AUTHOR=Xun Xiaoshuang , Qin Xu , Layden Alexander J. , Yin Qing , Swan Shanna H. , Barrett Emily S. , Bush Nicole R. , Sathyanarayana Sheela , Adibi Jennifer J. 

TITLE=Application of 4-way decomposition to the analysis of placental-fetal biomarkers as intermediary variables between maternal body mass index and birthweight

JOURNAL=Frontiers in Reproductive Health

VOLUME=Volume 4 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/reproductive-health/articles/10.3389/frph.2022.994436

DOI=10.3389/frph.2022.994436

ISSN=2673-3153

ABSTRACT=Human chorionic gonadotropin (hCG) is a placental hormone measured in pregnancy to predict individual level risk of fetal aneuploidy and other complications; yet may be useful in understanding placental origins of child development more generally. hCG was associated with maternal body mass index (BMI) and with birthweight. The aim here was to evaluate hCG as a mediator of maternal BMI effects on birthweight by causal mediation analysis. Subjects were 356 women from 3 U.S. sites (2010-2013). The 4-way decomposition method using med4way (STATA) was applied to screen for 5 types of effects of first trimester maternal BMI on birthweight: the total effect, the direct effect, mediation by hCG, additive interaction of BMI and hCG, and mediation in the presence of an additive interaction. Effect modification by fetal sex was evaluated, and a sensitivity analysis was performed to evaluate the assumption of unmeasured confounding. Additional placental-fetal biomarkers (pregnancy associated plasma protein A [PAPPA], second trimester hCG, inhibin-A, estriol, alpha fetoprotein) were analyzed for comparison. For first trimester hCG, there was a 0.20 standard deviation increase in birthweight at the 75th vs. 25th percentile of maternal BMI (95% CI 0.06, 0.33), which was twice as strong in male vs. female infants. In women carrying males, hCG did not mediate the relationship. In women carrying females, we observed mediation of the maternal BMI effect on birthweight by hCG in the reverse direction (-0.08, 95% CI: - 0.15, -0.01). Sensitivity analysis revealed potential bias in female infant effect estimates due to unmeasured confounders. BMI effects on birthweight occurred by mediation in the presence of interaction by PAPP-A. Second trimester hCG and other placental-fetal biomarkers showed no evidence of mediation or interaction. These findings motivate research to consider first trimester placental hCG and fetal sex when quantifying the effects of maternal adiposity on fetal growth.