In response to in utero insults, male vs. female infants have greater disadvantages in pregnancy outcome. We asked if this differential impact of fetal sex might extend to fetal growth in utero during preeclampsia. We first investigated the influence of relevant variables in normotensive pregnancy. We evaluated whether the impact of maternal pre-pregnancy body mass index (BMI), smoking and socioeconomic status were modified by sex and/or race in singleton offspring of 8,801 primiparous normotensive women enrolled in the Collaborative Perinatal Project. The mean head-to-chest circumference (HCC) decreased more or each 1kg/m² increase in pre-pregnancy BMI, while mean birthweight and ponderal index (PI) increased more for each 1kg/m ² increase in pre-pregnancy BMI among term females vs. males (p=0.07, p<0.01 and p=0.08, interaction respectively).

We then investigated whether the relationship between preeclampsia and fetal growth was modified by sex in offspring of 516 preeclamptic and 8801 normotensive primiparous women. Male vs. female preterm offspring of preeclamptic mothers had greater reductions in mean birthweight, head and chest circumferences (p=0.05, p=0.02, p=0.01; interaction respectively). The influence of preeclampsia on growth of term offspring was more modest, and the influence of sex was opposite that in preterm infants.

Next we investigated placentas from 735 preeclamptic and 21,185 normotensive primiparous and multiparous women, to determine which dimensions of placental growth are reduced in preeclamptic pregnancies. We then investigated if the relationship between these measures and birthweight was constant between offspring of normotensive and preeclamptic women, as well as across infant sex. We found that the smaller but not the larger placental diameter was an independent predictor of preeclampsia ((smaller diameter <15cm OR 1.27 95% CI 1.01, 1.59) and larger diameter <18 cm (OR 1.18 95% CI 0.90, 1.54)). We also found higher rates of increase in birth weight at lower placental weight and placental diameters in offspring of preeclamptic vs. normotensive women (all p<0.05, interaction). Additionally, we found that among the offspring of preeclamptic women, female offspring with smaller diameters above 20cm, had a reduction in birth weight while males did not (p=0.02, interaction).

This work yields meaningful public health findings by providing evidence that influences upon fetal and placental growth are different by infant sex. Studies of mechanisms affecting fetal growth should investigate interactions with fetal sex. We hope studies of the involved biological pathways will direct future research to reduce rates of growth restriction and later life chronic diseases.