Hypertension is the most common medical disorder of pregnancy, affecting 6% to 10% of pregnancies. It is a leading cause of maternal mortality; together with hemorrhage it accounts for about one-half of all maternal deaths worldwide. Hypertensive disorders are an important risk factor for fetal complications, including preterm birth, fetal growth restriction, and fetal/neonatal death. They also pose very significant anesthesia risks. Anesthesia providers play a critical role in the management of women with preeclampsia; they are well positioned to understand the pathophysiology, assist with assessment of the severity of preeclampsia, and assess the impact of the disease on the administration of anesthesia, cardiovascular monitoring, and critical care. Working as part of a multidisciplinary team that includes obstetricians, cardiologists, neonatologists, midwives, and critical care specialists, anesthesia providers play a critical role in ensuring optimal outcomes for women with preeclampsia.
KeywordsHypertension, Preeclampsia, Eclampsia, Anesthesia, Antihypertensive agents
Classification of Hypertensive Disorders, 840
Clinical Presentation, 848
Obstetric Management, 851
Anesthetic Management, 858
Postpartum Management, 865
Long-Term Outcomes, 865
Clinical Presentation and Diagnosis, 866
Obstetric Management, 866
Resuscitation and Seizure Control, 866
Anesthetic Management, 867
Long-Term Outcomes, 868
Hypertension is the most common medical disorder of pregnancy, affecting 6% to 10% of pregnancies. It is a leading cause of maternal mortality; together with hemorrhage it accounts for about one-half of all maternal deaths worldwide. Hypertensive disorders are an important risk factor for fetal complications, including preterm birth, fetal growth restriction, and fetal/neonatal death. They also pose very significant anesthesia risks.
Anesthesia providers play a critical role in the management of women with preeclampsia; they are well positioned to understand the pathophysiology, assist with assessment of the severity of preeclampsia, and assess the impact of the disease on the administration of anesthesia, cardiovascular monitoring, and critical care. Working as part of a multidisciplinary team that includes obstetricians, cardiologists, neonatologists, midwives, and critical care specialists, anesthesia providers play a critical role in ensuring optimal outcomes for women with preeclampsia.
Classification of Hypertensive Disorders
Hypertensive disorders of pregnancy encompass a range of conditions—chronic hypertension, gestational hypertension, preeclampsia, preeclampsia superimposed on chronic hypertension, and eclampsia—that can be difficult to differentiate because the clinical presentation is often similar despite complex differences in their underlying pathophysiologies and prognoses. In 2000, the National High Blood Pressure Education Program (NHBPEP) Working Group on High Blood Pressure in Pregnancy published a classification scheme ( Box 35.1 ). This classification was updated in 2013 when the American College of Obstetricians and Gynecologists (ACOG) Taskforce on Hypertension in Pregnancy reviewed available literature and published a summary of current knowledge and recommendations for the care of women with preeclampsia.
Preeclampsia without severe features
Chronic hypertension with superimposed preeclampsia
Gestational hypertension is the most frequent cause of hypertension during pregnancy, affecting approximately 5% of parturients. Gestational hypertension presents as elevated blood pressure after 20 weeks’ gestation without proteinuria (in the absence of chronic hypertension or systemic manifestations of preeclampsia) that resolves by 12 weeks postpartum. Most cases of gestational hypertension develop after 37 weeks’ gestation. Approximately one-fourth of patients diagnosed with gestational hypertension will develop preeclampsia. A definitive diagnosis of gestational hypertension can be made only in retrospect after delivery when the diagnosis of chronic hypertension can be excluded based on return to a normotensive state.
Preeclampsia is defined as the new onset of hypertension and proteinuria after 20 weeks’ gestation ( Box 35.2 ). The diagnosis of preeclampsia should also be considered in the absence of proteinuria when any of the following signs or symptoms of end-organ involvement are present: (1) persistent epigastric or right upper quadrant pain, (2) persistent cerebral symptoms, (3) fetal growth restriction, (4) thrombocytopenia, or (5) elevated serum liver enzymes. The term eclampsia is used when central nervous system (CNS) involvement results in the new onset of seizures in a woman with preeclampsia. HELLP syndrome refers to the development of hemolysis, elevated liver enzymes, and low platelet count in a woman with preeclampsia. This condition may be a variant of severe preeclampsia, but this classification is controversial because the disease may represent a pathophysiologically distinct entity.
Preeclampsia without Severe Features
Blood pressure greater than or equal to 140/90 mm Hg after 20 weeks’ gestation
Proteinuria (greater than or equal to 300 mg/24 h, protein-creatinine ratio greater than or equal to 0.3, or 1+ or greater on urine dipstick specimen)
Blood pressure greater than or equal to 160/110 mm Hg
Thrombocytopenia (platelet count less than 100,000/mm 3 )
Serum creatinine concentration greater than 1.1 mg/dL or greater than 2 times the baseline serum creatinine concentration
New-onset cerebral or visual disturbances
Impaired liver function
Chronic hypertension involves either (1) systolic blood pressure of 140 mm Hg or higher and/or diastolic blood pressure of 90 mm Hg or higher presenting before pregnancy or before 20 weeks’ gestation or (2) elevated blood pressure that fails to resolve after delivery. Chronic hypertension develops into preeclampsia in approximately one-fifth to one-fourth 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 preeclampsia develops in a woman with chronic hypertension before pregnancy. The diagnosis is made in the presence of new onset of proteinuria or a sudden increase in proteinuria or hypertension, or both, or when other manifestations of severe preeclampsia appear. Morbidity is increased for both the mother and fetus compared with preeclampsia alone.
The clinical findings in chronic hypertension, gestational hypertension, and preeclampsia are compared in Table 35.1 .
|Clinical Feature||Chronic Hypertension||Gestational Hypertension||Preeclampsia|
|Time of onset of hypertension||Before 20 weeks’ gestation||After 20 weeks’ gestation||After 20 weeks’ gestation|
|Severity of hypertension||Mild or severe||Mild||Mild or severe|
|Proteinuria a||Absent||Absent||Typically present|
|Serum uric acid greater than 5.5 mg/dL (0.33 mmol/L)||Rare||Absent||Present in almost all cases|
|Hemoconcentration||Absent||Absent||Present in severe disease|
|Thrombocytopenia||Absent||Absent||Present in severe disease|
|Hepatic dysfunction||Absent||Absent||Present in severe disease|
Preeclampsia is a multisystem disease unique to human pregnancy. It is characterized by diffuse endothelial dysfunction with maternal complications, including placental abruption, pulmonary edema, acute renal failure, liver failure, stroke, and neonatal complications, including indicated preterm delivery, fetal growth restriction, hypoxic-ischemic neurologic injury, and perinatal death. Although significant advances have been made in the understanding of the pathophysiology of the disease, the specific proximal cause remains unknown. Management is supportive; delivery of the infant and placenta remains the only definitive cure.
The clinical syndrome of preeclampsia is defined as the new onset of hypertension and proteinuria after 20 weeks’ gestation. Previous definitions included edema, but edema is no longer part of the diagnostic criteria because it lacks specificity and occurs in many healthy pregnant women. Preeclampsia is classified as preeclampsia with or without severe features (see Box 35.2 ). The ACOG now discourages use of the term mild for preeclampsia without severe features because preeclampsia may be rapidly progressive, and appropriate management involves frequent reevaluation for severe features.
Some authors suggest classifying preeclampsia into the early form (type I) , with symptom onset before 34 weeks’ gestation, or the late form (type II) , with symptom onset after 34 weeks’ gestation ( Table 35.2 ). Early-onset preeclampsia begins with abnormal placentation, has a high rate of recurrence, and has a strong genetic component. In contrast, late-onset preeclampsia generally occurs in women metabolically predisposed to the disease, and abnormal placentation may feature less prominently in the pathogenesis. These women, who often have long-standing hypertension, obesity, diabetes, or other forms of microvascular disease, are challenged to meet the demands of the growing fetoplacental unit and decompensate near term. Decompensation manifests as late-onset or, less frequently, postpartum preeclampsia.
|Early Onset||Late Onset|
|Onset of clinical symptoms||Before 34 weeks’ gestation||After 34 weeks’ gestation|
|Relative frequency||20% of cases||80% of cases|
|Association with fetal growth restriction||Yes||No|
|Clear familial component a||Yes||No|
|Placental morphology||Abnormal b||Normal b|
|Etiology||Primarily placental c||Primarily maternal d|
|Risk factor (relative risk)||Family history (2.9)||Diabetes (3.56) |
Multiple pregnancy (2.93)
Increased blood pressure at registration (1.38)
Increased body mass index (2.47)
Maternal age greater than or equal to 40 years (1.96)
Cardiovascular disorders (3.84)
b From Egbor M, Ansari T, Morris N, et al. Morphometric placental villous and vascular abnormalities in early- and late-onset preeclampsia with and without fetal growth restriction. BJOG. 2006;113:580–589.
Preeclampsia occurs in 3% to 4% of pregnancies in the United States. Delivery of the infant and placenta is the only definitive treatment; thus, preeclampsia is a leading cause of indicated preterm delivery in developed countries. Low-birth-weight and preterm infants born to women with preeclampsia present major medical, social, and economic burdens to families and societies. Preterm delivery is the most common indication for admission to the neonatal intensive care unit. Preeclampsia is also a leading indication for maternal peripartum admission to an intensive care unit.
The clinical findings of preeclampsia can manifest as a maternal syndrome (e.g., hypertension and proteinuria with or without other systemic abnormalities) with or without an accompanying fetal syndrome (e.g., fetal growth restriction, oligohydramnios, abnormal oxygen exchange). In approximately 75% of cases, preeclampsia occurs without severe features near term or during the intrapartum period. In contrast, disease onset before 34 weeks’ gestation correlates with increased disease severity and poorer outcomes for both the mother and fetus.
A significant increase in the incidence of hypertensive disorders of pregnancy has occurred, with a near doubling in the rate in the United States in the past quarter century ( Fig. 35.1 ). The increase is at least partially explained by major shifts in the demographics and clinical conditions of pregnant women in the United States and other developed countries. Average maternal age is increasing; advanced maternal age is a recognized risk factor for preeclampsia. Both the growing epidemic of obesity and the increased prevalence of diabetes and chronic hypertension in the developed world may also contribute to this trend. An increase in the use of assisted reproductive techniques and the use of donated gametes is contributory; these techniques increase the risk for the disease, potentially by altering the maternal-fetal immune reaction and by increasing the incidence of multiple gestation. Last, improvements in record keeping and the use of consistent disease definitions since 2000 may have contributed to the increased number of reported cases.
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 conditions, obstetric conditions, behavioral factors, and partner-related factors.
Advanced maternal age greater than 35 years
History of preeclampsia in previous pregnancy
Family history of preeclampsia
History of placental abruption, fetal growth restriction, or fetal death
Partner who fathered a preeclamptic pregnancy in another woman (through fetal genes)
Chronic renal disease
Antiphospholipid antibody syndrome
Systemic lupus erythematosus
Cigarette smoking (risk reduction)
Limited preconceptional exposure to paternal sperm
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. Teenage pregnancy may also be a risk factor for preeclampsia, but data are inconsistent.
Black women constitute a high-risk group, with increased rates of chronic hypertension, obesity, and preeclampsia. Black women with severe preeclampsia demonstrate more extreme hypertension, require more antihypertensive therapy, are more likely to develop eclampsia, and are more likely to die of the condition compared with women of other racial backgrounds. Hispanic ethnicity may also confer increased risk for developing preeclampsia and eclampsia.
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.
Medical and obstetric conditions.
Obesity is an important risk factor for preeclampsia, and risk escalates with increasing body mass index (BMI). A systematic review found that an increase in BMI of 5 to 7 kg/m 2 was associated with a twofold increased risk for preeclampsia. Obesity is strongly associated with insulin resistance, another risk factor for preeclampsia.
Women with chronic hypertension are also at increased risk for preeclampsia. Primary hypertension increases the odds of developing preeclampsia 10-fold, and secondary hypertension increases the odds nearly 12-fold. Chronic hypertension in association with other risk factors, including diabetes, renal disease, and collagen vascular disease, confers particularly elevated risk.
Diabetes mellitus is associated with an approximately twofold increase in the risk for development of preeclampsia. The prevalence of preeclampsia also increased with the severity of diabetes as determined by the White classification.
The metabolic syndrome, which occurs in about one-fifth of women of childbearing age in the United States, is characterized by the presence of obesity, hyperglycemia, insulin resistance, and hypertension. The metabolic syndrome increases the risk for preeclampsia. The insulin resistance and microvascular dysfunction observed in this condition have been implicated as a common factor in both preeclampsia and cardiovascular disease; these conditions may partially mediate the association of preeclampsia and increased risk for cardiovascular disease later in life.
Additional maternal medical conditions that are well-recognized risk factors for preeclampsia include chronic renal disease, antiphospholipid antibody syndrome, and systemic lupus erythematosus. Pregnancy-related conditions that increase placental mass, including multifetal gestation and hydatidiform mole, are associated with higher rates of preeclampsia as well.
Paradoxically, cigarette smoking during pregnancy has been associated with a decreased risk for preeclampsia, an effect consistently observed across studies in various countries. Women who smoke during pregnancy have a 30% to 40% lower risk for developing preeclampsia compared with women who do not smoke. The mechanism may include nicotine inhibition of thromboxane A 2 synthesis, simulation of nitric oxide release, or a combination of these factors.
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. Mechanistically, this may occur through exercise promoting placental growth, decreasing oxidative stress, enhancing endothelial function, and modulating the immune and inflammatory response.
Partner-related risk factors.
The unifying theme among partner-related risk factors is limited maternal exposure to paternal sperm antigens before conception, which suggests an immunologic role in the pathophysiology of preeclampsia. A leading risk factor for preeclampsia is nulliparity; the incidence is approximately threefold higher compared with parous women. Preeclampsia is also more common in (1) parous women who have conceived with a new partner, (2) women who have used barrier methods of contraception before conception, and (3) women who have conceived with donated sperm. Long-term sperm exposure with the same partner appears to be protective; this protective effect is lost in a pregnancy conceived with a new partner.
The exact pathogenic mechanisms responsible for the initiation and progression of preeclampsia are not known. The placenta is the focus of hypotheses regarding disease pathogenesis; delivery of the placenta results in resolution of the disease, and the disease can occur in the absence of a fetus (e.g., a molar pregnancy).
Preeclampsia as a Two-Stage Disorder
Contemporary hypotheses generally conceptualize preeclampsia as a two-stage disorder. The asymptomatic first stage occurs early in pregnancy with impaired remodeling of the spiral arteries (the end branches of the uterine artery that supply the placenta). In normal 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.
In contrast, in preeclamptic pregnancies, 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. This failure of normal angiogenesis results in superficial placentation. Abnormal placentation results in decreased placental perfusion and placental infarcts, predisposing the fetus to growth restriction ( Fig. 35.3 ). Placental ischemia worsens throughout pregnancy as narrowed vessels are increasingly unable to meet the needs of the growing fetoplacental unit.
In some women, the reduced perfusion of the intervillous space in the first stage leads to the symptomatic second stage, which is characterized by the release of antiangiogenic factors from the intervillous space into the maternal circulation; these factors cause widespread maternal endothelial dysfunction and an accentuated systemic inflammatory response. In the absence of preeclampsia, healthy endothelium prevents platelet activation, activates circulating anticoagulants, buffers the response to vasopressors, and maintains fluid in the intravascular compartment. These normal functions are disrupted in preeclampsia. As a result, the pregnant woman develops hypertension and proteinuria, and is at risk for other manifestations of severe systemic disease (e.g., HELLP syndrome, eclampsia, other end-organ damage). By definition, these clinical manifestations manifest after 20 weeks’ gestation.
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. The hypothesis that immune maladaptation may play a central role in predisposing to abnormal placentation and subsequent preeclampsia is supported by evidence showing that long-term exposure to paternal antigens in sperm is protective. Furthermore, the importance of an intact immune system in the development of preeclampsia is demonstrated by the lower incidence of preeclampsia in women with untreated human immunodeficiency virus; the incidence returns to baseline after treatment with antiretroviral therapy.
The immune cells present in the decidua—the endometrium in the nonpregnant state becomes the decidua in pregnancy—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 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. 35.4 ). Furthermore, introduction of these autoantibodies into pregnant mice increases production of soluble fms-like tyrosine kinase-1 (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.
Oxidative stress is another mechanism that has been postulated as an important component of impaired placentation. Oxidative stress and the resultant oxygen free radicals are known to contribute to atherosclerosis and thus may contribute to placental atherosis. Volatile organic compounds measured in a breath test, a marker for oxidative stress, are found in greater quantity in women with preeclampsia compared with healthy pregnant controls. Enthusiasm for this theory is tempered by the failure of antioxidant supplementation to decrease the risk for preeclampsia in clinical trials.
Maternal Systemic Disease
The symptomatic second stage of preeclampsia is marked by signs and symptoms attributable to the manifestations of widespread endothelial dysfunction specific to each organ system. This notion is supported by studies showing increased levels of biomarkers indicating endothelial activation or injury, or both, including endothelin-1, fibronectin, von Willebrand factor, and thrombomodulin. The central role of endothelial dysfunction is further evidenced by the fact that chronic conditions that cause prepregnancy endothelial injury, including chronic hypertension, preexisting diabetes, and renal disease, are risk factors for preeclampsia. A predilection for endothelial dysfunction may similarly explain the association of preeclampsia and future cardiovascular disease.
The mechanistic link between abnormal placentation and subsequent widespread endothelial dysfunction is an area of great interest and ongoing investigation. The prevailing hypothesis is that the placenta becomes relatively hypoxic as the pregnancy progresses, and this change results in an overexpression and release into the maternal circulation of placentally derived antiangiogenic factors, including sFlt-1 and soluble endoglin (sEng).
The vascular endothelium requires proangiogenic factors for normal function. sFlt-1 antagonizes the angiogenic growth factors, vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). 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, which is 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. 35.5 ). In a study in humans, elevated sFlt-1 levels and reduced levels of PlGF predicted the subsequent development of preeclampsia before the development of any maternal symptoms. In women presenting at less than 35 weeks’ gestation with a possible diagnosis of preeclampsia, a low PlGF level has a high sensitivity and negative predictive value for the development of preeclampsia within 14 days. Studies have also confirmed the importance of the sFlt-1–to–PlGF ratio as a marker of preeclampsia.
sEng is another placentally derived antiangiogenic protein that appears to be important in the pathogenesis of preeclampsia. Circulating levels of sEng are markedly increased in women who subsequently develop preeclampsia. Furthermore, if women have both elevated sEng and increased sFlt-1/PlGF ratios, their risk for preeclampsia is elevated approximately 30-fold compared with women who have normal levels of both factors/ratios.
The study of antiangiogenic proteins is an active area of current research, and rapid progress is being made in understanding the role of these proteins in the pathogenesis of preeclampsia. However, the importance of recent findings is tempered by the knowledge that preeclampsia does not develop in all women with high sFlt-1 and low PlGF levels, and the syndrome occurs in some women with low sFlt-1 and high PlGF levels. These observations are consistent with those from a large, longitudinal study involving 2246 singleton pregnancies that found that PlGF and sFlt-1 levels had limited sensitivity, specificity, and positive predictive value for predicting the development of preeclampsia.
Kanasaki et al. hypothesized that a molecular defect upstream from the soluble factors contributes to preeclampsia. The investigators demonstrated that pregnant mice deficient in catechol- O -methyltransferase (COMT) demonstrate a preeclampsia-like phenotype in response to the absence of 2-methoxyestradiol (2-ME), a natural metabolite of estradiol that is elevated during the third trimester of normal pregnancy. Administration of 2-ME to COMT-deficient mice suppresses placental hypoxia and sFlt-1 elevation. In addition, women with severe preeclampsia have significantly lower levels of COMT and 2-ME than women with healthy pregnancies. However, a subsequent study in humans failed to find a significant difference in placental COMT expression in women with early-onset, severe preeclampsia compared with normotensive women ; therefore, further research is needed to determine what role, if any, COMT plays in the pathogenesis of preeclampsia.
There is a strong genetic basis underlying the risk for preeclampsia that is attributable to both maternal and fetal genetic factors. 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 recent genome-wide association study in offspring from preeclamptic pregnancies reported that variants in the fetal genome near 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.
Various strategies to prevent preeclampsia have been studied. These include antiplatelet drugs, metformin, antioxidant and calcium supplementation, and dietary sodium restriction among other lifestyle modifications. A 2014 systematic review by the U.S. Preventive Services Task Force found that low-dose aspirin use is associated with a 2% to 5% absolute reduction in the risk for preeclampsia (depending on baseline risk) and a 2016 ACOG practice advisory suggests that consideration should be given for initiating prophylactic low-dose aspirin between 12 and 24 weeks’ gestation in women at high risk for preeclampsia.
Preeclampsia occurs more frequently in nulliparous women and most commonly presents during the third trimester, often near term. Women with early-onset disease (before 34 weeks’ gestation) have poorer outcomes than women with late-onset disease. The disease typically regresses rapidly after delivery, with resolution of symptoms within 48 hours. However, preeclampsia can also manifest postpartum with hypertension, proteinuria, or the occurrence of seizures (eclampsia). Postpartum preeclampsia usually presents within 7 days of delivery. Disease manifestations of severe preeclampsia occur in all body systems as the result of widespread endothelial dysfunction.
Identification of women at greatest risk for adverse maternal outcomes is potentially useful in guiding triage to high-risk centers and weighing the risks and benefits of expectant management. A 2011 multicenter prospective study involving 2023 women with preeclampsia admitted to tertiary care centers described a model (fullPIERS) for predicting which women will develop fatal or life-threatening complications. Unfavorable outcomes occurred in 261 patients. Predictors of unfavorable maternal outcome included early gestational age, chest pain or dyspnea, low oxygen saturation, low platelet count, and elevated creatinine and aspartate aminotransferase concentrations. The model showed excellent discrimination, with an area under the receiver operating characteristics (ROC) curve of 0.88 for adverse events within 48 hours of admission. It continued to perform well in predicting adverse events up to 7 days after admission. The fullPIERS model has recently been validated in low- and middle-income countries.
In further work on prediction of complications in early-onset preeclampsia, women were recruited from 53 maternity units in the United Kingdom to a large cohort study for the development of prognostic models for risk for complications. These models were externally validated in two large cohorts of patients and were found to be predictive of adverse maternal outcome risk, including preterm delivery. It was concluded that the models may have a role in triaging women who would benefit from referral for tertiary care.
A further advance in the prediction of disease severity relies on strong-ion analysis of maternal acid-base status. Early investigation suggests that preeclampsia is associated with greater offsetting of hypoalbuminemic alkalosis with hyperchloremic acidosis, although the overall base excess in severe preeclampsia is similar to that in healthy pregnancy. The magnitude of these opposing contributors may be a better indicator of disease severity than the overall base excess.
Central Nervous System
Although the term preeclampsia suggests that eclampsia is the end stage of preeclampsia, it is more accurate to consider eclampsia as the outward manifestation of disease progression in the brain, similar to other organ involvement. Central nervous system manifestations include severe headache, hyperexcitability, hyperreflexia, and coma. Visual disturbances can include scotoma, amaurosis, and blurred vision.
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 with preeclampsia and eclampsia. Hyperperfusion of the brain, particularly in the setting of the endothelial dysfunction that is present in preeclampsia, causes vasogenic edema. Failure of autoregulation occurs most commonly in the posterior circulation; these changes may result in the posterior reversible leukoencephalopathy syndrome (PRES).
Other neurologic markers of disease severity are being examined. Optic nerve sheath diameter (ONSD) is being investigated as a marker for increased intracranial pressure. 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 of greater than 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. Future investigations are necessary to understand whether the increase in ONSD is associated with raised intracranial pressure in preeclampsia or higher risk for eclampsia.
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, with the percent increase indirectly correlating with blood pressure.
In pregnant women, the internal diameter of the trachea is reduced because of mucosal capillary engorgement. In women with preeclampsia, these changes can be exaggerated with upper airway narrowing as a result of pharyngolaryngeal edema; these changes may compromise visualization of airway landmarks during direct laryngoscopy. Signs of airway obstruction include dysphonia, hoarseness, snoring, stridor, and hypoxemia.
Obstructive sleep apnea (OSA) is a sleep-related breathing disorder characterized by recurrent episodes of upper airway collapse leading to hypoxia and sleep disturbance. A meta-analysis of available cohort studies suggests that parturients with OSA have a twofold increase in risk for developing preeclampsia. This is plausibly a causal association, as recurrent nocturnal desaturations might result in placental hypoxia, hypertension, and maternal endothelial dysfunction, all of which are associated with preeclampsia.
Women with preeclampsia have increased vascular tone and increased sensitivity to vasoconstrictors and circulating catecholamines, which result in the clinical manifestations of hypertension, vasospasm, and end-organ ischemia. In preeclampsia without severe features, plasma volume may be normal; however, it may be reduced as much as 40% in women with severe disease.
Severe preeclampsia is usually a hyperdynamic state. Many studies have attempted to characterize the hemodynamic characteristics of preeclampsia using invasive monitoring techniques such as pulmonary artery catheterization or echocardiography. Interpretation and comparison of the results of these studies have been difficult because of variation in patient populations, definitions of preeclampsia, disease severity, prior treatment, and the presence or absence of concomitant comorbid disease. Hemodynamic characteristics in preeclamptic women are more complex than originally thought. This is partly because hemodynamic measurements change with treatment and disease progression. In a large prospective series of normotensive nulliparous women who were assessed with transthoracic echocardiography (TTE) at 24 weeks’ gestation, 107 women developed preeclampsia (75 early- and 32 late-onset). Mean (± standard deviation) total vascular resistance was 1605 ± 248 dyne ⋅ s ⋅ cm –5 and 739 ± 244 dyne ⋅ s ⋅ cm –5 , and cardiac output was 4.49 ± 1.09 L/min and 8.96 ± 1.83 L/min in early- and late-onset preeclampsia, respectively, suggesting two different cardiovascular responses.
Overall, studies have found that the majority of affected women without clinical signs of pulmonary edema exhibit normal to increased cardiac output, hyperdynamic left ventricular function, and mild to moderately increased systemic vascular resistance, often associated with diastolic dysfunction. In severe preeclampsia, cardiac magnetic resonance imaging studies demonstrate that the myocardium may be edematous as well as hypertrophied.
Echocardiographic speckle-tracking is a new method of quantifying myocardial strain that appears to be a more sensitive marker of systolic dysfunction than the left ventricular ejection fraction in women with preeclampsia. Systolic dysfunction is more common in early- than late-onset disease and in some cases may present as severe cardiac failure with a low ejection fraction. This cardiac dysfunction is generally different from that which occurs in peripartum cardiomyopathy (see Chapter 41 ). The hypothesis that there are shared pathways of abnormal angiogenesis in preeclampsia and peripartum cardiomyopathy is controversial.
There is growing interest in the use of biomarkers such as brain natriuretic peptide (BNP) to identify cardiac dysfunction in preeclampsia. A systematic review found that serum BNP levels are higher in the third trimester in women with preeclampsia compared with healthy women. Studies included in this review found that elevated BNP levels correlated with echocardiographically demonstrated cardiac dysfunction as well as increased systemic vascular resistance, decreased cardiac output, and left ventricular diastolic dysfunction. Future studies are needed, however, to define BNP threshold values that have high sensitivity and specificity for heart failure in preeclampsia.
Pulmonary edema is a severe complication that occurs in approximately 3% of women with preeclampsia. It occurs infrequently in healthy, younger women; the risk increases in older multigravid women, in women with preeclampsia superimposed on chronic hypertension or renal disease, and among those whose preeclampsia leads to oliguria.
Plasma colloid osmotic pressure is reduced in normal pregnancy because of decreased plasma albumin concentration, and it is decreased even further in women with preeclampsia. 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. Decreased colloid osmotic pressure, in combination with increased vascular permeability due to abnormalities of the pulmonary endothelial glycocalyx and the loss of intravascular fluid and protein into the interstitium, increases the risk for pulmonary edema. In addition, increased intravascular hydrostatic pressure due to fluid overload and/or increased left ventricular end diastolic pressure, and occasional systolic heart failure, may cause pulmonary edema. All of these factors may coexist in a single patient.
Lung ultrasonography may be a useful adjunct to identify lung pathology. 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 artefacts 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 in addition to cardiac dysfunction.
Thrombocytopenia is the most common hematologic abnormality in women with preeclampsia, and preeclampsia is the most common cause of severe thrombocytopenia in the second half of pregnancy (see Chapter 44 ). Platelet counts less than 100,000/mm 3 occur most commonly in women with severe disease or HELLP syndrome and correlate with the severity of the disease process.
Studies using thromboelastography have found that women with preeclampsia without severe features are hyper coagulable relative to women without preeclampsia and that those with severe disease are relatively hypo coagulable . In contrast to normal pregnancies and other hypertensive disorders, platelets are activated in preeclampsia ; subsequent platelet degranulation is believed to account for the decreases in platelet function, and aggregation appears to account for the decrease in platelet count.
The syndrome of disseminated intravascular coagulation (DIC) occurs in some women with preeclampsia, generally in the setting of severe liver involvement, intrauterine fetal demise, placental abruption, or postpartum hemorrhage. Activation of the coagulation system is marked by consumption of procoagulants, increased levels of fibrin degradation products, and end-organ damage secondary to microthrombi formation. In advanced DIC, procoagulants (e.g., fibrinogen, platelets) decrease to a level that may lead to spontaneous hemorrhage.
Hepatic manifestations of preeclampsia include periportal hemorrhage and fibrin deposition in hepatic sinusoids. Hepatic involvement frequently presents as right upper quadrant or epigastric pain. Damage ranges from mild hepatocellular necrosis to the more ominous HELLP syndrome and can be associated with subcapsular bleeding and risk for hepatic rupture. Spontaneous hepatic rupture is rare but is associated with a 32% maternal mortality rate.
Renal manifestations of preeclampsia include persistent proteinuria, changes in the glomerular filtration rate, and hyperuricemia. The presence of proteinuria is a defining element of preeclampsia but is no longer considered essential for diagnosis if other evidence of end-organ injury is present. 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 glomerular filtration rate (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. 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 despite significantly decreased GFR relative to healthy pregnant 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 predictor of preeclampsia.
Oliguria is a possible late manifestation of severe preeclampsia and parallels the severity of disease. Persistent oliguria requires immediate assessment of intravascular volume status. Progression to renal failure is rare and is typically preceded by hypovolemia, placental abruption, or DIC.
Uteroplacental perfusion can 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.
Optimal management of the woman with preeclampsia requires a team approach. There is considerable overlap in areas of concern to the obstetrician and the anesthesia provider. Obstetric management of preeclampsia centers on (1) decisions regarding the timing and route of delivery, (2) fetal and maternal surveillance, (3) treatment of hypertension, and (4) seizure prophylaxis.
Delivery remains the only cure for preeclampsia. Obstetric care of women with preeclampsia without severe features differs little from routine management of healthy pregnant women, except for careful monitoring to detect the development of severe features. 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. 35.6 ), 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 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.