Review Article
Konstantinos A. Toulis, MD1; Alex Stagnaro-Green, MD, MHPE2; Roberto Negro, MD3 ABSTRACT Objective: The association between subclinical hypothyroidism (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 identified. 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.
Submitted for publication October 28, 2013 Accepted for publication November 27, 2013 From 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] Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org on date January 21, 2014. DOI:10.4158/EP13440.RA To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2014 AACE.
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 further investigation. (Endocr Pract. 2014;20:703-714) Abbreviations: CI = confidence interval; GDM = gestational diabetes mellitus; OR = odds ratio; SCH = subclinical hypothyroidism; TSH = thyroid-stimulating hormone INTRODUCTION Both hypothyroidism and diabetes mellitus occur frequently during pregnancy. Subclinical hypothyroidism (SCH), defined as an elevated thyroid-stimulating hormone (TSH) with a normal free thyroxine level, occurs in between 2 and 10% of pregnant women (1). Similarly, gestational diabetes mellitus (GDM), that is glucose intolerance 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 innerring 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 diabetes mellitus in women whose thyroid and/or metabolic disease first manifested during pregnancy.
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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 studies, 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 considered 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 metaanalysis of published articles that have explored the association between SCH and GDM. METHODS A computerized search was conducted in the electronic databases MEDLINE and EMBASE from their inceptions to July 2013 using various combinations of following search terms: “thyroid dysfunction,” “thyroid diseases,” “subclinical hypothyroidism,” “hypothyroxinemia,” “thyrotropin,” “gestational diabetes,” “hyperglycemia in pregnancy,” and “adverse pregnancy outcomes.” The search was complemented by the perusal of the reference 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 extraction. 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_epidemiology/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 confounding 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 estimates, logarithmic transformation was used for calculation, followed by exponentiation. Heterogeneity was measured 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 studies 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 double 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 metaanalysis, 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 significantly higher in pregnant women with SCH when using
705
Supplementary Table 1 Literature Search Terms and Results 1
2 3 4 5 6 7 8 9
10 11
Search (“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]) “thyroid diseases”[MeSH Terms] OR (“thyroid”[All Fields] AND “diseases”[All Fields]) OR “thyroid diseases”[All Fields] subclinical[All Fields] AND (“hypothyroidism”[MeSH Terms] OR “hypothyroidism”[All Fields]) hypothyroxinemia[All Fields] “thyrotropin”[MeSH Terms] OR “thyrotropin”[All Fields] 1 or 2 or 3 or 4 or 5 “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]) (“hyperglycaemia”[All Fields] OR “hyperglycemia”[MeSH Terms] OR “hyperglycemia”[All Fields]) AND (“pregnancy”[MeSH Terms] OR “pregnancy”[All Fields]) 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]) 7 or 8 or 9 6 and 10
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 estimates 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(+) category were used, this finding did not retain statistical significance (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
MEDLINE 16,900
EMBASE 25,108
124,870
222,136
2,367
3,374
327 40,397 155,042 11,252
425 56,081 246,148 14,693
2,524
4,050
21,498
13,693
33,060 360
30,027 674
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-resistant 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 glucose transporter 2 (GLUT2) resulting in decreased insulinstimulated glucose transport rate (23), and decreased selenium levels (24) have all been implicated. Epidemiological data suggesting that thyroid hormones are positively associated 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 individuals 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 2 List of the Studies Excluded on a Full-text Basis Title
Year
Reason(s) for exclusion
1
[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 group
4
Hypothyroidism complicating pregnancy
1988
No control group
5
Outcome of thyroid function in newborns from mothers treated with amiodarone
1992
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 group
9
Maternal thyroid deficiency and pregnancy complications: implications for population screening.
2000
Outcome of interest (GDM) not routinely investigated and/or reported
10
Sex hormone-binding globulin in gestational diabetes
2000
Case-control design
11
High frequency of antithyroid autoantibodies in pregnant women at increased risk of gestational diabetes mellitus
2000
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 crosssectional 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
2004
Case-control design
19
Trimester-specific reference intervals for thyroxine and triiodothyronine in pregnancy in iodine-sufficient women using isotope dilution tandem mass spectrometry and immunoassays
2004
Outcome of interest (GDM) not routinely investigated and/or reported
20
High maternal hemoglobin and ferritin values as risk factors for gestational diabetes
2004
Exposure of interest (SCH) not routinely investigated and/or reported
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]
2005
Outcome of interest (GDM) not routinely investigated and/or reported
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 evidence
24
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, review
25
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
2005
Outcome of interest (GDM) not routinely investigated and/or reported
(Continued next page)
707 Supplementary Table 2 (Continued) List of the Studies Excluded on a Full-text Basis Title Subclinical Hypothyroidism and Pregnancy Outcomes
Year 2005
27
Adverse effects of thyroid dysfunction on pregnancy and pregnancy outcome: epidemiologic study in Slovenia
2006
28
Thyroid function abnormalities and antithyroid antibody prevalence in pregnant women at high risk for gestational diabetes mellitus Adverse effects of thyroid dysfunction on pregnancy and pregnancy outcome: epidemiologic study in Slovenia Relationship of treated maternal hypothyroidism and perinatal outcome
2006
Reason(s) for exclusion Outcome of interest (GDM) not routinely investigated and/or reported Outcome of interest (GDM) not routinely investigated and/or reported Retrospective design Case-control design
2006
Retrospective in design
2006 2008
32
Thyroid function tests and thyroid autoantibodies in an unselected population of women undergoing first trimester screening for aneuploidy Maternal use of thyroid hormones in pregnancy and neonatal outcome
Exposure and outcome of interest (SCH and GDM) not reported Outcome of interest (GDM) not routinely investigated and/or reported
33
Is thyroid autoimmunity associated with gestational diabetes mellitus?
2008
34
Thyroid hormones according to gestational age in pregnant Spanish women 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 The impact of isolated maternal hypothyroxinemia on perinatal morbidity Thyroid function in early pregnancy in Japanese healthy women: relation to urinary iodine excretion, emesis, and fetal and child development Clinical analysis of pregnancy combined with thyroid disorder Association Between Oxidative Stress and Thyroid Diseases of Pregnant Women How significant is sub-clinical hypothyroidism in pregnancy outcome?
2009
2010
47
Perinatal outcome associated with thyroid-peroxidase antibodies in gestational diabetes Diabetes in pregnancy: Risk factor analysis from a clinic in the United Arab Emirates Screening thyroid function in pregnancy: Should all pregnant women be screened Hypothyroidism as a risk factor in pregnancy Subclinical hypothyroidism does not adversely affect pregnancy outcomes after assisted reproduction Gestational diabetes leading to diagnosis and management of multiple endocrine neoplasia type 2a Thyroid hormone early adjustment in pregnancy (The THERAPY) trial
48
Bad obstetric history: A prospective study
2010
49 50
Screening for gestational diabetes in Bulgaria--preliminary results Pregnancy outcomes in women with thyroid peroxidase antibodies
2010 2010
51
[Maternal autoimmune thyroid disease and pregnancy complication]
2010
26
29 30 31
35 36 37 38 39 40 41 42 43 44 45 46
2008
2009 2009 2009
Exposure of interest (SCH) not routinely investigated and/or reported Exposure of interest (SCH) not routinely investigated and/or reported Outcome of interest (GDM) not routinely investigated and/or reported Outcome of interest (GDM) not routinely investigated and/or reported Exposure of interest (SCH) not routinely investigated and/or reported Outcome of interest (GDM) not routinely investigated and/or reported
2009 2009
Abstract, no extractable data Abstract, no extractable data
2009
Abstract *reports that no significant increase in the incidence of gestational diabetes Abstract, no extractable data
2010 2010 2010 2010 2010 2010
Retrospective, no difference in TSH among diabetic pregnant groups Outcome of interest (GDM) not reported - abstract Abstract, not extractable data IVF setting - Outcome of interest (GDM) not routinely investigated and/or reported Case-study Outcome of interest (GDM) not routinely investigated and/or reported Subpopulation of women with an unfortunate obstetric outcome in a previous pregnancy Case-control Exposure and outcome of interest (SCH and GDM) not reported No extractable data
(Continued next page)
708 Supplementary Table 2 (Continued) List of the Studies Excluded on a Full-text Basis 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77
Title Subclinical elevations of thyroid-stimulating hormone and assisted reproductive technology outcomes Abnormal one-hour 50-gram glucose challenge test and perinatal outcomes
Year 2011
Reason(s) for exclusion IVF setting
2011
Maternal selenium status during early gestation and risk for preterm birth Effect of autoimmune thyroid disease in older euthyroid infertile woman during the first 35 days of an IVF cycle Thyroid Antibody Positivity in the First Trimester of Pregnancy Is Associated with Negative Pregnancy Outcomes Thyroid disease in pregnant women with systemic lupus erythematosus: Increased preterm delivery The prevalence of thyroid peroxidase anti body positive results in a population of overt hypothyroid pregnant saudi women and its effects on obstetrical complications Prevalence of thyroid dysfunction and autoimmunity in pregnant women with gestational diabetes and diabetes type 1 Fetal thyroid hormone level at birth is associated with fetal growth
2011
2011
Retrospective study, Exposure and outcome of interest (SCH and GDM) not investigated / reported Exposure and outcome of interest (SCH and GDM) not reported IVF setting - Outcome of interest (GDM) not reported No women with subclinical hypothyroidism were included Outcome of interest (GDM) not routinely investigated and/or reported Abstract, no extractable data
2011
Case-control design
2011
Lower Free Thyroxin Associates with a Less Favorable Metabolic Phenotype in Healthy Pregnant Women 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 Pregnancy Loss and Neonatal Outcomes in Women with Thyroid Dysfunction in the First Trimester of Pregnancy Free thyroid hormone levels, second-hand smoke, and pregnancy outcomes Maternal Early Pregnancy and Newborn Thyroid Hormone Parameters: The Generation R Study Detection of thyroid dysfunction in early pregnancy
2011
Outcome of interest (GDM) not routinely investigated and/or reported Outcome of interest (GDM) not routinely investigated and/or reported Abstract, no extractable data
2011 2011 2011
2012 2012
Gestational diabetes and thyroid autoimmunity The prevalence of hypothyroidism based on risk factors in pregnant women referred to Shahid Dadbin clinic, Kerman, Iran The effect of thyroid antibody positivity in euthyroid women undergoing in vitro fertilization-embryo transfer cycle (IVF-ET) A clinical study on relationship between thyroid autoimmunity and pregnancy outcomes in in-vitro fertilization women Relationship of subclinical thyroid disease to the incidence of gestational diabetes Incidence of hypothyroidism in Saudi pregnant women
2012 2012
Outcome of interest (GDM) not routinely investigated and/or reported Abstract, no extractable data, retrospective evidence Outcome of interest (GDM) not routinely investigated and/or reported Outcome of interest (GDM) not routinely investigated and/or reported Case-control design Cross-sectional study
2012
IVF setting, no extractable data, abstract
2012
IVF setting, no extractable data, abstract
2012
Double publication bias
2012
Association and predictive accuracy of high TSH serum levels in first trimester and adverse pregnancy outcomes First trimester high TSH serum levels associated with an increased risk of adverse pregnancy outcomes Is Age a Risk Factor for Hypothyroidism in Pregnancy? An Analysis of 5223 Pregnant Women Pregnancy as influencing factor on metabolic syndrome Adverse pregnancy outcomes in cases involving extremely young maternal age
2012
Outcome of interest (GDM) not reported - abstract Outcome of interest (GDM) not investigated and/or reported Outcome of interest (GDM) not investigated and/or reported - abstract Outcome of interest (GDM) not investigated and/or reported Abstract, no extractable data Young pregnant compared to older pregnants; no extractable data
2012 2012 2012
2012 2012 2012 2012
(Continued next page)
709 Supplementary Table 2 (Continued) List of the Studies Excluded on a Full-text Basis Title
Year
Reason(s) for exclusion
78
Predictors of emergency department and outpatient visits for hypoglycemia in type 2 diabetes: An analysis of a large US administrative claims database
2012
Exposure of interest (SCH) not routinely investigated and/or reported
79
Effects of maternal subclinical hypothyroidism on obstetrical outcomes during early pregnancy
2012
Outcome of interest (GDM) not investigated and/or reported
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 reported
82
Thyroid Diseases and Adverse Pregnancy Outcomes in a Contemporary US Cohort
2013
Exposure of interest (SCH) not routinely investigated and/or reported
83
High prevalence of subclinical hypothyroidism during first trimester of pregnancy in North India
2013
Outcome of interest (GDM) not investigated and/or reported
84
Evaluating the extent of pregravid risk factors of gestational diabetes mellitus in women in Tehran
2013
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 identified
86
Evaluation of thyroid dysfunction in pregnant women with gestational and pre-gestational diabetes
2013
Case-control design
87
Effect of maternal chronic disease on obstetric complications in twin pregnancies in a United States cohort
2013
Exposure of interest (SCH) not routinely investigated and/or reported
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 reported
90
The character of the course of pregnancy and labor in patients with obesity
2013
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 reported
92
Pregnancy outcomes with thyroxine replacement for subclinical hypothyroidism: Role of thyroid autoimmunity
2013
No outcome of interest (GDM) not reported - abstract
93
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 design
95
Thyroid peroxidase antibody in hypothyroidism: It’s effect on pregnancy
2013
Exposure of interest (SCH) not routinely investigated and/or reported
GDM = Gestational diabetes mellitus; IVF = in vitro fertilization; SCH: subclinical hypothyroidism
710
Fig. 1. Flow chart of the search strategy and results.
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 compensated glucose homeostasis in pregnancy, as implied by Karakosta et al (13). Such investigation (as well as exploration 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.
711
Table 1 Main characteristics of the cohort studies investigating the association between maternal SCH and GDM na
Study
SCH definition
SCH prevalence
SCH cohort characteristics
GDM diagnosis
Covariates
Quality (NOS)
Karakosta et al, 2012 (13), Greece
1,170
TSH> 97.5th pct (2.53) and fT4 12.2319.69 pmol/L
79 (6.7%)
BMI: 24.3, age: 29.6 Ab(+): 42%
100 g, 3-h oGTT at 2428 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: 28.6 Ab(+): 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: 27.2 Ab(+): not reported
100 g, 3-h oGTT (NDDG) in the subset with abnormal glucose challenge test
None
3
ClearyGoldman 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: 29.8 Ab(+): 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: 26.6 TPOab(+) 31%
Not reported
Age, race, parity, weight
6
Abbreviations: fT4 = free thyroxine; GDM = gestational diabetes mellitus; NDDG = National Diabetes Data Group; NOS = NewcastleOttawa scale; oGTT = oral glucose tolerance test; pct = percentile; SCH = subclinical hypothyroidism; TSH = thyroid-stimulating hormone; TPOab = thyroid peroxidase antibodies; TGabs = thyroglobulin antibodies a 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 considered 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 pregnant 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
13.
14.
15.
16. 17. 18.
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 diabetes, 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 increased 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 neonatal 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.
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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. Männistö T, Väärasmäki M, Pouta A, et al. Thyroid dysfunction and autoantibodies during pregnancy as predictive factors of pregnancy complications and maternal morbidity in later life. J Clin Endocrinol Metab. 2010;95:1084-1094. 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. 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. Bazelier M, de Boer A, de Vries F. Acid suppressants and hip fracture: duplicate publication bias? Bone. 2012;49:920; author reply 921. 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. Duntas LH, Orgiazzi J, Brabant G. The interface between thyroid and diabetes mellitus. Clin Endocrinol (Oxf). 2011;75:1-9. Garduno-Garcia Jde J, Alvirde-Garcia U, LópezCarrasco G, et al. TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects. Eur J Endocrinol. 2010;163:273-278. Handisurya A, Pacini G, Tura A, Gessl A, KautzkyWiller 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. 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. 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. Hawkes WC, Alkan Z, Lang K, King JC. Plasma selenium decrease during pregnancy is associated with glucose intolerance. Biol Trace Elem Res. 2004;100:19-29. Lambadiari V, Mitrou P, Maratou E, et al. Thyroid hormones are positively associated with insulin resistance early in the development of type 2 diabetes. Endocrine. 2011;39:28-32. 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. Mueller A, Schöfl C, Dittrich R, et al. Thyroid-stimulating hormone is associated with insulin resistance independently of body mass index and age in women with polycystic ovary syndrome. Hum Reprod. 2009;24:2924-2930. 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. Luo L, Yano N, Luo JZ. The molecular mechanism of EGF receptor activation in pancreatic beta-cells by thyrotropin-releasing hormone. Am J Physiol Endocrinol Metab. 2006;290:E889-899.
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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. Mulla CM, Geras-Raaka E, Raaka BM, Gershengorn MC. High levels of thyrotropin-releasing hormone receptors activate programmed cell death in human pancreatic precursors. Pancreas. 2009;38:197-202. Abbassi-Ghanavati M, Casey BM, Spong CY, McIntire DD, Halvorson LM, Cunningham FG. Pregnancy outcomes in women with thyroid peroxidase antibodies. Obstet Gynecol. 2010;116:381-386. Feki M, Omar S, Menif O, et al. Thyroid disorders in pregnancy: frequency and association with selected diseases and obstetrical complications in Tunisian women. Clin Biochem. 2008;41:927-931.
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. 3 6. 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 diabetes mellitus in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Fertil Steril. 2009; 92:667-677. 34.
Konstantinos A. Toulis, MD1; Alex Stagnaro-Green, MD, MHPE2; Roberto Negro, MD3 ABSTRACT Objective: The association between subclinical hypothyroidism (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 identified. 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.
Submitted for publication October 28, 2013 Accepted for publication November 27, 2013 From 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] Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org on date January 21, 2014. DOI:10.4158/EP13440.RA To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2014 AACE.
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 further investigation. (Endocr Pract. 2014;20:703-714) Abbreviations: CI = confidence interval; GDM = gestational diabetes mellitus; OR = odds ratio; SCH = subclinical hypothyroidism; TSH = thyroid-stimulating hormone INTRODUCTION Both hypothyroidism and diabetes mellitus occur frequently during pregnancy. Subclinical hypothyroidism (SCH), defined as an elevated thyroid-stimulating hormone (TSH) with a normal free thyroxine level, occurs in between 2 and 10% of pregnant women (1). Similarly, gestational diabetes mellitus (GDM), that is glucose intolerance 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 innerring 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 diabetes mellitus in women whose thyroid and/or metabolic disease first manifested during pregnancy.
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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 studies, 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 considered 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 metaanalysis of published articles that have explored the association between SCH and GDM. METHODS A computerized search was conducted in the electronic databases MEDLINE and EMBASE from their inceptions to July 2013 using various combinations of following search terms: “thyroid dysfunction,” “thyroid diseases,” “subclinical hypothyroidism,” “hypothyroxinemia,” “thyrotropin,” “gestational diabetes,” “hyperglycemia in pregnancy,” and “adverse pregnancy outcomes.” The search was complemented by the perusal of the reference 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 extraction. 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_epidemiology/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 confounding 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 estimates, logarithmic transformation was used for calculation, followed by exponentiation. Heterogeneity was measured 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 studies 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 double 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 metaanalysis, 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 significantly higher in pregnant women with SCH when using
705
Supplementary Table 1 Literature Search Terms and Results 1
2 3 4 5 6 7 8 9
10 11
Search (“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]) “thyroid diseases”[MeSH Terms] OR (“thyroid”[All Fields] AND “diseases”[All Fields]) OR “thyroid diseases”[All Fields] subclinical[All Fields] AND (“hypothyroidism”[MeSH Terms] OR “hypothyroidism”[All Fields]) hypothyroxinemia[All Fields] “thyrotropin”[MeSH Terms] OR “thyrotropin”[All Fields] 1 or 2 or 3 or 4 or 5 “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]) (“hyperglycaemia”[All Fields] OR “hyperglycemia”[MeSH Terms] OR “hyperglycemia”[All Fields]) AND (“pregnancy”[MeSH Terms] OR “pregnancy”[All Fields]) 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]) 7 or 8 or 9 6 and 10
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 estimates 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(+) category were used, this finding did not retain statistical significance (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
MEDLINE 16,900
EMBASE 25,108
124,870
222,136
2,367
3,374
327 40,397 155,042 11,252
425 56,081 246,148 14,693
2,524
4,050
21,498
13,693
33,060 360
30,027 674
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-resistant 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 glucose transporter 2 (GLUT2) resulting in decreased insulinstimulated glucose transport rate (23), and decreased selenium levels (24) have all been implicated. Epidemiological data suggesting that thyroid hormones are positively associated 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 individuals 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 2 List of the Studies Excluded on a Full-text Basis Title
Year
Reason(s) for exclusion
1
[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 group
4
Hypothyroidism complicating pregnancy
1988
No control group
5
Outcome of thyroid function in newborns from mothers treated with amiodarone
1992
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 group
9
Maternal thyroid deficiency and pregnancy complications: implications for population screening.
2000
Outcome of interest (GDM) not routinely investigated and/or reported
10
Sex hormone-binding globulin in gestational diabetes
2000
Case-control design
11
High frequency of antithyroid autoantibodies in pregnant women at increased risk of gestational diabetes mellitus
2000
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 crosssectional 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
2004
Case-control design
19
Trimester-specific reference intervals for thyroxine and triiodothyronine in pregnancy in iodine-sufficient women using isotope dilution tandem mass spectrometry and immunoassays
2004
Outcome of interest (GDM) not routinely investigated and/or reported
20
High maternal hemoglobin and ferritin values as risk factors for gestational diabetes
2004
Exposure of interest (SCH) not routinely investigated and/or reported
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]
2005
Outcome of interest (GDM) not routinely investigated and/or reported
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 evidence
24
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, review
25
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
2005
Outcome of interest (GDM) not routinely investigated and/or reported
(Continued next page)
707 Supplementary Table 2 (Continued) List of the Studies Excluded on a Full-text Basis Title Subclinical Hypothyroidism and Pregnancy Outcomes
Year 2005
27
Adverse effects of thyroid dysfunction on pregnancy and pregnancy outcome: epidemiologic study in Slovenia
2006
28
Thyroid function abnormalities and antithyroid antibody prevalence in pregnant women at high risk for gestational diabetes mellitus Adverse effects of thyroid dysfunction on pregnancy and pregnancy outcome: epidemiologic study in Slovenia Relationship of treated maternal hypothyroidism and perinatal outcome
2006
Reason(s) for exclusion Outcome of interest (GDM) not routinely investigated and/or reported Outcome of interest (GDM) not routinely investigated and/or reported Retrospective design Case-control design
2006
Retrospective in design
2006 2008
32
Thyroid function tests and thyroid autoantibodies in an unselected population of women undergoing first trimester screening for aneuploidy Maternal use of thyroid hormones in pregnancy and neonatal outcome
Exposure and outcome of interest (SCH and GDM) not reported Outcome of interest (GDM) not routinely investigated and/or reported
33
Is thyroid autoimmunity associated with gestational diabetes mellitus?
2008
34
Thyroid hormones according to gestational age in pregnant Spanish women 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 The impact of isolated maternal hypothyroxinemia on perinatal morbidity Thyroid function in early pregnancy in Japanese healthy women: relation to urinary iodine excretion, emesis, and fetal and child development Clinical analysis of pregnancy combined with thyroid disorder Association Between Oxidative Stress and Thyroid Diseases of Pregnant Women How significant is sub-clinical hypothyroidism in pregnancy outcome?
2009
2010
47
Perinatal outcome associated with thyroid-peroxidase antibodies in gestational diabetes Diabetes in pregnancy: Risk factor analysis from a clinic in the United Arab Emirates Screening thyroid function in pregnancy: Should all pregnant women be screened Hypothyroidism as a risk factor in pregnancy Subclinical hypothyroidism does not adversely affect pregnancy outcomes after assisted reproduction Gestational diabetes leading to diagnosis and management of multiple endocrine neoplasia type 2a Thyroid hormone early adjustment in pregnancy (The THERAPY) trial
48
Bad obstetric history: A prospective study
2010
49 50
Screening for gestational diabetes in Bulgaria--preliminary results Pregnancy outcomes in women with thyroid peroxidase antibodies
2010 2010
51
[Maternal autoimmune thyroid disease and pregnancy complication]
2010
26
29 30 31
35 36 37 38 39 40 41 42 43 44 45 46
2008
2009 2009 2009
Exposure of interest (SCH) not routinely investigated and/or reported Exposure of interest (SCH) not routinely investigated and/or reported Outcome of interest (GDM) not routinely investigated and/or reported Outcome of interest (GDM) not routinely investigated and/or reported Exposure of interest (SCH) not routinely investigated and/or reported Outcome of interest (GDM) not routinely investigated and/or reported
2009 2009
Abstract, no extractable data Abstract, no extractable data
2009
Abstract *reports that no significant increase in the incidence of gestational diabetes Abstract, no extractable data
2010 2010 2010 2010 2010 2010
Retrospective, no difference in TSH among diabetic pregnant groups Outcome of interest (GDM) not reported - abstract Abstract, not extractable data IVF setting - Outcome of interest (GDM) not routinely investigated and/or reported Case-study Outcome of interest (GDM) not routinely investigated and/or reported Subpopulation of women with an unfortunate obstetric outcome in a previous pregnancy Case-control Exposure and outcome of interest (SCH and GDM) not reported No extractable data
(Continued next page)
708 Supplementary Table 2 (Continued) List of the Studies Excluded on a Full-text Basis 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77
Title Subclinical elevations of thyroid-stimulating hormone and assisted reproductive technology outcomes Abnormal one-hour 50-gram glucose challenge test and perinatal outcomes
Year 2011
Reason(s) for exclusion IVF setting
2011
Maternal selenium status during early gestation and risk for preterm birth Effect of autoimmune thyroid disease in older euthyroid infertile woman during the first 35 days of an IVF cycle Thyroid Antibody Positivity in the First Trimester of Pregnancy Is Associated with Negative Pregnancy Outcomes Thyroid disease in pregnant women with systemic lupus erythematosus: Increased preterm delivery The prevalence of thyroid peroxidase anti body positive results in a population of overt hypothyroid pregnant saudi women and its effects on obstetrical complications Prevalence of thyroid dysfunction and autoimmunity in pregnant women with gestational diabetes and diabetes type 1 Fetal thyroid hormone level at birth is associated with fetal growth
2011
2011
Retrospective study, Exposure and outcome of interest (SCH and GDM) not investigated / reported Exposure and outcome of interest (SCH and GDM) not reported IVF setting - Outcome of interest (GDM) not reported No women with subclinical hypothyroidism were included Outcome of interest (GDM) not routinely investigated and/or reported Abstract, no extractable data
2011
Case-control design
2011
Lower Free Thyroxin Associates with a Less Favorable Metabolic Phenotype in Healthy Pregnant Women 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 Pregnancy Loss and Neonatal Outcomes in Women with Thyroid Dysfunction in the First Trimester of Pregnancy Free thyroid hormone levels, second-hand smoke, and pregnancy outcomes Maternal Early Pregnancy and Newborn Thyroid Hormone Parameters: The Generation R Study Detection of thyroid dysfunction in early pregnancy
2011
Outcome of interest (GDM) not routinely investigated and/or reported Outcome of interest (GDM) not routinely investigated and/or reported Abstract, no extractable data
2011 2011 2011
2012 2012
Gestational diabetes and thyroid autoimmunity The prevalence of hypothyroidism based on risk factors in pregnant women referred to Shahid Dadbin clinic, Kerman, Iran The effect of thyroid antibody positivity in euthyroid women undergoing in vitro fertilization-embryo transfer cycle (IVF-ET) A clinical study on relationship between thyroid autoimmunity and pregnancy outcomes in in-vitro fertilization women Relationship of subclinical thyroid disease to the incidence of gestational diabetes Incidence of hypothyroidism in Saudi pregnant women
2012 2012
Outcome of interest (GDM) not routinely investigated and/or reported Abstract, no extractable data, retrospective evidence Outcome of interest (GDM) not routinely investigated and/or reported Outcome of interest (GDM) not routinely investigated and/or reported Case-control design Cross-sectional study
2012
IVF setting, no extractable data, abstract
2012
IVF setting, no extractable data, abstract
2012
Double publication bias
2012
Association and predictive accuracy of high TSH serum levels in first trimester and adverse pregnancy outcomes First trimester high TSH serum levels associated with an increased risk of adverse pregnancy outcomes Is Age a Risk Factor for Hypothyroidism in Pregnancy? An Analysis of 5223 Pregnant Women Pregnancy as influencing factor on metabolic syndrome Adverse pregnancy outcomes in cases involving extremely young maternal age
2012
Outcome of interest (GDM) not reported - abstract Outcome of interest (GDM) not investigated and/or reported Outcome of interest (GDM) not investigated and/or reported - abstract Outcome of interest (GDM) not investigated and/or reported Abstract, no extractable data Young pregnant compared to older pregnants; no extractable data
2012 2012 2012
2012 2012 2012 2012
(Continued next page)
709 Supplementary Table 2 (Continued) List of the Studies Excluded on a Full-text Basis Title
Year
Reason(s) for exclusion
78
Predictors of emergency department and outpatient visits for hypoglycemia in type 2 diabetes: An analysis of a large US administrative claims database
2012
Exposure of interest (SCH) not routinely investigated and/or reported
79
Effects of maternal subclinical hypothyroidism on obstetrical outcomes during early pregnancy
2012
Outcome of interest (GDM) not investigated and/or reported
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 reported
82
Thyroid Diseases and Adverse Pregnancy Outcomes in a Contemporary US Cohort
2013
Exposure of interest (SCH) not routinely investigated and/or reported
83
High prevalence of subclinical hypothyroidism during first trimester of pregnancy in North India
2013
Outcome of interest (GDM) not investigated and/or reported
84
Evaluating the extent of pregravid risk factors of gestational diabetes mellitus in women in Tehran
2013
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 identified
86
Evaluation of thyroid dysfunction in pregnant women with gestational and pre-gestational diabetes
2013
Case-control design
87
Effect of maternal chronic disease on obstetric complications in twin pregnancies in a United States cohort
2013
Exposure of interest (SCH) not routinely investigated and/or reported
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 reported
90
The character of the course of pregnancy and labor in patients with obesity
2013
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 reported
92
Pregnancy outcomes with thyroxine replacement for subclinical hypothyroidism: Role of thyroid autoimmunity
2013
No outcome of interest (GDM) not reported - abstract
93
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 design
95
Thyroid peroxidase antibody in hypothyroidism: It’s effect on pregnancy
2013
Exposure of interest (SCH) not routinely investigated and/or reported
GDM = Gestational diabetes mellitus; IVF = in vitro fertilization; SCH: subclinical hypothyroidism
710
Fig. 1. Flow chart of the search strategy and results.
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 compensated glucose homeostasis in pregnancy, as implied by Karakosta et al (13). Such investigation (as well as exploration 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.
711
Table 1 Main characteristics of the cohort studies investigating the association between maternal SCH and GDM na
Study
SCH definition
SCH prevalence
SCH cohort characteristics
GDM diagnosis
Covariates
Quality (NOS)
Karakosta et al, 2012 (13), Greece
1,170
TSH> 97.5th pct (2.53) and fT4 12.2319.69 pmol/L
79 (6.7%)
BMI: 24.3, age: 29.6 Ab(+): 42%
100 g, 3-h oGTT at 2428 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: 28.6 Ab(+): 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: 27.2 Ab(+): not reported
100 g, 3-h oGTT (NDDG) in the subset with abnormal glucose challenge test
None
3
ClearyGoldman 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: 29.8 Ab(+): 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: 26.6 TPOab(+) 31%
Not reported
Age, race, parity, weight
6
Abbreviations: fT4 = free thyroxine; GDM = gestational diabetes mellitus; NDDG = National Diabetes Data Group; NOS = NewcastleOttawa scale; oGTT = oral glucose tolerance test; pct = percentile; SCH = subclinical hypothyroidism; TSH = thyroid-stimulating hormone; TPOab = thyroid peroxidase antibodies; TGabs = thyroglobulin antibodies a 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.
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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 considered 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 pregnant 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
13.
14.
15.
16. 17. 18.
The authors have no multiplicity of interest to disclose.
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