RELATIONSHIP BETWEEN ADVANCED MATERNAL AGE AND ADVERSE FOETAL OUTCOMES
There have been a large number of studies which have explored the relationship between maternal age and adverse foetal outcomes. A meta-analysis of observational studies performed in 2017 included 63 cohort studies and 12 case–control studies [8▪▪]. The primary outcome of interest was stillbirth; the meta-analysis included 44 studies reporting the outcome of 44 723 207 births, including 185 234 stillbirths. This found that the pooled odds ratio (OR) for stillbirth for women at least 35 years of age was 1.76 (95% confidence interval (95% CI 1.63–1.90); meta-regression identified that increasing maternal age was associated with increasing risk of stillbirth (R 2 = 0.61, Fig. 2) [8▪▪]. Critically, there was no difference in this relationship between geographical location or the year of study. There was significant heterogeneity between estimates of the effect size between studies, suggesting that other factors may mediate some of the increased risk of stillbirth. Due to its size, this systematic review also explored the relationship between factors which could account for the increased risk of stillbirth in women at least 35 years; these included maternal comorbidities (e.g. obesity, diabetes, hypertension) and the use of ART. Only maternal hypertension was correlated with stillbirth in women over the age of 35, suggesting that maternal age is an independent risk factor for stillbirth [8▪▪].
Although this meta-analysis was able to provide clear evidence of the association between stillbirth and maternal age at least 35 years, it was not able to determine the origins of this increased risk. Earlier studies identified that stillbirths in women over the age of 35 more frequently occur in late pregnancy, with an apparent shift in the increased stillbirth rate seen at 41 weeks in younger women (one in 1333) to 40 weeks in women at least 35 years of age (one in 735) [9▪]. A study of 637 stillbirths occurring in women over the age of 35 found that in this population stillbirths were more commonly due to major congenital anomalies [relative risk ratio (RRR) 2.0, 95% CI 1.3–3.0], mechanical causes (RRR 1.6), maternal disorders (RRR 2.1, 95% CI 1.2–3.6), and associated obstetric factors (RRR 2.1, 95% CI 1.1–3.9) . On the contrary, this study employed the classification system employed by Centre for Maternal and Child Enquiries, using which results in a high proportion of deaths (29%) with no relevant factors identified, in part because this classification system had no means to record foetal growth restriction (FGR) or placental conditions as a cause for stillbirth, both of which are important risk factors. The association of maternal age at least 35 years with conditions which are strongly associated with placental disorders, such as small for gestational age (SGA) infants and preeclampsia, raises the possibility that AMA could be associated with increased risk of stillbirth by placental dysfunction.
The relationship between maternal age at least 35 years and other adverse foetal outcomes was also explored in the systematic review by Lean et al., although there were fewer studies exploring these outcomes. Meta-analysis defined an increased risk of SGA (OR 1.16, 95% CI 1.06–1.27; 25 studies of 16 949 750 births), low birth weight less than 2500 g (OR 1.37, 95% CI 1.26–1.50; 35 studies of 18 360 387 births), preterm birth (<37-week gestation, OR 1.45, 95% CI 1.38–1.53; 46 studies of 24 551 442 births), neonatal death (OR 1.48, 95% CI 1.30–1.67; 27 studies of 13 245 799 births) and admission to neonatal ICU (OR 1.49, 95% CI 1.34–1.66; 20 studies of 645 661 births) in women at least 35 years [8▪▪]. In general, the risk of adverse outcomes increased in women aged over 40 years and was highest in women over 45 years of age, suggesting risk increases with advancing age [8▪▪,11]. As this meta-analysis pooled data from observational studies, it is possible AMA is linked to adverse foetal outcome(s) by confounding factors which were not measured by this analysis. Significantly, women over the age of 35 are more likely to have higher levels of education, higher income, and are more likely to be employed and attend prenatal classes, all of which reduce the risk of adverse pregnancy outcomes [12,13]. Thus, despite these favourable characteristics, AMA still appears to be an independent risk factor for adverse foetal outcome(s).
RELATIONSHIP BETWEEN ADVANCED MATERNAL AGE AND ADVERSE MATERNAL OUTCOMES
The relationship between maternal age and maternal mortality has been explored in international studies, which demonstrate a nonlinear increase in the maternal mortality ratio with maternal age, with the highest maternal mortality rates in women in the oldest age groups [14,15]. A UK case–control study of 105 maternal deaths identified factors which were significantly associated with maternal deaths in women at least 35 years compared with those less than 35 years of age; these were: cigarette smoking during pregnancy [adjusted OR (aOR) 2.1, 95% CI 1.1–3.8], inadequate use of antenatal care (aOR 23.6, 95% CI 8.8–63.5), medical comorbidities (aOR 5.9, 95% CI 3.6–9.9) and previous pregnancy complications (aOR 2.1, 95% CI 1.2–3.5) [16▪]. In this study, the odds of maternal death increased by 12% per year increase in age. Comorbidities that were highlighted in cases of maternal death were cardiac disease, hypertension, infection, musculoskeletal disorders, asthma, mental health disorders and neurological diseases [16▪]. Importantly, the greater number of risk factors for maternal mortality that were present, the greater the risk of maternal mortality (one risk factor OR 2.8, 95% CI 1.4–5.4, three risk factors OR 26.1, 95% CI 10.9–62.3). This study highlighted the importance of high-quality antenatal care for women over the age of 35, particularly those with medical comorbidities. In their systematic review and meta-analysis Lean et al. [8▪▪] described an association between maternal complications of pregnancy and maternal age at least 35 including preeclampsia (OR 2.0, 95% CI 1.6–2.4; 38 studies of 10 230 730 births), placental abruption (OR 1.5, 95% CI 1.4–1.7; 32 studies of 8843 049 births) and gestational diabetes (OR 2.8, 95% CI 2.5–3.3; 28 studies of 1694 232 births). These findings suggest that medical comorbidities, particularly those affecting the maternal cardiovascular and endocrine systems, may mediate some of the effects of age on maternal morbidity and mortality.
EVIDENCE FROM BASIC SCIENCE STUDIES OF ADVANCED MATERNAL AGE
In addition to epidemiological studies, basic science investigations have been carried out to explore potential pathophysiological mechanisms underpinning the increased risk of adverse outcome in mothers at least 35 years of age. Placentas from normal outcomes in women at least 35 years have increased placental weight and decreased foetal : placental weight ratio compared with women aged 20–30 years [17▪]. Foetal : placental weight ratio is decreased in SGA and FGR pregnancies, which is thought to result from increased placental size in an attempt to increase nutrient transfer to the foetus [18–20]. At a microscopic level, trophoblast proliferation is reduced and the presence of syncytial nuclear aggregates (also termed syncytial knots) is increased [17▪]. These changes are also seen in postterm pregnancies and in FGR stillbirths [21–23], thus these observations are consistent with a hypothesis of accelerated placental ageing in mothers at least 35 years of age, which could explain the increased risk of stillbirth from 40-week gestation seen at 42-week gestation in women less than 35 years of age [9▪]. Ageing is a complex process involving oxidative stress and inflammation. Preliminary data suggest that women at least 35 years of age with normal pregnancy outcomes have increased total antioxidant capacity, decreased anti-inflammatory cytokines (IL-10 and IL-1RA) and increased proinflammatory cytokines (IFN-γ, TNF-α, IL-8 and IL-1α) in their blood compared with women aged 20–30 years, whereas those mothers at least 35 with adverse outcomes have increased evidence of oxidative stress and a further reduction in anti-inflammatory cytokines .
The effect of AMA has been explored in two animal models (mouse and rat). There are important similarities in pregnancy outcome in these models and pregnancy outcome in women at least 35 years of age with increased foetal loss rate and high levels of FGR. Both rodent models of AMA had larger placentas and lower foetal : placental weight ratios [17▪,25,26]. There were also some changes in vascular behaviour with the mouse model showing increased endothelial-dependent relaxation in AMA and there was increased myogenic responses in systematic and uterine arteries in AMA rats [17▪,26]. AMA mice also showed reduced uterine artery remodelling during pregnancy compared with young controls . There was also reduced placental amino-acid transport in the AMA mouse model compared with young mice which indicates a reduction in placental efficiency [17▪]. These findings support the human data, suggesting that abnormal placental function is evident in AMA. Further research is needed to determine the origins of the observed reduction of placental function, and whether it is amenable to therapeutic intervention.
INTERVENTION STUDIES IN MOTHERS OF ADVANCED MATERNAL AGE
As women have an increased risk of adverse foetal and maternal outcome, particularly stillbirth in late pregnancy, consideration has been given to whether women at least 35 years of age should have additional antenatal surveillance and earlier birth advised . The increased incidence of FGR has led to the recommendation that maternal age at least 40 years should be considered an indication for regular assessment of foetal growth in late pregnancy and women aged at least 35 years should have this in the presence of other risk factors for FGR . Consideration should also be given to screening for gestational diabetes and hypertensive disorders of pregnancy. Various studies report that earlier delivery is currently offered to women at least 35 years [30,31]; a survey published in 2012 found that 37% of obstetricians offered induction of labour (IOL) at term to women aged 40–44, rising to 55% for women aged at least 45 . This practice raised concerns that this intervention could precipitate an increase in Caesarean section or instrumental vaginal births as women at least 35 years of age have an increased risk of these procedures . In nulliparous women, there is a linear association between maternal age and birth by emergency Caesarean section . This concern was addressed by the 35–39 trial, a randomized controlled trial of IOL at 39 + 0–39 + 6-week gestation compared with expectant management. The primary outcome of this trial was Caesarean section, which did not differ between the two groups with 98/304 in the induction group and 103/314 in the expectant management group (relative risk 0.99, 95% CI 0.87–1.14) [33▪▪]. There was also no difference in the incidence of the secondary outcomes (including: placental abruption, postpartum haemorrhage, Apgar score less than 7 at 5 min, admission to neonatal intensive care unit) between groups. This trial concluded that IOL in women at least 35 years of age at 39-week gestation was not associated with a change in the rate of Caesarean section or adverse maternal or neonatal outcomes [33▪▪]. A cost–utility analysis performed alongside the trial based upon quality of life measures and estimates of resource use found that IOL at 39 weeks was associated with a cost-saving of £263 .
There were no stillbirths amongst participants of the 35–39 trial, which was unsurprising as there were 619 participants, and the trial was not statistically powered to investigate a change in stillbirth rate. However, the potential effect of IOL in nulliparous women at least 35 years of age was compared with expectant management using routinely collected data from English hospitals between 2009 and 2014. This analysis of 77 327 women, 33% of whom had IOL, found IOL at 40-week gestation was associated with a lower incidence of in hospital perinatal death compared with women who had expectant management (0.08 vs. 0.26% (adjusted risk ratio, aRR 0.33, 95% CI 0.13–0.80) and a lower risk of meconium aspiration syndrome (0.44 vs. 0.88%, aRR 0.52, 95% CI 0.35–0.78) [35▪▪]. However, in this analysis there was increased risk of instrumental delivery (aRR 1.06, 95% CI 1.01–1.11) and emergency Caesarean section (aRR 1.05, 95% CI 1.01–1.09). This study noted that there was a high number needed to treat to prevent one stillbirth, for women aged at least 35, 562 IOLs need to be performed to reduce one perinatal death [35▪▪].
Epidemiological data have demonstrated that women over the age of 35 have increased risk of adverse maternal and neonatal outcomes, with increasing risk with increasing age. It is uncertain whether all these risks are greater in nulliparous women, but the risk of adverse outcome appears greater when comorbidities are present. The reasons for the increased risk of adverse outcomes are not completely understood and potentially include age-related changes in the maternal cardiovascular, immune and endocrine systems. The association with stillbirth, SGA infants, preeclampsia and placental abruption all suggest a placental component to adverse neonatal outcome which is supported by evidence from scientific studies. Consequently, women at least 35 years of age should have risk-factors for adverse outcome assessed at booking and have ultrasound assessment of foetal growth in the third trimester if other risk factors for FGR are present and women at least 40 should be offered aspirin 150 mg once a day and regular assessment of foetal growth in the third trimester. The increased risk of stillbirth (even with a normally grown baby) should be discussed with mothers at least 35 years of age and women should be offered IOL (unless vaginal birth is contraindicated) at 39-week gestation. There is now sufficient data from recently published trials and analyses to inform women about the number needed to treat and the likelihood that there is little effect on the incidence of vaginal birth. Importantly, women may interpret data differently as illustrated by the proportion of women (60.8%) that declined to participate in the 35–39 study [33▪▪]. However, unbiased information should be provided to women so they can make an informed decision. A policy of IOL in women over 35 years of age in a maternity unit of 5000 births (of which 1115 women would be ≥35) would be expected to prevent approximately two perinatal deaths per year. Thus, this strategy would be unlikely to produce a significant reduction in stillbirth in isolation but would contribute to the goal of reducing stillbirth and neonatal death by 50% by 2025.
Financial support and sponsorship
The work and the Manchester Advanced Maternal Age Study was financially supported by Tommy's, UK.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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Keywords:Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.
advanced maternal age; induction of labour; perinatal mortality; stillbirth