Male sex bias in placental dysfunction

Several reports suggest a male fetal preponderance in a variety of complications of pregnancy attributable to severe placental dysfunction (SPD). However, the underlying mechanisms remain unknown. Our primary objective was to explore the relationship between fetal sex and the spectrum of conditions implicated in abnormal placentation. We identified singleton pregnancies with a fetus delivered between 20 + 0 and 32 + 6 weeks of gestation with one or more pregnancy complications attributed to SPD (severe pre-eclampsia, intra-uterine fetal death, intra-uterine growth restriction, abnormal Doppler studies, abruption) at a single institution between 1999 and 2007. Pedigrees of index cases were created to define the relationship between fetal sex and the risk of SPD. We identified 132 index cases, 97/132 (73%) were male. Eighty-four index cases had a total of 133 sibs, of which 37/133 (28%) were affected with SPD (22 male, 15 female). A male sex preponderance persisted across all manifestations of PD in index cases with sibs. In families with the absence of maternal chronic hypertension (cHTN; n = 70), the index case was 5.9 (95% CI 2.28-16.15; P <0.001) times more likely to be male and most (12/14) affected sibs of male index cases were male, while female index cases had no affected sibs. Our results confirm a male fetal sex preponderance in SPD. In a subgroup analysis of families without cHTN, a significant male bias was found to extend to sibs of index cases. This suggests a potential genetic mechanism predisposing the male fetus to abnormal placental development.