Hypertensive Disorders

INTRODUCTION

Hypertension is the most common medical disorder of pregnancy, affecting approximately 18 million women and 6% to 10% of pregnancies worldwide. Hypertensive disorders of pregnancy can significantly impact both mother and fetus. Almost 50,000 women worldwide die from hypertensive disorders of pregnancy each year, and while the vast majority occur in low-resource settings, these disorders account for up to one-in-six maternal deaths in high-resource countries. Being diagnosed with a hypertensive disorder also carries an increased future risk of cardiovascular diseases, renal failure, and diabetes. Hypertensive disorders also heavily impact the fetus, leading to fetal growth restriction, preterm birth, and over 500,000 perinatal deaths worldwide each year. The immediate financial impact of neonatal care for these pregnancies is estimated to be greater than $1 billion annually in the United States alone.

Preeclampsia represents a clinically significant form of the hypertension spectrum. Although important advances have been made in understanding the pathophysiology, the proximal cause of preeclampsia remains unknown. Risk factor assessment aids in identifying patients for closer monitoring or prophylactic treatment; however, most cases of preeclampsia occur in nulliparous mothers without known risk factors. Once preeclampsia has been diagnosed, medications can be used to temporize the disease with blood pressure control or prevention of seizures; however, delivery of the fetus is the only definitive treatment.

Anesthesia providers play an important role in the management of women with preeclampsia; they are well positioned, with a thorough understanding of pathophysiology, to assist with assessment and management of complications, cardiovascular monitoring, and critical care. Working as part of a multidisciplinary team that includes obstetricians, nurses, cardiologists, neonatologists, midwives, and critical care specialists, anesthesia providers can play a critical role in ensuring optimal outcomes for women with preeclampsia.

CLASSIFICATION

Hypertensive disorders of pregnancy encompass a range of conditions that may differ in their prognoses but can be difficult to differentiate because the clinical presentations are often similar. The classification of hypertensive disorders of pregnancy was updated by the American College of Obstetricians and Gynecologists (ACOG) Taskforce on Hypertension in Pregnancy in 2013 and has been substantially adopted by other major societies. Hypertension in pregnancy is defined as either (1) systolic blood pressure ≥ 140 mm Hg and/or (2) diastolic blood pressure ≥ 90 mm Hg; this must be confirmed on at least two measurements. The classification of hypertensive disorders consists of gestational hypertension, chronic hypertension, chronic hypertension with superimposed preeclampsia, and preeclampsia with or without severe features ( Box 35.1 ). The International Society for the Study of Hypertension in Pregnancy (ISSHP) includes the categories of white coat hypertension and masked hypertension . White coat hypertension can be associated with normal blood pressures when not in the physician’s office and may not need to be treated; however, it can progress to preeclampsia and should be closely monitored. Masked hypertension is associated with normal blood pressures in the clinic, but high blood pressures in the ambulatory setting—it is suspected when there is evidence of end-organ disease, but no elevated blood pressure when assessed in the clinic.

Box 35.1

Classification of Hypertensive Disorders in Pregnancy

Adapted from the American College of Obstetricians and Gynecologists. Hypertension in pregnancy: report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol . 2013;122:1122–1131; and Magee LA, Brown MA, Hall DR, et al. The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis & management recommendations for international practice. Pregnancy Hypertens . 2022;27:148–169.

•
Gestational hypertension
•
Preeclampsia without severe features
•
Preeclampsia with severe features
•
Chronic hypertension
•
Chronic hypertension with superimposed preeclampsia
•
White coat hypertension
•
Masked hypertension
•
Eclampsia

Gestational hypertension is the most common hypertensive disorder of pregnancy, affecting approximately 5% of parturients. This disorder presents as hypertension after 20 weeks’ gestation that resolves by 12 weeks postpartum. Approximately one-fourth of patients diagnosed with gestational hypertension will develop preeclampsia.

Chronic hypertension involves hypertension presenting before pregnancy or before 20 weeks’ gestation, or hypertension that fails to resolve after delivery. Chronic hypertension develops into preeclampsia in approximately 20% to 25% of affected patients. However, even in the absence of preeclampsia, chronic hypertension is an important risk factor for unfavorable maternal and fetal pregnancy outcomes.

Chronic hypertension with superimposed preeclampsia occurs when a woman with chronic hypertension develops new onset or a sudden increase in proteinuria and/or hypertension, or when other manifestations of preeclampsia with severe features appear. Morbidity is increased for both the mother and fetus compared with preeclampsia alone.

Preeclampsia is defined as the new onset of hypertension and proteinuria after 20 weeks’ gestation. The diagnosis of preeclampsia should also be considered in the absence of proteinuria when signs or symptoms of end-organ involvement are present. Preeclampsia is classified as preeclampsia with or without severe features . Both the ACOG and ISSHP discourage use of the term mild preeclampsia for women without severe features because preeclampsia may be rapidly progressive, and appropriate management involves frequent reevaluation for severe features. The diagnostic set of features that identify severe disease are manifestations of end-organ injury ( Box 35.2 ). Evidence of uteroplacental insufficiency (e.g., intrauterine growth restriction, abnormal uterine artery doppler flow velocities) is no longer considered a severe feature in the ACOG classification, but remains present in the ISSHP diagnostic set of features due to the association with angiogenic imbalance. The ISSHP diagnostic set of severe features also includes other evidence of hematologic or neurologic dysfunction.

Box 35.2

Diagnostic Criteria for Preeclampsia

Modified from American College of Obstetricians and Gynecologists. ACOG Practice Bulletin Number 222: Gestational hypertension and preeclampsia (reaffirmed 2023). Obstet Gynecol . 2020;135:e237–e260.

Preeclampsia Without Severe Features

•
Blood pressure ≥ 140/90 mm Hg after 20 weeks’ gestation
•
Proteinuria (≥300 mg/24 h, protein-creatinine ratio ≥ 0.3, or urine dipstick specimen ≥ 1+)

Preeclampsia With Severe Features

•
Blood pressure ≥ 160 mm Hg systolic, or ≥ 110 mm Hg diastolic, or both
•
Thrombocytopenia (platelet count < 100,000/mm ³)
•
Serum creatinine concentration > 1.1 mg/dL or greater than two times the baseline serum creatinine concentration
•
Pulmonary edema
•
New-onset, persistent cerebral or visual disturbances
•
Twofold increase in AST or ALT, or persistent right upper quadrant or epigastric pain

ALT , Alanine transaminase; AST , aspartate transferase.

Early-onset preeclampsia , with symptom onset before 34 weeks’ gestation, is more often associated with abnormal placentation, has a high rate of recurrence, and may have a stronger genetic component. Early-onset preeclampsia also results in greater fetal and maternal morbidity.

Late-onset preeclampsia more often occurs in women metabolically predisposed to the disease, and abnormal placentation may feature less prominently in the pathogenesis. These women may have long-standing hypertension, obesity, diabetes, or other forms of microvascular disease. They are challenged to meet the demands of the growing fetoplacental unit and decompensate near term.

HELLP syndrome refers to the development of hemolysis, elevated liver enzymes, and low platelet count in a woman with preeclampsia. Women with HELLP syndrome may not have the classical findings of preeclampsia and often do not have hypertension at the time of diagnosis.

Eclampsia is defined as a new onset of seizures in a pregnant woman without an identifiable cause. Eclampsia most often occurs in woman who have been diagnosed with preeclampsia, but rarely may also appear as the first sign of a hypertensive disorder.

EPIDEMIOLOGY

The incidence of all hypertensive disorders of pregnancy has tripled in the United States in the past quarter century, reaching almost 16% of all births ( Fig. 35.1 ). The highest prevalence occurs among women over the age of 35 years, and among racial and ethnic minorities. The recent increase is primarily driven by higher rates of pregnancy-related hypertension, while the frequency of chronic hypertension increased modestly. The rapid rise in incidence after the publication of the 2013 ACOG guidelines suggests that more aggressive screening and diagnosis contributed to the reported rise. The increased incidence is primarily due to major shifts in the demographic characteristics and medical comorbidities among pregnant women. Preeclampsia occurs in 3% to 4% of pregnancies in the United States. Eclampsia is significantly more common in underresourced settings, while the incidence in high-resource countries is likely less than 0.1% of pregnancies.

A line graph shows a rising trend in hypertensive disorders of pregnancy from 1993 to 2019. — Fig. 35.1

Risk Factors

Numerous preconception and pregnancy-related risk factors associated with the development of preeclampsia have been identified ( Box 35.3 ). Risk factors for preeclampsia can be divided into maternal demographic factors, genetic factors, medical and obstetric conditions, behavioral factors, and partner-related factors.

Box 35.3

Risk Factors for Preeclampsia

Demographic Factors

•
Advanced maternal age > 35 y
•
Black race
•
Hispanic ethnicity

Maternal Factors

•
Nulliparity
•
History of preeclampsia in previous pregnancy
•
Family history of preeclampsia
•
History of placental abruption, fetal growth restriction, or fetal death

Medical Conditions

•
Obesity
•
Chronic hypertension
•
Diabetes mellitus
•
Chronic renal disease
•
Antiphospholipid antibody syndrome
•
Systemic lupus erythematosus

Obstetric Conditions

•
Multiple gestation
•
Hydatidiform mole

Behavioral Factor

•
Cigarette smoking (risk reduction)
•
Regular exercise (risk reduction)

Demographic Factors

Advanced maternal age has consistently been shown to be a risk factor for preeclampsia, with women who are 40 years of age or older having an approximately twofold increase in risk compared with women between 20 and 29 years of age. This risk may be independent of the increased prevalence of medical conditions and obesity that accompany advancing age.

Race and ethnicity are associated with hypertensive disorders of pregnancy. Black women have increased rates of chronic hypertension, preexisting diabetes, and obesity; however, after adjusting for these preexisting conditions, there remains a higher incidence of preeclampsia, with more extreme hypertension requiring greater amounts of antihypertensive medication. Black women are also more likely to develop eclampsia and have higher rates of both morbidity and mortality due to their hypertensive disorder of pregnancy. Women of Native American descent and Hispanic ethnicity may also have a small increased risk for developing preeclampsia and eclampsia compared to White women.

Genetic Factors

Maternal genetic factors are known to be important risk factors for the development of preeclampsia. Pregnant women with a family history of preeclampsia are approximately twice as likely to develop the disorder. It is estimated that approximately one-third of the variance in liability to preeclampsia is caused by maternal genetic factors.

In a study of 1.7 million births in the Medical Birth Registry of Norway, men who fathered one preeclamptic pregnancy were found to be nearly twice as likely to father a preeclamptic pregnancy with a different woman, irrespective of her previous obstetric history. Therefore, paternal genes (in the fetus) contribute significantly to a pregnant woman’s risk for preeclampsia. It is estimated that approximately one-fifth of the variance in liability for preeclampsia is conferred through the fetal genes.

Women with a history of preeclampsia in a previous pregnancy are at increased risk for preeclampsia in a subsequent pregnancy, particularly if the preeclampsia was of early onset. Risk for recurrence increases with multiple affected pregnancies. In addition, women with a history of previous placental abruption and fetal growth restriction are at increased risk for preeclampsia in a subsequent pregnancy, and women with a history of preeclampsia are at risk for these outcomes even in the absence of recurrent preeclampsia. These associations suggest that some women harbor a susceptibility (potentially genetically mediated) to obstetric conditions caused by placental dysfunction, which manifests differently in different pregnancies.

It is estimated that approximately one-fifth of the variance in disease risk is attributable to fetal genetic effects, and one-third is attributable to maternal genetic factors. A genome-wide association study in offspring from preeclamptic pregnancies reported that variants in the fetal genome near fms-like tyrosine kinase-1 gene ( FLT1 ) are associated with risk for preeclampsia. With the possible exception of thrombophilia genes, no genetic variants in the maternal genome have been robustly associated with preeclampsia.

Medical and Obstetric Conditions

Metabolic syndrome occurs in about one-fifth of women of childbearing age in the United States and is characterized by the presence of obesity, hyperglycemia, insulin resistance, and hypertension. Women with chronic hypertension are at a 10- to 12-fold increased risk for developing preeclampsia. When associated with other risk factors, including diabetes, renal disease, and collagen vascular disease, chronic hypertension confers even greater risk. Obesity is also a major independent risk factor; an increase in body mass index (BMI) of 5 to 7 kg/m ² is associated with a twofold increased risk for preeclampsia. Diabetes mellitus is associated with an approximately twofold increase in the risk for development of preeclampsia. Other maternal medical conditions that are well-recognized risk factors for preeclampsia include chronic renal disease, antiphospholipid antibody syndrome, and systemic lupus erythematosus.

Behavioral Factors

Paradoxically, cigarette smoking during pregnancy confers a 30% to 40% lower risk for developing preeclampsia, an effect consistently observed across studies in various countries. A possible mechanism is that nicotine restores endothelial function by stimulating placental growth factor (PlGF) and inhibiting the antiangiogenic impact of soluble fms-like tyrosine kinase-1 and soluble endoglin.

Recreational Physical Activity

Recreational physical activity during pregnancy has been associated with a decrease in the risk for gestational hypertensive disorder, particularly in nonobese women. Exercise in pregnancy is strongly recommended due to the health benefits that may result.

Pregnancy-Related Risk Factors

Nulliparity is a leading risk factor for hypertensive disorders of pregnancy; first-time mothers are three times more likely to be diagnosed compared to parous women. Preeclampsia is also more common in parous women who have conceived with a new partner. It is not clear whether this is the impact of exposure to a new partner or the length of time between pregnancies, which often accompanies births with different partners. Multifetal gestation and hydatidiform mole are associated with higher rates of preeclampsia, likely due to an increased placental oxygen demand that exceeds supply. Additionally, assisted reproductive techniques and the use of donated gametes increase the risk for hypertensive disorders, potentially by altering the maternal-fetal immune reaction and by its association with an increased incidence of multiple gestation.

PATHOGENESIS

The exact pathogenic mechanisms responsible for the initiation of preeclampsia are not known, but significant advances in knowledge of the disease have been made in recent years. The current description of the pathophysiology of preeclampsia focuses on chronic placental hypoxia inducing the release of antiangiogenic proteins, leading to widespread maternal endothelial injury. The placenta is central to the development of the disease, as evidenced by delivery resulting in its resolution. Further, the disease can occur in the absence of a fetus (e.g., a molar pregnancy). Angiogenic imbalance is a fundamental characteristic of women with preeclampsia, notably demonstrated by a decrease in the proangiogenic and increase in antiangiogenic factors.

Placental-Derived Angiogenic Imbalance

In a healthy pregnancy, embryo-derived cytotrophoblasts invade the decidual and myometrial segments of the spiral arteries, replacing endothelium and causing remodeling of vascular smooth muscle and the inner elastic lamina ( Fig. 35.2 ). The luminal diameter of the spiral arteries increases fourfold, resulting in the creation of flaccid tubes that provide a low-resistance vascular pathway to the intervillous space. Furthermore, the remodeled arteries are unresponsive to vasoactive stimuli. These alterations in maternal vasculature ensure adequate blood flow to nourish the growing fetus and placenta. Healthy endothelium prevents platelet activation, activates circulating anticoagulants, buffers the response to vasopressors, and maintains fluid in the intravascular compartment.

A histologic comparison of spiral arteries in nonpregnant and late pregnant uterus is shown in two labeled sections A and B. — Fig. 35.2

In women with early-onset preeclampsia, cytotrophoblast invasion is incomplete and only the decidual segments undergo change; the myometrial spiral arteries are not invaded and remodeled and thus remain small, constricted, and hyperresponsive to vasomotor stimuli. Abnormal placentation results in decreased placental perfusion and placental infarcts, predisposing the fetus to growth restriction ( Fig. 35.3 ). The cellular stress and damage in the nascent placental cytotrophoblasts can be detected by the increased release of extracellular vesicles as early as 11 to 14 weeks’ gestation. Moreover, the contents of extracellular vesicles derived from the placenta of near-term women with preeclampsia are able to induce vascular dysfunction in both animal and human cell cultures. Placental ischemia worsens throughout pregnancy as restricted vessels are increasingly unable to meet the needs of the growing fetoplacental unit. In later-onset preeclampsia, placental ischemia may result from other factors, such as a preexisting maternal disease, infarction, or twin pregnancy.

An occluded decidual vessel contains lipid-laden cells labeled L and fibrin deposition labeled F. — Fig. 35.3

The fetal cytotrophoblasts release key antiangiogenic factors when exposed to chronic hypoxia. Thus, as the placenta becomes relatively hypoxic with progression of the pregnancy, placentally derived, antiangiogenic factors are overexpressed and released into the maternal circulation. Soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) are among the most studied antiangiogenic factors. Each of these factors is a partial receptor for the angiogenic hormone, which normally binds angiogenic hormone leading to angiogenesis. sFlt-1 antagonizes the angiogenic growth factors, vascular endothelial growth factor (VEGF) and placental growth factor ( PlGF) (a member of the VEGF family due to the sharing of structure and receptors). The release of these antiangiogenic factors from the intervillous space into the maternal circulation causes widespread maternal endothelial dysfunction and an accentuated systemic inflammatory response. Studies have demonstrated that sFlt-1 increases several weeks prior to the diagnosis of preeclampsia, and that both VEGF and PlGF are reduced.

Evidence for a central role of sFlt-1 in the pathogenesis of preeclampsia comes from both animal and human studies. Maynard et al. demonstrated that sFlt-1 levels increase during gestation and fall after delivery and that increased circulating sFlt-1 levels reduce circulating levels of free VEGF and PlGF, causing endothelial dysfunction that can be rescued by exogenous VEGF and PlGF. Furthermore, these investigators found that the administration of sFlt-1 to pregnant rats induced hypertension, proteinuria, and glomerular endotheliosis, the classic renal lesion of preeclampsia. When administered in vitro , VEGF and PlGF cause rat renal arteriolar relaxation, which is blocked by sFlt-1. In response to increased circulating levels of sFlt-1, VEGF and PlGF levels are reduced, resulting in endothelial dysfunction in maternal vessels ( Fig. 35.4 ). Importantly, elevated sFlt-1 levels and reduced levels of PlGF not only predict the subsequent development of preeclampsia, but do so with a “dose-response effect”—a greater ratio is found with more severe disease. The use of this information for early screening and diagnosis has been examined extensively and endorsed by the UK National Institute for Health and Care Excellence, but is currently hampered by lack of standardization of measurement. Knowledge of the state of angiogenic biomarkers can lead to earlier diagnosis of preeclampsia, and may help identify women who will develop adverse outcomes due to their disease.

A comparative diagram illustrates normal pregnancy and preeclampsia through uteroplacental blood flow, endothelial function, and organ outcomes. — Fig. 35.4

Abnormal Placentation

The basis for abnormal uteroplacental development has not been fully elucidated and is likely due to a complex interaction of immunologic, vascular, environmental, and genetic factors. Hypothetically, immune maladaptation may play a central role in predisposing to abnormal placentation. Immune cells present in the decidua, derived from the endometrium in the nonpregnant state, include macrophages, dendritic cells, and natural killer (NK) cells. Macrophages and dendritic cells are found in greater density in preeclamptic placentas than in control placentas. Similarly, levels of chemokines that attract these immune cells are also elevated. Excess macrophages in the decidua are associated with impaired trophoblast invasion, suggesting that excess inflammation may be one of the causal components of impaired placentation. NK cells may also be important in regulating vascular development during placentation. NK cells interact with fetal trophoblast cell markers via killer immunoglobulin receptors (KIR) to influence trophoblastic invasion. Specific genotypic combinations of maternal KIR and trophoblastic human leukocyte antigen C (HLA-C) may mediate the risk for preeclampsia.

Aberrant hemostatic activation during placental development has also been proposed to contribute to the abnormal placentation that is a hallmark of pregnancies destined to develop preeclampsia. Increased tissue factor expression may cause inappropriate activation of clotting pathways, which in turn may impair trophoblast invasion of the decidua. Abnormal protease-activated receptor 1 (PAR 1) may also play a role in the failure of trophoblasts to convert to an endothelial phenotype.

Agonistic autoantibodies to the angiotensin type 1 receptor (AT ₁) are present in many women with preeclampsia in association with defective remodeling of the uteroplacental vasculature. These autoantibodies activate AT ₁ receptors on trophoblast cells, endothelial cells, and vascular smooth muscle cells. They appear to block trophoblastic invasion and may induce the production of reactive oxygen species and thus play a significant role in the pathophysiology of preeclampsia ( Fig. 35.5 ). Furthermore, introduction of these autoantibodies into pregnant mice increases production of sFlt-1 and results in hypertension and proteinuria. Thus, these autoantibodies may play an important role in the pathogenesis of preeclampsia at several different stages.

A diagram illustrates the causes and effects of placental dysfunction in preeclampsia, including genetic, immune, and oxidative factors. — Fig. 35.5

CLINICAL PRESENTATION AND COMPLICATIONS

Hypertensive disorders of pregnancy can present simply as increased blood pressure (chronic and gestational hypertension) or preeclampsia, which is a multisystem disease unique to human pregnancy characterized by diffuse endothelial dysfunction. Preeclampsia can manifest as a maternal syndrome consisting of hypertension and proteinuria with or without other systemic abnormalities. Women with the disease may develop multisystem injury, and preeclampsia is leading indication for maternal peripartum admission to an intensive care unit. The disease may also be associated with a fetal syndrome (fetal growth restriction, oligohydramnios), which carries a high rate of medically indicated, preterm delivery in developed countries, and is the most common indication for admission to the neonatal intensive care unit. Preeclampsia can occur any time after 20 weeks’ gestation until 1 to 2 weeks after delivery ; onset before 34 weeks’ gestation is associated with increased disease severity and poorer outcomes for both the mother and fetus. The disease typically regresses within 48 hours after delivery.

Cardiovascular

Women with preeclampsia have pathophysiologic changes to the cardiovascular system directly caused by dysfunction of the endothelium. These changes include hypertension characterized by increased vascular resistance and sensitivity to vasoconstrictors and circulating catecholamines. In addition, alterations of endothelial permeability impact fluid balance and tissue edema. The added load on the heart also alters myocardial structure and function.

Arterial Vascular Function

Compared to a woman with a normotensive pregnancy, a woman with preeclampsia has higher blood pressure on average as early as the 9th week of gestation, as well as subtle measures of arterial stiffness. Two physiologic hypothesis explaining the hypertension are proposed: (1) constricted physiology (elevated vascular resistance, reduced central volume and cardiac index), or (2) a hyperdynamic state (elevated myocardial mass, systolic function, and cardiac output, with marginally increased resistance). Data from the landmark study by Visser and Wallenburg showed that women with severe preeclampsia had dramatically elevated systemic vascular resistance with a reduced cardiac index compared to normotensive women. Importantly, the authors also recorded hemodynamic values from a cohort of women with severe preeclampsia who had started receiving treatment (fluids, antihypertensive, and antiseizure medications), who had only a slightly elevated resistance compared to normotensive women. Some data suggest that the increase in arterial resistance is primarily due to the decrease in capillary bed volume, with later increases due to decreased arterial compliance.

An alternative hypothesis holds that the underlying arterial vascular resistance may not be elevated, even in the untreated patient, but that the hypertension is a result of a hyperdynamic state. For example, echocardiographic studies of both treated and untreated women with preeclampsia show only mildly elevated vascular resistance in a setting of increased left ventricular mass, normal-to-increased cardiac output, and left ventricular contractility. One possible reason for these different findings may be the duration of symptomatic preeclampsia, as pregnant women are more carefully observed and diagnosed earlier in the current era. Further, studies using pulmonary artery catheterization or echocardiography have reported variations in patient population, definition of preeclampsia, disease severity, prior treatment, and the presence or absence of concomitant comorbid disease. Finally, the gestational age at onset of preeclampsia may be associated with different hemodynamic patterns. For example, a prospective series of transthoracic echocardiography (TTE) in 1345 normotensive nulliparous women at 24 weeks’ gestation subsequently identified 107 women who developed preeclampsia, 75 of whom were early onset and 32 late onset. Systemic vascular resistance was considerably higher, and cardiac output lower among women with early- compared to late-onset preeclampsia, suggesting varying cardiovascular responses.

Myocardial Structure and Function

The left ventricle of women with preeclampsia is characterized by echocardiographic evidence of increased left ventricular mass, increased global systolic function, and evidence of a hyperdynamic state. Microscopically, there is evidence of decreased capillary bed volume, suggesting the antiangiogenic stress results in compensatory hypertrophy. The edematous and hypertrophied myocardium can be visualized on cardiac magnetic resonance imaging (MRI) ; the hypertrophy leads to diastolic dysfunction and subclinical systolic dysfunction. Overt systolic dysfunction, however, is less common but occurs more frequently in early- than late-onset disease, and in some cases may present as severe cardiac failure with a low ejection fraction. A well-documented relationship between severe preeclampsia and peripartum cardiomyopathy may be mediated by the antiangiogenic milieu in women with preexisting genetic risk. Of interest, TTE in women with peripartum cardiomyopathy, higher sFlt-1 levels are associated with worse outcomes, while elevated relaxin-2, which promotes VEGF activity, is associated with improved postpartum outcome.

Circulating Blood Volume

The central blood volume status of women with preeclampsia varies considerably and is impacted by both the severity of the disease and the degree of fetal involvement. Among women with a reduced plasma volume, body water is redistributed to the extracellular space, leading to nondependent edema. Pathologic endothelial cell permeability further contributes to nondependent edema. Several studies have demonstrated that the maternal plasma volume is reduced proportionately with fetal birth weight.

Determining a patient’s central blood volume status can be challenging. Previous guidelines recommended the placement of a pulmonary artery catheter to inform management decisions in women with pulmonary edema or renal failure. No randomized trials have evaluated the use of the pulmonary artery catheter for fluid management in women with preeclampsia. Further, interpretation of the data is challenging as left ventricular compliance and cardiovascular conditions vary widely, and a poor correlation exists between pulmonary capillary wedge pressure and left ventricular end-diastolic volume, especially in women with diastolic dysfunction. The placement of a pulmonary artery catheter is not a benign procedure; risks are well recognized. Both immediate and delayed maternal deaths have been attributed to the use of central venous catheters. The insertion of pulmonary artery catheters for management of preeclampsia should be done only after careful consideration of risks and benefits.

Point-of-care TTE may be useful for assessing cardiopulmonary status in the peripartum period. Valuable information about volume status, chamber size, wall thickness, and ventricular function may be gleaned. In the setting of low urine output, TTE assessment of stroke volume changes occurring with passive leg raise may predict fluid responsiveness but further work is needed to understand the clinical impact of this finding.

Pulmonary edema

Pulmonary edema is a severe complication that occurs in approximately 3% of women with preeclampsia. The risk increases in older multigravid women, among women with preeclampsia superimposed on chronic hypertension, and among those with acute or chronic renal disease. The clinical presentation is characterized by worsening dyspnea and orthopnea with concomitant signs of respiratory compromise, including tachypnea, rales, and hypoxemia. A large proportion of cases of pulmonary edema occur postpartum, usually within 2 to 3 days after delivery, and management is directed toward the underlying cause. Initial treatment includes standard treatments such as supplemental oxygen, fluid restriction, and diuretic therapy (e.g., furosemide).

Preeclampsia is associated with multiple factors that promote pulmonary edema: decreased colloid osmotic pressure, increased vascular permeability due to pulmonary endothelial dysfunction, increased intravascular hydrostatic pressure due to arterial hypertension, and increased venous pressure from diastolic dysfunction. Plasma colloid osmotic pressure, which is reduced in normal pregnancy because of decreased plasma albumin concentration, decreases even further in women with preeclampsia, likely due to proteinuria. Women with normal pregnancies have a mean osmotic pressure of approximately 22 mm Hg in the third trimester and approximately 17 mm Hg during the early postpartum period. In contrast, a study of women with preeclampsia demonstrated a mean colloid osmotic pressure of approximately 18 mm Hg before delivery and 14 mm Hg after delivery.

TTE may be helpful in distinguishing the etiology of heart failure with low ejection fraction, and in the identification of other cardiac comorbidities contributing to pulmonary edema. Lung ultrasonography may be a useful adjunct to identify lung pathology. In the absence of respiratory symptoms, women with preeclampsia and healthy women have similar appearing lung ultrasonography images. In a study of 20 asymptomatic women with severe preeclampsia and healthy controls, interstitial edema, which precedes alveolar edema, was identified by sonographic B-line artifacts in 25% of the cases. High lung “echo comet scores” were associated with increased left ventricular end-diastolic pressure. Another investigation in women with preeclampsia found echo comet scores were higher before delivery than 4 days after delivery, although tissue Doppler indices did not change after delivery. The authors concluded that increased extravascular lung water before delivery may be associated with increased pulmonary capillary permeability and cardiac dysfunction.

Pulmonary

Obstructive sleep apnea (OSA) is a sleep-related breathing disorder characterized by recurrent episodes of upper airway collapse leading to hypoxia and sleep disturbance. Even in nonpregnant persons, OSA is strongly associated with hypertension. A metaanalysis of cohort studies suggests that pregnant women with OSA have a twofold increased risk for developing preeclampsia. The precise nature of this relationship is not known, and several mechanisms have been proposed. Further studies examining the impact of OSA treatment on maternal and neonatal outcomes are needed.

A review of anesthesia-related maternal deaths in Michigan described a series of postoperative and postpartum deaths attributed to airway obstruction or hypoventilation . One death was complicated by severe preeclampsia and sleep-disordered breathing likely associated with opioid analgesia-related respiratory depression after cesarean delivery. Such findings highlight the need for close monitoring and consistent vigilance in the postoperative care of women with severe preeclampsia—particularly those with generalized edema, known OSA, airway swelling, snoring, and obesity.

Central Nervous System

Central nervous system manifestations of preeclampsia include persistent or severe headache, hyperexcitability, hyperreflexia, eclampsia, and coma. Approximately 25% of women with preeclampsia have visual disturbances, such as scotoma, amaurosis, and blurred vision; these symptoms may be the initial presenting finding.

Noninvasive measurements of cerebral blood flow and resistance, along with other neuroimaging approaches, suggest that the loss of cerebral vascular autoregulation and vascular barotrauma occur. Hyperperfusion of the brain, particularly in the setting of the endothelial dysfunction, causes vasogenic edema. Consequently, these changes may result in the posterior reversible leukoencephalopathy syndrome (PRES) . Measures of cerebrospinal fluid content have demonstrated stark changes in protein content among women with preeclampsia, especially those with neurologic symptoms. Eclampsia is believed to be the manifestation of vasogenic brain edema; MRI findings mimic those of nonpregnant patients with PRES. One review of MRI findings in women with eclampsia found signs consistent with PRES in 46 of 47 women.

Obtaining improved assessment of central nervous system injury would be helpful. Optic nerve sheath diameter (ONSD) is a marker for increased intracranial pressure in the nonobstetric population. In a study that compared women with preeclampsia and healthy controls, the median ONSD was greater in women with disease. Nineteen percent of women with preeclampsia had ONSD > 5.8 mm, a value that had previously been associated with a 95% risk for raised intracranial pressure in nonobstetric settings. However, this study found no association between ONSD and the severity of preeclampsia. Understanding the clinical impact of this finding, given the lack of an accurate, alternate measure of intracranial pressure, requires further investigation. Regional cerebral hemoglobin oxygen saturation (rcSO ₂) has been measured using near-infrared spectroscopy in women with severe preeclampsia and was found to be lower in women with preeclampsia compared with healthy women. The rcSO ₂ increased after the administration of magnesium sulfate; the percent increase indirectly correlated with blood pressure.

Stroke and Other Intracranial Pathology

Although the absolute risk for pregnancy-associated stroke is low, the risk for intracerebral and subarachnoid hemorrhage and ischemic stroke are markedly increased in women with preeclampsia. Pregnant women with stroke are more likely to have had preeclampsia with severe features, eclampsia, or chronic hypertension. Stroke remains a leading cause of death in women with preeclampsia. Most strokes occur postpartum, and have a high mortality rate because the stroke is likely to be hemorrhagic.

Reversible cerebral edema is a common CNS feature of preeclampsia or eclampsia. The loss of cerebral autoregulation causes hyperperfusion that, compounded by endothelial disruption, leads to interstitial or vasogenic edema. The vascular hyperreactivity can lead to vasospasm, which can be seen on angiographic exams as segmental narrowing in some women with severe preeclampsia and eclampsia. Calle-Fleming syndrome is a reversible cerebral vasoconstriction syndrome (RCVS) , also known postpartum angiopathy when it occurs within 1 week of delivery. RCVS may cause recurrent, severe headaches in these women, and when severe, can result in cerebral ischemia. Microvascular hemorrhage is a common feature of preeclampsia and can lead to intracranial hemorrhage.

Mean arterial blood pressure and diastolic blood pressure may not reflect the true risk for stroke. A review of 28 case histories of women with severe preeclampsia who suffered a stroke revealed that (1) systolic blood pressure in excess of 160 mm Hg was a far superior predictor of stroke than diastolic hypertension or elevated mean arterial pressure, (2) the majority of strokes were hemorrhagic (93%) as opposed to thrombotic (7%), and (3) the majority of strokes (57%) occurred in the postpartum period. Close attention to blood pressure control throughout the peripartum period is the mainstay of stroke prevention. In keeping with this goal, ergot alkaloids should generally be avoided in hypertensive patients because their administration can result in severe hypertension.

Hematologic

Several hematologic changes occur in women with preeclampsia. Most common is a relative increase in plasma hemoglobin concentration due to hemoconcentration. In addition, the oxyhemoglobin dissociation curve is shifted to the left compared to healthy pregnancies, with a mean (± standard deviation) P ₅₀ of 25.1 ± 0.38 mm Hg versus 30.4 ± 0.20 mm Hg, at near-term gestation. Despite a higher hemoglobin concentration, the red blood cells of women with severe preeclampsia have less deformability and are prone to destruction under sheer forces, which makes these patients prone to hemolysis.

Thrombocytopenia , defined as a platelet count < 150,000/mm ³, occurs in approximately 10% of uncomplicated pregnancies, but impacts roughly 50% of patients with preeclampsia with severe features. Platelet counts < 100,000/mm ³ occur rarely in women with uncomplicated pregnancies, but are a hallmark of HELLP syndrome. More than a quarter of patients with HELLP syndrome have a platelet count < 80,000/mm ³. Platelets contribute to coagulation by exposing a phospholipid surface as a catalytic site, and through adhesive and cohesive functions, facilitate the formation of the hemostatic plug. Studies using thromboelastography have found that women with preeclampsia without severe features have measurements similar to women with normal blood pressures, and that those with severe disease and thrombocytopenia (platelet count < 100,000/mm ³) have relatively decreased maximum amplitude. In contrast to healthy pregnancies and other hypertensive disorders, platelets are activated in preeclampsia ; activated platelets release adenosine diphosphate, serotonin, thromboxane A ₂, adhesive proteins and coagulation factors, and growth factors (see Chapter 44 ). Platelet degranulation is believed to account for some of the decrease in platelet function, while the decrease in platelet count is explained by splenic sequestration and possibly placental sequestration.

Hepatic

Hepatic manifestations of preeclampsia include periportal hemorrhage and fibrin deposition in hepatic sinusoids. Hepatic involvement frequently presents as right upper quadrant or epigastric pain, which may represent pathologies ranging from mild hepatocellular necrosis to subcapsular bleeding.

Subcapsular Hematoma

Rupture of a subcapsular hematoma of the liver is a life-threatening complication of severe preeclampsia and HELLP syndrome that manifests as abdominal pain, nausea and vomiting, and headache. The pain worsens over time and becomes localized to the epigastric area or right upper quadrant. Hypotension and shock typically develop with rupture. Diagnosis is confirmed with ultrasonography, computed tomography, or MRI of the liver ( Fig. 35.6 ). Subcapsular hematoma rupture with shock is a surgical emergency that requires immediate multidisciplinary treatment that includes intravascular volume resuscitation and blood and plasma transfusions. In some circumstances, selective arterial embolization by an interventional radiologist may be useful. Patients with fulminant hepatic failure may require liver transplantation. Prompt surgical intervention and refinements in surgical technique have substantially reduced the maternal mortality rate associated with spontaneous hepatic rupture to less than 20%. The most common causes of death are coagulopathy and exsanguination.

HELLP Syndrome

In 1982 Weinstein described a series of 29 cases and coined the acronym HELLP syndrome, characterized by hemolysis, elevated levels of liver enzymes, and a low platelet count. Sibai proposed standardized laboratory diagnostic criteria ( Table 35.1 ). Diagnosis can be especially challenging because other medical and surgical disorders can mimic HELLP syndrome, including acute fatty liver of pregnancy, hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, and lupus ( Box 35.4 ).

TABLE 35.1

Diagnostic Criteria for Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome

Modified from Sibai BM. The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): Much ado about nothing? Am J Obstet Gynecol . 1990;162:311–316.

Criteria	Laboratory Tests
Hemolysis	Abnormal peripheral blood smear
	Increased bilirubin > 1.2 mg/dL
	Increased LDH > 600 IU/L
Elevated liver enzyme levels	Increased AST ≥ 70 IU/L
Elevated liver enzyme levels	Increased LDH > 600 IU/L
Thrombocytopenia	Platelet count < 100,000/mm ³

AST , Aspartate transferase; LDH , lactic dehydrogenase.

Box 35.4

Differential Diagnosis of Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome

From O’Brien JM, Barton JR. Controversies with the diagnosis and management of HELLP syndrome. Clin Obstet Gynecol . 2005;48:460–477.

•
Acute fatty liver of pregnancy
•
Appendicitis
•
Cholestasis of pregnancy
•
Diabetes insipidus
•
Cholecystitis
•
Gastroenteritis
•
Glomerulonephritis
•
Hemolytic-uremic syndrome
•
Hepatic encephalopathy
•
Hyperemesis gravidarum
•
Idiopathic thrombocytopenia
•
Nephrolithiasis
•
Peptic ulcer disease
•
Systemic lupus erythematosus
•
Thrombotic thrombocytopenic purpura
•
Viral hepatitis

HELLP syndrome is associated with increased maternal morbidity and preterm delivery; the degree of thrombocytopenia is associated with outcome ( Table 35.2 ). Most cases of HELLP syndrome are diagnosed after 34 weeks’ gestation. Hemolysis, defined as the presence of microangiopathic hemolytic anemia, is the classic hallmark of HELLP syndrome; the peripheral blood smear demonstrates schistocytes, burr cells, and echinocytes. Common histopathologic findings are periportal hepatic necrosis and hemorrhage. Maternal signs and symptoms include right upper quadrant or epigastric pain, nausea and vomiting, headache, hypertension, and proteinuria. Notably, clinical presentation varies; 12% to 18% of women may be normotensive, and proteinuria is absent in approximately 13% of affected women.

TABLE 35.2

Serious Maternal Complications in a Series of 442 Patients With Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome

Modified from Sibai BM, Ramadan MK, Usta I, et al. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J Obstet Gynecol . 1993;169:1000–1006.

Complication	Number of Patients	Percent
Disseminated intravascular coagulation	92	21
Placental abruption	69	16
Acute renal failure	33	8
Severe ascites	32	8
Pulmonary edema	26	6
Pleural effusion	26	6
Cerebral edema	4	1
Retinal detachment	4	1
Laryngeal edema	4	1
Subcapsular liver hematoma	4	1
Acute respiratory distress syndrome	3	1
Maternal death	4	1

Patients with HELLP syndrome are poor candidates for expectant management ; however, deferred delivery for 24 to 48 hours to allow for corticosteroid administration to accelerate fetal lung maturity may be appropriate for women less than 34 weeks’ gestation if the maternal and fetal condition remain stable. Women with HELLP syndrome who have not yet reached 34 weeks’ gestation should be managed in a tertiary care facility with a neonatal intensive care unit capable of caring for a compromised preterm neonate. Clinical management aligns with that for preeclampsia with severe features and includes intravenous magnesium sulfate for seizure prophylaxis and antihypertensive medications to maintain systolic blood pressure < 160 mm Hg and a diastolic blood pressure < 110 mm Hg.

The platelet count can fall precipitously and may remain depressed up to 48 hours after delivery. The decision to initiate neuraxial analgesia or anesthesia is complex and must take into account the rate of change in platelet count and other factors such as signs and symptoms of bleeding or bruising. Women with a platelet count < 50,000/mm ³ may be at risk for bleeding, and for spinal epidural hematoma with neuraxial anesthesia.

Platelet transfusions are indicated in the presence of significant bleeding and in all parturients with a platelet count < 20,000/mm ³. For women with a platelet count < 40,000/mm ³ who are scheduled for cesarean delivery, the preincision administration of platelets has been recommended. As the risk for postpartum hemorrhage is significantly increased in patients with HELLP syndrome, large-bore intravenous access should be obtained, and compatible red blood cell units should be available.

Renal

Renal manifestations of preeclampsia include proteinuria, changes in the glomerular filtration rate (GFR), and hyperuricemia . Proteinuria is found in 75% of women with preeclampsia and is a defining element, but its presence is no longer considered essential for diagnosis when other evidence of end-organ injury is evident. Additionally, the presence of proteinuria may be challenging to interpret among women with preexisting renal dysfunction. The characteristic renal histologic lesion of preeclampsia is glomerular capillary endotheliosis, which manifests as glomerular enlargement and endothelial and mesangial cell swelling. Increasing urinary excretion of protein likely results from changes in the pore size or charge selectivity of the glomerular filter and impaired proximal tubular reabsorption.

During normal pregnancy, the GFR increases by 40% to 60% during the first trimester, with a resulting decrease in the serum markers of renal clearance, including blood urea nitrogen (BUN), creatinine, and uric acid (see Chapter 2 ). In preeclampsia, this increase in GFR is blunted compared with normal pregnancy. Notably, women with preeclampsia may have BUN and creatinine measurements in the normal range for nonpregnant women.

The association between preeclampsia and hyperuricemia was recognized as early as 1917. Most evidence suggests that decreased renal clearance is the primary mechanism for elevated uric acid levels. Because levels of serum uric acid begin to increase as early as 25 weeks’ gestation, it has been investigated as a possible early marker of preeclampsia.

Renal Failure

Acute renal failure is a rare but serious complication of severe preeclampsia. The true incidence remains unknown. Acute renal failure is divided into three categories: (1) prerenal , which refers to renal hypoperfusion; (2) intrarenal , which suggests intrinsic renal parenchymal damage; and (3) postrenal , which implies obstructive uropathy. The majority of cases (83% to 90%) of acute renal failure in preeclampsia result from prerenal and intrarenal pathologic processes (most commonly acute tubular necrosis) and resolve completely after delivery. In contrast, bilateral renal cortical necrosis is a rare and serious condition associated with considerable maternal and perinatal morbidity and mortality. It occurs most commonly in association with known renal parenchymal disease, chronic hypertension with superimposed preeclampsia, placental abruption, disseminated intravascular coagulation (DIC), HELLP syndrome, sepsis, or fetal death.

Oliguria is a possible late manifestation of severe preeclampsia and parallels the severity of disease. Persistent oliguria requires immediate assessment of intravascular volume status; however, hypovolemia should not be assumed. Progression to renal failure is rare and is typically preceded by hypovolemia, placental abruption, or DIC.

CLINICAL AND OBSTETRIC MANAGEMENT

Obstetric management of preeclampsia centers on (1) fetal and maternal surveillance, (2) treatment of hypertension, (3) seizure prophylaxis, and (4) timing and route of delivery.

Maternal and Fetal Surveillance

Maternal surveillance is indicated for all women with preeclampsia. In women with preeclampsia without severe features, the goal is early detection of progression to severe disease. In women with severe disease, the goal is detection of worsening organ dysfunction. Initial laboratory investigations for the pregnant woman who develops hypertension after 20 weeks’ gestation are listed in Table 35.3 . The admission platelet count is an excellent predictor of subsequent thrombocytopenia. For women with a platelet count exceeding 100,000/mm ³, further coagulation testing is not required because coagulopathy is rarely present in severely preeclamptic women who have a normal platelet count. If the platelet count is less than 100,000/mm ³, other hemostatic abnormalities (e.g., prolonged prothrombin time [PT] and activated partial thromboplastin time [aPTT], reduced fibrinogen concentration) may be present. Further coagulation studies may be useful, particularly if risk factors for DIC are present (e.g., placental abruption, liver dysfunction, HELLP syndrome). Liver function tests are obtained in all women with preeclampsia because abnormal levels indicate severe disease and may prompt delivery. Approximately 20% of women with preeclampsia have elevated serum aminotransferase levels. The value of uric acid testing is controversial, with conflicting evidence regarding its association with increased fetal or maternal risk for complications.

TABLE 35.3

Initial Laboratory Investigations for Women in Whom Hypertension Develops After 20 Weeks’ Gestation

Modified from Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol . 2000;183:S1–S22; and American College of Obstetricians and Gynecologists Taskforce on Hypertension in Pregnancy. Hypertension in Pregnancy . American College of Obstetricians and Gynecologists; 2013.

Test	Rationale
Hemoglobin and hematocrit	Hemoconcentration supports diagnosis of preeclampsia and is an indicator of severity. Values are decreased if hemolysis is present.
Platelet count	Thrombocytopenia suggests preeclampsia with severe features.
Urine protein-creatinine ratio or 24-h urine protein excretion	Presence of proteinuria distinguishes preeclampsia from gestational hypertension.
Serum creatinine level	Abnormal or rising creatinine level suggests preeclampsia with severe features, especially in presence of oliguria.
Serum aminotransferase levels	Elevated serum aminotransferase levels suggest preeclampsia with severe features with hepatic involvement.

The frequency of subsequent laboratory evaluation is guided by the initial findings and the severity of illness and disease progression. A diagnosis of preeclampsia without severe features should prompt at least weekly laboratory investigations, with the frequency modified based on subsequent clinical findings. In the expectant management of preeclampsia with severe features, hemoglobin, platelet count, liver function tests, creatinine, and coagulation function should be assessed daily or every other day. For women undergoing induction of labor for whom initial laboratory measurement or platelet counts are suspicious for HELLP syndrome, serial platelet counts at least every 6 hours may guide decision-making about the timing of delivery and analgesic or anesthetic technique. Finally, for women with indicated delivery, an active blood type and screen is indicated with consideration of type and cross-match of red blood cells for patients with thrombocytopenia or other abnormalities in coagulation tests.

Preeclampsia is a known risk factor for perinatal death. The ACOG Taskforce on Hypertension in Pregnancy recommended daily fetal movement counts with either nonstress testing or biophysical profile testing at the time of diagnosis (see Chapter 6 ) and at regular intervals thereafter. Ultrasonography is used to estimate fetal weight and amniotic fluid volume. Doppler ultrasonography is used to measure fetal blood flow velocimetry if fetal growth restriction is suspected.

Corticosteroid Administration

To accelerate fetal lung maturity, all women who develop preeclampsia with severe features or HELLP syndrome between 24 and 34 weeks’ gestation should receive a course of corticosteroid therapy. A randomized double-blind trial of 218 women with severe preeclampsia at 26 to 34 weeks’ gestation found that the infants of those receiving betamethasone, compared with the infants of those receiving placebo, exhibited a significant reduction in the rate of the neonatal respiratory distress syndrome and reduced rates of neonatal intraventricular hemorrhage, infection, and death. The available data also suggest that treatment with corticosteroids results in improvement in the maternal platelet count in women with HELLP syndrome, with dexamethasone being more efficacious than betamethasone. However, these studies do not show a clear benefit of corticosteroid treatment on the endpoints of severe maternal morbidity or mortality.

Uteroplacental Perfusion

Uteroplacental perfusion may be impaired in pregnancies complicated by preeclampsia. In contrast with normal pregnancy, fetal umbilical artery flow waveforms demonstrate an increase in downstream resistance, a decrease in diastolic flow velocity, and an increase in the systolic-to-diastolic flow velocity ratio. The systolic-to-diastolic ratio, calculated from Doppler ultrasonographic determination of blood flow velocities, reflects intrinsic arterial resistance in the chorionic plate of the placenta. Pathophysiologic changes can result in fetal growth restriction (the fetal syndrome) in some pregnancies complicated by severe preeclampsia.

Placental Abruption

Placental abruption occurs in approximately 2% of women with preeclampsia and results in increased perinatal morbidity and mortality. A 2006 retrospective case-control study of 161 women with placental abruption and 2000 women without abruption found a threefold increased risk for placental abruption in women with preeclampsia. The incidence is also increased in women with underlying chronic hypertension. Management depends on the extent of abruption and associated hypotension, coagulopathy, or fetal compromise (see Chapter 37 ). Placental abruption is also associated with the development of DIC (see Chapter 44 ).

Treatment of Acute Hypertension

Antihypertensive medications are used to treat severe hypertension (systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 110 mm Hg) with the goal of preventing adverse maternal sequelae such as hypertensive encephalopathy, cerebrovascular hemorrhage, myocardial ischemia, and congestive heart failure.

Although acute control of maternal blood pressure is critical, rapid changes in maternal perfusion pressure may adversely affect uteroplacental perfusion and oxygen delivery to the fetus. Antihypertensive medications should be carefully titrated to avoid abrupt changes in maternal blood pressure. The ISSHP targets treatment to a diastolic blood pressure of 85 mm Hg or less, regardless of systolic pressure, while the ACOG does not provide specific targets due to lack of evidence of benefit. In either case, blood pressure in the severe range (≥160/110 mg Hg) is considered an emergency and treatment should be administered within 30 to 60 minutes. Commonly used drugs include labetalol, hydralazine, and nifedipine ( Table 35.4 ). Nicardipine and esmolol may be considered second-line agents. Historically, sodium nitroprusside was also a second-line agent. However, because it is a highly potent smooth muscle vasodilator, and careful titration is required to avoid acute hypotension, it is seldom used in the current management of preeclampsia.

TABLE 35.4

Treatment of Acute Severe Hypertension in Preeclampsia/Eclampsia

Modified from American College of Obstetricians and Gynecologists. ACOG Practice Bulletin, Number 222: Gestational hypertension and preeclampsia (reaffirmed 2023). Obstet Gynecol . 2020;135:e237–e260.

Medication	Onset of Action (min)	Dose
Labetalol	1–2	10–20 mg IV, then 20–80 mg every 10–30 min if needed, up to a maximum cumulative dose of 300 mg
Hydralazine	10–20	5 mg IV or IM, then 5–10 mg IV every 20–40 min if needed, up to a maximum cumulative dose of 20 mg
Nifedipine	5–10	10–20 mg orally, repeat in 20 min if needed; then 10–20 mg every 2–6 h; maximum daily dose of 180 mg
Nicardipine	10–15	Initial infusion 5 mg/h, increase by 2.5 mg/h every 5 min if needed; maximum dose of 15 mg/h
Esmolol	1–2	500 µg/kg loading dose, infusion 50 µg/kg/min, titrate upward by 50 µg/kg/min increments if needed; maximum dose 200 µg/kg/min

IM , Intramuscularly; IV , intravenously.

Systematic review and metaanalysis of available studies show insufficient data regarding the relative efficacy of these commonly used agents and recommend selection based on clinician familiarity and adverse effects. The authors of the systematic review do, however, suggest that some agents are inferior and recommend avoiding diazoxide, ketanserin, nimodipine, and magnesium sulfate for the treatment of severe hypertension in pregnancy (although magnesium is recommended for maternal seizure prophylaxis). The ACOG practice bulletin on the treatment of acute hypertension recommends intravenous labetalol, intravenous or intramuscular hydralazine, or oral nifedipine as a first-line treatment for acute-onset, severe hypertension in pregnant or postpartum patients.

Specific Medications

Labetalol is a combined alpha- and beta-adrenergic receptor antagonist with a 1:7 ratio of alpha- to beta-adrenergic receptor antagonism when administered intravenously. Labetalol should be avoided in women with severe asthma or congestive heart failure.

A metaanalysis concluded that intravenous labetalol has efficacy similar to intravenous hydralazine but with fewer maternal side effects, although evidence was limited to four small, randomized controlled trials. Neonates born to mothers exposed to beta-adrenergic receptor antagonists during delivery, including labetalol, demonstrate increased rates of neonatal hypoglycemia and bradycardia.

Hydralazine has been used safely in pregnant women for decades and is also considered a first-line drug for treating severe hypertension in pregnancy. Hydralazine exerts a potent direct vasodilating effect. Plasma volume expansion before administration decreases the risk for maternal hypotension. Other side effects include tachycardia, palpitations, headache, and neonatal thrombocytopenia. In a randomized clinical trial, hydralazine was associated with more maternal tachycardia and palpitations and less neonatal bradycardia and hypotension than labetalol.

Nifedipine is a calcium entry–blocking agent that lowers blood pressure by relaxing arterial and arteriolar smooth muscle. It can be administered as a long-acting oral medication once the severe hypertension has stabilized. Nifedipine immediate-release capsules should not be administered to women with known coronary artery disease, long-standing diabetes mellitus or aortic stenosis, or to women older than 45 years of age because of an increased risk for sudden cardiac death. In the absence of contraindications, nifedipine is now recommended as a first-line agent in women for whom intravenous access is difficult to secure.

Although earlier reports suggested that the coadministration of nifedipine with magnesium sulfate causes adverse effects in both the mother and fetus, including severe maternal hypotension, neuromuscular blockade, and nonreassuring fetal heart rate (FHR) patterns, subsequent data suggest that these drugs can be used together safely. Oral nifedipine has been found to be as efficacious and safe as intravenous labetalol.

Nicardipine is a calcium entry–blocking agent that can be administered by intravenous infusion and has been shown to achieve rapid decreases in systolic and diastolic blood pressures in pregnant women. It is an excellent option for treating severe hypertension that is not responsive to labetalol or hydralazine.

Esmolol is a short-acting beta-adrenergic receptor antagonist that can be used to treat acute hypertension accompanied by maternal tachycardia. Concerns regarding the use of esmolol during pregnancy arose in 1989 after a report of dose-dependent prolonged fetal bradycardia in a study of gravid ewes receiving esmolol by stepped infusion. Subsequent human case reports have reported variable responses, but in most cases fetal bradycardia was transient and FHR returned to baseline after discontinuation of the drug. Placental transfer is rapid, and clinicians should expect to observe the effects of beta-adrenergic receptor blockade in the fetus. Maternal administration of esmolol produces a greater degree of beta-adrenergic receptor blockade in the fetal lamb than that observed after maternal administration of an equipotent dose of labetalol.

Seizure Prophylaxis and Treatment

In the setting of preeclampsia and eclampsia, magnesium sulfate is indicated for both seizure prophylaxis and treatment.

Seizure Prophylaxis

The routine use of magnesium sulfate for seizure prophylaxis in women with preeclampsia with severe features is an established obstetric practice. There is clear evidence that magnesium sulfate is the best available agent for prevention of recurrent seizures in women with eclampsia.

A metaanalysis of the available data identified six trials involving 11,444 women that compared magnesium sulfate for prevention of eclampsia with either placebo or no anticonvulsant. Magnesium decreased the risk for developing eclampsia (relative risk [RR], 0.41; 95% confidence interval [CI], 0.29 to 0.58); there was also a trend toward lower risk for maternal death (RR, 0.54; 95% CI, 0.26 to 1.10), but no effect on serious maternal morbidity. Additionally, magnesium therapy reduced the risk for placental abruption. It did not adversely affect fetal and/or neonatal outcomes, including stillbirth, perinatal death, or neurosensory disability. Treatment with magnesium increased the risk for maternal respiratory depression (RR, 1.98; 95% CI, 1.24 to 3.15) and cesarean delivery (RR, 1.05; 95% CI, 1.01 to 1.10). Other side effects that were significantly more common in those treated with magnesium included feeling warm or flushed, nausea/vomiting, muscle weakness, hypotension, dizziness, drowsiness/confusion, and headache. Magnesium sulfate is not indicated for seizure prevention in preeclampsia without severe features. Studies have failed to show a difference in the number of women who progressed to severe preeclampsia.

The mechanism of the anticonvulsant effect of magnesium is not well understood. It was previously believed that eclamptic seizures were the result of cerebral vasospasm and that the cerebral vasodilating properties of magnesium reduced the rate of eclamptic seizures by relieving vasospasm. However, there is evidence that abrupt, sustained blood pressure elevation overwhelms myogenic vasoconstriction and causes forced dilation of the cerebral vessels, hyperperfusion, and cerebral edema. This raises the question of how magnesium sulfate—a vasodilator—could be effective in seizure prophylaxis, as magnesium would be expected to worsen cerebral hyperperfusion and edema. Using a rat model, Euser and Cipolla demonstrated that the mesenteric vessels are more sensitive to magnesium-induced vasodilation than are cerebral vessels, suggesting that part of the effect may be mediated through decreasing peripheral vascular resistance. Further animal studies suggest that magnesium may ameliorate neuroinflammation and brain edema in an eclampsia-like seizure model. Magnesium may also protect the blood-brain barrier, or act centrally at N -methyl- d -aspartate receptors to raise the seizure threshold.

No consensus exists regarding (1) the ideal time to initiate treatment with magnesium sulfate, (2) the best loading and maintenance doses, or (3) the optimal duration of therapy. Many obstetricians administer a loading dose of 4 to 6 g over 20 to 30 minutes, followed by a maintenance infusion of 1 to 2 g/h. The infusion is commonly initiated once the decision is made to deliver the fetus and is continued for 24 hours postpartum. Expert opinion recommends that women with preeclampsia with severe features undergoing cesarean delivery should receive magnesium sulfate at least 2 hours before the procedure, during surgery, and for 24 hours postpartum.

Magnesium sulfate is eliminated almost entirely by renal excretion, and serum levels may become dangerously high in the presence of renal insufficiency. Side effects of hypermagnesemia include chest pain and tightness, palpitations, nausea, blurred vision, sedation, transient hypotension, and, rarely, pulmonary edema. In untreated patients, the normal range for serum magnesium concentrations is 1.7 to 2.4 mg/dL. The therapeutic range lies between 5 and 9 mg/dL. Reflex testing is used as a clinical screen for hypermagnesemia; when deep tendon reflexes are preserved, the more serious side effects are usually avoided. Patellar reflexes are lost at serum magnesium levels of approximately 12 mg/dL. Respiratory arrest occurs at levels between 15 and 20 mg/dL, and asystole occurs when the level exceeds 25 mg/dL. Serial measurement of serum magnesium levels may be helpful in the management of women with renal dysfunction because magnesium toxicity can occur with usual dosing regimens.

Treatment of suspected magnesium toxicity includes immediate discontinuation of the infusion and the intravenous administration of calcium gluconate (1 g) over 10 minutes. In the rare event of respiratory compromise, the patient may require tracheal intubation and mechanical ventilation until spontaneous ventilation returns.

Seizure Treatment

Immediate goals are to stop convulsions, establish a patent airway, and prevent major complications (e.g., hypoxemia, aspiration). Further obstetric management includes antihypertensive therapy, induction or augmentation of labor, and expeditious (preferably vaginal) delivery. Fetal bradycardia typically begins during or immediately after a seizure but does not mandate immediate delivery unless it is persistent.

During the seizure, oxygenation may prove impossible, but supplemental oxygen should be delivered by means of a face mask ( Box 35.5 ). Attempts to insert an oral airway should be withheld until the seizure abates. As soon as breathing resumes, ventilation may be gently augmented with a bag-and-mask device. Pulse oximetry should be used to assess maternal oxygenation. Blood pressure and the electrocardiogram should be monitored to identify hypertension, arrhythmia, or cardiac arrest. While initial resuscitation is underway, an assistant should establish intravenous access, which may be difficult in a combative postictal woman. Judicious sedation may be required to allow further treatment in some patients.

Box 35.5

Eclampsia: The ABCs of Eclamptic Seizure Control

Airway

•
Turn patient to the left side; apply jaw thrust.
•
Attempt bag-and-mask ventilation (F io ₂ = 1.0) or administer oxygen by face mask.
•
Insert oral airway if necessary.

Breathing

•
Continue bag-and-mask ventilation (F io ₂ = 1.0) or administer oxygen by face mask.
•
Apply pulse oximeter and monitor Sp o ₂.

Circulation

•
Secure intravenous access.
•
Check blood pressure at frequent intervals.
•
Monitor electrocardiogram.

Drugs

•
Magnesium sulfate
- •
  4–6 g IV over 20 min
- •
  1–2 g/h IV for maintenance therapy
- •
  2–4 g IV over 10 min for recurrent seizures
•
Antihypertensive agents
- •
  Labetalol or hydralazine as needed to treat hypertension (see Table 35.4 )

IV , Intravenously.

Magnesium sulfate is preferred to diazepam for the prevention of further seizures in eclampsia. The administration of magnesium sulfate in women with eclampsia is associated with significantly lower maternal death rates. An initial intravenous bolus of 4 to 6 g is administered, followed by an infusion at 1 to 2 g/h, assuming the patient has adequate renal function. Recurrent convulsions should prompt administration of an additional bolus of 2 to 4 g, infused over 5 to 10 minutes. The patient should be carefully monitored for signs of magnesium toxicity. Should there be recurrent uncontrolled seizures, small doses of midazolam or diazepam may be used to raise the seizure threshold.

Decision and Route of Delivery

Delivery remains the only cure for preeclampsia; however, the delivery of women with preeclampsia without severe features is not urgent. Data suggest that induction of labor for pregnancies beyond 37 weeks’ gestation in women with gestational hypertension or preeclampsia without severe features is associated with improved maternal outcomes compared with expectant management. Outcomes in these pregnancies are similar to those in uncomplicated pregnancies. In general, delivery is recommended for women presenting with preeclampsia with severe features at 34 weeks’ gestation or later.

For women with preeclampsia with severe features at less than 34 weeks’ gestation ( Fig. 35.7 ), expectant management may improve fetal outcomes without substantially endangering the mother, but data are few. Delay of delivery for 24 to 48 hours allows for the administration of corticosteroids to facilitate fetal lung maturity and transfer to a facility with maternal and neonatal intensive care resources. Expedited delivery, regardless of corticosteroid administration, is indicated for patients with eclampsia, pulmonary edema, DIC, placental abruption, abnormal fetal surveillance, a previable or nonviable fetus, or intrauterine fetal demise. If a woman develops refractory severe hypertension despite maximum doses of antihypertensive agents or persistent cerebral symptoms (e.g., headache, visual disturbance) while receiving magnesium sulfate, delivery should occur within 24 to 48 hours, regardless of gestational age or corticosteroid administration. Expectant management before 34 weeks’ gestation should be undertaken at facilities with neonatal and maternal intensive care resources.

A clinical flowchart outlines management steps for severe preeclampsia before 34 weeks of gestation. — Fig. 35.7

Vaginal delivery should be attempted in all women with preeclampsia without severe features, assuming no other indications for cesarean delivery exist. Vaginal delivery should also be attempted in most women with severe disease, especially those beyond 34 weeks’ gestation. Cesarean delivery is appropriate when the maternal or fetal condition mandates immediate delivery or when other indications for cesarean delivery exist.

Postpartum venous thromboembolism (VTE) is a leading cause of maternal mortality in pregnancy. Both cesarean delivery and preeclampsia are independent risk factors for postpartum VTE. Prophylaxis and treatment of VTE are discussed in Chapter 38 .

ANESTHETIC MANAGEMENT

The anesthetic management of the woman with hypertensive disorder of pregnancy must consider pathophysiologic changes in the maternal airway and cardiovascular system, and increased potential for complications such as pulmonary edema. Additionally, the potential for rapid progression to the severe form of preeclampsia or eclampsia mandates continual reassessment of the patient.

Preanesthetic Evaluation

The preanesthetic assessment of women with confirmed or suspected preeclampsia should assess, at a minimum, the airway, maternal hemodynamic parameters and fluid balance, and coagulation status. Laboratory analysis should include a complete blood count, including hemoglobin concentration and platelet count. Other assessments of coagulation (e.g., PT, PTT, fibrinogen concentration) should be considered if the patient demonstrates thrombocytopenia or severe features. In addition, the clinician should assess renal function (creatinine concentration, recent urine output, and fluid administration over the last 24 to 48 hours). The clinician should reassess the airway prior to the initiation of anesthesia for a surgical procedure, as the appearance can change rapidly during labor. Finally, the patient should be assessed for the presence of pulmonary edema. Placement of an arterial catheter for invasive blood pressure monitoring may be considered.

Blood Pressure Assessment

The assessment and management of blood pressure is vital to the care of patients with hypertensive disorders of pregnancy. Noninvasive blood pressure monitoring is appropriate in patients with hypertensive disorder without severe disease, although automated devices may underestimate blood pressure in preeclampsia. The clinician may consider insertion of an intraarterial catheter for (1) accurate, continuous blood pressure monitoring, especially with poorly controlled hypertension; (2) frequent venous or arterial sampling, especially in patients with difficult venous access or in the context of pulmonary edema; and (3) to estimate intravascular volume status using calculated systolic pressure variation. Pulse waveform analysis has been suggested as a minimally invasive method to measure cardiac output and has been shown to closely match those obtained from thermodilution in women with preeclampsia.

Coagulation Status

Among the hematologic considerations for neuraxial procedures in women with hypertensive disorders of pregnancy are the platelet count and trend over time, along with any coexisting coagulopathy. Women with preeclampsia without severe features are typically hypercoagulable relative to women with an uncomplicated pregnancy and should not be denied neuraxial labor analgesia. Women with preeclampsia with severe features and those with HELLP syndrome may develop thrombocytopenia and other coagulation abnormalities, which increases the risk for bleeding into the epidural or spinal space during a neuraxial procedure (see Chapter 31 ).

The incidence of neuraxial hematoma among women with hypertensive disorders of pregnancy cannot be precisely stated due to the challenge of determining the denominator of all such women who have received neuraxial procedures. The low incidence of coagulopathy combined with careful screening has led to an exceptionally low incidence of epidural hematoma in contemporary obstetric anesthesia practice, estimated at 0.4 to 0.6 per 100,000. The risk for epidural hematoma formation exists not only at the time of epidural catheter placement but also at the time of its removal. Clinicians should use the same criteria for removal as they do for placement.

Platelet Count

While the precise platelet count at which risk of a spinal-epidural hematoma increases is unknown, in the absence of preeclampsia with severe features, a recent platelet count > 100,000/mm ³ is sufficient prior to initiating a neuraxial procedure. Women with preeclampsia with thrombocytopenia or other severe features should be assessed more carefully prior to a neuraxial procedure. A recent reassuring platelet count may help avoid general anesthesia.

The Society for Obstetric Anesthesia and Perinatology (SOAP) interdisciplinary consensus statement on neuraxial procedures in obstetric patients with thrombocytopenia suggests a low risk of bleeding complications when the platelet count is greater than 70,000/mm ³ among patients with gestational thrombocytopenia, idiopathic thrombocytopenia, and preeclampsia without HELLP syndrome. Consensus suggests that a platelet count < 50,000/mm ³ typically precludes the administration of neuraxial anesthesia. For women with a platelet count between 50,000 and 70,000/mm ³, the risks and benefits of neuraxial anesthesia must be weighed against the risks associated with general anesthesia for the individual patient if emergency cesarean delivery is required, including whether anatomic features of the patient’s airway are favorable. A neuraxial procedure may be considered with careful documentation of the decision-making process and best practices for the procedure; an example of such a pathway is presented in Box 35.6 . Among patients with HELLP syndrome, the SOAP statement recommends determination of the platelet count within 6 hours of the neuraxial procedure due to the rapid decrease that is often observed with this disease.

Box 35.6

Suggested Actions for Neuraxial Procedures in Women With Preeclampsia If Thrombocytopenia Is Present

•
The most skilled anesthesia provider available should perform the neuraxial procedure to minimize the number of needle passes.
•
Neuraxial ultrasonography may be considered to reduce the number of needle passes.
•
A single-shot spinal technique may be preferable to an epidural technique (when appropriate) because of the smaller needle size (supporting data are lacking).
•
Use of a flexible wire–embedded epidural catheter may reduce epidural vein trauma.
•
Careful monitoring after delivery for neurologic signs that may signal spinal-epidural hematoma, which may present up to 48 h after the procedure.
•
Check platelet count within 6 h of initiating neuraxial procedure in women with HELLP syndrome or high risk of coagulopathy.
•
Check platelet count postpartum in women with HELLP syndrome before removing epidural catheter for evidence of return toward normal (at least 75,000–80,000/mm ³).
•
Immediate neurologic or neurosurgical consultation and neuraxial imaging are necessary if there is any suspicion of epidural hematoma.

Only gold members can continue reading. Log In or Register to continue

Anesthesia Key

Fastest Anesthesia & Intensive Care & Emergency Medicine Insight Engine

Hypertensive Disorders

INTRODUCTION

CLASSIFICATION

Preeclampsia Without Severe Features

Preeclampsia With Severe Features

EPIDEMIOLOGY

Risk Factors

Demographic Factors

Maternal Factors

Medical Conditions

Obstetric Conditions

Behavioral Factor

Demographic Factors

Genetic Factors

Medical and Obstetric Conditions

Behavioral Factors

Recreational Physical Activity

Pregnancy-Related Risk Factors

PATHOGENESIS

Placental-Derived Angiogenic Imbalance

Abnormal Placentation

CLINICAL PRESENTATION AND COMPLICATIONS

Cardiovascular

Arterial Vascular Function

Myocardial Structure and Function

Circulating Blood Volume

Pulmonary edema

Pulmonary

Central Nervous System

Stroke and Other Intracranial Pathology

Hematologic

Hepatic

Subcapsular Hematoma

HELLP Syndrome

Renal

Renal Failure

CLINICAL AND OBSTETRIC MANAGEMENT

Maternal and Fetal Surveillance

Corticosteroid Administration

Uteroplacental Perfusion

Placental Abruption

Treatment of Acute Hypertension

Specific Medications

Seizure Prophylaxis and Treatment

Seizure Prophylaxis

Seizure Treatment

Airway

Breathing

Circulation

Drugs

Decision and Route of Delivery

ANESTHETIC MANAGEMENT

Preanesthetic Evaluation

Blood Pressure Assessment

Coagulation Status

Platelet Count

Share this:

Related

Related posts:

Stay updated, free articles. Join our Telegram channel

Full access? Get Clinical Tree