Advanced maternal age (AMA) is defined as childbearing in mothers greater than or equal to35 years of age and is becoming increasingly prevalent in high income countries. AMA has been associated with increased risk of adverse pregnancy outcomes, particularly stillbirth. Although AMA mothers have higher rates of chromosomal abnormalities and maternal co-morbidities, AMA remains an independent risk factor for stillbirth. Despite these findings, the etiology behind this increased risk is unknown. We hypothesise that an altered maternal environment, including increased oxidative stress and inflammation, due to ageing causes placental dysfunction which increases AMA mothers' vulnerability to stillbirth.A holistic approach was applied to investigate placental dysfunction in AMA. Firstly, a systematic review and meta-analysis comprehensively reviewed existing data on AMA and associated adverse pregnancy outcomes. Secondly, Manchester Advanced Maternal Age Study (MAMAS), a multi-centre prospective observational cohort study, was conducted to investigate risk factors for composite adverse pregnancy outcome (CAPO) in AMA. MAMAS utilised both uni- and multivariate analysis on demographic and clinical data, and measuring biomarkers of ageing and placental dysfunction by ELISA in maternal circulation during the third trimester of pregnancy. Utero-placental dysfunction was directly investigated in uncomplicated AMA pregnancies by quantifying placental morphology, placental nutrient transport capabilities and both placental and maternal uterine vascular responses. Finally, a C57BL/6J murine model of AMA was developed and characterised to further investigate maternal age on pregnancy outcome and the role of the placenta. In the meta-analysis, maternal age was linearly associated with increased risk of stillbirth and other adverse outcomes strongly associated with placental dysfunction (fetal growth restriction, preeclampsia and placental abruption). In MAMAS, smoking status and primiparity were predictive of CAPO. After adjustment, AMA mothers had an odd ratio of 2.05-3.43 of CAPO compared to 20-30 year old mothers. AMA mothers showed evidence of increased oxidative stress and pro-inflammatory bias. AMA mothers who suffered CAPO showed reduced placental endocrine capacity seen in placental dysfunction. Placentas from uneventful AMA pregnancies showed evidence of accelerated ageing and placental adaptation with increased nutrient transport, increased placental weight but reduced efficiency, and altered vascular function. AMA mice showed many similar aspects to human AMA with increased fetal loss, fetal growth restriction and increased placental size. These studies provide robust evidence for increased incidence of adverse pregnancy outcome due to placental dysfunction in pregnancies of women of AMA. This finding requires the appropriate recognition in a clinical context, with a greater focus on personalised obstetric care in an attempt to reduce stillbirth rates in this high risk population. By optimising antenatal and obstetric care for AMA mothers, we could reduce stillbirth rates by 4.7% - the population attributable risk due to AMA. These studies highlight key areas of future research that will further understanding into stillbirth risk in AMA pregnancy, test predictive models and test therapies and clinical care interventions an ultimately improve pregnancy outcome in mothers of AMA.
- Advanced Maternal Age
- Fetal Growth Restriction