Placental polyamine metabolism differs by fetal sex, fetal growth restriction, and preeclampsia.

Abstract

Preeclampsia and fetal growth restriction (FGR) are major causes of the >5 million perinatal and infant death occurring globally each year and both are associated with placental dysfunction. The risk of perinatal and infant death is greater in males but the mechanisms are unclear. We studied data and biological samples from the Pregnancy Outcome Prediction study (POPs), a prospective cohort study which followed 4,212 women having first pregnancies from their dating ultrasound scan through to delivery. We tested the hypothesis that fetal sex would be associated with altered placental function using multi-omic and targeted analyses. We found that spermine synthase (SMS) escapes-chromosome inactivation (XCI) in the placenta, is expressed at lower levels in male primary trophoblast cells and male cells were more sensitive to olyamine depletion. The spermine metabolite, N1,N12-diacetylspermine DiAcSpm), was higher in the female placenta and in the serum of women pregnant with a female fetus. Higher maternal serum levels of DiAcSpm increased the risk of preeclampsia but decreased the risk of FGR. DiAcSpm is the first maternal biomarker to demonstrate opposite associations with preeclampsia and FGR, and this is the first evidence to implicate polyamine metabolism in sex-related differences in placentallyrelated complications of human pregnancy.