Human Reproduction Update 1998, Vol. 4, No. 2 pp.

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European Society for Human Reproduction and Embryology

Clinical aspects of pregnancy after the age of 35 years: a review of the literature
C.van Katwijk1,3 and L.L.H.Peeters2
1Department Obstetrics

and Gynecology, De Wever Hospital Heerlen, PO Box 4446, 6401 CX Heerlen and 2Department Obstetrics and Gynecology, University Hospital Maastricht, PO Box 5800, 6201AZ Maastricht, The Netherlands

TABLE OF CONTENTS Introduction Maternal mortality Common age-related disease states Labour Perinatal mortality Pregnancy in postmenopausal women Discussion References 185 186 187 190 190 191 192 193

to increase progressively with the number of years elapsed since the onset of postmenopause. Key words: maternal age/menopause/pregnancy/risks Introduction All over the world women are delaying childbearing for various reasons. Persuit of career or financial goals, better contraception, longer life expectancy, higher education etc., have been mentioned as possible reasons for this phenomenon. (Hansen, 1986; Bobrowski and Bottoms, 1995) Traditionally pregnant women older than 35 years are considered of advanced age (Kirz et al., 1985; Bianco et al., 1996) and also at increased risk for complications during pregnancy and labour. Increased incidence of preterm labour, hypertensive disorders, Caesarean birth, and maternal and perinatal mortality have been reported. However, it has also been suggested that, if these women do not have hypertension or diabetes, the course and outcome of pregnancy will be comparable to that in gravidas of younger age. The cohort of women >35 years old and in their first ongoing pregnancy is increasing. By the year 2000, as many as 10% of all newborns in the USA may be delivered by women >35 years old (Newcomb, 1991). The womans ability to conceive declines with age, particularly after the age of 35 years (Schwartz and Mayaux, 1982; Scott and Hofmann, 1995). The outcome of pregnancy in relation to maternal age is different in women whose pregnancy is conceived naturally, compared to those who conceived by assisted reproduction, as the latter are generally older (Marcus and Brinsden, 1996). Recent developments in infertility treatment and procreational requests from women in their peri-menopausal years necessitate an understanding of the potential health hazards of such developments. This review gives an update of the literature on pregnancy course and outcome in women older than 35 years including those that are postmenopausal.

The objective of this report is to provide an update of our current knowledge about the impact of maternal age on pregnancy outcome. Pregnancy in women 35 years old is associated with a higher maternal and perinatal mortality. The older gravida also has a higher chance of being delivered by Caesarean section. Most of the complications associated with older age are caused by age-related confounders such as leiomyomas, type II diabetes, hypertension and multiparity. Diabetes and hypertension increase almost linearly with age. Pregnant women with diabetes or hypertension are at increased risk of adverse pregnancy outcome irrespective of age. The currently available literature indicates that premenopausal pregnant women of advanced age who are in good health do not need special care besides the normal obstetric practice. At present, establishing pregnancy in postmenopausal women is more an ethical than a medical issue, partly because the information reported on pregnancy in postmenopausal women is insufficient to determine a reliable risk profile. In these women cardiovascular ageing accelerates. Therefore, until proven otherwise, postmenopausal women should be considered particularly at increased risk for vascular complications during pregnancy. This risk is likely
3To

whom correspondence should be addressed. Tel: + 31 45 576 6513; Fax: +31 45 576 6625

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Maternal mortality
Epidemiology of maternal mortality

The average maternal mortality rate (MMR) throughout the world amounts to ~1020 per 105 live births and increases as a function of maternal age (Hansen, 1986; OReilly-Green and Cohen, 1993). The MMR is strongly influenced by social class, race, culture and both local infrastructure and health care system (Rochat et al., 1988; OReilly-Green and Cohen, 1993). It follows that the MMR not only differs markedly between developing and developed countries, but also within countries between various social and ethnic subpopulations. In general, the MMR is highest in women who are black, unmarried, poor, lack proper prenatal care and have a high parity (Berg et al., 1996). Nevertheless, in the USA it is evident that the MMR per 105 life births has declined steadily over recent decades, from 376 in 1940 to 37 in 1960 and 9 in 1980 (Atrash et al., 1990). In this respect, it is noteworthy that the MMR data may not always be reliable due to underreporting and unreliable differentiation between pregnancy- and non-pregnancy-related causes. By definition, maternal mortality unrelated or related to pregnancy differ from one another by cause, whereas the latter varies also by time of occurrence, that is to say during pregnancy or in the first year postpartum (Atrash et al., 1995). In the latter report 69, 25 and 6% of the pregnancy-related maternal deaths occurred within 1 week postpartum, between 1 and 6 weeks postpartum and in the remainder of the first year, respectively. Worldwide, ~25% of women of reproductive age are living in developed countries. However, only 1% of all cases of maternal death occur in these countries. The enormous excess in maternal

mortality in developing countries emphasizes that substandard care and poor socio-economic conditions have a major impact on the MMR. Recently, the contribution of pregnancy-related causes to the MMR in Saudi Arabia (18%) has been calculated taking into account the effect of maternal age (Al-Meshari et al., 1996). Haemorrhage, embolism, hypertensive disorders and infection accounted for 68% of the MMR. About one-quarter of the MMR in this subgroup was due to complications associated with surgical procedures (infections) or pre-existing cardiovascular disease. In this Arab population the risk of pregnancy-related death was 9-fold higher in women >35 years than in those <20 years of age. Interestingly, the relative risk for grande multiparas (more than six previous births) of dying from a pregnancy-related complication was 5.4. Because of cultural factors and strict criteria for induced (illegal) abortions, the authors assume that underreporting played a minor role in their data. Mertz et al. (1992) reported on maternal mortality in New Jersey in three subgroups of women in consecutive 5 year time intervals. A striking finding in that study was the enormous discrepancy in pregnancy-related MMR between whites (13.2%) and non-whites (48%). Fewer than half of all deaths were classified as preventable. For the whole study period the pregnancy-related MMR for physician-preventable deaths was 48-fold higher in non-whites, which raises doubt about the implementation of the equal opportunity principle in the American obstetric care system. It should be emphasized that excess mortality in non-whites was largely due to more ectopic pregnancies, abortions and anaesthesia complications which are at least in part related to socio-economic status (Rochat et al., 1988).

Table I. List of most common causes of maternal mortality and their presumed risk factorsa
Causes of mortality Haemorrhage Hypertensive disorders of pregnancy Infection Pulmonary embolism Ectopic pregnancy Placental abruption 6 10 7 4 Incidence (%) 23 18 Presumed risk factors Multiparityb, excessive uterine distension, myomab, placenta praevia, clotting problems, Pre-existent cardiovascular diseaseb, diabetesb, thrombophilia Caesarean section, pyelitis, sepsis, HIV Multiparityb, Caesarean sectionb, cancerb PIDb, sterilizationb, myomab Chronic hypertension

aCompiled from: Hansen (1986), Sachs et al. (1987), Atrash et al. (1990, 1995), Newcomb (1991), OReillyGreen and Cohen (1993) and Berg et al. (1996). bAge-related confounders. MMR = maternal mortality rate; HIV = human immunodeficiency virus; PID = pelvic inflammatory disease.

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Maternal mortality and maternal age

The most important causes of pregnancy-related MMR are listed in Table I. In the 1950s infection and haemorrhage were the leading causes of maternal mortality (Sachs et al., 1987). In the last two decades trauma, embolism and infection with viruses affecting the immune system have become increasingly important. It should be stressed that various important contributors to maternal mortality such as cardiovascular disease, diabetes and multiparity increase with advancing age (Evans and Williams, 1992). They are indirectly responsible for the observed agedependence of hypertensive disorders, abnormal fetal growth, placental abruption and Caesarean-section-related complications (Brassil et al. 1987; Lehmann and Chism, 1987; Yasin and Beydoun, 1988; Cnattingius et al., 1992). Another example for a confounder being responsible for an age-related complication in pregnancy is tubal pathology. The latter leads to subfertility and with it a delay of pregnancy to an older age. This abnormality is also associated with an increased risk for ectopic pregnancy. Thus, the apparent rise in ectopic pregnancies with age is probably a result of an age-dependent rise in the prevalence of underlying confounders. The relation between diabetes and hypertension on the one hand, and age on the other hand, will be discussed in more detail in a separate paragraph. By analysing 714 cases of maternal deaths, the overall relative risk (RR) for a woman to die from a pregnancy-related complication such as infections, embolism, hypertensive disease, hemorrhage, cerebrovascular accidents and abortion, was more than doubled in women >30 years relative to their younger counterparts (Rochat et al., 1988). The overall MMR per 105 live births has declined gradually over recent decades to reach a nadir of 7.2 in 1986. Since then the MMR has increased again, reaching 10 per 105 in 1996. This phenomenon was thought to result from more accurate registration since the mid-1980s (Berg et al., 1996). Most studies report an age-related increase in pregnancy-related maternal mortality with the largest increase in black women >40 years of age. The reported overall MMR 105 live births in the USA for women >40 years between 1979 and 1986 was 56, which is ~6-fold higher than in the general population (MMR = 9.1) (OReilly-Green and Cohen, 1993). Another approach of evaluating mortality risk in the older gravida is to study the outcome of pregnancies accomplished by assisted reproduction techniques in women >40 years of age. Antinori et al. (1995) found no maternal deaths in a series of 113 women aged 4563 years participating in an oocyte donation programme. In these

patients 44 ongoing pregnancies were achieved resulting in 44 live births. All patients were thoroughly screened prior to treatment and found to be in excellent health, however 300 patients were left out for various reasons, predominantly because of cardiovascular disease, hypertension, smoking and obesity. In six (13.6%) of these patients pregnancy was complicated by a hypertensive disorder, a finding comparable to that in the general obstetrical population. Diabetes, renal or hepatic diseases were not encountered. In summary, pregnancy-related maternal mortality is a rare event. Since 1940 mortality figures have declined steadily, but have increased again since 1987 probably in conjunction with improved registration. The most common causes of maternal death are related to hypertensive disorders, embolism, ectopic pregnancies and infectious disorders. The typical woman dying from pregnancy-related complications is black, unmarried, poor and >35 years of age, thus emphasizing the overwhelming impact of socio-economic factors on the MMR. In most cases the higher incidence of maternal death among older women is related to confounders of age. Common age-related disease states It is generally assumed that women >35 years have an increased risk for complications during pregnancy. However, most reported age-related risk factors are only indirectly related to age through their association with age-dependent confounders such as hypertension, diabetes, high parity, uterine myomas and a history of infertility. Among them, hypertension and diabetes will be discussed separately as they are not only characterized by a high prevalence in the ageing general population, but also by important implications for pregnancy.
Hypertension

It is well-known that cardiovascular disorders increase with age (Burt et al., 1995). The relationship between hypertension and age for women is illustrated in Figure 1. Although less progressive, this correlation is already discernible in the reproductive period: the prevalence of chronic hypertension in 2530 year old women amounts to ~1.5% and increases almost 4-fold in the subsequent decade (Kirz et al., 1985; Burt et al., 1995). The most important effect of ageing on the cardiovascular system is a gradual loss of compliance. This is suggested by histological studies of the vessel wall and supported by an age-dependent decline in vascular responsiveness to endothelium-dependent vasodilators (Taddei et al., 1995). The associated fall in functional reserve capacity is

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Figure 1. Relation between age and blood pressure, adapted form Kaplan (1994).

reflected in a lower capacity of heart and arterial tree to yield during systole. During reproductive age the functional effects, if any, may only become manifest during strenuous exercise, but also during pregnancy. Loss of myocardial compliance can be expected to reduce the maximum stroke volume whereas a stiffer aortic arch is likely to generate less wind kessel effect and consequently less aortic flow during diastole (Docherty, 1990). The lower ability to store kinetic energy in the aortic arch is associated with a rise in systolic blood pressure, a well-known effect of ageing (Kaplan, 1994). After the sixth decade the cardiac wall begins to increase in size at the expense of the end-diastolic ventricular volume (Lakatta et al., 1990). It is tempting to speculate that this effect develops in response to a chronically elevated afterload, which would be a logical consequence of a less compliant arterial tree. A smaller end-diastolic ventricular volume has a negative impact on stroke volume (Lakatta et al., 1990). In the last decades of life the cardiac reserve capacity is further reduced by a fall in maximum heart rate (Docherty, 1990; Kaplan, 1994). An important adaptation of pregnancy is the institution of a high flow/low resistance circulation. More specifically, mean arterial blood pressure decreases by ~510 mm Hg and cardiac output increases by ~35%, almost entirely through a rise in stroke volume (Duvekot and Peeters, 1994a). Animal studies have shown that in pregnancy the compliance of the large arteries is ~15% higher than in the non-pregnant state thus contributing to the observed afterload reduction (Slangen et al., 1997). The so-called hyperdynamic circulation of pregnancy triggers plasma volume expansion by as much as 1 litre (Duvekot and Peeters, 1994b). The direction of the normal changes in pregnancy seems to be opposite to that noted

with ageing. One could say that the vascular bed evolves towards a younger age during pregnancy, and thus that the normal haemodynamic adaptation to pregnancy is to become more difficult with advancing age. The impact of cardiovascular ageing on pregnancy is reflected in an age-dependent rise in cardiovascular complications during pregnancy. The incidence of pregnancy-induced hypertension (PIH) in 2529 year old nulliparous and multiparous women amounts to ~7 and 3%, respectively. By the age of 35 years in women matched with the controls, these incidences have doubled to 14 and 7% respectively (Kane, 1967; Prysak et al., 1995). Pre-eclampsia affects three times as many gravidas >35 years than those of younger age, irrespective of parity (Bobrowski and Bottoms, 1995; Bianco et al., 1996). The incidence of chronic hypertension increases with age (Bobrowski and Bottoms, 1995). Pre-eclampsia occurs more frequently in women with pre-existent hypertension than in previously normotensive women; the incidence varies from 10 to 50% (Kaplan, 1994). Hypertensive disorders of pregnancy are responsible for 18% of the maternal mortality in the USA (Cowley et al., 1994). The management of these pregnancy complications goes beyond the scope of this review.

Diabetes mellitus

Diabetes is a chronic metabolic disease with secondary cardiovascular complications. The clinical expression of diabetes is a direct consequence of the inability of insulin-sensitive cells to utilize glucose for their energy supply due to a relative or absolute lack of insulin. In order to fuel their oxidative metabolism these cells rely on metabolic substrates derived from accelerated lipolytic and proteinolytic activity. Therefore, the nutrient profile in the circulating blood is characterized by both raised glucose levels and increased levels of lipolytic and proteinolytic metabolites (Joslin, 1985). There are two forms of diabetes mellitus. Type I diabetes is characterized by an absolute insulin deficiency presumed to be caused by an auto-immune destruction of -cells in the pancreas. Its onset is usually in childhood or young adolescence. Type I diabetes does not correlate with age (Prysak et al., 1995; see also Figure 2). Type II diabetes is characterized by a relative insulin deficiency presumed to be caused by either a reduced peripheral insulin sensitivity or a diminished capacity of the pancreas to release sufficient amounts of insulin in response to peak demand (postprandial). Its onset is usually at later age than type I diabetes and therefore is often called adult-onset diabetes (Joslin, 1985).

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Figure 2. Relationship between incidence of type I (insulin-dependent diabetes mellitus; IDDM) and type II diabetes (non-insulin-dependent diabetes mellitus; NIDDM) and age. Adapted from Joslins Diabetes Mellitus (1985).

Only the prevalence of the latter form increases as a function of age (see also Figure 2) which can be explained as follows. With advancing age the islets of Langerhans in the pancreas become increasingly fibrotic, a change that can be expected to interfere with insulin reserve capacity (Metzger et al., 1993). The biological rate of decline in insulin reserves with advancing age is not only determined by this biological predisposition, but also by the presence of environmental confounders such as obesity, traumas/infections of the pancreas, and by whether or not a subject possesses the susceptibility gene for diabetes (Alcolado and Alcolado, 1991). The vascular complications of diabetes consist of accelerated non-specific atherosclerosis and a more specific microangiopathy particularly affecting the eye and kidneys (King et al., 1996). In conditions of stress (pregnancy, infection, severe trauma, obesity) asymptomatic type II diabetics may become symptomatic indicated by elevated postprandial glucose levels, most likely in conjunction with raised levels of insulin-antagonizing hormones in the peripheral blood. Nevertheless, even in such stressful conditions these subjects are difficult to identify since they tend to remain normoglycaemic between meals. Their blood glucose levels are kept within the physiological range at the expense of hyperinsulinaemia, a condition known to accelerate atherosclerosis (Stout, 1996). Therefore, type II diabetes may seem a fairly mild form of diabetes, but the chronic state of hyperinsulinaemia may have compromised the subjects cardiovascular reserve capacity. In the second half of pregnancy insulin resistance increases 23-fold (Metzger and Freinkel, 1990). If the limited insulin reserves are insufficient, particularly postprandially when insulin

requirements are highest, gestational diabetes will develop (Langer and Langer, 1993). In most cases the clinical consequence is limited to macrosomia. However, if pregnancy is preceded by several years of hyperinsulinaemia, it is conceivable that the vascular reserves may have been eroded or even subclinical angiopathy may have developed, giving rise to an increased risk for vascular complications during pregnancy such as pregnancy-induced hypertension, (pre-)eclampsia, and fetal growth restriction. In that case the development of macrosomia as an early warning sign of gestational diabetes may be blunted, which would delay the institution of intensified surveillance of the endangered fetus. If occult angiopathy is suspected, it is recommended to rule out renal damage (microalbuminuria) or (borderline) hypertension before pregnancy or in the first trimester. In the context of this review the group of undiagnosed type II diabetics presents the most important target group which is characterized by usually minimal diabetic symptoms. By screening of high-risk groups including women >30 years of age, ~50% of all gestational diabetics can be identified (Coustan et al., 1989). The American Council on Obstetrics and Gynecology (ACOG) recommends screening for gestational diabetes in all pregnant women >30 years. The rationale behind this recommendation is the unanimous observation of a strong positive relationship between gestational diabetes and age, the median rise between 25 and 40 years being more than 5-fold (Table II). Diabetes and hypertension are associated with obesity, a condition that correlates strongly with age (Naeye, 1990; Metzger et al., 1993). Therefore in theory, the age-dependency of type II diabetes may be in part related to the also increasing prevalence of obesity with age, a condition associated with diminished insulin sensitivity. During pregnancy the most important objective of clinical management of diabetes is to achieve normoglycaemia from conception until delivery (ACOG, 1986). Normoglycaemia in the periconceptional period and during the first trimester minimizes the risk of the typical congenital anomalies (Langer and Langer, 1993). These complications apply almost exclusively to type I diabetics because gestational (type II) diabetes does not develop before the second half of pregnancy in concert with the development of the physiological insulin resistence. Normoglycaemia between 12 weeks and term can be expected to reduce the incidence of stillbirth, polyhydramnios and macrosomia. If the latter complication does develop, it will be associated with an increased risk for preterm labour, pre-eclampsia and placental abruption. For a detailed description of the management of diabetes in pregnancy, the reader is referred to the available literature on this subject (Garner et al., 1990; Oats, 1991)

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Table II. Incidence (%) of gestational diabetes according to age

2029 years Kaltreider (1959) Grimes and Gross (1981) Kirz et al. (1985) Edge and Laros (1993) Prysak (1995) Bianco et al. (1996) Median 0.6 0.8 1.3 1.1 2.8 4.3 1.2 >35 years 1.7 8.6 6.2 5.1 6.4 10.5 6.3 P < 0.01 < 0.05 < 0.001 < 0.01

Table III. Mode of delivery in different age groupsa

Age group (years) 2029 (n = 6978) Operative vaginal births (%) Nulliparae Multiparae Caesarean births (%) Nulliparae Multiparae 18.3 8.9 38.9 24.7 3.1 (2.63.7) 3.3 (2.64.1) 30.6 8.7 35.9 13.6 2.4 (1.92.9) 1.5 (1.21.9) 40 (n = 1404) Adjusted odds ratio (95% CI)

aAdapted from Bianco et al. (1996). CI = confidence interval.

Labour Data reported on the relationship between prematurity and maternal age are conflicting, some providing evidence for a rise (Milner et al., 1992; Ezra et al., 1995), others for a fall, with age (Kirz et al., 1985; Barkan and Bracken, 1987; Bianco et al., 1996). To the best of our knowledge, there are no reports in the English literature suggesting an age-dependent increase in postmaturity. Recently, it has been demonstrated that the rate of Caesarean births increases with age, irrespective of parity (Piper et al., 1991; Peipert and Bracken, 1993; Bianco et al., 1996; Irwin et al., 1996). The data of the largest of these studies are summarized in Table III. Apparently, the probability of delivering vaginally decreases with advancing age. In part, this phenomenon can be explained by a higher Caesarean section rate in conjunction with the following age-related confounders (listed in parentheses): fetal distress (cardiovascular disorders with superimposed gestosis), multiple pregnancy (multiple ovulation), non-vertex presentation (e.g. leiomyomas, multiparity giving rise to reduced support

from relaxed pelvic muscles), macrosomia (gestational diabetes), placenta praevia (multiparity) and repeat Caesarean (multiparity). Other reported medical reasons to deliver a patient of advanced age by Caesarean section are contracted pelvis and maternal distress. The agedependency of those conditions is less clear, although it is conceivable that they represent the often inevitable outcome of protracted labour. The incidence of protracted labour increases with age (Berkowitz et al., 1990) and has been suggested to be the functional consequence of less efficient myometrial gap junctions (Bianco et al., 1996) or less sensitive myometrial oxytocin receptors (Ezra et al., 1995). There is also evidence for an age-related loss of elasticity of the pelvic joints (White et al., 1993), a phenomenon likely to contribute to the increased resistence of the birth canal during the second stage of labour. From a theoretical point of view the expulsion force may be lower in the woman >35 years old in the second stage of labour, as a direct consequence of an age-dependent fall in skeletal muscle mass including the muscles of the abdominal wall (Hurley, 1995). The possible contribution of the mother being physically less trained to expel the fetus, and of psychological factors including the more indulgent attitude of the obstetrician to terminate pregnancy by a Caesarean section, awaits confirmation by a properly designed study. In summary, a possible rise in prematurity or postmaturity with age is not supported by scientific evidence. On the other hand, labour is more often dysfunctional in the older gravida giving rise to a higher rate of Caesarean births. At least part of this phenomenon is a consequence of age-related confounders possibly in combination with age-dependent structural/functional changes of the birth canal. It has never been determined whether the physicians attitude contributes to the higher rate of Caesarean births in older gravidas by considering them to be at high risk or their pregnancies to be more precious. Perinatal mortality Perinatal mortality rate (PMR) in older women is in most cases associated with multiparity, low socio-economic status, preterm birth, intrauterine growth restriction, congenital anomalies and peripartum complications such as asphyxia, birth injuries and infections (Kielly et al., 1986; Cnattingius et al., 1992). In the 1970s and 1980s PMR in 35 year old gravidas has decreased from 72 to 14 per 1000 live births (Grimes and Gross, 1981; Kirz et al., 1985; Rosenfeld, 1990). Nevertheless, the age-dependent rise in PMR by ~3% per year of age is still present (Selvin and Garfunkel, 1976). Interestingly, there are strong indications to support the view that the entire

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age-dependent increase in PMR is caused by obstetric complications resulting from age-dependent confounders such as hypertension and diabetes (Stein et al., 1983; Yasin et al., 1988; Ezra et al., 1995). It follows that when 35 year old patients with these health problems are excluded from the analysis, the PMR may approach the rate observed in younger gravidas. Pregnancy in postmenopausal women Since 1993 several authors have reported succesful pregnancies in peri- and post-menopausal women (Antinori et al., 1993, 1995; Sauer et al., 1993, 1996). Establishing pregnancy in postmenopausal women is undoubtedly a breakthrough attracting worldwide attention. By means of in-vitro fertilization (IVF) procedures, oocytes donated by younger women are fertilized and than transferred to the peri- or postmenopausal recipient. A screening test for ovarian reserve may help to identify women with reduced ovarian reserve, to whom oocyte donation with IVF could be offered (Marcus and Brinsden, 1996). Nowadays the worldwide demand by patients in their fifties to establish a pregnancy using these techniques is rapidly increasing. Leaving aside ethical aspects such as the reliance on donor oocytes and the lower life expectancy of the older gravida, it must be emphasized that the risk to pregnancy in a postmenopausal woman is not higher than in a younger woman, provided a thorough prepregnancy medical check-up has confirmed her excellent state of health (Narayan et al., 1992; Sauer et al., 1993; Antinori et al., 1995). It should be emphasized, though, that this conclusion is based on studies performed in small groups of women, most of whom were <55 years of age. The possible effects of pregnancy on the ageing postmenopausal body and vice versa will be discussed in the next two paragraphs.
Impact of the ageing body on pregnancy

Pregnancy puts extra strain upon (i) the cardiovascular system, (ii) the reserve capacity of the pancreatic -islets, (iii) the volume regulatory system including the kidneys, (iv) the decidualized endometrium to provide proper growing conditions for the trophoblast/placenta, (v) the uterine cavity to accommodate the growing conceptus, and (vi) the myometrium, abdominal muscles and birth canal to enable expulsion of the conceptus. In women atherosclerotic changes in the cardiovascular system accelerate after the onset of postmenopause (Evans and Williams, 1992). This is for example reflected in a more rapid rise in the incidence of hypertension (Kaplan,

1994). Accelerated atherosclerosis is the result of the changed steroid environment and consequently the atherogenetic lipid and carbohydrate profiles (Gaspard et al., 1995). Postmenopausal women tend to become more obese, giving rise to more insulin resistance. The latter either triggers a state of chronic hyperinsulinaemia or overt type II diabetes, both effects further potentiating the development of atherosclerosis (King et al., 1996). These phenomena are paralleled by a natural loss of cardiovascular compliance and cardiac reserve capacity (Shewman, 1994; Taddei et al., 1995). It follows that the risk for cardiovascular complications during pregnancy, such as pregnancy-induced hypertension, (pre-)eclampsia, fetal growth restriction, are likely to increase exponentially with the number of years elapsed since the onset of postmenopause. Volume regulation is markedly altered during pregnancy (Lindheimer and Katz, 1991; Duvekot and Peeters, 1994b). Essential hypertension is preceded by a long latent phase characterized by for example a compensatory reduction of the plasma volume (Kaplan, 1994). In early pregnancy plasma volume increases rapidly (Davison and Noble, 1981; Duvekot and Peeters, 1994b). In a recent study in ex-pre-eclamptic women we found the plasma volume to be chronically reduced (Duvekot et al., 1995; van Beek et al., 1997). The data suggested that subnormal plasma volume before pregnancy may predispose for vascular complications during pregnancy. With respect to endometrial ageing there is still controversy. The high rate of implantation and pregnancy in older donor embryo recipients has challenged the concept that uterine receptiveness declines with age (Devroey et al., 1996). In a large series, the rate of spontaneous abortions did not increase with the age of the donor-embryo recipient (Devroey et al., 1996). It should be emphasized that most of these recipients were <50 years old. Whether the accelerated vascular ageing in the postmenopause affects also the spiral arteries remains to be determined. The postmenopausal uterus is perfectly capable of accomodating the growing fetus until term. The theory of uterine senescense is not supported by experimental evidence. (Antinori et al., 1993; Flamigni et al., 1993). When the embryos from the same cohort of young donated oocytes were simultaneously transferred to young and older recipients, the rate of ongoing pregnancy was similar (Navot et al., 1994). Information about the effect of pregnancy on regressed fibromyomas in postmenopausal women is lacking. The high levels of circulating oestrogens may induce growth. The majority of women with fibromyomas will have no problem during pregnancy.

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In older pregnant women a higher incidence of (for example) recurrent miscarriage, placental abruption and mechanical problems during labour have been described, possibly caused by myomas. For details regarding clinical management the reader is referred to the related literature (Hasan et al., 1991). Besides myomas there is also an age-dependent increase in the incidence of protracted labour culminating in more Caesarean sections. Postsurgical complications are well-known to increase as a function of age (Abyad, 1995). Therefore, we speculate that the increasing rate of Caesarean sections with more years elapsed since onset of the postmenopause can be expected to lead to more postoperative complications such as thromboembolism and infections.

Impact of pregnancy on the ageing body

Already by the eighth week of pregnancy a hyperdynamic circulation is instituted with an ~30% higher cardiac output accompanied by a 5% decrease in mean arterial pressure (Duvekot and Peeters, 1994a) and an ~30% increase in plasma volume (Duvekot and Peeters, 1994b). These changes impose extra strain upon the cardiovascular system as (for example) reflected in the mild physiological myocardial hypertrophy induced by pregnancy (Duvekot et al., 1993). The cardiovascular reserves of postmenopausal women (for example) >60 years of age are reduced by the biological effects of ageing: loss of cardiovascular compliance, increase in myocardial wall thickness and fall in maximum heart rate. Moreover, simply because of their age these women have a higher chance of suffering from some cardiovascular disorder than their younger counterparts (Metcalfe et al., 1986; Evans and Williams, 1992). On the basis of this information the impact of pregnancy on maternal haemodynamics can be deduced. If the reserve capacity of the cardiovascular system is sufficient, the impact of pregnancy on the maternal haemodynamic function may be relatively mild, restricted to the course of pregnancy: mild fetal growth restriction, pregnancy-induced hypertension, intra-uterine fetal death and (pre-)eclampsia. However, if the cardiovascular reserves are marginal or the subject has some pre-existent (sub)clinical cardiovascular disorder, maternal haemodynamic function may deteriorate with the most severe complication being congestive heart failure and cardiac arrest (Metcalfe et al., 1986; James et al., 1994). The risk of thromboembolism may also be increased as a result of the higher mechanical stress during systole imposed upon the platelets by the more rigid arteries, an effect that may lead to activation of the clotting cascade.

In postmenopausal women reduced pancreatic -cell sensitivity and increased peripheral insulin resistance act in concert to progressively reduce glucose tolerance (Evans and Williams, 1992). The insulin resistance of pregnancy develops in the second half of pregnancy. Therefore, the incidence of gestational diabetes in postmenopausal women can be expected to increase exponentially as a function of age. The consequences of type II diabetes have been described in a previous paragraph. Regarding skeletal structures, postmenopausal women suffer more than their premenopausal counterparts from rheumatic disorders and osteoporosis (White et al., 1993); whether this leads to substantial bone injuries during pregnancy could not be confirmed by the available literature. Obviously, protracted labour and Caesarean section rate can be expected to increase with age, also in postmenopause. In this respect it should be emphasized that postsurgical morbidity also increases with age. In summary, oocyte donation to postmenopausal women disengages the reproductive period in a woman from its biological boundaries. As a consequence, ageing of a key organ system, such as the cardiovascular system, may evolve to a new upper boundary for pregnancy outcome. The available literature suggests that pregnancy outcome is good in women found to be in good health on the basis of a thorough prepregnancy medical screening. However, many reports on pregnancy in postmenopausal women are hampered by either selection bias or the use of very small study populations. It follows that the medical implications of pregnancy in the postmenopause are still highly speculative. From a theoretical point of view, the impact of cardiovascular ageing on pregnancy in postmenopausal women is particularly worrisome and should be subject to properly designed studies before oocyte donation to postmenopausal women is introduced as a routine procreational option. Discussion Maternal mortality increases as a function of maternal age. Age alone cannot be held responsible for this observation. Associated risk factors such as hypertension and diabetes are seen more frequently in the older gravida and account for increased incidences of placental abruption, intra-uterine growth retardation and (pre-)eclamptic disease, all of them being associated with a higher risk for (emergency) Caesarean section. In turn, the latter is associated with a higher risk for haemorrhage and infectious complications. Most studies report an age-related increase in maternal mortality especially among black, poor women aged >40 years.

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Women >35 years of age also have a higher risk for complications during their pregnancy. Nowadays, biological limits to reproduction imposed by ageing oocytes have been largely overcome since the introduction of IVF techniques using donor oocytes. Further refinement of the procedure to optimize endometrial receptiveness is subject to current research. The myometrium is also subject to change with age: the incidence of myomas is increased and the expulsion of the uterine contents seems to be less adequate, giving rise to a higher rate of dysfunctional labour and consequently a higher rate of Caesarean births. One aspect which is less easily influenced by modern techniques is the ageing of the cardiovascular system, a phenomenon which can be expected to interfere with the normal haemodynamic adaptation of pregnancy. Even if a pregnant woman 35 years old is normotensive she will have at least twice the risk of having her pregnancy complicated by pregnancy-induced hypertension or pre-eclampsia than her younger counterpart. Also diabetes increases as a function of age, but is easily manageable by supplemental insulin once the diagnosis is made. There is still controversy about the relationship between maternal age and neonatal outcome in terms of prematurity and neonatal mortality. Most recent reports indicate a lower incidence of prematurity in older pregnant women than in their younger counterparts. In large retrospective studies it was shown that PMR in pregnant women >40 years of age is slightly higher than in younger women, when chronic diseases such as hypertension and diabetes were excluded. This can partly be explained by the age-related increase in confounders such as congenital anomalies. A new era has begun in which the modern woman is able to postpone childbearing to her own desire, even to the period in which reproduction normally ends. Oocyte donation is commonplace in non-ovulating recipients as well as in the postmenopausal. At present oocyte donation to postmenopausal women is practised under close medical care. Theoretically, the latter women are at increased risk for adverse pregnancy outcome. However, this needs to be confirmed in future studies.

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Received on January 29, 1998; accepted on March 30, 1998