Advanced Maternal Age: Identifying Mechanisms Underlying Vulnerability to Stillbirth

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Abstract

Advanced maternal age (AMA) is defined as childbearing in mothers ≥35 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.

Layman's Abstract

Pregnant mothers over the age of 35 years old are classified as advanced maternal age (AMA). AMA is known to be associated with increased risks in pregnancy, including the baby being born too small or dying before birth (stillbirth). This risk of stillbirth in AMA is even true independently of the genetic defects in the eggs and maternal diseases that are more often seen in these women due to their age. However, it is not know why this increased risk of stillbirth occurs in AMA mothers. The placenta is a vital organ in pregnancy that regulates blood and nutrient supply to the baby and is known to not work properly (known a placental dysfunction) in pregnancies where the baby doesn’t grow properly or is stillborn. We propose that changes in the mother due to her age will affect the way that her placenta works and this is the reason why more babies are born small or are stillborn in AMA mothers compared to younger mothers. Firstly, we reviewed existing studies to see how many have found evidence of pregnancy diseases known to be caused by placental dysfunction in AMA pregnancies. We set up a clinical study called Manchester Advanced Maternal Age Study (MAMAS) and recruited pregnant mothers to investigate lifestyle risk factors for having poor outcomes (with placental links) in AMA. We collected mothers’ blood to see if higher levels of markers of ageing were detectable in AMA and if they were related to increased risk of poor outcome. The placentas from these mothers were used to measure their size, whether the cells were dividing or dying and how well they could transport nutrients from mother to baby. Placental and uterine vessels were tested to see how well they can control blood flow to the baby during pregnancy. Finally, a mouse model of AMA was developed and characterised to further investigate maternal age on pregnancy outcome and the role of the placenta.Previous studies showed that AMA was more strongly linked to increased risk of pregnancy outcomes that are associated with placental dysfunction than those that are not. In MAMAS, smoking and carrying a first pregnancy made mothers and being AMA increased risk of suffering a poor outcome. AMA mothers who had normal outcomes showed evidence of increased ageing markers but also increased mechanisms to counteract ageing related damage in their blood. AMA mothers who had poor outcome had higher levels of age related damage and inflammatory responses to that damage. They had lower levels of placental hormones indicating placental dysfunction. Placentas from AMA pregnancies had to work harder to keep the baby healthy by increasing their size, nutrient transport and altering placental and maternal vascular function. However, they still functioned less efficiently than placentas from younger mothers. Our mouse model of AMA showed many similar aspects to human AMA with small pups, high rates of stillbirth and larger placentas. These studies provide robust evidence for placental dysfunction can explain why mothers over the age of 35 years are more at risk of having small babies or stillborn babies. This finding should be recognised by doctors and midwives when deciding how to manage their pregnancies. If so, we could reduce national stillbirth rates by 4.7%. The mouse model offers a way for us to test interventions in AMA pregnancies to improve their outcome.

Keyword(s)

Advanced Maternal Age; Fetal Growth Restriction; Placenta; Pregnancy; Stillbirth

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