Abstract
In developed countries, an increase in the average age of the gravida has been documented. The mean age of primiparous women in Austria rose from 25 years in 1991 to 28 years in 2008. In Germany in 2006, most gravidas were between the ages of 30 and 34 years whereas in the 1970s, most babies were born to women aged 20–24 years. Delayed childbearing and increased maternal age are associated with increased obstetrical and perinatal complications and, therefore, require adjustments in obstetrical management. Increasing maternal age is associated with pre-existing maternal risk factors such as diabetes mellitus, hypertension, myomas or obesity. In addition to lower fecundability and higher rates of chromosomal aberrations, higher rates of spontaneous early abortion are also common complications in early pregnancy among older women. In ongoing pregnancies, complications such as gestational diabetes, hypertensive disorders and low birth weight are associated with increasing maternal age. Furthermore, gravidas of advanced age are at a higher risk for stillbirth and perinatal morbidity and mortality. At delivery, increased maternal age is associated with an increased rate of malpresentation and represents an independent odds ratio for cesarean section. Owing to these facts, obstetric management in the older gravida needs to be adapted in order to manage the possible complications.
In developed countries, a steady increase in the age of the gravida is evident and this is due to economic, educational and social factors. In one study, 152 patients aged 35 years or older who were seeking assisted reproductive technology for their first planned pregnancies were asked about their reasons for delaying childbearing [1]. The most commonly reported reasons were not having a partner (50%) and wanting financial security (32%) or a career (19%) before having a family. According to this study, 18% of the women were not aware of the impact of age on fertility. In Germany in the 1970s, most babies were born to mothers aged 20–24 years; however, in 2006, most babies in Germany were born to 30–34-year-old women [2]. According to Montan, the mean maternal age of primiparous women in Sweden was 24 years in 1973; this rose to 28 years of age in 2003 [3]. Furthermore, the percentage of primiparous women aged 35 years or older rose from 2% in 1973 to 19% in 2003. In Austria, the mean maternal age of primiparous rose from 25 to 28 years between 1991 and 2008 [101].
Furthermore, advancing age results in a decrease in fecundability. Therefore, the use of reproductive medicine increases in older women. However, reproductive medicine itself might be one reason as to why more and more women are delaying childbearing and hoping for late babies with help of reproductive medicine.
Although some patients are aware of the risk of lower fecundability and may even be aware of elevated rates of chromosomal aberrations or higher abortion rates associated with increasing age, the risks that occur with pregnancy in the older gravida are often unknown by patients [4]. Preconceptional counseling and education regarding this aspect might need some more attention in the future in order to inform younger women about the possible consequences of delaying childbearing before they make the decision whether or not to do so.
New risks occur with perimenopausal women becoming pregnant after the use of artificial reproductive medicine and ovum donation; however, these issues are manifold and are therefore outside of the scope of this review.
The risks for older gravidas are discussed differently in the literature and this article will give an overview by discussing the risks occurring with advanced maternal age during the different stages of pregnancy and delivery. Furthermore, proposals for the management of these risks will be discussed.
Early pregnancy
With increasing age, the risk of miscarriage increases. Approximately 13–15% of all pregnancies end in miscarriage with over 90% being early abortions before 12 weeks of pregnancy. A significant correlation between maternal age and miscarriage rates can be demonstrated. Whereas women aged 20–24 years have a miscarriage rate of approximately 10%, women aged 35–39 years have a risk of 25% and women aged 40–44 years have a 50% risk for miscarriage, which increases to more than 90% for women over 45 years of age [5]. This high miscarriage rate is one of the main reasons for decreasing fertility in older women. According to Heffner, karyotyping the products of conception after miscarriage demonstrates chromosomal abnormalities in two-thirds of the cases [5]. The association between maternal age and chromosomal abnormalities is well known and Hook et al. demonstrated a risk of having a child with Down syndrome of one in 1667 for women of 20 years of age compared with one in 106 at 40 years of age and one in 30 at 45 years of age [6]. Besides lowered fecundability, this elevated risk of chromosomal aberration together with the increased risk of miscarriage owing to other reasons that occur more often with advancing age (e.g., myomas and diabetes mellitus) represent the main reasons for lower fertility with increasing age.
Ongoing pregnancy after 20 gestational weeks
Obesity, pre-existing diabetes, pre-existing hypertension and multiple pregnancies, among others, are known risk factors for hypertensive disorders in pregnancy including all various forms of preeclampsia [7]. All these factors occur more commonly with advancing maternal age [8]. Furthermore, maternal age is an independent risk factor for preeclampsia itself. In a case–control study of 468 pregnant women aged 40 years or older, a risk of 6.6% for preeclampsia was demonstrated compared with a risk of 3.9% in patients aged 20–29 years (p < 0.01) [9]. These findings reflect the findings from a number of other studies [8,10,11] that identify advanced maternal age as a risk factor for hypertensive disorders in pregnancy and preeclampsia. Therefore, the advanced age gravidas should be screened carefully for possible risk factors for hypertensive disorders in pregnancy. To date, the only routinely used method to evaluate the risk of preeclampsia, besides an accurate anamnesis of family and medical history, is Doppler sonography of the uterine arteries. Nevertheless, this method, as a single test, is not a valid screening method and is therefore not used in many centers. A number of biochemical agents have been assessed as markers for predicting preeclampsia. Until now, none have been used in the clinical routine. However, some promising markers have been identified, such as placenta protein 13 (PP-13), soluble fms-like tyrosine kinase-1 (sFLT-1) and soluble endogline, which might allow screening at a relatively early stage of pregnancy. When combined with Doppler sonography, these markers demonstrate relatively high predictive values [7]. Further large studies to evaluate these biochemical markers are needed; however, advanced age gravidas should be one of the first groups in which these screening methods are implemented.
Obesity has become one of the most serious problems for all healthcare systems in the western world, and, as mentioned previously, the rate of obesity is increasing with age. Salihu et al. demonstrated the prevalence of obesity (BMI >30) to be 11.3% in pregnant women at 20–24 years of age rising slightly with advancing age up to 18.6% for gravidas of over 40 years of age [7]. As reported by Robinson et al. from a Canadian cohort study, in 1988, 3.2% of pregnant women were obese compared with 10.2% in 2002 [12]. In this study, it was shown that moderately obese women were at a 2.38-fold higher risk for hypertensive disorders in pregnancy, a 2.17-fold higher risk for venous thromboembolism in pregnancy, a 1.94-fold higher risk for labor induction, a 1.6-fold higher risk for cesarean section and a 1.67-fold higher risk for consecutive wound infection. Furthermore, severely obese women had a 2.01-fold increased risk for anesthesia complications. Owing to these facts, obese women of any age should be counseled regarding their risks from a possible pregnancy before conception.
The prevalence of insulin-dependent diabetes and other forms of diabetes, including gestational diabetes, increases significantly with advancing maternal age [3,8,9]. The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study demonstrated that with increasing maternal glucose levels, the frequencies of birth weights above the 90th percentile, undergoing primary cesarean section, clinical neonatal hypoglycemia and cord-blood serum C-peptide being greater than the 90 th percentile were increased [13]. Furthermore, it was shown that with increasing glucose levels, the risks for preeclampsia, shoulder dystocia or birth injury increased. Regarding these results, ideally, a 75-g glucose tolerance test should be carried out in all gravidas, but owing to the fact that older gravidas are at a higher risk for gestational diabetes, this test should be mandatory for gravidas older than 35 years of age. Nevertheless, there is continuing debate as to whether all pregnant women should be screened or whether to restrict screening to women with risk factors since risk-based screening could overlook up to 50% of cases of gestational diabetes.
The data for preterm delivery and small-for-gestational-age (SGA) infants in pregnant women of advanced age remain the subject of discussion. A cohort study from 1990 that evaluated data from 3917 patients aged 20 years or older demonstrated no evidence that women aged 30–34 years or women aged over 35 years have an increased risk for preterm delivery or SGA infants [14]. In contrast to this, later studies demonstrated that advanced maternal age is associated with preterm delivery. A study of 24,32 gravidas aged 40 years or older demonstrated significantly higher rates of SGA births in older nulliparous and multiparous women compared with nulliparous and multiparous women of 20–29 years of age [15]. The rate of SGA infants in older multiparous women was 2.5% compared with 1.4% in the younger control group. For older multiparous women, the rate of SGA births was 1.4% compared with 1.0% in the younger control group. The mean birth weight of infants delivered by older nulliparous women was significantly lower (3201 ± 10 g) compared with the younger control group (3317 ± 1 g), whereas in multiparous women, there was no significant difference between older and younger mothers (3381 ± 5 g and 3387 ± 1 g, respectively). In older nulliparous and multiparous women, gestational age at delivery was significantly lower than in the younger control groups. Nevertheless, it remains unclear whether advanced maternal age is an independent risk factor for preterm delivery and SGA infants or whether risk factors that occur more frequently with advanced maternal age lead to these results [16].
A study of 123,941 pregnancies between 1980 and 1993 evaluated the risk of uteroplacental bleeding disorders in pregnancy in relation to advanced maternal age [17]. The risks of placental abruption, placenta previa and uterine bleeding of unknown etiology were examined. The frequencies of placental abruption and uterine bleeding of unknown etiology showed no increase with advancing maternal age. The risks of placental abruption and placenta previa were associated with higher partity among younger women but not with advanced maternal age. However, it was demonstrated that the risk of placenta previa dramatically increased with advanced maternal age. In this cohort, gravidas older than 40 years of age had a nearly ninefold greater risk for placenta previa than women under the age of 20 years. These data were confirmed by Ziadeh and Yahaya; however, in this study of 468 patients aged 40 years or older, antepartum vaginal bleeding also occurred more frequently in the older group compared with gravidas of 20–29 years of age [9].
Therefore, in our opinion, all gravidas, irrespective of their age, should have an accurate examination of the location of the placenta conducted in the second trimester, as detection of placenta previa would change the required management and the recommendation towards having an (earlier) elective cesarean delivery.
Delivery
Delaying childbearing seems to have contributed significantly to the rising rates of cesarean delivery. Gilbert et al. reported data from 24,32 women at the age of 40 years or older from a cohort of 1,160,000 women who delivered between 1992 and 1993 in California, USA [15]. The group of older gravidas aged 40 years or older was compared with gravidas at aged 20–29 years. Each group was separated into nulliparous and multiparous women. The cesarean delivery rate for older nulliparous women was 47% compared with 22.5% in the younger nulliparous women. In the older multiparous patients, the cesarean section rate was 29.6 compared with 17.8% in the younger control group [15].
The operative vaginal delivery rate in the older group was 14.2% for nulliparous and 6.3% for multiparous women. Asphyxia (rate: 6%) and malpresentation at term (rate: 11%) occurred significantly more frequently in the older nulliparous group compared with the younger nulliparous group (4 and 6%, respectively). The rates for asphyxia and malpresentation increased similarly in the multiparous group (3.4 and 6.9%, respectively) compared with the younger multiparous group (2.4 and 3.7%, respectively).
In this study, older nulliparous women aged 40 years and over had babies of significantly lower birth weights and significantly lower gestational age [15]. In spite of these facts, cesarean delivery rates have been demonstrated to be increasing, which might be largely explained by other increasing risk factors during pregnancy in these patients.
These results were confirmed by another study of 3715 nulliparous women who were divided into age groups of younger than 25 years, 25–25 years, 35–39 years and older than 40 years of age [18]. The rate of malpresentation rose from 2.7% in those aged younger than 25 years to 5.6% in the older than 40 years age group. The increase in malpresentation was partly explained by an increase in multiple gestations among older women (>25 years of age: 0.3%; 25–35 years of age: 1.4%; 35–39 years of age: 3%; and >40 years of age: 4.1%). The cesarean delivery rates increased significantly with advancing maternal age, from 11.6% in the older than 25 years age group to 43.1% in the older than 40 years age group. Older women were more likely to undergo cesarean delivery without labor. Indications for cesarean delivery without labor that were more prevalent in the older age groups were malpresentation and prior myomectomy. However, even in women with spontaneous or induced labor, older women were more likely to have a cesarean section than younger women.
The effect of delayed childbearing on primary cesarean delivery rates has also been studied by Smith et al. [19]. Among 583,843 nulliparous women in Scotland between 1980 and 2005, a linear increase in odds ratios (ORs) for cesarean delivery with advancing maternal age from 16 years upwards was demonstrated (adjusted OR for a 5-years increase in age: 1.49; 95% CI: 1.48–1.50). Furthermore, an association of longer duration of labor (0.49 h longer for a 5-year increase in age; 95% CI: 0.46–0.51) was demonstrated, as well as an increased risk of operative vaginal delivery, with advancing maternal age (adjusted OR for a 5-year increase in age: 1.49; 95% CI: 1.48–1.50). According to Smith's data, in Scotland, over the period from 1980 to 2005, the proportion of women aged 30–34 years increased threefold, the proportion of women aged 35–40 years increased sevenfold and the proportion of women aged over 40 years increased more than tenfold. In the same period, the cesarean rate among nulliparous women more than doubled. In a very interesting calculation model, the authors estimated that approximately 38% of these additional cesarean deliveries would have been avoided if the maternal age distribution had stayed at the level that it was in 1980. In the same study, the effect of advancing maternal age on the contractility of uterine smooth muscle was studied. It was shown that with increasing maternal age, spontaneous activity was reduced and the likelihood of multiphasic spontaneous myometrial contractions increased. The authors of this study concluded that the association between increasing maternal age and the rising risk of intrapartum cesarean delivery is likely to have a biological basis [19].
Similar findings were found in many other studies from different countries (e.g., England [20] and Taiwan [21]). In all studies, advanced maternal age was associated with increased cesarean delivery rates.
Stillbirth & perinatal mortality
Advanced maternal age is associated with an increased risk of stillbirth. In one of the largest studies to evaluate the influence of maternal age on stillbirth risk, Reddy et al. conducted an analysis of more than 5 million singleton deliveries. In this analysis, advanced maternal age was associated with a higher rate of stillbirth, with a peak risk period for stillbirth occurring among older mothers between 37 and 41 weeks of gestation [22].
Smith and Fretts presented data from a literature search. They presented an OR for stillbirth of 1.8–2.2 for women between 35 and 39 years of age and an OR of 1.8–3–3 for women over 40 years of age. Other epidemiological risk factors were nulliparity (OR: 1.2–1,4), smoking (OR: 1.7–3.0), obesity (BMI >30; OR: 2.1–2.8), having had a previous SGA infant (OR: 2.0–4.6), multiple gestations compared with singleton gestations and black compared with white race (OR: 2.0–2.2) [23].
A total of 6,239,399 singleton pregnancies in the USA were analyzed by Bahtiyar et al. in order to evaluate the influence of advancing maternal age on stillbirth [24]. The ORs were referred to the group of 25–29-year-old mothers who had the lowest stillbirth risk. When compared with this group, the odds of stillbirth at term increased significantly with advancing maternal age (OR for mothers aged 30–34 years: 1.24; OR for mothers aged 35–39 years: 1,45; and OR for mothers aged 40–45 years: 3.04).
Interestingly, the risk of stillbirth for women aged 40–44 years at 39 weeks of gestation is comparable with women aged 25–29 years at 42 gestational weeks.
Therefore, the authors concluded that a strategy of antenatal testing beginning at 38 gestational weeks for women over the age of 40 years may be considered. According to the authors, delivery by 39 weeks may also be considered for women over 40 years of age since the cumulative risk of stillbirth in women aged 40–44 years at 39 weeks is nearly identical to the risk in those aged 25–29 years at 42 weeks.
Future perspective
Obstetric management of gravidas of advanced age will become more and more important. Owing to social development and reproductive medicine in the future, even more women will delay childbearing and become older mothers.
Advanced maternal age is associated with increasing risks during pregnancy and delivery. The increasing cesarean delivery rates in older gravidas are only partially caused by increasing gestational complications. Nevertheless, cesarean delivery rates will probably show a steady increase in the future, especially in mothers of advanced age.
With increasing numbers of women delaying childbearing, in many cases, pregnancy and delivery will become a single event in a mother's life, and therefore, will be of more importance to the families. Therefore, not only the quality of medical treatment but also the quality of support and service during pregnancy and delivery will become essential and might be a reason for increasing cesarean delivery rates. Where affordable, hotel-like delivery clinics with high medical standards for ‘the one birth’ of wealthy patients might become a concept for the future.
Between 10 and 15 years ago, women over 35 years of age were treated as being at high risk for pregnancies and gravidas aged over 40 were rare cases. In the future, the gravida aged over 40 years will probably become as common as the gravida aged over 35 years currently is. With modern obstetric management, most of the occurring complications can be managed successfuly. However, more counseling of younger women before delaying childbearing regarding their later risks of lower fertility and the higher pregnancy complication rates is needed.
Executive summary
The mean age of women at delivery is rising in developed countries.
Many women are not aware of the consequences of delaying childbearing.
With advancing age, fertility and fecundity decrease.
With increasing age, the risk of miscarriage increases.
Women aged over 45 years have a 90% risk of miscarriage.
The association between maternal age and chromosomal aberrations, and malformations without chromosomal aberrations, is well known.
The risk of hypertensive disorders in pregnancy increases with advanced age.
– No valid screening method is currently available besides the anamnesis of medical and family history.
With advanced age, the risk of pre-existing diabetes increases.
The risk of gestational diabetes.
– An oral glucose tolerance test should be carried out in all parturients, at least in those with maternal ages of 35 years or over.
Obesity increases with advanced age.
With advanced age, the risk of small-for-gestational-age infants increases.
The risk of preterm delivery increases with advanced age.
With advanced age, the risk of placenta previa increases.
– The exact localization of the placenta should be examined at the second trimester screening.
Cesarean delivery rates increase with advanced maternal age.
Vaginal operative delivery rates increase with advanced maternal age.
If the maternal age distribution had stayed at the level that it was in 1980, 38% of these additional cesarean deliveries would have been avoided.
With increasing maternal age, spontaneous activity of the uterine smooth muscle is reduced and multiphasic spontaneous myometrial contractions increase.
Therefore, the association between increasing maternal age and the risk of intrapartum cesarean delivery could have a biological basis.
Advanced maternal age is associated with an increased risk of stillbirth.
The risk of stillbirth for women aged between 40 and 44 years of age at 39 weeks of gestation is comparable with that of women aged 25–29 years at 42 gestational weeks.
Therefore, a strategy of antenatal testing beginning at 38 gestational weeks for women over the age of 40 years may be considered.
Delivery by 39 weeks may also be considered for women over 40 years of age as the cumulative risk of stillbirth in women of 40–44 years of age at 39 weeks is nearly identical to the risk in those of 25–29 years of age at 42 gestational weeks.
Footnotes
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.