Does Maternal Normal Range Thyroid Function Play a Role in Offspring Birth Weight? Evidence From a Mendelian Randomization Analysis

Abstract

Background The association between normal range thyroid function and offspring birth weight has been postulated, but evidence from observational studies is prone to be confounded. We conducted a two-sample Mendelian randomization (MR) study to explore the causal effects of maternal thyroid stimulating hormone (TSH) and free thyroxine (FT4) on birth weight. Methods We utilized public shared summary-level statistics from European-ancestry genome wide association studies. We obtained 40 and 21 single nucleotide polymorphisms as instrumental variables, which were associated with TSH and FT4 levels at genome-wide significance ( P < 5 × 10 −8 ). Partitioned maternal effects on birth weight were retrieved from datasets contributed by the Early Growth Genetics Consortium. Inverse-variance weighted method was employed in the primary MR analysis and multiple sensitivity analyses were implemented. Results Genetically determined normal range thyroid function was not causally associated with offspring birth weight. Each one standard deviation (SD) increase in maternal TSH was associated with 0.002 SD higher of birth weight (95% confidence interval [CI], −0.021 to 0.025; P = 0.87). Similarly, change in birth weight was −0.001 SD (95% CI, −0.031 to 0.029; P = 0.94) per one SD higher in maternal FT4. Consistent results were yielded via additional MR methods. Sensitivity analyses demonstrated no presence of horizontal pleiotropy or heterogeneity. Conclusion This MR study did not identify a causality between normal range thyroid function and offspring birth weight in the Europeans.

Genome-wide association studies of thyroid-related hormones, dysfunction, and autoimmunity among 85,421 Chinese pregnancies

“…Nonetheless, we cannot exclude the possibility that thyroid dysfunction and autoimmunity may contribute to other adverse outcomes. Consistent with a previous MR study[44], we also did not identify an MR association between maternal TSH levels within the reference range and birth weight. Notably, our MR analyses provide evidence suggesting that maternal TSH levels during pregnancy may potentially influence gestational duration, although the effect may be nonlinear.…”

“…High-quality Mendelian randomization studies in clinical thyroidology are deemed crucial for gaining valuable insights into the relationship between thyroid functions and birth outcomes[43]. However, to date, only one MR study has explored the causal effect of TSH and FT4 levels within the normal range on birth weight and did not identify statistically significant causal associations [44].…”

Preconception thyroid‐stimulating hormone levels and adverse pregnancy outcomes

“…Euthyroidism is essential for establishing and maintaining a healthy pregnancy. Although the relationships between TSH levels and various adverse perinatal outcomes have been reported, conclusions are inconsistent 2,4,15,21–23 . A nested prospective cohort study observed a positive linear relationship between log‐transformed maternal TSH levels and the risk of subsequent child loss 24 .…”

“…Another meta‐analysis reported a tendency toward an increased risk of LGA among hypothyroid mothers 3 . Recently a two‐sample Mendelian randomization study did not identify any causality between normal‐range thyroid function and offspring birth weight 21 . In the present study, a positive association was shown between increased TSH levels with SGA when TSH level was between 1.5 and 3.5 mIU/L, and elevated preconception TSH level, >4.20 or >2.50 mIU/L (Figure S1) was associated with a higher risk of SGA.…”

“…Although the relationships between TSH levels and various adverse perinatal outcomes have been reported, conclusions are inconsistent. 2,4,15,[21][22][23] A nested prospective cohort study observed a positive linear relationship between log-transformed maternal TSH levels and the risk of subsequent child loss. 24 In our study, increased preconception TSH levels were positively associated with pregnancy loss until a TSH level of 2.1 mIU/L.…”