Pregnancy: A Stress Test for Life

Pregnancy may be the first stress test a woman undergoes, in that it challenges maternal carbohydrate, lipid, and inflammatory pathways and vascular function. Although pregnancy complications provide a screen for the later occurrence of hypertension and diabetes, it remains uncertain whether the pregnancy unmasks underlying metabolic or vascular disease; whether it induces damage to vascular endothelium, becoming the pathway for microvascular dysfunction; or whether it triggers inflammatory, autoimmune, or other responses. The evidence in the following sections validates that a history of preeclampsia and hypertensive disorders of pregnancy should be incorporated into routine cardiovascular risk assessment for women.

Hypertensive Disorders of Pregnancy

Hypertensive disorders are the most common complications of pregnancy, with a prevalence of 6% to 8%. Hypertensive disorders of pregnancy (HDP) include chronic hypertension, gestational hypertension, and preeclampsia, either occurring de novo or superimposed on hypertension. In a nationwide 1986 to 2006 United States inpatient sample, chronic hypertension, gestational hypertension, and severe preeclampsia increased in prevalence over time; only mild preeclampsia showed no change.

Hypertensive Disorders of Pregnancy

Hypertensive disorders are the most common complications of pregnancy, with a prevalence of 6% to 8%. Hypertensive disorders of pregnancy (HDP) include chronic hypertension, gestational hypertension, and preeclampsia, either occurring de novo or superimposed on hypertension. In a nationwide 1986 to 2006 United States inpatient sample, chronic hypertension, gestational hypertension, and severe preeclampsia increased in prevalence over time; only mild preeclampsia showed no change.

Preeclampsia and Subsequent Cardiovascular Disease: Epidemiologic Data

Cardiovascular risk data are most abundant for preeclampsia. Preeclampsia occurs in about 3% of pregnancies and is defined as the onset of hypertension (≥140/90 mm Hg) and proteinuria (0.3 g/24 hours) after 20 weeks of gestation. It is most common with a first pregnancy and abates with the delivery of the placenta. Preeclampsia is more common and more severe in African-Americans than Caucasian women and is more prominent with lower socioeconomic status. Earlier, preeclampsia was considered a self-limited problem, but contemporary evidence shows that it imparts long-lasting cardiovascular risk.

Preeclampsia demonstrates a number of pathophysiologic features in common with atherosclerosis, including endothelial dysfunction, activation of the coagulation cascade, insulin resistance, and lipid abnormalities that include an increase in low-density lipoprotein (LDL) cholesterol and triglyceride levels and a decrease in high-density lipoprotein cholesterol level. Early preeclampsia (occurring before 37 weeks of gestation) increases the likelihood that preeclampsia will recur in a subsequent pregnancy. Recurrent preeclampsia increases by sevenfold the likelihood of hypertension later in life. In general, early preeclampsia is considered to impart a greater risk of future cardiovascular events than “severe” preeclampsia. However, severe preeclampsia, which is associated with preterm delivery, fetal growth retardation, and fetal death, is associated with greater cardiovascular risk than mild preeclampsia.

Epidemiologic data comparing preeclampsia with other risk factors for cardiovascular disease identify the magnitude of its adverse impact. Information from >2 million women followed for 13 to 15 years revealed that preeclampsia, regardless of its severity, imparted a 2.6-fold increase in fatal myocardial ischemic events and preeclampsia with preterm compared with term delivery an eightfold increase in cardiovascular mortality. Even preeclampsia only in the first pregnancy (with a subsequent normal pregnancy) was associated with increased cardiovascular mortality. In comparison, cigarette smoking is associated with a two to fourfold increase in cardiovascular risk, obesity with a threefold increase, and metabolic syndrome with a two to threefold increase. A meta-analysis shows that after preeclampsia, the relative excess risk for maternal hypertension is 3.70, for ischemic heart disease 2.16, for stroke 1.81, and for venous thromboembolism 1.79. Of note, preeclampsia is not associated with an increased cardiovascular risk for the father.

Further data, based on 50 reports in a systematic review and 43 in a meta-analysis, identify that women with preeclampsia or eclampsia have an odds ratio (OR) of cardiovascular disease of 2.28, OR of cerebrovascular disease of 1.76, and a relative risk for the development of hypertension of 3.13. This study showed no evidence that preeclampsia associated with preterm delivery further increased cardiovascular risk, in contrast to findings in other meta-analyses. The investigators recommended that preeclamptic women should be made aware of their increased cardiovascular risk and might benefit from cardiovascular risk factor screening.

That cardiovascular risk may appear early after preeclampsia is evident from a study of 1,234 Dutch preeclamptic women studied 6 to 12 months postpartum. Sixty-five percent of these women developed hypertension, and 10% to 20% had hyperhomocysteinemia and metabolic syndrome, both rates significantly higher than for the general Dutch female population. An obvious limitation is the lack of prepregnancy data.

Other important challenges to the epidemiologic data aforementioned are the variable duration of follow-up in the studies, and that many women in these reviews were not yet menopausal, when the appearance of risk factors characteristically escalates in the general population. Also, different epidemiologic studies provided variable adjustment for age, diabetes mellitus, metabolic syndrome, smoking, and socioeconomic status, but relevant is that increased cardiovascular risk persisted in those studies in which adjustments were undertaken.

HDP and Subsequent Morbidity and Diabetes

An English registry (1978 to 2007) examined gestational hypertension and mild and severe preeclampsia among 782,287 first single-term deliveries and 536,419 two first consecutive single-term deliveries. Median follow-up of the cohort was 14.6 years. The risk for subsequent hypertension increased 5.31× with gestational hypertension, 3.61× with mild preeclampsia, and 6.07× with severe preeclampsia. The risk for subsequent diabetes increased 3.12× with gestational hypertension and 4.6× with severe preeclampsia. The risk for subsequent hypertension increased sixfold when 2 pregnancies were complicated by preeclampsia, 2.7-fold with preeclampsia solely in the first pregnancy, and 4.34-fold with preeclampsia only in the second pregnancy. The risk for subsequent venous thromboembolism was increased 1.03× with gestational hypertension, 1.53× with mild preeclampsia, and 1.91× with severe preeclampsia. These data were adjusted for preterm delivery, small for gestational age, placental abruption, and stillbirth; a second model was adjusted for the development of diabetes.

Other Prospective Cohort Data

In a prospective population-based Norwegian cohort (1967 to 2002), cardiovascular death in women who had preeclampsia with a first pregnancy was concentrated in women who had no additional births. The hazard ratio for cardiovascular death was 1.6 with term preeclampsia and 3.7 with preterm preeclampsia. The investigators question whether health problems in these women discouraged future pregnancies. The cardiovascular death risk was only moderately elevated in preeclamptic women with additional pregnancies.

Another study examined a small population of 45 women with early-onset preeclampsia, 45 women with late-onset preeclampsia, and 50 women with a normotensive pregnancy and included assessment of 47 offspring. During the subsequent 6 to 13 years, there was greater occurrence of hypertension in women with early-onset preeclampsia and increased hypertension in the offspring with early- compared with late-onset preeclampsia.

Heart Failure and Arrhythmia After Maternal Placental Syndromes: The HAD MPS Study

This retrospective study in Ontario, Canada, followed 75,342 women with gestational hypertension with preeclampsia for a median duration of 7.8 years; the prespecified primary composite outcome was hospitalization for heart failure or atrial or ventricular arrhythmia within the 1 year after delivery. HDP imparted a 61% increase in the relative risk of heart failure or atrial arrhythmias but no significant increase in ventricular arrhythmias. There was greater risk with more serious maternal placental syndromes. The effect persisted after adjusting for coronary disease, hypertension, and metabolic syndrome, evidence that a history of maternal placental syndrome is an early marker for cardiovascular risk.

Pregnancy Complications and Cardiovascular Risk and Risk Factors in Middle Age

The Avon Longitudinal Study of Parents and Children involved a prospective cohort of 3,416 women with an 18-year follow-up; mean age was 48 years at outcome assessment. Thirty-six percent of the index pregnancies were complicated by HDP, gestational diabetes, preterm delivery, or fetal growth restriction. These pregnancy complications were associated with a 20% to 300% increase in the risk of cardiovascular disease. Specifically, HDP and gestational diabetes independently increased the calculated 10-year risk of cardiovascular disease by the same risk score: preeclampsia OR 1.31, gestational hypertension OR 1.27, gestational diabetes OR 1.26, and small for gestational age OR 1.10. Preeclampsia appeared as the best predictor for future cardiovascular disease events.

Biochemical Cardiovascular Risk Factors After HDP

A systematic review and meta-analysis of 22 studies showed increased levels of glucose, insulin, triglycerides, total cholesterol, LDL cholesterol, and microalbumin after a pregnancy with hypertensive disorders and decreased high-density lipoprotein cholesterol level. The investigators recommended counseling such women on cardiovascular risk reduction.