Maternal age over 40 years and pregnancy outcome: a hospital-based survey
Luca Marozio, Elisa Picardo, Claudia Filippini, Erika Mainolfi, Paola Berchialla, Franco Cavallo, Annalisa Tancredi & Chiara Benedetto
Luca Marozioa,b, Elisa Picardoa,b, Claudia Filippinia, Erika Mainolfia,b, Paola Berchiallac, Franco
Cavallod, Annalisa Tancredia,b and Chiara Benedettoa,b
aDepartment of Surgical Sciences, University of Turin, Turin, Italy;
bDepartment of Obstetrics and Gynecology 1, University of Turin, Turin, Italy; cDepartment of Clinical and Biological Sciences, University of Turin, Turin, Italy; dDepartment of Public Health and Paediatrics, University of Turin, Turin, Italy
ABSTRACT
Objective: Increased risk for adverse pregnancy outcomes with advancing maternal age has been described but the strength of association remains debated, particularly in presence of confounding
factors such as parity, twin pregnancy and pregnancy from assisted reproductive technologies. The aim of this study was to evaluate pregnancy outcomes in a large cohort of
women aged over 40 years. The hypothesis was that advanced maternal age may be an independent risk factor for adverse pregnancy outcome.
Study design: We reviewed the clinical records of 56,211 women who delivered at Sant’Anna University Hospital, Turin, Italy, in the period between 2009 and 2015. Of these, 3798 women aged over 40 years were divided into two age groups (4044 years and 45 years). Women of
any parity, with singleton or twin pregnancies, or with assisted reproductive technology pregnancies were included. Women aged less than 40 years were considered as controls. Primary
outcome measures were maternal and perinatal complications. Comparisons were performed using Chi-square test and Fisher’s exact test. Univariate analysis and logistic regression analysis were performed to test the possible independent role of maternal age as a risk factor for adverse pregnancy outcome.
Results: Maternal age was an independent risk factor for gestational diabetes (age 40–44 years: odds ratios (OR) 2.10, 95% CI 1.80–2.45; age 45 years: OR 2.83, 95% CI 1.79–4.46) and earlyonset preeclampsia (age 40–44 years: OR 2.10, 95% CI 1.63–2.70; age 45 years: OR 3.16, 95% CI
1.68–5.94). The risk for placenta praevia was higher in the women aged 40–44 years (OR 1.87, 95% CI 1.36–2.57). Neonatal outcomes were similar among groups, except for the rate of birth weight less than 2500 g, which was higher in women aged 40–44 years (OR 1.27, 95% CI 1.12–1.42). However, older women showed an overall higher incidence of preterm birth. Conclusions: Maternal age over 40 years is an independent risk factor for adverse pregnancy outcomes, particularly for the mother. Pregnancies in women over 40 years should be considered at risk and carefully monitored with individualized care protocols.
Introduction
More and more women are delaying first pregnancy or planning another pregnancy after the fourth decade of life, accounting for over 5% of pregnancies in Western countries [1–4]. The trend toward delaying pregnancy is mainly driven by social and cultural changes, a better control of pre-existing chronic diseases, and advances in assisted reproductive technologies (ART) [5–7].
Nonetheless, advanced maternal age is a known risk factor for chromosomal abnormalities of the fetus and early complications of pregnancy such as miscarriage and ectopic pregnancy [5–8]. Studies have reported an association between advanced maternal age and adverse pregnancy outcomes, including low birth weight, preterm birth, fetal death and stillbirth, preeclampsia, abruption, placenta praevia, and maternal death [9–12]. However, the extent to which specific outcomes are related to advanced maternal age and the strength of the association remain controversial due to small study sample size and confounding factors, including parity, twinning, and ART. Moreover, because today’s older mothers often enjoy a higher socioeconomic status and education level and are of lower parity than the mothers over age 40 in the past [11], comparing the datasets of cohorts from 30 or more years ago may lead to conflicting findings.
The aim of the present study was to investigate maternal and perinatal outcomes in a large hospital-based cohort of women over 40 years of any parity, including twin pregnancies and ART pregnancies. Materials and methods
This retrospective cohort study was performed at the Department of Obstetrics and Gynecology, Sant’Anna University Hospital, University of Turin, Italy, which is a regional tertiary referral center. The study included all women who delivered in our department at 24 weeks’ gestation or beyond over the 7-year period from January 2009 to December 2015. The data were obtained from the hospital’s computerized obstetric and neonatal database which includes information on maternal demographics, obstetric history, pregnancy and labor/delivery events, and short-term maternal and neonatal outcome. The validity and accuracy of the database is periodically controlled by a specific internal committee. Data included maternal age, prepregnancy body mass index (BMI, weight in kilograms divided by height in meters squared), parity, pre-existing chronic diseases (particularly chronic hypertension and diabetes), mode of conception, gestational age at delivery, complications of pregnancy, mode of delivery, post-partum complications, and neonatal outcome.
Since many women over 40 years have twin pregnancy and/or ART pregnancies, women with twin pregnancies and ART pregnancies were included in the study.
The primary outcomes were the rate of adverse pregnancy outcomes (maternal and/or perinatal) in women aged 40–44 years and those over 45 years.
Complications of pregnancy included gestational diabetes, late-onset (34 weeks’ gestation) and earlyonset (<33+6 weeks’ gestation) preeclampsia, placenta praevia, abruption, and post-partum
hemorrhage.
Gestational diabetes was diagnosed in previously nondiabetic women according to American Diabetes Association criteria [13]. According to the protocol of our department, gestational diabetes should be tested in all women over 35 years and in women under 35 years with risk factors. In our series, oral glucose tolerance test was performed in 93.3% of women over 35 years and in 79.2% of women under 35 years.
Preeclampsia was diagnosed in previously normotensive and non-proteinuric women according to American College of Obstetricians and Gynecologists criteria [14].
Perinatal outcomes included preterm birth either spontaneous or indicated (<34 weeks’ gestation), birth weight >4000 g,<2500 g, and <1500 g, Apgar score <7 at 5 min, major fetal anomalies, and perinatal death. Perinatal death included stillbirth, defined as the birth of a baby without any signs of life after 24 weeks’ gestation, and neonatal death defined as death before 7 completed days after birth.
The results are presented as frequencies and percentage or as mean ± SD for categorical and continuous variables, respectively. For categorical variables, between-group comparisons were performed using Chi-square or Fisher’s exact test, as appropriate. Univariate analysis was performed using ANOVA to compare the mean values of continuous variables between groups. Logistic
regression models were performed for significantly different variables to assess the possible independent role of maternal age as a risk factor for adverse pregnancy outcomes. The results are presented showing odds ratios (OR) and 95% confidence interval (CI) estimates. All statistical tests were two-sided. p Values of .05 or less were considered statistically significant. Statistical analysis was conducted using the SAS software package, version 9.3 for Windows (SAS Institute, Cary, NC). The study was approved by the local Ethics Committee (8 November 2016, protocol n 0108566). Results
A total of 58,744 women delivered during the study period. Two thousand five hundred and thirty-three pregnancies missing one or more data (4.5%) were excluded from the study; the final analyzed cohort was 56 211 women. Among these, 3798 aged over 40 years at delivery (6.8%) formed the study group (3541 aged 40–44 years, and 257 aged >45 years). Ten women were aged over 50 years. The women aged less than 40 years who delivered during the same period (52413) were considered as controls. Three hundred and thirty-seven women were aged <19 years (0.6%), and although teenage pregnancy is considered a risk factor for adverse pregnancy outcomes, we did not exclude them from the study, due to the very small number of subjects. The demographic and clinical characteristics of the subjects are reported in Table 1. As expected, the percentage of multiparous women was higher in the study group. Also, the rates of twin pregnancies (5.5% versus 4.1%, p<.001) and ART pregnancies (9.0% versus 3.3%, p<.0001) were significantly higher in the study group. Most women aged over 40 years were of Italian origin. No differences in smoking and prepregnancy BMI between the groups were observed.
As compared with the controls, women over 40 years were noted to have higher rates of previous spontaneous miscarriages (35.0% versus 18.1%, p<.001), previous preterm birth (13.8% versus 9.3%, p<.0001), and previous caesarean section (17.9% versus 11.0%, p<.0001). Women over 40 also had higher rates of chronic hypertension (3.5% versus 2.0%, p<.001) and pre-existing diabetes (2.3% versus 1.6%, p<.001) (data not shown in table).
A significantly higher incidence of pregnancy and delivery complications was observed in the study group (Table 2). The incidence of gestational diabetes, preeclampsia, and placenta praevia in the women over 40 years was significantly higher than in the control group. Subgroup analysis of women aged 40–44 years compared to women >45 years revealed that the incidence of gestational diabetes (p<.001) and earlyonset preeclampsia (p<.0001) was higher in those over age 45 years. No
differences in the rates of placental abruption and post-partum hemorrhage were observed. The rates of caesarean delivery not in labor were significantly higher in the women aged 40–44 years and those over 45 years than in the control group (41.2% versus 44.8% versus 25.0%, respectively; both
p<.001). Most caesarean sections not in labor (67%) were done for obstetrical and/or medical indications (prior caesarean section or prior myomectomy, fetal malpresentation, placenta praevia, monochorionic twin pregnancy, early-onset preeclampsia, fetal growth restriction, failed induction); however, in 33% of cases, caesarean section was indicated by advanced maternal age itself. Among the indications for caesarean section not in labor, the rate of failed induction was higher in the older women (3.5% in women aged <40 years; 7.9% in those aged 40–44 years; 13.3% in those aged >45 years). No differences in the rates of caesarean section during labor and instrumental vaginal delivery were observed.
Table 3 presents the perinatal outcomes. The rates of preterm birth at <34 weeks’ gestation and low birth weight newborns were significantly higher in the study groups. The risk of preterm birth and of birth weight <2500 g was particularly high in women aged over 45 years. The rates of spontaneous preterm birth were similar across groups (8% in those aged <40 years; 9% in those aged 40–44 years; 11% in those aged >45 years). No differences in major fetal anomalies, Apgar score, and perinatal mortality were observed.
We then divided the study group into three subgroups composed of women with singleton pregnancies, twin pregnancies, or ART pregnancies, and calculated the odds ratios for GDM, early-onset preeclampsia, placenta praevia, preterm birth <34 weeks’ gestation, and birth weight <2500 g. Women aged <40 years with singleton pregnancies, twin pregnancies, and ART pregnancies were considered as the reference groups. In women aged over 40 years with singleton pregnancy, the risk of adverse maternal and perinatal outcomes was significantly higher (Table 4), but it was not related to parity. In women with twin pregnancy (Table 5), the major risk linked to advanced maternal age was for developing early-onset preeclampsia.
In ART pregnancies (Table 6), advanced maternal age was a significant risk factor for earlyonset preeclampsia and placenta praevia. Parity did not affect the outcomes in ART pregnancies.
Unfortunately, we cannot provide data on the outcome of pregnancy in women over 40 years who underwent oocyte-donation or embryo-donation because the procedure was not allowed in Italy during the study period and because there was no specific field for this information on the clinical records. Nine% of women aged 40–44 years and 31% of those aged >45 years stated they had received oocyte-donation at medical history collection, but it is reasonable to assume that the true percentage is higher. Table 7 shows the results of multivariate logistic regression adjusted for parity, twin pregnancy, and ART pregnancy. Advanced maternal age was an independent risk factor for gestational diabetes and earlyonset preeclampsia. Maternal age was an independent risk factor also for placenta praevia and low birth weight in women aged 40–44 years.
Discussion
The rate of pregnancies in advanced maternal age has steadily increased and may increase in the years to come. Most of the studies on maternal and perinatal outcomes of pregnancies in women aged over 40 years carried on small sample populations [1,2,5,9,12,15–22] have reported a high rate of pregnancy complications; however, the specific outcomes related to advanced maternal age and the strength of the association remain debated. Our study, which involved a large series of women from a single center, provides evidence that advanced maternal age is a strong risk factor for adverse pregnancy outcome, and that the extent of the risk increases with increasing maternal age. Since our groups have been recruited in a tertiary referral centre, the prevalence of pregnancy complications may be higher than in the general population.
We observed a significant age-related increase in the incidence of gestational diabetes and
hypertensive disorders of pregnancy, and of early-onset preeclampsia in particular. This observation is shared by several previous studies [1,16,17,20,22]. The incidence of earlyonset preeclampsia is closely related to maternal age, with a two-fold and four-fold increase in women aged 40–44 years and 45 years, respectively, as compared with the control group. Although the prevalence of chronic hypertension in our series was significantly higher in older women than in controls (p<.0001), the rate of preeclampsia superimposed to chronic hypertension did not differ between groups, suggesting that the high incidence of preeclampsia is not sustained by chronic hypertension. A plausible explanation for the higher risk of developing gestational hypertension and preeclampsia is a possible age-related dysfunction of the vascular endothelium, which is unable to cope with the physiologic hemodynamic changes of pregnancy. This hypothesis is also suggested in a recent study by Grotegut et al. [23] on a very large population in the USA. The study attempted to explain the finding of a high incidence of severe cardiovascular complications during pregnancy in women aged 45 years and older, who were more likely to die at the time of delivery, though the absolute risk was low. The significant correlation we found between advanced maternal age and gestational diabetes may be explained by potential impairment of carbohydrate metabolism associated with aging. The high rate of gestational diabetes does not seem to be related to maternal weight, since no
differences in BMI were found between the groups.
Moreover, women with pre-existing diabetes were not included in the group diagnosed with gestational diabetes. We observed a higher incidence of placenta praevia in women over 40. This finding is shared by those reported by Timofeev et al. [10] and Grotegut et al. [23], and corroborates observations by Saleh Gargari et al. [24] that the most important risk factor for the occurrence of placenta praevia was advanced maternal age. Unlike Timofeev et al. [10], we did not observe an increased risk of placental abruption and postpartum hemorrhage.
Moreover, pregnant women aged over 40 years are more likely to undergo a caesarean section not in labor. In our series, caesarean section was performed in 41.2% of women aged 40–44 years and in 44.8% of those aged 45 years and older. While most caesarean sections not in labor were done for obstetrical and/or medical indications, in one-third of cases, the indication was advanced maternal age itself. The high rate of caesarean section we observed is in line with published data
[1,10,11,16,17,23]. It remains questionable, however, whether advanced maternal age can be considered an indication for caesarean section. Our finding of more frequent caesarean section for failed induction with increasing maternal age suggests that in women over 40, and particularly in those over 45, without spontaneous onset of labor at term, the option of elective caesarean section instead of induction of labor should be investigated. Surprisingly, we did not observe a higher rate of caesarean section in labor or instrumental delivery in women over 40, although we expected a higher risk of failure to progress in labor.
In our population sample, advanced maternal age was strictly related with low birth weight and preterm birth. Up to 20% of newborns from mothers over age 45 years weighed less than 2500 g and were delivered before 34 weeks’ gestation. Since the rate of spontaneous preterm birth was similar between groups, the higher rate of low birth weight and preterm birth was mainly due to preterm birth indicated for pregnancy complications. Although Apgar scores and perinatal mortality did not differ between the groups, our data contrast with those of Kanungo et al. [9] who found that among preterm newborns the odds of survival without major morbidity improved with increasing maternal age, in what they called a “social paradox”.
At the time of writing, we do not have the results of long-term follow-up of the infants born to the women in our series.
Subgroup analysis performed according to parity (singleton pregnancies, twin pregnancies, and ART pregnancies) revealed that advanced maternal age is a strong risk factor for pregnancy complications particularly in singleton pregnancies, in both nulliparous and pluriparous women, whereas the strength of association was weaker in twin pregnancies and ART pregnancies, regardless of parity (Tables 4–6). This finding suggests that twin pregnancy and ART pregnancy are strong risk factors in themselves, masking or reducing the weight of advanced maternal age, as reported in previous studies [25,26]. Multivariate logistic analysis adjusted for parity, twin pregnancy, and ART pregnancy showed that advanced maternal age is an independent risk factor for developing pregnancy
complications, i.e. gestational diabetes, early-onset preeclampsia, placenta praevia, and low birth weight. This higher risk should not be underestimated, since even a healthy woman becoming pregnant at age over 40 years is at high risk of complications.
In conclusion, our findings demonstrate that pregnant women over 40 years are at higher risk for developing complications and should, therefore, be managed with appropriate care protocols, particularly in cases of twin pregnancy and/or ART pregnancy. Follow-up data on the health of these women and their babies later in life need to be carefully recorded.
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Table 1. Demographic and clinical characteristics of the subjects included in the study. Characteristic <40 years No. 52,413 (93.2%) 40–44 years No. 3541 (6.3%) >45 years No. 257 (0.5%) p Value
Maternal age (year, mean ± SD) 31.6 ± 4.6 41.1 ± 1.2 48.9 ±
2.3 <.0001
Gestational age at delivery (weeks,
mean ± SD) 38.5 ± 2.2 38.2 ± 2.3 37.7 ±2.7 <.0001
Italian origin no. (%) 41,465
(79.1) 3161 (89.3) (90.3)232 <.0001
Smokers no. (%) 4497 (8.6) 320 (9.0) 17 (6.6) NS
Prepregnancy BMI (kg/m2, mean ±
SD) 24.1 ± 71 23.8 ± 4.6 24.4 ±5.6 NS
Primiparous no. (%) 29,927
(57.1) 1446 (40.8) (48.6)125 <.0001
Twin pregnancy no. (%) 2137 (4.1) 171 (4.8) 39
(15.2) <.0001
ART pregnancy no. (%) 1704 (3.3) 280 (7.9) 61
(23.7) <.0001
Table 2. Pregnancy and delivery outcomes in the study groups. <40 years No. 52,413 (93.2%) Outcome No. (%) 40–44 years No. 3541 (6.3%) No. (%) >45 years No. 257 (0.5%) No. (%) p Value Gestational diabetes 1430 (2.7) 203 (5.7) 21 (8.2) <.000 1 Preeclampsia 1241 (2.4) 147 (4.2) 16 (6.2) <.000 1 Late-onset preeclampsia 925 (1.7) 108 (3.0) 8 (3.1) .0001 Early-onset preeclampsia 316 (0.6) 39 (1.1) 8 (3.1) <.000 1 Eclampsia 59 (0.1) 7 (0.2) 1 (0.4) NS Preeclampsia superimposed to CH 63 (0.1) 6 (0.2) 1 (0.4) NS Placenta praevia 321 (0.6) 46 (1.3) 3 (1.2) <.000 1 Placental abruption 314 (0.6) 35 (1.0) 1 (0.4) NS Postpartum hemorrhage 339 (0.7) 28 (0.8) / NS
Caesarean delivery not in labor 13,078
(25.0) 1458 (41.2) (44.8)115 <.0001
Caesarean delivery in labor 5486 (10.4) 331 (9.4) 23 (9.0) NS
Instrumental delivery (vacuum) 1310 (2.5) 57 (1.6) 4 (1.6) NS
Table 3. Neonatal outcomes in the study groups. Outcomes <40 years No. 52,413 (93.2%) 40–44 years No. 3541 (6.3%) >45 years No. 257 (0.5%) p Value
Birth weight, singleton (g,
mean ± SD) 3202 ± 543 3154 ±573 3114 ±590 NS
Birth weight, twin (g, mean ±
SD) 2180 ± 574 2246 ±551 2155 ±578 NS
Birth weight >4000 g, no. (%) 2415 (4.6) 159 (4.5) 12 (4.7) NS
Birth weight <2500 g, no. (%) 5174 (9.9) 424
(12.0) (19.8)51 <.0001
Birth weight <1500 g, no. (%) 1011 (1.9) 76 (2.1) 11 (1.0) .0173
Preterm birth (<34 weeks), no.
(%) 2779 (5.3) 320 (9.0) (18.6)48 <.0001
Apgar score, < 7 at 5 min, no.
(%) 838 (1.6) 81 (2.3) 7 (2.7) NS
Major fetal anomalies, no. (%) 516 (1.0) 39 (1.1) 4 (1.6) NS
Perinatal mortality, no. (%) 157 (0.3) 13 (0.4) 1 (0.4) NS
SD: standard deviation; NS: not significant.
Table 4. Maternal and perinatal outcome in women aged over 40 years with singleton pregnancies.
Nulliparousa
Pluriparousb
40–44 years 45 years 40–44 year <=
45 years
(No. 1115) (No. 51) (No. 3167) (No. 122)
ADJ OR (95% CI) ADJ OR (95% CI) ADJ OR (95% CI) ADJ OR (95% CI)
Gestational diabetes 1.41 (1.29–1.55) 1.46 (1.30–1.63) 2.22 (1.52–3.23) 2.58
(1.66–3.88)
Early onset preeclampsia 1.75 (1.37–2.23) 1.76 (1.28–2.39) 3.38 (1.49–7.66) 1.33
(0.15–4.84)
Placenta praevia 2.11 (1.56–2.85) 1.82 (1.27–2.54) 4.10 (1.51–11.13) 5.19
(1.71–12)
Preterm delivery (<34 weeks) 1.25 (1.07–1.46) 1.25 (1.03–1.49) 2.23 (1.27–3.94) 2.01
(0.92–3.80)
Birth weight <2500 g 1.26 (1.13–1.41) 1.31 (1.15–1.50) 1.85 (1.18–2.90) 1.89
(1.07–3.12)
ADJ: adjusted for ART pregnancy.
aReference group: singleton pregnancies in nulliparous women aged less than 40 years (no. 25,197). bReference group: singleton pregnancies in pluriparous women aged less than 40 years (no. 26,683).
Table 5. Maternal and perinatal outcome in women aged over 40 years with twin pregnancies.
Nulliparousa Pluriparousb
<=40 years <=40 years
(No. 105) (No. 131)
ADJ OR (95% CI) ADJ OR (95% CI)
Gestational diabetes 1.45 (0.63–3.32) 0.25 (0.03–1.86)
Early-onset preeclampsia 3.45 (2.12–5.62) 1.88 (0.76–4.69)
Placenta praevia 0.47 (0.06–3.60) 3.60 (0.36–34.71)
Preterm delivery (<34 weeks) 0.95 (0.63–1.43) 1.14 (0.66–2.00)
Birth weight <2500 g 0.75 (0.50–1.11) 1.14 (0.71–1.83)
ADJ: adjusted for ART pregnancy.
aReference group: twin pregnancies in nulliparous women aged less than 40 years (no. 1141).
bReference group: twin pregnancies in pluriparous women aged less than 40 years (no. 1022). Due
to the small number of subjects >45 (no. 19), women over 40 have been grouped together to make logistic regression possible.
Table 6. Maternal and perinatal outcome in women aged over 40 years with pregnancies from ART.
Nulliparousa Pluriparousb
40–44 year >= 45 years 40–44 years >=45 years
(No. 193) (No. 33) (No. 137) (No. 28)
ADJ OR (95% CI) ADJ OR (95% CI) ADJ OR (95% CI) ADJ OR
(95% CI) Gestational diabetes 1.20 (0.72–2.01) 0.89 (0.26–3.01) 0.67 (0.35–1.28) 2.13 (0.85–5.29) Early-onset preeclampsia 3.44 (1.49–7.92) 16.69 (6.17–45.15) 1.09 (0.43–2.71) 1.32 (0.86–4.87) Placenta praevia 5.19 (2.31–11.65) 1.79 (0.22–14.47) 2.51 (0.50–12.61) 8.64 (1.38–54.03)
Preterm birth (<34 weeks) 1.17 (0.76–1.81) 2.06 (0.92–4.58) 0.75 (0.38–1.37) 0.39 (0.16–1.01)
Birth weight (<2500 g) 1.43 (1.00–2.05) 2.34 (1.14–4.79) 0.91 (0.47–1.71)1.09 (0.50–2.39)
ADJ: adjusted for twin pregnancy; ART: assisted reproduction technologies.
aReference group: ART pregnancies in nulliparous women aged less than 40 years (no. 585). bReference group: ART pregnancies in pluriparous women aged less than 40 years (no. 340).
Table 7. Multivariate logistic regression analysis for the listed outcomes among women aged 40–44 years and 45 years and older compared to women aged less than 40 years. Outcomes 40–44 years, no. 3541 ADJ OR (95% CI) 45 years, no. 257 ADJ OR (95% CI) Gestational diabetes 2.10 (1.80–2.45) 2.83 (1.79–4.46) Early-onset preeclampsia 2.10 (1.63–2.70) 3.16 (1.68–5.94) Placenta praevia 1.87 (1.36– 2.57) 1.33 (0.42–4.22) Preterm birth <34 weeks 1.18 (0.98–1.42) 1.34 (0.82–2.21)
