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. 2022 Dec 5:4:994436.
doi: 10.3389/frph.2022.994436. eCollection 2022.

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

Xiaoshuang Xun  1 , Xu Qin  2 , Alexander J Layden  1 , Qing Yin  3 , Shanna H Swan  4 , Emily S Barrett  5 , Nicole R Bush  6 , Sheela Sathyanarayana  7 , Jennifer J Adibi  1   8
Affiliations

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

Xiaoshuang Xun et al. Front Reprod Health. .

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 primary 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 0.04, 0.36). Once stratified, the direct effect association was null in women carrying females. In women carrying males, hCG did not mediate the relationship. In women carrying females, there was a mediated effect of maternal BMI on birthweight by hCG in the reverse direction (-0.06, 95% CI: -0.12, 0.01), and a mediated interaction in the positive direction (0.06, 95% CI 0.00, 0.13). In women carrying males, the maternal BMI effect on birthweight was reverse mediated by PAPPA (-0.09, 95% CI: -0.17, 0.00). Sex-specific mediation was mostly present in the first trimester. Second trimester AFP was a positive mediator of maternal BMI effects in male infants only (0.06, 95% CI: -0.01, 0.13). Effect estimates were robust to potential bias due to unmeasured confounders. These findings motivate research to consider first trimester placental biomarkers and sex-specific mechanisms when quantifying the effects of maternal adiposity on fetal growth.

Keywords: birthweight; causal mediation analysis; maternal BMI; placental hormones; reproductive epidemiology.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Directed acyclic graph (DAG) for the impact of maternal first trimester BMI on birthweight when treating placental-fetal biomarkers as an intermediary variable. X, exposure – maternal first trimester body mass index; M, mediator – maternal serum placental-fetal biomarkers; Y, outcome – birthweight z-score; C1, confounders of X-Y, the BMI and birthweight association; C2, confounders of X-M, the BMI and placental-fetal biomarker association; C3, confounders of M-Y, the placental-fetal biomarker and birthweight association The med4way macro does not distinguish between the C1, C2, C3 sets.
Figure 2
Figure 2
Linear associations between (A) maternal first trimester BMI and birthweight; (B) first trimester BMI and hCG; (C) first trimester hCG and birthweight for women carrying male and female fetuses in the infant development and environment study (TIDES), 2010–2013. Solid lines represent women carrying male fetuses, and dashed lines represent women carrying female fetuses. 95% confidence intervals are shaded around the lines. BMI, body mass index; hCG, human chorionic gonadotropin.
See this image and copyright information in PMC

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