Obstetrics & Gynecology:
The Perinatal Effects of Delayed Childbearing
Joseph, K S. MD, PhD1; Allen, Alexander C. MD1; Dodds, Linda PhD1; Turner, Linda Ann PhD3; Scott, Heather MD2; Liston, Robert MB4
From the 1Perinatal Epidemiology Research Unit, Departments of Obstetrics and Gynaecology and Pediatrics, and the 2Division of Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, Dalhousie University, and the IWK Health Centre, Halifax, Nova Scotia, Canada; 3the Centre for Studies in Family Medicine, the University of Western Ontario, London, Ontario, Canada; and 4the Department of Obstetrics and Gynaecology, Children's & Women's Health Centre of British Columbia and the University of British Columbia, Vancouver, British Columbia, Canada.
Drs. Joseph and Dodds are supported by Clinical Scholar awards from the Dalhousie University Faculty of Medicine. Dr. Joseph is a Peter Lougheed New Investigator and Dr. Dodds is a New Investigator of the Canadian Institutes of Health Research. This study was funded by a grant from the Canadian Institutes of Health Research (MOP-43992).
The authors thank the Small Area and Administrative Data Division of Statistics Canada, especially Pat Grainger, Eric Olson, Jeffrey Smith, Linda Standish, Bill Steele, Tom Swoger and Kathleen Trudeau, for database linkage and analysis. They also thank the Reproductive Care Program of Nova Scotia for access to the data.
Address reprint requests to: Dr. K. S. Joseph, Division of Neonatal Pediatrics, IWK Health Centre, 5980 University Avenue, Halifax, Nova Scotia, Canada B3K 6R8; e-mail: email@example.com.
Received November 17, 2004. Received in revised form February 25, 2005. Accepted March 3, 2005.
OBJECTIVE: To determine if the rates of pregnancy complications, preterm birth, small for gestational age, perinatal mortality, and serious neonatal morbidity are higher among mothers aged 35–39 years or 40 years or older, compared with mothers 20–24 years.
METHODS: We performed a population-based study of all women in Nova Scotia, Canada, who delivered a singleton fetus between 1988 and 2002 (N = 157,445). Family income of women who delivered between 1988 and 1995 was obtained through a confidential linkage with tax records (n = 76,300). The primary outcome was perinatal death (excluding congenital anomalies) or serious neonatal morbidity. Analysis was based on logistic models.
RESULTS: Older women were more likely to be married, affluent, weigh 70 kg or more, attend prenatal classes, and have a bad obstetric history but less likely to be nulliparous and to smoke. They were more likely to have hypertension, diabetes mellitus, placental abruption, or placenta previa. Preterm birth and small-for-gestational age rates were also higher; compared with women aged 20–24 years, adjusted rate ratios for preterm birth among women aged 35–39 years and 40 years or older were 1.61 (95% confidence interval [CI] 1.42–1.82; P < .001) and 1.80 (95% CI 1.37–2.36; P < .001), respectively. Adjusted rate ratios for perinatal mortality/morbidity were 1.46 (95% CI 1.11–1.92; P = .007) among women 35–39 years and 1.95 (95% CI 1.13–3.35; P = .02) among women 40 years or older. Perinatal mortality rates were low at all ages, especially in recent years.
CONCLUSION: Older maternal age is associated with relatively higher risks of perinatal mortality/morbidity, although the absolute rate of such outcomes is low.
LEVEL OF EVIDENCE: II-2
In 1950, Waters and Wagner1 coined the hapless term “elderly primigravida” as a descriptor of obstetric risk. Five decades later, older maternal age is increasingly an issue of perinatal concern at the individual, clinical, and population health level. In Canada,2–4 live births to women aged 30–34 years increased from 18.9% of all live births in 1982 to 30.6% in 2002. The relative change in live births to women 35 years or older was even larger, with the proportion of live births to women 35–39 years increasing from 4.7% in 1982 to 14.1% in 2002 and those among women 40 years of age or older increasing from 0.6% to 2.6%. Similar increases in older maternal age categories have been observed in other industrialized countries.5,6
These changes in childbearing patterns have occurred, to a large extent, because of the expanded professional role of women in society and against a backdrop of dramatic improvements in obstetric and neonatal care. Nevertheless, studies have shown clear differences between the psychological experiences of younger and older women in labor. Older women typically believe that their age makes their infant vulnerable.7 Although there is clear justification for concern with regard to some maternal age effects (eg, for the elevated risk of Down syndrome and other trisomy8), information with regard to several other outcomes (eg, perinatal mortality) is inconsistent. Several studies have shown that older maternal age is associated with a significantly increased risk for perinatal death,9–20 although several other studies21–29 have failed to show such an increase in mortality. Both positive and negative studies included hospital and population-based investigations of differing size, with varying emphasis on control for confounding (by other maternal characteristics such as prepregnancy weight, smoking, economic status, and obstetric history) and on clinical mechanisms and outcomes.
We performed a comprehensive population-based study of the perinatal effects of delayed childbearing which examined pertinent clinical mechanisms and outcomes after carefully controlling for potential confounding due to marital status, smoking, pre-pregnancy weight, economic status, parity, prenatal class attendance, previous cesarean delivery, previous low birth weight, previous perinatal death, and time period.
MATERIALS AND METHODS
The study population included all women residents of Nova Scotia, Canada, who delivered a singleton fetus between 1988 and 2002. Information on the pregnancy, labor and delivery, and neonatal follow-up of these women was obtained from the Nova Scotia Atlee Perinatal Database. This population-based database contains detailed clinical information extracted from antenatal and medical charts by trained personnel using standardized forms. An ongoing data quality assurance program, which performs periodic abstraction studies, and validation studies30 show that the information in the database is reliable. Live births and stillbirths with a birth weight of less than 500 g or a gestational age of less than 20 weeks were excluded to avoid temporal and regional differences in birth registration.
We categorized maternal age into 5-year age groups (< 20, 20–24, 25–29, 30–34, 35–39, ≥ 40 years) and contrasted outcome rates in older maternal age categories with outcomes rates among women aged 20–24 years of age. Perinatal mortality (excluding deaths due to congenital anomalies) or serious neonatal morbidity was the primary outcome; perinatal mortality encompassed fetal and neonatal death, whereas serious neonatal morbidity included a 5-minute Apgar score of ≤ 3, severe respiratory distress syndrome (requiring assisted ventilation), bronchopulmonary dysplasia, intraventricular hemorrhage (grade 3 or 4), periventricular leukomalacia, severe retinopathy of prematurity, and necrotizing enterocolitis.
Complications of pregnancy (ie, hypertensive disorders, diabetes mellitus, other chronic medical disease, placenta previa, placental abruption, and gestational diabetes) were studied as intermediate outcomes in the causal pathway between older maternal age and perinatal mortality/morbidity. Hypertensive disorders included chronic hypertensive disease, severe pregnancy-induced hypertension, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, and eclampsia. Other chronic medical disease included cardiovascular disease, renal disease, gastrointestinal disorders, major psychiatric illness, neurologic disorders, endocrine disease, neoplastic disease, and blood dyscrasias.
We also examined the relationship between older maternal age and both preterm birth and fetal growth restriction by considering very preterm birth (< 32 weeks), preterm birth (< 37 weeks), and small-for-gestational age (< 10th percentile and < 3rd percentile of birth weight for gestational age of a Canadian standard31) rates. The association between maternal age and rates of obstetric intervention, including rates and indications for labor induction and cesarean delivery, was assessed. Gestational-age–specific rates of labor induction and/or cesarean delivery and rates of perinatal mortality/morbidity at different maternal ages were contrasted using the fetuses-at-risk approach.32–34
The perinatal effects of older maternal age were quantified after controlling for potential confounders such as marital status (single, married, common law, other), smoking status at delivery (0, 1–9 cigarettes, ≥ 10 cigarettes), pre-pregnancy weight (< 55, 55–59, 60–69, ≥ 70 kg), economic status (see below), parity (nulliparous, 1, 2, ≥ 3), prenatal class attendance (yes/no), and period (1988–1991, 1992–1994, 1995–1997, 1998–2002). Previous cesarean delivery (yes/no), previous low-birth-weight infant (yes/no), and previous perinatal death (yes/no) were other potential confounders considered among multiparous women. Complications of pregnancy, preterm birth, and small-for-gestational age were considered to be intermediate steps in the causal pathway between older maternal age and perinatal mortality/morbidity and not included as independent variables in models of perinatal mortality/morbidity.35
Information regarding the economic status of study subjects and their families was obtained through a linkage between the Nova Scotia Atlee Perinatal Database and the federal income tax (T1) Family Files for 1988–1995 maintained by the Small Area and Administrative Data Division of Statistics Canada, Ottawa. Permission to link the two databases was obtained for the years 1988–1995 and linkage was performed using a combination of deterministic and probabilistic methods. The confidential linkage and economic analyses were performed by Small Area and Administrative Data Division personnel in secure Small Area and Administrative Data Division offices and study investigators did not have access to income tax Family File records of individuals at any point. Tabular analyses involving income data that resulted in cells with counts below 15 were suppressed and all counts were rounded to the nearest 10.
Income information was obtained for each woman and her family in the year of delivery. Family income was adjusted for family size by dividing total family income by the number of members (oldest adult received a weight of 1, other members 16 years or older and the first child in a single parent family received a weight of 0.4, and children under 16 years received a weight of 0.3) and for inflation (all income in 1988 Canadian dollars). For analysis purposes, size-adjusted family income was categorized into quintiles (< $7,500, $7,500–$12,199, $12,200–$17,199, $17,200 –$23,699 and ≥ $23,700). In addition to family income, we also modeled (registered retirement) investments made in the year of delivery (yes/no) as an additional measure of socioeconomic status. Supplementary analyses were done using after-tax income (instead of pretax income) and the correlation between family income in the year before and during which the delivery occurred was also assessed.
The effects of maternal age were modeled using logistic regression; odds ratios obtained from such regression were taken to approximate rate ratios because all outcomes were relatively rare. Analyses were performed separately for all women and for the subset of nulliparous women. Variance estimates were adjusted (using SAS Proc Genmod, SAS 8.2; SAS Institute Inc, Cary, NC) to account for the potential nonindependence of observations because women could have had more than one delivery during the study period. Results of regression (ie, adjusted odds ratios) were not rounded or suppressed (as done for tabular analyses involving information on income status). Regression models based on information available before pregnancy were used to develop a simple scoring system to predict the risk of perinatal death (excluding death due to congenital anomalies).36 The contribution of older maternal age to maternal complications of pregnancy and to perinatal mortality and serious neonatal morbidity (ie, the population attributable proportion) was calculated using the standard formula for multicategory determinants.37 The confidential linkage between the Nova Scotia Atlee Perinatal Database and the income tax Family Files was approved by the Policy Committee at Statistics Canada. The study was approved by the Dalhousie University Research Ethics Board.
There were 157,445 singleton deliveries in Nova Scotia between 1988 and 2002, of which 69,824 were to nulliparous women. Older women were more likely to be married, affluent, and weigh 70 kg or more but less likely to be nulliparous and to smoke (Table 1). Nulliparous older women were more likely to attend prenatal class. Multiparous older women were more likely to have had a previous cesarean delivery, previous low birth weight infant or previous perinatal death.
Pregnancy complications such as hypertensive disorders, diabetes mellitus, other chronic medical disease, placenta previa, and placental abruption were more common among older women, with significant excess risks being evident among women 25–29 years and older (Table 2). Rates of gestational diabetes and adjusted rate ratios were also higher among older women (data not shown). Similar relationships between maternal age and each pregnancy complication were also seen among nulliparous women.
The rates of labor induction and cesarean delivery were higher among older women (Table 3). The indications underlying the higher rates of labor induction among nulliparous older women (35–39 years and ≥ 40 vs 20–24 years) included post-dates, hypertensive disorders, premature rupture of membranes, diabetes, oligohydramnios and other indications. Higher rates of cesarean delivery among older women were for indications such as dystocia, suspected fetal distress, previous cesarean delivery (among multiparous women), breech, hypertension, placenta previa, other malpresentation and other indications. Gestational age-specific rates of obstetric intervention (labor induction and/or cesarean delivery) are shown in Figure 1. Rates of forceps or vacuum use were approximately 2-fold higher among nulliparous older women (Table 3).
Adjusted rate ratios for preterm birth (< 37 weeks) were significantly higher among mothers 25–29 years of age and older, while adjusted small-for-gestational age (< 10th percentile) rates were significantly higher among women 30–34 years or older (relative to mothers 20–24 years, Table 4). Adjusted preterm birth rates were 80% higher (P < .001) and adjusted small-for-gestational age (< 10th percentile) rates were 66% higher (P < .001) among women ≥ 40 years. Rates of preterm birth and small-for-gestational age among nulliparous women were also significantly higher among women 25–29 years, 30–34 years and 35–39 years compared with women 20–24 years. Small numbers of nulliparous women precluded statistically significant differences for preterm birth in the ≥ 40 years category.
Adjusted perinatal mortality rates (excluding death due to congenital anomalies) were 63% (P = .04) and 183% (P = .01) higher among women 35–39 years and ≥ 40 years, respectively, than among women 20–24 years (Table 5). Compared with women 20–24 years, adjusted perinatal mortality/morbidity rates were 46% (P = .007) higher among women 35–39 years and 95% (P = .02) higher among women ≥ 40 years (Table 5). Table 6 provides a simple scoring system for estimating the risk of perinatal death (excluding death due to congenital anomalies) and a summary of various risks based on maternal characteristics.
In 1988–91, 2.6% and 0.7% of perinatal mortality/morbidity was attributable (population attributable proportion) to women aged 35–39 years and ≥ 40 years, respectively. This fraction increased to 4.7% and 1.5% in 1998–2002. The contribution of older maternal age to maternal complications of pregnancy was higher; in 1988–91, 7.5% and 1.8% of hypertensive disorders were attributable to women 35–39 years and ≥ 40 years, respectively, and these proportions increased to 13.6% and 4.0% in 1998–2002. The proportion of cases of placenta previa attributable to women 35–39 years of age increased from 18.5% in 1988–91 to 33.4% in 1998–2002, while those due to women ≥ 40 years increased from 3.5% to 7.7%.
Perinatal mortality and perinatal mortality/morbidity rates among women without pregnancy complications (4.2 per 1,000 total births and 8.9 per 1,000 total births, respectively) were substantially lower than among women with pregnancy complications (16.1 and 46.7 per 1,000 total births, respectively). Older maternal age was associated with significantly higher rates of perinatal mortality/morbidity even among women without pregnancy complications (adjusted rate ratio 1.48, 95% CI 1.05 to 2.10, P = .03 for women 35–39 years and 2.16, 95% CI 1.11 to 4.19, P = .02 for women ≥ 40 years, compared with women 20–24 years). Perinatal mortality (excluding death due to congenital anomalies) rates declined substantially by period among all maternal age categories; the adjusted rate ratio for 1998–2002 vs 1988–91 was 0.59 (95% CI 0.44 to 0.79, P < .001). Temporal changes in rates of perinatal mortality/morbidity were not statistically significant (adjusted rate ratio 1998–2002 vs 1988–91 = 0.89, 95% CI 0.75 to 1.05, P = .18) and the relationship between older maternal age and perinatal mortality/morbidity was not modified by period.
Analyses carried out to additionally control for potential confounding by economic status (family income quintile and investments) did not substantially alter the effect of maternal age. For instance, the adjusted rate ratios expressing the effect of maternal age (35–39 years and ≥ 40 years vs 20–24 years) on preterm birth were 1.50 (95% CI 1.24 to 1.80) and 1.86 (95% CI 1.24 to 2.79), respectively, before control for economic status (i.e., adjusted for parity, prepregnancy weight, parity, prenatal class attendance, previous low birth weight and period) and 1.54 (95% CI 1.27 to 1.87) and 1.91 (95% CI 1.27 to 2.88), respectively, after additional adjustment for economic status (data for 1988–95 only).
Supplementary analyses yielded essentially the same results. The effect of additional control for prepregnancy smoking status and smoking at the first prenatal visit did not alter the results. The maternal age distribution of women with missing information on some determinants (who were not included in the final regression models) was similar to that of all women in the study. Crude and partial models showed that the relationships between maternal age and common outcomes (pregnancy complications, preterm birth, etc) among women with missing information were similar to those seen among women with no missing information.
Our study shows that older maternal age is associated with substantial increases in hypertensive disorders, diabetes mellitus, other chronic medical disease, placenta previa, placental abruption and gestational diabetes. The increased frequency of these pregnancy complications at older maternal ages and other mechanisms are responsible for higher rates of preterm birth, fetal growth-restriction, perinatal mortality and serious neonatal morbidity. Adjusted perinatal mortality/morbidity rates were 1.46 (95% CI 1.11 to 1.92) times higher among women aged 35–39 years and 1.95 (95% CI 1.13–3.35) times higher among women 40 years or older, compared with women 20–24 years of age.
Rates of labor induction and cesarean delivery were also higher among older mothers (Figure 1); observed differences in perinatal mortality/morbidity by maternal age may have been larger but for such intervention. The large excess risk of pregnancy complications (eg, approximately 2- to 6-fold increase in hypertensive disorders, placenta previa among women 40 years or older versus women 20–24 years) and the relatively smaller excess risk of perinatal mortality/morbidity (approximately 2-fold increase) are probably reflections of the efficacy of obstetric intervention. It is noteworthy that relative to women 20–24 years, significantly higher rates of pregnancy complications (Table 2), preterm birth, and small-for-gestational age (Table 4) were evident among women 25–29 years or 30–34 years and older. The lack of a significant increase in perinatal mortality/morbidity among women aged 25–29 and 30–34 years may be a consequence of the relative paucity of information in these age categories (ie, inadequate study size given lower outcome frequencies and a smaller effect size).
In our study population, about 10% of births and 13% of perinatal mortality/morbidity occurred among women 35 years of age and older. The relationship between maternal age and various behavioral and clinical risk factors for adverse perinatal outcomes (Table 1) is striking, however, and underscores the need for careful control of confounding in studies on older maternal age. The higher rates of other chronic medical disease among older women may partly represent increases in the fecundity of older women with chronic illnesses in recent years. Although the older maternal age effect on perinatal mortality/morbidity is mediated partly through higher rates of recognized pregnancy complications, our study shows that other mechanisms operate as well. Adverse outcome rates were higher even among older women without pregnancy complications.
The limitations of our study include an inability to control for educational status. Older women are likely to have had more years of education than younger women and educational status is associated with perinatal outcomes.3 This limitation may not be a serious one, however, because we did adjust for various correlates of education including marital status, attendance at prenatal classes, smoking status, pre-pregnancy weight, parity, and economic status. Another minor limitation of our study pertains to the noninclusion of home births, which are not routinely recorded in the Nova Scotia Atlee Perinatal Database. However, such births constituted less than 0.5% of births in Nova Scotia during the study period and their inclusion is unlikely to have altered our results. Other limitations of our study include a lack of information on assisted reproduction and some missing values for risk factors that were included in regression models. Nevertheless, our final regression models were based on 108,846 women, and supplementary analyses suggest that the missing information is unlikely to have altered our estimates of effect substantially.
It has been said that older women can be “cautiously optimistic” about the perinatal risks associated with delayed childbearing.38 Despite the relatively higher rates of perinatal mortality compared to younger women, older women can take encouragement from the fact that perinatal death rates are at their lowest point historically and women with healthy lifestyles and without chronic disease have very low absolute rates of perinatal mortality. However, continued increases in older maternal age will impact on population health trends and on the demand for health care services including rates of cesarean delivery.39 Also, it is of concern that the temporal declines in perinatal mortality observed in this study were not matched by corresponding declines in perinatal mortality/morbidity. Higher rates of obstetric intervention and improved neonatal care, although successful in reducing stillbirth and neonatal death rates over the span of the study period, did not reduce the burden of serious neonatal morbidity.
In summary, we have shown that despite higher rates of obstetric intervention, older mothers have higher rates of pregnancy complications, preterm birth, fetal growth restriction, perinatal mortality, and serious neonatal morbidity. The recent social trend toward delayed childbearing will thus have an increasing impact on the demand for health care services and population health trends. Nevertheless, low absolute rates of perinatal mortality/morbidity and recent reductions in perinatal death rates mean that most older mothers will have the desired pregnancy outcome.
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© 2005 The American College of Obstetricians and Gynecologists