Advanced maternal age and adverse pregnancy outcomes: A systematic review and meta-analysis

Abstract

Background: Advanced maternal age (AMA; ≥35 years) is an increasing trend and is reported to be associated with various pregnancy complications.

Objective: To determine the risk of stillbirth and other adverse pregnancy outcomes in women of AMA.

Search strategy: Embase, Medline (Ovid), Cochrane Database of Systematic Reviews, ClinicalTrials.gov, LILACS and conference proceedings were searched from ≥2000.

Selection criteria: Cohort and case-control studies reporting data on one or more co-primary outcomes (stillbirth or fetal growth restriction (FGR)) and/or secondary outcomes in mothers ≥35 years and <35 years.

Data collection and analysis: The effect of age on pregnancy outcome was investigated by random effects meta-analysis and meta-regression. Stillbirth rates were correlated to rates of maternal diabetes, obesity, hypertension and use of assisted reproductive therapies (ART).

Main results: Out of 1940 identified titles; 63 cohort studies and 12 case-control studies were included in the meta-analysis. AMA increased the risk of stillbirth (OR 1.75, 95%CI 1.62 to 1.89) with a population attributable risk of 4.7%. Similar trends were seen for risks of FGR, neonatal death, NICU unit admission restriction and GDM. The relationship between AMA and stillbirth was not related to maternal morbidity or ART.

Conclusions: Stillbirth risk increases with increasing maternal age. This is not wholly explained by maternal co-morbidities and use of ART. We propose that placental dysfunction may mediate adverse pregnancy outcome in AMA. Further prospective studies are needed to directly test this hypothesis.

Fig 1. PRISMA flow diagram of systematic review search strategies.

Fig 2. Quality assessment: Risk of bias assessment for included studies in meta-analysis classified as high, low or unclear.

Fig 3. Forest plot of odds ratios of stillbirth stratified by maternal age group (≥35, 35–39, ≥40, 40–49, ≥45 and ≥50 years of age) weighted from random effects analysis shows increased risk of stillbirth in AMA population (OR 1.75; 95%CI 1.62–1.89).

Heterogeneity was classified as severe (Cochran’s χ²_, I² = 95.0%).

Fig 4. Stillbirth and co-morbidities.

A) Meta-regression showed a linear association between stillbirth rates and maternal age (R² = 0.45) and B) contour enhanced funnel plot representing no small study effects (Harbord’s test). Correlation between population rates (% of total population) of maternal co-morbidities C) obesity, D) diabetes, E) hypertension and F) assisted reproductive therapies with stillbirth for mothers ages <35, ≥35 and ≥40 years of age. Population rates of stillbirth were positively correlated with rates of hypertension in ≥35 year old population only (p = 0.002) and negatively correlated with ART in the ≥40 year old population only (p = 0.017). Spearman rank correlations.