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Figure 1.
Flowchart of the Study and Participant Selections
Flowchart of the Study and Participant Selections
Figure 2.
Association of Thyroid Function Test Abnormalities With Preterm Birth
Association of Thyroid Function Test Abnormalities With Preterm Birth

All analyses were adjusted for maternal age, body mass index, ethnicity, smoking, parity, gestational age at blood sampling, and fetal sex. Euthyroid was defined as the 2.5th-97.5th cohort-specific percentile for thyrotropin (often referred to as thyroid-stimulating hormone or TSH) and free thyroxine (FT4) concentrations; subclinical hypothyroidism, increased thyrotropin concentration with a normal FT4 concentration; subclinical hyperthyroidism, decreased thyrotropin concentration with a normal FT4 concentration; overt hyperthyroidism, decreased thyrotropin concentration with an increased FT4 concentration; and isolated hypothyroxinemia, a normal thyrotropin concentration with a decreased FT4 concentration. These clinical entities were calculated for cohorts that had thyrotropin concentration, FT4 concentration, and thyroid peroxidase antibody data available. Absolute differences and corresponding 95% CIs were back-calculated from the results of multivariable models and adjusted for baseline risk imprecision.

aThere were too few samples to conduct a reliable analysis.

Figure 3.
Association of Thyrotropin and Free Thyroxine (FT4) Concentrations With Preterm Birth
Association of Thyrotropin and Free Thyroxine (FT4) Concentrations With Preterm Birth

Preterm birth was defined as less than 37 weeks’ gestational age and very preterm birth was defined as less than 32 weeks’ gestational age. The thyrotropin and FT4 concentrations for all cohorts were log transformed and then standardized to population-specific standard deviation scores after removal of outliers (±4 SD from the mean) to enable comparison between different cohorts and assays. All analyses were adjusted for maternal age, body mass index, ethnicity, smoking, parity, gestational age at blood sampling, and fetal sex. OR indicates odds ratio.

Figure 4.
Association of Thyroid Peroxidase (TPO) Antibody Positivity With Preterm Birth
Association of Thyroid Peroxidase (TPO) Antibody Positivity With Preterm Birth

All analyses were adjusted for maternal age, body mass index, ethnicity, smoking, parity, gestational age at blood sampling, and fetal sex. Absolute differences and corresponding 95% CIs were back-calculated from the results of multivariable models and adjusted for baseline risk imprecision.

aThyroid peroxidase antibody–positive women and thyrotropin (often referred to as thyroid-stimulating hormone) concentrations within the normal range or higher than 2.5 mIU/L and 4 mIU/L were compared with TPO antibody–negative women regardless of their thyrotropin concentration.

bThere were too few samples to conduct a reliable analysis.

Table.  
Characteristics of the Total Study Population (N = 47 045)
Characteristics of the Total Study Population (N = 47 045)
Supplement 2.

eMethods. Details on search strategy and systematic search and statistics

eTable 1A. Maternal demographics per cohort

eTable 1B. Maternal thyroid function test results per cohort

eTable 1C. Description of euthyroidism and thyroid function test abnormalities per cohort

eTable 1D. Description of pregnancy characteristics per cohort

eTable 1E. Percentage of missing data of covariates per cohort

eTable 2. Date and place of data collection for the included cohorts

eTable 3. Newcastle - Ottawa Quality Assessment Scale per cohort

eTable 4. Cohort-specific cut-offs of TSH and FT4 for defining thyroid function test abnormalities

eTable 5. Comparison of TSH and FT4 concentrations and TPOAb positivity between women with or without data on gestational age at birth

eTable 6. The association of TSH and FT4 concentrations or TgAb positivity with preterm birth

eTable 7. Association of thyroid function test abnormalities, TSH or FT4 concentrations, TPOAb or TgAb positivity with gestational age at birth (weeks)

eTable 8. Association of TPOAb positivity with mutual adjustments with TSH and FT4 or subclinical hypothyroidism or hypothyroxinemia with preterm birth

eTable 9. Sensitivity analyses for the association of TPOAb cut-offs with preterm birth

eTable 10. P values for the interaction terms between TPOAb, TgAb, TSH or FT4 with BMI, parity or gestational age at the time of blood sampling in association with preterm birth (<37 weeks)

eTable 11. Association of FT4 or TSH with preterm birth (<37 weeks) according to gestational age at the time of blood sampling or BMI or parity

eFigure 1A. Two‐step meta‐analyses and funnel plots for the association of subclinical hypothyroidism with preterm and very preterm birth

eFigure 1B. Two‐step meta‐analyses and funnel plots for the association of subclinical hyperthyroidism with preterm and very preterm birth

eFigure 1C. Two‐step meta‐analyses and funnel plots for the association of hypothyroxinemia with preterm and very preterm birth

eFigure 1D. Two‐step meta‐analyses and funnel plots for the association of overt hyperthyroidism with preterm birth

eFigure 2. Two‐step meta‐analyses and funnel plots for the association of TPOAb positivity with preterm and very preterm birth

Supplemental acknowledgements and grant details

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Original Investigation
August 20, 2019

Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis

The Consortium on Thyroid and Pregnancy—Study Group on Preterm Birth
JAMA. 2019;322(7):632-641. doi:10.1001/jama.2019.10931
Key Points

Question  Are thyroid function test abnormalities or thyroid autoimmunity a risk factor for preterm birth?

Findings  In this individual participant data meta-analysis of 19 prospective cohort studies including 47 045 women, subclinical hypothyroidism (odds ratio [OR], 1.29), isolated hypothyroxinemia (OR, 1.46), and thyroid peroxidase antibody positivity (OR, 1.33) were each significantly associated with a higher risk of preterm birth.

Meaning  These findings provide evidence that subclinical hypothyroidism, isolated hypothyroxinemia, and thyroid peroxidase antibody positivity in pregnant women are risk factors for preterm birth.

Abstract

Importance  Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth.

Objective  To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth.

Data Sources and Study Selection  Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded.

Data Extraction and Synthesis  The primary authors provided individual participant data that were analyzed using mixed-effects models.

Main Outcomes and Measures  The primary outcome was preterm birth (<37 weeks’ gestational age).

Results  From 2526 published reports, 35 cohorts were invited to participate. After the addition of 5 unpublished data sets, a total of 19 cohorts were included. The study population included 47 045 pregnant women (mean age, 29 years; median gestational age at blood sampling, 12.9 weeks), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive; 2357 (5.0%) had a preterm birth. The risk of preterm birth was higher for women with subclinical hypothyroidism than euthyroid women (6.1% vs 5.0%, respectively; absolute risk difference, 1.4% [95% CI, 0%-3.2%]; odds ratio [OR], 1.29 [95% CI, 1.01-1.64]). Among women with isolated hypothyroxinemia, the risk of preterm birth was 7.1% vs 5.0% in euthyroid women (absolute risk difference, 2.3% [95% CI, 0.6%-4.5%]; OR, 1.46 [95% CI, 1.12-1.90]). In continuous analyses, each 1-SD higher maternal thyrotropin concentration was associated with a higher risk of preterm birth (absolute risk difference, 0.2% [95% CI, 0%-0.4%] per 1 SD; OR, 1.04 [95% CI, 1.00-1.09] per 1 SD). Thyroid peroxidase antibody–positive women had a higher risk of preterm birth vs TPO antibody–negative women (6.6% vs 4.9%, respectively; absolute risk difference, 1.6% [95% CI, 0.7%-2.8%]; OR, 1.33 [95% CI, 1.15-1.56]).

Conclusions and Relevance  Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were significantly associated with higher risk of preterm birth. These results provide insights toward optimizing clinical decision-making strategies that should consider the potential harms and benefits of screening programs and levothyroxine treatment during pregnancy.

Introduction

Preterm birth complicates 5% to 15% of births worldwide. It is the most important direct cause of morbidity and mortality in children younger than 5 years,1 and is an important risk factor for psychiatric, metabolic, cardiovascular, and renal disease later in life.2,3 However, in the majority of cases, no known risk factors can be identified.4,5

Thyroid hormone regulates metabolism, growth, and development in most tissues of the human body, including various physiological processes related to preterm birth, such as placental development and function, fetal growth, and expression of neuropeptides involved in the onset of labor.6-9 Overt hypothyroidism and hyperthyroidism during pregnancy are well-known risk factors for preterm birth and occur in approximately 0.5% and 0.05% of pregnancies, respectively.10,11 During pregnancy, thyroid function test abnormalities (subclinical hypothyroidism and isolated hypothyroxinemia) and thyroid autoimmunity are much more frequent than overt thyroid disease.11 However, it remains to be determined whether such thyroid function test abnormalities are risk factors for preterm birth.

Estimates for the association of subclinical hypothyroidism or isolated hypothyroxinemia with preterm birth in previous observational studies range from odds ratios (ORs) of 0.57 to 3.3.12-15 The interpretation of these studies is limited by 2 main factors. First, the studies have used different upper limits for thyrotropin (often referred to as thyroid-stimulating hormone or TSH; ranging from >2.5 to >6.0 mIU/L). Second, most are single-center studies and lack statistical power. Furthermore, only a few studies have investigated whether isolated hypothyroxinemia could be a risk factor for adverse pregnancy outcomes.

This study assessed whether thyroid function test abnormalities and thyroid peroxidase (TPO) antibody positivity were associated with preterm birth.

Methods

The Consortium on Thyroid and Pregnancy is a collaboration of prospective birth cohorts that aims to study the association of maternal thyroid function and autoimmunity with adverse pregnancy and child outcomes. For the current study, we followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for Individual Patient Data and preregistered the study protocol (CRD42016043494), which appears in Supplement 1 along with an outline of protocol deviations.

To identify studies for inclusion, we conducted a systematic literature search for articles on the association of thyroid function or autoimmunity with preterm birth published from database inception to March 18, 2018, without language restrictions, using the Ovid MEDLINE, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar databases (eMethods in Supplement 2). In addition, unpublished data were identified via open invitations sent to relevant journals,16,17 international conferences, social media, and personal contacts. The search was repeated on June 19, 2019, to identify studies published after March 18, 2018, that would have been eligible for inclusion.

We included prospective cohort studies that included participants consecutively without selection criteria related to health status (such as comorbidities or thyroid disease) and had data on thyrotropin concentration, free thyroxine (FT4) concentration, or TPO antibody measurements and data on gestational age at birth. We excluded studies in which participants received treatment based on abnormal thyroid function tests (predominantly hospital-based cohorts) or studies that only included women with overt thyroid disease.

Possible studies for inclusion were independently assessed for suitability by 2 of the authors (T.I.M.K. and P.N.T.) and any disagreement was resolved by discussion with a third author (R.P.P.). Investigators from each eligible study were invited to join the consortium. Study quality and risk of bias were assessed using the Newcastle-Ottawa scale.

Local institutional review board approval and participant informed consent was obtained for all separate cohorts; no additional approvals were obtained for the current study. After obtaining individual participant data, all participants with data on thyrotropin concentration, FT4 concentration, or TPO antibody concentration, and gestational age at birth were included. We excluded participants who had a miscarriage or perinatal death, preexisting thyroid disease, thyroid-interfering medication use, in vitro fertilization, or multiple pregnancies.

Primary and Secondary Outcomes

The primary outcome was preterm birth defined as a gestational age at birth of less than 37 weeks. Gestational age was assessed using either ultrasound measurements or time after the last menstrual period. Secondary outcomes were very preterm birth (<32 weeks’ gestational age) and the gestational age at birth.

Exposures

Exposure variables included thyroid function test abnormalities, continuous thyroid function test measurements (thyrotropin and FT4 concentrations), TPO antibody positivity, and thyroglobulin antibody positivity. Thyroid function test abnormalities were defined according to cohort-specific 2.5th and 97.5th population percentiles for thyrotropin and FT4 concentrations after exclusion of TPO antibody–positive women. Subclinical hypothyroidism was defined as a thyrotropin concentration above the 97.5th percentile and a FT4 concentration within the normal range (ie, 2.5th-97.5th percentile). Overt hyperthyroidism was defined as a thyrotropin concentration below the 2.5th percentile and a FT4 concentration above the 97.5th percentile. Subclinical hyperthyroidism was defined as a thyrotropin concentration below the 2.5th percentile and a FT4 concentration within the normal range. Isolated hypothyroxinemia was defined as a FT4 concentration below the 2.5th percentile and a thyrotropin concentration within the normal range. Thyroid peroxidase antibody positivity and thyroglobulin antibody positivity were defined in a cohort-specific manner according to cutoffs recommended by the manufacturer. For analyses with continuous thyrotropin and FT4 concentrations as exposure variables, the concentrations for all cohorts were log-transformed and then standardized to population-specific standard deviation scores after removal of outliers (±4 SD from the mean) to enable comparisons among different cohorts and assays.

Statistical Analyses
Primary Analyses

We studied the association of thyroid function test abnormalities (the reference group was women with normal thyroid), thyrotropin and FT4 concentrations continuously, and TPO and thyroglobulin antibody positivity with preterm birth and very preterm birth using generalized linear mixed models with a random intercept for each cohort. For the same exposures, the association with gestational age at birth was studied using linear mixed models with a random intercept for each cohort.

The primary analyses were repeated with a 2-step approach by using random-effect models according to the DerSimonian and Laird method to pool estimates and the Firth bias reduction method in case of near or complete separation in smaller cohorts. Heterogeneity across studies was assessed using the I2 statistic. To evaluate potential publication bias, funnel plots and Egger tests were used. All analyses were adjusted for maternal age, body mass index (BMI), ethnicity, smoking, parity, gestational age at blood sampling, and fetal sex. We used multilevel multiple imputation18 for missing data on covariates. Five imputed data sets were created and pooled for analyses using Rubin rules.19

Secondary and Sensitivity Analyses

We performed a prespecified sensitivity analysis for which analyses on thyroid function or thyroid function test abnormalities were additionally adjusted for TPO antibody positivity. A post hoc sensitivity analysis assessed whether the association of TPO antibody positivity with preterm birth and very preterm birth differed for each increase in continuous thyrotropin concentration by adding a product interaction term into the models and stratification of analyses according to thyrotropin cutoffs recommended by the guidelines of the American Thyroid Association.20 To assess TPO antibody positivity, a post hoc sensitivity analysis explored different cutoffs based on a recent study showing a dose-dependent effect on thyroid function (alternative cutoffs: 94th population percentile, higher absolute concentrations of >100 and >500 mIU/L, and higher relative concentrations of 2 ×  and 5 ×  the assay cutoff).21 In addition, a prespecified analysis explored whether the association of thyrotropin concentration, FT4 concentration, or TPO antibody positivity differed according to differences in gestational age at the time of blood sampling, BMI, or parity.

A 2-sided threshold for statistical significance of <.05 was used. Because no adjustment was made for multiple testing, findings from the secondary analyses and sensitivity analyses should be interpreted as exploratory. All statistical analyses were performed using R version 3.4.4 (R Project for Statistical Computing).

Results

From 2526 published reports, 133 remained eligible for inclusion based on screening of the title and abstract (Figure 1). After reading the full text, a total of 35 cohorts were invited to participate. Five unpublished data sets were added via personal contacts and responses from open invitations. Four studies were published after the index date of our systematic search that otherwise would have been eligible for inclusion. A total of 19 cohorts from Europe, the United States, Chile, Australia, Pakistan, and Japan responded to the invitation and were able to participate.

After exclusions, the final study population comprised 47 045 participants (Figure 1), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive. Preterm birth and very preterm birth occurred in 2357 (5.0%) and 349 (0.7%) pregnancies, respectively (Table). Cohort-specific population characteristics, details on data collection, cohort-specific number of participants with available thyroid function and gestational age at birth, data quality assessment by the Newcastle-Ottawa scale (indicating high-quality data for all cohorts), and cohort-specific percentile cutoffs for thyroid function test abnormalities (thyrotropin and FT4 concentrations) appear in eTables 1-4 in Supplement 2.

Data on specific covariates were missing for up to 33% of the women and from as many as 3 cohorts (total percentage of missing data for maternal age: 0.3% [0 cohorts]; gestational age at the time of blood sampling: 0.4% [0 cohorts]; parity: 5.8% [1 cohort]; smoking status: 7.2% [1 cohort]; sex of the child: 21.4% [2 cohorts]; BMI: 32.9% [3 cohorts]). The women that were not included due to missing data on gestational age at birth had similar mean standardized thyrotropin concentrations in SDs vs those who were included (−0.03 vs 0, respectively; P = .28), but different mean standardized FT4 concentrations in SDs (0.06 vs 0; P = .05) and different proportions with TPO antibody positivity (13.0% vs 7.5%; P < .001) (eTable 5 in Supplement 2).

Preterm and Very Preterm Birth
Thyroid Function Test Abnormalities

Women with subclinical hypothyroidism had a higher risk of preterm birth vs euthyroid women (6.1% vs 5.0%, respectively; absolute risk difference, 1.4% [95% CI, 0% to 3.2%]; OR, 1.29 [95% CI, 1.01 to 1.64]), but not of very preterm birth (0.7% vs 0.8%; absolute risk difference, 0% [95% CI, −0.3% to 0.8%]; OR, 1.03 [95% CI, 0.52 to 1.20]; Figure 2). Women with isolated hypothyroxinemia had a higher risk of preterm birth vs euthyroid women (7.1% vs 5.0%, respectively; absolute risk difference, 2.3% [95% CI, 0.6% to 4.5%]; OR, 1.46 [95% CI, 1.12 to 1.90]) and a higher risk of very preterm birth (1.9% vs 0.8%; absolute risk difference, 1.2% [95% CI, 0.4% to 2.5%]; OR, 2.57 [95% CI, 1.55 to 4.27]). Among women with overt hyperthyroidism, there was no statistically significant difference in the rate of preterm birth vs euthyroid women (4.0% vs 5.0%, respectively; absolute risk difference, −1.2% [95% CI, −2.8% to 1.7%]; OR, 0.76 [95% CI, 0.43 to 1.34]; Figure 2).

Continuous Analyses of Thyroid Function

Continuous analyses showed that each 1-SD higher maternal thyrotropin concentration was significantly associated with a 4% higher relative risk of preterm birth (absolute risk difference, 0.2% [95% CI, 0% to 0.4%] per 1 SD; OR, 1.04 [95% CI, 1.00 to 1.09] per 1 SD), but not very preterm birth (absolute risk difference, 0% [95% CI, −0.05% to 0.10%] per 1 SD; OR, 1.04 [95% CI, 0.93 to 1.16] per 1 SD; Figure 3 and eTable 6 in Supplement 2). Each 1-SD higher maternal FT4 concentration was not associated with preterm birth, but was significantly associated with a 12% lower risk of very preterm birth (absolute risk difference, −0.10% [95% CI, −0.20% to −0.01%] per 1 SD; OR, 0.88 per 1 SD [95% CI, 0.79 to 0.95]; Figure 3 and eTable 6 in Supplement 2).

TPO Antibody and Thyroglobulin Antibody Positivity

Thyroid peroxidase antibody–positive women had a higher risk of preterm birth vs TPO antibody–negative women (6.6% vs 4.9%, respectively; absolute risk difference, 1.6% [95% CI, 0.7% to 2.8%]; OR, 1.33 [95% CI, 1.15 to 1.56]; Figure 4) and very preterm birth (1.7% vs 0.7%; absolute risk difference, 1.0% [95% CI, 0.6% to 1.7%]; OR, 2.45 [95% CI, 1.81 to 3.32]; Figure 4). There was no significant association of thyroglobulin antibody positivity with preterm birth vs those with thyroglobulin antibody negativity (4.3% vs 4.4%, respectively; absolute risk difference, −0.5% [95% CI, −1.6% to 0.9%]; OR, 0.88 [95% CI, 0.64 to 1.20]; eTable 6 in Supplement 2).

Gestational Age at Birth

The results relating to the gestational age at birth were similar to those for preterm and very preterm birth (eTable 7 in Supplement 2).

Sensitivity Analyses

In the prespecified sensitivity analysis, the results for thyrotropin concentration, FT4 concentration, and TPO antibody positivity remained similar when all 3 exposures were added to the same model, but the association of subclinical hypothyroidism with preterm birth was no longer statistically significant after additional adjustment for TPO antibody positivity (eTable 8 in Supplement 2).

In the post hoc sensitivity analysis on the association of TPO antibody positivity with preterm and very preterm birth, the P value for interaction for risk of preterm birth with higher thyrotropin concentrations among TPO antibody–positive women was .08; for very preterm birth, P < .001 for interaction; and for gestational age at birth continuously, P = .006 for interaction. Subsequent stratified analyses showed that TPO antibody–positive women and a thyrotropin concentration above 4.0 mIU/L had an excess risk of preterm birth vs TPO antibody–negative women (7.1% vs 4.9%, respectively; absolute risk difference, 2.7% [95% CI, 0.2%-6.3%]; OR, 1.55 [95% CI, 1.05-2.27]). However, stratified analyses could not be performed for very preterm birth (Figure 4).

In a post hoc sensitivity analysis, alternative TPO antibody concentration cutoffs were significantly associated with a higher risk of preterm birth, but the results were similar to those identified for manufacturer-based cutoffs (eTable 9 in Supplement 2). In the prespecified analysis on the association of thyroid function with preterm birth, TPO antibody positivity or thyroglobulin antibody positivity did not differ significantly according to the gestational age at the time of blood sampling, BMI, or parity (P > .07 for interaction for all analyses without meaningful differences after stratification; eTables 10 and 11 in Supplement 2).

The primary analyses were similar using a 2-step approach; however, some cohort-specific analyses with very few cases exhibited inflated ORs (eFigures 1 and 2 in Supplement 2). The funnel plots did not indicate any bias and the I2 values were mostly less than 40%. However, for the analyses of TPO antibody–positive women, the I2 values were 77% for preterm birth and 69% for very preterm birth (eFigure 2 in Supplement 2).

Discussion

Subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were associated with higher risk for preterm birth. Isolated hypothyroxinemia and TPO antibody positivity were associated with higher risk for very preterm birth. The association of TPO antibody positivity with preterm birth did not appear to be related to differences in thyroid function, but was modified by the thyrotropin concentration as exemplified by the higher risk of preterm birth in TPO antibody–positive women and a thyrotropin concentration above 4.0 mIU/L.

Because randomized trials of treatment of thyroid function test abnormalities during pregnancy are scarce, observational studies form the basis of clinical guidelines on thyroid function and pregnancy.20 However, previous observational studies on the association of thyroid function and autoimmunity with preterm birth have used widely different definitions for thyroid function test abnormalities. This variation limits the ability to develop clearly defined recommendations in international guidelines and perform aggregate data meta-analysis. Furthermore, most studies lacked statistical power to study the risk of very preterm birth, a more clinically relevant outcome related to high mortality and morbidity, the demand for specialist neonatal services, and financial burdens.22-24 By collecting individual participant data, the current study allowed for standardization of the definition of thyroid function test abnormalities.

To our knowledge, the current study is the first individual participant data meta-analysis that shows isolated hypothyroxinemia is associated with a higher risk of preterm birth and very preterm birth and produced estimates in the same range as well-known risk factors such as adolescent or older maternal age, low BMI, obesity, smoking, and bacterial vaginosis.12,13,25-27 These results are in line with those from a previous population-based study, but opposite to those from an aggregate data meta-analysis including 5 studies.15,28 Isolated hypothyroxinemia is a pregnancy-specific disease entity with a multifactorial underlying pathophysiology that has remained relatively understudied.29

Available evidence predominantly links isolated hypothyroxinemia to suboptimal neurocognitive development of the offspring,29,30 but international guidelines do not recommend levothyroxine treatment in women with isolated hypothyroxinemia because randomized clinical trials have not proven a beneficial effect on child IQ.20 In 2 large randomized clinical trials in which women with isolated hypothyroxinemia were treated with levothyroxine during the first half of pregnancy, there was no statistically significant difference in preterm birth with treatment. In 1 trial of pregnant women with either subclinical hypothyroidism or isolated hypothyroxinemia, preterm birth occurred in 5.6% of the levothyroxine group vs 7.9% of the control group.31 In the second trial with pregnant women who had isolated hypothyroxinemia, preterm birth occurred in 12% of the levothyroxine group vs 8% of the placebo group and birth at less than 34 weeks’ gestational age occurred in 4% of the levothyroxine group and 3% of the placebo group.32

Consistent with the results of the current study, women with isolated hypothyroxinemia in the 2 trials31,32 had higher preterm birth rates than euthyroid women did in the current meta-analysis. The results of the current study provide further insights on potential risks of isolated hypothyroxinemia that may help to optimize clinical decision-making strategies, taking into account all potential harms and benefits of screening programs and subsequent levothyroxine treatment. Further studies will be required to elucidate the underlying pathophysiology of isolated hypothyroxinemia and to study if it is also a risk factor for other adverse pregnancy outcomes.

In the current study, TPO antibody positivity was associated with a higher risk of preterm birth, consistent with previous smaller meta-analyses using aggregate data and studies on miscarriage.12,13 Two recent clinical trials showed that preconception treatment of euthyroid TPO antibody–positive women who had either a previous miscarriage or fertility treatment with low-dose levothyroxine neither reduced the rate of preterm birth, nor any other pregnancy or neonatal outcomes.33,34 These studies did not include women with thyroid function test abnormalities.33,34 The results of the current study show a higher risk for TPO antibody–positive women and a thyrotropin concentration higher than 4.0 mIU/L, which confirms the results from a small randomized clinical trial showing that levothyroxine treatment in TPO antibody–positive women lowers preterm birth rates only if the thyrotropin concentration was higher than 4.0 mIU/L.35

Taken together, the results of this study are in alignment with the recommendation of the American Thyroid Association that different thyrotropin cutoffs should be used for TPO antibody–positive women vs TPO antibody–negative women.20 A sensitivity analysis showed that the association of subclinical hypothyroidism with preterm birth was no longer apparent after additional adjustment for TPO antibody positivity, suggesting that it is the TPO antibody positivity that occurs in one-third of women with subclinical hypothyroidism that underlies any associations of subclinical hypothyroidism with preterm birth. However, this study lacked statistical power for a subgroup analysis on the association of TPO antibody positivity in combination with a thyrotropin concentration higher than 2.5 mIU/L for preterm birth or higher than 4.0 mIU/L for very preterm birth.

There remains an important role for observational studies in the evaluation of thyroid function test abnormalities during pregnancy. For example, observational studies have indicated that the interpretation of the results of large randomized trials31-34 may be limited because of risks related to potential overtreatment, a late start of levothyroxine therapy, or sole inclusion of women with normal thyroid.36-39 Moreover, observational studies are needed to study detrimental clinical outcomes with a relatively low incidence such as very preterm birth, given the impracticality of randomized trials for such outcomes. For example, to study if levothyroxine therapy could reverse excess preterm birth risks as identified in this study for isolated hypothyroxinemia, TPO antibody positivity, and TPO antibody positivity with a thyrotropin concentration greater than 4.0 mIU/L, a total of 3674, 6090, and 3814 women, respectively, would have to be randomized, which in the case of population screening would translate to the screening of 196 470, 95 530, and 448 706 women (with a 2-sided α level of .05, a power level of 80%, and a lost to follow-up rate or declined participation rate of 15%).

The results of the current study do not change the consideration that there is currently insufficient evidence for a benefit of routine thyroid function screening in pregnant women; the potential harms and benefits of levothyroxine for other clinically meaningful outcomes should be taken into account as well. The results support the concept of a reflex TPO antibody measurement in women with a thyrotropin concentration higher than 4.0 mIU/L, and gestational thyrotropin monitoring for TPO antibody–positive women prior to conception. The current study in itself does not validate a reflex FT4 concentration or TPO antibody measurement for women with a normal thyrotropin concentration until further randomized trials are performed.

The results of the current study add to the limited knowledge on the complicated and multifactorial mechanisms underlying preterm and very preterm birth.40 Because thyroid hormone regulates key processes in placental and fetal growth and development, the associations for FT4 concentration could be mediated via effects on either placental function, fetal growth, or both.8,9,11,40,41 Alternatively, thyroid hormone and TPO antibody positivity could be involved in infectious and inflammatory pathways leading to preterm birth.42,43 Another potential mechanism by which low thyroid hormone availability could be associated with preterm birth is that it may lead to an earlier onset of labor via an increase in oxytocin and vasopressin, but a decrease in progesterone, or through thyroid hormone effects specific for the cervix, endometrium, or fetal membranes.7,44-47 Further studies on pathways via which thyroid hormone is involved in the pathogenesis of preterm birth are needed to further optimize risk identification.

Limitations

This study has several limitations. First, there was a lack of statistical power to optimally investigate the risk of very preterm birth in specific clinically relevant subgroups. Although very preterm birth is clinically more relevant than late preterm birth, the relatively sparse occurrence of TPO antibody positivity combined with a thyrotropin concentration higher than 2.5 or 4.0 mIU/L necessitates an even larger data set than that available in the current study to examine associations with very preterm birth.

Second, only 5 of the 19 studies had data available on thyroglobulin antibodies. Although this association was studied in a large number of women, data were only available for 40.0% of included women, which may have affected the results.

Third, pregnancy-related changes in thyroid-binding proteins could interfere with FT4 immunoassays. However, the use of assay-specific reference ranges as advocated by the current American Thyroid Association guidelines and standardization of FT4 concentrations per cohort or assay should mostly eliminate the potential between-assay differences in absolute FT4 concentrations.

Fourth, studies that were published while conducting statistical analyses for the current study could not be included. Fifth, because the included studies were observational, residual or unmeasured confounding cannot be excluded. However, the analysis of individual participant data allowed for adjustment for multiple relevant confounders. Sixth, causality cannot be determined from observational studies.

Conclusions

Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were significantly associated with higher risk of preterm birth. These results provide insights toward optimizing clinical decision-making strategies that should consider the potential harms and benefits of screening programs and levothyroxine treatment during pregnancy.

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Article Information

Corresponding Author: Tim I. M. Korevaar, MD, PhD, Academic Center for Thyroid Diseases, Erasmus Medical Center, Room Na-2913, Postbus 2040, 3000 CA, Rotterdam, the Netherlands (t.korevaar@erasmusmc.nl).

Accepted for Publication: July 8, 2019.

Authors/The Consortium on Thyroid and Pregnancy—Study Group on Preterm Birth: Tim I. M. Korevaar, MD, PhD; Arash Derakhshan, MD, MSc; Peter N. Taylor, MRCP, PhD; Marcel Meima, PhD; Liangmiao Chen, MD, PhD; Sofie Bliddal, MD; David M. Carty, MD; Margreet Meems, MD, PhD; Bijay Vaidya, FRCP, PhD; Beverley Shields, PhD; Farkhanda Ghafoor, PhD; Polina V. Popova, MD, PhD; Lorena Mosso, MD, PhD; Emily Oken, MD, MPH; Eila Suvanto, MD, PhD; Aya Hisada, PhD; Jun Yoshinaga, PhD; Suzanne J. Brown; Judith Bassols, MD; Juha Auvinen, MD, PhD; Wichor M. Bramer; Abel López-Bermejo, MD, PhD; Colin Dayan, MD, PhD; Laura Boucai, MD, MSc; Marina Vafeiadi, PhD; Elena N. Grineva, MD, PhD; Alexandra S. Tkachuck, MD; Victor J. M. Pop, MD, PhD; Tanja G. Vrijkotte, PhD; Mònica Guxens, MD, PhD; Leda Chatzi, MD, PhD; Jordi Sunyer, MD, PhD; Ana Jiménez-Zabala, PhD; Isolina Riaño, MD, PhD; Mario Murcia, PhD; Xuemian Lu, MD, PhD; Shafqat Mukhtar, MD; Christian Delles, MD; Ulla Feldt-Rasmussen, MD, DMSc; Scott M. Nelson, MRCOG, PhD; Erik K. Alexander, MD; Layal Chaker, MD, PhD; Tuija Männistö, MD, PhD; John P. Walsh, MB, PhD; Elizabeth N. Pearce, MD; Eric A. P. Steegers, MD, PhD; Robin P. Peeters, MD, PhD.

Affiliations of Authors/The Consortium on Thyroid and Pregnancy—Study Group on Preterm Birth: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands (Korevaar, Derakhshan, Meima, Chaker, Peeters); Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands (Korevaar, Derakhshan, Meima, Chaker, Peeters); Thyroid Research Group, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, England (Taylor); Department of Endocrinology and Rui’an Center of the Chinese-American Research Institute for Diabetic Complications, Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China (Chen, Lu); Department of Medical Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark (Bliddal, Feldt-Rasmussen); Department of Diabetes, Endocrinology, and Clinical Pharmacology, Glasgow Royal Infirmary, Glasgow, Scotland (Carty); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland (Carty, Delles); Departments of Medical and Clinical Psychology, Tilburg University, Tilburg, the Netherlands (Meems, Pop); Department of Endocrinology, Royal Devon and Exeter Hospital NHS Foundation Trust, University of Exeter Medical School, Exeter, England (Vaidya); Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, England (Shields); National Health Research Complex, Shaikh Zayed Medical Complex, Lahore, Pakistan (Ghafoor); Almazov National Medical Research Centre, St Petersburg, Russia (Popova, Grineva, Tkachuck); Department of Internal Diseases and Endocrinology, St Petersburg Pavlov State Medical University, St Petersburg, Russia (Popova, Grineva, Tkachuck); Department of Endocrinology, Pontificia Universidad Catolica de Chile, Santiago (Mosso); Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School, Boston, Massachusetts (Oken); Harvard Pilgrim Health Care Institute, Boston, Massachusetts (Oken); Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts (Oken); Department of Obstetrics and Gynecology and Medical Research Center Oulu, University of Oulu, Oulu, Finland (Suvanto); Center for Preventive Medical Science, Chiba University, Chiba, Japan (Hisada); Faculty of Life Sciences, Toyo University, Gunma, Japan (Yoshinaga); Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Australia (Brown); Maternal-Fetal Metabolic Research Group, Girona Biomedical Research Institute, Dr Josep Trueta Hospital, Girona, Spain (Bassols, Walsh); Medical Research Center Oulu, Oulu University Hospital, Center for Life Course Health Research, University of Oulu, Oulu, Finland (Auvinen); Medical Library, Erasmus University Medical Center, Rotterdam, the Netherlands (Bramer); Pediatric Endocrinology Research Group, Girona Biomedical Research Institute, Dr Josep Trueta Hospital, Girona, Spain (López-Bermejo); Thyroid Research Group, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, England (Dayan); Division of Endocrinology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell University, New York, New York (Boucai); Department of Social Medicine, University of Crete, Heraklion, Greece (Vafeiadi); Department of Public Health, Amsterdam University Medical Center, University of Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands (Vrijkotte); ISGlobal, Centre for Research in Environmental Epidemiology, Barcelona, Spain (Guxens, Sunyer); Pompeu Fabra University, Barcelona, Spain (Guxens, Sunyer); Spanish Consortium for Research on Epidemiology and Public Health, Instituto de Salud Carlos III, Madrid, Spain (Guxens, Sunyer, Riaño, Murcia); Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Sophia Children’s Hospital, Rotterdam, the Netherlands (Guxens); Keck School of Medicine, Department of Preventive Medicine, University of Southern California, Los Angeles (Chatzi); Hospital del Mar Medical Research Institute, Barcelona, Spain (Sunyer); Biodonostia Health Research Institute, San Sebastian, Spain (Jiménez-Zabala); Public Health Division of Gipuzkoa, Basque Government, San Sebastian, Spain (Jiménez-Zabala); AGC Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Spain (Riaño); Epidemiology and Environmental Health Joint Research Unit, FISABIO−Universitat Jaume I−Universitat de València, Valencia, Spain (Murcia); Department of Gynecology and Obstetrics, Shaikh Zayed Medical Complex, Lahore, Pakistan (Mukhtar); School of Medicine, University of Glasgow, Glasgow, Scotland (Nelson); National Institute for Health Research, Bristol Biomedical Research Centre, Bristol, England (Nelson); Division of Endocrinology, Hypertension, and Diabetes, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (Alexander); Northern Finland Laboratory Center Nordlab and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland (Männistö); Medical School, University of Western Australia, Crawley (Walsh); Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, Massachusetts (Pearce); Department of Obstetrics and Gynaecology, Erasmus University Medical Center, Rotterdam, the Netherlands (Steegers).

Author Contributions: Drs Korevaar and Derakhshan had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Korevaar and Derakhshan contributed equally.

Concept and design: Korevaar, Derakhshan, Bliddal, Ghafoor, Oken, Suvanto, Delles, Feldt-Rasmussen, Alexander, Nelson, Chaker, Männistö, Peeters.

Acquisition, analysis, or interpretation of data: Korevaar, Derakhshan, Taylor, Meima, Chen, Bliddal, Carty, Meems, Vaidya, Shields, Popova, Mosso, Oken, Hisada, Yoshinaga, Brown, Bassols, Auvinen, Bramer, López-Bermejo, Dayan, Boucai, Vafeiadi, Grineva, Tkachuck, Pop, Vrijkotte, Guxens, Chatzi, Sunyer, Jiménez-Zabala, Riaño, Murcia, Lu, Mukhtar, Delles, Alexander, Nelson, Chaker, Männistö, Walsh, Pearce, Steegers, Peeters.

Drafting of the manuscript: Korevaar, Derakhshan, Meima, Mosso, Suvanto, Tkachuck, Alexander, Peeters.

Critical revision of the manuscript for important intellectual content: Korevaar, Derakhshan, Taylor, Meima, Chen, Bliddal, Carty, Meems, Vaidya, Shields, Ghafoor, Popova, Oken, Hisada, Yoshinaga, Brown, Bassols, Auvinen, Bramer, López-Bermejo, Dayan, Boucai, Vafeiadi, Grineva, Pop, Vrijkotte, Guxens, Chatzi, Sunyer, Jiménez-Zabala, Riaño, Murcia, Lu, Mukhtar, Delles, Feldt-Rasmussen, Alexander, Nelson, Chaker, Männistö, Walsh, Pearce, Steegers, Peeters.

Statistical analysis: Korevaar, Derakhshan, Brown, Pop, Chaker, Walsh, Peeters.

Obtained funding: Korevaar, Bliddal, Oken, Vrijkotte, Guxens, Chatzi, Delles, Nelson, Walsh, Peeters.

Administrative, technical, or material support: Korevaar, Derakhshan, Bliddal, Meems, Ghafoor, Popova, Mosso, Oken, Hisada, Yoshinaga, Brown, Bassols, Auvinen, Dayan, Vafeiadi, Grineva, Tkachuck, Jiménez-Zabala, Riaño, Lu, Mukhtar, Peeters.

Supervision: Korevaar, Meima, Chen, Bliddal, Mosso, Boucai, Chatzi, Sunyer, Riaño, Alexander, Steegers, Peeters.

Conflict of Interest Disclosures: Dr Korevaar reported receiving personal fees from Berlin Chemie, Goodlife Healthcare, and Quidel. Dr Vaidya reported receiving honoraria from Berlin-Chime. Dr Oken reported receiving grants from the National Institutes of Health. Dr Vrijkotte reported receiving grants from the Netherlands Organization for Health Research and Development. Dr Delles reported receiving grants from the Chief Scientist Office (Scotland) and the British Heart Foundation. Dr Nelson reported receiving grants from the Chief Scientist Office (Scotland). Dr Chaker reported serving as a consultant to Pfizer. Dr Männistö reported serving as a consultant to Abbott Diagnostics and Roche. Dr Pearce reported receiving grants from the Sociedad Quimica y Minera de Chile and personal fees from the Institut Biochimique SA. Dr Peeters reported serving as a consultant to Berlin-Chemie AG, GoodLife Fertility BV, and Institut Biochimique SA. No other disclosures were reported.

Funding/Support: This work was supported by replication studies grant 401.16.020 from the Netherlands Organization for Scientific Research. Cohort-specific grants appear in Supplement 2.

Role of the Funder/Sponsor: The Netherlands Organization for Scientific Research had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We gratefully acknowledge the contributions of the study participants across all cohorts included in the current study and extend our gratitude to study staff, data managers, general practitioners, hospitals, and midwives who have made these separate studies possible. We also gratefully acknowledge the contributions of Amna Pirzada, MD (Shifa College of Medicine, Shifa Tameer-e-Millat University), for data management; and Andrew Hattersley, FRS, Beatrice Knight, MD, Rachel Freathy, PhD, and Robin Beaumont, PhD (all with the University of Exeter), for data collection and management. None of these persons received compensation for their contributions.

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