A Prospective Cohort Study providing Insights for Markers of Adverse Pregnancy Outcome in Women of Advanced Maternal Age

Background: Advanced maternal age (AMA; ≥35 years) is associated with increased rates of adverse pregnancy outcome. Better understanding of underlying pathophysiological processes may improve identification of AMA mothers who are at greatest risk of adverse outcome. This study aimed to investigate changes in oxidative stress and inflammation in AMA women and identify clinical and biochemical predictors of adverse pregnancy outcome in women of AMA. Methods: The Manchester Advanced Maternal Age Study (MAMAS) was a multicentre, observational, prospective cohort study of 527 mothers. Participants were divided into three age groups for comparison 20-30 years (n=158), 35-39 years (n=212) and ≥40 years (n=157). Demographic and medical data were collected along with maternal blood samples at 28 and 36 weeks’ gestation. Multivariable analysis was conducted to identify variables associated with adverse outcome, defined as one or more of: small for gestational age (<10 th centile), FGR (<5 th centile), stillbirth, NICU admission, preterm birth <37 weeks gestation or Apgar score <7 at 5 minutes. Biomarkers of inflammation, oxidative stress and placental dysfunction were quantified in maternal serum. Univariate and multivariable statistical analyses were used to identify associations with composite adverse fetal outcome. Results: : Maternal smoking was associated with adverse outcome in older mothers (Adjusted Odds Ratio (AOR) 4.34, 95% Confidence Interval (95%CI) 1.88, 9.99), whereas multiparity reduced the odds (AOR 0.56, 95% CI 0.34, 0.99). In uncomplicated AMA pregnancies, lower circulating anti-inflammatory IL-10, IL-RA and increased antioxidant capacity (TAC) were seen. In AMA with adverse outcome, TAC and oxidative stress markers were increased and levels of maternal circulating placental hormones (hPL, PlGF and sFlt-1) were reduced ( p <0.05). Of these, placental growth factor had the strongest predictive accuracy (Area Under the Receiver Operator Characteristic (AUROC) = 0.74) followed by TAC (AUROC=0.69). Conclusions: : This study identified alterations in circulating inflammatory and oxidative stress markers in AMA women and in AMA women with adverse pregnancy outcome providing preliminary evidence of mechanistic links. Further, larger studies are required to determine if these markers can be developed into a predictive model of an individual AMA woman’s risk of APO, enabling a reduction in stillbirth rates whilst minimising unnecessary intervention.