Abstract
Many regard childbearing as the most life-changing and perhaps the most desirable aspect of a women's life. Correspondingly, reduced fertility has a significant negative impact on a woman and her family. To this end, gynecologists work to preserve and restore fertility. Recently, however, in developed countries, more women are becoming pregnant later in life, whether by choice or circumstance. This could be a direct result of the increasing availability of both effective contraception and infertility treatment, but perhaps more pertinently the changing lifestyles and career choices that modern women make. This article offers a perspective on pregnancy after the age of 40, the impact on maternal and fetal outcomes, the social implications and the importance of prenatal counseling.
Fertility trends in the UK have changed over the last 50 years. The general fertility rate was at its highest in the 1960s and fell sharply in the 1970s and 1980s. By the 21st century it has reached its lowest ebb, below 50 births/1000 women. This is due to the fact that fertility rates in women aged between 25 and 30 years have fallen dramatically (by 56% over the past 45 years) and have been overtaken by those in their 30s and 40s [101–103]. The percentage of all births to women aged 35 years or over has doubled in the last 10 years, while the percentage of women having a first birth at 35 years or over has nearly trebled in the same time [104]. In England and Wales alone between 1991 and 2001, the number of women giving birth between the ages of 40 and 44 years increased from 5.1 to 8.4 live births/1000 women, and in women at 45 years or older the rise was from 0.3–0.5/1000 women [105].
Fertility rates have increased in all age groups, however the trend towards later childbearing has continued. The mean age for women at first birth has gradually increased to 27.5 years, although the mean age overall of women giving birth remains at 29.4 years [106,107]. It appears that women are choosing to have fewer babies, and are also choosing to have them later in life. Although fertility in women above 30 years has been gradually increasing, the fertility rates are still below that in the 1960s [102]. The projection assumptions conclude that trends toward childbearing at older ages will continue, so we should expect even more pregnancies in women over 40 years old.
More effective contraception combined with safe, legal termination means that the era of excess fertility, unplanned pregnancies and unwanted children has receded in most cases. Many other factors might also account for the new patterns of family formation seen in the last few decades, especially in the western world: increased female education, economic autonomy, need for a second income in the household, religious convictions, poverty, competition in career development, and higher chances of separation and divorce, to name a few. On the one hand, the level of highly educated women has increased, yet on the other they are more likely to be childless and without a partner by 40 [1]. It is difficult to pinpoint any particular factor as the most important in determining fertility trends as they vary between countries and between different strata of the society within countries.
Infertility
Menopause is often preceded by menstrual irregularities and ovulatory dysfunction, typically in the later half of the fifth decade. Reproductive capacity is most likely to end 10–15 years before the menopause [2–4]. It is difficult to quantify the effect of aging on fertility; however, cross-sectional population-based studies have defined advanced maternal age, pertaining to fecundity and fertility, as 35 years and above [5]. There is almost a 50% decrease in the fertility rate at age 40 or older compared with younger women [6]. The annual conception rate for women aged 40 years and above in England and Wales is 10.2 per 1000 [108,109]. Although social factors play a role, physiological factors are more overwhelming.
According to statistics provided by the Human Fertilization and Embryology Authority, male factors contribute 32% and female factors contribute 29% as causes of infertility [7]. Studies have evaluated that female age is an independent factor for reduced fertility independent of any male or pelvic fertility factors [8,9]. Transition to a less fertile state is mainly governed by the rate at which a woman depletes her follicular reserves. Once a woman falls below a certain threshold, fertility is compromised, ultimately transiting to a menopausal stage. Reduction of ovarian reserve becomes accelerated in the latter half of the fourth decade of life. This may be due to increasing levels of follicle-stimulating hormone (FSH), which recruits increased number of follicles, resulting in greater depletion of oocytes per cycle [10,11]. Whether this process is primarily regulated by ovary or neuroendocrine changes (increased FSH) is unknown.
Risk of fetal loss from spontaneous abortion, ectopic pregnancy and stillbirth according to maternal age at conception.
In older ovulatory women, reduced fertility is likely to be the result of an aging uterus and its diminished receptiveness, aging of oocyte, embryo quality or both. The uterus plays a predominant role in limiting reproductive efficiency. Histologically there is no consistent change with aging and the uterus is similar to that of a younger woman [12]. Age-related changes in the pattern of hormonal stimulation such as high incidence of luteal-phase deficiency seen at extremes of reproductive age, may affect endometrial receptivity to the embryo [13]. In older women, treatments for luteal-phase deficiency have not shown any dramatic improvement in pregnancy rates, implying there are other factors at work. Studies have shown that egg quality is a major factor responsible for waning reproductive function. Changes responsible for the aging oocyte and its pathophysiology are not clearly known [13]. There is no morphological difference seen in mature oocytes and early embryos from younger and older women undergoing IVF [14]. There is a decrease in the number of ovarian follicles, increasingly poor oocyte quality, and rising miscarriage rates caused by rising rates of chromosomal abnormalities such as aneuploidy, Down's syndrome and other genetic disorders [15,16]. For women aged over 40 years, congenital abnormalities complicate 152 births in every 10,000 with a 1 in 84 risk of Down's syndrome. There is an increased rate of spontaneous miscarriages and stillbirths [17,110]. The miscarriages in patients undergoing egg donation are correlated to the age of the donor, implicating the oocyte as the primary factor responsible for the high rate of aneuploidy [18].
It is important not to overestimate the effect of aging on fertility because a number of other conditions such as pelvic inflammatory disease (PID), tubal diseases, fibroids and endometriosis also increase in frequency with age. There may also be decreased frequency of coitus in older couples.
Assisted reproduction
Success rate with in vitro fertilization (IVF) also decreases with advancing age, similar to the decline noted in natural cycles, even after controlling for diminished ovarian response to stimulation [19].
For women aged 40–42 years, the average success rate of IVF treatment in the UK using fresh eggs is 10% and with donor insemination is 4.5%, though pregnancy rates can be improved with donor eggs. Infertility treatment also places a great burden on personal finances, as IVF treatment is not available on the UK National Health Service (NHS) for women aged over 39 years [20]. The typical cost of a cycle alone is up to £3000, with additional costs for consultation, tests and drugs. Other procedures such as embryo freezing are charged separately [7]. In a study conducted by Seng and colleagues of IVF treatment in women aged 40 years and above, the pregnancy rates were found to be much lower compared with women aged below 40 years (12.3 vs 32.9%) [16]. This was due to a reduced number of oocytes retrieved and lower implantation rate. The success of embryo transfer, even with donor eggs, was also decreased, thereby reducing the overall chance of a successful pregnancy [16].
Fertility and miscarriage rates with maternal age.
Risks associated with IVF and related assisted reproduction technologies include complications of ovarian stimulation, surgical procedures and the pregnancy itself. IVF pregnancies have a higher risk of serious complications secondary to advanced maternal age, including a higher incidence of ectopic [21] and multiple pregnancies [17] when compared with the general population. Ovarian hyperstimulation syndrome (OHSS) is the most common complication of ovulation induction, ranging from mild to life-threatening disease. The incidence is 0.7–1.7%/cycle, whatever the number of cycles, and it is more common after embryo transfer than ovulation stimulation alone [20,22]. It has pulmonary manifestations, and can cause thromboembolic events, cerebral infarction and death [23]. Apart from OHSS, there is a risk of infection and bleeding from the oocyte collection site [20]. Up to 1–5% of IVF pregnancies have been reported to be ectopic, and 0.1–0.3% heterotrophic. Estimates of IVF pregnancies ending in miscarriage have varied from 15–23% [22,24].
Owing to the novelty of IVF treatments, many studies have been carried out on the short-term health effects on the mother and the baby, but less is known about the long-term consequences [25]. Women who have been exposed to fertility drugs with IVF seem to have a transient increase in the risk of having breast or uterine cancer diagnosed in the first year after treatment, though the overall incidence is no greater than expected, and this may be an ascertainment artifact. Unexplained infertility has been associated with an increased risk of a diagnosis of ovarian or uterine cancer [26]. The all-cause mortality rates in IVF patients (treated and untreated) are significantly lower than in the general female population of the same age. Lower mortality has been reported in Australia among women who received IVF compared with women who had registered for IVF but never received the treatment. These observations could be due to social class differences and the ‘healthy patient’ selection process [27].
Maternal & fetal outcomes
As has always been the case, advanced maternal age (aged 35 years or more at delivery) is regarded as a high-risk factor for adverse maternal and fetal outcomes. This is supported by numerous studies, although some challenge this well-established view.
One large prospective multicenter study of singleton pregnancies (28,398 women aged <35 years; 6294 aged 35–39 years and 1364 aged ≥40 years) was entitled the First And Second Trimester Evaluation of Risk (FASTER) trial (1999–2002) [28]. After adjusting for various confounding variables such as race, parity, body mass index (BMI), education, marital status, smoking, medical history and the use of assisted conception, the authors found that increasing age was significantly associated with chromosomal abnormalities (adjusted odds ratio 4.0 for 35–39-year-olds and 9.9 for women ≥40 years) and miscarriage (adjusted odds ratio 2.0 for 35–39-year-olds and 2.4 for women ≥40 years). They also found a higher incidence of congenital anomalies, gestational diabetes, placenta previa and cesarean delivery for both the 35–39-year-olds and the 40 years and over age group (the odds ratio for the ≥40-year-olds was higher in each case). Furthermore, women aged 40 years or over were at a significantly greater risk of placental abruption (adjusted odds ratio 2.3), preterm delivery (adjusted odds ratio 1.4), low birthweight (adjusted odds ratio 1.6), and perinatal mortality (adjusted odds ratio 2.2). Interestingly, in contrast with previous studies that showed an increased risk of hypertensive complications [29–31], this study found that increasing maternal age was not associated with complications such as pre-eclampsia. Nevertheless, the conclusion was that although the likelihood of adverse outcomes increased along with maternal age, overall maternal and fetal outcomes were favorable.
With regards to fetal loss, most studies have consistently shown a rise in adverse outcomes with age. Andersen and colleagues conducted a prospective register linkage study in Denmark on 634,272 women and 221,546 pregnancy outcomes [17]. They found that the risk of a spontaneous miscarriage was 8.9% in women aged 20–24 years and 74.7% in those aged 45 years or more. High maternal age was a significant risk factor for spontaneous miscarriage irrespective of the number of previous miscarriages, parity, or calendar period. The risk of an ectopic pregnancy and stillbirth also increased with increasing maternal age.
In a different retrospective comparative study of 539 deliveries among very old mothers (≥50 years), it was found that among singleton gestations, the risks for low birthweight, preterm and very preterm infants were tripled and the occurrence of very low birthweight, small for gestational age, and fetal mortality were approximately doubled compared with young mothers (20–29 years) [32]. Furthermore, those aged 50 years or over were found to have a greater risk for fetal morbidity and mortality compared with 40–49-year-olds.
The majority of published data support the view that increasing maternal age increases the risk of delivery by intervention (cesarean, forceps, vacuum etc.) [28,31,33–38]. Whether the increased risk of operative delivery is explained solely by an increase in complications is debatable. Maternal and physician anxiety might also be contributory in pushing up intervention rates [39,40]. Assigning the ‘high-risk’ label and a preference for intervention among both patients and obstetricians have also been postulated as reasons [40–43].
In a retrospective study of 22,689 deliveries occurring in 1985–1989 at The Prince of Wales Hospital (Hong Kong, China) for neonatal outcomes, maternal age was not found to have an effect on the incidence of fetal distress, Apgar score, the development of respiratory disease, the need for intubation and ventilation, nor on subsequent neonatal CNS complications. There was also no association between maternal age and either perinatal mortality or the incidence of congenital malformations at birth [36].
In contrast to the above-mentioned studies, a 3-year study of 1023 pregnancies in women aged 35 years or older found few statistical differences between the different raised maternal age groups [41]. Similarly, Ales and colleagues found that peripartum maternal complications were no more frequent in a group of 1328 women aged 35 years or over in New York (NY, USA), although operative delivery was significantly more common [44]. The perinatal mortality was found to be lower; fewer infants with congenital anomalies were born and there were no more frequent adverse outcomes of infants in the 35 years or over age group. Both these studies are hampered by being retrospective, without adjustment for confounding variables. Both were conducted in large tertiary care centers where there may have been more opportunity for early booking, early termination for congenital anomalies and better monitoring.
The incidence of multiple pregnancies (twins and triplets) is higher with increasing maternal age (both with spontaneous pregnancies after 40 years and with IVF). This can affect both the mother and the children, as they are more likely to be born prematurely or growth restricted and have an increased risk of cerebral palsy. The mortality rate is four-times higher for twins and seven-times higher for triplets than for a singleton birth [7].
Poor outcomes place an additional burden on maternity and neonatal services with significant cost implications for the health services. However, on the other hand, older women are more likely to have successful careers and have paid taxes for longer.
Social implications
Women have come very far in the last century. With the expansion of higher education and increased participation of women in the labor force, the role of women in society has changed dramatically. It is the norm nowadays for women to be both economically active and have a family [111].
Social status has been found to be related to fertility in different countries. Social policies will influence the feasibility of the crucial issue of the combining work and family. All things being equal, a rational woman will want to estimate what is the optimal time in her career to have a child and minimize any reproductive risk. Long-term standard of living and income security are clearly relevant when making a long-term decision to have a child. Presently, women from higher social strata are having fewer children on average. To achieve and maintain high status requires time-demanding investments [45]. High professional demands, inflexible working hours and lack of gender equality in the domestic sphere are other practicalities of life interfering with the balance between career and family [111]. Such events could lead to women (and men) investing several precious years of their useful reproductive lives. In a recent report by the Institute for Public Policy Research, it was found that British women have to pay a financial ‘fertility penalty’ if they have children at an earlier age [112]. Almost a third return to a less well paid job than before. These sorts of realities could lead women to a crossroads where they are often forced to make a choice between career progression and higher salary on the one hand versus having a family and spending time with their children on the other.
A fit woman in her 40s is more likely to have a successful pregnancy than an unhealthy woman in her twenties, although she runs a greater risk than if she was fit in her twenties [113]. Jolly and colleagues showed that older women are less likely to be late-bookers and have a positive attitude towards breast-feeding [46]. Many women embark on the journey to older motherhood out of circumstance rather than by choice. An older mother is more likely to married or in a stable relationship, well supported at home and economically successful. She may be more secure, mature and clear about what she wants.
A woman at some given age, say 25, faces more uncertainty about the advantages and disadvantages of childbearing in a population that is increasingly exhibiting a late pattern of childbearing compared with an identical woman in a population with early childbearing. Higher uncertainty in turn implies a further incentive to delay childbearing. The desire to have a baby can be the same at 45 as 25. Age does not determine the ability to be a great parent.
Appropriate prenatal counseling and good perinatal care can achieve good results. But are women of today really adequately well informed about the higher risks of pregnancy at an advanced age? Would the procession of celebrity mothers over 40 make them think that the medical facts cannot really be that bad? Do they realize that peri- and postmenopausal pregnancies are achieved with donor eggs? Maybe women hope that ‘it'll happen to someone else’. Even if she is aware of the risk of adverse outcomes, the modern older mother may offset these fears by rationalizing that she will feel more prepared to raise a child, both emotionally and financially. Well-informed women with flexible career opportunities could make a balanced decision on the merits or otherwise of pregnancy. It is also important that men become more educated; a potential father also has a significant involvement in the prepregnancy decision-making process and often has a considerable influence on the initial delay in initiating pregnancy.
Assisted reproduction is a delicate and often debated area of medical ethics. In March 2005, the Human Fertilization and Embryology Authority commissioned polling experts MORI to carry out a research study, interviewing 1929 adults across the UK to assess public attitudes towards fertility treatment. The overall attitude towards fertility treatment was very positive, being viewed as a major scientific advance. A total of 63% of women between the ages of 45–54 years supported the view that the benefits outweigh the risks, whereas 22% of those in the 15–24 age group believed the risks outweigh the benefits. Many people still have concerns about the long-term and unknown consequences of fertility treatment [114].
There are strong views expressed by some people on the morality of interfering with a natural process, when it was actually suppressed at its prime. These are not medical issues and doctors should not be moral judges.
A rising trend of maternal age is associated with poorer outcomes for the mother and child, not to mention a financial burden on health services. It is right that healthcare providers highlight the demographic shift in maternal age and the risks of pregnancy at an advanced age both to the general population and individual prospective mothers. They should also draw attention to the social and economic forces influencing the trends.
Future perspective
We should all continue to celebrate the joy and happiness that the birth of a baby brings, whatever the maternal age. However, obstetricians and gynecologists see the reverse side of the coin, in terms of the more private grief of infertility, pregnancy loss and complications.
We are living in a changed world and pregnancy after the age of 40 years is here to stay. Many women do not have the free and unconstrained choice to get pregnant in the ‘optimum’ age bracket, as it would not be logical to defer childbearing to a time of reproductive hazard without other pressures bearing on them. It is not just health services, but society as a whole that needs to adapt to the changing demography, and show more understanding. It requires giving women more opportunities to make independent decisions on their own reproductive choices. It is only by encouraging and creating an environment for women to flourish, both in their professional as well as personal lives, that they can make choices without later regrets.
Executive summary
Fertility trends have shown rising numbers of women becoming pregnant after the age of 40 years.
Cross-sectional population-based studies have defined advanced maternal age, pertaining to fecundity and fertility, as 35 years and above with a 50% decrease in the fertility rate at age 40 years or older compared with younger women.
A decrease in the number of ovarian follicles, increasingly poor oocyte quality, and rising miscarriage rates caused by rising rates of chromosomal abnormalities such as aneuploidy, Down's syndrome and other genetic disorders contribute to this decline in fertility with age.
Average success rate of in vitro fertilization (IVF) treatment in UK for women aged over 40 years using fresh eggs is 10% and with donor insemination is 4.5%, though pregnancy rates can be improved with donor eggs.
Risks associated with IVF and related assisted reproduction technologies include complications of ovarian stimulation, surgical procedures and the pregnancy itself.
Women aged 40 years or over are at a significantly greater risk of placental abruption, preterm delivery, low birthweight and perinatal mortality.
Higher incidence of congenital anomalies, ectopic pregnancy, gestational diabetes, preeclampsia, placenta previa and cesarean delivery for both the 35–39year-old-age group and those aged 40 years or over.