maternal subclinical hypothyroidsm and gestational diabetes mellitus: a meta-analysis

ENDOCRINE PRACTICE Vol 20 No. 7 July 2014 703

Review Article

Konstantinos A. Toulis, MD1; Alex Stagnaro-Green, MD, MHPE2; Roberto Negro, MD3

Submitted for publication October 28, 2013Accepted for publication November 27, 2013From the 1Department of Endocrinology, Diabetes & Metabolism, 424 General Military Hospital, Thessaloniki, Greece; 2University of Illinois College of Medicine; 3Division of Endocrinology, “V. Fazzi” Hospital, Lecce, Italy. Address correspondence to Dr. Roberto Negro; Division of Endocrinology, “V. Fazzi” Hospital. 73100, Lecce, Italy. E-mail: [email protected] as a Rapid Electronic Article in Press at http://www.endocrinepractice.org on date January 21, 2014. DOI:10.4158/EP13440.RATo purchase reprints of this article, please visit: www.aace.com/reprints.Copyright © 2014 AACE.

ABSTRACT

Objective: The association between subclinical hypo-thyroidism (SCH) and gestational diabetes mellitus (GDM) is controversial. This review evaluates whether the risk of GDM is different in pregnant women with SCH compared to euthyroid pregnant women. Methods: A computerized search of the MEDLINE and EMBASE databases was conducted from their inceptions to July 2013 and was complemented with the perusal of the reference sections of the retrieved articles. Prespecified criteria were applied to assess eligibility, and standard meta-analytic methodology was employed for evidence synthesis. Results: Six cohort studies, reporting data on 35,350 pregnant women (1,216 women with SCH), were identi-fied. The risk of GDM in pregnant women with SCH was found to be substantially higher compared to euthyroid pregnant women (5 studies, pooled unadjusted odds ratio [OR]: 1.35, 95% confidence interval [CI]: 1.05-1.75, I2: 41%, Harbord test P = .44). Similarly, the risk of GDM was estimated to be significantly higher in pregnant women with SCH when using adjusted estimates (3 studies, pooled adjusted OR: 1.39, 95% CI: 1.07-1.79, I2: 0%). Neither finding remained significant in sensitivity analyses.

Conclusion: A modestly increased risk of GDM might be present in pregnant women with SCH compared to euthyroid pregnant women. Assuming a 5% baseline risk of GDM and that SCH increases the risk of GDM by 50% (in odds) compared to a euthyroid population, then there would be 1 extra case of GDM in every 43 pregnant women with SCH. This preliminary finding warrants fur-ther investigation. (Endocr Pract. 2014;20:703-714)

Abbreviations:CI = confidence interval; GDM = gestational diabetes mellitus; OR = odds ratio; SCH = subclinical hypothy-roidism; TSH = thyroid-stimulating hormone

INTRODUCTION

Both hypothyroidism and diabetes mellitus occur frequently during pregnancy. Subclinical hypothyroidism (SCH), defined as an elevated thyroid-stimulating hor-mone (TSH) with a normal free thyroxine level, occurs in between 2 and 10% of pregnant women (1). Similarly, ges-tational diabetes mellitus (GDM), that is glucose intoler-ance first recognized in pregnancy (2), occurs in 2 to 10% of all pregnancies (3). Interestingly, both SCH and GDM are the outcome of normal physiological changes that occur during pregnancy that exceed the compensatory abilities of the gravid individual. Normal pregnancy requires a 50% increase in thyroid hormone production (due to increased iodine renal excretion, the impact of human chorionic gonadotrophin [hCG] on the thyrotrope receptor, increase in serum thyroxine binding globulin [TBG]), and inner-ring deiodination of T3 and T4 by the placenta) and is a state of enhanced insulin resistance. In instances where an individual has decreased thyroidal reserve, or early insulin resistance prior to pregnancy, SCH and GDM can occur. It is noteworthy that long-term postpartum follow-up reveals a high incidence of overt hypothyroidism and type 2 dia-betes mellitus in women whose thyroid and/or metabolic disease first manifested during pregnancy.

704

SCH has been reported to be associated with an increased incidence of GDM (4,5), and a high prevalence of SCH has been found in patients with GDM (6), although the latter was not a universal finding (7). In registry stud-ies, it has been shown that primary hypothyroidism was associated with a 1.6-fold greater risk of GDM (8) and that maternal use of thyroxine was associated with an increased rate of GDM compared to the reference population (9). Although not directly assessed, it is likely that women with SCH might have been included in these study populations.SCH and GDM are frequent diseases during pregnancy, both resulting from an inability to adapt to the normal physiological stresses of pregnancy. SCH may be con-sidered as an insulin resistant state because it predisposes to higher glucose and insulin levels, so it is reasonable to question whether there is an association between SCH and GDM. Consequently, the present study consists of a meta-analysis of published articles that have explored the asso-ciation between SCH and GDM.

METHODS

A computerized search was conducted in the elec-tronic databases MEDLINE and EMBASE from their inceptions to July 2013 using various combinations of following search terms: “thyroid dysfunction,” “thyroid diseases,” “subclinical hypothyroidism,” “hypothyroxin-emia,” “thyrotropin,” “gestational diabetes,” “hypergly-cemia in pregnancy,” and “adverse pregnancy outcomes.” The search was complemented by the perusal of the refer-ence sections of the retrieved articles and relevant reviews. A detailed overview of the search strategy is presented in the Supplementary Appendix (Supplementary Table 1). A study was included in the meta-analysis if it 1) was cohort in design and 2) reported extractable data on the incidence of GDM in pregnant women with SCH and euthyroid pregnant women. On the basis of prespecified exclusion criteria, a study was excluded from evidence synthesis if 1) it was case-control or cross-sectional in design, 2) SCH was diagnosed prior to pregnancy (as opposed to SCH diagnosed during pregnancy), 3) it was a re-evaluation of data from a previously published cohort, or 4) it referred to patients undergoing assisted reproductive technologies (ART). Cases-series, reviews, abstracts, and letters to the editor were not eligible. Standardized data extraction forms with a special focus on potential confounders were used for data extrac-tion. The procedure was performed independently by 2 reviewers. Study quality assessment was performed on the basis of Newcastle-Ottawa scale (NOS) for cohort studies (http://www.ohri.ca/programs/clinical_epidemiol-ogy/oxford.asp). In each study, the incidence of GDM in women with SCH compared to that of euthyroid controls was expressed both as crude and adjusted ORs with the corresponding 95% confidence intervals (CIs). Adjusted

estimates were used to minimize the potential confound-ing effect of patient-characteristics (such as age, body mass index [BMI], and parity) on the risk of GDM. Because the baseline risk was expected to be low, relative risks were considered as conservative approximations of ORs (10). Pooled unadjusted and adjusted estimates were calculated using a fixed-effects (FE) model and a generic-inverse variance method, followed by sensitivity analyses in which a random effects (RE) model was used. For adjusted esti-mates, logarithmic transformation was used for calcula-tion, followed by exponentiation. Heterogeneity was mea-sured with the I2 test (I2>50%: significant heterogeneity), and small study effects were explored using Harbord test. Analyses were conducted in Stata/MP 10.0 for Windows (StataCorp LP, College Station, TX).

RESULTS

From a total of 853 potentially eligible titles, 6 stud-ies were finally included in the meta-analysis (11-15). A detailed list of the studies excluded on a full-text basis, as well as documentation for exclusion, may be found in the Supplementary Appendix (Supplementary Table 2). A flow chart summarizing the search results is presented in Figure 1. A study by Tudela et al (16) was excluded to avoid dou-ble publication bias (17) because it was a re-evaluation of data from a previously published cohort (11), which was included in the meta-analysis. The 6 studies, which were included in the meta-analysis, reported data on 35,350 pregnant women (1,216 women with SCH and 34,134 euthyroid pregnant women). The main characteristics of the studies included in the meta-analysis are presented in Table 1. The prevalence of SCH across studies ranged from 1.9 to 6.7%, whereas the incidence of GDM in women diagnosed with SCH in pregnancy was up to 8.8%. The included studies were comparable in terms of the methodology applied for the measurement of thyroid hormones (chemiluminescent immunoassays) and study design characteristics (singleton pregnancies, prospective enrollment and trimester-specific, population-based reference ranges [with the exception of 1 study]), whereas they differed in the diagnostic protocol for GDM and subjects’ baseline characteristics.

Quantitative Data Synthesis

Unadjusted (Crude) Analysis The risk of GDM in pregnant women with SCH was found to be substantially different compared to euthyroid pregnant women (6 studies, pooled OR: 1.35, 95% CI: 1.05-1.75, I2: 41%, Harbord test P = .44, Fig. 2).

Adjusted Analysis Similarly, the risk of GDM was estimated to be sig-nificantly higher in pregnant women with SCH when using

705

Supplementary Table 1Literature Search Terms and Results

Search MEDLINE EMBASE1 (“thyroid gland”[MeSH Terms] OR (“thyroid”[All Fields] AND “gland”[All

Fields]) OR “thyroid gland”[All Fields] OR “thyroid”[All Fields] OR “thyroid (usp)”[MeSH Terms] OR (“thyroid”[All Fields] AND “(usp)”[All Fields]) OR “thyroid (usp)”[All Fields]) AND (“physiopathology”[Subheading] OR “physiopathology”[All Fields] OR “dysfunction”[All Fields])

16,900 25,108

2 “thyroid diseases”[MeSH Terms] OR (“thyroid”[All Fields] AND “diseases”[All Fields]) OR “thyroid diseases”[All Fields]

124,870 222,136

3 subclinical[All Fields] AND (“hypothyroidism”[MeSH Terms] OR “hypothyroidism”[All Fields])

2,367 3,374

4 hypothyroxinemia[All Fields] 327 4255 “thyrotropin”[MeSH Terms] OR “thyrotropin”[All Fields] 40,397 56,0816 1 or 2 or 3 or 4 or 5 155,042 246,1487 “diabetes, gestational”[MeSH Terms] OR (“diabetes”[All Fields] AND

“gestational”[All Fields]) OR “gestational diabetes”[All Fields] OR (“gestational”[All Fields] AND “diabetes”[All Fields])

11,252 14,693

8 (“hyperglycaemia”[All Fields] OR “hyperglycemia”[MeSH Terms] OR “hyperglycemia”[All Fields]) AND (“pregnancy”[MeSH Terms] OR “pregnancy”[All Fields])

2,524 4,050

9 adverse[All Fields] AND (“pregnancy outcome”[MeSH Terms] OR (“pregnancy”[All Fields] AND “outcome”[All Fields]) OR “pregnancy outcome”[All Fields] OR (“pregnancy”[All Fields] AND “outcomes”[All Fields]) OR “pregnancy outcomes”[All Fields])

21,498 13,693

10 7 or 8 or 9 33,060 30,02711 6 and 10 360 674

adjusted estimates (3 studies, pooled adjusted OR: 1.39, 95% CI: 1.07-1.79, I2: 0%, Fig. 3).

Sensitivity Analysis In the study by Karakosta et al (13), the adjusted esti-mates for pregnant women with SCH were presented in thyroid antibodies (ab) categories and thus, only data from the ab(−) category were used in the calculation of the latter adjusted pooled estimate. When data from the ab(+) cate-gory were used, this finding did not retain statistical signifi-cance (RE pooled adjusted OR: 1.74, 95% CI: 0.83-3.64, I2: 77%]. When a re-analysis was performed only using data from those studies in which ascertainment of the outcome (GDM) was adequately described, we found that the risk of GDM was not significantly different in women with SCH compared to controls (2 studies, FE pooled adjusted OR: 1.18, 95% CI: 0.72-1.93, I2: 0%).

DISCUSSION

The present meta-analysis found that a modestly increased risk of GDM might be present in pregnant women with SCH compared to euthyroid pregnant women. This

finding is in contrast to a published pooled estimate, which failed to detect a significant difference (18). However, new data have been added to the literature since then. Although not evaluated in any of the studies included in the present meta-analysis, prior research has described potential pathophysiological mechanisms linking SCH to GDM. In fact, SCH may be considered as an insulin-resis-tant state (19) because it predisposes to higher glucose and insulin levels (20). Increased levels of free fatty acids (21), impaired ability of insulin to increase blood flow rate to insulin-sensitive tissues (22), abnormal translocation of glu-cose transporter 2 (GLUT2) resulting in decreased insulin-stimulated glucose transport rate (23), and decreased sele-nium levels (24) have all been implicated. Epidemiological data suggesting that thyroid hormones are positively asso-ciated with insulin resistance (IR) early in the development of type 2 diabetes (25) and that TSH is associated with IR in women with polycystic ovary syndrome (PCOS) (26,27) may also be considered as indirect corroborating evidence. Moreover, an increase in fasting insulin levels in individu-als with SCH, with a normalization of insulin levels upon treatment with levothyroxine, has been documented (28). It is therefore feasible that enhanced insulin resistance

706

Supplementary Table 2List of the Studies Excluded on a Full-text Basis

Title Year Reason(s) for exclusion1 [Thyroid disorders and gestational diabetes (author’s transl)] 1981 No extractable data

2 [Functional activity of the thyroid in pregnant women at risk for fetal macrosomia]

1988 No extractable data

3 Hypothyroidism complicating pregnancy 1988 No control group4 Hypothyroidism complicating pregnancy 1988 No control group5 Outcome of thyroid function in newborns from mothers treated with

amiodarone1992 No control group

6 Perinatal outcome in hypothyroid pregnancies. 1993 Outcome of interest (GDM) not routinely investigated and/or reported

7 Thyroid autoimmunity in pregnant women at risk for GDM 1997 Exposure of interest (SCH) not routinely investigated and/or reported

8 [Thyroid gland function in pregnant diabetic patients] 1997 No control group9 Maternal thyroid deficiency and pregnancy complications: implications

for population screening.2000 Outcome of interest (GDM) not routinely

investigated and/or reported10 Sex hormone-binding globulin in gestational diabetes 2000 Case-control design11 High frequency of antithyroid autoantibodies in pregnant women at

increased risk of gestational diabetes mellitus2000 Case-control design

12 Thyroid peroxidase antibodies in Mexican-born healthy pregnant women, in women with type 2 or gestational diabetes mellitus, and in their offspring

2000 Case-control design

13 Psychomotor and audiological assessment of infants born to mothers with subclinical thyroid dysfunction in early pregnancy

2000 Outcome of interest (GDM) not routinely investigated and/or reported

14 The Sardinian Autoimmunity Study. 4. Thyroid and islet cell autoantibodies in Sardinian pregnant women at delivery: A cross-sectional study

2001 Exposure and outcome of interest (SCH and GDM) not reported

15 Obstetric and prenatal outcome in menopausal women: A 12-year clinical study

2003 IVF (oocyte donor) setting

16 [Thyroid dysfunction in pregnant women and correlation with clinical and metabolical status of their newborns]

2003 No control group

17 Plasma selenium decrease during pregnancy is associated with glucose intolerance

2004 Exposure of interest (SCH) not routinely investigated and/or reported

18 Neonatal hyperthyrotropinemia in gestational diabetes mellitus and perinatal complications


19 Trimester-specific reference intervals for thyroxine and triiodothyronine in pregnancy in iodine-sufficient women using isotope dilution tandem mass spectrometry and immunoassays


20 High maternal hemoglobin and ferritin values as risk factors for gestational diabetes


21 Thyroid function after assisted reproductive technology in women free of thyroid disease

2005 IVF setting

22 [Detection of subclinical hypothyroidism in pregnant women with different gestational ages]


23 Maternal hypothyroidism in early and late gestation: effects on neonatal and obstetric outcome

2005 Outcome of interest (GDM) not routinely investigated and/or reported, retrospective

evidence24 Is thyroid inadequacy during gestation a risk factor for adverse

pregnancy and developmental outcomes?2005 Outcome of interest (GDM) not routinely

investigated and/or reported, review25 Prevalence of abnormal thyroid stimulating hormone and thyroid

peroxidase antibody-positive results in a population of pregnant women in the Samara region of the Russian Federation


(Continued next page)

707

Supplementary Table 2 (Continued)List of the Studies Excluded on a Full-text Basis

Title Year Reason(s) for exclusion26 Subclinical Hypothyroidism and Pregnancy Outcomes 2005 Outcome of interest (GDM) not routinely

investigated and/or reported27 Adverse effects of thyroid dysfunction on pregnancy and pregnancy

outcome: epidemiologic study in Slovenia2006 Outcome of interest (GDM) not

routinely investigated and/or reported - Retrospective design

28 Thyroid function abnormalities and antithyroid antibody prevalence in pregnant women at high risk for gestational diabetes mellitus


29 Adverse effects of thyroid dysfunction on pregnancy and pregnancy outcome: epidemiologic study in Slovenia

2006 Retrospective in design

30 Relationship of treated maternal hypothyroidism and perinatal outcome 2006 Exposure and outcome of interest (SCH and GDM) not reported

31 Thyroid function tests and thyroid autoantibodies in an unselected population of women undergoing first trimester screening for aneuploidy


32 Maternal use of thyroid hormones in pregnancy and neonatal outcome 2008 Exposure of interest (SCH) not routinely investigated and/or reported

33 Is thyroid autoimmunity associated with gestational diabetes mellitus? 2008 Exposure of interest (SCH) not routinely investigated and/or reported

34 Thyroid hormones according to gestational age in pregnant Spanish women


35 Pattern of thyroid function during early pregnancy in women diagnosed with subclinical hypothyroidism and treated with L-thyroxine is similar to that in euthyroid controls


36 The impact of isolated maternal hypothyroxinemia on perinatal morbidity


37 Thyroid function in early pregnancy in Japanese healthy women: relation to urinary iodine excretion, emesis, and fetal and child development


38 Clinical analysis of pregnancy combined with thyroid disorder 2009 Abstract, no extractable data39 Association Between Oxidative Stress and Thyroid Diseases of

Pregnant Women2009 Abstract, no extractable data

40 How significant is sub-clinical hypothyroidism in pregnancy outcome? 2009 Abstract *reports that no significant increase in the incidence of gestational

diabetes41 Perinatal outcome associated with thyroid-peroxidase antibodies in

gestational diabetes2010 Abstract, no extractable data

42 Diabetes in pregnancy: Risk factor analysis from a clinic in the United Arab Emirates

2010 Retrospective, no difference in TSH among diabetic pregnant groups

43 Screening thyroid function in pregnancy: Should all pregnant women be screened

2010 Outcome of interest (GDM) not reported - abstract

44 Hypothyroidism as a risk factor in pregnancy 2010 Abstract, not extractable data45 Subclinical hypothyroidism does not adversely affect pregnancy

outcomes after assisted reproduction2010 IVF setting - Outcome of interest (GDM)

not routinely investigated and/or reported46 Gestational diabetes leading to diagnosis and management of multiple

endocrine neoplasia type 2a2010 Case-study

47 Thyroid hormone early adjustment in pregnancy (The THERAPY) trial 2010 Outcome of interest (GDM) not routinely investigated and/or reported

48 Bad obstetric history: A prospective study 2010 Subpopulation of women with an unfortunate obstetric outcome in a

previous pregnancy49 Screening for gestational diabetes in Bulgaria--preliminary results 2010 Case-control50 Pregnancy outcomes in women with thyroid peroxidase antibodies 2010 Exposure and outcome of interest (SCH

and GDM) not reported51 [Maternal autoimmune thyroid disease and pregnancy complication] 2010 No extractable data


708


Title Year Reason(s) for exclusion52 Subclinical elevations of thyroid-stimulating hormone and assisted

reproductive technology outcomes2011 IVF setting

53 Abnormal one-hour 50-gram glucose challenge test and perinatal outcomes

2011 Retrospective study, Exposure and outcome of interest (SCH and GDM)

not investigated / reported54 Maternal selenium status during early gestation and risk for preterm

birth2011 Exposure and outcome of interest (SCH

and GDM) not reported55 Effect of autoimmune thyroid disease in older euthyroid infertile

woman during the first 35 days of an IVF cycle2011 IVF setting - Outcome of interest (GDM)

not reported56 Thyroid Antibody Positivity in the First Trimester of Pregnancy Is

Associated with Negative Pregnancy Outcomes2011 No women with subclinical

hypothyroidism were included57 Thyroid disease in pregnant women with systemic lupus

erythematosus: Increased preterm delivery2011 Outcome of interest (GDM) not routinely

investigated and/or reported58 The prevalence of thyroid peroxidase anti body positive results in a

population of overt hypothyroid pregnant saudi women and its effects on obstetrical complications

2011 Abstract, no extractable data

59 Prevalence of thyroid dysfunction and autoimmunity in pregnant women with gestational diabetes and diabetes type 1


60 Fetal thyroid hormone level at birth is associated with fetal growth 2011 Outcome of interest (GDM) not routinely investigated and/or reported

61 Lower Free Thyroxin Associates with a Less Favorable Metabolic Phenotype in Healthy Pregnant Women


62 Increased Pregnancy Losses and Poor Neonatal Outcomes in Women with First-Trimester TSH Levels between 2.5 and 4 mIU/L Compared to Euthyroid Women with TSH Less Than or Equal to 2.5

2012 Abstract, no extractable data

63 Pregnancy Loss and Neonatal Outcomes in Women with Thyroid Dysfunction in the First Trimester of Pregnancy


64 Free thyroid hormone levels, second-hand smoke, and pregnancy outcomes

2012 Abstract, no extractable data, retrospective evidence

65 Maternal Early Pregnancy and Newborn Thyroid Hormone Parameters: The Generation R Study


66 Detection of thyroid dysfunction in early pregnancy 2012 Outcome of interest (GDM) not routinely investigated and/or reported

67 Gestational diabetes and thyroid autoimmunity 2012 Case-control design68 The prevalence of hypothyroidism based on risk factors in pregnant

women referred to Shahid Dadbin clinic, Kerman, Iran2012 Cross-sectional study

69 The effect of thyroid antibody positivity in euthyroid women undergoing in vitro fertilization-embryo transfer cycle (IVF-ET)

2012 IVF setting, no extractable data, abstract

70 A clinical study on relationship between thyroid autoimmunity and pregnancy outcomes in in-vitro fertilization women

2012 IVF setting, no extractable data, abstract

71 Relationship of subclinical thyroid disease to the incidence of gestational diabetes

2012 Double publication bias

72 Incidence of hypothyroidism in Saudi pregnant women 2012 Outcome of interest (GDM) not reported - abstract

73 Association and predictive accuracy of high TSH serum levels in first trimester and adverse pregnancy outcomes

2012 Outcome of interest (GDM) not investigated and/or reported

74 First trimester high TSH serum levels associated with an increased risk of adverse pregnancy outcomes

2012 Outcome of interest (GDM) not investigated and/or reported - abstract

75 Is Age a Risk Factor for Hypothyroidism in Pregnancy? An Analysis of 5223 Pregnant Women


76 Pregnancy as influencing factor on metabolic syndrome 2012 Abstract, no extractable data77 Adverse pregnancy outcomes in cases involving extremely young

maternal age2012 Young pregnant compared to older

pregnants; no extractable data


709


Title Year Reason(s) for exclusion78 Predictors of emergency department and outpatient visits for

hypoglycemia in type 2 diabetes: An analysis of a large US administrative claims database


79 Effects of maternal subclinical hypothyroidism on obstetrical outcomes during early pregnancy


80 Prevalence, associated risk factors and effects of hypothyroidism in pregnancy: A study from north India

2012 Exposure of interest (SCH) not substantiated (treatment instituted after

diagnosis)81 Thyroid disease and gestational diabetes mellitus (GDM): Is there a

connection?2013 Exposure of interest (SCH) not routinely

investigated and/or reported82 Thyroid Diseases and Adverse Pregnancy Outcomes in a Contemporary

US Cohort2013 Exposure of interest (SCH) not routinely

investigated and/or reported83 High prevalence of subclinical hypothyroidism during first trimester of

pregnancy in North India2013 Outcome of interest (GDM) not

investigated and/or reported84 Evaluating the extent of pregravid risk factors of gestational diabetes

mellitus in women in Tehran2013 Retrospective, cross-sectional, exposure of

interest (SCH) not routinely investigated and/or reported,

85 Subsequent Pregnancy Outcomes in Women Previously Diagnosed with Subclinical Hypothyroidism

2013 Risk of gestational diabetes assessed in a pregnancy that followed the index one in which women with subclinical

hypothyroidism were identified86 Evaluation of thyroid dysfunction in pregnant women with gestational

and pre-gestational diabetes2013 Case-control design

87 Effect of maternal chronic disease on obstetric complications in twin pregnancies in a United States cohort


88 Subclinical hypothyroidism after vascular complicated pregnancy 2013 Outcome of interest (GDM) not routinely investigated and/or reported

89 Thyroid autoimmunity and obstetric outcomes in women with recurrent miscarriage: a case–control study

2013 Women with recurrent miscarriages enrolled, outcome of interest (GDM) not

routinely investigated and/or reported90 The character of the course of pregnancy and labor in patients with

obesity2013 Abstract, no extractable data

91 Assessment of thyroid peroxidase antibody and thyroid stimulating hormone in first trimester of pregnancy

2013 Cross-sectional study, outcome of interest (GDM) not routinely investigated and/or

reported92 Pregnancy outcomes with thyroxine replacement for subclinical

hypothyroidism: Role of thyroid autoimmunity2013 No outcome of interest (GDM) not

reported - abstract93 Thyroid disease and GDM: Is there a connection? 2013 Abstract, Exposure of interest (SCH) not

routinely investigated and/or reported, retrospective, no extractable data

94 Pregnancy, gestational diabetes, thyroid function: Our experience 2013 Retrospective design95 Thyroid peroxidase antibody in hypothyroidism: It’s effect on

pregnancy2013 Exposure of interest (SCH) not routinely

investigated and/or reported

GDM = Gestational diabetes mellitus; IVF = in vitro fertilization; SCH: subclinical hypothyroidism

710

during pregnancy in women with SCH could be additive to the normal physiological insulin resistance of pregnancy resulting in GDM. Future studies will need to explore this possibility. Another potential mechanism for an increased incidence of GDM in women with SCH is the impact of TSH-releasing hormone (TRH) signaling on pancreatic beta-cells (29) or thyroid autoimmunity (30). However, the role of TRH in beta-cell biology appears to be restricted to fetal pancreatic precursors (31), and no role for thyroid autoimmunity per se was documented in the studies of this meta-analysis that evaluated thyroid autoimmunity and in which a higher risk of GDM was found in women with SCH (11,13). The latter observation is consistent with prior reports (32-34) that failed to detect an association between thyroid autoimmunity and GDM. On the other hand, this does not preclude the possibility that the interaction between thyroid autoimmunity and SCH during pregnancy (i.e., the effect of the co-presence of thyroid autoimmunity

and SCH as opposed to their individual effects) is what provides the extra “burden” (the second “hit”) on a com-pensated glucose homeostasis in pregnancy, as implied by Karakosta et al (13). Such investigation (as well as explora-tion of a potential dose-response relationship, as implied in Tudela et al (16)) was not feasible in the present study, as it would require individual patient data. The results of the present study should be interpreted with caution as the increase in risk of GDM between euthyroid women and women with SCH did not remain significant in the sensitivity analyses (using the RE model). However, this is not uncommon when the effect is small (35), and unfortunately, newer statistical approaches are not indicated for small meta-analyses (36). Secondly, the baseline risk factors for the development of GDM, such as GDM diagnosis in a previous pregnancy or PCOS (37), were not routinely taken into consideration and might have undermined the risk estimation in individual studies.

Fig. 1. Flow chart of the search strategy and results.

711

Table 1Main characteristics of the cohort studies investigating the association between maternal SCH and GDM

Study naSCH

definitionSCH

prevalence SCH cohort

characteristicsGDM

diagnosis CovariatesQuality(NOS)

Karakosta et al, 2012 (13), Greece

1,170 TSH> 97.5th pct (2.53) and fT4 12.23-19.69 pmol/L

79 (6.7%) BMI: 24.3, age: 29.6Ab(+): 42%

100 g, 3-h oGTT at 24-28 weeks (Carpenter and Coustan)

Age, education, prepregnancy BMI

7

Negro et al (34), 2011, Italy

4,562 TSH>2.5 and fT4 12.0-33.5 pmol/L

34 (1.9%) Age: 29, Ab(+): 8.5%

Not reported Age, parity 7

Mannisto et al, 2010 (14), Finland

5,805 TSH>95th pct (3.6) and fT4 (pmol/L) in 5th (11.96) to 95th pct (20.5)

224 (3.9%) BMI: 22.6, age: 28.6Ab(+): 40.2%

Questionnaire Age, parity, BMIc

6

Sahu et al (15), 2010, India

633 TSH>5.5 and normal (for the laboratory) fT4

41 (6.5%) Weight: 54.5, age: 27.2Ab(+): not reported

100 g, 3-h oGTT (NDDG) in the subset with abnormal glucose challenge test

None 3

Cleary-Goldman et al (12), 2008, USA

10,990 TSH>97.5th pct (4.28) and fT4 (pmol/L) in 2.5th (0.72) to 97.5th pct (1.46)

240 (2.2%) BMI: 24.5, Age: 29.8Ab(+): 15% b

100 g, 3-h oGTT (criteria not specified)

Age, parity, BMI, study site

7

Casey et al (11), 2007, USA

17,298 (mostly Hispanic)

TSH>97.5th pct (3.0) and fT4 (pmol/L) in 2.5th (0.86) to 97.5th pct (1.90)

598 (3.4%) BMI: 32, age: 26.6TPOab(+) 31%

Not reported Age, race, parity, weight

6

Abbreviations: fT4 = free thyroxine; GDM = gestational diabetes mellitus; NDDG = National Diabetes Data Group; NOS = Newcastle-Ottawa scale; oGTT = oral glucose tolerance test; pct = percentile; SCH = subclinical hypothyroidism; TSH = thyroid-stimulating hormone; TPOab = thyroid peroxidase antibodies; TGabs = thyroglobulin antibodiesa refers to the total sample, data used may be a subset of the total study population b in the total cohort (group-specific prevalence not reported)c adjustments not available for the outcome-of-interest measurement units (unless otherwise specified): TSH (mU/L), fT4 (ng/dL), TP0ab, TGab (IU/mL)

712

Fig. 2. A forest plot (unadjusted pooled odds ratio) comparing the risk of gestational diabetes mellitus in pregnant women with subclinical hypothyroidism (SCH) with that in euthyroid pregnant controls.

Fig. 3. A forest plot (adjusted pooled odds ratio) comparing the risk of gestational diabetes mellitus in pregnant women with subclinical hypothyroidism (SCH) with that in euthyroid pregnant controls.

713

CONCLUSION

Given the above limitations and the relative paucity of studies that have explored the relationship between SCH and GDM, the findings of the present study should be con-sidered preliminary. Nevertheless, it would be intriguing to place the reported increased risk of GDM into a clinical context. Specifically, assuming a 5% baseline risk of GDM and that SCH increases the risk of GDM by 50% compared to a euthyroid population, there would be 1 extra case of GDM in every 43 pregnant women with SCH. Given the potential adverse maternal and fetal impacts of GDM, the present finding of an increased incidence of GDM in preg-nant women with SCH provides additional evidence in favor of screening for SCH among women with GDM and screening for GDM among women with SCH.

DISCLOSURE

The authors have no multiplicity of interest to disclose.

REFERENCES

1. Stagnaro-Green A, Pearce E. Thyroid disorders in pregnancy. Nat Rev Endocrinol. 2012;8:650-658.

2. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-1197.

3. National Institutes of Health. National Diabetes Statistics, 2011. Available at: http:// http://diabetes.niddk.nih.gov/dm/pubs/statistics/#Gestational

4. Izzo T, Lo Dico G, Richiusa P. Pregnancy, gestational dia-betes, thyroid function: Our experience. Giornale Italiano di Ostetricia e Ginecologia. 2013;35: 466-470.

5. Vojvodić L, Sulović V, Terzić M. Course and outcome of pregnancy in patients with hypothyroidism [in Serbian]. Srp Arh Celok Lek. 1992;121:62-64.

6. Olivieri A, Valensise H, Magnani F, et al. High frequency of antithyroid autoantibodies in pregnant women at increa-sed risk of gestational diabetes mellitus. Eur J Endocrinol. 2000;143:741-747.

7. Agarwal MM, Dhatt GS, Punnose J, Bishawi B, Zayed R. Thyroid function abnormalities and antithyroid antibody prevalence in pregnant women at high risk for gestational diabetes mellitus. Gynecol Endocrinol. 2006;22:261-266.

8. Mannisto T, Mendola P, Grewal J, Xie Y, Chen Z, Laughon SK. Thyroid diseases and adverse pregnancy outcomes in a contemporary US cohort. J Clin Endocrinol Metab. 2013;98:2725-2733.

9. Wikner BN, Sparre LS, Stiller CO, Källén B, Asker C. Maternal use of thyroid hormones in pregnancy and neona-tal outcome. Acta Obstet Gynecol Scand. 2008;87:617-627.

10. Sinclair JC, Bracken MB. Clinically useful measures of effect in binary analyses of randomized trials. J Clin Epidemiol. 1994;47:881-889.

11. Casey BM, Dashe JS, Spong CY, McIntire DD, Leveno KJ, Cunningham GF. Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet Gynecol. 2007;109:1129-1135.

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

13. Karakosta P, Alegakis D, Georgiou V, et al. Thyroid dysfunction and autoantibodies in early pregnancy are associated with increased risk of gestational diabetes and adverse birth outcomes. J Clin Endocrinol Metab. 2012;97: 4464-4472.

14. Männistö T, Väärasmäki M, Pouta A, et al. Thyroid dys-function and autoantibodies during pregnancy as predictive factors of pregnancy complications and maternal morbidity in later life. J Clin Endocrinol Metab. 2010;95:1084-1094.

15. Sahu MT, Das V, Mittal S, Agarwal A, Sahu M. Overt and subclinical thyroid dysfunction among Indian pregnant women and its effect on maternal and fetal outcome. Arch Gynecol Obstet. 2010;281:215-220.

16. Tudela CM, Casey BM, McIntire DD, Cunningham FG. Relationship of subclinical thyroid disease to the incidence of gestational diabetes. Obstet Gynecol. 2012;119:983-988.

17. Bazelier M, de Boer A, de Vries F. Acid suppressants and hip fracture: duplicate publication bias? Bone. 2012;49:920; author reply 921.

18. van den Boogaard E, Vissenberg R, Land JA, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update. 2011;17:605-619.

19. Duntas LH, Orgiazzi J, Brabant G. The interface bet-ween thyroid and diabetes mellitus. Clin Endocrinol (Oxf). 2011;75:1-9.

20. Garduno-Garcia Jde J, Alvirde-Garcia U, López-Carrasco G, et al. TSH and free thyroxine concentrations are associated with differing metabolic markers in euthy-roid subjects. Eur J Endocrinol. 2010;163:273-278.

21. Handisurya A, Pacini G, Tura A, Gessl A, Kautzky-Willer A. Effects of T4 replacement therapy on glucose metabolism in subjects with subclinical (SH) and overt hypothyroidism (OH). Clin Endocrinol (Oxf). 2008;69: 963-969.

22. Dimitriadis G, Mitrou P, Lambadiari V, et al. Insulin action in adipose tissue and muscle in hypothyroidism. J Clin Endocrinol Metab. 2006;91:4930-4937.

23. Maratou E, Hadjidakis DJ, Kollias A, et al. Studies of insulin resistance in patients with clinical and subclinical hypothyroidism. Eur J Endocrinol. 2009;160:785-790.

24. Hawkes WC, Alkan Z, Lang K, King JC. Plasma sele-nium decrease during pregnancy is associated with glucose intolerance. Biol Trace Elem Res. 2004;100:19-29.

25. Lambadiari V, Mitrou P, Maratou E, et al. Thyroid hor-mones are positively associated with insulin resistance early in the development of type 2 diabetes. Endocrine. 2011;39:28-32.

26. Dittrich R, Kajaia N, Cupisti S, Hoffmann I, Beckmann MW, Mueller A. Association of thyroid-stimulating hormone with insulin resistance and androgen parameters in women with PCOS. Reprod Biomed Online. 2009;19:319-325.

27. Mueller A, Schöfl C, Dittrich R, et al. Thyroid-stimulating hormone is associated with insulin resistance indepen-dently of body mass index and age in women with polycy-stic ovary syndrome. Hum Reprod. 2009;24:2924-2930.

28. Bilic-Komarica E, Beciragic A, Junuzovic D. Effects of treatment with L-thyroxin on glucose regulation in patients with subclinical hypothyroidism. Med Arh. 2012;66: 364-368.

29. Luo L, Yano N, Luo JZ. The molecular mechanism of EGF receptor activation in pancreatic beta-cells by thyro-tropin-releasing hormone. Am J Physiol Endocrinol Metab. 2006;290:E889-899.

714

30. Matejková-Behanová M, Zamrazil V, Vondra K, et al. Autoimmune thyroiditis in non-obese subjects with initial diagnosis of Type 2 diabetes mellitus. J Endocrinol Invest. 2002;25:779-784.

31. Mulla CM, Geras-Raaka E, Raaka BM, Gershengorn MC. High levels of thyrotropin-releasing hormone recep-tors activate programmed cell death in human pancreatic precursors. Pancreas. 2009;38:197-202.

32. Abbassi-Ghanavati M, Casey BM, Spong CY, McIntire DD, Halvorson LM, Cunningham FG. Pregnancy out-comes in women with thyroid peroxidase antibodies. Obstet Gynecol. 2010;116:381-386.

33. Feki M, Omar S, Menif O, et al. Thyroid disorders in pregnancy: frequency and association with selected disea-ses and obstetrical complications in Tunisian women. Clin Biochem. 2008;41:927-931.

34. Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A. Thyroid antibody positivity in the first trimester of pregnancy is associated with negative pregnancy outcomes. J Clin Endocrinol Metab. 2011;96: E920-924.

35. Walker E, Hernandez AV, Kattan MW. Meta-analysis: Its strengths and limitations. Cleve Clin J Med. 2008;75: 431-439.

36. Kontopantelis E, Springate DA, Reeves D. A re-analysis of the Cochrane Library data: the dangers of unobserved heterogeneity in meta-analyses. PLoS One. 2013;8:e69930.

37. Toulis KA, Goulis DG, Kolibianakis EM, Venetis CA, Tarlatzis BC, Papadimas I. Risk of gestational diabe-tes mellitus in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Fertil Steril. 2009; 92:667-677.

maternal subclinical hypothyroidsm and gestational diabetes mellitus: a meta-analysis

Documents