Pregnancy: a stress test for life David Williams Purpose of review This review describes how the physiological demands of pregnancy act as a maternal stress test that can predict a woman’s health in later life. Pregnancy transiently catapults a woman into a metabolic syndrome that predisposes to vascular endothelial dysfunction. Women who are already predisposed to this phenotype develop gestational hypertension or diabetes mellitus, which re-emerge in later life as the metabolic syndrome returns. Pregnancy can also temporarily unmask sub-clinical disease, which may return in later life when the effects of ageing diminish the limited reserves of a vulnerable organ. Recent findings Recent studies have attempted to assess how gestational syndromes affect the risk for a woman of developing a diverse range of diseases in later life. As well as cardiovascular disease and diabetes mellitus, pregnancy can reveal a vulnerability to thyroid and pituitary disorders, liver and renal disease, depression, thrombosis and even cancer. Summary Although our knowledge of this phenomenon is incomplete, women who have had gestational syndromes, in particular pregnancy-induced hypertension/preeclampsia or gestational diabetes, should make lifestyle changes that will reduce their risk of cardiovascular disease in later life. Keywords pre-eclampsia, metabolic syndrome, hypertension, gestational diabetes mellitus, ischaemic heart disease Curr Opin Obstet Gynecol 15:465–471.
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During pregnancy, almost every organ of the mother’s body has to work harder in order to meet the demands of the developing fetus. Each maternal organ adapts in a different way and at a different time [1]. Gestational syndromes develop when an organ system is unable to meet the increased physiological demands of pregnancy. In general these demands become greater as pregnancy progresses and therefore gestational syndromes are more common in the third trimester. Delivery induces remission, but it is only transient. Some or all of the components of the clinical syndrome reappear in later life when the cumulative effects of ageing diminish the reserves of an already vulnerable organ (system), or the age-related return to a pro-atherogenic state triggers the metabolic syndrome that leads to cardiovascular disease and diabetes mellitus. Pregnancy therefore acts as a medical stress test for the mother. This is particularly evident in women who conceive with chronic medical disorders. The limited reserves of an impaired organ will be unmasked and the organ fails to increase its function during pregnancy. As a consequence the already impaired maternal organ can be irreparably damaged and fetal outcome compromised. This review will focus on gestational syndromes that emerge in previously ‘healthy’ women and how pregnancy outcome can predict a woman’s risk of disease in later life.
2003 Lippincott Williams & Wilkins.
Department of Academic Obstetrics and Gynaecology, Imperial College London, Chelsea and Westminster Hospital, London, UK Correspondence to Dr David Williams PhD, MRCP, Senior Lecturer Obstetric Medicine, Department of Academic Obstetrics and Gynaecology, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK Tel: +44 20 8237 5175; fax: +44 20 8237 5089; e-mail:
[email protected] Current Opinion in Obstetrics and Gynecology 2003, 15:465–471 Abbreviations DVT GDM IHD LVEF
Introduction
deep vein thrombosis gestational diabetes mellitus ischaemic heart disease left ventricular ejection fraction
# 2003 Lippincott Williams & Wilkins 1040-872X
Preeclampsia and pregnancy-induced hypertension As healthy pregnancy progresses the mother is propelled into an increasingly proatherogenic metabolic syndrome [2 .,3 .]. Shortly after conception she develops a high cardiac output [4], hypercoagulability [5] and increased inflammatory activity [6]. After 20 weeks she develops insulin resistance [3 .,7] with dyslipidaemia [8]. Each of these adaptations is more pronounced in women with pregnancy-induced hypertension and preeclampsia [3 .,4–8]. In later life women who have had preeclampsia or pregnancy-induced hypertension are at increased risk of cardiovascular disease [2 .,9–13,14 . .]. Pregnancy, therefore, transiently unmasks a woman’s tendency to the metabolic syndrome of insulin resistance that may re-emerge permanently in later life. The massive Norwegian medical birth registry has proved a useful resource for the study of long-term follow up of women who have had preeclampsia. Irgens et al. [13] followed-up women for a median of 13 years
DOI: 10.1097/01.gco.0000103846.69273.ba
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after their preeclampsia. They found that those who delivered preterm (before 37 weeks), but not those who delivered after 37 weeks, had an 8.12 fold (95% CI 4.31– 15.33) increased risk of death from cardiovascular disease and a 5.08 fold (95% CI 2.09–12.35) increased risk of death from stroke compared with women who had a normotensive pregnancy. Women who simply had preterm delivery (before 37 weeks) without preeclampsia also had an increased risk of death in later life from cardiovascular disease of 2.95 (95% CI 2.12–4.11) [13]. These observations suggest that a different pathophysiology may explain early preeclampsia, which is associated with low birth-weight babies and late preeclampsia, which is associated with high birth-weight babies [15]. There may also be shared pathology for preeclampsia and preterm labour that predisposes to cardiovascular disease in later life [12,13]. A pathophysiological link between early preeclampsia, preterm labour, low birth weight and maternal cardiovascular disease is further suggested by the observations of Smith et al. [12]. They linked information on obstetric outcome for a first singleton pregnancy in 129 920 Scottish women with death or admission for ischaemic heart disease (IHD) 15–19 years later. They found that the maternal risk for IHD was increased by 1.9 (95% CI 1.5–2.4) if a woman had a baby in the lowest birth weight quintile for gestational age. Those giving birth to babies weighing less than 2500 g had an 11 times greater risk of death from IHD compared with those giving birth to babies weighing more than 3500 g. In women who had preterm labour the risk of IHD increased by 1.8 (95% CI 1.3–2.5) and if preeclampsia developed the risk of IHD increased by 2.0 (95% CI 1.5–2.5). If all three obstetric outcomes were present in the same individual, then her risk of death or admission for IHD in later life was increased sevenfold (95% CI 3.3–14.5) [12]. Another group in Scotland studied 3593 women and found that, compared with women who had a normotensive pregnancy, women who had isolated pregnancyinduced hypertension had an adjusted relative risk of hypertension in later life of 1.13–3.72 and for those who had preeclampsia the adjusted risk was 1.40–3.98 [14 . .]. The adjusted risk for death from stroke for the preeclampsia group was 3.59 (95% CI 1.04–12.4) [14 . .]. The risk of hypertension in later life following preeclampsia is further increased if preeclampsia develops in a second pregnancy [16]. Chesley [17] and Bryans [18] followed-up a group of women who developed eclampsia in their first pregnancy, for 33 years and 14 years respectively. They found no excess of hypertension compared with agespecific averages taken from other epidemiological studies [17,18]. More recently, Marin et al. [10] also
found that the prevalence of hypertension 13.7 years after an eclamptic pregnancy (14%) was similar to that found in women who had a normotensive pregnancy. Unlike Chesley and Bryans, Marin et al. found that the prevalence of late hypertension was higher in women who had had pregnancy-induced hypertension (54%) and preeclampsia (38%). Furthermore, Sibai et al. [16] followed-up 210 previously normotensive women who had eclampsia in their first pregnancy for an average 7.2 years. Although they did not compare this cohort with a group of women who had a normotensive pregnancy, they found that the highest incidence of chronic hypertension (17.9%) was in those women who had eclampsia before 30 weeks gestation and the lowest incidence (4.8%) was in those who had eclampsia after 37 weeks. If the subsequent pregnancy was complicated by preeclampsia then the incidence of hypertension 7.2 years later was 25%, compared with 2% for women who had a normotensive pregnancy following their eclamptic pregnancy [16]. An explanation for the discrepancy between early studies that followed-up women who had eclampsia (termed ‘true preeclampsia’ by Chesley) and more recent studies that followed-up women with preeclampsia, is that the epidemiological groups chosen to represent a normal population were themselves marginally hypertensive [17,18]. Fisher et al. [19] made the same observation in a group of 53 preeclamptic women who were followed-up for an average of 6 years and were found to have the same prevalence of hypertension as the national average. However, women who had a normotensive, term pregnancy had a substantially lower prevalence of hypertension compared with the national average 6 years later [19]. Indeed, most women remain normotensive throughout a term pregnancy. An uneventful obstetric history bodes well for maternal health during subsequent pregnancies and places these women in a privileged position with a low risk of cardiovascular disease in later life [13,19].
Gestational hypertension and cardiovascular disease in later life: a common pathology Obesity and polycystic ovary syndrome predispose to insulin-resistance, which may also exist as a sub-clinical condition in apparently healthy women [20]. When these women are exposed to the additional metabolic and cardiovascular changes of pregnancy, a previously sub-clinical condition manifests as gestational hypertension or diabetes mellitus [3 .,20–23]. Women who develop pregnancy-induced hypertension or preeclampsia after 37 weeks gestation tend to have larger babies [15]. It is possible that these women are insulin resistant and the associated hyperdynamic circulation enhances, rather than diminishes, utero-placental blood flow.
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Conversely, women with early (before 37 weeks) preeclampsia tend to have smaller babies than normotensive gestation-matched controls [15]. In this group of women utero-placental ischaemia generating a pro-oxidant environment may be an additional trigger to maternal endothelial dysfunction. Savvidou et al. [24 . .] recently used Doppler ultrasound to measure brachial artery flow-mediated dilatation (a measure of vascular endothelial function) to demonstrate that women who had high resistance utero-placental blood flow at 24 weeks gestation already had impaired maternal endothelial function, prior to the onset of clinical preeclampsia. The origins of preeclampsia clearly lie before 24 weeks gestation and in some women, if not all, predate pregnancy. Preeclampsia runs in families and any number of genes that contribute to the metabolic syndrome that predisposes to cardiovascular disease may also contribute to preeclampsia [25,26]. After a pregnancy affected by preeclampsia, but before the onset of clinical cardiovascular disease, there is evidence of sub-clinical maternal endothelial dysfunction. Chambers et al. [27] used brachial artery flowmediated dilatation to demonstrate that women who had preeclampsia had impaired endothelial function compared with a group of women who had an uncomplicated pregnancy, a median 3 years after delivery. The metabolic syndrome also persists postpartum; this may either be clinically apparent, as judged by an elevated body mass index, compared with those who had a normotensive pregnancy, or subclinical, as judged by elevated blood pressure, triglycerides and total and low-density lipoprotein cholesterol [22]. Longer follow-up has shown that 15–25 years after pre-eclampsia, women have higher circulating levels of vascular adhesion molecules and evidence of insulin resistance compared with women who had normotensive pregnancies [28,29 .]. Taken together these studies show that the metabolic syndrome evident during preeclampsia persists postpartum and may explain the increased risk of cardiovascular disease in later life. It must be remembered that preeclampsia is a heterogeneous syndrome whose pathology is probably different between the early and late onset condition [30] and differs from non-proteinuric, pregnancy-induced hypertension [3 .]. There is no single pathophysiological pathway to clinical preeclampsia. Until we know more about the pathogenesis of different categories of this syndrome, we will be limited in our ability to predict the long-term health of women who have suffered the condition.
Preeclampsia and cancer Irgens et al. [13] found that women with pre-term preeclampsia had a trend towards a reduced risk of death from cancer 0.36 (95% CI 0.12–1.11). This is not a unique finding. Vatten et al. [31 .], using a similar database of 694 657 women, found that women who had gestational hypertension in their first pregnancy had a 19% lower risk (95% CI 9–29%) of having breast cancer compared with parous women who had a normotensive pregnancy. One possible reason for this observation is the ubiquitous finding that smoking protects against preeclampsia [32]. The mechanism for this protective effect is unknown, but it is possible that women who smoked during their pregnancies and avoided preeclampsia continued to smoke long-term and subsequently died of cancer. However, the benefit of smoking in order to reduce the risk of preeclampsia is more than compensated by the harmful effects of smoking on perinatal outcome. These include an increased risk of intra-uterine growth restriction, placental abruption, preterm rupture of membranes, placenta praevia and ectopic pregnancy [32]. It has also been suggested that low levels of oestrogen may predispose to preeclampsia and protect against breast cancer [33].
Thrombophilia in pregnancy In anticipation of haemorrhage at childbirth, normal pregnancy is characterized by low grade, chronic intravascular coagulation within both the maternal and utero-placental circulation. As a consequence a deep venous thrombosis (DVT) is more common during pregnancy and up to 6 weeks postpartum [5]. Inherited thrombophilias may lead to thrombosis only in combination with the hypercoagulable environment of healthy pregnancy [34]. A DVT during pregnancy needs to be treated with heparin until at least 6 weeks postpartum [5]. Once anticoagulation is completed a thrombophilia screen and family history of thrombosis will assess her future risk of thrombosis. However, women who have had a DVT are at increased risk of morbidity in later life due to post-thrombotic syndrome [5]. Hypercoagulation is also part of the metabolic syndrome that leads to atherosclerosis and preeclampsia [2 .]. Thrombophilias have been associated with preeclampsia in some studies but not in others [35]. It is interesting that the risk of future thrombosis in women who have had preeclampsia appears to be slightly increased 2.2 (95% CI 1.3–3.7) [36].
Gestational diabetes mellitus Gestational diabetes mellitus (GDM) emerges in the second half of pregnancy in those women who have a degree of preexisting insulin resistance or who have pancreatic beta cells with a limited capacity to increase insulin secretion in response to gestational insulin
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resistance [37]. As soon as the placenta is delivered the additional insulin resistance of pregnancy disappears and glucose tolerance usually returns to normal. This is a temporary situation until a further pregnancy again leads to GDM or non-gestational diabetes develops in later life. Depending on the severity of their insulin resistance, women who have had GDM have a 20–60% risk of developing type 2 diabetes mellitus within 5–16 years of the index pregnancy [37]. It is routine practice therefore to check glucose tolerance in all women who have had GDM at 6 weeks post-partum and every 3 years thereafter [37]. Fewer than 50% of women who had GDM will return for postpartum screening. In order to stratify those at highest risk of persistent diabetes, a special effort should be made with women who had a highest fasting plasma glucose above 6.05 mmol/l during pregnancy [38 .]. These women have a 21-fold (95% CI 4.6–96) increased odds ratio of developing diabetes mellitus (36.7%) compared with women who had a maximum gestational fasting plasma glucose below 4.75 mmol/l, with an odds ratio of developing diabetes mellitus of 0.5% [38 .]. Further follow-up to encourage weight-loss, a healthy diet and blood glucose and blood pressure monitoring will limit the emergence of type 2 diabetes mellitus.
Gestational diabetes insipidus During healthy pregnancy the placenta produces an enzyme, vasopressinase, which degrades vasopressin [39]. In response, the maternal posterior pituitary produces up to four times as much vasopressin in order to sustain water homeostasis [39]. During the third trimester, when the placenta is expressing the highest concentrations of vasopressinase, women who are unable to increase their pituitary output of vasopressin develop diabetes insipidus [40]. They have polyuria and polydipsia until the source of increased vasopressinase, the placenta, is removed. During the third trimester these women can be safely treated with 1-desamino-8-Darginine vasopressin (DDAVP), which can be stopped postpartum. Although there are no long-term follow up studies of these women, transient gestational diabetes insipidus recurs in the third trimester of subsequent pregnancies [40]. Imaging of the pituitary is important to determine pathology.
Almost half of all women who develop postpartum thyroid dysfunction and who have thyroid peroxidase antibodies will remain hypothyroid more than 6 years later [42]. Twenty-four percent of euthyroid women who have a family history of thyroid disease have thyroid peroxidase antibodies [43]. The association of thyroid peroxidase antibody with the future development of thyroid failure, especially in association with pregnancy, is an indication to check thyroid function at least once during pregnancy and again 6 weeks postpartum.
Peripartum cardiomyopathy Peripartum cardiomyopathy (PC) is an idiopathic form of heart failure that affects 1:10 000 pregnancies. Peripartum cardiomyopathy can be fatal or cause a mild reduction in left ventricular ejection fraction (LVEF) that recovers fully. In general, the amount of residual cardiac function after recovery from PC dictates maternal survival and cardiac function in a future pregnancy [44]. In women who make a good recovery (LVEF450%) the haemodynamic demands of the next pregnancy lead to an average 20% fall in LVEF that usually recovers back to more than 50% postpartum [44]. However, 20% of women who recovered well from PC and 44% of women who did not recover so well (LVEF550%) had a marked fall in LVEF during a first subsequent pregnancy. This may be due to recurrence of the idiopathic process that causes cardiomyopathy, or due to the increased strain of pregnancy-related haemodynamic overload [44]. Six years following PC, 14% of women who had an LVEF over 50% had depressed cardiac function, as did 31% of those who had an LVEF below 50% [44]. At present there are no longer term survival studies, but it would seem likely that over time women with the lowest LVEFs would show a progressive deterioration in LVEF.
Kidney disease
Thyroid disease
In the first half of pregnancy, asymptomatic proteinuria suggests underlying renal disease or infection. In the second half of pregnancy proteinuria may be associated with preeclampsia, which itself may be related to underlying renal disease. Women with proteinuria recognized during pregnancy should be followed-up postpartum, until either the proteinuria disappears or a diagnosis is made.
Thyroid disease is common in young women. Hyperthyroidism affects 0.2% of pregnancies and hypothyroidism about 2.5% [41]. Women who have thyroid peroxidase antibodies (approximately 10% in early pregnancy) have an increased risk of developing hypothyroidism during pregnancy and, if it does not develop during pregnancy, they have a 50% chance of postpartum thyroid dysfunction [41]. Overall, 5–9% of women develop postpartum thyroid dysfunction [41].
Preeclampsia is more common in women who are known to have underlying renal disease, especially when associated with chronic hypertension [45]. Conversely, the prevalence of renal disease in women with preeclampsia depends on how hard and for how long you look for it. At a time when hypertensive pregnant women had a routine renal biopsy postpartum, renal disease was evident in 12 out of 104 (11.5%) primi-
Pregnancy: a stress test for life Williams 469
gravidae and 19 out of 72 (26.4%) multiparous women [19]. Women who had the classic renal histology of preeclampsia, (glomerular capillary endotheliosis), also had nephrosclerosis or other renal disease in eight out of 87 (9.2%) primigravida and 10 of 27 (37%) multiparous women [19]. This study makes the point that preeclampsia occurring in a multiparous women should alert the clinician to look harder for underlying renal disease. Another cohort of 87 women who had preeclampsia were followed-up for between 3 months and 6 years and only two (2.3%) women were identified with renal disease [46]. Similarly, only two out of 99 women with pregnancy-induced hypertension were later found to have underlying renal disease [46]. A 10-year follow-up study found significant microalbuminuria in 11 of 47 (23%) women who had preeclampsia, nine of 54 (16%) who had pregnancy-induced hypertension and only one of 46 (3%) women who had a normotensive pregnancy [47]. Higher concentrations of microalbuminuria and hypertension have also been found in a group of Samoan women following preeclampsia [48]. These observations are in keeping with the increased risk of cardiovascular disease following preeclampsia, for which microalbuminuria is a risk factor [49].
Liver disease Healthy pregnancy is a cholestatic condition. As pregnancy progresses the liver metabolizes increasing concentrations of steroid hormones and secretes them into bile [50]. As a consequence, women with previously sub-clinical cholestatic disorders including specific bile acid transporter defects [51 .], gall-stones, hepatitis C or cholangitis are at increased risk of developing symptomatic cholestasis when the concentration of steroid hormone overwhelms their limited ability to excrete the metabolites into bile [51 .]. This usually develops in the third trimester and presents with pruritis and hepatic necrosis; raised alanine aminotransferase (ALT) and aspartate aminotransferase (AST). It is assumed that bile acids cause itching in areas where skin blood flow is greatest (i.e. palms and soles). The almost consistent recurrence of obstetric cholestasis in subsequent pregnancies further suggests an underlying maternal cholestatic disorder that is overwhelmed towards the end of each pregnancy. If liver function does not return to normal postpartum, women with ‘obstetric cholestasis’ should be investigated for sub-clinical hepatobiliary disease. The long-term sequelae for women who have had obstetric cholestasis is likely to relate to the underlying defect, but is not yet known. Acute fatty liver of pregnancy and preeclampsia/haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome can lead to serious liver disease [52]. The long-term survival of women who have had hepatic
failure in association with these conditions is good if they recover from the multi-system complications of the acute liver dysfunction [52].
Postpartum depression Almost half of all women develop the ‘maternity blues’. Approximately 10% of women develop nonpsychotic postnatal depression 4–6 weeks postpartum and these women are at an increased risk of developing depression in later life. Less than 2 per 1000 women develop a severe postpartum psychiatric disorder, which is associated with a 70-fold increased risk of suicide in the first postnatal year [53]. A 23-year follow-up of 64 women who had been admitted to a psychiatric hospital within 6 months of childbirth revealed that 29% had recurrent puerperal psychiatric illness and 75% had further psychiatric illness, not related to pregnancy [54].
Pregnancy in later life The menopause arrives at a time of life when the metabolic syndrome that leads to atherosclerosis is likely to be more advanced and ageing may have diminished an organ’s ability to accommodate the physiological demands of pregnancy. Women in the developed world now often ignore this timely and natural end to their fertility. There is a vogue to delay pregnancy until later life, which exposes a woman to a physiological challenge that would have optimally taken place up to 30 years earlier. The prevalence of preeclampsia, gestational diabetes and other complications is much greater in women over 40 years [55]. Even so this does not stop some women over 50 years old becoming pregnant by oocyte donation and ‘running the gauntlet’ of pregnancy induced complications to have a child [56].
Conclusion During pregnancy a transient metabolic syndrome (insulin resistance) develops, similar to that which predisposes to atherosclerosis. Women who develop pregnancy-induced hypertension, pre-eclampsia or gestational diabetes mellitus are at increased risk of developing cardiovascular disease in later life. These women should be advised to adjust their life-style postpartum by adjusting their diet, exercising regularly and having their blood pressure and plasma glucose levels monitored periodically. Such measures associated with timely and appropriate intervention should minimise their risk of developing cardiovascular disease in later life. Other transient gestational syndromes result from the physiological demands of pregnancy unmasking the limited reserves of a vulnerable organ system. At present our knowledge of the long-term outcome for women who have had pregnancy-related syndromes is still incomplete. A past obstetric history may however prove useful in determining the origin and pathology of
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diseases in later life. In this regard, the link between preeclampsia and a reduced risk of breast cancer is particularly intriguing.
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