Abstract
Pregnancies in women of advanced maternal age (AMA) are susceptible to fetal growth restriction (FGR) and stillbirth. We hypothesised that maternal ageing is associated with utero-placental dysfunction, predisposing to adverse fetal outcomes. Women of AMA (≥35 years) and young controls (20–30 years) with uncomplicated pregnancies were studied. Placentas from AMA women exhibited increased syncytial nuclear aggregates and decreased proliferation, and had increased amino acid transporter activity. Chorionic plate and myometrial artery relaxation was increased compared to controls. AMA was associated with lower maternal serum PAPP-A and sFlt and a higher PlGF:sFlt ratio. AMA mice (38–41 weeks) at E17.5 had fewer pups, more late fetal deaths, reduced fetal weight, increased placental weight and reduced fetal:placental weight ratio compared to 8–12 week controls. Maternofetal clearance of 14C-MeAIB and 3H-taurine was reduced and uterine arteries showed increased relaxation. These studies identify reduced placental efficiency and altered placental function with AMA in women, with evidence of placental adaptations in normal pregnancies. The AMA mouse model complements the human studies, demonstrating high rates of adverse fetal outcomes and commonalities in placental phenotype. These findings highlight placental dysfunction as a potential mechanism for susceptibility to FGR and stillbirth with AMA.
Highlights
Abnormal placental function is apparent in fetal growth restriction (FGR) and stillbirths
This study addressed the hypothesis that utero-placental dysfunction is an underlying mechanism for susceptibility to FGR and stillbirth in advanced maternal age (AMA) pregnancies
Detailed characterisation studies revealed increased placental weight, but reduced placental efficiency, in pregnancies from women of AMA, together with alterations in placental morphology and function resembling the placental phenotype in FGR and stillborn pregnancies
Summary
Abnormal placental function is apparent in FGR and stillbirths. Reduced placental amino acid transport has been reported in FGR23, 24, including a reduction in amino acid transporters system A25 and TauT activity[26]. Clinical measures of placental dysfunction, including abnormal Doppler ultrasound resistance indices in both umbilical and uterine arteries (indicating increased vascular resistance and impaired spiral artery adaptations) are more prevalent in FGR and stillbirth[30, 31]. Consistent with these clinical observations, chorionic plate resistance arteries in FGR exhibit reduced constriction and exacerbated relaxation[32] as assessed by wire myography. Myometrial arteries show attenuated relaxation in FGR33 Whether any of these aspects of placental development, structure or function are altered in mothers of AMA and whether they underpin the susceptibility to FGR and stillbirth is unknown. Using a broad array of investigations in both human pregnancies and a murine model of AMA we identified multiple features of placental and utero-placental dysfunction, providing a potential mechanistic link for the increased FGR and stillbirth rates with AMA
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