Association of thyroid dysfunction and autoantibody positivity with the risk of preterm birth: a hospital-based cohort study

A hospital-based cohort study of pregnant women who received prenatal examinations between April 2012 and August 2016 was conducted in 2018 [14, 15]. All pregnant women who visited during the period were included in the cohort. At the first visit, maternal characteristics, such as maternal age, resident location, parity, and conception model, were investigated. Thyroid function was recommended at recruitment. They were then followed up until the 42nd day after the birth. During this period, pregnancy complications (e.g., gestational diabetes mellitus and preeclampsia) and outcomes (e.g., fetal gender, gestational weeks at delivery, weight, and congenital malformations) were identified [14, 15]. Inclusion criterions of subjects included for the analysis in the present study referred to women with singleton pregnancy, who received at least a thyroid function test, and those with confirmed birth outcome. Exclusion criterion referred to pregnant women with multiple pregnancies, without a thyroid function test, and those lost to follow-up. Basic characteristics between women included for analysis and those who were lost to follow-up were imbalanced [15]. Because treatment information was not collected for women with gestational thyroid diseases (e.g., subclinical hypothyroidism, overt hypothyroidism, hyperthyroidism, thyroiditis, thyroid nodules) in the present study, these women were further excluded from the analysis since some drugs (e.g., antithyroid drug) might affect the association between thyroid dysfunction and risk of preterm birth [16]. The reference ranges for the TSH concentration (uIU/mL) in the hospital were 0.05–5.17, 0.39–5.22, and 0.60–6.84 for women who had the test between 1 and 12, 13–28, and 29–40 weeks of gestation; while 12.91–22.35, 9.81–17.26, and 9.12–15.71 for the FT4 concentration (pmol/L), respectively.

The primary outcome was preterm birth, which was defined as infants born before 37 weeks of gestation. Secondary outcome was very preterm birth (e.g., < 32 weeks of gestation).

Thyroid function, including production of TSH, free and total triiodothyronine (FT3, TT3), FT4, TT4, thyroperoxidase (TPO), TSH receptor (TR), and thyroglobulin (Tg) antibodies were measured with an electrochemiluminescence immunoassay (Roche Elecsys, Germany) at the first visit to the hospital (range from 4 to 39 weeks, with a median of 15.4 weeks of gestation) [14]. The median gestational weeks for the test did not show a significant difference between women with and without a preterm birth baby (P = 0.633). Since only 33.5% (13971) of the included women received the test twice and 14.2% (5929) had three measurements. These measurements were not included for analysis (e.g., repeated measurements) in the present study.

Gestational age-specific percentiles of the FT4 and TSH concentrations were used for the definition of thyroid function, including euthyroid (both FT4 and TSH within the range between 2.5th and 97.5th percentile), subclinical hypothyroidism (TSH > 97.5th percentile; 2.5th ≤ FT4 ≤ 97.5th percentile), overt hypothyroidism (TSH > 97.5th percentile; FT4 < 2.5th percentile), isolated hypothyroxinemia (2.5th ≤ TSH ≤ 97.5th percentile, FT4 < 2.5th percentile), isolated hyperthyroxinemia (2.5th ≤ TSH ≤ 97.5th percentile, FT4 > 97.5th percentile), subclinical hyperthyroidism (TSH < 2.5th percentile, 2.5th ≤ FT4 ≤ 97.5th percentile), and hyperthyroidism (TSH < 2.5th percentile, FT4 > 97.5th percentile). TPOAb, TgAb, and TRAb were regarded as positive if the concentrations were > 34 IU/mL, 115 IU/mL, and 1.75 IU/L, respectively [14].

Covariates included maternal age (< 25, 25–34, or ≥ 35 years), residence (local or nonlocal), parity (nulliparous or pluriparous), assisted conception (yes or no), fetal sex (male or female), preeclampsia (yes or no), and gestational diabetes mellitus (yes or no) [14]. Preeclampsia is defined as the onset of hypertension and proteinuria after 20 weeks of gestation [17]. Gestational diabetes was diagnosed based on a 75-g oral glucose tolerance test conducted between the 24th and 28th weeks of gestation [18].

Prevalence (95% confidence interval, 95% CI) of the outcomes was estimated. Difference between women with and without a preterm birth baby was compared by Chi-squared/Fisher’s exact test (e.g., category variables) or Mann-Whitney U test (e.g., continuous variables). Odds ratio (OR) for the risk of preterm birth among women with thyroid dysfunction was calculated compared with euthyroid women. Adjusted ORs were estimated after controlling for the covariates.

The risk of outcomes in women positive for thyroid antibodies was also assessed relative to those negative for the marker. In these analyses, women without thyroid antibody tests were also included as an unknown antibody status group. Basic characteristics and outcomes (preterm and very preterm birth) were compared among women with and without antibody tests. We conducted sensitivity analyses restricting to those negative for thyroid antibodies. Preeclampsia is an obvious risk factor for preterm birth and women with a TSH concentration > the upper target of the reference might receive potential treatment. Therefore, we further performed sensitivity analyses limited to women without preeclampsia and those with a TSH concentration ≤ the upper targets to exclude these potential impacts. Stratification analyses were performed according to gestation age at the thyroid test (e.g., first, second, or third trimester).

The associations of TSH and FT4 concentrations with the risk of preterm birth were further probed. Outliers (mean ± 4 SD) of the TSH or FT4 concentrations were removed before the analyses. Interaction term analyses were performed to estimate the potential modification of gestational age at the thyroid test on these associations. Stratification analyses were conducted according to the thyroid testing time (e.g., ≤ or > 18 weeks of gestation) because that the fetal thyroid gland is not functionally mature until 18–20 weeks of gestation [19] and that the gestational age specific (12–18 weeks of gestation) association between thyroxine concentration and risk of congenital heart defects was identified in our previous study [15]. Gestational age-specific Z scores or percentiles of the FT4 and TSH were further used in assessing their association with the risk of preterm birth.

A total of 40,214 (77.3%) women were included in the analysis after excluding women with multiple pregnancies, gestational thyroid disease, and who were lost to follow-up (Fig. 1). Basic characteristics except assisted conception, fetal gender were imbalanced between women with and without antibody tests (Table S1 in the supplementary). Among the included women, 1905 infants were born before 37 weeks of gestation, with a preterm birth rate of 4.74% (95% CI: 4.53 to 5.00) and 0.37% (95% CI: 0.31–0.42) of very preterm birth. Compared with women with a term birth infant, women who delivered a preterm birth baby had a higher positive rate for TPOAb, were older, and were more likely to complicate preeclampsia or gestational diabetes (Table 1).

Figure 2 shows the association between thyroid dysfunction and the risk of preterm birth. No significant associations were found for variants of thyroid dysfunction. In the sensitivity analysis that we restricted to women negative for TPOAb, overt hypothyroidism was related to a higher risk of preterm birth (OR = 4.94, 95% CI: 1.64–14.84) (Table S2 in the supplementary). Sensitivity analysis restricted to women without preeclampsia and those with a TSH concentration ≤ the upper targets of the reference did not produce significant associations (Table S3 in the supplementary).

Stratification analyses according to the trimesters of the thyroid function test indicated that women with hyperthyroidism diagnosed at the third trimester had a higher but not significant risk to deliver a preterm birth baby compared with euthyroid women (OR, 2.63, 95% CI: 0.91–7.61, P = 0.074, Table S3 in supplementary).

Thyroid autoantibody positivity was not significantly associated with preterm birth. However, women positive for TPOAb in the first trimester were significantly related to an increased risk of preterm birth relative to those negative for TPOAb (OR, 1.49, 95% CI: 1.17–1.90, P = 0.001) in stratification analyses (Table S4 in the supplementary). There were no significant associations of thyroid dysfunction and antibody positive with the risk of very preterm birth (Table 2).

Stratification analyses according to the thyroid function testing time (≤ or > 18 weeks of gestation) did not produce different results for the interaction between TSH and gestational week. Nevertheless, modification effects of gestational age were found for women who had the test ≤18 weeks and > 18 weeks, the corresponding OR for the interaction between FT4 concentrations and gestational age at test was 0.99 (95% CI: 0.98–1.00) and 1.02 (95% CI: 1.00–1.03), respectively (Table 3). Continuous FT4 measurements were associated with a higher risk of preterm birth (OR, 1.13, 95% CI: 1.00–1.28) in women with a test ≤18 weeks of gestation, while a negative relationship for those with a test > 18 weeks of gestation (OR = 0.68, 95% CI: 0.48–0.97). Similar interaction effect was identified in Fig. 3.

No association between the FT4/TSH concentration Z scores and risk of preterm birth (OR = 1.01 [95% CI: 0.95–1.06] and 0.97 [95% CI: 0.92–1.02], respectively). Figure 4 shows the relationship between the FT4/TSH concentration percentiles and the risk of preterm birth. Women with the lowest percentiles (mean the highest gestational age-specific concentrations) had a higher risk of preterm birth, the risk declined slowly with the increase of percentiles.

The large sample size in the present study ensured a high statistical power to detect the association between thyroid dysfunction and preterm birth and further probe the specificity of the associations. However, there were some limitations. Firstly, the present study was a single-center study in Shanghai where the iodine status of pregnant women was iodine deficient [30]. In addition, a high loss to follow-up rate (18.2%), imbalanced basic characteristics between women with and with antibody tests, and some important covariates (e.g., maternal BMI and smoking exposure) were not collected in the present study. These disadvantages might result in a potential selection bias and then affect the results. Therefore, multiple-center studies in regions with various iodine statuses for pregnant women are warranted to identify the generalizability of our results. Secondly, thyroid function was measured at different gestational ages rather than a dynamical observation. Thus, we can’t discriminate such specific associations were consequences of hyperthyroidism-persistent effects or results of gestational age-specific functions. Furthermore, treatment information was lacking in the present study. Thus, studies on the impact of dynamic thyroid function measurements and the treatment of gestational thyroid dysfunction on preterm birth were warranted. Finally, the interpretation of causal relationships should be cautious in observational studies.