Long-Term Effects of Preeclampsia on Mothers and Offspring

Increased Maternal Cardiovascular Risk

Several large population-based studies over the last two decades have demonstrated that women experiencing any form of hypertensive disorder of pregnancy or fetal growth restriction are, as a group, at increased risk of developing cardiovascular disease, compared to women with normal pregnancies. The risk increases with more severe hypertensive disorders of pregnancy forms, particularly when complicated by fetal growth restriction, as well as with recurrent preeclampsia (as reviewed in ). Women with previous gestational hypertension or late-onset preeclampsia are at lower risk for cardiovascular disease than after early-onset preeclampsia. ^{, ,} A dose–response effect of hypertensive disorders of pregnancy on cardiovascular death is reflected in the highest risk for major coronary and cardiovascular events among women with preeclampsia and a premature delivery of a small for gestational age (SGA) offspring and in women with repeated preeclampsia. Unfortunately, many studies have not registered, and therefore not adjusted for, prepregnancy risk factors for cardiovascular disease. A study from Norway showed that much of the elevated risk for future hypertension after preeclampsia was mediated by prepregnancy risk factors. However, the associations were still significant after these adjustments. Other subsequent population-based studies simultaneously shown increased risk for hypertension following hypertensive disorders of pregnancy, even after adjustment for other risk factors. ^, Two recent studies from Norway confirmed that the association between hypertensive disorders of pregnancy and cardiovascular disease remained after statistical adjustment strategies and that the risk is partly attributable to modifiable cardiovascular disease risk factors. ^,

Women who go on to have normotensive, uncomplicated pregnancies after having a first pregnancy with preeclampsia only have a modestly elevated CV death risk. Women with a history of preeclampsia are also at increased risk of developing diabetes, which in itself also confers higher cardiovascular disease risks. A history of preeclampsia also increases the relative risk for end-stage kidney disease, and the risk increases with recurrent preeclampsia or delivery of a low-birth-weight baby. An increased risk of future hypothyroidism has also been found in women following preeclampsia. A recent nationwide study from Denmark showed a threefold risk of vascular-related dementia, whereas the risk for Alzheimer syndrome was quite modest (hazard ratio 1.45, 95% CI 1.40–1.99). The association with vascular dementia was stronger for late- than early-onset disease (hazard ratios 6.53 vs. 2.32). Adjustment for cardiovascular disease, hypertension, and diabetes moderately attenuated the hazard rations. The differing effects of preeclampsia on vascular and Alzheimer's variant of dementia are likely due to Alzheimer's pathogenesis not involving the blood vessels. See Chapter 13 for more details of cerebrovascular consequences of preeclampsia.

The most widely held hypothesis used to explain the epidemiological link between preeclampsia and maternal long-term cardiovascular disease is that the two disorders share common risk factors, such as higher age and BMI, dyslipidemia, hypertension, insulin resistance/hyperglycemia, diabetes mellitus, renal disease, etc. An alternative hypothesis, not excluding the first, suggests that pregnancy in general and preeclampsia (and other placental disorders) in particular worsen preexisting, subclinical cardiovascular disease risk factors or even induce a new risk of cardiovascular disease. As preeclampsia is a syndrome potentially affecting the entire vasculature and many organ systems, it is also not surprising that many organs may be affected after hypertensive disorders of pregnancy, resulting in long-term effects. Indeed, the impact of hypertensive pregnancies on later-life maternal cardiovascular health has been demonstrated in the rat reduced uteroplacental perfusion pressure (RUPP) model of preeclampsia (see Chapter 20 on animal models) whereby vascular dysfunction continued into the postpartum period, suggesting that a pregnancy complicated by preeclampsia may predispose women to later-life cardiovascular disease via ongoing vascular dysfunction.

Staff and colleagues have argued that placental dysfunction acts as a proxy for future cardiovascular disease risk, possibly by mediating it. There are several possibilities for a mechanistic association, among them that low maternal circulating PlGF (placental growth factor) levels in pregnancy, typically seen prior to and during the development of preeclampsia and fetal growth restriction, could possibly impair endothelial progenitor cell recruitment. In line with the concept of using pregnancy biomarkers as predictors for maternal cardiovascular health, a recent follow-up of singleton pregnancies revealed that low mid-pregnancy maternal PlGF levels predicted cardiac structural changes and elevated systolic blood pressure 6–9 years later, independent of hypertensive disease. A recent systematic review of 84 studies (including almost 29 million patients) confirmed this concept of placental dysfunction as a risk biomarker, identifying not only preeclampsia and gestational hypertension as pregnancies having high future cardiovascular disease risk but also pregnancies complicated by placental abruption, preterm birth, gestational diabetes, and stillbirth, all representing variants of a dysfunctional placental syndrome.

Whether the duration of preeclampsia and the timing of delivery in clinically stable preeclampsia impact future maternal cardiovascular disease is not known, but is currently under debate. The balance between prolonging a preeclamptic pregnancy or delivery shifts as the pregnancy progresses toward term (GA 37 weeks). By delaying delivery, the risk of severe maternal (and thereby fetal death) complications of preeclampsia increases, whereas the risk of complications associated with prematurity of the newborn diminishes. Whether earlier delivery in pregnancies with no short-term imminent risks to the mother, e.g., delivery from gestational week 34, might also benefit the woman's long-term cardiovascular health remains to be seen. A recent retrospective study from New York indicated that prolonging expectant management more than 7 days after the diagnosis of new-onset hypertension in pregnancy may have adverse CV effects on the mother, when assessed 5 years (median follow-up time) later.

It has been proposed that failure of the maternal cardiovascular system to adapt to pregnancy may be the primary mechanism leading to placental dysfunction in preeclampsia. Adverse structural echocardiogram findings have been identified both prior to preeclampsia development in pregnancy and also in previously preeclamptic women at 1 year postpartum. Preeclampsia and adult cardiovascular disease share several risk factors, and pregnancy exerts a substantial cardiovascular load on the maternal heart. However, the updated placental model of preeclampsia presented in Chapter 1 does indeed take into account the maternal cardiovasculature, which is preset at a higher inflammatory and potential dysfunctional stage in many women with epidemiological preeclampsia risk factors (e.g., chronic hypertension, obesity, and diabetes mellitus). The placenta is however a mandatory prerequisite for all preeclampsia development, as no man nor nonpregnant woman ever develops preeclampsia, even if he or she suffers from cardiovascular disease. A heart model for preeclampsia is also inconsistent with many preeclampsia risk factors, such as primiparity and change of partner, which fit better with inappropriate placentation due to immune maladaptation, such as depicted in the placental model of preeclampsia.

Reduced Risk for Maternal Breast Cancer After Preeclampsia

This section is updated from text originally published in the fourth edition of Chesley's Hypertensive Diseases of Pregnancy, from the chapter named “Epidemiology of Pregnancy-Related Hypertension” by Janet W. Rich-Edwards, Roberta B. Ness, and James M. Roberts.

Parity involves a transient increase in breast cancer risk directly following the pregnancy, an effect that may last up to a decade. Parity represents on the other side a well-established long-term risk reduction for breast cancer. Older age at first pregnancy and nulliparity increases the risk for breast cancer, whereas breastfeeding reduces the risk. Since the early 1990s, studies have largely reported that women with a history of preeclampsia have a reduced risk of breast cancer. A study from Norway showed that this reduced risk was consistently shown for hypertensive disease in any pregnancy, for recurrent hypertensive disorders of pregnancy, and pertains to breast cancer diagnoses identified before or after 50 years of age. A recent large Nordic study of breast cancer (n > 116,000) verified that prepregnancy hypertension, gestational hypertension, and preeclampsia had similar reduced risks for breast cancer (OR 0.87–0.91). In a 2013 meta-analysis by Kim et al., 10 out of 13 qualifying studies reported breast cancer hazard ratios ranging from 0.24 to 0.87 (overall HR: 0.86) for women with a history of preeclampsia, compared to woman with no such history. Two studies reporting the opposite trend come from the same Jerusalem Perinatal Cohort, ^, a population where it has been suggested that the increased prevalence of the “BReast CAncer gene” (BRCA) mutation obscures the relative risk of breast cancer associated with nongenetic factors. Studies have been inconclusive as to why preeclampsia seems to have this protective effect. Initial research suggested that the protective effect of preeclampsia on breast cancer risk came from decreased levels of circulating estrogens in preeclampsia, though this was not supported by later studies. However, androgen levels have been found to be significantly higher in preeclamptic pregnancies, ^{, ,} possibly suggesting a protective androgenic effect on breast cancer risk. Consistent with this theory, women with preeclampsia carrying a male fetus showed greater breast cancer risk reduction than women who delivered a daughter. ^, Women with preeclampsia also have evidence of a circulating antiangiogenic state, including decreased PlGF and increased sFlt-1 (soluble fms-like tyrosine kinase-1) levels, and it has been speculated that these women manifest diminished tumor growth and development. ^, Blood samples from a Norwegian cohort, however, did not show correlations between pregnancy levels of three angiogenic factors (PlGF, sFlt-1, and s-endoglin) and later diagnosis of breast cancer, regardless of preeclampsia status. A recent study of two UK and Norwegian cohorts did not show any differences in pregnancy hormones (estradiol, testosterone, hCG and prolactin), PlGF, or sFlt-1 among women developing breast cancer after pregnancy and those who did not. Kim and others ^, have proposed that AFP (alpha-fetoprotein), a low-affinity estrogen binding protein that prevents estrogen transport across the placenta in rodent fetuses, plays some role in the relationship between breast cancer and preeclampsia. AFP may decrease mammary gland estrogen exposure and breast cancer risk.

Although there are intriguing patterns between intrauterine factors, preeclampsia, and breast cancer, the mechanisms underlying the interactions remain still to be elucidated, as should their relation to genetic predisposing factors. A recent analysis of white, non-Hispanic, women within the California Teachers Study included 137 women with self-reported previous preeclampsia. The study was a nested case–control group of 80 women developing breast cancer after study start and 57 without breast cancer. The authors found that a single-nucleotide polymorphism (SNP) in the Insulin-like growth factor 1 receptor (rs2016347) is associated with a significant reduction in breast cancer risk following preeclampsia, most marked for hormone receptor positive breast cancer and in women with age at first birth below 30 years.