Maternal health

Immediate, short-, and long-term complications following pregnancy

Gil Gutvirtz, Omri Zamstein, and Eyal Sheiner

Introduction

Pregnancy is a period of extreme change, as maternal physiology needs to adapt rapidly to sustain a growing fetus. Among the various physiological processes involved in the adaptation to the pregnant state, the cardiovascular and metabolic changes are probably the most pronounced and are thought to act as a “stress test” for the mother that might attribute to later maternal morbidity.

It was commonly assumed that women’s physiology returns to its pre-pregnancy state relatively soon after birth, but growing evidence shows that pregnancy, and specifically pregnancy metabolic and cardiovascular complications, such as hypertensive disorders and diabetes mellitus, may have important consequences on future maternal health.

It is unclear whether predisposing maternal conditions that were expressed during pregnancy eventually caused chronic morbidity or is it pregnancy itself that causes long-term effects on maternal health? Whatever the reason may be, pregnancy can be viewed as a window for future maternal health.

In this chapter, we review current data on future maternal health following pregnancies complicated with vascular and metabolic complications such as hypertensive disorders and diabetes mellitus.

Placental syndromes

The complex process of placentation in early pregnancy requires many vascular changes in order to allow appropriate maternal blood flow to the placenta. The process involves many cytokines and other anti-inflammatory mediators to prepare a receptive vascular bed for the growing placenta. It has been hypothesized that placental malfunction, and specifically defective deep placentation that was first described in preeclampsia and intrauterine growth restriction (IUGR) (1), may be associated with “the great obstetrical syndromes,” also known as “placental syndromes,” such as preeclampsia, IUGR, intrauterine fetal demise and preterm labor (2). These syndromes are now being investigated for their association with increased risk of vascular diseases in maternal future life.

In general, mothers whose pregnancy was complicated with “‘placental syndromes” are at increased risk for early all-cause mortality, as the lifetime risk for chronic hypertension and cardiovascular and cerebrovascular disease is elevated.

Some epidemiologic data suggest that the increased risk of future cardiovascular morbidity/mortality in these women can be attributed to underlying maternal genetic factors and risk factors that are common to both disorders (3), and pregnancy acts as a cardiovascular stress test in the same way that it is a metabolic stress test for future development of diabetes. It is also possible that placental syndromes during pregnancy, and specifically hypertensive disorders, induce physiologic and metabolic changes associated with cardiovascular disease (CVD), such as endothelial dysfunction (4), insulin resistance, sympathetic overactivity, pro-inflammatory activity, and abnormal lipid profile (5), that remain after delivery, leading to late CVD (6) and other disorders associated with these abnormalities.

Hypertension in pregnancy

Hypertension (defined as systolic blood pressure [BP] ≥140 mm Hg and/or diastolic BP ≥90 mm Hg) is probably the most common medical problem encountered during pregnancy, complicating up to 10% of pregnancies (7). Hypertensive disorders during pregnancy (HDP) are generally classified into four categories: (1) chronic hypertension (elevated BP before 20 weeks’ gestation or persisting beyond 12 weeks postpartum), (2) preeclampsia (new-onset BP elevations after 20 weeks’ gestation coupled with m proteinuria or end-organ dysfunction), (3) preeclampsia superimposed on chronic hypertension, and (4) gestational hypertension (GH) (new onset of hypertension at ≥20 weeks of gestation in those who do not meet the criteria for preeclampsia) (8).

HDP are associated with increased perinatal morbidity and mortality, which is primarily due to the need for elective premature delivery and uteroplacental insufficiency resulting in a compromise of blood flow to the fetus (9).

Maternal consequences of hypertensive disorders during pregnancy

Women with HDP appear to be at increased risk for early all-cause mortality and some cause-specific mortality (ischemic heart disease [IHD], stroke, diabetes) (10). The risk is related to the severity of preeclampsia, the gestational age at onset (early onset usually defined as <34 weeks’ gestation), and the number of disease recurrences (11). Importantly, the severe form is usually with earlier onset and is associated with poor placentation and fetal growth restriction, leading to a greater risk for adverse maternal outcomes.

Immediate and short-term (up to 10 years) consequences of HDP

Maternal immediate and short-term outcome of HDP is usually benign as complete resolution of the maternal signs and symptoms of the disease normally occurs in the postpartum period, with some symptoms quickly disappearing (e.g., headache), while others may take weeks or months (e.g., proteinuria). Hypertension may worsen during the first or second postpartum week but normalizes in most women within 4 weeks postpartum (12). Nevertheless, progression to severe disease and eclampsia may present after delivery, with approximately 11%–44% of cases of eclampsia occurring postpartum (13). Although most cases of postpartum eclampsia occur within the first 48 hours, some cases can develop beyond 48 hours postpartum and have been reported as late as 23 days postpartum (13).

In the short term, even after resolution of symptoms, an elevated risk for cardiovascular morbidity was suggested in many publications. The maternal cardiovascular system recovery postpartum from preeclampsia seems to affect both arterial and venous systems, as asymptomatic left ventricle systolic and diastolic dysfunction can persist at 1 year postpartum in women with preeclampsia (14).

An elevated risk for subsequent hypertension in the few years following delivery was demonstrated in various studies. Black et al. (15) studied almost 6,000 women who were normotensive prior to pregnancy and found that women who developed HDP had more than twice the risk of developing prehypertension or hypertension in the year after delivery compared to those without HDP. A year later, Behrens et al. reported an even higher risk, with 12-to 25-fold higher rates of hypertension in the year after delivery for women with HDP compared to normotensive pregnancies (16). The rates remained up to 10-fold higher from 1 to 10 years postpartum. Most recently, Egeland et al. published their results from a population-based Norwegian cohort and found that preeclampsia and GH were associated with six- and sevenfold increased risk of pharmacologically treated hypertension, respectively, within 10 years of delivery (17).

Women with HDP have also been found to be at increased risk for CVD as soon as 5 years after delivery. In a retrospective study of more than 300,000 women, Cain et al. found that the risk for CVD (such as coronary heart disease, cerebrovascular disease, peripheral artery disease, or congestive heart failure) in women with preeclampsia/eclampsia was 42% higher, even after adjusting for multiple factors including preexisting CVD risk factors and behavioral and sociodemographic factors (18). The risk for CVD was also 18% higher for women with GH alone, but its significance was attenuated after adjustment. In addition, women with prior HDP have a roughly 2.4-fold greater adjusted odds of hospitalization due to cardiovascular causes within 3 years of delivery compared with normotensive women (19).

Long-term consequences of HDP

Cardiovascular disease

Future maternal CVD is probably the most studied long-term consequence of HDP, as multiple systematic reviews of controlled studies evaluated the risk of late cardiovascular events in women with and without a history of HDP (20–23). To note, of all HDP, the association between preeclampsia and future CVD risk is the most pronounced. Table 9.1 summarizes the major findings of these studies.

In 2007, Bellamy et al. (20) published their results of a systematic review and meta-analysis on the risk for future cardiovascular morbidity of women who experienced preeclampsia. They analyzed 25 studies including more than 3 million women, of whom about 5% had a history of preeclampsia, and reported the relative risk (RR) for hypertension to be 3.70 (95% confidence interval [CI] 2.70–5.05), for IHD 2.16 (95% CI 1.86–2.52), for stroke 1.81 (95% CI 1.45–2.27), and for venous thromboembolism 1.79 (95% CI 1.37–2.33). In their analysis, there was also a RR of 1.49 (95% CI 1.05–2.14) for overall mortality after preeclampsia.

A year later, McDonald et al. (21) published a meta-analysis that included case-control and cohort studies, and found that the odds ratio for cardiac disease was 2.47 (95% CI 1.22–5.01) in the case-control studies, and the RR in the cohort studies was 2.33 (95% CI 1.95–2.78). They also reported an increased risk of cerebrovascular disease (RR 2.03, 95% CI 1.54–2.67) and cardiovascular mortality (RR 2.29, 95% CI 1.73–3.04).

Brown et al. in 2013 published a review including 50 articles and of these conducted a meta-analysis for 43 eligible articles to assess and quantify the risk of CVD, cerebrovascular events, and hypertension associated with prior preeclampsia. Their results were similar to the previous reviews by Bellamy and McDonald, and they concluded that preeclampsia is associated with an approximate twofold increase in odds of CVD and cerebrovascular disease, and a threefold increased risk of hypertension (23).

More recently, in 2017, Wu et al. (22) analyzed 22 studies with more than 6.4 million women including more than 258,000 women with preeclampsia. Adjusting for potential confounders, such as age, body mass index (BMI), and diabetes mellitus (DM), they demonstrated that preeclampsia was independently associated with an increased risk of future heart failure (RR, 4.19; 95% CI, 2.09–8.38), coronary heart disease (RR, 2.50; 95% CI, 1.43–4.37), CVD death (RR, 2.21; 95% CI, 1.83–2.66), and stroke (RR, 1.81; 95% CI, 1.29–2.55), highlighting once again the importance of lifelong monitoring of cardiovascular risk factors in women with a history of preeclampsia.

The strength of these data has already led the American Heart Association (AHA) in 2011 to consider a history of preeclampsia or pregnancy-induced hypertension a major risk factor for development of CVD (24). The American College of Obstetricians and Gynecologists (ACOG) published a presidential advisory with the AHA providing specific recommendations for CVD risk factor screening for women with prior preeclampsia that was preterm (<37 weeks) or recurrent (25). In this group of women, ACOG recommends yearly screening of blood pressure, lipids, fasting blood sugar, and BMI. This recommendation relates only to women with preterm or recurrent preeclampsia, as they are at the highest risk for cardiovascular mortality, whereas the issue of screening for women with term preeclampsia is not addressed.

The observation made by the ACOG between term and preterm preeclampsia is important as the magnitude of the previous findings is further emphasized by the severity, recurrence, and gestational age of onset of the hypertensive disorder.

Early and late onset of preeclampsia

Women with early onset preeclampsia are at a significantly higher risk for vascular disease compared to late-onset preeclampsia (Figure 9.1). A Norwegian population-based cohort study of 626,272 deliveries found that women who had preeclampsia had a 1.2-fold higher long-term risk of death (95% CI 1.02–1.37) than women who did not have preeclampsia. When stratified by term or preterm birth, given that preeclampsia might be more severe if onset is preterm, the risk increased to 2.71 (1.99–3.68) in women with preeclampsia and preterm delivery compared to women without preeclampsia who delivered at term. Furthermore, the risk of death from cardiovascular causes among women with preeclampsia and preterm delivery was 8.12-fold higher (4.31–15.33) than women without preeclampsia who delivered at term, whereas women with preeclampsia who delivered at term had only a 1.6-fold (1.01–2.7) higher risk of cardiovascular death (26). Likewise, in the California Health and Development Study, women with prior preterm preeclampsia (onset of preeclampsia <34 weeks) had a 9.5-fold increased risk for cardiovascular death compared to women with normotensive pregnancies, in contrast to a 2.1-fold risk among women with previous late-onset preeclampsia (27). Similar results were reported a couple of years later in another Norwegian study, where the hazard ratio (HR) for cardiovascular death associated with preterm preeclampsia (delivery <37 weeks) was 3.7 times higher but only 1.6 times higher among women with prior term preeclampsia, both compared to normotensive pregnancies (28).

A dose-response relationship has been observed between the severity of preeclampsia and the long-term risk of CVD (Figure 9.2). In 2015, Kessous et al. (11) also reported a significant association between preeclampsia and cardiovascular morbidity and showed a linear association between the severity of preeclampsia (no preeclampsia, mild preeclampsia, severe preeclampsia, and eclampsia) and the risk of future cardiovascular morbidity (2.75 versus 4.5% versus 5.2% versus 5.7%, respectively, p = 0.001). Similar results were published in earlier studies (29,30) and were also found in the previously mentioned meta-analysis by McDonald et al., as mild, moderate, and severe preeclampsia were associated with RR of 2.00, 2.99, and 5.36, respectively, of developing future CVD (21).

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