The influence of fetal sex on maternal blood pressure in pregnancy.

Background: Pregnancy with a male fetus carries a higher risk of term pre-eclampsia than pregnancy with a female fetus. Based on evidence that maternal blood pressure (BP) may be raised in pregnancies with Beckwith-Wiedemann syndrome (fetal overgrowth), a possible contributing factor to the association between male sex and term pre-eclampsia is that males grow faster, reaching ~130 g higher birth weight, on average, than females. The association between fetal sex and maternal BP in healthy pregnancies is not known. We hypothesized that male sex would be associated with higher maternal BP in healthy pregnancies, and that this association would be explained by birth weight differences between males and females. Methods and findings: We tested the association between fetal sex and maternal systolic (SBP) and diastolic blood pressure (DBP), measured at ~28 weeks of gestation, in a meta-analysis of five different cohorts of mother-child pairs (n up to 109,842). Maternal BP was analyzed as both a continuous and dichotomized (high BP: yes or no) outcome. Linear regression models were constructed with and without adjustment for birth weight to assess whether any difference in maternal BP was explained by the difference in birth weight between male and female babies. Lastly, we constructed a fetal genetic score for birth weight using 186 own-birth-weight-associated single-nucleotide polymorphisms (SNPs) to test whether birth-weight-raising-alleles in the fetus were associated with maternal BP in pregnancy (n up to 32,232). Both maternal SBP and DBP were higher in pregnancy when carrying a male fetus compared to a female fetus (mean difference 0.35 mmHg [95%CI: 0.15-0.55] and 0.35 mmHg [95%CI: 0.21-0.49], for SBP and DBP, respectively). An independent effect of fetal sex remained when including birth weight but attenuated slightly (0.22 mmHg [95%CI: 0.02-0.42] and 0.31 mmHg [95%CI: 0.17-0.45], for SBP and DBP respectively). A positive effect estimate was found for odds of experiencing high maternal BP given pregnancy with a male fetus, but confidence intervals were wide (OR 1.05 [95%CI: 0.98-1.12]). No evidence for an association was found between a fetal birth weight genetic score and SBP or DBP when conditioned on maternal genotype. Conclusions: We found strong evidence to support a small effect of male fetal sex on higher maternal BP in pregnancy and that larger fetal size at birth does not contribute to a substantial part of this association. Our findings do not indicate a difference in maternal BP that would warrant changes to routine monitoring in clinical practice but do suggest that male sex may be a contributing risk factor for BP-related complications.