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).
Keywords: advanced maternal age, ART, maternal mortality, pregnancy
1. INTRODUCTION
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.
2. MATERIALS AND METHODS
2.1. Search strategy and selection criteria
This review was performed according to a protocol designed a priori and recommended for systematic review. 14 Electronic databases (i.e., MEDLINE, Scopus, ClinicalTrials.gov, EMBASE, Sciencedirect, the Cochrane Library at the CENTRAL Register of Controlled Trials, Scielo) were searched from their inception until March 2021. 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 by electronic searches. The electronic search and the eligibility of the studies were independently assessed by two authors (GC, GS). Differences were discussed and consensus was reached.
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.
2.2. 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 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).
2.3. 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
2.4. Statistical analysis
Data extraction and data analysis were completed independently by two authors (VDV, GS) using review manager v. 5.3 (The Nordic Cochrane Centre, Cochrane Collaboration, 2014). The completed analyses were then compared, and any difference was resolved by discussion.
Data from each eligible study were extracted without modification of original data onto custom‐made data collection forms. For dichotomous variables, a 2‐by‐2 table was assessed, and relative risk (RR) was computed. For continuous outcomes, means ± standard deviation were extracted and imported into review manager v. 5.3, and mean difference (MD) was calculated.
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). 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).
3. RESULTS
3.1. Study selection and study characteristics
Twenty‐seven studies were included in the meta‐analysis 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 (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). The overall quality of the included studies was moderate to high. The vast majority of the included studies were retrospective cohort studies (21/27), four were population‐based studies, and two were cross‐sectional studies. Publication bias, assessed by visual inspection of funnel plot (Figure 2), showed no publication bias.
FIGURE 1.
Flow diagram of studies identified in the systematic review. (PRISMA template [preferred reporting item for systematic reviews and meta‐analyses])
TABLE 1.
Characteristics of the included studies
| Study location | Study group, year | Control group, year | Assisted reproductive technology | Study design | |
|---|---|---|---|---|---|
| Abu 2000 17 | Jordan | >45 (n = 114) | 20–29 (n = 121) | Not reported | Retrospective cohort |
| Canterino 2004 18 | USA | 40–44 (n = 424 820)45–49 (n = 16 739) |
15–19 (n = 2 728 602) 20–24 (n = 5 440 685) 25–29 (n = 6 000 811) 30–34 (n = 4 970 770) 35–39 (n = 2 028 446) |
Not reported | Retrospective cohort |
| Jacobsson 2004 19 | Sweden |
40–44 (n = 31 662) > 45 (n = 1205) |
20–29 (n = 876 361) | Not reported | Population‐based |
| Dieijomaoh 2006 20 | Kuwait | 40–47 (n = 168) | 25–30 (n = 160) | Not reported | Retrospective cohort |
| Hoffman 2007 21 | Miami, FL, USA | >40 (n = 3953) |
<35 (n = 108 547) 35–39 (n = 13 902) |
Not reported | Retrospective cohort |
| Donoso 2008 22 | Chile | >50 (n = 217) | 20–34 (n = 2 817 742) | Not reported | Population‐based |
| Jahromi 2008 23 | Iran | >40 (n = 200) | 20–30 (n = 200) | Not reported | Retrospective cohort |
| Salihu 2008 24 | Missouri, USA | >40 (n = 13 453) |
20–24 (n = 429 647) 25–29 (n = 441 718) 30–34 (n = 265 167) 35–39 (n = 85 322) |
Not reported | Retrospective cohort |
| Hsieh 2010 25 | Taiwan | >40 (n = 721) |
20–34 (n = 33 881) 35–39 (n = 5161) |
20–34 (n = 624) 35–39 (n = 243) > 40 (n = 24) |
Retrospective cohort |
| Arnold 2012 26 | Australia | >40 (n = 2148) | <40 (n = 60 203) |
<40 (n = 2820) > 40 (n = 323) |
Retrospective cohort |
| Ates 2012 27 | Turkey | >40 (n = 97) | 20–29 (n = 97) | Not reported | Population‐based |
| Favilli 2012 28 | Italy | >40 (n = 317) | 20–30 (n = 312) |
20–30 (n = 0) > 40 (n = 10) |
Retrospective cohort |
| Kenny 2013 29 | UK | >40 (n = 7066) |
20–29 (n = 122 307) 30–34 (n = 62 371) 35–39 (n = 33 966) |
Not reported | Population‐based |
| Khalil 2013 30 | UK | >40 (n = 4061) |
<35 (n = 55 772) 35–39 (n = 16 325) |
Not reported | Retrospective cohort |
| Ngowa 2013 31 | Cameroon | >40 (n = 585) | 20–29 (n = 1816) | Not reported | Retrospective cohort |
| Seckin 2013 32 | Turkey | >40 (n = 190) | 20–30 (n = 600) | Not reported | Retrospective cohort |
| Timofeev 2013 33 | Washington, USA |
40–45 (n = 5931) > 45 (n = 391) |
<20 (n = 19 638) 20–24 (n = 51 011) 25–30 (n = 56 480) 31–34 (n = 45 715) 35–39 (n = 24 351) |
Not reported | Retrospective cohort |
| Laopiboon 2014 34 | Thailand |
40–44 (n = 7015) > 45 (n = 1527) |
20–34 (n = 238 504) 35–39 (n = 29 245) |
Not reported | Cross‐sectional |
| Mutz 2014 35 | Austria | >40 (n = 2272) |
25–34 (n = 43 313) 35–39 (n = 10 932) |
Not reported | Retrospective cohort |
| Waldenstrom 2014 36 | Sweden, and Norway | >40 (n = 11 430) |
25–29 (n = 342 012) 30–34 (n = 222 883) 35–39 (n = 67 859) |
Not reported | Retrospective cohort |
| Traisrislip 2015 37 | Thailand | >40 (n = 797) | 20–30 (n = 18 802) | Not reported | Retrospective cohort |
| Goisis 2017 38 | Finland | >40 (n = 2903) |
10–19 (n = 2183) 20–24 (n = 20 562) 25–29 (n = 45 946) 30–34 (n = 37 580) 35–39 (n = 14 924) |
Not reported | Retrospective cohort |
| Marozio 2017 39 | Italy |
40–44 (n = 3541) > 45 (n = 257) |
<40 (n = 52 413) |
<40 (n = 1704) 40–44 (n = 280) > 45 (n = 61) |
Retrospective cohort |
| Ogawa 2017 40 | Japan |
40–44 (n = 28 797) > 45 (n = 924) |
30–34 (n = 204 181) 35–39 (n = 131 515) |
30–34 (n = 4963) 35–39 (n = 8641) 40–44 (n = 3987) > 45 (n = 201) |
Cross sectional study |
| Frederiksen 2018 41 | Denmark | >40 (n = 9743) |
20–34 (n = 300 863) 35–39 (n = 58 910) |
20–34 (n = 15 515) 35–39 (n = 6877) > 40 (n = 1898) |
Retrospective cohort |
| Rydahl 2019 42 | Denmark | >40 (n = 31 361) |
<30 (n = 517 450) 30–34 (n = 398 873) 35–39 (n = 175 280) |
Not reported | Retrospective cohort |
| Rademaker 2020 43 | Netherlands |
40–44 (n = 112 952) 45–49 (n = 4631) > 50 (n = 157) |
25–29 (n = 1 085 447) |
25–29 (n = 5916) 40–44 (n = 4543) 45–49 (n = 290) > 50 (n = 51) |
Retrospective cohort |
FIGURE 2.
Funnel plot for publication bias
Regarding the study group, it was >40 in 23 studies, 19 , 21 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 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.
3.2. Synthesis of results
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. Increased risks of maternal and perinatal complications were still significant in the group of women older than 45 years (Table 3).
TABLE 2.
| Sample size | Stillbirth | Perinatal mortality | IUGR | Neonatal death | NICU admission | Pre‐eclampsia | Preterm birth | Cesarean delivery | Maternal mortality | |
|---|---|---|---|---|---|---|---|---|---|---|
| Abu 2000 17 | 114 vs 121 | 9/114 vs 4/121 | NR | 3/114 vs 1/121 | 4/114 vs 1/121 | NR | 14/114 vs 2/121 | 9/114 vs 6/121 | 37/114 vs 13/121 | NR |
| Canterino 2004 18 | 441 559 vs 21 169 314 | 3347/441 559 vs 94 770/21 169 314 | NR | NR | NR | NR | NR | NR | NR | NR |
| Jacobsson 2004 19 | 32 867 vs 876 361 | 217/32 867 vs 2785/876 361 | 363/32 867 vs 5246/876 361 | NR | 146/32 867 vs 2461/876 361 | NR | 775/32 867 vs 25 547/876 361 | 2875/32 867 vs 54 309/876 361 | 7790/32 867 vs 90 599/876 361 | NR |
| Dieijomaoh 2006 20 | 168 vs 160 | NR | NR | 4/168 vs 1/160 | NR | NR | NR | NR | 52/168 vs 26/160 | NR |
| Hoffman 2007 21 | 3953 vs 122 449 | 119/3953 vs 2179/122 449 | NR | NR | NR | NR | 368/3953 vs 7491/122 449 | NR | NR | NR |
| Donoso 2008 22 | 217 vs 2 281 774 | 4/217 vs 13 952/2 281 774 | NR | NR | 13/217 vs 17 396/2 281 774 | NR | NR | NR | NR | 0/217 vs 686/2 281 774 |
| Jahromi 2008 23 | 200 vs 200 | 15/200 vs 8/200 | NR | NR | NR | NR | 36/200 vs 9/200 | 62/200 vs 38/200 | 116/200 vs 71/200 | NR |
| Salihu 2008 24 | 14,425 vs 1 299 252 | 141/14 425 vs 5264/1 299 252 | NR | NR | NR | NR | NR | NR | NR | NR |
| Hsieh 2010 25 | 721 vs 39 042 | 12/721 vs 339/39 042 | NR | NR | 8/721 vs 307/39 042 | 71/721 vs 2,482/39,042 | NR | 151/721 vs 4,738/39,042 | 461/721 vs 15,661/39,042 | NR |
| Arnold 2012 26 | 2148 vs 60 203 | 6/2148 vs 67/60 203 | NR | NR | NR | NR | NR | NR | NR | NR |
| Ates 2012 27 | 97 vs 97 | 5/97 vs 0/97 | NR | NR | NR | 5/97 vs 1/97 | NR | 15/97 vs 10/97 | 64/97 vs 54/97 | NR |
| Favilli 2012 28 | 317 vs 312 | 1/317 vs 0/312 | NR | NR | NR | 1/317 vs 1/312 | NR | NR | 138/317 vs 63/312 | NR |
| Kenny 2013 29 | 7066 vs 218 644 | 52/7066 vs 1057/218 644 | NR | NR | 16/7066 vs 485/218 644 | NR | NR | 564/7066 vs 15 600/218 644 | 2397/7066 vs 47 980/218 644 | NR |
| Khalil 2013 30 | 4061 vs 72 097 | 88/4061 vs 270/72 097 | NR | NR | NR | NR | 130/4061 vs 1568/72 097 | 91/4061 vs 1190/72 097 | 1512/4061 vs 18 011/72 097 | NR |
| Ngowa 2013 31 | 585 vs 1816 | 20/585 vs 33/1816 | 20/585 vs 33/1,816 | NR | NR | 82/585 vs 218/1816 | 13/585 vs 14/1816 | 69/585 vs 167/1816 | 102/585 vs 194/1816 | NR |
| Seckin 2013 32 | 190 vs 600 | 15/190 vs 13/600 | NR | 19/190 vs 30/600 | 12/190 vs 16/600 | 18/190 vs 46/600 | 30/190 vs 22/600 | 55/190 vs 120/600 | 112/190 vs 185/600 | NR |
| Timofeev 2013 33 | 6322 vs 197 195 | 46/6322 vs 884/197 195 | 74/6,322 vs 1,540/197,195 | NR | 28/6322 vs 656/197 195 | 966/6322 vs 24 261/197 195 | NR | NR | 2994/6322 vs 54 909/197 195 | NR |
| Laopiboon 2014 34 | 8542 vs 267 749 | 300/8542 vs 5247/267 749 | 383/8,542 vs 7,393/267,749 | NR | NR | 705/8542 vs 16 542/267 749 | NR | 650/8542 vs 16 316/267 749 | 2957/8542 vs 77 140/267 749 | NR |
| Mutz 2014 35 | 2272 vs 52 245 | 18/2272 vs 167/52 245 | 25/2,272 vs 283/52,245 | NR | 7/2272 vs 116/52 245 | NR | NR | 287/2272 vs 4247/52 245 | 813/2272 vs 12 753/52 245 | NR |
| Waldenstrom 2014 36 | 11 430 vs 632 754 | 128/11 430 vs 3741/632 754 | NR | NR | 52/11 430 vs 1951/632 754 | NR | NR | 1338/11 430 vs 59 315/632 754 | NR | NR |
| Traisrislip 2015 37 | 797 vs 18 802 | 105/797 vs 768/18 802 | NR | 68/797 vs 1045/18 802 | NR | NR | NR | 280/797 vs 4323/18 802 | 273/797 vs 3912/18 802 | NR |
| Goisis 2017 38 | 2903 vs 121 195 | NR | NR | NR | NR | NR | NR | 171/2903 vs 4325/121 195 | 563/2903 vs 15 817/121 195 | NR |
| Marozio 2017 39 | 3808 vs 52 403 | NR | 14/3808 vs 157/52 403 | NR | NR | NR | 163/3808 vs 1241/52 403 | 368/3808 vs 2779/52 403 | 1927/3808 vs 18 564/52 403 | NR |
| Ogawa 2017 40 | 29 721 vs 335 696 | NR | 235/29 721 vs 2397/335 696 | NR | NR | NR | 1601/29 721 vs 12 774/335 696 | 5602/29 721 vs 57 319/335 696 | 13 022/29 721 vs 104 133/335 696 | NR |
| Frederiksen 2018 41 | 9743 vs 359 773 | 38/9743 vs 1007/359 773 | NR | NR | NR | NR | NR | 178/9743 vs 4274/359 773 | NR | NR |
| Rydahl 2019 42 | 31 361 vs 1 091 603 | NR | 191/31 361 vs 3637/1 091 603 | NR | NR | NR | 1160/31 361 vs 30 859/1 091 603 | NR | NR | NR |
| Rademaker 2020 43 | 117 740 vs 1 085 447 | NR |
711/117 740 5103/1 085 447 |
NR | NR | 4528/117 740 vs 28 905/1 085 447 | NR | 9156/117 740 vs 76 043/1 085 447 | 24 666/117 740 vs 139 072/1 085 447 | 12/117 740 vs 37/1 085 447 |
| Total | 733 327 vs 30 357 304 | 4686/547 626 (0.85%) vs 132 555/28 206 768 (0.46%) | 2016/233 219 (0.86%) vs 25 789/3 960 515 (0.65%) | 94/1269 (7.41%) vs 1077/19 683 (5.47) |
286/61 199 (0.47%) vs 23 389/ 4 834 704 (0.48%) |
6379/134 514 (4.74%) vs 72 456/ 15 922 258 (4.55%) |
4290/106 860 (4.01%) vs 79 527/2 553 346 (3.11%) |
21 921/232 857 (9.41%) vs 305 119/4 135 042 (7.38%) |
59 996/218 491 (27.46%) vs 599 157/3 555 686 (16.85%) |
12/117 957 (0.01%) vs 723/3 903 189 (0.01%) |
| RR (95% CI) | – | 2.16 (1.86–2.51) | 1.54 (1.33–1.79) | 1.62 (1.31–2.01) | 1.88 (1.28–2.75) | 1.34 (1.24–1.46) | 1.66 (1.35–2.04) | 1.39 (1.29–1.50) | 1.78 (1.57–2.03) | 3.18 (1.68–5.98) |
| I 2 | – | 88% | 100% | 0% | 85% | 73% | 96% | 95% | 100% | 0% |
Abbreviations: CI, confidence interval; IUGR, intrauterine growth restriction; NICU, neonatal intensive care unit; NR, not reported; RR, relative risk.
Data are presented as number in the group of women >40 years versus number in the group of women <40 years.
Boldface data are statistically significant.
FIGURE 3.
Forest plot for the risk of stillbirth in women older than 40 years
FIGURE 4.
Forest plot for the risk of perinatal death in women older than 40 years
FIGURE 5.
Forest plot for the risk of cesarean delivery in women older than 40 years
TABLE 3.
Primary and secondary outcome in subgroup analysis in women >45 yearsa,b
| Stillbirth | Perinatal mortality | IUGR | Neonatal death | NICU admission | Preeclampsia | Preterm birth | Cesarean delivery | Maternal mortality | |
|---|---|---|---|---|---|---|---|---|---|
| Abu 2000 17 | 9/114 vs 4/121 | NR | 3/114 vs 1/121 | 4/114 vs 1/121 | NR | 14/114 vs 2/121 | 9/114 vs 6/121 | 37/114 vs 13/121 | NR |
| Canterino 2004 18 | 120/16,739 vs 94 770/21 169 314 | NR | NR | NR | NR | NR | NR | NR | NR |
| Jacobsson 2004 19 | 14/1205 vs 2785/876 361 | 17/1205 vs 5246/876 361 | NR | 6/1205 vs 2461/876 361 | NR | 26/1205 vs 25 547/876 361 | 113/1205 vs 54 309/876 361 | 365/1205 vs 90 599/876 361 | NR |
| Donoso 2008 22 | 4/217 vs 13 952/2 281 774 | NR | NR | 13/217 vs 17 396/2 281 774 | NR | NR | NR | NR | 0/217 vs 686/2 281 774 |
| Timofeev 2013 33 | 5/391 vs 884/197 195 | 7/391 vs 1540/197 195 | NR | 2/391 vs 656/197 195 | 70/391 vs 24 261/197 195 | NR | NR | 220/391 vs 54 909/197 195 | NR |
| Laopiboon 2014 34 | 65/1527 vs 5247/267 749 | 80/1527 vs 7393/267 749 | NR | NR | 72/1527 vs 16 542/267 749 | NR | 102/1527 vs 16 316/267 749 | 348/1527 vs 77 140/267 749 | NR |
| Marozio 2017 39 | NR | 1/257 vs 157/52 403 | NR | NR | NR | 17/257 vs 1241/52 403 | 48/257 vs 2779/52 403 | 138/257 vs 18 564/52 403 | NR |
| Ogawa 2017 40 | NR | 11/924 vs 2397/335 696 | NR | NR | NR | 73/924 vs 12 774/335 696 | 192/924 vs 57 319/335 696 | 506/924 vs 104 133/335 696 | NR |
| Rademaker 2020 43 | NR | 35/4788 vs 5103/1 085 447 | NR | NR | 284/4788 vs 28 905/1 085 447 | NR | 504/4788 vs 76 043/1 085 447 | 1276/4788 vs 139 072/1085 447 | 2/4788 vs 37/1 085 447 |
| Total |
217/20 193 vs 117 642/25 328 482 |
151/9092 vs 21 836/2 814 851 |
3/114 vs 1/121 |
25/1927 vs 20 514/3 891 419 |
426/6706 vs 69 708/1 550 391 |
130/2500 vs 39 564/1 264 581 |
968/8815 vs 206 772/2 617 777 |
2890/9206 vs 484 430/2 814 972 |
2/5005 vs 723/3 903 189 |
| RR (95% CI) | 2.32 (1.71–3.16) | 1.85 (1.58–2.17) | 3.18 (0.34–30.17) | 3.54 (2.31–5.44) | 1.36 (0.72–2.58) | 1.59 (1.34–1.90) | 1.58 (1.23–2.03) | 1.82 (1.36–2.42) | 11.60 (3.27–41.11) |
| I 2 | 64% | 0% | Not applicable | 84% | 97% | 90% | 92% | 99% | 0% |
Abbreviations: CI, confidence interval; IUGR, intrauterine growth restriction; NICU, neonatal intensive care unit; NR, not reported; RR, relative risk.
Data are presented as number in the group of women >45 years versus number in the group of women <40 years.
Boldface data are statistically significant.
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.
TABLE 4.
| Stillbirth | Perinatal mortality | Neonatal death | NICU admission | Preterm birth | Cesarean delivery | Maternal mortality | |
|---|---|---|---|---|---|---|---|
| Donoso 2008 22 | 4/217 vs 13 952/2 281 774 | NR | 13/217 vs 17 396/2 281 774 | NR | NR | NR | 0/217 vs 686/2 281 774 |
| Rademaker 2020 43 | NR | 4/157 vs 5103/1 085 447 | NR | 19/157 vs 28 905/1 085 447 | 41/157 vs 76 043/1 085 447 | 73/157 vs 139 072/1 085 447 | 2/157 vs 37/1 085 447 |
| Total |
4/217 (1.84%) vs 13,952/2 281 774 (0.50%) |
4/157 (2.54%) vs 5103/1 085 447 (0.47%) |
13/217 (5.60%) vs 17 396/2 2 81 774 (0.62%) |
19/157 (12.10%) vs 28 905/1 085 447 (2.66%) |
41/157 (26.11%) vs 76 043/1 085 447 (7.01%) |
73/157 (46.50%) vs 139 072/1 085 447 (12.81%) |
2/374 (0.53%) vs 723/3 903 189 (0.02%) |
| RR (95% CI) | 3.72 (1.42–9.83) | 5.42 (2.06–14.26) | 9.70 (5.73–16.44) | 4.54 (2.98–6.93) | 3.73 (2.87–4.85) | 3.63 (3.07–4.29) | 42.76 (12.36–147.92) |
| I 2 | Not applicable | Not applicable | Not applicable | Not applicable | Not applicable | Not applicable | 90% |
Abbreviations: CI, confidence interval; NICU, neonatal intensive care unit; NR, not reported; RR, relative risk.
Data are presented as number in the group of women >50 years versus number in the group of women <40 years.
Boldface data are statistically significant.
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 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 years (RR 60.40, 95% CI 13.28–274.74).
TABLE 5.
Indirect meta‐analysis for the risk of stillbirth, cesarean delivery, maternal mortality according to maternal age a
| Women >45 years | Women 40–45 years | Relative risk (95% confidence interval) | |
|---|---|---|---|
| Stillbirth | 105/19 688 (0.53%) | 1508/456 596 (0.33%) | 1.61 (1.33–1.97) |
| Cesarean delivery | 2853/9092 (31.38%) | 53 660/186 741 (28.73%) | 1.09 (1.06–1.13) |
| Maternal mortality | 2/5005 (0.04%) | 10/112 952 (0.01%) | 4.51 (0.99–20.59) |
| Women > 50 years | Women 40–45 years | Relative risk (95% confidence interval) | |
|---|---|---|---|
| Stillbirth | 4/217 (1.84%) | 1508/456 596 (0.33%) | 5.58 (2.11–14.76) |
| Cesarean delivery | 73/157 (46.50%) | 53 660/186 741 (28.73%) | 1.62 (1.37–1.91) |
| Maternal mortality | 2/374 (0.53%) | 10/112 952 (0.01%) | 60.40 (13.28–274.74) |
| Women > 50 years | Women 45–50 years | Relative risk (95% confidence interval) | |
|---|---|---|---|
| Stillbirth | 4/217 (1.84%) | 82/16 739 (0.49%) | 3.76 (1.39–10.17) |
| Cesarean delivery | 73/157 (46.50%) | 1203/4631 (25.98%) | 1.79 (1.50–2.13) |
| Maternal mortality | 2/374 (0.53%) | 31/4631 (0.67%) | 0.80 (0.19–3.32) |
Boldface data are statistically significant.
4. DISCUSSION
4.1. 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.
4.2. Implications
Advanced age is a risk factor for female infertility, pregnancy loss, fetal abnormalities, stillbirth, and obstetric adverse outcomes. Infertility increases from 10% at 34 years old to over 85% by the age of 44. 45 The outcome of in vitro fertilization in women aged 45 years and older who use autologous oocytes is very poor, with an overall delivery rate of 3%. 46
In recent years the mean age of mothers at first birth has increased, with women delaying childbearing to pursue educational and career goals. 47 , 48 As a result, reproductive medicine specialists are facing more patients with age‐related infertility, and maternal‐fetal medicine specialists are treating women with pregnancies complicated by both age and chronic diseases, such as hypertension or diabetes. The media portrayal of a youthful but older woman, able to schedule her reproductive needs and balance family and job, has fueled the myth that “you can have it all,” rarely characterizing 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.
4.3. 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.
CONFLICTS OF INTEREST
The authors report no conflicts of interest.
AUTHOR CONTRIBUTIONS
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.
ACKNOWLEDGMENTS
Open Access Funding provided by Universita degli Studi di Bologna within the CRUI‐CARE Agreement. [Correction added on 09‐May‐2022, after first online publication: CRUI‐CARE funding statement has been added.]
Saccone GP, Gragnano E, Ilardi B, et al. Maternal and perinatal complications according to maternal age: A systematic review and meta‐analysis. Int J Gynecol Obstet. 2022;159:43–55. doi: 10.1002/ijgo.14100
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
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Data Availability Statement
Data sharing is not applicable to this article as no new data were created or analyzed in this study.