lable at ScienceDirect

Seminars in Fetal & Neonatal Medicine 15 (2010) 89–93

Contents lists avai

Seminars in Fetal & Neonatal Medicine

journal homepage: www.elsevier .com/locate/s iny

Obesity and gestational diabetes

T. Sathyapalan a, D. Mellor b, S.L. Atkin a,*

a Department of Diabetes, Endocrinology and Metabolism, Hull York Medical School, Hull, UKb Department of Diabetes, Endocrinology and Metabolism, University of Hull, Hull, UK

keywords:Gestational diabetesObesityOral glucose tolerance testPregnancy

* Corresponding author. Address: Michael White Churst Building, Hull Royal Infirmary, Anlaby Road, Hul675365; Fax: þ44 1482 5370.

E-mail address: Stephen.atkin@hyms.ac.uk (S.L. At

1744-165X/$ – see front matter � 2009 Elsevier Ltd.doi:10.1016/j.siny.2009.09.002

s u m m a r y

The prevalence of both obesity and gestational diabetes mellitus (GDM) is increasing worldwide. GDMaffects about 7% of all pregnancies and is defined as any degree of impaired glucose tolerance duringgestation. The presence of obesity has a significant impact on both maternal and fetal complicationsassociated with GDM. These complications can be addressed, at least in part, by good glycaemic controlduring pregnancy. The significance and impact of obesity in women with GDM are discussed in thisarticle, together with treatment options, the need for long-term risk modification and postpartumfollow-up.

� 2009 Elsevier Ltd. All rights reserved.

1. Introduction

Pregnancy is associated with physiological insulin resistanceand hyperinsulinaemia, features that predispose susceptiblewomen to develop diabetes during pregnancy. This resistancestems from placental secretion of diabetogenic hormones,including growth hormone, cortisol, placental lactogen, andprogesterone, as well as increased maternal adipose deposition,reduced exercise, and increased caloric intake. These physiologicalmetabolic changes ensure that the fetus has an ample supply of‘fuel’ and nutrients. Gestational diabetes mellitus (GDM) occurswhen maternal pancreatic islet function is insufficient to match theinsulin resistance associated with pregnancy. GDM is defined as anydegree of impaired glucose tolerance recognised during pregnancy.Most women with GDM have impaired glucose tolerance manifestonly in pregnancy, but some may have type 2 diabetes that wasunrecognised prior to pregnancy.

The insulin resistance, which is particularly prominent in thesecond half of pregnancy, is increased by any co-existent conditionsassociated with increased insulin resistance, so contributing to thedevelopment of GDM. In particular, obesity increases insulinresistance1,2 by a mechanism that may involve higher plasma levelsof triglycerides and non-esterified fatty acids, and lower plasmalevels of adiponectin.

entre for Diabetes, Brockle-l HU3 2JZ, UK. Tel.: þ44 1482

kin).

All rights reserved.

2. Obesity and GDM

The incidence of GDM in pregnancy in women who are obese ishigher than that of the general obstetric population (6–12% versus2–4%).3,4 GDM occurs in about 8.8% of pregnancies in the developedworld and the risk of GDM is directly proportional to maternal bodymass index (BMI; kg/m2). The overall risk of developing GDM forwomen is reported to be 2.9-fold with BMI�30 compared with BMI�20,5 but estimates vary with the population and BMI cut-offemployed, with levels of risk as high as 20-fold reported.6 Inaddition to the increased risk of obese women developing GDM,there is also an increased risk of type 2 diabetes, characterised bywhole-body insulin resistance and higher plasma insulin concen-trations. Weight loss and healthy lifestyle can help to prevent type 2diabetes and also appear to reduce the risk of GDM.7,8 On the otherhand, inter-pregnancy weight gain and increasing maternal ageworsens the risk of developing GDM.9,10

The rate of fetal or neonatal death in the offspring of womenwith type 2 diabetes or GDM is higher than in non-diabeticcontrols11; this mainly occurs as late fetal death. There is alsoa strong relationship between the perinatal mortality rate andmaternal obesity in pregnant women with type 2 diabetes. Majorcomplications of labour in obese women (pre-gravid BMI �30,compared with controls with pre-gravid BMI �30) include labourinduction failure, failure to progress in the first stage of labour,meconium-stained amniotic fluid, malpresentation, and shoulderdystocia.12 It has been reported that pre-gravid obesity and theseverity of GDM predicted an increase in congenital malformationsincluding cleft lip/palate, cardiac, genitourinary, digestive tract andskeletal abnormalities observed in the offspring in 4% of births.13

The programming of obesity and metabolic syndrome in the

T. Sathyapalan et al. / Seminars in Fetal & Neonatal Medicine 15 (2010) 89–9390

offspring of such pregnancies has the potential to exact an evengreater burden on future generations.14

3. Significance of GDM

Several adverse outcomes including pre-eclampsia, poly-hydramnios, fetal macrosomia, birth trauma, operative delivery,perinatal mortality and neonatal complications (hypoglycaemia,hyperbilirubinaemia, hypocalcaemia, erythremia) are associatedwith increasing levels of glucose impairment.15,16 There are alsopotential long-term consequences to the infant, such as develop-ment of obesity and diabetes during childhood, impaired fine andgross motor functions and higher rates of inattention and/orhyperactivity.17,18 In the mother, there is a 10% per year risk ofmaternal development of diabetes mellitus after the index preg-nancy with GDM. Glucose intolerance associated with GDMgenerally resolves postpartum; however, obese women witha history of GDM have a 2-fold increased prevalence of subsequenttype 2 diabetes compared with non-obese women.19

4. Screening for GDM

Further evaluation of any woman who has a random serumglucose value �11.1 mmol/L or a fasting serum glucose value�7.0 mmol/L is unnecessary, because these findings alone arediagnostic of diabetes, if confirmed on a subsequent day.20 The riskfactors of raised BMI, previous macrosomic baby, previous GDM,family history of diabetes, and family origin with a high prevalenceof diabetes should alert the clinician to screen those pregnantwomen for GDM. The 2 h 75 g oral glucose tolerance test (OGTT) isrecommended and interpreted according to the World HealthOrganization’s diagnostic criteria for GDM, that is fasting bloodglucose <7.8 mmol/L and 2 h postprandial 7.8–11 mmol/L. Womenwho have had GDM in a previous pregnancy can be offered earlyself-monitoring or an OGTT at 16–18 weeks and a further OGTT at28 weeks if the results are normal; in women with any of the otherrisk factors for GDM an OGTT can be offered at 24–28 weeks.Screening using fasting plasma glucose, random blood glucose orurine analysis for glucose is not recommended as they are tooinsensitive. Although screening is performed optimally at 24–28weeks of gestation, it could be done as early as the first antenatalvisit if there is a high degree of suspicion that the woman hasundiagnosed type 2 diabetes [e.g. marked obesity (BMI �35),personal history of GDM, glycosuria, or a strong family history ofdiabetes].20

Risk factors to guide testing for GDM in routine antenatal careinclude:

� body mass index >30;� previous macrosomic baby (�4.5 kg);� previous GDM;� family history of diabetes (first degree relative with diabetes);� family origin with a high prevalence of diabetes (South Asian,

black Caribbean, or Middle Eastern).

Within this context it should also be noted that the Hypergly-cemia and Adverse Pregnancy Outcome (HAPO) Trial showed thatthe association between glucose concentration and macrosomiawas a continuous relationship, and began at fasting concentrations>4.2 mmol/L].16 The HAPO trial further emphasised that universalscreening is the best method to improve a pregnancy outcomebecause hyperglycaemia can affect the fetus even if the mother hasnot met the criteria for the diagnosis of GDM and therefore it isbetter to treat ‘borderline’ cases rather than adopt an expectantattitude.

5. Treatment of GDM

Identifying women with GDM is important because appropriatetherapy can decrease maternal and fetal morbidity, particularlymacrosomia. In a large randomised trial comparing use of a regimenof diet/blood glucose monitoring/insulin as needed for routine careof women with mild GDM,15 infants of women in the treatmentgroup had a significantly lower composite rate of perinatal compli-cations (death, shoulder dystocia, bone fracture, nerve palsy: 1% vs4%), and a lower frequency of macrosomia (10% vs 21%), but a higherrate of admission to the neonatal intensive care unit (71% vs 61%).Diagnosis and treatment of GDM did not increase the frequency ofcaesarean delivery (31–32% for both groups), but did increase thefrequency of labour induction (39% vs 29%). Diagnosis and treatmentof GDM did not reduce the incidence of neonatal metaboliccomplications such as hypoglycaemia treated with intravenoustherapy or jaundice treated with phototherapy.

6. Medical nutrition therapy

All patients with GDM should receive nutritional counselling bya registered dietician (when possible) upon diagnosis and be placedon an appropriate diet. The goals of medical nutritional therapy areto achieve normoglycaemia, prevent ketosis, provide adequateweight gain and contribute to fetal well-being.

The major components to consider when creating a nutritionalplan for women with GDM are caloric allotment, carbohydrate intake,and calorie distribution. Calorie allotment is based upon ideal bodyweight. The suggested caloric intakes are about 30 kcal per kg currentweight per day (kcal/kg/day) in pregnant women with BMI 22–25,24 kcal/kg/day in overweight pregnant women (BMI 26–29),12–15 kcal/kg/day for obese pregnant women (BMI>30), and 40 kcal/kg/day in pregnant women with BMI <22.21 Caloric restriction isuseful in treating overweight and obese women with GDM.22

After prescribing the caloric allotment, it is important to payattention to subsequent changes in weight. A retrospective cohortstudy in women with GDM showed that those with appropriateweight gain had optimal outcomes, whereas excessive weight gainwas associated with a significantly increased risk of having a largefor gestational age infant, preterm birth, and caesarean delivery.23

Carbohydrate intake is restricted to 33–40% of calories, with theremainder divided between protein (about 20%) and fat (about40%).20,21,24,25 With this calorie distribution, 75–80% of womenwith GDM will achieve normoglycaemia. Postprandial bloodglucose concentrations are directly dependent upon the carbohy-drate content of a meal.24 The postprandial glucose rise, therefore,can be blunted if the diet is carbohydrate-restricted. Complexcarbohydrates, such as those in starches and vegetables, are morenutrient dense and raise postprandial blood glucose concentrationsless than simple sugars. Non-caloric sweeteners, such as aspartame,may be used in moderation. Most programmes suggest three mealsand three snacks; however, in overweight and obese women thesnacks are often eliminated.

Unfortunately, macrosomia may not be prevented by dietarytherapy alone. A Cochrane review involving women with GDM,treated with primary dietary therapy or no specific treatment,found no differences in birth weight >4000 g or caesarean deliv-eries.26 Nonetheless, nutritional therapy should be considered inwomen even with a small rise in blood glucose but who fall short ofthe criteria for GDM, in view of the HAPO trial detailed above.16

7. Glucose monitoring during pregnancy with a GDM

Women with GDM should measure their blood glucoseconcentration at least four times daily (fasting and 1 h after the first

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bite of each meal) to determine whether hyperglycaemia severeenough to increase fetal risk is occurring.20 The value of post-prandial versus preprandial measurement was illustrated in a studythat randomly assigned patients to have their diabetes managedaccording to results of preprandial or postprandial monitoring ofblood glucose concentrations.27 One-hour postprandial monitoringwas associated with better glycaemic control (HbA1c value 6.5% vs8.1%), lower incidence of large-for-gestational age infants (12% vs42%) and a lower incidence of large-for-gestational age infants (12%vs 42%) compared with preprandial monitoring.

8. Management strategies to achieve glucose control

Insulin or oral hypoglycaemic agent administration should beconsidered if blood glucose concentrations reach the values (fastingblood glucose concentration �5 mmol/L or 1 h postprandial bloodglucose concentration �6.7 mmol/L) on two or more occasionswithin a two-week interval despite dietary therapy.21,28 The mainpurpose of drug intervention at these levels is to minimise theincidence of macrosomia, and its associated risks of shoulderdystocia, birth trauma, and possibly childhood obesity and meta-bolic syndrome.15,29 The aim is to bring preprandial blood glucoseconcentrations <5 mmol/L and 1 h postprandial blood concentra-tions <6.7 mmol/L.21 Glycosylated haemoglobin (HbA1C) is a help-ful ancillary test in assessing glycaemic control during pregnancyand reflects glycaemic control over the preceding two months. Itshould be noted that A1C values tend to be lower in pregnantcompared with non-pregnant women because the average bloodglucose concentration is about 20% lower in pregnant women and,in the first half of pregnancy, there is a rise in red cell mass anda slight decrease in red blood cell life span.30

9. Exercise

Cardiovascular conditioning appears to improve glycaemiccontrol primarily from increased tissue sensitivity to insulin. Asa result, both fasting and postprandial blood glucose concentra-tions can be reduced and, in some women with GDM, the need forinsulin may be reduced or avoided.31 A regular programme ofexercise before pregnancy appears to lower the risk of developingGDM, similar to the effect observed for reducing the risk of type 2diabetes mellitus.5

10. Medical therapy

If normoglycaemia cannot be maintained by medical nutritionaltherapy, then antihyperglycaemic agents should be initiated. Thetwo options for pregnant patients who require medical therapyaimed at controlling blood glucose are insulin (and some insulinanalogues) and oral antihyperglycaemic agents.

11. Insulin

Approximately 15% of women with GDM are placed on insulintherapy because target glucose levels are exceeded despite dietarytherapy. In addition, randomised trials have suggested thatrestricting insulin administration to the subgroup of women withindirect evidence of fetal hyperinsulinaemia (e.g. ultrasoundshowing abdominal circumference >75th percentile early in thethird trimester) allows targeted treatment of those at highest risk ofdelivering a macrosomic infant and avoids treatment of those atlow risk.20,32,33 Some of these women have no or mildhyperglycaemia.

The dose of insulin varies in different populations because ofvaried rates of obesity, ethnic characteristics, and other

demographic criteria, but the majority of studies have reporteda total insulin dose ranging from 0.7 to 2 units/kg (presentpregnant weight) to achieve glucose control. The dose and type ofinsulin used is calculated based upon the specific abnormality ofblood glucose noted during monitoring. If insulin is requiredbecause the fasting blood glucose concentration is high, anintermediate-acting insulin, such as NPH (Neutral ProtamineHagedorn) insulin, is given before bedtime with an initial dose ofaround 0.2 units/kg body weight. If postprandial blood glucoseconcentrations are high, we suggest insulin aspart or insulin lis-pro before meals at a dose calculated at 1.5 units/10 g carbohy-drate in the breakfast meal and 1 unit/10 g carbohydrate in thelunch and dinner meals. If both pre- and postprandial bloodglucose concentrations are high, or if the woman’s postprandialglucose levels can only be blunted if starvation ketosis occurs,then a four-injection per day regimen should be considered. Ina morbidly obese woman, the initial doses of insulin may need tobe increased to 1.5–2.0 units/kg to overcome the combined insulinresistance of pregnancy and obesity. The insulin is dividedaccording to the following schedule: 50% as NPH insulin (given inthree equal doses before breakfast, before dinner and beforebedtime) and 50% as three preprandial rapid-acting insulininjections. This regimen improved glycaemic control and perinataloutcome compared to a twice-daily regimen.34

The titration of insulin dose to blood glucose levels is basedupon frequent self-monitoring. Four or more glucose measure-ments each day are needed to optimise therapy and ensurea smooth increase of insulin as insulin requirements increase withpregnancy progression. Twin gestations have an approximatedoubling of the insulin requirement throughout pregnancy. There isno evidence to suggest that insulin pumps would benefit womenwith GDM.

12. Type of insulin

Use of insulin preparations of low antigenicity will minimise thedevelopment and transplacental transport of insulin antibodies:human insulin is the least immunogenic of the commerciallyavailable preparations. The three rapid-acting insulin analogues(lispro, aspart, glulisine) are comparable in immunogenicity tohuman regular insulin, but only lispro and aspart have beeninvestigated in pregnancy and been shown to have acceptablesafety profiles, minimal transfer across the placenta, and noevidence of teratogenesis. Neonatal outcomes are similar to thoseof women treated with regular insulin.35 These two insulinanalogues both improve postprandial excursions compared tohuman regular insulin and are associated with lower risk of delayedpostprandial hypoglycaemia. Long-acting insulin analogues(insulin glargine, insulin detemir) have not been studied exten-sively in pregnancy.

13. Oral antihyperglycaemic agents

A systematic review has shown that maternal glucose levels didnot differ substantially between gravidae treated with insulinversus those treated with oral glucose-lowering agents and therewas no consistent evidence of an increase in any adverse maternalor neonatal outcome with use of glibenclamide (glyburide), acar-bose, or metformin compared with use of insulin.35 Tolbutamide orchlorpropamide (older sulphonylureas) therapy in women withGDM is not recommended since these drugs cross the placenta andcan cause fetal hyperinsulinaemia, which can lead to macrosomiaand prolonged neonatal hypoglycaemia.36 In contrast to older sul-phonylureas, transplacental passage of glyburide appears to beminimal. Studies have generally found that maternal use of

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glibenclamide was not associated with an excess of neonatalhypoglycaemia or congenital anomalies and that it was an effectivetreatment of GDM, particularly in women with mild to moderatedegrees of hyperglycaemia. Four percent of women in the gliben-clamide group required insulin therapy.37

Several observational series have reported generally goodoutcomes with use of metformin in subjects with pre-GDM. Ameta-analysis of pregnancy outcome after first trimester exposureto metformin did not find an increased risk of major malforma-tions.38 Second and third trimester metformin treatment of GDMalso appears to be safe and effective. In a recent randomised trial ofmetformin versus insulin therapy in GDM there were no seriousadverse effects related to metformin use and clinical outcomeswere similar between the two groups; however, almost one-half ofthe women taking metformin also required supplemental insulin toachieve glycaemic control,39 although overall insulin requirementswere lower. The women preferred metformin to insulin treatment.Thus metformin is an alternative to insulin for treatment of GDM.Metformin may ‘prevent’ GDM since it is an oral anti-hyperglycaemic agent and would be expected to maintain eugly-caemia in some women who would otherwise be diagnosed withGDM. In one study in patients with polycystic ovary syndrome,GDM occurred in 3% of women taking metformin (2550 mg)compared with 23% not taking metformin.40 According to thesefindings, metformin would have to be given to five women withPCOS to prevent GDM in one. In addition, an observational study inwomen with PCOS suggested that metformin therapy reduced therisk of GDM in a subsequent pregnancy both in women whose priorpregnancy was complicated by GDM and in those with no history ofGDM.41

Acarbose, an alpha glucosidase inhibitor, is poorly absorbedfrom the gastrointestinal tract. Two preliminary studies have sug-gested efficacy in reducing postprandial glucose excursions inGDM, but with the expected frequency of abdominal cramping.Since a small proportion of this drug may be absorbed systemically,further study should evaluate potential transplacental passage. Useof thiazolidinediones, glitinides and GLP-1 during pregnancy isconsidered experimental.

14. Peripartum management

Insulin can usually be withheld during labour and delivery; aninfusion of normal saline is usually sufficient to maintain nor-moglycaemia. Maternal hyperglycaemia should be avoided duringlabour to prevent fetal hyperinsulinaemia, fetal acidosis andsubsequent neonatal hypoglycaemia. The risk of adverse meta-bolic outcomes (hypoglycaemia, hyperbilirubinaemia, hypo-calcaemia, erythremia) appears to increase with the degree ofmaternal hyperglycaemia. Therefore, maternal blood glucoseconcentration should be maintained between 3.9 and 5 mmol/L.Blood glucose should be measured on the day after delivery toensure that the mother no longer has hyperglycaemia, usingcriteria established for non-pregnant individuals. A woman withGDM should be able to resume a regular diet postpartum.However, maintaining a diet low in carbohydrate content willfacilitate postpartum weight loss.

15. Contraception

Any type of contraception is acceptable. Low dose estrogen–progestin oral contraceptives may be used in women with a historyof GDM as long as the usual medical contraindications to their use

are absent. Progestin-only (but not combined estrogen–progestin)oral contraceptives (OCs) have been associated with an increasedrisk of developing type 2 diabetes in women with recent GDM. Ina study of Hispanic women with recent GDM who were breast-feeding, the use of progestin-only OCs was associated with anincreased risk of type 2 diabetes.42

16. Future risks

Nearly all women (�90%) with GDM are normoglycaemicafter delivery. However, they are at risk for recurrent GDM,impaired glucose tolerance, and overt diabetes. One-third totwo-thirds of women with GDM will have GDM in a subsequentpregnancy. Women who have a recurrence tend to be older, havehigher parity, and have a greater increase in weight betweentheir pregnancies than women without a recurrence.43 Higherinfant birth weight in the index pregnancy and higher maternalpre-pregnancy weight have also been associated with recurrentGDM.44 Regarding long-term risks, as many as 20% of womenwith GDM have impaired glucose tolerance during the earlypostpartum period.45 The cumulative incidence of future dia-betes ranges from 2.6% to 70%, with the greatest increase in riskin the first five years after a pregnancy with GDM, and a plateauin risk after ten years.46 Waist circumference and BMI are thestrongest anthropometric measures associated with developmentof type 2 diabetes in women with GDM.35 Type 2 diabetesdevelops in 50–75% of obese women with a history of GDM vs<25% of women with GDM who achieve ideal body weight afterdelivery.19 Additional risk factors for impaired glucose toleranceand overt diabetes later in life include autoantibodies (e.g.glutamic acid decarboxylase, insulinoma antigen-2), gestationalrequirement for insulin, high fasting blood glucose concentra-tions during pregnancy and early postpartum, early gestationalage at the time of diagnosis (i.e. <24 weeks of gestation), higherfasting blood glucose at diagnosis of GDM and high glucoselevels in oral glucose tolerance testing, neonatal hypoglycaemia,and GDM in more than one pregnancy.35 Parity, high birthweight, and diabetes in a first degree relative are less correlatedwith later diabetes. GDM is also a risk factor for the develop-ment of type 1 diabetes. Specific HLA alleles (DR3 or DR4) maypredispose to the development of type 1 diabetes postpartum, asdoes the presence of islet-cell autoantibodies.47 A systematicreview has shown that 10–31% of parous women with diabetesexperienced a pregnancy complicated by GDM prior to theirdiagnosis.48

17. Follow-up

Hypoglycaemic therapy should be discontinued immediatelyafter the birth in women who are diagnosed with GDM. Theirblood glucose should be checked to exclude persisting hyper-glycaemia, and women should be reminded about the symptomsof hyperglycaemia. Where possible breastfeeding should besupported, as this can reduce the future risk of diabetes both tothe mother and potentially the infant, and will also help weightloss postpartum. Lifestyle advice should be offered (on weightcontrol, diet, and exercise) and a fasting plasma glucosemeasurement (but not an OGTT) at the six-week postnatalcheck, and annually thereafter. Information should be providedabout the risk of GDM in future pregnancies, screening offeredfor diabetes when planning future pregnancies, and the offer ofearly self-monitoring of blood glucose or an OGTT in futurepregnancies.49

Practice points

� Obesity increases the risk of poor pregnancy outcome inpatients with GDM.� Identifying women with GDM is important, as appro-

priate therapy can decrease maternal and fetalmorbidity.� GDM should be managed by appropriate lifestyle

modifications (including dietary changes, physicalactivity and self-monitoring of blood glucose), oralhypoglycaemic agents and insulin.� Lifestyle advice with appropriate follow-up arrange-

ments should be implemented postpartum in womenwith GDM since they are at higher risk of developmentof type 2 diabetes.

T. Sathyapalan et al. / Seminars in Fetal & Neonatal Medicine 15 (2010) 89–93 93

Conflict of interest statementNone declared.

Funding sourcesNone.

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