Hypertensive disorders of pregnancy consist of a broad spectrum of medical complications including gestational hypertension, preeclampsia, eclampsia, and pregestational hypertension. The incidence is estimated to be between 3% and 10% of all pregnancies.30,94 Worldwide, preeclampsia and related conditions are among the leading causes of maternal mortality.30 Although maternal death caused by preeclampsia is less common in developed countries, maternal morbidity remains high. Hypertensive disorders of pregnancy are also the leading cause of fetal growth restriction and indicated preterm deliveries, with the associated complications of prematurity such as neonatal deaths and serious long-term morbidity being substantial.30,39 Preeclampsia is a pregnancy-specific syndrome that is clinically recognized by new onset hypertension and proteinuria after 20 weeks’ gestation. Vascular dysfunction is central to the systemic maternal manifestations of preeclampsia, including increased peripheral vascular resistance, heightened sensitivity to vasopressors, endothelial dysfunction, vasospasm, ischemia, inflammation, activation of the coagulation cascade, and platelet aggregation leading to multiorgan damage.76 The term eclampsia is derived from the Greek, meaning “sudden flashing” or “lightening”, and refers to the seizures that can accompany this syndrome. Although the Egyptians and Indians described this disorder more than 2000 years bce, the only known cure for preeclampsia remains delivery of the fetus and placenta. Precise classification of the hypertensive disorders of pregnancy has remained challenging because of the changing nomenclature over time, with terms such as toxemia and gestational hypertension now considered outdated. Furthermore, varying diagnostic criteria are used in different regions of the world.55,89 The classification system most commonly used in the United States is based on the Working Group Report on High Blood Pressure in Pregnancy published in 2000 and revised in 2013 by the American College of Obstetricians and Gynecologists (ACOG) Working Group for Hypertensive Disorders of Pregnancy.2a,37 The goals of the Working Group were to evaluate the existing evidence and update the classification system, as well as management of hypertensive disorders of pregnancy.2a Four major categories are described: gestational hypertension, preeclampsia–eclampsia, chronic hypertension, and preeclampsia superimposed on chronic hypertension (Table 18-1).37 TABLE 18-1 Classification of Hypertensive Disorders of Pregnancy Preeclampsia (Table 18-1) is defined as new onset of elevated blood pressure and new onset of proteinuria after 20 weeks of gestation; or in the absence of proteinuria, hypertension with any of the following: thrombocytopenia (platelet count of less than 100,000/µL), impaired liver function blood (elevated blood concentrations of liver transaminases to twice the normal concentration), the new development of renal insufficiency (elevated serum creatinine of greater than 1.1 mg/dL or doubling of serum creatinine in the absence of other renal disease), pulmonary edema, or new onset of cerebral or visual disturbances. The term “mild” preeclampsia has been replaced by “preeclampsia without severe features” to emphasize the need for ongoing vigilance as well as the progressive and systemic nature of this syndrome. Severe features of preeclampsia include: • Systolic blood pressure of 160 mm Hg or higher, or diastolic blood pressure of 110 mm Hg or higher on two occasions at least 4 hours apart while a patient is on bed rest (unless antihypertensive therapy is initiated before this time) • Thrombocytopenia (platelet count < 100,000/µL) • Impaired liver function as indicated by abnormally elevated blood concentrations of liver enzymes (to twice the normal concentration), severe persistent right upper quadrant or epigastric pain unresponsive to medication and not accounted for by alternative diagnoses, or both • Progressive renal insufficiency (serum creatinine concentration of > 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease) Eliminating the dependence on proteinuria from the diagnosis of preeclampsia is a major revision from the previous diagnostic criteria, with the intent to recognize the systemic and progressive nature of preeclampsia. This is more consistent with other diagnostic criteria used internationally. Fetal growth restriction was also removed from the diagnosis, but remains an important aspect in the evaluation and management of women with preeclampsia. As in the 2000 Working Group Recommendations, an increase of 30 mm Hg systolic or 15 mm Hg diastolic blood pressure from baseline in early pregnancy measurements is not included in the diagnostic criteria, because women with these changes alone are not at increased risk for adverse outcomes.63,99 Although edema may raise clinical suspicion for preeclampsia, it is not a diagnostic criterion for preeclampsia because nondependent edema occurs in 10% to 15% of women who remain normotensive throughout pregnancy and is neither a sensitive nor specific sign of preeclampsia. A major criticism of the various classification systems is that none have been independently evaluated for the ability to identify the subgroup of women who are at increased risk of adverse pregnancy outcomes. Furthermore, there is disagreement regarding the degree of hypertension, presence or absence of proteinuria, and criteria for disease severity among the different classification systems used internationally.55 These inconsistencies have led to challenges in comparing and generalizing epidemiologic and other research findings. Recent studies have sought to develop clinically relevant definitions guided by the evidence and based on predictors of adverse outcomes.93 The most recent ACOG Working Group recommendations address many of these issues. The incidence of preeclampsia is increasing in the United States and is likely related to the higher prevalence of predisposing disorders such as hypertension, diabetes and obesity, and to delay in child-bearing, as well as to the use of assisted reproductive technologies with their associated increase in multifetal gestation.29,94 The global impact of preeclampsia is profound, with short- and long-term effects on both mother and baby. In a systematic review by the World Health Organization, hypertensive disorders of pregnancy account for 16% of all maternal deaths in developed countries and as high as 26% in Latin America and the Caribbean.48 In areas in which maternal deaths are high, mortality is largely attributable to eclampsia, rather than preeclampsia.30 Based on data from the United States National Hospital Discharge Survey, the rate of preeclampsia increased by 25% between 1987 and 2004; however, there was a trend toward a decrease in eclampsia by 22%.94 Although maternal mortality owing to hypertensive disorders is less common in high-income countries, rates of severe morbidity, including renal failure, stroke and permanent neurologic impairment, cardiac dysfunction or arrest, respiratory compromise, coagulopathy, and liver failure, are high. In a study of hospitals managed by the Health Care America Corporation, preeclampsia was the second-leading cause of pregnancy-related admission to intensive care units after obstetric hemorrhage.69 Recurrence of preeclampsia varies between 7% and 20%. This wide variation in the estimates is based on the quality of the diagnostic criteria used. The risk of recurrent preeclampsia is even higher with two prior preeclamptic pregnancies or with earlier gestational age of preeclampsia onset.40,58 A landmark study published in 1976 demonstrated that women who had eclampsia in any pregnancy after their first had a mortality risk that was two- to fivefold higher over the next 35 years compared with controls.20 Since that time several large epidemiologic studies have confirmed that women with preeclampsia in any pregnancy have an increased risk of cardiovascular diseases later in life and related mortality.59 This risk is higher among women with preeclampsia that was recurrent, that necessitated a preterm delivery, or that was associated with fetal growth restriction. Hypertension, dyslipidemia, insulin resistance, endothelial dysfunction, and vascular impairment have all been observed months to years after the preeclamptic pregnancy, further supporting the link between preeclampsia and cardiovascular disease.59 In 2011, the American Heart Association added preeclampsia to its list of recognized risk factors for cardiovascular disease. Based on these data, women with a history of preeclampsia should have ongoing, close surveillance to prevent or detect cardiovascular disease. Further investigation is needed to resolve whether common risk factors lead to the development of both preeclampsia and subsequent cardiovascular disease or whether preeclampsia itself contributes to this future risk. Fetal and neonatal outcomes related to hypertensive disorders vary widely around the world related to resource availability, presence of neonatal intensive care facilities, as well as limits of viability as defined by gestational age and birth weight. In developing countries, one quarter of stillbirths and neonatal deaths are associated with preeclampsia-eclampsia. Infant mortality is three times higher in low-resource settings compared to high-income countries, largely due to the lack of neonatal intensive care facilities.30 It is estimated that 12% to 25% of fetal growth restriction and small for gestational age (SGA) infants as well as 15% to 20% of all preterm births are attributable to preeclampsia.39 These preterm births are generally indicated, because the only known cure for preeclampsia is delivery of the fetus and placenta. The associated complications of prematurity are substantial, including neonatal deaths and serious long-term morbidity. The risk of complications is inversely associated with gestational age at delivery. Extremely premature infants (<25 weeks) have the highest mortality rate, and if they survive, they are at substantial risk for long-term issues. These include neurodevelopmental impairment such as impaired cognitive skills, motor deficits with fine and/or gross motor delay, cerebral palsy, vision problems, hearing loss, and behavioral and psychological problems, as well as recurrent hospitalization and chronic lung problems and other health problems.2 Prematurity also impacts adult health and has been associated with increased insulin resistance, hypertension, and cardiovascular disease.42,47 There is growing evidence suggesting that the in utero environment affects later life health and disease (termed the Barker hypothesis) with particular focus on fetal growth restriction and later life cardiovascular disease (see also Chapter 17.) A systematic review of 18 studies that included 45,249 individuals demonstrated that cardiovascular risk factors, specifically, blood pressure and body mass index (BMI), were increased in children and young adults born to preeclamptic pregnancies.25 Thus, preeclampsia and related complications may be associated with long-term sequelae in both the mother and infant. Risk factors for preeclampsia reflect the heterogeneous nature of the syndrome and can be broadly classified into pregnancy-specific characteristics and maternal pre-existing features (Box 18-1). Nulliparity is a strong risk factor, almost tripling the risk of preeclampsia.29 It is estimated that two thirds of cases occur in first pregnancies. New paternity also increases the risk of preeclampsia in a subsequent pregnancy. Excess placental volume, as with multifetal gestations and hydatidiform moles, is also associated with the development of preeclampsia.26,29,65 The disease process may occur earlier and have more severe manifestations in these cases. The risk progressively increases with each additional fetus. Extremes of childbearing age have been associated with preeclampsia.94 However, when adjustments for parity are made in the younger age group (because most first pregnancies occur at a younger age), the association between younger age and preeclampsia is lost.29 Women who were 40 years of age or older had almost twice the risk of developing preeclampsia after controlling for baseline differences such as chronic medical conditions.15 The association between race and preeclampsia has been confounded by the higher prevalence of chronic hypertension among African-American women, which is often undiagnosed. Whereas some studies demonstrate a higher risk of preeclampsia among African-American women,36,50 larger prospective studies that controlled for other risk factors and rigorously defined preeclampsia did not find a significant association between preeclampsia and African-American race.84,85 More severe forms of preeclampsia may be associated with maternal nonwhite race. A family history of preeclampsia nearly triples the risk of preeclampsia, whereas a personal history of preeclampsia in a previous pregnancy increases the risk of recurrence by sevenfold.29,40,58 Cardiovascular risk factors such as pre-existing hypertension, diabetes, obesity, and vascular disorders (renal disease, systemic lupus erythematosus, antiphospholipid antibody syndrome) also increase the risk of preeclampsia.29 This risk correlates with the severity of the underlying disorder. Obesity increases the overall risk of preeclampsia by approximately two- to theefold.17 The risk of preeclampsia progressively increases with increasing BMI, even within the normal range. Importantly, it is not only the late or mild forms that are increased, but also early-onset and severe preeclampsia, which are associated with greater perinatal morbidity and mortality.16 Given the obesity epidemic in the United States and around the world, this is one of the largest attributable and potentially modifiable risk factors for preeclampsia. Paradoxically, cigarette smoking during pregnancy is associated with a reduced risk of preeclampsia.35 Although research in this area is extensive and ongoing, the precise pathophysiology remains incompletely understood. Preeclampsia has been described as occurring in two stages.75 The first stage consists of inadequate remodeling of the maternal spiral arteries by the invasive placental trophoblasts, which results in reduced placental perfusion. The second stage describes the maternal systemic vascular dysfunction, which leads to the clinical features, including multiorgan involvement (Figure 18-1). Some women enter pregnancy with vascular disease (e.g., chronic hypertension, diabetes, renal disease, lupus), which may result in poor placental implantation (stage I) and/or a susceptibility to the vascular damage associated with preeclampsia (stage II), thereby increasing the risk of developing preeclampsia. The placenta plays a critical role in the pathophysiology of preeclampsia. The placenta, but not necessarily the fetus (as with hydatidiform moles), is requisite for the development of preeclampsia.65 Greater placental volume, as with multifetal gestation, hydatidiform moles, and hydropic placentas, is associated with a higher risk of preeclampsia.29 Importantly, delivery of the placenta is the cure for preeclampsia. In normal pregnancy, the cytotrophoblast cells of the developing placenta invade the uterine spiral arteries within the decidua and myometrium of the uterus and remodel the small-caliber, high-resistance arteries into large-caliber, low-resistance vessels. Persistence of the uterine artery smooth muscle renders these vessels susceptible to local and circulating vasoconstrictors as well as poor perfusion, which can result in placental ischemia-hypoxia and generation of potentially harmful reactive oxygen species.89 The precise factor(s) linking stage I and stage II has been the focus of numerous studies in this field. There is evidence to support the role of angiogenic factors, inflammatory cytokines, circulating placental microparticles, and oxidative stress, to name a few.89 Preeclampsia has been called the “disease of theories”—and it is likely that this syndrome is heterogeneous with multiple different pathways, either individually or in combination, that converge to result in vascular dysfunction and clinical features of the syndrome. Classifying preeclampsia into subtypes may facilitate research and a better understanding of pathophysiology. For example, experts have proposed a “placental preeclampsia” in which placental dysfunction and fetal growth restriction are major features.88 Pro-angiogenic factors, placental growth factor (PlGF), and vascular endothelial growth factor (VEGF), as well as the antiangiogenic factors, soluble VEGF receptor 1 (soluble fms-like tyrosine kinase-1 [sFlt-1]), and soluble endoglin (co-receptor for transforming growth factor (TGF-β) have gained increasing attention for their role in the pathogenesis of preeclampsia. It is proposed that circulating sFlt-1 from the placenta binds and inactivates VEGF and PlGF, thus competing with receptors located on the endothelium and resulting in impaired vascular function.57 Soluble endoglin inhibits TGF-β1 signaling in endothelial cells, disrupting nitric oxide–induced vasodilation. Compared with normotensive women, circulating sFlt-1 and soluble endoglin levels are higher and PlGF levels lower in preeclampsia, even weeks prior to the recognition of the clinical condition, and also correlate with disease severity.53,54 Soluble Flt-1 administered to pregnant rats induces preeclampsia-like features (hypertension, proteinuria, glomerular endotheliosis).57 Soluble endoglin potentiates these effects in pregnant rats, resulting in features of severe preeclampsia, HELLP syndrome, and fetal growth restriction.91 Placental ischemia and hypoxia is hypothesized to trigger sFlt-1 release from the placenta.38 Prior exposure to paternal antigens appears to be protective against preeclampsia, whereas less exposure to paternal antigens is associated with a higher risk of preeclampsia, such as with nulliparous women, new paternity, longer interpregnancy interval, barrier contraceptive use, and pregnancies achieved by intracytoplasmic sperm injection.77 These epidemiologic observations support the role of immunologic factors in stage I of preeclampsia. The immunologic abnormalities observed with preeclampsia have been compared to transplant organ rejection.62 The only known polymorphic histocompatibility antigens on the fetal trophoblast are HLA-C molecules. Maternal decidual natural killer (NK) cells express killer immunoglobulin receptors (KIRs) that recognize specific HLA-C molecules and interact with the invasive trophoblast cells to regulate placental implantation. The conflict between maternal and paternal genes observed in preeclampsia may lead to increased NK activity and abnormal placental implantation. Some HLA-C and KIR isoforms predispose to preeclampsia.62 Placental bed biopsies from women with preeclampsia also demonstrate increased numbers of dendritic cells (antigen presenting cells) in the decidua, which may also affect placental implantation and/or maternal immunologic responses.71 Compared with the nonpregnant state, normal pregnancy is an inflammatory state; this is even more exaggerated in women with preeclampsia, which likely contributes to stage II and generalized endothelial dysfunction. Circulating inflammatory markers, C-reactive protein, tumor necrosis factor-α, and interleukin-6, are all elevated in preeclampsia compared with uncomplicated, normotensive pregnancy.23,96 Placenta hypoxia and reperfusion can result in oxidative stress, with subsequent apoptosis and necrosis of the syncytiotrophoblast with release of these materials into the maternal circulation, which can stimulate inflammation.71 These circulating placental microparticles and trophoblastic debris have been shown to be bioactive and even containing antiangiogenic factors.70,71 Normal pregnancy is characterized by vasodilation and resistance to vasopressors.79 Despite the decrease in systemic vascular resistance, levels of renin, angiotensin, and aldosterone are increased with normal pregnancy. With preeclampsia there is increased sensitivity to angiotensin II and other vasoconstrictors. Circulating autoantibodies to the angiotensin II type 1 receptor have been demonstrated in women with preeclampsia.95 This autoantibody is an agonistic antibody similar to angiotensin II that is able to activate the receptor and result in hypertension and vascular injury that are characteristic of preeclampsia. In a rodent model, injection of these antibodies results in some of the clinical features of preeclampsia, further supporting the pathogenic nature of these autoantibodies.100 Epidemiologic associations of preeclampsia with positive family history, preeclampsia in a prior pregnancy (see “Risk Factors”), or male partner who has fathered a preeclamptic pregnancy indicate a genetic basis for preeclampsia. A number of candidate genes have been studied with positive findings in small cohorts, but subsequent larger studies have not confirmed their association with preeclampsia. Genome-wide association studies have been performed and have shown modest associations, but the findings are not consistent across different populations.8,44 Genetic studies are likely confounded by the heterogeneity of preeclampsia, inconsistent definitions, and population variation. Recent investigations are turning toward evaluating environmental influences such as hypoxia and epigenetic modifications that may be associated with preeclampsia.21
Hypertensive Disorders of Pregnancy
Classification of Hypertensive Disorders of Pregnancy
Preeclampsia
HELLP Syndrome
Epidemiology of Preeclampsia
Maternal Effects
Short Term
Recurrence in Subsequent Pregnancies
Long-Term Cardiovascular Risks
Fetal and Neonatal Effects
Risk Factors
Pregnancy-Specific Characteristics
Maternal Characteristics
Pathophysiology
Angiogenic Factors
Immunologic/Inflammatory Factors
Renin Angiotensin System
Genetics
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Hypertensive Disorders of Pregnancy
