmol/l; and/

Chapter 9

164

or 2HG ≥8.5 mmol/l).20,21 The evidence that these new diagnostic criteria improve pregnancy outcomes is limited. In the Netherlands, the WHO-2013 criteria have not yet been implemented.

The research described in this thesis aimed to evaluate the current Dutch national guidelines for diagnosis and treatment of GDM i.e. what is the outcome of GDM pregnancies using this guideline? And what are consequences when the current diagnostic criteria of GDM are to be revised?

In Chapter 1 we provided a general introduction and outlined the aim of this thesis. In Chapter 2 we reviewed the existing literature and we provided a more extensive overview of the current knowledge regarding GDM and the unmet needs of this condition. We reviewed the diagnostic criteria, different treatment regimens available, and the long-term health consequences of GDM.

PART A: EVALUATION OF THE CURRENT NATIONAL GUIDELINE

In Chapter 3, we retrospectively evaluated the pregnancies outcomes of 820 singleton pregnancies complicated by GDM after implementation of the 2010 Dutch Society of Obstetrics and Gynaecology guideline “Diabetes and Pregnancy” on systematic screen-ing and treatment of GDM. These women were diagnosed and treated for GDM in the UMCG and Martini Hospital, between 2011 and 2014. The outcomes were compared between women treated with diet-only and women treated with additional insulin therapy. The pregnancies outcomes of the general obstetric population in the northern region of the Netherlands served as a reference population. We found that neonates born to mothers in the GDM population were more likely to be large-for-gestational-age (LGA; defined as a birth weight >90th percentile) compared with neonates born to mothers in the general obstetric population, 20% versus 11%. The incidence of adverse pregnancy outcomes was low in the GDM cohort. Moreover, there were no major dif-ferences in neonatal and obstetric outcomes between women with GDM treated with diet only or additional insulin therapy. We concluded that the current Dutch guideline is successful in achieving a low incidence of adverse pregnancy outcomes, however the percentage LGA neonates was significantly higher in GDM pregnancies compared to the general obstetric population.

In Chapter 4, we allowed the recognition of a more “complex-care” group of insulin-treated women with GDM, but on the other hand a potential “low-risk” group of women treated with diet alone and likely to have good obstetric and/or neonatal outcomes. In last years, the number of women referred for GDM treatment in secondary care has largely increased. The study was performed in the same 820

Summary

165

9

singleton GDM pregnancies as mentioned before. We found various predictors of need for additional insulin therapy: - Previous GDM; - Family history of diabetes mellitus; - A previous infant weighing ≥4500 g at birth; - Ethnicity, in particular Middle Eastern/North-African descent; - Multiparity;- Overweight, defined as pre-gestational body mass index (BMI) ≥30 kg/m2; - A markedly increased fasting and 2-h glucose level after a 75-g OGTT at time of

GDM diagnosis.A fasting glucose level ≥5.5 mmol/l at time of GDM diagnosis was the strongest pre-dictor of need for insulin therapy. Furthermore, the study showed that primiparous women and women with higher weight gain during pregnancy had more pregnancy complications. We concluded that the predictors found for insulin therapy might be helpful to recognise a complex-care group of insulin treated women with GDM. However, it was not possible to identify a low risk diet-treated group from our data based on pregnancy outcomes.

In Chapter 5, we investigated the potential effect of thyroid function tests TSH and FT4 on maternal and neonatal outcomes in women with GDM. We retrospec-tively reviewed the medical files of 222 singleton euthyroid GDM pregnancies. Thyroid function (TSH and FT4 levels) was measured at the first visit at the UMCG diabetes outpatient clinic, between 24-29 weeks of gestation. We tested the hypoth-esis that women with lower FT4 levels (in the normal rage) are more likely to have a higher weight gain and possibly unfavourable pregnancy outcomes. We showed no major differences in unfavourable neonatal outcomes across quartiles of FT4 and TSH levels within the normal range. However, women with GDM and with low FT4 levels (and/or high TSH levels) had a higher pre-gestational BMI and showed a trend towards a higher weight gain during pregnancy compared with women with higher FT4 levels. This last finding is in agreement with our hypothesis.

In Chapter 6, we aimed to evaluate the postpartum GDM care in primary- and secondary care. And in addition we aimed to evaluate the lifestyle of women with a history of GDM. In this cross-sectional follow-up survey we invited 215 women, who were treated for GDM in the UMCG between January 2011 and December 2012, to participate in the study. In total 77 women responded. We also invited the general practitioners (GPs) of these women and in total 61 GPs responded. We found that 90% of the women visited the DM outpatient clinic. However we found very low rates of longer-term follow-up postpartum glucose testing in primary care. Of the 61 GPs, 12 GPs reported that they performed glucose testing within 12-14 months after delivery and only two women were tested for three consecutive years. More-

Chapter 9

166

over, we found a suboptimal performance of adherence to a healthy lifestyle for women with a history of GDM, defined according the Dutch guidelines for a healthy diet and Dutch guidelines for healthy exercise. We concluded that in women with a history of GDM postpartum follow-up care was far from optimal.

PART B: EVALUATION OF NEW INTERNATIONAL DIAGNOSTIC CRITERIA

In Chapter 7, we investigated the possible impact on GDM prevalence and pregnancy outcomes of applying the new WHO-2013 criteria instead of the older WHO-1999 criteria. Data on screening were available from 10,642 women who underwent a 75-g OGTT between January 2011 and September 2016 due to risk factors or signs sugges-tive of GDM. Data on pregnancy outcomes were available for 4,431 women and were compared between a normal glucose tolerance control group and different GDM classification groups. We found that applying the new WHO-2013 criteria would have resulted in a higher incidence of women with GDM than using the WHO-1999 criteria (31% versus 22%). We also showed that the new criteria identified a group of women (i.e. women with FG ≥5.1-≤6.9 mmol/l) with unfavourable characteristics (high BMI and more often hypertensive disorders) and more adverse pregnancy outcomes when compared to women with normal glucose tolerance (women with a normal OGTT i.e. women with FG <5.1 and 2HG <7.8 mmol/l) or with the general obstetric popula-tion in the northern region of the Netherlands. The women potentially missed due to the higher 2HG cut-off of the WHO-2013 criteria (i.e. women with 2HG ≥7.8-≤8.4 mmol/l) had similar pregnancy outcomes to women with normal glucose tolerance, however these women were actively treated for GDM with nutritional advice or (20%) additional insulin therapy according the national guideline.

In Chapter 8, we evaluated maternal characteristics and pregnancy outcomes in two cohorts in the Netherlands which applied different diagnostic criteria for GDM i.e. WHO-2013 and WHO-1999. As mentioned earlier, the Dutch national guideline recommends the WHO-1999 criteria for GDM diagnosis. Notwithstanding that, a few hospitals in the Netherlands already implemented the new IADPSG/WHO-2013 criteria for diagnosis of GDM. This study was in collaboration with the Deventer Hos-pital, this hospital implemented the IADPSG/WHO-2013 criteria in 2012. Women in both cohorts were treated based on the national guideline for GDM. We retrospec-tively evaluated the medical files of 1386 singleton GDM pregnancies (437 women WHO-2013 cohort and 949 women WHO-1999 cohort). In this study we showed that women in the WHO-2013-cohort were more often overweight and were often hypertensive during pregnancy compared with women in the WHO-1999 cohort.

Summary

167

9

However, they were diagnosed earlier, less often needed additional insulin therapy, and had a higher percentage of spontaneous deliveries and a lower percentage of LGA neonates. No other differences in adverse pregnancy outcomes were seen between the two cohorts.

GENERAL DISCUSSION AND FUTURE PERSPECTIVES

Although there are new insights regarding hyperglycaemia during pregnancy and the increased risks of adverse pregnancy outcomes, there is much controversy regarding the optimal glucose thresholds to define GDM, the blood glucose targets for treatment, and even so the mode of treatment. As a result, there is an on-going national and international debate regarding the diagnosis and treatment of GDM and there are no uniformly accepted guidelines. The outcomes of the current na-tional guideline and new – more stringent – international diagnostic criteria will be discussed and future perspectives are provided.

NATIONAL GUIDELINE VERSUS NEW INTERNATIONAL DIAGNOSTIC CRITERIA FOR GDM

Pregnancy outcomes in GDM Since the introduction of the current national GDM guideline there is a more active screening and treatment policy for GDM. However, until recently the effect of this guideline on the outcomes of GDM pregnancies was unclear. In this thesis we have shown that the current national GDM guideline (using the WHO-1999 diagnostic criteria; FG ≥7.0 mmol/l and/or 2HG ≥7.8 mmol/l) is successful in achieving a low incidence of adverse short-term birth outcomes. The number of adverse short-term birth outcomes was comparable with the general obstetric population in the northern region of the Netherlands. We also observed no major differences in pregnancy outcomes between the two treatment regimens: diet-only or additional insulin therapy. However, neonates born to mothers in the GDM population were more likely to be LGA when compared with neonates born to mothers in the general obstetric population (~20% versus 11%) (Chapter 3 and Chapter 7). This is an impor-tant finding, given the short-term and possible long-term consequences associated with LGA.

Chapter 9

168

Screening Despite the progress in screening and treatment of GDM, the national GDM guide-line is not optimal in reducing the number of LGA neonates. We found that a con-siderable proportion of women were diagnosed with GDM later than 28 weeks of gestation (Chapter 3 and 8). In these women, GDM treatment was therefore started late in pregnancy and this could have resulted in excessive foetal growth. This find-ing is supported by an elegant study of Hammoud et al., who demonstrated that GDM diagnosed by early screening is associated with a lower incidence of foetal macrosomia than GDM diagnosed following signs late in pregnancy.22

In the current guideline, it is recommended to perform the 75-g OGTT between 24 and 28 weeks of gestation in women with one or more risk factors for GDM.18 The risks factors currently used for GDM screening are successful in identifying women at higher risk for adverse pregnancy outcomes. In this thesis we found that women who were screened for GDM and exhibited normal glucose tolerance (i.e. women with FG <5.1 mmol/l and 2HG <7.8 mmol/l), still had a 7% higher rate of LGA neonates compared to women in the general obstetric population (Chapter 7). To further improve GDM screening there obviously is need for better planning of the OGTT. First, the OGTT could be scheduled more strictly or earlier in pregnancy in high-risk women. A recent study showed that women at high risk of GDM and diagnosed with GDM in early pregnancy (defined as diagnosed with GDM before 12 weeks of gestation) had rates of adverse pregnancies outcomes comparable to women with pre-existing DM.23 However, screening before 24 weeks of gestation would increase the number of false negative OGTTs, because it is well known that insulin resistance increases in second or third trimester. Therefore, another option is to provide a second screening test after 28 weeks of gestation, to identify women who developed GDM after second trimester or to identify women who test negative for GDM at the first screening test. Secondly, we have observed that by implementing the more stringent WHO-2013 diagnostic thresholds for GDM, women were earlier identified with GDM compared with the WHO-1999 diagnostic thresholds (Chapter 8). The women in the WHO-2013 cohort were treated earlier and the percentage LGA neonates was lower compared with the WHO-1999 cohort. Adopting the new diagnostic thresholds for GDM will probably result in earlier diagnosis of GDM.

There is also a lot of controversy in the literature about the screening of GDM, not only about the timing of screening but also regarding selective screening (only high risk women) or universal screening. Detailed discussion of these points is beyond the scope of this thesis.

Summary

169

9

Diagnosis – international diagnostic thresholds The current national and international discussion mainly focuses on the optimal diagnostic thresholds for GDM. It has been demonstrated previously that there is linear relationship between higher maternal fasting and 2-h post-load glucose levels and the increased risk of adverse pregnancy outcomes.3,5 However, for most of the pregnancy complications there is no clear threshold risk found and therefore it is unclear at which degree of maternal hyperglycaemia treatment should be provided.20

Fasting glucose levelAlthough many guideline committees have adopted the new IADPSG diagnostic criteria for GDM (75-g OGTT; FG glucose ≥5.1 mmol/l; and/or 1HG ≥10.0 mmol/l; and/or 2HG ≥8.5 mmol/l),20,21 evidence that applying these more stringent diag-nostic criteria (mainly more stringent regarding FG levels) improves short- and long-term pregnancy outcomes is limited (Chapter 2). Therefore, the question remains whether identifying women with mild GDM will indeed improve pregnancy outcomes, including reducing the number of LGA neonates.

In the current thesis, we showed that the lower FG cut-off value of the WHO-2013 criteria was successful in identifying a group of women (i.e. women with FG ≥5.1-≤6.9 mmol/l) with an increased risk of adverse pregnancy outcomes (Chapter 7). Moreover, when compared with the general obstetric population these women had a twofold higher rate of LGA neonates (21% versus 11%).These findings provide evidence that this category of high-risk women should not be left untreated and adjustment of the FG cut-off level in the national guideline is necessary to further improve pregnancy outcomes.

With the evidence that (untreated) mild GDM is associated with an increased risk of adverse pregnancy outcomes, the second question remains whether treating women with mild GDM improves pregnancy outcomes. We also demonstrated that women diagnosed with the WHO-2013 criteria and treated according the national guideline had a lower likelihood of having an LGA neonate, a reduced need for insu-lin treatment and more spontaneous deliveries when compared with women diag-nosed according the WHO-1999 criteria (Chapter 8). It has to be borne in mind that this multicentre study was performed in two different regions in the Netherlands. There might be some differences in the study populations and obstetric manage-ment between the hospitals. The women in the WHO-2013 cohort were diagnosed with GDM earlier in their pregnancy, and this may have influenced the results of the study. However, as stated before this last finding could also be a strength of the WHO-2013 criteria.

Chapter 9

170

Two-hour glucose levelBy implementing the WHO-2013 diagnostic thresholds with a higher 2HG cut-off value may exclude a group of women who are currently diagnosed and treated for GDM according the WHO-1999 criteria (i.e. women with 2HG ≥7.8-≤8.4 mmol/l). There is a lack of data on whether women with a 2HG level between 7.8 and 8.5 mmol/l can be safely left untreated. We demonstrated that this category of women had pregnancy outcomes comparable to those of women with normal glucose tolerance (Chapter 7). Based on these findings, it seems that these women could be safely untreated. However, according to the current guideline these women were treated for GDM, and all received dietary counselling, while 20.5% were treated additionally with insulin according to our treatment protocol. We postulate that withholding treatment in these women will increase the proportion of LGA neo-nates in this group by 10-30%. A recent exciting study by Farrar et al., demonstrated that even women with a two-hour post load glucose level ≥7.5 mmol/l are at in-creased risk of adverse outcomes.3 The diagnostic 2HG thresholds (2HG ≥7.5 mmol/l for Caucasian women and 2HG ≥7.2 for South Asian women) proposed by these authors are therefore much lower when compared with the WHO-2013 criteria. Also In the United Kingdom, the National Institute for health and Care Excellence (NICE) guideline 2015, recommends diagnostic criteria which are different from the WHO-2013 thresholds (75-g OGTT; FG ≥5.6 mmol/l and/or 2HG ≥7.8 mmol/l).The NICE guideline recommends the older WHO-1999 2HG cut-off value for diagnosis of GDM, because of limited evidence and fears for medicalization of pregnancy by applying the WHO-2013 criteria.24

Prevalence of GDMThe prevalence of GDM largely depends on the screening strategy, the applied diagnostic strategies and the population studied.25 Studies have demonstrated that by implementing the new WHO-2013 criteria the prevalence of GDM will rise ex-tensively.26 In this thesis, we showed – in a selected cohort of women at high risk of GDM – that the prevalence of GDM was 22% if the WHO-1999 criteria were applied and 31% if the WHO-2013 criteria were used (Chapter 7). By applying the WHO-2013 criteria more women were classified as having GDM, but this is by default on the basis of the definition of 5.1 mmol/l as an elevated FG level. The WHO-2013 criteria also recommend an one-hour post load glucose value for GDM diagnosis. It should be noted that data for one-hour post load glucose value were not collected in our GDM cohort. It is therefore possible that the currently reported GDM prevalence is an underestimation.

Summary

171

9

Obesity – what are we treating?The prevalence of GDM is also rising due to increasing prevalence of overweight and obesity in women during reproductive age.26 Maternal obesity is a major risk factor for GDM and T2DM.27,28 Moreover, obesity and GDM are both associated with insulin resistance and hyperglycaemia.29 In our GDM populations, the majority of the women were overweight or obese and had other features of the metabolic syn-drome, such as chronic hypertension (Chapter 3, 7, 8). The women classified based on the FG cut-off value of the WHO-2013 criteria (FG ≥5.1-≤6.9 mmol/l) were more likely than women with normal glucose tolerance to be obese (BMI ≥30 kg/m2) and hypertensive.

Obesity and also maternal weight gain during pregnancy are major risk factors for adverse pregnancy outcomes, including LGA neonates.30-32 Maternal obesity and weight gain are also important confounders in the association between mild hyperglycaemia and adverse pregnancy outcomes. This is supported by an analysis from the HAPO cohort, which demonstrated that high maternal BMI, independent of maternal hyperglycaemia, is associated with increased risk of pregnancy com-plications.29 The HAPO cohort also showed that a combination of obesity and GDM pregnancy has a greater impact on adverse pregnancy outcomes than either of these risk factors alone.29

To reduce the short- and long term risks connected to GDM there is an urgent need for safe and effective lifestyle interventions. Women with obesity may profit from lifestyle changes during pregnancy to achieve and maintain adequate glucose control, however weight loss during pregnancy is not recommended.33,34 In addition, studies have demonstrated that treatment of obesity and reducing weight gain dur-ing pregnancy had almost no effect on delivering an LGA neonate.35 Therefore, it is a better suggestion that women with obesity receive standard lifestyle interventions before pregnancy, including advice about a healthy diet and aiming for and main-taining a healthy BMI. This is supported by a study of Zang et al., who showed that adherence to a healthy lifestyle (maintaining a healthy body weight, a healthy diet, regular exercise, and not smoking) before pregnancy was associated with a reduced risk of GDM.36 It should be debated to propose that all women with GDM risk factors (including having a family history of diabetes or having a history of GDM) and who tested negative for GDM should receive standard lifestyle intervention support, since we showed that GDM-high risk women with normal glucose tolerance (i.e. a normal OGTT) also had an increased risk of having an LGA neonate. A recent inter-vention study suggested that moderate lifestyle intervention in pregnant women who are at high risk for developing GDM reduced the incidence of GDM by 39%.37

Chapter 9

172

Thyroid function – maternal weight and GDMAnother risk factor for adverse pregnancy outcomes is thyroid dysfunction, includ-ing low and high FT4 levels within the normal range.38-40 Moreover, there are as-sociations reported between low FT4 levels throughout pregnancy and maternal weight.41,42 As mentioned earlier, maternal weight gain and obesity during preg-nancy are associated with GDM and also with an increased risk of adverse outcomes. Recently several studies have reported associations between thyroid function (low FT4) and the development of GDM.43-45 Haddow et al., showed a reciprocal relation-ship between FT4 and maternal weight and a higher GDM rate in second trimester of pregnancy.45 We found that euthyroid women with GDM and low FT4 levels in second or third trimester of pregnancy had a higher pre-gestational BMI and showed a trend to a higher weight gain during pregnancy (Chapter 5). We found no differences in adverse pregnancy outcomes, this may in part due to the limited sample size. More insight into the precise effect of thyroid function in GDM (includ-ing diabetes control, weight gain and obesity) is needed.

Impact on healthcareWe showed that about 20-30% (depending on the applied diagnostic criteria) of the women screened for GDM had abnormal OGTT results, necessitating referral, active counselling and treatment (Chapter 7). By adopting the new WHO-2013 diagnostic criteria the prevalence of GDM will increase and this will have a major impact on the costs and the capacity of healthcare systems. There is limited evidence on the cost-effectiveness of GDM treatment when diagnosed according the new diagnostic criteria. The study by Duran et al., evaluated the healthcare costs of the new diag-nostic criteria compared with the Carpenter and Coustan (CC) criteria (100-g OGTT, 2 abnormal values on; FG ≥5.3 mmol/l; and/or 1HG ≥10.0 mmol/l; and/or 2HG ≥8.6 mmol/l; and/or 3-h glucose value ≥7.8 mmol/l). This study showed that the use of new diagnostic criteria is associated with an improvement in pregnancy outcomes and that fewer women needed insulin therapy compared with the CC criteria. They concluded, that the new criteria did not increase total healthcare costs, because of lower rates of caesarean sections and neonate admission to the intensive care united.46

Shared-care modelAdopting the new diagnostic criteria will generate a group of women with mild GDM, who can be possible treated more often with lifestyle advice and therefore require less intensive monitoring than women with more severe GDM. In this thesis, we showed that the WHO-2013 criteria indeed reduced the need for insulin treat-

Summary

173

9

ment and there were more spontaneous deliveries when compared with women diagnosed according the WHO-1999 criteria (Chapter 8).

In this context, we allowed the recognition of a more complex-care group of insulin-treated women with GDM, but on the other hand potential low risk group of women who can be treated with diet alone, and would possibly be referred back to their midwives in primary care (Chapter 4). A few hospitals in the Netherlands already employ a shared-care model between primary and secondary care for GDM. We found various relevant factors predicting the need for additional insulin therapy in GDM. However, it was not possible to identify a circumscribed low risk diet-treated group from our data based on pregnancy outcomes. Therefore, there remains uncertainty regarding the possible development of pregnancy-related complications for an individual patient.

LONG-TERM HEALTH

Post-partum care – maternal type 2 diabetes Prevention of T2DM after GDM has become an increasingly important issue, since there has been a sharp rise in the incidence of women with obesity and GDM.26,47 Epidemiological studies have clearly shown that women with a history of GDM are at increased risk of developing pre-diabetes and T2DM.6,7 In addition, a recent study showed that women with a history of GDM are also at increased risk for the devel-opment of cardiovascular diseases, even in the absence of T2DM.48 The increasing incidence of obesity and diabetes will have a major impact on the medical cost in the upcoming years, and are estimated to increase by £1.9-2 billion/year in the United Kingdom by 2030.49 Therefore, early diagnosis of T2DM and perhaps better ways to identify those women who will develop cardiovascular diseases in women with GDM is important.

Although the current Dutch guidelines provide specific recommendations for the post-partum screening of women with GDM, until recently it was unclear how well these guidelines were implemented.18,19 We found that despite the extensive counselling and treatment in the hospital setting, follow-up of women with a history of GDM was unstructured, and the number of women who were regularly screened for health behaviour or development of T2DM in general practice was very small (Chapter 6). Due to the low numbers of postpartum glucose testing, data on development of T2DM after GDM in the Netherlands are very limited. Recently, these findings are supported by other investigators in the Netherlands.50 The study by Brink et al., also demonstrated that (long-term) postpartum screening was sub-optimal, only 33% of the women in their population were screened in the first year

Chapter 9

174

postpartum.50 Our findings underline the importance to improve communication between primary and secondary care and the awareness among women with a history of GDM.

The long-term postpartum follow-up clearly requires improvement in the Netherlands. In Table 1, we summarized several recommendations to improve the postpartum care for women with a history of GDM.

Moreover, there is clearly more need for lifestyle coaching programs/self-management for women with a history of GDM. These programs can help women to adopt a healthy lifestyle and make them aware about the future risk of T2DM. Lifestyle interventions after pregnancy can also reduce the risk of having GDM in a future pregnancy.

Neonates of mothers with GDM – foetal programmingThere is also growing evidence that obesity and T2DM prevalence is rising in the offspring of mothers with GDM.8-10 Metabolic changes during pregnancy (both under- nutrition and over nutrition) can lead to program adaptations in the foetus metabolism, with potential consequences for growth and metabolism in later life (Chapter 2).51 This topic is still contradictory and awaiting confirmation. Criticisms have suggested that the association between hyperglycaemia in utero and obesity in the offspring may be explained by confounding factors, such as an unhealthy lifestyle or obesity in the parents.52 However, there are data that obesity and T2DM in early adulthood is also more prevalent in offspring of women with type 1 DM, suggesting that hyperglycaemia in utero can contribute to programming of the offspring with a metabolic syndrome fenotype.8

Lifestyle interventions during pregnancy are necessary to achieve normal gly-caemic control and minimize the risk of hyperglycaemia in utero. Moreover, lifestyle interventions after pregnancy are also necessary for both the mother and child. As already mentioned, in women with a history of GDM lifestyle intervention after pregnancy can reduce the risk of T2DM and having GDM in a future pregnancy. In addition, lifestyle intervention for the mother and their families can stimulate and optimize family lifestyle.

Summary

175

9

TABLE 1. Recommendations to improve the postpartum care for women with a history of gestational diabetes mellitus.

Recommendations

Six-weeks postpartum visitInternist/GP - Evaluate glucose values, HbA1c, and lipid profile

- Give verbal and written information on future risk of T2DM and lifestyle advices- Give verbal and written advice to visit the GP for annual glucose testing

After the postpartum visit (and for women who did not visit the six-weeks postpartum visit):- Send a discharge letter to GP, including an advice to invite their patient for

follow-up glucose testing – every year for five years- Send a copy of the discharge letter to the patient with a brochure about

the future risk of T2DM. Include information about glucose screening at the GP, healthy weight (BMI calculator), Dutch Food Choice guidelines, Dutch guidelines physical activity, and useful suggestions for help/support to change lifestyle

Long-term follow-upGP

- Mark women with a history of GDM and connect them to a track system for five years

- Send a reminder for follow-up glucose testing to the women – once a year for the next five years

Annual follow-up glucose screening:- Evaluate glucose values, HbA1c, and lipid profile - Repeat the future risk of T2DM and lifestyle advices- Refer women with overweight/obesity to visit a dietician- Extra glucose screening preconception in women planning a new pregnancy

Public HealthEarly Childhood Centers

- Remind women to visit the GP for annual glucose testing- Organise regional meetings for women with a history of GDM about lifestyle,

including diet and physical activity- Advise and remind women about other regional meeting/activities at the

Early Childhood Center useful for women with a history of GDM (i.e. lifestyle, breastfeeding)

- Give information where women can find help/support to change their lifestyle

Abbreviations: GDM, gestational diabetes mellitus; GP, general practitioner; T2DM, type 2 diabetes mellitus.

Chapter 9

176

CONCLUSION

In conclusion, in this thesis we have shown that the currently used national guide-line for screening and treatment of GDM is successful in reducing the risk of short-term adverse pregnancy outcomes, but not in reducing the likelihood of having an LGA neonate with a possible unfavourable metabolic profile later in life. In order to further optimize GDM care and pregnancy outcomes, this thesis supports the use of a lower fasting glucose level in the Dutch national guideline for GDM diagnosis. At the moment, there is limited evidence to support a higher 2HG level for the diagno-sis of GDM. We have also shown that the long-term care for GDM is far from optimal and requires further improvement to lower the risk of T2DM after GDM.

Recommendations for further researchIn this general discussion there are several topics discussed that deserve further research. First, a randomized controlled trial directly comparing the diagnostic ap-proaches (WHO-1999 criteria versus WHO-2013 criteria) could determine whether treatment of women with mild GDM is beneficial and cost- effective. Secondly, we need more information whether women with a 2HG cut-off value between ≥7.8-≤8.4 mmol/l can be safely left untreated or whether even a stricter 2HG cut-off for establishing the diagnosis of GDM and instituting treatment may further improve pregnancy outcomes. Also the mode of treatment deserve further attention. Insulin therapy is the medication of choice in GDM as recommended in most international guidelines, although drug treatment in guidelines is highly variable. The use of blood glucose-lowering agents in GDM pregnancy has gained considerable interest as an alternative for insulin therapy. On the basis of current evidence, the use of metformin in pregnancy seems to be safe with similar outcomes to those treated with insulin therapy. However, there are uncertainties regarding metformin use and the possible short-term risk of premature delivery and this deserve further research. Thirdly, given the fact that several hospitals in the Netherlands employ a shared-care model between primary and secondary care for GDM, there appears to be a clear need for prospective studies investigating the safety of treating women with GDM who are managed with diet only in primary care. Questions are whether this can be done safely on a large scale, are there better ways to estimate risk of pregnancy-related complications, and what measures need to be taken to ensure proper care for the mother and the newborn in case of unexpected complications, for instance neonatal hypoglycaemia monitoring.

It has to stressed that, if we want to break the vicious circle of obesity, studies on preventive strategies like lifestyle interventions before/ during/ after pregnancy are warranted in the growing number of women with obesity and GDM carrying an

Summary

177

9

increased risk of T2DM after pregnancy. Such strategies well can be cost-effective, as they may reduce the number of referrals to a hospital because of GDM diagnosis, and may limit the need of exogenous insulin treatment. And finally, there is incon-sistency regarding the association between hyperglycaemia in utero and the risk of long-term health consequences for the offspring. Therefore there is an urgent need for long-term GDM-offspring studies regarding the role of foetal program-ming including adequate control for confounding factors. This should also include evaluation of the possible long-term consequences of specific treatments during pregnancy, given the concerns raised about the possible effects of metformin (Chapter 2), a frequently used diabetes drug, on gonadal function in offspring.

Chapter 9

178

REFERENCES


















18. The Dutch Society of Obstetrics and Gynaecology. Diabetes mellitus and pregnancy. Clinical guideline version 2.0. 2010. Available from: http://www.nvog-documenten.nl/index.php?pagina=/richtlijn/item/pagina.php&richtlijn_id=863, accessed 19 June 2017.

Summary

179

9

19. Rutten GEH, de Grauw WJC, Nijpels G, et al. NHG standard diabetes mellitus type 2. Huisarts Wet. 2013;56:512-25.


21. World Health Organization (WHO). Diagnostic criteria and Classification of Hyperglycemia First detected in pregnancy. 2013. Available from: http://apps.who.int/iris/bitstream/10665/85975/1/WHO_NMH_MND_13.2_eng.pdf, accessed 19 June 2017.

22. Hammoud NM, de Valk HW, Biesma DH, Visser GH. Gestational diabetes mellitus diagnosed by screening or symptoms: Does it matter? J Matern Fetal Neonatal Med. 2013;26:103-5.

23. Sweeting AN, Ross GP, Hyett J, et al. Gestational diabetes mellitus in early pregnancy: Evidence for poor pregnancy outcomes despite treatment. Diabetes Care. 2016;39:75-81.

24. National Institute for Health and Care Excellence. Diabetes in Pregnancy: Management of Diabe-tes and its Complications from Pre-conception to the postnatal period. Clinical Guideline NG3. 2015. Available from: https://www.nice.org.uk/guidance/ng3, accessed 19 June 2017.

25. Farrar D. Hyperglycemia in pregnancy: Prevalence, impact, and management challenges. Int J Womens Health. 2016;8:519-27.


27. Chu SY, Callaghan WM, Kim SY, et al. Maternal obesity and risk of gestational diabetes mellitus. Diabetes Care. 2007;30:2070-6.

28. Torloni M, Betrán A, Horta B, et al. Prepregnancy BMI and the risk of gestational diabetes: A systematic review of the literature with meta‐analysis. Obes Rev. 2009;10:194-203.

29. HAPO Study Cooperative Research Group. Hyperglycaemia and adverse pregnancy outcome (HAPO) study: Associations of GDM and obesity with pregnancy outcomes. Diabetes Care. 2012;35:780-6.

30. Ehrenberg HM, Mercer BM, Catalano PM. The influence of obesity and diabetes on the prevalence of macrosomia. Obstet Gynecol. 2004;191:964-8.

31. Black MH, Sacks DA, Xiang AH, Lawrence JM. The relative contribution of prepregnancy over-weight and obesity, gestational weight gain, and IADPSG-defined gestational diabetes mellitus to fetal overgrowth. Diabetes Care. 2013;36:56-62.

32. Dodd JM, Grivell RM, NGUYEN A, Chan A, Robinson JS. Maternal and perinatal health outcomes by body mass index category. Aust N Z J Obstet Gynaecol. 2011;51:136-40.

33. Langer O. Obesity or diabetes: Which is more hazardous to the health of the offspring? J Matern Fetal Neonatal Med. 2016;29:186-90.

34. Langer O. Management of obesity in GDM: Old habits die hard. J Matern Fetal Neonatal Med. 2008;21(3):165-171.

35. Oteng-Ntim E, Varma R, Croker H, Poston L, Doyle P. Lifestyle interventions for overweight and obese pregnant women to improve pregnancy outcome: Systematic review and meta-analysis. BMC med. 2012;10:1.

36. Zhang C, Tobias DK, Chavarro JE, et al. Adherence to healthy lifestyle and risk of gestational diabetes mellitus: Prospective cohort study. BMJ. 2014;349:g5450.

Chapter 9

180

37. Koivusalo SB, Rono K, Klemetti MM, et al. Gestational diabetes mellitus can be prevented by lifestyle intervention: The Finnish gestational diabetes prevention study (RADIEL): A randomized controlled trial. Diabetes Care. 2016;39:24-30.

38. Medici M, Korevaar TI, Schalekamp-Timmermans S, et al. Maternal early-pregnancy thyroid func-tion is associated with subsequent hypertensive disorders of pregnancy: The generation R study. J Clin Endocrinol Metab. 2014;99:E2591-8.

39. Korevaar TI, Chaker L, Medici M, et al. Maternal total T4 during the first half of pregnancy: Physi-ologic aspects and the risk of adverse outcomes in comparison with free T4. Clin Endocrinol (Oxf ). 2016;85:757-63.

40. Medici M, Timmermans S, Visser W, et al. Maternal thyroid hormone parameters during early pregnancy and birth weight: The generation R study. J Clin Endocrinol Metab. 2012;98:59-66.

41. Bassols J, Prats-Puig A, Soriano-Rodríguez P, et al. Lower free thyroxin associates with a less favor-able metabolic phenotype in healthy pregnant women. J Clin Endocrinol Metab. 2011;96:3717-23.

42. Knight BA, Shields BM, Hattersley AT, Vaidya B. Maternal hypothyroxinaemia in pregnancy is asso-ciated with obesity and adverse maternal metabolic parameters. Eur J Endocrinol. 2016;174:51-7.

43. Yang S, Shi F, Leung PC, Huang H, Fan J. Low thyroid hormone in early pregnancy is associated with an increased risk of gestational diabetes mellitus. J Clin Endocrinol Metab. 2016;101:4237-43.

44. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol. 2008;112:85-92.

45. Haddow JE, Craig WY, Neveux LM, et al. Free thyroxine during early pregnancy and risk for gesta-tional diabetes. PloS One. 2016;11:e0149065.

46. Duran A, Saenz S, Torrejon MJ, et al. Introduction of IADPSG criteria for the screening and diag-nosis of gestational diabetes mellitus results in improved pregnancy outcomes at a lower cost in a large cohort of pregnant women: The St. Carlos gestational diabetes study. Diabetes Care. 2014;37:2442-50.

47. Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: A systematic analysis for the global burden of disease study 2013. Lancet. 2014;384:766-81.

48. Retnakaran R, Shah BR. Role of type 2 diabetes in determining retinal, renal, and cardiovascular outcomes in women with previous gestational diabetes mellitus. Diabetes Care. 2017;40:101-8.

49. Wang YC, McPherson K, Marsh T, Gortmaker SL, Brown M. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet. 2011;378:815-25.

50. Brink HS, Alkemade M, van der Lely AJ, van der Linden J. Investigating screening for diabetes in women with a history of gestational diabetes. Neth J Med. 2016;74:429-33.

51. Hales CN, Barker DJP. Type 2 (non-insulin-dependent) diabetes mellitus: The thrifty phenotype hypothesis. Diabetologia. 1992;35:595-601.

52. Donovan LE, Cundy T. Does exposure to hyperglycaemia in utero increase the risk of obesity and diabetes in the offspring? A critical reappraisal. Diabet Med. 2015;32:295-304.

Samenvatting

185

Samenvatting

S

ZwangerschapsdiabetesZwangerschapsdiabetes wordt gedefinieerd als verhoogde bloedglucosewaarden die voor het eerst worden vastgesteld tijdens de zwangerschap. Indien zwanger-schapsdiabetes in het eerste trimester (vóór 12 weken) van de zwangerschap wordt vastgesteld, moet een al aanwezige (type 2) diabetes worden overwogen. Bij de meeste vrouwen met zwangerschapsdiabetes normaliseren de bloedglucose-waarden na de zwangerschap.1 Zwangerschapsdiabetes komt in ongeveer 14% van alle zwangerschappen voor en het aantal zal naar verwachting blijven stijgen.2

Onbehandelde zwangerschapsdiabetes verhoogt de kans op zwangerschap-scomplicaties zoals een kind met een te hoog geboortegewicht (macrosomie), geboortetrauma, preeclampsie en keizersnede.3-5 Na de zwangerschap hebben vrouwen met een doorgemaakte zwangerschapsdiabetes een verhoogde kans op het ontwikkelen van type 2 diabetes en hart- en vaatziekten.6-10 Ook is er steeds meer bewijs dat kinderen van moeders met zwangerschapsdiabetes op latere leeftijd een verhoogde kans hebben op het ontwikkelen van overgewicht en type 2 diabetes.11-13 Interventie studies hebben aangetoond dat vroege diagnose en adequate behandeling van vrouwen met zwangerschapsdiabetes de kans op zwangerschapscomplicaties kan verlagen.14,15 Echter er is wereldwijd geen duidelijk en uniform beleid rond de diagnose en de behandeling van zwangerschapsdiabe-tes.16

Nederlandse richtlijn voor screening en behandeling van zwangerschapsdiabetesIn Nederland wordt sinds 2010 gebruik gemaakt van de richtlijn “Diabetes Mellitus en Zwangerschap” van de Nederlandse Vereniging voor Obstetrie en Gynaecologie (NVOG) voor de screening en behandeling van zwangerschapsdiabetes. In deze richtlijn wordt geadviseerd om vrouwen met een verhoogde kans op zwanger-schapsdiabetes te screenen tussen 24 en 28 weken zwangerschapsduur met een 75-g orale glucose tolerantie test (OGTT).17 Voor de diagnose van zwangerschaps-diabetes wordt er gebruik gemaakt van de Wereldgezondheidsorganisatie (WHO) diagnostische criteria, welke dateren uit het jaar 1999; een nuchtere glucosewaarde ≥7,0 mmol/l en/of 2-uurs glucosewaarde ≥7,8 mmol/l.17,18

Alle vrouwen gediagnosticeerd met zwangerschapsdiabetes worden behandeld met als hoofddoel het bereiken van normale bloedglucosewaarden tijdens de zwangerschap. De eerste stap in de behandeling is het aanpassen van de voeding. Als met voedingsadvies niet het gewenste resultaat wordt bereikt, namelijk nor-male bloedglucosewaarden zowel nuchter als na de maaltijd, is insuline therapie de tweede stap.17 Verder adviseert de nationale richtlijn om na de zwangerschap de bloedglucosewaarden te controleren om een eventuele ontstaande type 2 diabetes

186

Samenvatting

in een vroeg stadium op te sporen. Er wordt geadviseerd om bloedglucosecontrole te doen zes weken na de bevalling, en vervolgens dit jaarlijks te herhalen gedurende de daarop volgende vijf jaar.17,19

Internationale richtlijnen voor zwangerschapsdiabetesIn de afgelopen jaren zijn er veel nieuwe bevindingen gerapporteerd met betrek-king tot verhoogde bloedglucosewaarden van de moeder tijdens de zwangerschap en een toegenomen kans op zwangerschapscomplicaties.3,5 Dit heeft geleid tot hernieuwde discussies, zowel in ons land als internationaal, over de meest optimale diagnostische criteria voor zwangerschapsdiabetes. In 2010 heeft de “International Association of Diabetes and Pregnany Study Groups” (IADPSG) nieuwe diagnostische criteria geïntroduceerd, welke vervolgens zijn overgenomen door verschillende expert groepen en richtlijn commissies, inclusief de WHO in 2013. De diagnose wordt nog steeds gesteld via een 75-g OGTT, en de nieuwe afkapwaarden voor de diagnose zwangerschapsdiabetes zijn gesteld op een nuchtere glucosewaarde ≥5,1 mmol/l; en/of 1-uurs glucosewaarde ≥10,0 mmol/l; en/of 2-uurs glucosewaarde ≥8,5 mmol/l.20,21 Er is echter nog weinig bewijs dat met deze nieuwe diagnostische criteria de zwangerschapsuitkomsten zullen verbeteren. Tot op heden zijn in Ned-erland deze nieuwe WHO-2013 criteria nog niet overgenomen.

Het onderzoek beschreven in dit proefschrift heeft als doel om de Nederlandse nationale richtlijn voor de diagnose en behandeling van zwangerschapsdiabetes te evalueren. Wij hebben ons ten doel gesteld te onderzoeken wat de zwangerschap-suitkomsten zijn van vrouwen met zwangerschapsdiabetes met het toepassen van deze richtlijn. En ook vroegen wij ons af wat consequenties zouden zijn wanneer de huidige diagnostische criteria voor zwangerschapsdiabetes zouden worden vervangen door de WHO-2013 criteria.

Hoofdstuk 1 bestaat uit een algemene inleiding en beschrijft de doelen van dit proefschrift. Hoofdstuk 2 geeft een overzicht van de huidige internationale ken-nis met betrekking tot zwangerschapsdiabetes en de diverse aspecten van deze aandoening, waarover meer kennis noodzakelijk is (de zogenaamde “unmet needs”). Wij hebben de wetenschappelijke literatuur beoordeeld met betrekking tot de diverse diagnostische criteria, de verschillende mogelijkheden van behan-deling (dieet, insuline therapie, en ook de voor- en nadelen van het gebruik van orale bloedglucoseverlagende middelen), en de lange-termijn consequenties van zwangerschapsdiabetes.

187

Samenvatting

S

DEEL A: EVALUATIE VAN DE HUIDIGE NATIONALE RICHTLIJN

In Hoofdstuk 3 hebben wij de zwangerschapsuitkomsten geëvalueerd uit de peri-ode van 2011-2014, na de invoering van de nationale NVOG-richtlijn “Diabetes en Zwangerschap” voor screening en behandeling van zwangerschapsdiabetes. In het totaal werden 820 vrouwen met een eenlingzwangerschap en gediagnosticeerd met zwangerschapsdiabetes die in deze periode in het UMCG en Martini Zieken-huis werden behandeld, retrospectief onderzocht. De zwangerschapsuitkomsten werden vergeleken tussen vrouwen die konden worden behandeld met dieet alleen en vrouwen die moesten worden behandeld met aanvullende insuline therapie. De zwangerschapsuitkomsten van de algemene zwangeren populatie in Noord-Nederland werden gebruikt als referentiepopulatie (controlegroep). Wij vonden dat pasgeborenen van moeders met zwangerschapsdiabetes vaker te zwaar waren voor de duur van de zwangerschap (gedefinieerd als een geboortegewicht boven de 90ste percentiel) vergeleken met pasgeborenen van moeders in de algemene bevolking, 20% tegenover 11%. Het aantal ernstige zwangerschapscomplicaties (bv. geboortesterfte) was laag in de vrouwen met zwangerschapsdiabetes. Boven-dien waren er geen grote verschillen in zwangerschapsuitkomsten tussen dieet behandelde vrouwen of vrouwen behandeld met aanvullende insuline therapie. Wij concludeerden dat de huidige Nederlandse richtlijn voor zwangerschapsdiabetes succesvol lijkt in het bereiken van een laag aantal ernstige zwangerschapscompli-caties. Echter het percentage pasgeborenen dat te zwaar is voor de duur van de zwangerschap was hoger bij vrouwen met zwangerschapsdiabetes vergeleken met de algemene bevolking.

Hoofdstuk 4 had als doel om te onderzoeken of wij bij de eerste consultatie die vrouwen konden identificeren, bij wie de meer complexe behandeling met insuline noodzakelijk was, en aan de andere kant een potentiële “laag-risico” groep van vrouwen die alleen hoefden te worden behandeld met een voedingsadvies/dieet, en met goede zwangerschapsuitkomsten. Het aantal vrouwen met een verwijzing voor zwangerschapsdiabetes behandeling in de tweede lijn (ziekenhuis) is in de laatste jaren flink gestegen. Voor deze studie is er gebruik gemaakt van de uitkom-sten van de 820 vrouwen met zwangerschapsdiabetes hierboven genoemd. Wij vonden dat verschillende factoren de behoefte van aanvullende insuline therapie voorspelden: - Eerdere zwangerschapsdiabetes;- Familielid met diabetes; - Een eerder kind met een geboortegewicht ≥4500 gram;- Etniciteit, met name afkomstig zijn uit het Midden-Oosten of Noord-Afrika; - Multipariteit (vrouwen die vaker dan één keer zijn bevallen);

188

Samenvatting

- Overgewicht, gedefinieerd als een body mass index (BMI) ≥30 kg/m2 voor de zwangerschap;

- Een verhoogde nuchtere en 2-uurs glucosewaarde na een 75-g OGTT op het moment van de diagnose zwangerschapsdiabetes.

Een nuchtere glucosewaarde ≥5,5 mmol/l op het moment van de diagnose zwangerschapsdiabetes bleek de sterkste voorspeller voor de noodzaak van insuline therapie. Verder toonde deze studie aan dat vrouwen, die voor de eerste keer zwanger waren, en vrouwen met een grotere gewichtstoename tijdens de zwangerschap, meer zwangerschapscomplicaties hadden. Wij concludeerden dat de gevonden voorspellers voor aanvullende insuline therapie nuttig kunnen zijn voor het herkennen van een “complexe-zorg” groep van vrouwen met zwangersc-hapsdiabetes. Echter, op basis van onze gegevens kunnen wij niet met zekerheid voorspellen welke vrouwen een grotere kans hebben op zwangerschapscomplica-ties en eventueel veilig kunnen worden terugverwezen naar de eerste lijn.

In Hoofdstuk 5 hebben wij het potentiële effect van de schildklierfunctie op zwangerschapsuitkomsten in vrouwen met zwangerschapsdiabetes onderzocht. Voor deze studie zijn de medische gegevens van 222 vrouwen met zwangerschaps-diabetes en een eenlingzwangerschap retrospectief bekeken. De schildklierfunctie testen TSH en FT4 waarden waren gemeten in het tweede trimester (tussen 24 en 29 weken), tijdens het eerste consult op de polikliniek. Hierbij hebben wij met name beoordeeld of een laag-normale of hoog-normale schildklierfunctie de kans op zwangerschapscomplicaties deed toenemen. Onze hypothese was dat vrouwen met lage FT4 waarden een grotere kans hebben op overmatige gewichtstoename tijdens de zwangerschap en mede daardoor ongunstige zwangerschapsuitkom-sten. Wij vonden echter geen grote verschillen in ongunstige uitkomsten voor het kind, of er nu sprake was van een relatief lage of relatief hoge (maar nog wel normale) schildklierfunctie. Vrouwen met zwangerschapsdiabetes en lage FT4 waarden (en/of hoog-normale TSH waarden) hadden echter een hogere BMI voor de zwangerschap en er was een trend dat zij méér in gewicht toenamen tijdens de zwangerschap dan vrouwen met hoog-normale FT4 waarden. Deze laatste bevind-ing is in overeenstemming met onze hypothese.

In Hoofdstuk 6 hebben wij de nazorg voor vrouwen met zwangerschapsdia-betes in de tweede lijn (ziekenhuis) en eerste lijn (huisarts) geëvalueerd. Daarnaast hebben wij de leefstijl van deze vrouwen middels een aantal vragenlijsten beter in kaart gebracht. In totaal zijn 215 vrouwen uitgenodigd om deel te nemen. Deze vrouwen waren in het UMCG behandeld vanwege zwangerschapsdiabetes in de jaren 2011 en 2012. In het totaal hebben 77 vrouwen de vragenlijsten ingevuld. De huisartsen van deze vrouwen werden ook gevraagd deel te nemen aan de studie en in totaal reageerden 61 huisartsen. Meer dan 90% van de vrouwen was 6

189

Samenvatting

S

weken na de bevalling voor poliklinische consultatie en bloedcontrole gezien in het Universitair Diabetescentrum. Zij werden vervolgens voor verdere begeleiding aan hun huisarts overgedragen, me het schriftelijke advies om conform de richtlijnen (NVOG 2010) tenminste jaarlijks de bloedglucosewaarden te controleren. Echter, de deelnemende vrouwen en hun huisartsen rapporteerden lage aantallen van lange termijn (jaarlijks) nazorg bezoeken en bloedglucosecontrole in de eerste lijn. Van de 61 huisartsen hebben 12 huisartsen aangegeven dat een bloedglucosecontrole was uitgevoerd binnen een periode van 12 tot 14 maanden na de zwangerschap; slechts twee vrouwen waren gedurende drie opeenvolgende jaren getest. Boven-dien vonden wij dat slechts weinig vrouwen daadwerkelijk een gezonde leefstijl had overgenomen, gedefinieerd aan de hand van de richtlijnen Goede Voeding en de Nederlandse Norm Gezond Bewegen. Op grond van deze gegevens werd de voorzichtige conclusie getrokken dat de lange-termijn nazorg voor vrouwen met doorgemaakte zwangerschapsdiabetes voor verbetering vatbaar is.

DEEL B: EVALUATIE VAN DE NIEUWE INTERNATIONALE DIAGNOSTISCHE CRITERIA

In Hoofdstuk 7 hebben wij onderzocht wat de invloed zou zijn van het invoeren van de nieuwe WHO-2013 criteria, in plaats van de verouderde WHO-1999 criteria, op de prevalentie van zwangerschapsdiabetes en de zwangerschapsuitkomsten. Hiervoor hadden wij de beschikking over de bloedglucose gegevens van 10.642 vrouwen die een 75-g OGTT hadden ondergaan tussen januari 2011 en september 2016, met als indicatie risicofactoren van zwangerschapsdiabetes of dan wel verschijnselen suggestief hiervoor (met name een naar verhouding groot kind, macrosomie). Mid-dels intensief statusonderzoek hebben wij de zwangerschapsuitkomsten van 4.431 vrouwen kunnen verzamelen via de deelnemende praktijken van verloskundigen, het Martini Ziekenhuis en het UMCG, en deze werden vergeleken met vrouwen met normale glucose tolerantie (een normale OGTT uitslag). Het percentage geteste vrouwen met zwangerschapsdiabetes neemt toe van 22% naar 31% wanneer de nieuwe WHO-2013 criteria werden toegepast in plaats van die van de WHO-1999 criteria. Wij hebben ook aangetoond dat bij toepassing van deze afkapwaarden een groep vrouwen werd geïdentificeerd (vrouwen met een nuchtere glucosewaarde tussen de 5,1 en 7,0 mmol/l) met meer ongunstige karakteristieken (hoog BMI en vaker een te hoge bloeddruk) vergeleken met vrouwen met een normale glucose tolerantie. Daarnaast hadden deze vrouwen vaker een ongunstige zwangersc-hapsuitkomst vergeleken met vrouwen met een normale glucose tolerantie of de algemene zwangeren populatie. De vrouwen die eventueel gemist zouden

190

Samenvatting

worden door de hogere 2-uurs glucosewaarde bij toepassing van de WHO-2013 criteria (vrouwen met een 2-uurs glucosewaarde tussen 7,8 en 8,5 mmol/l) hadden vergelijkbare zwangerschapsuitkomsten met vrouwen met een normale glucose tolerantie. Echter deze vrouwen werden behandeld voor zwangerschapsdiabetes volgens de nationale richtlijn, met zowel strenge voedingsadviezen als (20%) met insuline. Deze vrouwen niet behandelen zal hun zwangerschapsuitkomsten zeker ongunstig beïnvloeden.

TABEL 1. Diagnostische criteria voor zwangerschapsdiabetes en streefwaarden voor behandeling.

Diagnostische criteria voor zwangerschapsdiabetes

WHO-1999* WHO-2013*

Glucosewaarden (mmol/l)

Nuchter ≥7,0 ≥5,1

75-gram OGTT 1-uurs 2-uurs

-≥7,8

≥10,0≥8,5

Streefwaarden voor de behandeling van zwangerschapsdiabetes

Alleen voedingsadvies Aanvullende insuline therapie

Glucosewaarden (mmol/l)

Nuchter ≤5,3 >5,3

1-uur na de maaltijd ≤7,8 >7,8

Afkortingen: WHO, Wereldgezondheidsorganisatie; OGTT, orale glucose tolerantie test.* Eén abnormale waarde is voldoende voor de diagnose zwangerschapsdiabetes.

In Hoofdstuk 8 hebben wij de karakteristieken van de moeder en de zwangersc-hapsuitkomsten onderzocht van twee verschillende cohorten (groepen) zwangere vrouwen in Nederland, waarvan de eerste groep gediagnosticeerd en behandeld werd volgens de nieuwe WHO-2013 criteria, en de tweede volgens de ‘oude’ WHO-1999 criteria. Zoals eerder gesteld, hanteert de huidige Nederlandse nationale richtlijn de afkapwaarden van de WHO-1999 criteria voor de diagnose van zwanger-schapsdiabetes. Een aantal ziekenhuizen in Nederland heeft de nieuwe IADPSG/WHO-2013 criteria voor diagnose van zwangerschapsdiabetes al ingevoerd. Deze studie werd uitgevoerd in goede samenwerking met het Deventer Ziekenhuis, dat de nieuwe criteria in 2012 heeft ingevoerd. Vrouwen in beide cohorten werden be-handeld op basis van de nationale richtlijn voor zwangerschapsdiabetes (Tabel 1). Voor deze studie zijn de medische gegevens van 1386 vrouwen met zwangerschaps-diabetes en een eenlingzwangerschap retrospectief bekeken (437 vrouwen in het WHO-2013 cohort en 949 vrouwen in het WHO-1999 cohort). In deze studie hebben wij aangetoond dat vrouwen in het WHO-2013 cohort vaker overgewicht hadden en een te hoge bloeddruk tijdens de zwangerschap vergeleken met het WHO-1999 cohort. De vrouwen in het WHO-2013 cohort waren eerder gediagnosticeerd met

191

Samenvatting

S

zwangerschapsdiabetes, hadden minder vaak aanvullende insuline therapie nodig en hadden een hoger percentage spontane bevallingen en een lager percentage pasgeborenen te zwaar voor de zwangerschapsduur vergeleken met vrouwen in het WHO-1999 cohort. Geen andere verschillen in nadelige zwangerschapsuitkom-sten werden er gezien tussen de twee cohorten.

CONCLUSIE

In dit proefschrift hebben wij laten zien dat behandeling van vrouwen met zwanger-schapsdiabetes volgens de nationale richtlijn succesvol is in het verlagen van nadelige zwangerschapsuitkomsten. Echter onze behandeling is nog niet succesvol in het verlagen van de kans op het krijgen van een pasgeborene met een te hoog geboortegewicht voor de zwangerschapsduur. Dit is een belangrijk punt, aangezien deze kinderen een verhoogde kans hebben op een nadelig metabool profiel op latere leeftijd. Om de zorg voor zwangerschapsdiabetes verder te optimaliseren en zwangerschapsuitkomsten te verbeteren bevelen wij het gebruik aan van een la-gere nuchtere glucosewaarde voor de diagnose van zwangerschapsdiabetes. Op dit moment is er nog weinig bewijs om een hogere 2-uurs glucosewaarde te gebruiken voor de diagnose van zwangerschapsdiabetes. Wij hebben ook aangetoond dat de lange-termijn nazorg voor vrouwen met doorgemaakte zwangerschapsdiabetes niet optimaal is en er mogelijkheden liggen voor verbetering om de kans op het ontstaan van type 2 diabetes na zwangerschapsdiabetes te verkleinen.

192

Samenvatting

REFERENTIES

















17. Nederlandse Vereniging voor Obstetrie en Gynaecologie (NVOG). Diabetes en Zwangerschap. Richtlijn versie 2.0. Beschikbaar via: http://nvog-documenten.nl/index.php?pagina=/site/pagina.php&id=54321, geraadpleegd 5 juli 2017.


193

Samenvatting

S

19. Rutten GEH, de Grauw WJC, Nijpels G, et al. NHG standaard diabetes mellitus type 2. Huisarts Wet. 2013;56:512-25.

20. International Association of Diabetes and Pregnancy Study Groups Consensus Panel. Interna-tional association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33:676-82.

21. World Health Organization (WHO). Diagnostic criteria and Classification of Hyperglycemia first detected in pregnancy. Beschikbaar via: http://apps.who.int/iris/bitstream/10665/85975/1/WHO_NMH_MND_13.2_eng.pdf, geraadpleegd 5 juli 2017.

Acknowledgements/Dankwoord

Dankwoord

197

A

Dit proefschrift was niet tot stand gekomen zonder de inspanning en steun van vele mensen. Ik wil een aantal mensen in het bijzonder noemen.

Te beginnen met mijn promotoren prof. dr. B.H.R. Wolffenbuttel en prof. dr. P.P. van den Berg:

Beste Bruce, ik ben dankbaar dat je mij de kans hebt geboden om dit PhD traject te doen. Je hebt mij tijdens het gehele promotietraject veel vrijheid en vertrouwen gegeven en daardoor heb ik in de afgelopen drie jaar veel mogen leren. Ik heb altijd kunnen vertrouwen op je deskundigheid en wetenschappelijke inzicht. Daarnaast heb ik het erg gewaardeerd dat je ook tijd hebt gestoken in mijn persoonlijke ont-wikkeling. Bedankt!

Beste Paul, het was prettig om een tweede promotor en begeleider te hebben vanuit de afdeling Obstetrie & Gynaecologie. Op de belangrijke momenten heb je altijd even tijd gehad. Ook heb ik de maandelijkse overleggen met jou en Bruce erg gewaardeerd. Dit heeft mij het vertrouwen gegeven dat het echt allemaal wel goed zou komen. Bedankt dat je mijn tweede promotor wou zijn en bedankt voor je betrokkenheid.

Mijn copromotoren dr. H.L. Lutgers en dr. K. Hoogenberg:

Beste Helen, in het begin van mijn promotietraject was je mijn dagelijkse begelei-der en heb jij mij ontzettend goed op weggeholpen. Bedankt dat je altijd voor mij klaar stond wanneer ik je advies nodig had. Ik heb veel bewondering voor het feit dat je ondanks je drukke agenda altijd tijd gestoken hebt in mijn promotietraject, bedankt voor de fijne begeleiding.

Beste Klaas, bedankt voor je begeleiding vanuit het Martini Ziekenhuis. Je hebt altijd de tijd genomen om kritisch naar mijn manuscripten te kijken. Vaak belde jij mij nog even op om je feedback toe te lichten. Ik heb je eerlijkheid, directheid en deskundige uitleg zeer gewaardeerd. Bedankt voor de prettige samenwerking.

Prof. dr. H.M. Boezen, prof. dr. C. Mathieu en prof. dr. G.H.A. Visser hartelijk dank voor jullie tijd om mijn proefschrift als leescommissie te beoordelen.

Naast mijn promotieteam wil ik ook alle co-auteurs en mensen die mij hebben ge-holpen bij het tot stand komen van mijn manuscripten bedanken. Ik wil een aantal in het bijzonder bedanken:

198

Dankwoord

Dr. A.J. van Loon en Dr. F.J. Korteweg, beste Aren en Fleurisca, bedankt voor jullie hulp en betrokkenheid vanuit de afdeling Obstetrie & Gynaecologie van het Martini Ziekenhuis.

Dr. J.J. van Zanden, beste Jelmer, zonder de samenwerking en hulp vanuit Certe hadden wij nooit zoveel OGTT data kunnen verzamelen. Bedankt! Ook wil ik H. Hepkema-Geerligs bedanken, beste Hanny, bedankt dat je vanuit Certe mij hebt geholpen om alle verloskundigenpraktijken persoonlijk te benaderen.

Dr. J.J. Zwart en drs. E.A.R. Goedegebure, beste Joost en Rixt, hartelijk dank voor de prettige samenwerking vanuit Deventer.

Drs. C.A. Trompert, beste Chris, bedankt voor het meedenken vanuit de huisartsen-praktijk voor het postpartum artikel.

Dr. H. Groen, beste Henk, bedankt voor je hulp voor het verzamelen van de gege-vens van de algemene zwangeren populatie in Noord-Nederland.

Voor mijn laatste project is er veel data verzameld bij verschillende verloskundigen-praktijken. Zonder de hulp en gastvrijheid van deze praktijken was dit niet gelukt. Daarom wil ik de verloskundigen en overige medewerkers van de volgende prak-tijken graag bedanken: Fier! Verloskundigen, Verloskundigenpraktijk Hoogezand, Verloskundigenpraktijk La Vie, Verloskundigenpraktijk New Life, Verloskundige Stadspraktijk, Verloskundigenpraktijk ’t Stroomdal en Verloskundigenpraktijk Veen-dam.

Tevens zijn er meerdere geneeskundestudenten geweest die stage hebben gedaan op dit project en ook jullie wil ik bedanken: Bertine Schering, Dianne Klomp, Kirsten Scheuneman en Mick Baas. Jullie hebben mij ontzettend geholpen met het verza-melen en opschonen van de data.

Dianne jij was betrokken bij ons laatste project. Zonder jouw hulp was het verza-melen van de gegevens bij de verloskundigenpraktijken veel minder snel en soepel verlopen, bedankt. Ook wil ik Sebastian Klöppner en Julie van Amstel bedanken voor de hulp bij het verzamelen van de gegevens bij de verloskundigenpraktijken.

Dit promotietraject was in samenwerking met het Martini Ziekenhuis en daarom wil ik alle medewerkers betrokken bij de zwangerschapsdiabetes zorg van de afde-lingen Interne Geneeskunde (in het bijzonder dr. K. Hoogenberg, dr. A. Roos en dr.

Dankwoord

199

A

K. van Tol) en Obstetrie & Gynaecologie (in het bijzonder dr. A.J. van Loon en dr. F.J. Korteweg) bedanken.

Verder gaat mijn dank uit naar alle medewerkers van de afdeling Endocrinologie van het UMCG. In het bijzonder wil ik de (ex) kamergenoten noemen: Bernadette, Dineke, Edward, Jorien, Karin, Mariëlle, Marloes, Robert, Sandra en Thamara. Het is fijn om met medeonderzoekers op één kamer te zitten en de leuke en minder leuke dingen over onderzoek en niet-onderzoek gerelateerde onderwerpen met elkaar te kunnen delen. Iedereen bedankt voor de gezellige en leuke tijd!

Ook wil ik de medewerkers bedanken van de afdeling Obstetrie & Gynaecologie van het UMCG die mij hebben geholpen.

Mijn paranimfen: Sarah, we zijn al jaren vriendinnen en ik ben blij om zo’n lieve en waardevolle vriendin te hebben. Bedankt dat je mijn paranimf wil zijn. Dineke, wij kennen elkaar al sinds de master en uiteindelijk zijn we tegelijkertijd begonnen aan een promotietraject en bleven we ook nog eens kamergenoten. Je bent een super fijne collega en we hebben veel met elkaar kunnen delen (mailen) en lachen. Ik vind het daarom ook heel erg fijn dat je tijdens de verdediging als paranimf naast mij staat.

En als laatste mijn vriendinnen en (schoon)familie:

Antina, Christel, Laura, Maria, Mariëlle, en Sarah, ik ben dankbaar met vriendinnen als jullie. Bedankt voor alle gezelligheid en afleiding van de afgelopen jaren.

Peter en Jannie, Hanne en Jeroen, het is altijd fijn en gezellig om bij jullie thuis te komen. Bedankt voor al jullie belangstelling.

Anna en Marten, wat ben ik trots op jullie en wat hebben jullie een prachtig gezin. Daarnaast ben ik een enorm trotse tante van Laura en Twan. Bedankt voor alle gezelligheid en belangstelling.

Pap en Mam, bedankt voor jullie vertrouwen en steun. Ik ben heel erg blij met zulke lieve ouders die altijd voor ons klaar staan.

Rik, ik ben enorm dankbaar met zo’n lieve en geduldige vriend. Ondanks dat je regelmatig aan de andere kant van de wereld bent voor je werk, ben je er altijd voor mij.

About the author and list of publications

About the author and list of publications

203

A

ABOUT THE AUTHOR

Saakje Hillie (Sarah) Koning was born on December 29th 1989 in Zuidhorn, the Neth-erlands. In 2007 she graduated from Augustinus College Groningen. The same year she started her study Nutrition and Dietetics at the Hanzehogeschool Groningen and she received her Bachelor’s degree in 2011. From 2011-2012 she worked as a dietician. Her Master study on Health Sciences at the VU University in Amsterdam further nourished her enthusiasm for research. In 2014, she obtained her Master’s degree with a specialization in Nutrition and Health.

From 2014 till 2017 she worked as a PhD student under the supervision of prof. dr. B.H.R. Wolffenbuttel, prof. dr. P.P. van den Berg, dr. H.L. Lutgers and dr. K. Hoogen-berg at the department of Endocrinology and the department of Obstetrics and Gynaecology of the University Medical Center Groningen (UMCG). This PhD project was in collaboration with the Martini Hospital Groningen, department of Internal Medicine and department of Obstetrics and Gynaecology. During her PhD project she developed her skills as a researcher by presenting at several national and in-ternational conferences and by completing her training for the Graduate School of Medical Sciences Guide.

Sarah is working as a dietician at Diabeter Groningen and also as a researcher, in the field of diabetes, at the department of Endocrinology of the UMCG.

LIST OF PUBLICATIONS

1. Koning SH, Lutgers HL, Hoogenberg K, Trompert CA, van den Berg PP, Wolffenbuttel BH. Post-partum glucose follow-up and lifestyle management after gestational diabetes mellitus: general practitioner and patient perspectives. J Diabetes Metab Disord. 2016;15:56.

2. Koning SH, Hoogenberg K, Scheuneman KA, Baas MG, Korteweg FJ, Sollie KM, Schering BJ, van Loon AJ, Wolffenbuttel BH, van den Berg PP, Lutgers HL. Neonatal and obstetric outcomes in diet- and insulin-treated women with gestational diabetes mellitus: a retrospective study. BMC Endocr Disord. 2016;16:52.

3. Koning SH, Scheuneman KA, Lutgers HL, Korteweg FJ, van den Berg G, Sollie KM, Roos A, van Loon AJ, Links TP, van Tol KM, Hoogenberg K, van den Berg PP, Wolffenbuttel BH. Risk stratification for healthcare planning in women with gestational diabetes mellitus. Neth J Med. 2016;74:262-9.

4. Koning SH, Hoogenberg K, Lutgers HL, van den Berg PP, Wolffenbuttel BH. Gestational diabetes mellitus: current knowledge and unmet needs. J Diabetes. 2016;8:770-81.

5. Koning SH, Gansevoort RT, Mukamal KJ, Rimm EB, Bakker SJ, Joosten MM; PREVEND Study Group. Alcohol consumption is inversely associated with the risk of developing chronic kidney disease. Kidney Int. 2015;87:1009-16.