Maternal and perinatal complications according to maternal age: A systematic review and meta‐analysis

Abstract Objective To evaluate the risk levels for maternal and perinatal complications at > 40, > 45 and > 50 years old compared with younger controls. Methods Electronic databases were searched from their inception until March 2021. We included studies reporting pregnancy outcome in pregnant women aged 40, 45, and 50 years or older compared with controls at the time of delivery. Case reports and case series were excluded. The primary outcome was the incidence of stillbirth. Meta‐analysis was performed using the random effects model of DerSimonian and Laird, to produce summary treatment effects in terms of relative risk (RR) with 95% confidence interval (CI). Heterogeneity was measured using I 2 (Higgins I 2). Subgroup analyses in women older than 45 years and in those older than 50 years were performed. Results Twenty‐seven studies, including 31 090 631 women, were included in the meta‐analysis. The overall quality of the included studies was moderate to high. Most of the included studies were retrospective cohort studies (21/27), four were population‐based studies, and two were cross‐sectional studies. Women aged ≥40 years had significantly higher risk of stillbirth (RR 2.16, 95% CI 1.86–2.51), perinatal mortality, intrauterine growth restriction, neonatal death, admission to neonatal intensive care unit, pre‐eclampsia, preterm delivery, cesarean delivery, and maternal mortality compared with women younger than 40 years old (RR 3.18, 95% CI 1.68–5.98). The increased risks for maternal mortality were 42.76 and 11.60 for women older than 50 years and for those older than 45 years, respectively, whereas those for stillbirth were 3.72 and 2.32. The risk of stillbirth and cesarean delivery was significantly higher in women >45 years compared with those aged 40–45 years, and in those aged >50 years compared with those aged 45–50 years. The risk of maternal mortality was significantly higher in women aged >50 years compared with those aged 40–45 (RR 60.40, 95% CI 13.28–274.74). Conclusion The risk of stillbirth, cesarean delivery, and maternal mortality increases with advancing maternal age. The risk ratios for maternal mortality were 3.18, 11.60, and 42.76 in women older than 40, older than 45, and older than 50 years, respectively. These data should be used when women with advanced maternal age are counseled regarding their risk in pregnancy. Systematic Review Registration The review was registered with the PROSPERO International Prospective Register of Systematic Reviews (registration No.: CRD42020208788).


| INTRODUC TI ON
The trend of deferring childbirth to a later time in a woman's life is associated with an increased risk of infertility and the use of assisted reproductive technologies, including in vitro fertilization, intracytoplasmic sperm injection, or oocyte donation. Oocyte donation enables women with diseases such as premature ovarian insufficiency, genetic disorders, or surgical menopause to become pregnant. 1 The technique is also used to overcome natural perimenopausal or postmenopausal infertility, making motherhood possible for women even in their sixties. 2 Several studies have shown that assisted reproductive technologies (ART), including in vitro fertilization, intracytoplasmic sperm injection, or oocyte donation, are associated with an increased risk of maternal and perinatal complications compared with spontaneously conceived pregnancies. [3][4][5][6][7][8][9][10][11] Advanced maternal age, traditionally referred to pregnant women aged 35 years or older at the time of delivery, is associated with an increased risk of maternal and perinatal complications among singleton and multiple gestations. 12,13 The risk seems even higher in women aged 40 years or older, 14 but the literature is inconsistent and limited to retrospective data.
To address this inconsistency in knowledge, the aim of this systematic review was to evaluate the risk levels for maternal and perinatal complications at ≥40, ≥45, and > 50 years of age compared with younger controls.

| Search strategy and selection criteria
This review was performed according to a protocol designed a priori and recommended for systematic review. 14 Electronic databases Search terms used were the following text words: "maternal age", "advanced", "pregnancy", and "outcome" combined. No restriction for geographic location was applied. Only studies published in the English language were included. The search was restricted to publication year 2000 and later. In addition, the reference lists of all identified articles were examined to identify studies not captured These data should be used when women with advanced maternal age are counseled regarding their risk in pregnancy.  Differences were discussed and consensus was reached.

Systematic Review
We included all cohort studies reporting pregnancy outcome in pregnant women older than 40, 45, and 50 years compared with controls. Case-control studies, case reports, and case series were excluded. Studies published only as abstract were also excluded.

| Primary and secondary outcomes
Primary and secondary outcomes were defined before data extraction. The primary outcome was the incidence of stillbirth. The secondary outcomes were perinatal mortality, neonatal death, admission to neonatal intensive care unit (NICU), preterm birth, cesarean delivery, and maternal mortality. When possible, data on use of ART

TA B L E 2 (Continued)
were extracted. Subgroup analyses according to women older than 45 years and older than 50 years were performed. We also planned to perform indirect meta-analyses to compare risk of primary outcome (i.e., stillbirth), cesarean delivery, and maternal mortality according to maternal age at different cut-offs (40-45, >45, and >50 years).

| Study definition
Stillbirth was defined as intrauterine fetal death according to individual study gestational age cut-off. Pre-eclampsia was defined as blood pressure >140/90 mm Hg with significant proteinuria or as classified by authors where definition was not provided. Intrauterine growth restriction was defined as estimated fetal weight below the 10th centile adjusted for gestational age or related definitions specified by the original study. Neonatal death was defined as the death of a liveborn infant, regardless of gestational age at birth, within the first 28 completed days of life. Perinatal mortality was defined as either stillbirth or neonatal death. Preterm birth was defined as delivery before 37 weeks of gestation. 15 Meta-analysis was performed using the random effects model of DerSimonian and Laird, to produce summary treatment effects in terms of either an RR or MD with 95% confidence interval (CI).

| Statistical analysis
Heterogeneity was measured using I 2 (Higgins I 2 ). A P value less than 0.05 was considered statistically significant.
The meta-analysis was reported following the Preferred Reporting Item for Systematic Reviews and Meta-analyses (PRISMA) statement. 16 Before data extraction, the review was registered with the PROSPERO International Prospective Register of Systematic Reviews (registration no. CRD42020208788).

| Study selection and study characteristics
Twenty-seven studies were included in the meta-analysis  ( Figure 1). Overall, 31 090 631 participants were included in the review. Of them 733 327 were women older than 40 years, and 30 357 304 were women younger than 40 years ( Table 1) Regarding the study group, it was >40 in 23 studies, 19,21,23-43 >45 in one study, 17 40-49 in one study, 18 >50 in one study, 22 and 40-47 in one study. 20 Most of studies reported subgroup analyses according to different age cut-offs in both study group and control group. Table 2 shows the primary and secondary outcomes in the overall analysis. Women older than 40 years had significantly higher risk of stillbirth (Figure 3), perinatal mortality (Figure 4), intrauterine growth restriction, neonatal death, admission to NICU, pre-eclampsia, preterm delivery, cesarean delivery ( Figure 5), and maternal mortality.

| Synthesis of results
Increased risks of maternal and perinatal complications were still significant in the group of women older than 45 years ( Table 3). Table 4 shows the primary and secondary outcomes in women older than 50 years. Pooled data from the two included studies 22,43 showed that women older than 50 years had significantly higher risk of stillbirth (RR 3.72, 95% CI 1.42-9.83), perinatal mortality, neonatal death, admission to NICU, preterm birth, cesarean delivery, and maternal mortality (RR 42.76, 95% CI 12.36-147.92) compared with women younger than 40 years.
Findings from indirect meta-analyses according to maternal age for the risk of stillbirth, cesarean delivery, and maternal mortality are shown in Table 5. The risk of stillbirth and cesarean delivery was significantly higher in women aged >45 years compared with those

| Principal findings
This meta-analysis aimed to evaluate the risk of maternal and perinatal outcomes in women with advanced maternal age. The primary analyses showed that women aged >40 years had significantly higher risk of stillbirth, perinatal mortality, intrauterine growth restriction, neonatal death, admission to NICU, pre-eclampsia, preterm birth, cesarean delivery, and maternal mortality compared with those younger than 40 years. These findings were confirmed in subgroup analyses of women aged >45 years and >50 years with even higher RRs ( Table 3 and Table 4). Indirect meta-analyses also showed that the risk of stillbirth, cesarean delivery, and maternal mortality increased with advancing maternal age. The risk ratios for maternal mortality were 3.18, 11.60, and 42.76 in women older than 40, older than 45, and older than 50 years, respectively.
The most important limitation of the meta-analysis was the inclusion of retrospective non-randomized studies. The study design of the included studies limited our findings. Different confounders could impact the results of our meta-analysis. In the group of women with advanced maternal age, most could have had ART-conceived pregnancies. ART is an independent risk factor for adverse pregnancy outcomes, 44 and so the risk associated with maternal age per se may have been overestimated. Unfortunately, only a few studies reported separated data for women who underwent ART and therefore these planned subgroup analyses were not feasible.

| Implications
Advanced age is a risk factor for female infertility, pregnancy loss, fetal abnormalities, stillbirth, and obstetric adverse outcomes. the perils inherent in advanced-age reproduction. 48 Obstetricians should promote more realistic views of reproductive success according to patient age. The risk, in fact, is that losing time may lead to pregnancy in women over 45 or 50 years of age, using oocyte donation, with unjustifiable risks of maternal and perinatal complications.

| Conclusions
In summary, women with advanced maternal age have an increased risk of maternal and perinatal complications. Our meta-analysis showed that the higher the maternal age the higher the risk of adverse pregnancy outcomes. These data should be used when women with advanced maternal age are counseled regarding their risk in pregnancy.

CO N FLI C T S O F I NTE R E S T
The authors report no conflicts of interest.

AUTH O R CO NTR I B UTI O N S
GS designed the review, interpreted data, provided the statistical analysis, and reviewed the final version; EG and IS collected data and drafted the manuscript; BI designed the study and drafted the manuscript; VM interpreted data and revised the final manuscript; RV collected data and revised the final manuscript; VB designed the review and drafted and revised the manuscript; and FZ designed the review and revised the final manuscript.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.