Is the Association Between Pregnancy Weight Gain and Fetal Size Causal?: A Re-examination Using a Sibling Comparison Design.

Abstract

Observational cohort studies have consistently shown that maternal weight gain in pregnancy is positively associated with fetal size, but it is unknown whether the association is causal. This study investigated the effect of pregnancy weight gain on fetal growth using a sibling comparison design to control for unmeasured confounding by genetic and shared environmental factors. Our study population included 44,457 infants (21,680 women) with electronic medical records in the Stockholm-Gotland Obstetrical Database, 2008-2014. We standardized pregnancy weight gain into gestational age-specific z-scores. Fetal size was classified as birthweight (gram), and as small- and large-for-gestational-age birth (birthweight <10th or >90th percentiles, respectively). Our sibling comparison analyses used multivariable linear fixed effects models for birthweight and hybrid logistic fixed effects models for small- and large-for-gestational-age birth (SGA and LGA). We repeated analyses using conventional (unmatched) regression models. Sibling comparison analyses showed a clinically meaningful association between weight gain and fetal size (e.g., adjusted difference of +89 g birthweight [95% CI = 82, 95 g]; adjusted risk ratios [aRR] for SGA of 0.80 [95% CI = 0.75, 0.86] per 1 z-score increase in weight gain for a woman of body mass index [BMI] = 25). These findings were consistent across the range of BMI. Estimates were only modestly attenuated compared with conventional approach (+97 g [95% CI = 92, 102 g], aRR for SGA of 0.70 [95% CI = 0.67, 0.73] per 1 z-score increase in weight gain). The positive association between pregnancy weight gain and fetal size we found using a sibling comparison design suggests that this relation has minimal confounding by familial factors that remain constant between pregnancies.