TERMINOLOGY AND DIAGNOSIS
INCIDENCE AND RISK FACTORS
PREDICTION AND PREVENTION
How pregnancy incites or aggravates hypertension remains unsolved despite decades of intensive research. Indeed, hypertensive disorders remain among the most significant and intriguing unsolved problems in obstetrics.
Hypertensive disorders complicate 5 to 10 percent of all pregnancies, and together they are one member of the deadly triad—along with hemorrhage and infection—that contributes greatly to maternal morbidity and mortality. Of these disorders, the preeclampsia syndrome, either alone or superimposed on chronic hypertension, is the most dangerous. As subsequently discussed, new-onset hypertension during pregnancy—termed gestational hypertension—is followed by signs and symptoms of preeclampsia almost half the time, and preeclampsia is identified in 3.9 percent of all pregnancies (Martin, 2012).
The World Health Organization (WHO) systematically reviews maternal mortality worldwide, and in developed countries, 16 percent of maternal deaths were reported to be due to hypertensive disorders (Khan, 2006). This proportion is greater than three other leading causes that include hemorrhage—13 percent, abortion—8 percent, and sepsis—2 percent. In the United States from 1998 to 2005, Berg and colleagues (2010) reported that 12.3 percent of 4693 pregnancy-related maternal deaths were caused by preeclampsia or eclampsia. The rate was similar to that of 10 percent for maternal deaths in France from 2003 through 2007 (Saucedo, 2013). Importantly, more than half of these hypertension-related deaths were preventable (Berg, 2005).
TERMINOLOGY AND DIAGNOSIS
In this country for the past two decades, pregnancy hypertension was considered using the terminology and classification promulgated by the Working Group of the National High Blood Pressure Education Program—NHBPEP (2000). To update these, a Task Force was appointed by President James Martin for the American College of Obstetricians and Gynecologists (2013b) to provide evidence-based recommendations for clinical practice. The basic classification was retained, as it describes four types of hypertensive disease:
1. Gestational hypertension—evidence for the preeclampsia syndrome does not develop and hypertension resolves by 12 weeks postpartum
2. Preeclampsia and eclampsia syndrome
3. Chronic hypertension of any etiology
4. Preeclampsia superimposed on chronic hypertension.
Importantly, this classification differentiates the preeclampsia syndrome from other hypertensive disorders because it is potentially more ominous. This concept aids interpretation of studies that address the etiology, pathogenesis, and clinical management of pregnancy-related hypertensive disorders.
Diagnosis of Hypertensive Disorders
Hypertension is diagnosed empirically when appropriately taken blood pressure exceeds 140 mm Hg systolic or 90 mm Hg diastolic. Korotkoff phase V is used to define diastolic pressure. Previously, incremental increases of 30 mm Hg systolic or 15 mm Hg diastolic from midpregnancy blood pressure values had also been used as diagnostic criteria, even when absolute values were < 140/90 mm Hg. These incremental changes are no longer recommended criteria because evidence shows that such women are not likely to experience increased adverse pregnancy outcomes (Levine, 2000; North, 1999). That said, women who have a rise in pressure of 30 mm Hg systolic or 15 mm Hg diastolic should be observed more closely because eclamptic seizures develop in some of these women whose blood pressures have stayed < 140/90 mm Hg (Alexander, 2006). A sudden rise in mean arterial pressure later in pregnancy—also known as “delta hypertension”—may also signify preeclampsia even if blood pressure is < 140/90 mm Hg (Macdonald-Wallis, 2012; Vollaard, 2007).
Concept of “Delta Hypertension”
The systolic and diastolic blood pressure levels of 140/90 mm Hg have been arbitrarily used since the 1950s to define “hypertension” in nonpregnant individuals. As discussed in detail in Chapter 50 (p. 1000), these levels were selected by insurance companies for a group of middle-aged men. It seems more realistic to define normal-range blood pressures that fall between an upper and lower limit for blood pressure measurements for a particular population—such as young, healthy, pregnant women. A schematic example is shown in Figure 40-1 using arbitrary blood pressure readings. Data curves for both women show blood pressure measurements near the 25th percentile until 32 weeks. These begin to rise in patient B, who by term has substantively increased blood pressures. However, her pressures are still < 140/90 mm Hg, and thus she is considered to be “normotensive.” We termed this rather acute increase in blood pressure as “delta hypertension.” As discussed later, some of these women will develop eclamptic seizures or HELLP (hemolysis, elevated liver enzyme levels, low platelet count) syndrome while still normotensive.
FIGURE 40-1 Schematic shows normal reference ranges for blood pressure changes across pregnancy. Patient A (blue) has blood pressures near the 20th percentile throughout pregnancy. Patient B (red) has a similar pattern with pressures at about the 25th percentile until about 36 weeks when blood pressure begins to increase. By term, it is substantively higher and in the 75th percentile, but she is still considered “normotensive.”
This diagnosis is made in women whose blood pressures reach 140/90 mm Hg or greater for the first time after midpregnancy, but in whom proteinuria is not identified (Table 40-1). Almost half of these women subsequently develop preeclampsia syndrome, which includes findings such as headaches or epigastric pain, proteinuria, and thrombocytopenia. Even so, when blood pressure increases appreciably, it is dangerous to both mother and fetus to ignore this rise only because proteinuria has not yet developed. As Chesley (1985) emphasized, 10 percent of eclamptic seizures develop before overt proteinuria can be detected. Finally, gestational hypertension is reclassified by some as transient hypertension if evidence for preeclampsia does not develop and the blood pressure returns to normal by 12 weeks postpartum.
TABLE 40-1. Diagnostic Criteria for Pregnancy-Associated Hypertension
As emphasized throughout this chapter, preeclampsia is best described as a pregnancy-specific syndrome that can affect virtually every organ system. And, although preeclampsia is much more than simply gestational hypertension with proteinuria, appearance of proteinuria remains an important diagnostic criterion. Thus, proteinuria is an objective marker and reflects the system-wide endothelial leak, which characterizes the preeclampsia syndrome.
Abnormal protein excretion is arbitrarily defined by 24-hour urinary excretion exceeding 300 mg; a urine protein:creatinine ratio ≥ 0.3; or persistent 30 mg/dL (1+ dipstick) protein in random urine samples (Lindheimer, 2008a). None of these values is sacrosanct, and urine concentrations vary widely during the day, as do dipstick readings. Thus, assessment may show a dipstick value of 1+ to 2+ from concentrated urine specimens from women who excrete < 300 mg/day. As discussed on page 740, it is likely that determination of a spot urine:creatinine ratio is a suitable replacement for a 24-hour urine measurement (Chap. 4, p. 65).
It is now appreciated that overt proteinuria may not be a feature in some women with the preeclampsia syndrome (Sibai, 2009). Because of this, the Task Force (2013) suggested other diagnostic criteria, which are shown in Table 40-1. Evidence of multiorgan involvement may include thrombocytopenia, renal dysfunction, hepatocellular necrosis (“liver dysfunction”), central nervous system perturbations, or pulmonary edema.
Indicators of Preeclampsia Severity
The markers listed in Table 40-1 are also used to classify preeclampsia syndrome severity. Although many use a dichotomous “mild” and “severe” classification, the Task Force (2013) discourages the use of “mild preeclampsia.” It is problematic that there are criteria for the diagnosis of “severe” preeclampsia, but the default classification is either implied or specifically termed as “mild,” “less severe,” or “nonsevere” (Alexander, 2003; Lindheimer, 2008b). There are no generally agreed-on criteria for “moderate” preeclampsia—an elusive third category. We use the criteria listed in Table 40-2, which are categorized as “severe” versus “nonsevere.” Importantly, while it is pragmatic that nonsevere classifications include “moderate” and “mild,” these have not been specifically defined.
TABLE 40-2. Indicators of Severity of Gestational Hypertensive Disordersa
Some symptoms are considered to be ominous. Headaches or visual disturbances such as scotomata can be premonitory symptoms of eclampsia. Epigastric or right upper quadrant pain frequently accompanies hepatocellular necrosis, ischemia, and edema that ostensibly stretches Glisson capsule. This characteristic pain is frequently accompanied by elevated serum hepatic transaminase levels. Finally, thrombocytopenia is also characteristic of worsening preeclampsia as it signifies platelet activation and aggregation as well as microangiopathic hemolysis. Other factors indicative of severe preeclampsia include renal or cardiac involvement and obvious fetal-growth restriction, which also attests to its duration.
As will be discussed, the more profound these signs and symptoms, the less likely they can be temporized, and the more likely delivery will be required. A caveat is that differentiation between nonsevere and severe gestational hypertension or preeclampsia can be misleading because what might be apparently mild disease may progress rapidly to severe disease.
In a woman with preeclampsia, a convulsion that cannot be attributed to another cause is termed eclampsia. The seizures are generalized and may appear before, during, or after labor. The proportion who do not develop seizures until after 48 hours postpartum approximates 10 percent (Sibai, 2005). In some reports, up to a fourth of eclamptic seizures develop beyond 48 hours postpartum (Chames, 2002). Our experiences from Parkland Hospital, however, are that delayed postpartum eclampsia continues to occur in about 10 percent of cases—similar to what we first reported more than 20 years ago (Alexander, 2006; Brown, 1987). This lower percentage was also found in 222 women with eclampsia from The Netherlands (Zwart, 2008).
Preeclampsia Superimposed on Chronic Hypertension
Regardless of its cause, any chronic hypertensive disorder predisposes a woman to develop superimposed preeclampsia syndrome. Chronic underlying hypertension is diagnosed in women with documented blood pressures ≥ 140/90 mm Hg before pregnancy or before 20 weeks’ gestation, or both. Hypertensive disorders can create difficult problems with diagnosis and management in women who are not first seen until after midpregnancy. This is because blood pressure normally decreases during the second and early third trimesters in both normotensive and chronically hypertensive women (Chap. 50, p. 1003). Thus, a woman with previously undiagnosed chronic vascular disease who is seen before 20 weeks frequently has blood pressures within the normal range. During the third trimester, however, as blood pressures return to their originally hypertensive levels, it may be difficult to determine whether hypertension is chronic or induced by pregnancy. Even a careful search for evidence of preexisting end-organ damage may be futile, as many of these women have mild disease and no evidence of ventricular hypertrophy, retinal vascular changes, or renal dysfunction.
In some women with chronic hypertension, their blood pressure increases to obviously abnormal levels, and this is typically after 24 weeks. If new-onset or worsening baseline hypertension is accompanied by new-onset proteinuria or other findings listed in Table 40-1, then superimposed preeclampsia is diagnosed. Compared with “pure” preeclampsia, superimposed preeclampsia commonly develops earlier in pregnancy. It also tends to be more severe and often is accompanied by fetal-growth restriction. The same criteria shown in Table 40-2 are also used to further characterize severity of superimposed preeclampsia.
INCIDENCE AND RISK FACTORS
Young and nulliparous women are particularly vulnerable to developing preeclampsia, whereas older women are at greater risk for chronic hypertension with superimposed preeclampsia. The incidence is markedly influenced by race and ethnicity—and thus by genetic predisposition. By way of example, in nearly 2400 nulliparas enrolled in a Maternal-Fetal Medicine Units (MFMU) Network study, the incidence of preeclampsia was 5 percent in white, 9 percent in Hispanic, and 11 percent in African-American women (Myatt, 2012a,b).
Other factors include environmental, socioeconomic, and even seasonal influences (Lawlor, 2005; Palmer, 1999; Spencer, 2009). With consideration for these vicissitudes, in several worldwide studies reviewed by Staff and coworkers (2014), the incidence of preeclampsia in nulliparous populations ranged from 3 to 10 percent. The incidence of preeclampsia in multiparas is also variable but is less than that for nulliparas. Specifically, population studies from Australia, Canada, Denmark, Norway, Scotland, Sweden, and Massachusetts indicate an incidence of 1.4 to 4 percent (Roberts, 2011).
There are several other risk factors associated with preeclampsia. These include obesity, multifetal gestation, maternal age, hyperhomocysteinemia, and metabolic syndrome (Conde-Agudelo, 2000; Scholten, 2013; Walker, 2000). The relationship between maternal weight and the risk of preeclampsia is progressive. It increases from 4.3 percent for women with a body mass index (BMI) < 20 kg/m2 to 13.3 percent in those with a BMI > 35 kg/m2 (Fig. 48-5, p. 966). In women with a twin gestation compared with those with singletons, the incidence of gestational hypertension—13 versus 6 percent, and the incidence of preeclampsia—13 versus 5 percent, are both significantly increased (Sibai, 2000). It is interesting that this latter incidence is unrelated to zygosity (Maxwell, 2001).
Although smoking during pregnancy causes various adverse pregnancy outcomes, ironically, it has consistently been associated with a reduced risk for hypertension during pregnancy (Bainbridge, 2005; Zhang, 1999). Kraus and associates (2013) posit that this is because smoking upregulates placental adrenomedullin expression, which regulates volume homeostasis.
Women with preeclampsia in the first pregnancy are at greater risk in a second pregnancy compared with women normotensive during their first pregnancy (McDonald, 2009). And conversely, in the woman who was normotensive during her first pregnancy, the incidence of preeclampsia in a subsequent pregnancy is much lower than for a first pregnancy. In a population-based retrospective cohort analysis, Getahun and colleagues (2007) studied almost 137,000 second pregnancies in such women. The incidence for preeclampsia in secundigravida white women was 1.8 percent compared with 3 percent in African-American women.
Presumably because it is somewhat preventable by adequate prenatal care, the incidence of eclampsia has decreased over the years in areas where health care is more readily available. In countries with adequate resources, its incidence averages 1 in 2000 deliveries. Ventura and associates (2000) estimated that the incidence in the United States in 1998 was 1 in 3250 births. According to the Royal College of Obstetricians and Gynaecologists (2006), it approximates 1 in 2000 in the United Kingdom. Akkawi and coworkers (2009) reported it to be 1 in 2500 in Dublin, Andersgaard and associates (2006) as 1 per 2000 for Scandinavia, and Zwart and colleagues (2008) as 1 per 1600 for The Netherlands.
Any satisfactory theory concerning the etiology and pathogenesis of preeclampsia must account for the observation that gestational hypertensive disorders are more likely to develop in women with the following characteristics:
• Are exposed to chorionic villi for the first time
• Are exposed to a superabundance of chorionic villi, as with twins or hydatidiform mole
• Have preexisting conditions of endothelial cell activation or inflammation such as diabetes or renal or cardiovascular disease
• Are genetically predisposed to hypertension developing during pregnancy.
A fetus is not a requisite for preeclampsia to develop. And, although chorionic villi are essential, they need not be intrauterine. For example, Worley and associates (2008) reported a 30-percent incidence in women with an extrauterine pregnancy exceeding 18 weeks’ gestation. Regardless of precipitating etiology, the cascade of events leading to the preeclampsia syndrome is characterized by abnormalities that result in vascular endothelial damage with resultant vasospasm, transudation of plasma, and ischemic and thrombotic sequelae.
Phenotypic Expression of Preeclampsia Syndrome
The preeclampsia syndrome is widely variable in its clinical phenotypic expression. There are at least two major subtypes differentiated by whether or not remodeling of uterine spiral arterioles by endovascular trophoblastic invasion is defective. This concept has given rise to the “two-stage disorder” theory of preeclampsia etiopathogenesis. Ness and Roberts (1996) consider that the two-stage disorder includes “maternal and placental preeclampsia.” According to Redman and coworkers (2014), stage 1 is caused by faulty endovascular trophoblastic remodeling that downstream causes the stage 2 clinical syndrome. Importantly, stage 2 is susceptible to modification by preexisting maternal conditions that are manifest by endothelial cell activation or inflammation. Such conditions include cardiovascular or renal disease, diabetes, obesity, immunological disorders, or hereditary influences.
Such compartmentalization is artificial, and it seems logical to us that preeclampsia syndrome presents clinically as a spectrum of worsening disease. Moreover, evidence is accruing that many “isoforms” exist as discussed below. Examples include differences in maternal and fetal characteristics, placental findings, and hemodynamic findings (Phillips, 2010; Valensise, 2008; van der Merwe, 2010).
Writings describing eclampsia have been traced as far back as 2200 BC (Lindheimer, 2014). And, an imposing number of mechanisms have been proposed to explain its cause. Those currently considered important include:
1. Placental implantation with abnormal trophoblastic invasion of uterine vessels
2. Immunological maladaptive tolerance between maternal, paternal (placental), and fetal tissues
3. Maternal maladaptation to cardiovascular or inflammatory changes of normal pregnancy
4. Genetic factors including inherited predisposing genes and epigenetic influences.
Abnormal Trophoblastic Invasion
Normal implantation is characterized by extensive remodeling of the spiral arterioles within the decidua basalis as shown schematically in Figure 40-2 (Chap. 5, p. 93). Endovascular trophoblasts replace the vascular endothelial and muscular linings to enlarge the vessel diameter. The veins are invaded only superficially. In some cases of preeclampsia, however, there may be incomplete trophoblastic invasion. With this, decidual vessels, but not myometrial vessels, become lined with endovascular trophoblasts. The deeper myometrial arterioles do not lose their endothelial lining and musculoelastic tissue, and their mean external diameter is only half that of corresponding vessels in normal placentas (Fisher, 2014). In general, the magnitude of defective trophoblastic invasion is thought to correlate with severity of the hypertensive disorder (Madazli, 2000).
FIGURE 40-2 Schematic representation of normal placental implantation shows proliferation of extravillous trophoblasts from an anchoring villus. These trophoblasts invade the decidua and extend into the walls of the spiral arteriole to replace the endothelium and muscular wall to create a dilated low-resistance vessel. With preeclampsia, there is defective implantation characterized by incomplete invasion of the spiral arteriolar wall by extravillous trophoblasts. This results in a small-caliber vessel with high resistance to flow.
Using electron microscopy, De Wolf and coworkers (1980) examined arteries taken from the implantation site. They reported that early preeclamptic changes included endothelial damage, insudation of plasma constituents into vessel walls, proliferation of myointimal cells, and medial necrosis. Lipid accumulated first in myointimal cells and then within macrophages. These lipid-laden cell changes, shown in Figure 40-3, were referred to as atherosis by Hertig (1945). Nelson and colleagues (2014) completed placental examination in more than 1200 women with preeclampsia. These investigators reported that vascular lesions including spiral arteriole narrowing, atherosis, and infarcts were more common in placentas from women diagnosed with preeclampsia before 34 weeks.
FIGURE 40-3 Atherosis in a blood vessel from a placental bed. A. Photomicrograph shows disruption of the endothelium that results in a narrowed lumen because of subendothelial accumulation of plasma proteins and foamy macrophages. Some of the foamy macrophages are shown by curved arrows, and straight arrows highlight areas of endothelial disruption. B. Schematic diagram of the photomicrograph. (Modified from Rogers, 1999, with permission.)
Thus, the abnormally narrow spiral arteriolar lumen likely impairs placental blood flow. McMahon and colleagues (2014) have provided evidence that decreased soluble antiangiogenic growth factors may be involved in faulty endovascular remodeling. Diminished perfusion and a hypoxic environment eventually lead to release of placental debris or microparticles that incite a systemic inflammatory response (Lee, 2012; Redman, 2012). Fisher and Roberts (2014) have provided an elegant review of the molecular mechanisms involved in these interactions.
Defective placentation is posited to further cause the susceptible (pregnant) woman to develop gestational hypertension, the preeclampsia syndrome, preterm delivery, a growth-restricted fetus, and/or placental abruption (Brosens, 2011; Kovo, 2010; McElrath, 2008; Nelson, 2014). In addition, Staff and coworkers (2013) have hypothesized that acute atherosis identifies a group of women at increased risk for later atherosclerosis and cardiovascular disease.
Maternal immune tolerance to paternally derived placental and fetal antigens is discussed in Chapter 5 (p. 97). Loss of this tolerance, or perhaps its dysregulation, is another theory cited to account for preeclampsia syndrome (Erlebacher, 2013). Certainly, the histological changes at the maternal-placental interface are suggestive of acute graft rejection. Some of the factors possibly associated with dysregulation include “immunization” from a previous pregnancy, some inherited human leukocyte antigen (HLA) and natural killer (NK)-cell receptor haplotypes, and possibly shared susceptibility genes with diabetes and hypertension (Fukui, 2012; Ward, 2014).
Inferential data also suggest preeclampsia to be an immune-mediated disorder. For example, the risk of preeclampsia is appreciably enhanced in circumstances in which formation of blocking antibodies to placental antigenic sites might be impaired. In this scenario, the first pregnancy would carry a higher risk. Tolerance dysregulation might also explain an increased risk when the paternal antigenic load is increased, that is, with two sets of paternal chromosomes—a “double dose.” Namely, women with molar pregnancies have a high incidence of early-onset preeclampsia. Women with a trisomy 13 fetus also have a 30- to 40-percent incidence of preeclampsia. These women have elevated serum levels of antiangiogenic factors, and the gene for one of these factors, sFlt-1, is on chromosome 13 (Bdolah, 2006). Conversely, women previously exposed to paternal antigens, such as a prior pregnancy with the same partner, are “immunized” against preeclampsia. This phenomenon is not as apparent in women with a prior abortion. Strickland and associates (1986) studied more than 29,000 pregnancies at Parkland Hospital. These investigators reported that hypertensive disorder rates were decreased in women who previously had miscarried compared with nulligravidas. However, the difference, although statistically significant, was not great—22 versus 25 percent. Other studies have shown that multiparas impregnated by a new consort have an increased risk of preeclampsia (Mostello, 2002).
Redman and colleagues (2014) reviewed the possible role of immune maladaptation in preeclampsia pathophysiology. In women destined to be preeclamptic, extravillous trophoblasts early in pregnancy express reduced amounts of immunosuppressive nonclassic HLA G. Black women more commonly have the 1597ΔC allele that further predisposes to preeclampsia (Loisel, 2013). Zhou and coworkers (2012b) have shown this to be associated with high levels of placental oxidative products. These changes may contribute to defective placental vascularization in stage 1 of the preeclampsia syndrome (p. 732). Recall that as discussed in Chapter 4 (p. 56), during normal pregnancy, T-helper (Th) lymphocytes are produced so that type 2 activity is increased in relation to type 1—termed type 2 bias (Redman, 2012, 2014). Th2 cells promote humoral immunity, whereas Th1 cells stimulate inflammatory cytokine secretion. Beginning in the early second trimester in women who develop preeclampsia, Th1 action is increased and the Th1/Th2 ratio changes. Contributors to an enhanced immunologically mediated inflammatory reaction are stimulated by placental microparticles and by adipocytes (Redman, 2012, 2014).
Endothelial Cell Activation
In many ways, inflammatory changes are believed to be a continuation of the stage 1 changes caused by defective placentation as discussed above. In response to placental factors released by ischemic changes or by any other inciting cause, a cascade of events begins (Davidge, 2014). Thus, antiangiogenic and metabolic factors and other inflammatory mediators are thought to provoke endothelial cell injury.
Endothelial cell dysfunction may result from an extreme activated state of leukocytes in the maternal circulation (Faas, 2000; Gervasi, 2001). Briefly, cytokines such as tumor necrosis factor-α (TNF-α) and the interleukins (IL) may contribute to the oxidative stress associated with preeclampsia. This is characterized by reactive oxygen species and free radicals that lead to formation of self-propagating lipid peroxides (Manten, 2005). These in turn generate highly toxic radicals that injure endothelial cells, modify their nitric oxide production, and interfere with prostaglandin balance. Other consequences of oxidative stress include production of the lipid-laden macrophage foam cells seen in atherosis and shown in Figure 40-3; activation of microvascular coagulation manifest by thrombocytopenia; and increased capillary permeability manifest by edema and proteinuria.
These observations on the effects of oxidative stress in preeclampsia have given rise to increased interest in the potential benefit of antioxidants to prevent preeclampsia. Unfortunately, dietary supplementation with vitamins E (α-tocopherol) and C (ascorbic acid) to prevent preeclampsia has thus far proven unsuccessful (Task Force, 2013). This is discussed subsequently.
John and colleagues (2002) showed that in the general population, a diet high in fruits and vegetables with antioxidant activity is associated with decreased blood pressure. Zhang and associates (2002) reported that the incidence of preeclampsia was doubled in women whose daily intake of ascorbic acid was less than 85 mg. These studies were followed by randomized trials to study dietary supplementation. Villar and coworkers (2006) showed that calcium supplementation in populations with a low dietary calcium intake had a small effect to lower perinatal mortality rates but no effect on preeclampsia incidence (p. 748). According to the 2013 Task Force, in several trials, supplementation with the antioxidant vitamins C or E showed no benefits.
From a hereditary viewpoint, preeclampsia is a multifactorial, polygenic disorder. In their comprehensive review, Ward and Taylor (2014) cite an incident risk for preeclampsia of 20 to 40 percent for daughters of preeclamptic mothers; 11 to 37 percent for sisters of preeclamptic women; and 22 to 47 percent for twins. In a study by Nilsson and colleagues (2004) that included almost 1.2 million Swedish births, there was a genetic component for gestational hypertension and for preeclampsia. They also reported 60-percent concordance in monozygotic female twin pairs.
The hereditary predisposition for preeclampsia likely is the result of interactions of literally hundreds of inherited genes—both maternal and paternal—that control myriad enzymatic and metabolic functions throughout every organ system. Plasma-derived factors may induce some of these genes in preeclampsia (Mackenzie, 2012). Thus, the clinical manifestation in any given woman with the preeclampsia syndrome will occupy a spectrum as previously discussed. In this regard, phenotypic expression will differ among similar genotypes depending on interactions with environmental factors (Yang, 2013).
Hundreds of genes have been studied for their possible association with preeclampsia (Buurma, 2013; Ward, 2014). Several of those that may have positive significant association with preeclampsia are listed in Table 40-3. Polymorphisms of the genes for Fas receptor, hypoxia-inducible factor-1α protein (HIF-1α), IL-1β, lymphotoxin-α, transforming growth factor beta 3 (TGF-β3), apolipoprotein E (ApoE), and TNF-α have also been studied with varying results (Borowski, 2009; Hefler, 2001; Jamalzei, 2013; Lachmeijer, 2001; Livingston, 2001; Wilson, 2009). Because of the heterogeneity of the preeclampsia syndrome and especially of the other genetic and environmental factors that interact with its complex phenotypic expression, it is doubtful that any one candidate gene will be found responsible. Indeed, Majander and associates (2013) have linked preeclampsia predisposition to fetal genes on chromosome 18.
TABLE 40-3. Genes with Possible Associations with Preeclampsia Syndrome
Other Genetic Variables
An extensive list of other variables affect genotypic and phenotypic expression of the preeclampsia syndrome. Some include maternal and paternal genotypes, associated disorders, genomic ethnicity, gene-gene interactions, epigenetic phenomena, and gene-environmental interactions. Combinations of these are infinite. Ethnoracial factors are important as discussed regarding the high incidence of preeclampsia in African-American women. It may be that Latina women have a lower prevalence because of interactions of American Indian and white race genes (Shahabi, 2013).
The concept of vasospasm with preeclampsia was advanced by Volhard (1918) based on his direct observations of small blood vessels in the nail beds, ocular fundi, and bulbar conjunctivae. It was also surmised from histological changes seen in various affected organs (Hinselmann, 1924; Landesman, 1954). Endothelial activation causes vascular constriction with increased resistance and subsequent hypertension. At the same time, endothelial cell damage causes interstitial leakage through which blood constituents, including platelets and fibrinogen, are deposited subendothelially. Wang and associates (2002) have also demonstrated disruption of endothelial junctional proteins. Suzuki and coworkers (2003) described ultrastructural changes in the subendothelial region of resistance arteries in preeclamptic women. The much larger venous circuit is similarly involved, and with diminished blood flow because of maldistribution, ischemia of the surrounding tissues can lead to necrosis, hemorrhage, and other end-organ disturbances characteristic of the syndrome. One important clinical correlate is the markedly attenuated blood volume seen in women with severe preeclampsia (Zeeman, 2009).
Endothelial Cell Injury
As discussed on page 733, during the past two decades, endothelial cell injury has become the centerpiece in the contemporary understanding of preeclampsia pathogenesis (Davidge, 2014). In this scheme, protein factor(s)—likely placental—are secreted into the maternal circulation and provoke activation and dysfunction of the vascular endothelium. Many of the facets of the clinical syndrome of preeclampsia are thought to result from these widespread endothelial cell changes. Grundmann and associates (2008) have reported that circulating endothelial cell—CEC—levels are elevated fourfold in the peripheral blood of preeclamptic women. Similarly, Petrozella and colleagues (2012) demonstrated increased levels of circulating endothelial microparticles—EMPs—in preeclamptic women.
Intact endothelium has anticoagulant properties, and endothelial cells blunt the response of vascular smooth muscle to agonists by releasing nitric oxide. Damaged or activated endothelial cells may produce less nitric oxide and secrete substances that promote coagulation and increase sensitivity to vasopressors (Gant, 1974). Further evidence of endothelial activation includes the characteristic changes in glomerular capillary endothelial morphology, increased capillary permeability, and elevated blood concentrations of substances associated with endothelial activation. These latter substances are transferable, and serum from women with preeclampsia stimulates some of these substances in greater amounts. It seems likely that multiple factors in plasma of preeclamptic women combine to have these vasoactive effects (Myers, 2007; Walsh, 2009).
Increased Pressor Responses
As discussed in Chapter 4 (p. 61), pregnant women normally develop refractoriness to infused vasopressors (Abdul-Karim, 1961). Women with early preeclampsia, however, have increased vascular reactivity to infused norepinephrine and angiotensin II (Raab, 1956; Talledo, 1968). Moreover, increased sensitivity to angiotensin II clearly precedes the onset of gestational hypertension (Gant, 1974).
Several prostanoids are thought to be central to preeclampsia syndrome pathophysiology. Specifically, the blunted pressor response seen in normal pregnancy is at least partially due to decreased vascular responsiveness mediated by endothelial prostaglandin synthesis. For example, compared with normal pregnancy, endothelial prostacyclin (PGI2) production is decreased in preeclampsia. This action appears to be mediated by phospholipase A2 (Davidge, 2014). At the same time, thromboxane A2 secretion by platelets is increased, and the prostacyclin:thromboxane A2 ratio decreases. The net result favors increased sensitivity to infused angiotensin II and, ultimately, vasoconstriction (Spitz, 1988). These changes are apparent as early as 22 weeks in women who later develop preeclampsia (Chavarria, 2003).
This potent vasodilator is synthesized from L-arginine by endothelial cells. Withdrawal of nitric oxide results in a clinical picture similar to preeclampsia in a pregnant animal model (Conrad, 1989). Inhibition of nitric oxide synthesis increases mean arterial pressure, decreases heart rate, and reverses the pregnancy-induced refractoriness to vasopressors. In humans, nitric oxide likely is the compound that maintains the normal low-pressure vasodilated state characteristic of fetoplacental perfusion (Myatt, 1992; Weiner, 1992). It also is produced by fetal endothelium, and here it is increased in response to preeclampsia, diabetes, and sepsis (Parra, 2001; von Mandach, 2003).
The effects of nitric oxide production in preeclampsia are unclear (Davidge, 2014). It appears that the syndrome is associated with decreased endothelial nitric oxide synthase expression, thus increasing nitric oxide inactivation. These responses may be race related, with African-American women producing more nitric oxide (Wallace, 2009).
These 21-amino acid peptides are potent vasoconstrictors, and endothelin-1 (ET-1) is the primary isoform produced by human endothelium (George, 2011). Plasma ET-1 levels are increased in normotensive pregnant women, but women with preeclampsia have even higher levels (Ajne, 2003; Clark, 1992). According to Taylor and Roberts (1999), the placenta is not the source of increased ET-1 concentrations, and they likely arise from systemic endothelial activation. Interestingly, treatment of preeclamptic women with magnesium sulfate lowers ET-1 concentrations (Sagsoz, 2003).
Angiogenic and Antiangiogenic Proteins
Placental vasculogenesis is evident by 21 days after conception. There is an ever-expanding list of pro- and antiangiogenic substances involved in placental vascular development. The families of vascular endothelial growth factor (VEGF) and angiopoietin (Ang) are most extensively studied. Angiogenic imbalance is used to describe excessive amounts of antiangiogenic factors that are hypothesized to be stimulated by worsening hypoxia at the uteroplacental interface. Trophoblast of women destined to develop preeclampsia overproduces at least two antiangiogenic peptides that enter the maternal circulation (Karumanchi, 2014):
1. Soluble Fms-like tyrosine kinase 1 (sFlt-1) is a variant of the Flt-1 receptor for placental growth factor (PlGF) and for VEGF. Increased maternal sFlt-1 levels inactivate and decrease circulating free PlGF and VEGF concentrations, leading to endothelial dysfunction (Maynard, 2003). As shown in Figure 40-4, sFlt-1 levels begin to increase in maternal serum months before preeclampsia is evident. Haggerty and colleagues (2012) observed that these high levels in the second trimester were associated with a doubling of the risk for preeclampsia. This divergence from normal levels appears to occur even sooner with early-onset preeclampsia (Vatten, 2012).
2. Soluble endoglin (sEng) is a placenta-derived 65-kDa molecule that blocks endoglin, which is a surface coreceptor for the TGFβ family. Also called CD105, this soluble form of endoglin inhibits various TGFβ isoforms from binding to endothelial receptors and results in decreased endothelial nitric oxide-dependent vasodilatation (Levine, 2006; Venkatesha, 2006). Serum levels of sEng also begin to increase months before clinical preeclampsia develops (Haggerty, 2012).
FIGURE 40-4 Angiogenic and antiangiogenic factors in normotensive (NT) and preeclamptic (PE) women across pregnancy. Both pairs of factors are significantly divergent by 23 to 26 weeks. sFlt = soluble Fms-like tyrosine kinase 1; PlGF = placental growth factor. (Data from Myatt, 2013.)
The cause of placental overproduction of antiangiogenic proteins remains an enigma. Concentrations of the soluble forms are not increased in the fetal circulation or amnionic fluid, and their levels in maternal blood dissipate after delivery (Staff, 2007). Research currently is focused on immunological mechanisms, oxidative stress, mitochondrial pathology, and hypoxia genes (Karumanchi, 2014). Clinical research is directed at use of antiangiogenic proteins in the prediction and diagnosis of preeclampsia. In a systematic review, Widmer and associates (2007) concluded that third-trimester elevation of sFlt-1 levels and decreased PlGF concentrations correlate with preeclampsia development after 25 weeks. These results require verification in prospective studies. Subsequently, Haggerty and coworkers (2012) reported that doubling of expressions of sFlt-1 and sEng increased the preeclampsia risk 39 and 74 percent, respectively.
Although the cause of preeclampsia remains unknown, evidence for its manifestation begins early in pregnancy with covert pathophysiological changes that gain momentum across gestation and eventually become clinically apparent. Unless delivery supervenes, these changes ultimately result in multiorgan involvement with a clinical spectrum ranging from an attenuated manifestation to one of cataclysmic deterioration that is life threatening for both mother and fetus. As discussed, these are thought to be a consequence of endothelial dysfunction, vasospasm, and ischemia. Although the many maternal consequences of the preeclampsia syndrome are usually described in terms of individual organ systems, they frequently are multiple, and they overlap clinically.
Severe disturbances of normal cardiovascular function are common with preeclampsia syndrome. These are related to: (1) increased cardiac afterload caused by hypertension; (2) cardiac preload, which is affected negatively by pathologically diminished hypervolemia of pregnancy and is increased by intravenous crystalloid or oncotic solutions; and (3) endothelial activation with interendothelial extravasation of intravascular fluid into the extracellular space and importantly, into the lungs.
Hemodynamic Changes and Cardiac Function
The cardiovascular aberrations of pregnancy-related hypertensive disorders vary depending on several modifiers. These factors include hypertension severity, underlying chronic disease, preeclampsia severity, and in which part of the clinical spectrum these are studied. In some women, these cardiovascular changes may precede hypertension onset (De Paco, 2008; Easterling, 1990; Khalil, 2012; Melchiorre, 2013). Nevertheless, with the clinical onset of preeclampsia, cardiac output declines, due at least in part to increased peripheral resistance. When assessing cardiac function in preeclampsia, consideration is given to echocardiographic measures of myocardial function and to clinically relevant ventricular function.
Myocardial Function. Serial echocardiographic studies have documented in preeclampsia evidence for ventricular remodeling that is accompanied by diastolic dysfunction in 40 percent of women (Melchiorre, 2012). In some of these women, functional differences persisted up to 16 months after delivery (Evans, 2011). Ventricular remodeling was judged to be an adaptive response to maintain normal contractility with the increased afterload of preeclampsia. In the otherwise healthy pregnant woman, these changes are usually clinically inconsequential. But when combined with underlying ventricular dysfunction—for example, concentric ventricular hypertrophy from chronic hypertension—further diastolic dysfunction may cause cardiogenic pulmonary edema as discussed in Chapters 47 (p. 943) and 49 (p. 990).
Ventricular Function. Despite the relatively high frequency of diastolic dysfunction with preeclampsia, in most women clinical cardiac function is appropriate. This has been shown by several studies in which ventricular function was assessed using invasive hemodynamic methods (Hibbard, 2014). Importantly, both normally pregnant women and those with preeclampsia syndrome can have normal or slightly hyperdynamic ventricular function (Fig. 40-5). Thus, both have a cardiac output that is appropriate for left-sided filling pressures. Data from preeclamptic women obtained by invasive hemodynamic studies are confounded because of the heterogeneity of populations and interventions that also may significantly alter these measurements. Some of these are crystalloid infusions, antihypertensive agents, and magnesium sulfate.
FIGURE 40-5 Ventricular function in normally pregnant women (striped area) and in women with eclampsia (boxed area) is plotted on a Braunwald ventricular function curve. Normal values are from Clark, 1989, and those for eclampsia are from Hankins, 1984. LVSWI = left ventricular stroke work index; PCWP = pulmonary capillary wedge pressure.
Ventricular function studies of preeclamptic women from several investigations are shown in Figure 40-6. Although cardiac function was hyperdynamic in all women, filling pressures were dependent on the volume of intravenous fluids. Specifically, aggressive hydration resulted in overtly hyperdynamic ventricular function in most women. However, this was accompanied by elevated pulmonary capillary wedge pressures. In some of these women, pulmonary edema may develop despite normal ventricular function because of an alveolar endothelial-epithelial leak. This is compounded by decreased oncotic pressure from a low serum albumin concentration (American College of Obstetricians and Gynecologists, 2012b).
FIGURE 40-6 Ventricular function in women with severe preeclampsia–eclampsia plotted on the Braunwald ventricular function curve. The pulmonary capillary wedge pressures (PCWP) are lower in those managed with restricted fluid administration (striped area inA) compared with women managed with aggressive fluid therapy (striped area inB). In those managed with aggressive fluid infusions, eight developed pulmonary edema despite normal to hyperdynamic ventricular function in all but one. LVSWI = left ventricular stroke work index. (Data for A from Benedetti, 1980; Hankins, 1984; data for B from Rafferty, 1980; Phelan, 1982.)
Thus, increased cardiac output and hyperdynamic ventricular function is largely a result of low wedge pressures and not a result of augmented myocardial contractility. By comparison, women given appreciably larger volumes of fluid commonly had filling pressures that exceeded normal, but their ventricular function remained hyperdynamic because of concomitantly increased cardiac output.
From these studies, it is reasonable to conclude that aggressive fluid administration to otherwise normal women with severe preeclampsia substantially elevates normal left-sided filling pressures and increases a physiologically normal cardiac output to hyperdynamic levels.
For nearly 100 years, hemoconcentration has been a hallmark of eclampsia. This was not precisely quantified until Zeeman and colleagues (2009) expanded the previous observations of Pritchard and associates (1984) and showed in eclamptic women that the normally expected hypervolemia is severely curtailed (Fig. 40-7). Women of average size should have a blood volume of nearly 4500 mL during the last several weeks of a normal pregnancy. In nonpregnant women, this volume approximates only 3000 mL. With eclampsia, however, much or all of the anticipated normal excess 1500 mL is lost. Such hemoconcentration results from generalized vasoconstriction that follows endothelial activation and leakage of plasma into the interstitial space because of increased permeability. In women with preeclampsia, and depending on its severity, hemoconcentration is usually not as marked. Women with gestational hypertension, but without preeclampsia, usually have a normal blood volume (Silver, 1998).
FIGURE 40-7 The two bar graphs on the left compare mean blood volumes in nonpregnant and term normally pregnant women. On the right, graphs display values for a group of 29 women with eclampsia and their nonpregnant values. The red bar reflects values for a subset of 14 who had a subsequent normotensive pregnancy. Extensions above bars represent one standard deviation. Comparison between values with identical lowercase letters, that is, a-a, b-b, c-c, d-d, are significant p < .001. (Data from Zeeman, 2009, with permission.)
For women with severe hemoconcentration, it was once taught that an acute fall in hematocrit suggested resolution of preeclampsia. In this scenario, hemodilution follows endothelial healing with return of interstitial fluid into the intravascular space. Although this is somewhat correct, it is important to recognize that a substantive cause of this fall in hematocrit is usually the consequence of blood loss at delivery(Chap. 41, p. 783). It may also partially result from increased erythrocyte destruction as subsequently described. Vasospasm and endothelial leakage of plasma may persist for a variable time after delivery as the endothelium is restored to normalcy. As this takes place, vasoconstriction reverses, and as the blood volume increases, the hematocrit usually falls. Thus, women with eclampsia:
• Are unduly sensitive to vigorous fluid therapy administered in an attempt to expand the contracted blood volume to normal pregnancy levels
• Are sensitive to amounts of blood loss at delivery that are considered normal for a normotensive woman.
Several hematological abnormalities are associated with the preeclampsia syndrome. Among those commonly identified is thrombocytopenia, which at times may become severe enough to be life threatening. Occasionally, the levels of some plasma clotting factors may be decreased, and erythrocytes display abnormal morphology and undergo rapid hemolysis.
Decreased platelet concentrations with eclampsia were described as early as 1922 by Stancke. The platelet count is routinely measured in women with any form of gestational hypertension. The frequency and intensity of thrombocytopenia vary and are dependent on the severity and duration of the preeclampsia syndrome and the frequency with which platelet counts are performed (Heilmann, 2007; Hupuczi, 2007). Overt thrombocytopenia—defined by a platelet count < 100,000/μL—indicates severe disease (see Table 40-2). In general, the lower the platelet count, the higher the rates of maternal and fetal morbidity and mortality (Leduc, 1992). In most cases, delivery is advisable because thrombocytopenia usually continues to worsen. After delivery, the platelet count may continue to decline for the first day or so. It then usually increases progressively to reach a normal level within 3 to 5 days. As discussed on page 768, in some instances with HELLP syndrome, the platelet count continues to fall after delivery. If these do not reach a nadir until 48 to 72 hours, then preeclampsia syndrome may be incorrectly attributed to one of the thrombotic microangiopathies (George, 2013). These syndromes are discussed in Chapter 56 (p. 1116).
Other Platelet Abnormalities
In addition to thrombocytopenia, there are myriad other platelet alterations described with the preeclampsia syndrome. These were reviewed by Kenny and coworkers (2014) and include platelet activation with increased α-degranulation producing β-thromboglobulin, factor 4, and increased clearance. Paradoxically, in most studies, in vitro platelet aggregation is decreased compared with the normal increase characteristic of pregnancy. This likely is due to platelet “exhaustion” following in vivo activation. Although the cause is unknown, immunological processes or simply platelet deposition at sites of endothelial damage may be implicated. Platelet-bound and circulating platelet-bindable immunoglobulins are increased, which suggest platelet surface alterations.
Severe thrombocytopenia does not develop in the fetus or infant born to preeclamptic women despite severe maternal thrombocytopenia (Kenny, 2014; Pritchard, 1987). Importantly, maternal thrombocytopenia in hypertensive women is not a fetal indication for cesarean delivery.
Severe preeclampsia is frequently accompanied by evidence of hemolysis as manifest by elevated serum lactate dehydrogenase levels and decreased haptoglobin levels. Other evidence comes from schizocytosis, spherocytosis, and reticulocytosis in peripheral blood (Cunningham, 1985; Pritchard, 1954, 1976). These derangements result in part from microangiopathic hemolysis caused by endothelial disruption with platelet adherence and fibrin deposition. Sanchez-Ramos and colleagues (1994) described increased erythrocyte membrane fluidity with HELLP syndrome. Cunningham and coworkers (1995) postulated that these changes were due to serum lipid alterations, and Mackay and associates (2012) found substantively decreased long-chain fatty acid content in erythrocytes of preeclamptic women. Erythrocytic membrane changes, increased adhesiveness, and aggregation may also promote a hypercoagulable state (Gamzu, 2001).
HELLP Syndrome. Subsequent to reports of hemolysis and thrombocytopenia with severe preeclampsia, descriptions followed that abnormally elevated serum liver transaminase levels were commonly found and were indicative of hepatocellular necrosis (Chesley, 1978). Weinstein (1982) referred to this combination of events as the HELLP syndrome—and this moniker now is used worldwide. Also, and as shown in Table 40-2, facets of the HELLP syndrome are included in criteria that differentiate severe from nonsevere preeclampsia. The HELLP syndrome is discussed in further detail on page 742.
Subtle changes consistent with intravascular coagulation, and less often erythrocyte destruction, commonly are found with preeclampsia and especially eclampsia (Kenny, 2014). Some of these changes include increased factor VIII consumption, increased levels of fibrinopeptides A and B and of D-dimers, and decreased levels of regulatory proteins—antithrombin III and protein C and S. Except for thrombocytopenia discussed above, coagulation aberrations generally are mild and are seldom clinically significant (Kenny, 2014; Pritchard, 1984). Unless there is associated placental abruption, plasma fibrinogen levels do not differ remarkably from levels found in normal pregnancy. Fibrin degradation products such as d-dimers are elevated only occasionally. Fibronectin, a glycoprotein associated with vascular endothelial cell basement membrane, is elevated in women with preeclampsia (Brubaker, 1992). As preeclampsia worsens, so do abnormal findings with thromboelastography (Pisani-Conway, 2013). Despite these changes, routine laboratory assessments of coagulation, including prothrombin time, activated partial thromboplastin time, and plasma fibrinogen level, were found to be unnecessary in the management of pregnancy-associated hypertensive disorders (Barron, 1999).
The normal pregnancy-induced extra- and intracellular volume increases that are accompanied by vasodilatation undergo further complex shifts with the preeclampsia syndrome. In addition to blood volume changes shown in Figure 40-7, there are many hormonal, fluid, and electrolyte aberrations.
Plasma levels of renin, angiotensin II, angiotensin 1–7, aldosterone, and atrial natriuretic peptide are substantively increased during normal pregnancy. Deoxycorticosterone (DOC) is a potent mineralocorticoid that is also increased remarkably in normal pregnancy (Chap. 4, p. 71). This compound results from conversion of plasma progesterone to DOC rather than increased maternal adrenal secretion. Because of this, DOC secretion is not reduced by sodium retention or hypertension. This may explain why women with preeclampsia retain sodium (Winkel, 1980). In pregnancy, the mineralocorticoid receptor becomes less sensitive to aldosterone (Armanini, 2012).
Vasopressin levels are similar in nonpregnant, normally pregnant, and preeclamptic women even though the metabolic clearance is increased in the latter two (Dürr, 1999).
Atrial natriuretic peptide is released during atrial wall stretching from blood volume expansion, and it responds to cardiac contractility (Chap. 4, p. 61). Serum levels rise in pregnancy, and its secretion is further increased in women with preeclampsia (Borghi, 2000; Luft, 2009). Levels of its precursor—proatrial natriuretic peptide—are also increased in preeclampsia (Sugulle, 2012).
Fluid and Electrolyte Changes
In women with severe preeclampsia, the volume of extracellular fluid, manifest as edema, is usually much greater than that in normal pregnant women. The mechanism responsible for pathological fluid retention is thought to be endothelial injury (Davidge, 2014). In addition to generalized edema and proteinuria, these women have reduced plasma oncotic pressure. This reduction creates a filtration imbalance and further displaces intravascular fluid into the surrounding interstitium.
Electrolyte concentrations do not differ appreciably in women with preeclampsia compared with those of normal pregnant women. This may not be the case if there has been vigorous diuretic therapy, sodium restriction, or administration of free water with sufficient oxytocin to produce antidiuresis.
Following an eclamptic convulsion, the serum pH and bicarbonate concentration are lowered due to lactic acidosis and compensatory respiratory loss of carbon dioxide. The intensity of acidosis relates to the amount of lactic acid produced—metabolic acidosis—and the rate at which carbon dioxide is exhaled—respiratory acidosis.
During normal pregnancy, renal blood flow and glomerular filtration rate are increased appreciably (Chap. 4, p. 63). With development of preeclampsia, there may be a number of reversible anatomical and pathophysiological changes. Of clinical importance, renal perfusion and glomerular filtration are reduced. Levels that are much less than normal nonpregnant values are infrequent and are the consequence of severe disease.
A small degree of decreased glomerular filtration may result from reduced plasma volume. Most of the decrement, however, is from increased renal afferent arteriolar resistance that may be elevated up to fivefold (Conrad, 2014; Cornelis, 2011). There are also morphological changes characterized by glomerular endotheliosis blocking the filtration barrier. This is discussed further subsequently. Diminished filtration causes serum creatinine levels to rise to values seen in nonpregnant individuals, that is, 1 mg/mL, and sometimes even higher (Lindheimer, 2008a). Abnormal values usually begin to normalize 10 days or later after delivery (Spaan, 2012a).
In most preeclamptic women, urine sodium concentration is elevated. Urine osmolality, urine:plasma creatinine ratio, and fractional excretion of sodium also indicate that a prerenal mechanism is involved. Kirshon and coworkers (1988) infused dopamine intravenously into oliguric women with preeclampsia, and this renal vasodilator stimulated increased urine output, fractional sodium excretion, and free water clearance. As was shown in Figure 40-6, sodium-containing crystalloid infusion increases left ventricular filling pressure, and although oliguria temporarily improves, rapid infusions may cause clinically apparent pulmonary edema. Intensive intravenous fluid therapy is not indicated as “treatment” for preeclamptic women with oliguria. Exceptions are diminished urine output from hemorrhage or fluid loss from vomiting or fever.
Plasma uric acid concentration is typically elevated in preeclampsia. The elevation exceeds the reduction in glomerular filtration rate and likely is also due to enhanced tubular reabsorption (Chesley, 1945). At the same time, preeclampsia is associated with diminished urinary excretion of calcium, perhaps because of increased tubular reabsorption (Taufield, 1987). Another possibility is from increased placental urate production compensatory to increased oxidative stress.
As shown in Table 40-1, some degree of proteinuria will establish the diagnosis of preeclampsia syndrome. Proteinuria may develop late, and some women may already be delivered or have had an eclamptic convulsion before it appears. For example, 10 to 15 percent of women with HELLP syndrome did not have proteinuria at presentation (Sibai, 2004). In another report, 17 percent of eclamptic women did not have proteinuria by the time of seizures (Zwart, 2008).
Problematically, the optimal method of establishing abnormal levels of either urine protein or albumin remains to be defined. Chen and associates (2008) have shown that clean-catch and catheterized urine specimens correlate well. But dipstick qualitative determinations depend on urinary concentration and are notorious for false-positive and -negative results. For a 24-hour quantitative specimen, the “consensus” threshold value used is > 300 mg/24 h (Task Force, 2013). Tun and colleagues (2012) have shown equivalent efficacy using protein excretion of 165 mg in a 12-hour sample. Importantly, these values have not been irrefutably established.
Determination of urinary protein:creatinine ratio may supplant the cumbersome 24-hour quantification (Ethridge, 2013; Kyle, 2008; Morris, 2012). In a systematic review, Papanna and associates (2008) concluded that random urine protein:creatinine ratios that are below 130 to 150 mg/g, that is, 0.13 to 0.15, indicate a low likelihood of proteinuria exceeding 300 mg/day. Midrange ratios, that is, 300 mg/g or 0.3 have poor sensitivity and specificity. Stout and colleagues (2013) found that values < 0.08 or > 1.19 had negative- or positive-predictive values of 86 and 96 percent, respectively. At this time, most recommend that with midrange ratio values, 24-hour protein excretion should be quantified.
There are several methods used to measure proteinuria, and none detect all of the various proteins normally excreted (Nayeri, 2013). A more accurate method involves measurement of albumin excretion. Albumin filtration exceeds that of larger globulins, and with glomerular disease such as preeclampsia, most of the protein in urine is albumin. There are test kits that permit rapid measurement of urinary albumin:creatinine ratios in an outpatient setting (Kyle, 2008).
Although worsening or nephrotic-range proteinuria has been considered by most to be a sign of severe disease, this does not appear to be the case (Airoldi, 2007). Certainly, this concept was not accepted by the 2013 Task Force. Finally, increasing proteinuria is more common in multifetal pregnancy complicated by preeclampsia (Zilberberg, 2013).
Sheehan and Lynch (1973) commonly found changes identifiable at autopsy by light and electron microscopy in the kidneys of eclamptic women. Glomeruli are enlarged by approximately 20 percent, they are “bloodless,” and capillary loops variably are dilated and contracted. Endothelial cells are swollen—termed glomerular capillary endotheliosis by Spargo and associates (1959). Endothelial cells are often so swollen that they block or partially block the capillary lumens (Fig. 40-8). Homogeneous subendothelial deposits of proteins and fibrin-like material are seen.
FIGURE 40-8 Schematic showing glomerular capillary endotheliosis. The capillary of the normal glomerulus shown on the left has wide endothelial fenestrations, and the pedicels emanating from the podocytes are widely spaced (arrow). The illustration on the right is of a glomerulus with changes induced by the preeclampsia syndrome. The endothelial cells are swollen and their fenestrae narrowed, as are the pedicels that now abut each other.
Endothelial swelling may result from angiogenic factor “withdrawal” caused by free angiogenic proteins complexing with the circulating antiangiogenic protein receptor discussed on page 735 (Conrad, 2014; Eremina, 2007; Karumanchi, 2009). The angiogenic proteins are crucial for podocyte health, and their inactivation leads to podocyte dysfunction and endothelial swelling. One marker of this is excretion of podocyte proteins such as nephrin, podocalyxin, and βig-h3 (transforming growth factor, β-induced) (Wang, 2012b). Also, eclampsia is characterized by increased excretion of urinary podocytes, a phenomenon shared by other proteinuric disorders (Garrett, 2013; Wagner, 2012). Of interest, podocytes are epithelia, and thus renal pathology involves both endothelial and epithelial cells (see Fig. 40-8).
Acute Kidney Injury
Rarely is acute tubular necrosis caused by preeclampsia alone. Although mild degrees are encountered in neglected cases, clinically apparent renal failure is invariably induced by coexistent hemorrhage with hypovolemia and hypotension (Chap. 41, p. 814). This is usually caused by severe obstetrical hemorrhage for which adequate blood replacement is not given. Drakeley and coworkers (2002) described 72 women with preeclampsia and renal failure. Half had HELLP syndrome, and a third had placental abruption. As discussed on page 742, Haddad and colleagues (2000) reported that 5 percent of 183 women with HELLP syndrome had kidney injury. Half of these, however, also had a placental abruption, and most had postpartum hemorrhage. Rarely, irreversible renal cortical necrosis develops (Chap. 53, p. 1064).
Hepatic changes in women with fatal eclampsia were described in 1856 by Virchow. The characteristic lesions were regions of periportal hemorrhage in the liver periphery. In their elegant autopsy studies, Sheehan and Lynch (1973) described that some degree of hepatic infarction accompanied hemorrhage in almost half of women who died with eclampsia. These corresponded with reports that had appeared during the 1960s describing elevated serum hepatic transaminase levels. Along with the earlier observations by Pritchard and associates (1954), who described hemolysis and thrombocytopenia with eclampsia, this constellation of hemolysis, hepatocellular necrosis, and thrombocytopenia was later termed HELLP syndrome by Weinstein (1985) to call attention to its seriousness (p. 742).
Lesions as extensive as those shown in Figure 40-9 are unusual, even in the autopsy series by Sheehan and Lynch (1973). From a pragmatic point, liver involvement with preeclampsia may be clinically significant in several circumstances.
FIGURE 40-9 Gross liver specimen from a woman with preeclampsia who died from aspiration pneumonitis. Periportal hemorrhagic necrosis was seen microscopically. (From Cunningham, 1993.)
First, symptomatic involvement is considered a sign of severe disease. It typically manifests by moderate to severe right-upper quadrant or midepigastric pain and tenderness. In many cases, such women also have elevated levels of serum aminotransferase, namely, aspartate aminotransferase (AST) or alanine aminotransferase (ALT). In some cases, however, the amount of hepatic tissue involved with infarction may be surprisingly extensive yet still clinically insignificant. In our experiences, infarction may be worsened by hypotension from obstetrical hemorrhage, and it occasionally causes hepatic failure—so-called shock liver (Alexander, 2009).
Second, asymptomatic elevations of serum hepatic transaminase levels—AST and ALT—are also considered markers for severe preeclampsia. Values seldom exceed 500 U/L, but have been reported to be greater than 2000 U/L in some women (Chap. 55, p. 1085). In general, serum levels inversely follow platelet levels, and they both usually normalize within 3 days following delivery as previously discussed on page 738.
In a third example of liver involvement, hemorrhagic infarction may extend to form a hepatic hematoma. These in turn may extend to form a subcapsular hematoma that may rupture. They can be identified using computed tomography (CT) scanning or magnetic resonance (MR) imaging as shown in Figure 40-10. Unruptured hematomas are probably more common than clinically suspected and are more likely to be found with HELLP syndrome (Carlson, 2004; Vigil-De Gracia, 2012). Although once considered a surgical condition, contemporaneous management usually consists of observation and conservative treatment of hematomas unless hemorrhage is ongoing. In some cases, however, prompt surgical intervention may be lifesaving. Vigil-De Gracia and coworkers (2012) reviewed 180 cases of hepatic hematoma or rupture. More than 90 percent had HELLP syndrome, and in 90 percent, the capsule had ruptured. The maternal mortality rate was 22 percent, and the perinatal mortality rate was 31 percent. In rare cases, liver transplant is necessary (Hunter, 1995; Wicke, 2004).
FIGURE 40-10 Abdominal CT imaging performed postpartum in a woman with severe HELLP syndrome and right-upper quadrant pain. A large subcapsular hematoma (asterisk) is seen confluent with intrahepatic infarction and hematoma (arrowhead). Numerous flame-shaped hemorrhages are seen at the hematoma interface (arrows).
Last, acute fatty liver of pregnancy is sometimes confused with preeclampsia (Nelson, 2013; Sibai, 2007a). It too has an onset in late pregnancy, and often there is accompanying hypertension, elevated serum transaminase and creatinine levels, and thrombocytopenia (Chap. 55, p. 1086).
There is no universally accepted strict definition of this syndrome, and thus its incidence varies by investigator. When it is identified, the likelihood of hepatic hematoma and rupture is substantially increased. In a multicenter study, Haddad and colleagues (2000) described 183 women with HELLP syndrome of whom 40 percent had adverse outcomes including two maternal deaths. The incidence of subcapsular liver hematoma was 1.6 percent. Other complications included eclampsia—6 percent, placental abruption—10 percent, acute kidney injury—5 percent, and pulmonary edema—10 percent. Other serious complications included stroke, coagulopathy, acute respiratory distress syndrome, and sepsis.
Women with preeclampsia complicated by the HELLP syndrome typically have worse outcomes than those without these findings (Kozic, 2011; Martin, 2012, 2013). In their review of 693 women with HELLP syndrome, Keiser and coworkers (2009) reported that 10 percent had concurrent eclampsia. Sep and associates (2009) also described a significantly increased risk for complications in women with HELLP syndrome compared with those with “isolated preeclampsia.” These included eclampsia—15 versus 4 percent; preterm birth—93 versus 78 percent; and perinatal mortality rate—9 versus 4 percent, respectively. Because of these marked clinical differences, these investigators postulate that HELLP syndrome has a distinct pathogenesis. Others have shown a difference in the ratio of antiangiogenic and inflammatory acute-phase proteins in these two conditions and have reached similar conclusions (Reimer, 2013). Given all of the variables contributing to the incidence and pathophysiology of preeclampsia as discussed on page 736, this is a reasonable conclusion. Sibai and Stella (2009) have discussed some of these aspects under the rubric of “atypical preeclampsia-eclampsia.”
According to Sheehan and Lynch (1973), there are no convincing data that the pancreas has special involvement with preeclampsia syndrome. If so, the occasional case reports of concurrent hemorrhagic pancreatitis are likely unrelated (Swank, 2012). That said, severe hemoconcentration may predispose to pancreatic inflammation.
Headaches and visual symptoms are common with severe preeclampsia, and associated convulsions define eclampsia. The earliest anatomical descriptions of brain involvement came from autopsy specimens, but CT- and MR-imaging and Doppler studies have added many important insights into cerebrovascular involvement.
Most gross anatomical descriptions of the brain in eclamptic women are taken from eras when mortality rates were high. One consistent finding was that brain pathology accounted for only about a third of fatal cases such as the one shown in Figure 40-11. In fact, most deaths were from pulmonary edema, and brain lesions were coincidental. Thus, although gross intracerebral hemorrhage was seen in up to 60 percent of eclamptic women, it was fatal in only half of these (Melrose, 1984; Richards, 1988; Sheehan, 1973). As shown in Figure 40-12, other principal lesions found at autopsy of eclamptic women were cortical and subcortical petechial hemorrhages. The classic microscopic vascular lesions consist of fibrinoid necrosis of the arterial wall and perivascular microinfarcts and hemorrhages. Other frequently described major lesions include subcortical edema, multiple nonhemorrhagic areas of “softening” throughout the brain, and hemorrhagic areas in the white matter. There also may be hemorrhage in the basal ganglia or pons, often with rupture into the ventricles.
FIGURE 40-11 This autopsy brain slice shows a fatal hypertensive hemorrhage in a primigravida with eclampsia.
FIGURE 40-12 Composite illustration showing location of cerebral hemorrhages and petechiae in women with eclampsia. Insert shows the level of the brain from which the main image was constructed. (Data from Sheehan, 1973.)
Clinical, pathological, and neuroimaging findings have led to two general theories to explain cerebral abnormalities with eclampsia. Importantly, endothelial cell dysfunction that characterizes the preeclampsia syndrome likely plays a key role in both. The first theory suggests that in response to acute and severe hypertension, cerebrovascular overregulation leads to vasospasm (Trommer, 1988). This presumption is based on the angiographic appearance of diffuse or multifocal segmental narrowings suggestive of vasospasm (Ito, 1995). In this scheme, diminished cerebral blood flow is hypothesized to result in ischemia, cytotoxic edema, and eventually tissue infarction. Although this theory was widely embraced for many years, there is little objective evidence to support it.
The second theory is that sudden elevations in systemic blood pressure exceed the normal cerebrovascular autoregulatory capacity (Hauser, 1988; Schwartz, 2000). Regions of forced vasodilation and vasoconstriction develop, especially in arterial boundary zones. At the capillary level, disruption of end-capillary pressure causes increased hydrostatic pressure, hyperperfusion, and extravasation of plasma and red cells through endothelial tight-junction openings. This leads to vasogenic edema. This theory is incomplete because very few eclamptic women have mean arterial pressures that exceed limits of autoregulation—approximately 160 mm Hg.
It seems reasonable to conclude that the most likely mechanism is a combination of the two. Thus, a preeclampsia-associated interendothelial cell leak develops at blood pressure (hydraulic) levels much lower than those usually causing vasogenic edema and is coupled with a loss of upper-limit autoregulation (Zeeman, 2009). With imaging studies, these changes manifest as facets of the reversible posterior leukoencephalopathy syndrome (Hinchey, 1996). This subsequently became referred to as the posterior reversible encephalopathy syndrome—PRES. This term is misleading because although PRES lesions principally involve the posterior brain—the occipital and parietal cortices—in at least a third of cases, they also involve other brain areas (Edlow, 2013; Zeeman, 2004a). The most frequently affected region is the parietooccipital cortex—the boundary zone of the anterior, middle, and posterior cerebral arteries. Also, in most cases, these lesions are reversible (Cipolla, 2014).
Cerebral Blood Flow
Autoregulation is the mechanism by which cerebral blood flow remains relatively constant despite alterations in cerebral perfusion pressure. In nonpregnant individuals, this mechanism protects the brain from hyperperfusion when mean arterial pressures increase to as high as 160 mm Hg. These are pressures far greater than those seen in all but a very few women with eclampsia. Thus, to explain eclamptic seizures, it was theorized that autoregulation must be altered by pregnancy. Although species differences must be considered, studies by Cipolla and colleagues (2007, 2009, 2014) have convincingly shown that autoregulation is unchanged across pregnancy in rodents. That said, some, but not others, have provided evidence of impaired autoregulation in women with preeclampsia (Janzarik, 2014; van Veen, 2013).
Zeeman and associates (2003) showed that cerebral blood flow during the first two trimesters of normal pregnancy is similar to nonpregnant values, but thereafter, it significantly decreases by 20 percent during the last trimester. These investigators also documented significantly increased cerebral blood flow in women with severe preeclampsia compared with that of normotensive pregnant women (Zeeman, 2004b). Taken together, these findings suggest that eclampsia occurs when cerebral hyperperfusion forces capillary fluid interstitially because of endothelial damage, which leads to perivascular edema characteristic of the preeclampsia syndrome. In this regard, eclampsia is an example of the posterior reversible encephalopathy syndrome as previously discussed.
There are several neurological manifestations of the preeclampsia syndrome. Each signifies severe involvement and requires immediate attention. First, headache and scotomata are thought to arise from cerebrovascular hyperperfusion that has a predilection for the occipital lobes. According to Sibai (2005) and Zwart and coworkers (2008), 50 to 75 percent of women have headaches and 20 to 30 percent have visual changes preceding eclamptic convulsions. The headaches may be mild to severe and intermittent to constant. In our experiences, they are unique in that they do not usually respond to traditional analgesia, but they do improve after magnesium sulfate infusion is initiated.
Convulsions are a second potential manifestation and are diagnostic for eclampsia. These are caused by excessive release of excitatory neurotransmitters—especially glutamate; massive depolarization of network neurons; and bursts of action potentials (Meldrum, 2002). Clinical and experimental evidence suggest that extended seizures can cause significant brain injury and later brain dysfunction.
As a third manifestation, blindness is rare with preeclampsia alone, but it complicates eclamptic convulsions in up to 15 percent of women (Cunningham, 1995). Blindness has been reported to develop up to a week or more following delivery (Chambers, 2004). There are at least two types of blindness as discussed subsequently.
Last, generalized cerebral edema may develop and is usually manifest by mental status changes that vary from confusion to coma. This situation is particularly dangerous because fatal transtentorial herniation may result.
With CT imaging, localized hypodense lesions at the gray- and white-matter junction, primarily in the parietooccipital lobes, are typically found in eclampsia. Such lesions may also be seen in the frontal and inferior temporal lobes, the basal ganglia, and thalamus (Brown, 1988). The spectrum of brain involvement is wide, and increasing involvement can be identified with CT imaging. Edema of the occipital lobes or diffuse cerebral edema may cause symptoms such as blindness, lethargy, and confusion (Cunningham, 2000). In the latter cases, widespread edema shows as a marked compression or even obliteration of the cerebral ventricles. Such women may develop signs of impending life-threatening transtentorial herniation.
Several MR imaging acquisitions are used to study eclamptic women. Common findings are hyperintense T2 lesions—posterior reversible encephalopathy syndrome (PRES)—in the subcortical and cortical regions of the parietal and occipital lobes (Fig. 40-13). There is also relatively common involvement of the basal ganglia, brainstem, and cerebellum (Brewer, 2013; Zeeman, 2004a). Although these PRES lesions are almost universal in women with eclampsia, their incidence in women with preeclampsia is less frequent. They are more likely to be found in women who have severe disease and who have neurological symptoms (Schwartz, 2000). And although usually reversible, a fourth of these hyperintense lesions represent cerebral infarctions that have persistent findings (Loureiro, 2003; Zeeman, 2004a).
FIGURE 40-13 Cranial magnetic resonance imaging in a nullipara with eclampsia. Multilobe T2-FLAIR high-signal lesions are apparent. FLAIR = fluid-attenuated inversion recovery. (Image contributed by Dr. Gerda Zeeman.)
Visual Changes and Blindness
Scotomata, blurred vision, or diplopia are common with severe preeclampsia and eclampsia. These usually improve with magnesium sulfate therapy and/or lowered blood pressure. Blindness is less common, is usually reversible, and may arise from three potential areas. These are the visual cortex of the occipital lobe, the lateral geniculate nuclei, and the retina. In the retina, pathological lesions may be ischemia, infarction, or detachment (Roos, 2012).
Occipital blindness is also called amaurosis—from the Greek dimming. Affected women usually have evidence of extensive occipital lobe vasogenic edema on imaging studies. Of 15 women cared for at Parkland Hospital, occipital blindness lasted from 4 hours to 8 days, but it resolved completely in all cases (Cunningham, 1995). Rarely, extensive cerebral infarctions may result in total or partial visual defects (Fig. 40-14).
FIGURE 40-14 Cranial magnetic resonance imaging performed 3 days postpartum in a woman with eclampsia and HELLP syndrome. Neurovisual defects persisted at 1 year, causing job disability. (From Murphy, 2005, with permission.)
Blindness from retinal lesions is caused either by serous retinal detachment or rarely by retinal infarction, which is termed Purtscher retinopathy (Fig. 40-15). Serous retinal detachment is usually unilateral and seldom causes total visual loss. In fact, asymptomatic serous retinal detachment is relatively common (Saito, 1998). In most cases of eclampsia-associated blindness, visual acuity subsequently improves, but if caused by retinal artery occlusion, vision may be permanently impaired (Lara-Torre, 2002; Roos, 2012). In some women, these findings are additive. Moseman and Shelton (2002) described a woman with permanent blindness due to a combination of retinal infarctions and bilateral lesions in the lateral geniculate nuclei.
FIGURE 40-15 Purtscher retinopathy caused by choroidal ischemia and infarction in preeclampsia syndrome. A. Ophthalmoscopy shows scattered yellowish, opaque lesions of the retina (arrows). B. The late phase of fluorescein angiography shows areas of intense hyperfluorescence representing pooling of extravasated dye. (From Lam, 2001, with permission.)
Clinical manifestations suggesting widespread cerebral edema are worrisome. During 13 years at Parkland Hospital, 10 of 175 women with eclampsia were diagnosed with symptomatic cerebral edema (Cunningham, 2000). Symptoms ranged from lethargy, confusion, and blurred vision to obtundation and coma. In most cases, symptoms waxed and waned. Mental status changes generally correlated with the degree of involvement seen with CT and MR imaging studies. These women are very susceptible to sudden and severe blood pressure elevations, which can acutely worsen the already widespread vasogenic edema. Thus, careful blood pressure control is essential. In the 10 women with generalized edema, three became comatose and had imaging findings of impending transtentorial herniation. One of these three died from herniation. Consideration is given for treatment with mannitol or dexamethasone.
Long-Term Neurocognitive Sequelae
Women with eclampsia have been shown to have some cognitive decline when studied 5 to 10 years following an eclamptic pregnancy. This is discussed further on page 770.
Defects in endovascular trophoblastic invasion and placentation germane to development of the preeclampsia syndrome and fetal-growth restriction were discussed on page 732. Of immense clinical importance, compromised uteroplacental perfusion is almost certainly a major culprit in the increased perinatal morbidity and mortality rates. Thus, measurement of uterine, intervillous, and placental blood flow would likely be informative. Attempts to assess these in humans have been hampered by several obstacles that include inaccessibility of the placenta, the complexity of its venous effluent, and the need for radioisotopes or invasive techniques.
Measurement of uterine artery blood flow velocity has been used to estimate resistance to uteroplacental blood flow (Chap. 17, p. 345). Vascular resistance is estimated by comparing arterial systolic and diastolic velocity waveforms. By the completion of placentation, impedance to uterine artery blood flow is markedly decreased, but with abnormal placentation, abnormally high resistance persists (Everett, 2012; Ghidini, 2008; Napolitano, 2012). Earlier studies were done to assess this by measuring peak systolic:diastolic velocity ratios from uterine and umbilical arteries in preeclamptic pregnancies. The results were interpreted as showing that in some cases, but certainly not all, there was increased resistance (Fleischer, 1986; Trudinger, 1990).
Another Doppler waveform—uterine artery “notching”—has been reported to be associated with increased risks for preeclampsia or fetal-growth restriction (Groom, 2009). In the MFMU Network study reported by Myatt and colleagues (2012a), however, notching had a low predictive value except for early-onset severe disease.
Matijevic and Johnson (1999) measured resistance in uterine spiral arteries. Impedance was higher in peripheral than in central vessels—a so-called ring-like distribution. Mean resistance was higher in all women with preeclampsia compared with that in normotensive controls. Ong and associates (2003) used MR imaging and other techniques to assess placental perfusion ex vivo in the myometrial arteries removed from women with preeclampsia or fetal-growth restriction. These investigators confirmed that in both conditions myometrial arteries exhibited endothelium-dependent vasodilatory response. Moreover, other pregnancy conditions are also associated with increased resistance (Urban, 2007). One major adverse effect, fetal-growth restriction, is discussed in Chapter 44 (p. 874).
Pimenta and colleagues (2013) assessed placental vascularity using a three-dimensional power Doppler histogram. These researchers described the placental vascularity index, which was decreased in women with any pregnancy-associated hypertensive disorders—11.1 percent compared with 15.2 percent in normal controls.
Despite these findings, evidence for compromised uteroplacental circulation is found in only a few women who go on to develop preeclampsia. Indeed, when preeclampsia develops during the third trimester, only a third of women with severe disease have abnormal uterine artery velocimetry (Li, 2005). In a study of 50 women with HELLP syndrome, only a third had abnormal uterine artery waveforms (Bush, 2001). In general, the extent of abnormal waveforms correlates with severity of fetal involvement (Ghidini, 2008; Groom, 2009).
PREDICTION AND PREVENTION
Measurement during early pregnancy—or across pregnancy—of various biological, biochemical, and biophysical markers implicated in preeclampsia syndrome pathophysiology has been proposed to predict its development. Attempts have been made to identify early markers of faulty placentation, impaired placental perfusion, endothelial cell activation and dysfunction, and activation of coagulation. For the most, these have resulted in testing strategies with poor sensitivity and with poor positive-predictive value for preeclampsia (Conde-Agudelo, 2014; Lindheimer, 2008b; Odibo, 2013). Currently, no screening tests are predictably reliable, valid, and economical (Kleinrouweler, 2012). There are, however, combinations of tests, some yet to be adequately evaluated, that may be promising (Dugoff, 2013; Kuc, 2011; Navaratnam, 2013; Olsen, 2012).
The list of predictive factors evaluated during the past three decades is legion. Although most have been evaluated in the first half of pregnancy, some have been tested as predictors of severity in the third trimester (Chaiworapongsa, 2013; Mosimann, 2013; Rana, 2012). Others have been used to forecast recurrent preeclampsia (Demers, 2014). Some of these tests are listed in Table 40-4, which is by no means all inclusive. Conde-Agudelo and coworkers (2014) have recently provided a thorough review of many of these testing strategies.
TABLE 40-4. Predictive Tests for Development of the Preeclampsia Syndrome
Vascular Resistance Testing and Placental Perfusion
Most of these are cumbersome, time consuming, and overall inaccurate.
Provocative Pressor Tests. Three tests have been extensively evaluated to assess the blood pressure rise in response to a stimulus. The roll-over test measures the hypertensive response in women at 28 to 32 weeks who are resting in the left lateral decubitus position and then roll over to the supine position. Increased blood pressure signifies a positive test. The isometric exercise test employs the same principle by squeezing a handball. The angiotensin II infusion test is performed by giving incrementally increasing doses intravenously, and the hypertensive response is quantified. In their updated metaanalysis, Conde-Agudelo and associates (2014) found sensitivities of all three tests to range from 55 to 70 percent, and specificities approximated 85 percent.
Uterine Artery Doppler Velocimetry. Faulty trophoblastic invasion of the spiral arteries, which is depicted in Figure 40-2, results in diminished placental perfusion and upstream increased uterine artery resistance. Increased uterine artery velocimetry determined by Doppler ultrasound in the first two trimesters should provide indirect evidence of this process and thus serve as a predictive test for preeclampsia (Gebb, 2009a,b; Groom, 2009). As described on page 745 and in Chapter 10 (p. 220), increased flow resistance results in an abnormal waveform represented by an exaggerated diastolic notch. These have value for fetal-growth restriction but not preeclampsia (American College of Obstetricians and Gynecologists, 2013a). Several flow velocity waveforms—alone or in combination—have been investigated for preeclampsia prediction. In some of these, predictive values for early-onset preeclampsia were promising (Herraiz, 2012). At this time, however, none is suitable for clinical use (Conde-Agudelo, 2014; Kleinrouweler, 2012; Myatt, 2012a).
Pulse Wave Analysis. Like the uterine artery, finger arterial pulse “stiffness” is an indicator of cardiovascular risk. Investigators have preliminarily evaluated its usefulness in preeclampsia prediction (Vollebregt, 2009).
Fetal-Placental Unit Endocrine Function
Several serum analytes that have been proposed to help predict preeclampsia are shown in Table 40-4. Newer ones are continuously added (Jeyabalan, 2009; Kanasaki, 2008; Kenny, 2009). Many of these gained widespread use in the 1980s to identify fetal malformations and were also found to be associated with other pregnancy abnormalities such as neural-tube defects and aneuploidy (Chap. 14, p. 289). Although touted for hypertension prediction, in general, none of these tests has been shown to be clinically beneficial for that purpose.
Tests of Renal Function
Serum Uric Acid. One of the earliest laboratory manifestations of preeclampsia is hyperuricemia (Powers, 2006). It likely results from reduced uric acid clearance from diminished glomerular filtration, increased tubular reabsorption, and decreased secretion (Lindheimer, 2008a). It is used by some to define preeclampsia, but Cnossen and coworkers (2006) reported that its sensitivity ranged from 0 to 55 percent, and specificity was 77 to 95 percent.
Microalbuminuria. As a predictive test for preeclampsia, microalbuminuria has sensitivities ranging from 7 to 90 percent and specificities between 29 and 97 percent (Conde-Agudelo, 2014). Poon and colleagues (2008) likewise found unacceptable sensitivity and specificity for urine albumin:creatinine ratios.
Endothelial Dysfunction and Oxidant Stress
As discussed on page 733, endothelial activation and inflammation are major participants in the pathophysiology of the preeclampsia syndrome. As a result, compounds such as those listed in Table 40-4 are found in circulating blood of affected women, and some have been assessed for their predictive value.
Fibronectins. These high-molecular-weight glycoproteins are released from endothelial cells and extracellular matrix following endothelial injury (Chavarria, 2002). More than 30 years ago, plasma concentrations were reported to be elevated in women with preeclampsia (Stubbs, 1984). Following their systematic review, however, Leeflang and associates (2007) concluded that neither cellular nor total fibronectin levels were clinically useful to predict preeclampsia.
Coagulation Activation. Thrombocytopenia and platelet dysfunction are integral features of preeclampsia as discussed on page 738. Platelet activation causes increased destruction and decreased concentrations, and mean platelet volume rises because of platelet immaturity (Kenny, 2014). Although markers of coagulation activation are increased, the substantive overlap with levels in normotensive pregnant women stultifies their predictive value.
Oxidative Stress. Increased levels of lipid peroxides coupled with decreased antioxidant activity have raised the possibility that markers of oxidative stress might predict preeclampsia. For example, malondialdehyde is a marker of lipid peroxidation. Other markers are various prooxidants or their potentiators. These include iron, transferrin, and ferritin; blood lipids, including triglycerides, free fatty acids, and lipoproteins; and antioxidants such as ascorbic acid and vitamin E (Bainbridge, 2005; Conde-Agudelo, 2014; Mackay, 2012; Powers, 2000). These have not been found to be predictive, and treatment to prevent preeclampsia with some of them has been studied as discussed on page 748.
Hyperhomocysteinemia causes oxidative stress and endothelial cell dysfunction and is characteristic of preeclampsia. Although women with elevated serum homocysteine levels at midpregnancy had a three- to fourfold risk of preeclampsia, these tests have not been shown to be clinically useful predictors (D’Anna, 2004; Mignini, 2005; Zeeman, 2003).
Angiogenic Factors. As discussed on page 735, evidence has accrued that an imbalance between proangiogenic and antiangiogenic factors is related to preeclampsia pathogenesis. Serum levels of some proangiogenic factors—vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)—begin to decrease before clinical preeclampsia develops. And, recall as shown in Figure 40-4 that at the same time levels of some antiangiogenic factors such as sFlt-1 and sEng become increased (Maynard, 2008). In one study, these abnormalities were identified coincidentally with rising uterine artery Doppler resistance (Coolman, 2012).
Conde-Agudelo and colleagues (2014) reviewed the predictive accuracy of some of these factors for severe preeclampsia. Sensitivities for all cases of preeclampsia ranged from 30 to 50 percent, and specificity was about 90 percent. Their predictive accuracy was higher for early-onset preeclampsia. These preliminary results suggest a clinical role for preeclampsia prediction. However, until this role is better substantiated, their general clinical use is not currently recommended (Boucoiran, 2013; Kleinrouweler, 2012; Widmer, 2007). Automated assays are being studied, and the World Health Organization (WHO) began a multicenter trial in 2008 to evaluate these factors (Sunderji, 2009).
Cell-Free Fetal DNA
As discussed in Chapter 13 (p. 279), cell-free fetal DNA can be detected in maternal plasma. It has been reported that fetal-maternal cell trafficking is increased in pregnancies complicated by preeclampsia (Holzgreve, 1998). It is hypothesized that cell-free DNA is released by accelerated apoptosis of cytotrophoblasts (DiFederico, 1999). From their review, Conde-Agudelo and associates (2014) concluded that cell-free fetal DNA quantification is not yet useful for prediction purposes.
Proteomic, Metabolomic, and Transcriptomic Markers
Methods to study serum and urinary proteins and cellular metabolites have opened a new vista for preeclampsia prediction. Preliminary studies indicate that these may become useful (Bahado-Singh, 2013; Carty, 2011; Liu, 2013; Myers, 2013).
Various strategies used to prevent or modify preeclampsia severity have been evaluated. Some are listed in Table 40-5. In general, none of these has been found to be convincingly and reproducibly effective.
TABLE 40-5. Some Methods to Prevent Preeclampsia That Have Been Evaluated in Randomized Trials
Dietary manipulation—low-salt diet, calcium or fish oil supplementation
Exercise—physical activity, stretching
Cardiovascular drugs—diuretics, antihypertensive drugs
Antioxidants—ascorbic acid (vitamin C), α-tocopherol (vitamin E), vitamin D
Antithrombotic drugs—low-dose aspirin, aspirin/dipyridamole, aspirin + heparin, aspirin + ketanserin
Modified from Staff, 2014.
Dietary and Lifestyle Modifications
A favorite of many theorists and faddists for centuries, dietary “treatment” for preeclampsia has produced some interesting abuses as chronicled by Chesley (1978).
Low-Salt Diet. One of the earliest research efforts to prevent preeclampsia was salt restriction (De Snoo, 1937). This interdiction was followed by years of inappropriate diuretic therapy. Although these practices were discarded, it ironically was not until relatively recently that the first randomized trial was done and showed that a sodium-restricted diet was ineffective in preventing preeclampsia in 361 women (Knuist, 1998). Guidelines from the United Kingdom National Institute for Health and Clinical Excellence (2010) recommend against salt restrictions.
Calcium Supplementation. Studies performed in the 1980s outside the United States showed that women with low dietary calcium intake were at significantly increased risk for gestational hypertension (Belizan, 1980; López-Jaramillo, 1989; Marya, 1987). Calcium supplementation has been studied in several trials, including one by the National Institute of Child Health and Human Development (NICHD) that included more than 4500 nulliparous women (Levine, 1997). In one recent metaanalysis, Patrelli and coworkers (2012) reported that increased calcium intake lowered the risk for preeclampsia in high-risk women. In aggregate, most of these trials have shown that unless women are calcium deficient, supplementation has no salutary effects (Staff, 2014).
Fish Oil Supplementation. Cardioprotective fatty acids found in some fatty fishes are plentiful in diets of Scandinavians and American Eskimos. The most common dietary sources are EPA—eicosapentaenoic acid, ALA—alpha-linoleic acid, and DHA—docosahexaenoic acid. With proclamations that supplementation with these fatty acids would prevent inflammatory-mediated atherogenesis, it was not a quantum leap to posit that they might also prevent preeclampsia. Unfortunately, randomized trials conducted thus far have shown no such benefits (Makrides, 2006; Olafsdottir, 2006; Olsen, 2000; Zhou, 2012a).
Exercise. There are a few studies done to assess the protective effects of physical activity on preeclampsia. In their systematic review, Kasawara and associates (2012) reported a trend toward risk reduction with exercise. More research is needed in this area (Staff, 2014).
Because of the putative effects of sodium restriction, diuretic therapy became popular with the introduction of chlorothiazide in 1957 (Finnerty, 1958; Flowers, 1962). In their metaanalysis, Churchill and colleagues (2007) summarized nine randomized trials that included more than 7000 pregnancies. They found that women given diuretics had a decreased incidence of edema and hypertension but not of preeclampsia.
Because women with chronic hypertension are at high risk for preeclampsia, several randomized trials—only a few placebo-controlled—have been done to evaluate various antihypertensive drugs to reduce the incidence of superimposed preeclampsia. A critical analysis of these trials by Staff and coworkers (2014) failed to demonstrate salutary effects.
There are inferential data that an imbalance between oxidant and antioxidant activity may play an important role in the pathogenesis of preeclampsia (p. 747). Thus, naturally occurring antioxidants—vitamins C, D, and E—might decrease such oxidation. Indeed, women who developed preeclampsia were found to have reduced plasma levels of these antioxidants (De-Regil, 2012; Raijmakers, 2004). There have now been several randomized studies to evaluate vitamin supplementation for women at high risk for preeclampsia (Poston, 2006; Rumbold, 2006; Villar, 2007). The one by the MFMU Network included almost 10,000 low-risk nulliparas (Roberts, 2009). None of these studies showed reduced preeclampsia rates in women given vitamins C and E compared with those given placebo. The recent metaanalysis by De-Regil and colleagues (2012) likewise showed no benefits of vitamin D supplementation.
The rationale for the use of statins to prevent preeclampsia is that they stimulate hemoxygenase-1 expression that inhibits sFlt-1 release. There are preliminary animal data that statins may prevent hypertensive disorders of pregnancy. The MFMU Network plans a randomized trial to test pravastatin for this purpose (Costantine, 2013).
There are sound theoretical reasons that antithrombotic agents might reduce the incidence of preeclampsia. As discussed on page 734, the syndrome is characterized by vasospasm, endothelial cell dysfunction, and inflammation, as well as activation of platelets and the coagulation-hemostasis system. Moreover, prostaglandin imbalance(s) may be operative, and other sequelae include placental infarction and spiral artery thrombosis (Nelson, 2014).
Low-Dose Aspirin. In oral doses of 50 to 150 mg daily, aspirin effectively inhibits platelet thromboxane A2 biosynthesis but has minimal effects on vascular prostacyclin production (Wallenburg, 1986). However, clinical trials have shown limited benefits. For example, results in Table 40-6 are from the MFMU Network, and none of the outcomes shown were significantly improved. Some reports are more favorable. For example, the Paris Collaborative Group performed a metaanalysis that included 31 randomized trials involving 32,217 women (Askie, 2007). For women assigned to receive antiplatelet agents, the relative risk for development of preeclampsia, superimposed preeclampsia, preterm delivery, or any adverse pregnancy outcome was significantly decreased by 10 percent. Another review and metaanalysis reported marginal benefits for low-dose aspirin and severe preeclampsia (Roberge, 2012). A recent small Finnish multicenter trial included 152 women at high risk for preeclampsia (Villa, 2013). Although there were no benefits to low-dose aspirin, the accompanying metaanalysis reported a lowering of risk. The 2013 Task Force recommended the use of low-dose aspirin in some high-risk women to prevent preeclampsia.
TABLE 40-6. Maternal-Fetal Medicine Units Network Trial of Low-Dose Aspirin in Women at High Risk for Preeclampsia
Low-Dose Aspirin plus Heparin. In women with lupus anticoagulant, treatment with low-dose aspirin and heparin mitigates thrombotic sequelae (Chap. 59, p. 1175). Because of the high prevalence of placental thrombotic lesions found with severe preeclampsia, observational trials have been done to evaluate such treatments for affected women. Sergis and associates (2006) reviewed effects of prophylaxis with low-molecular-weight heparin plus low-dose aspirin on pregnancy outcomes in women with a history of severe early-onset preeclampsia and low-birthweight neonates. They reported better pregnancy outcomes in women given low-molecular-weight heparin plus low-dose aspirin compared with those given low-dose aspirin alone. Similar findings were reported in a trial that included 139 women with thrombophilia and a history of early-onset preeclampsia (de Vries, 2012). Despite these small trials, evidence is insufficient to recommend these regimens to prevent preeclampsia (National Institute for Health and Clinical Excellence, 2010; Staff, 2014).
Pregnancy complicated by gestational hypertension is managed based on severity, gestational age, and presence of preeclampsia. With preeclampsia, management varies with the severity of endothelial cell injury and multiorgan dysfunction.
Preeclampsia cannot always be diagnosed definitively (p. 728). Thus, the Task Force of the American College of Obstetricians and Gynecologists (2013b) recommends more frequent prenatal visits if preeclampsia is “suspected.” Increases in systolic and diastolic blood pressure can be either normal physiological changes or signs of developing pathology. Increased surveillance permits more prompt recognition of ominous changes in blood pressure, critical laboratory findings, and clinical signs and symptoms (Macdonald-Wallis, 2012).
The basic management objectives for any pregnancy complicated by preeclampsia are: (1) termination of pregnancy with the least possible trauma to mother and fetus, (2) birth of an infant who subsequently thrives, and (3) complete restoration of health to the mother. In many women with preeclampsia, especially those at or near term, all three objectives are served equally well by induction of labor. One of the most important clinical questions for successful management is precise knowledge of fetal age.
Early Diagnosis of Preeclampsia
Traditionally, the frequency of prenatal visits is increased during the third trimester, and this aids early detection of preeclampsia. Women without overt hypertension, but in whom early developing preeclampsia is suspected during routine prenatal visits, are seen more frequently. The protocol used successfully for many years at Parkland Hospital for women with new-onset diastolic blood pressures > 80 mm Hg but < 90 mm Hg or with sudden abnormal weight gain of more than 2 pounds per week includes, at minimum, return visits at 7-day intervals. Outpatient surveillance is continued unless overt hypertension, proteinuria, headache, visual disturbances, or epigastric discomfort supervene. Women with overt new-onset hypertension—either diastolic pressures ≥ 90 mm Hg or systolic pressures ≥ 140 mm Hg—are admitted to determine if the increase is due to preeclampsia, and if so, to evaluate its severity. Women with persistent severe disease are generally delivered, as discussed subsequently. Conversely, women with apparently mild disease can often be managed as outpatients, although there should be a low threshold for continued hospitalization for the nullipara, especially if there is proteinuria.
Hospitalization is considered at least initially for women with new-onset hypertension, especially if there is persistent or worsening hypertension or development of proteinuria. A systematic evaluation is instituted to include the following:
• Detailed examination, which is followed by daily scrutiny for clinical findings such as headache, visual disturbances, epigastric pain, and rapid weight gain
• Weight determined daily
• Analysis for proteinuria or urine protein:creatinine ratio on admittance and at least every 2 days thereafter
• Blood pressure readings in the sitting position with an appropriate-size cuff every 4 hours, except between 2400 and 0600 unless previous readings had become elevated
• Measurements of plasma or serum creatinine and hepatic aminotransferase levels and a hemogram that includes platelet quantification. The frequency of testing is determined by hypertension severity. Some recommend measurement of serum uric acid and lactic acid dehydrogenase levels and coagulation studies. However, the value of these tests has been called into question (Cnossen, 2006; Conde-Agudelo, 2014; Thangaratinam, 2006).
• Evaluation of fetal size and well-being and amnionic fluid volume, with either physical examination or sonography.
Goals of management include early identification of worsening preeclampsia and development of a management plan for timely delivery. If any of these observations lead to a diagnosis of severe preeclampsia as previously defined by the criteria in Table 40-2, further management is subsequently described.
Reduced physical activity throughout much of the day is likely beneficial, but as the 2013 Task Force concluded, absolute bed rest is not desirable. Ample protein and calories should be included in the diet, and sodium and fluid intake should not be limited or forced. Further management depends on: (1) preeclampsia severity, (2) gestational age, and (3) condition of the cervix.
Fortunately, many cases are sufficiently mild and near enough to term that they can be managed conservatively until labor commences spontaneously or until the cervix becomes favorable for labor induction. Complete abatement of all signs and symptoms, however, is uncommon until after delivery. Almost certainly, the underlying disease persists until delivery is accomplished.
Consideration for Delivery
Termination of pregnancy is the only cure for preeclampsia. Headache, visual disturbances, or epigastric pain are indicative that convulsions may be imminent, and oliguria is another ominous sign. Severe preeclampsia demands anticonvulsant and frequently antihypertensive therapy, followed by delivery. Treatment is identical to that described subsequently for eclampsia. The prime objectives are to forestall convulsions, to prevent intracranial hemorrhage and serious damage to other vital organs, and to deliver a healthy newborn.
When the fetus is preterm, the tendency is to temporize in the hope that a few more weeks in utero will reduce the risk of neonatal death or serious morbidity from prematurity. As discussed, such a policy certainly is justified in milder cases. Assessments of fetal well-being and placental function are performed, especially when the fetus is immature. Most recommend frequent performance of various tests to assess fetal well-being as described by the American College of Obstetricians and Gynecologists (2012a). These include the nonstress test or the biophysical profile (Chap. 17, pp. 338 and 341). Measurement of the lecithin-sphingomyelin (L/S) ratio in amnionic fluid may provide evidence of lung maturity (Chap. 34, p. 655).
With moderate or severe preeclampsia that does not improve after hospitalization, delivery is usually advisable for the welfare of both mother and fetus. This is true even when the cervix is unfavorable (Tajik, 2012). Labor induction is carried out, usually with preinduction cervical ripening from a prostaglandin or osmotic dilator (Chap. 26, p. 525). Whenever it appears that induction almost certainly will not succeed or attempts have failed, then cesarean delivery is indicated.
For a woman near term, with a soft, partially effaced cervix, even milder degrees of preeclampsia probably carry more risk to the mother and her fetus-infant than does induction of labor (Tajik, 2012). The decision to deliver late-preterm fetuses is not clear. Barton and coworkers (2009) reported excessive neonatal morbidity in women delivered before 38 weeks despite having stable, mild, nonproteinuric hypertension. The Netherlands study of 4316 newborns delivered between 340/7 and 366/7 weeks also described substantive neonatal morbidity in these cases (Langenveld, 2011). Most of these deliveries were before 36 weeks, and the higher cesarean delivery rates were associated with more respiratory complications. Conversely, one randomized trial of 756 women with mild preeclampsia supported delivery after 37 weeks (Koopmans, 2009).
Elective Cesarean Delivery
Once severe preeclampsia is diagnosed, labor induction and vaginal delivery have traditionally been considered ideal. Temporization with an immature fetus is considered subsequently. Several concerns, including an unfavorable cervix, a perceived sense of urgency because of preeclampsia severity, and a need to coordinate neonatal intensive care, have led some to advocate cesarean delivery. Alexander and colleagues (1999) reviewed 278 singleton liveborn neonates weighing 750 to 1500 g delivered of women with severe preeclampsia at Parkland Hospital. In half of the women, labor was induced, and the remainder underwent cesarean delivery without labor. Induction was successful in accomplishing vaginal delivery in a third, and it was not harmful to the very- low-birthweight infants. Alanis and associates (2008) reported similar observations. The results of a systematic review also confirmed these conclusions (Le Ray, 2009).
Hospitalization versus Outpatient Management
For women with mild to moderate stable hypertension—whether or not preeclampsia has been confirmed—surveillance is continued in the hospital, at home for some reliable patients, or in a day-care unit. At least intuitively, reduced physical activity throughout much of the day seems beneficial. Several observational studies and randomized trials have addressed the benefits of inpatient care and outpatient management.
Somewhat related, Abenhaim and coworkers (2008) reported a retrospective cohort study of 677 nonhypertensive women hospitalized for bed rest because of threatened preterm delivery. When outcomes of these women were compared with those of the general obstetrical population, bed rest was associated with a significantly reduced relative risk—RR 0.27—of developing preeclampsia. In a review of two small randomized trials totaling 106 women at high risk for preeclampsia, prophylactic bed rest for 4 to 6 hours daily at home was successful in significantly lowering the incidence of preeclampsia but not gestational hypertension (Meher, 2006).
These and other observations support the claim that restricted activity alters the underlying pathophysiology of the preeclampsia syndrome. That said, complete bed rest is not recommended by the 2013 Task Force. First, this is pragmatically unachievable because of the severe restrictions it places on otherwise well women. Also, as discussed in Chapter 52 (p. 1029), it likely also predisposes to thromboembolism (Knight, 2007).
High-Risk Pregnancy Unit
The concept of prolonged hospitalization for women with hypertension arose during the 1970s. At Parkland Hospital, an inpatient antepartum unit was established in 1973 by Dr. Peggy Whalley in large part to provide care for such women. Initial results from this unit were reported by Hauth (1976) and Gilstrap (1978) and their colleagues. Most hospitalized women have a beneficial response characterized by amelioration or improvement of hypertension. These women are not “cured,” and nearly 90 percent have recurrent hypertension before or during labor. By 2013, more than 10,000 nulliparas with mild to moderate early-onset hypertension during pregnancy had been managed successfully in this unit. Provider costs—not charges—for this relatively simple physical facility, modest nursing care, no drugs other than iron and folate supplements, and few essential laboratory tests are minimal compared with the cost of neonatal intensive care for a preterm infant. None of these women have suffered thromboembolic disease.
Home Health Care
Many clinicians believe that further hospitalization is not warranted if hypertension abates within a few days, and this has legitimized third-party payers to deny hospitalization reimbursement. Consequently, many women with mild to moderate hypertension are managed at home. Outpatient management may continue as long as preeclampsia syndrome does not worsen and fetal jeopardy is not suspected. Sedentary activity throughout the greater part of the day is recommended. These women are instructed in detail to report symptoms. Home blood pressure and urine protein monitoring or frequent evaluations by a visiting nurse may prove beneficial. Caution is exercised regarding use of certain automated home blood pressure monitors (Lo, 2002; Ostchega, 2012).
In an observational study by Barton and associates (2002), 1182 nulliparas with mild gestational hypertension—20 percent had proteinuria—were managed with home health care. Their mean gestational ages were 32 to 33 weeks at enrollment and 36 to 37 weeks at delivery. Severe preeclampsia developed in approximately 20 percent, about 3 percent developed HELLP syndrome, and two women had eclampsia. Perinatal outcomes were generally good. In approximately 20 percent, there was fetal-growth restriction, and the perinatal mortality rate was 4.2 per 1000.
Several prospective studies have been designed to compare continued hospitalization with either home health care or a day-care unit. In a pilot study from Parkland Hospital, Horsager and colleagues (1995) randomly assigned 72 nulliparas with new-onset hypertension from 27 to 37 weeks either to continued hospitalization or to outpatient care. In all of these women, proteinuria had receded to less than 500 mg per day when they were randomized. Outpatient management included daily blood pressure monitoring by the patient or her family. Weight and dipstick spot urine protein determinations were evaluated three times weekly. A home health nurse visited twice weekly, and the women were seen weekly in the clinic. Perinatal outcomes were similar in each group. The only significant difference was that women in the home care group developed severe preeclampsia significantly more frequently than hospitalized women—42 versus 25 percent.
A larger randomized trial reported by Crowther and coworkers (1992) included 218 women with mild gestational nonproteinuric hypertension. After evaluation, half remained hospitalized, whereas the other half was managed as outpatients. As shown in Table 40-7, the mean duration of hospitalization was 22.2 days for women with inpatient management compared with only 6.5 days in the home-care group. Preterm delivery before 34 and before 37 weeks was increased twofold in the outpatient group, but maternal and infant outcomes otherwise were similar.
TABLE 40-7. Randomized Clinical Trials Comparing Hospitalization versus Routine Care for Women with Mild Gestational Hypertension or Preeclampsia
Another approach, popular in European countries, is day care (Milne, 2009). This approach has been evaluated by several investigators. In the study by Tuffnell and associates (1992), 54 women with hypertension after 26 weeks’ gestation were assigned to either day care or routine outpatient management (see Table 40-7). Progression to overt preeclampsia and labor inductions were significantly increased in the routine management group. Turnbull and coworkers (2004) enrolled 395 women who were randomly assigned to either day care or inpatient management (see Table 40-7). Almost 95 percent had mild to moderate hypertension. Of enrolled women, 288 were without proteinuria, and 86 had ≥ 1+ proteinuria. There were no perinatal deaths, and none of the women developed eclampsia or HELLP syndrome. Surprisingly, costs for either scheme were not significantly different. Perhaps not surprisingly, general satisfaction favored day care.
Summary of Hospitalization versus Outpatient Management
From the above, either inpatient or close outpatient management is appropriate for a woman with mild de novo hypertension, including those with nonsevere preeclampsia. Most of these studies were carried out in academic centers with dedicated management teams. That said, the key to success is close follow-up and a conscientious patient with good home support.
Antihypertensive Therapy for Mild to Moderate Hypertension
The use of antihypertensive drugs in attempts to prolong pregnancy or modify perinatal outcomes in pregnancies complicated by various types and severities of hypertensive disorders has been of considerable interest. Treatment for women with chronic hypertension complicating pregnancy is discussed in detail in Chapter 50 (p. 1005).
Drug treatment for early mild preeclampsia has been disappointing as shown in representative randomized trials listed in Table 40-8. Sibai and colleagues (1987a) evaluated the effectiveness of labetalol and hospitalization compared with hospitalization alone in 200 nulliparas with gestational hypertension from 26 to 35 weeks’ gestation. Although women given labetalol had significantly lower mean blood pressures, there were no differences between the groups in terms of mean pregnancy prolongation, gestational age at delivery, or birthweight. The cesarean delivery rates were similar, as were the number of infants admitted to special-care nurseries. The frequency of growth-restricted infants was doubled in women given labetalol—19 versus 9 percent. The three other studies listed in Table 40-8 were performed to compare labetalol or the calcium-channel blockers, nifedipine and isradipine, with placebo. Except for fewer episodes of severe hypertension, none of these studies showed any benefits of antihypertensive treatment. Moreover, there may have been treatment-induced adverse fetal growth (Von Dadelszen, 2002).
TABLE 40-8. Randomized Placebo-Controlled Trials of Antihypertensive Therapy for Early Mild Gestational Hypertension
Abalos and associates (2007) reviewed 46 randomized trials of active antihypertensive therapy compared with either no treatment or placebo given to women with mild to moderate gestational hypertension. Except for a halving of the risk for developing severe hypertension, active antihypertensive therapy had no beneficial effects. They further reported that fetal-growth restriction was not increased in treated women. In this vein, it is also controversial whether β-blocking agents cause fetal-growth restriction if given for chronic hypertension (August, 2014; Umans, 2014). Thus, any salutary or adverse effects of antihypertensive therapy seem minimal at most.
Up through the early 1990s, it was the practice that all women with severe preeclampsia were delivered without delay. During the past 25 years, however, another approach for women with preterm severe preeclampsia has been advocated. This approach calls for “conservative” or “expectant” management with the aim of improving neonatal outcome without compromising maternal safety. Aspects of such management always include careful daily—and usually more frequent—inpatient monitoring of the mother and her fetus.
Expectant Management of Preterm Severe Preeclampsia
Theoretically, antihypertensive therapy has potential application when severe preeclampsia develops before intact neonatal survival is likely. Such management is controversial, and it may be dangerous. In one of the first studies, Sibai and the Memphis group (1985) attempted to prolong pregnancy because of fetal immaturity in 60 women with severe preeclampsia between 18 and 27 weeks. The results were disastrous. The perinatal mortality rate was 87 percent. Although no mothers died, 13 suffered placental abruption, 10 had eclampsia, three developed renal failure, two had hypertensive encephalopathy, and one each had an intracerebral hemorrhage and a ruptured hepatic hematoma.
Because of these catastrophic outcomes, the Memphis group redefined their study criteria and performed a randomized trial of expectant versus aggressive management for 95 women who had severe preeclampsia but with more advanced gestations of 28 to 32 weeks (Sibai, 1994). Women with HELLP syndrome were excluded from this trial. Aggressive management included glucocorticoid administration for fetal lung maturation followed by delivery in 48 hours. Expectantly managed women were observed at bed rest and given either labetalol or nifedipine orally if there was severe hypertension. In this study, pregnancy was prolonged for a mean of 15.4 days in the expectant management group. An overall improvement in neonatal outcomes was also reported.
Following these experiences, expectant management became more commonly practiced, but with the caveat that women with HELLP syndrome or growth-restricted fetuses were usually excluded. But in a subsequent follow-up observational study, the Memphis group compared outcomes in 133 preeclamptic women with and 136 without HELLP syndrome who presented between 24 and 36 weeks (Abramovici, 1999). Women were subdivided into three study groups. The first group included those with complete HELLP syndrome. The second group included women with partial HELLP syndrome—defined as either one or two but not all three of the defining laboratory findings. The third group included women who had severe preeclampsia without HELLP syndrome laboratory findings. Perinatal outcomes were similar in each group, and importantly, outcomes were not improved with procrastination. Despite this, the investigators concluded that women with partial HELLP syndrome and those with severe preeclampsia alone could be managed expectantly.
Sibai and Barton (2007b) reviewed expectant management of severe preeclampsia from 24 to 34 weeks. More than 1200 women were included, and although the average time gained ranged from 5 to 10 days, the maternal morbidity rates were formidable. As shown in Table 40-9, serious complications in some of these and in later studies included placental abruption, HELLP syndrome, pulmonary edema, renal failure, and eclampsia. Moreover, perinatal mortality rates averaged 90 per 1000. Fetal-growth restriction was common, and in the study from The Netherlands by Ganzevoort and associates (2005a,b), it was an astounding 94 percent. Perinatal mortality rates are disproportionately high in these growth-restricted infants, but maternal outcomes were not appreciably different from pregnancies in women without growth-restricted fetuses (Haddad, 2007; Shear, 2005).
TABLE 40-9. Maternal and Perinatal Outcomes Reported Since 2005 with Expectant Management of Severe Preeclampsia from 24 to 34 Weeks
The MEXPRE Latin Study was a multicenter trial that randomly assigned 267 women with severe preeclampsia at 28 to 32 weeks to prompt delivery or to expectant management (Vigil-De Gracia, 2013). The perinatal mortality rate approximated 9 percent in each group, and these investigators found no improvements in composite neonatal morbidity with expectant management. On the other hand, fetal-growth restriction—22 versus 9 percent—and placental abruption—7.6 versus 1.5 percent—were significantly higher in the group managed expectantly.
Barber and associates (2009) conducted a 10-year review of 3408 women with severe preeclampsia from 24 to 32 weeks. They found that increasing lengths of antepartum hospital stays were associated with slight but significantly increased rates of maternal and neonatal morbidity.
Expectant Management of Midtrimester Severe Preeclampsia
Several small studies have focused on expectant management of severe preeclampsia syndrome before 28 weeks. In their review, Bombrys and coworkers (2008) found eight such studies that included nearly 200 women with severe preeclampsia with an onset < 26 completed weeks. Maternal complications were common. Because there were no neonatal survivors in women presenting before 23 weeks, the Task Force of the American College of Obstetricians and Gynecologists (2013b) recommends pregnancy termination. For women with slightly more advanced pregnancies, however, the decision is less clear. For example, at 23 weeks’ gestation, the perinatal survival rate was 18 percent, but long-term perinatal morbidity is yet unknown. For women with pregnancies at 24 to 26 weeks, perinatal survival approached 60 percent, and it averaged almost 90 percent for those at 26 weeks.
There have been at least five studies published since 2005 of women with severe midtrimester preeclampsia who were managed expectantly (Abdel-Hady, 2010; Belghiti, 2011; Bombrys, 2008; Budden, 2006; Gaugler-Senden, 2006). Maternal complications developed in 60 percent, and there was one death. Perinatal mortality was 65 percent. At this time, there are no comparative studies attesting to the perinatal benefits of such expectant treatment versus early delivery in the face of serious maternal complications that approach 50 percent.
Glucocorticoids for Lung Maturation
In attempts to enhance fetal lung maturation, glucocorticoids have been administered to women with severe hypertension who are remote from term. Treatment does not seem to worsen maternal hypertension, and a decrease in the incidence of respiratory distress and improved fetal survival has been cited. That said, there is only one randomized trial of corticosteroids given to hypertensive women for fetal lung maturation. This trial, by Amorim and colleagues (1999), included 218 women with severe preeclampsia between 26 and 34 weeks who were randomly assigned to betamethasone or placebo administration. Neonatal complications, including respiratory distress, intraventricular hemorrhage, and death, were decreased significantly when betamethasone was given compared with placebo. On the heavily weighted negative side, there were two maternal deaths and 18 stillbirths. We add these findings to buttress our unenthusiastic acceptance of attempts to prolong gestation in many of these women (Alexander, 2014; Bloom, 2003).
Corticosteroids to Ameliorate HELLP Syndrome
Almost 30 years ago, Thiagarajah and associates (1984) suggested that glucocorticoids might aid treatment of the laboratory abnormalities associated with HELLP syndrome. Subsequently, Tompkins (1999) and O’Brien (2002) and their colleagues reported less than salutary effects. Martin and coworkers (2003) reviewed observational outcomes of almost 500 such women treated at their institution and reported salutary results with treatment. Unfortunately, their subsequent randomized trial compared two corticosteroids and did not include a nontreated group (Isler, 2001).
Since these observational studies, at least two prospective randomized trials have addressed this question. Fonseca and associates (2005) randomly assigned 132 women with HELLP syndrome to either dexamethasone or placebo administration. Outcomes assessed included duration of hospitalization, recovery time of abnormal laboratory test results, resolution of clinical parameters, and complications that included acute renal failure, pulmonary edema, eclampsia, and death. None of these was significantly different between the two groups. In another randomized study, Katz and coworkers (2008) assigned 105 postpartum women with HELLP syndrome to treatment with dexamethasone or placebo. They analyzed outcomes similar to the Fonseca study and found no advantage to dexamethasone. Shown in Figure 40-16 are recovery times for platelet counts and serum aspartate aminotransferase (AST) levels. These times were almost identical in the two groups. For these reasons, the 2013 Task Force does not recommend corticosteroid treatment for thrombocytopenia with HELLP syndrome. A caveat is that in women with dangerously low platelet counts, corticosteroids might serve to increase platelets.
FIGURE 40-16 Recovery times for platelet counts and serum aspartate aminotransferase (AST) levels in women with HELLP syndrome assigned to receive treatment with dexamethasone or placebo. (Data from Katz, 2008.)
Expectant Managment—Risks versus Benefits—Recommendations
Taken in toto, these studies do not show overwhelming benefits compared with risks for expectant management of severe preeclampsia in those with gestations from 24 to 32 weeks. The Society for Maternal-Fetal Medicine (2011) has determined that such management is a reasonable alternative in selected women with severe preeclampsia before 34 weeks. The Task Force of the American College of Obstetricians and Gynecologists (2013b) supports this recommendation. As shown in Figure 40-17, such management calls for in-hospital maternal and fetal surveillance with delivery prompted by evidence for worsening severe preeclampsia or maternal or fetal compromise. Although attempts are made for vaginal delivery in most cases, the likelihood of cesarean delivery increases with decreasing gestational age.
FIGURE 40-17 Schematic clinical management algorithm for suspected severe preeclampsia at < 34 weeks. HELLP = hemolysis, elevated liver enzyme levels, low platelet count; L&D = labor and delivery; MgSO4 = magnesium sulfate; UOP = urine output. (Adapted from the Society for Maternal-Fetal Medicine, 2011.)
Our view is more conservative. Undoubtedly, the overriding reason to terminate pregnancies with severe preeclampsia is maternal safety. There are no data to suggest that expectant management is beneficial for the mother. Indeed, it seems obvious that a delay to prolong gestation in women with severe preeclampsia may have serious maternal consequences such as those shown in Table 40-9. Notably, placental abruption develops in up to 20 percent, and pulmonary edema in as many as 4 percent. Moreover, there are substantive risks for eclampsia, cerebrovascular hemorrhage, and especially maternal death. These observations are even more pertinent when considered with the absence of convincing evidence that perinatal outcomes are markedly improved by the average prolongation of pregnancy of about 1 week. If undertaken, the caveats that mandate delivery shown in Table 40-10 should be strictly heeded.
TABLE 40-10. Indications for Delivery in Women < 34 Weeks’ Gestation Managed Expectantly
Corticosteroid Therapy for Lung Maturationa and Delivery after Maternal Stabilization:
Uncontrolled severe hypertension
Disseminated intravascular coagulation
Nonreassuring fetal status
Corticosteroid Therapy for Lung Maturation—Delay Delivery 48 hr If Possible:
Preterm ruptured membranes or labor
Thrombocytopenia < 100,000/μL
Hepatic transaminase levels twice upper limit of normal
Reversed end-diastolic Doppler flow in umbilical artery
Worsening renal dysfunction
aInitial dose only, do not delay delivery.
From the Society for Maternal-Fetal Medicine, 2011, and the Task Force of the American College of Obstetricians and Gynecologists, 2013b.
Preeclampsia complicated by generalized tonic-clonic convulsions appreciably increases the risk to both mother and fetus. Mattar and Sibai (2000) described outcomes in 399 consecutive women with eclampsia from 1977 through 1998. Major maternal complications included placental abruption—10 percent, neurological deficits—7 percent, aspiration pneumonia—7 percent, pulmonary edema—5 percent, cardiopulmonary arrest—4 percent, and acute renal failure—4 percent. Moreover, 1 percent of these women died.
European maternity units also report excessive maternal and perinatal morbidity and mortality rates with eclampsia. In a report from Scandinavia, Andersgaard and associates (2006) described 232 women with eclampsia. Although there was but a single maternal death, a third of the women experienced major complications that included HELLP syndrome, renal failure, pulmonary edema, pulmonary embolism, and stroke. The United Kingdom Obstetric Surveillance System (UKOSS) audit reported by Knight (2007) described no maternal deaths in 214 eclamptic women, but five women experienced cerebral hemorrhage. In The Netherlands, there were three maternal deaths among 222 eclamptic women (Zwart, 2008). From Dublin, Akkawi and coworkers (2009) reported four maternal deaths among 247 eclamptic women (Akkawi, 2009). Data from Australia are similar (Thornton, 2013). Thus, in developed countries, the maternal mortality rate approximates 1 percent in women with eclampsia. In perspective, this is a thousand-fold increase above the overall maternal death rates for these countries.
Almost without exception—but at times unnoticed—preeclampsia precedes the onset of eclamptic convulsions. Depending on whether convulsions appear before, during, or after labor, eclampsia is designated as antepartum, intrapartum, or postpartum. Eclampsia is most common in the last trimester and becomes increasingly frequent as term approaches. In more recent years, the incidence of postpartum eclampsia has risen. This is presumably related to improved access to prenatal care, earlier detection of preeclampsia, and prophylactic use of magnesium sulfate (Chames, 2002). Importantly, other diagnoses should be considered in women with convulsions more than 48 hours postpartum or in women with focal neurological deficits, prolonged coma, or atypical eclampsia (Sibai, 2009, 2012).
Immediate Management of Seizure
Eclamptic seizures may be violent, and the woman must be protected, especially her airway. So forceful are the muscular movements that the woman may throw herself out of her bed, and if not protected, her tongue is bitten by the violent action of the jaws (Fig. 40-18). This phase, in which the muscles alternately contract and relax, may last approximately a minute. Gradually, the muscular movements become smaller and less frequent, and finally the woman lies motionless. After a seizure, the woman is postictal, but in some, a coma of variable duration ensues. When the convulsions are infrequent, the woman usually recovers some degree of consciousness after each attack. As the woman arouses, a semiconscious combative state may ensue. In severe cases, coma persists from one convulsion to another, and death may result. In rare instances, a single convulsion may be followed by coma from which the woman may never emerge. As a rule, however, death does not occur until after frequent convulsions. Finally and also rarely, convulsions continue unabated—status epilepticus—and require deep sedation and even general anesthesia to obviate anoxic encephalopathy.
FIGURE 40-18 Hematoma of tongue from laceration during an eclamptic convulsion. Thrombocytopenia may have contributed to the bleeding.
Respirations after an eclamptic convulsion are usually increased in rate and may reach 50 or more per minute in response to hypercarbia, lactic acidemia, and transient hypoxia. Cyanosis may be observed in severe cases. High fever is a grave sign as it likely emanates from cerebrovascular hemorrhage.
Proteinuria is usually, but not always, present as discussed on page 730. Urine output may be diminished appreciably, and occasionally anuria develops. There may be hemoglobinuria, but hemoglobinemia is observed rarely. Often, as shown in Figure 40-19, peripheral and facial edema is pronounced, but it may also be absent.
FIGURE 40-19 Severe edema in a young nullipara with antepartum preeclampsia. (Photograph contributed by Dr. Nidhi Shah.)
As with severe preeclampsia, an increase in urinary output after delivery is usually an early sign of improvement. If there is renal dysfunction, serum creatinine levels should be monitored. Proteinuria and edema ordinarily disappear within a week postpartum. In most cases, blood pressure returns to normal within a few days to 2 weeks after delivery (Berks, 2009). As subsequently discussed, the longer hypertension persists postpartum and the more severe it is, the more likely it is that the woman also has chronic vascular disease (Podymow, 2010).
In antepartum eclampsia, labor may begin spontaneously shortly after convulsions ensue and may progress rapidly. If the convulsions occur during labor, contractions may increase in frequency and intensity, and the duration of labor may be shortened. Because of maternal hypoxemia and lactic acidemia caused by convulsions, it is not unusual for fetal bradycardia to follow a seizure (Fig. 40-20). Bradycardia usually recovers within 3 to 5 minutes. If it persists more than about 10 minutes, however, then another cause such as placental abruption or imminent delivery must be considered.
FIGURE 40-20 Fetal heart rate tracing shows fetal bradycardia following an intrapartum eclamptic convulsion. Bradycardia resolved and beat-to-beat variability returned approximately 5 minutes following the seizure.
Pulmonary edema may follow shortly after eclamptic convulsions or up to several hours later. This usually is caused by aspiration pneumonitis from gastric-content inhalation during vomiting that frequently accompanies convulsions. In some women, pulmonary edema may be caused by ventricular failure from increased afterload that may result from severe hypertension and further aggravated by vigorous intravenous fluid administration (Dennis, 2012b). Such pulmonary edema from ventricular failure is more common in morbidly obese women and in those with previously unappreciated chronic hypertension.
Occasionally, sudden death occurs synchronously with an eclamptic convulsion, or it follows shortly thereafter. Most often in these cases, death results from a massive cerebral hemorrhage (see Fig. 40-11). Hemiplegia may result from sublethal hemorrhage. Cerebral hemorrhages are more likely in older women with underlying chronic hypertension as discussed on page 761. Rarely, they may be due to a ruptured cerebral berry aneurysm or arteriovenous malformation (Witlin, 1997a).
In approximately 10 percent of women, some degree of blindness follows a seizure. The causes of blindness or impaired vision are discussed on page 744. Blindness with severe preeclampsia without convulsions is usually due to retinal detachment (Vigil-De Gracia, 2011). Conversely, blindness with eclampsia is almost always due to occipital lobe edema (Cunningham, 1995). In both instances, however, the prognosis for return to normal function is good and is usually complete within 1 to 2 weeks postpartum.
Up to 5 percent of women with eclampsia have substantively altered consciousness, including persistent coma, following a seizure. This is due to extensive cerebral edema, and transtentorial herniation may cause death as discussed on page 744 (Cunningham, 2000).
Rarely, eclampsia is followed by psychosis, and the woman becomes violent. This may last for several days to 2 weeks, but the prognosis for return to normal function is good, provided there was no preexisting mental illness. It is presumed to be similar to postpartum psychosis discussed in detail in Chapter 61 (p. 1210). Antipsychotic medications have proved effective in the few cases of posteclampsia psychosis treated at Parkland Hospital.
Generally, eclampsia is more likely to be diagnosed too frequently rather than overlooked. Epilepsy, encephalitis, meningitis, brain tumor, neurocysticercosis, amnionic fluid embolism, postdural puncture cephalgia, and ruptured cerebral aneurysm during late pregnancy and the puerperium may simulate eclampsia. Until other such causes are excluded, however, all pregnant women with convulsions should be considered to have eclampsia.
Management of Eclampsia
It has been long recognized that magnesium sulfate is highly effective in preventing convulsions in women with preeclampsia and in stopping them in those with eclampsia. In his review, Chesley (1978) cited observational data by Pritchard and colleagues (1955, 1975) from Parkland Hospital and from his own institution, Kings County Hospital in Brooklyn. At that time, most eclampsia regimens used in the United States adhered to a similar philosophy still in use today, the tenets of which include the following:
1. Control of convulsions using an intravenously administered loading dose of magnesium sulfate that is followed by a maintenance dose, usually intravenous, of magnesium sulfate
2. Intermittent administration of an antihypertensive medication to lower blood pressure whenever it is considered dangerously high
3. Avoidance of diuretics unless there is obvious pulmonary edema, limitation of intravenous fluid administration unless fluid loss is excessive, and avoidance of hyperosmotic agents
4. Delivery of the fetus to achieve a remission of preeclampsia.
Magnesium Sulfate to Control Convulsions
In more severe cases of preeclampsia and in eclampsia, magnesium sulfate administered parenterally is an effective anticonvulsant that avoids producing central nervous system depression in either the mother or the infant. It may be given intravenously by continuous infusion or intramuscularly by intermittent injection (Table 40-11). The dosages for severe preeclampsia are the same as for eclampsia. Because labor and delivery is a more likely time for convulsions to develop, women with preeclampsia-eclampsia usually are given magnesium sulfate during labor and for 24 hours postpartum.
TABLE 40-11. Magnesium Sulfate Dosage Schedule for Severe Preeclampsia and Eclampsia
Continuous Intravenous (IV) Infusion
Give 4- to 6-g loading dose of magnesium sulfate diluted in 100 mL of IV fluid administered over 15–20 min
Begin 2 g/hr in 100 mL of IV maintenance infusion. Some recommend 1 g/hr
Monitor for magnesium toxicity:
Assess deep tendon reflexes periodically
Some measure serum magnesium level at 4–6 hr and adjust infusion to maintain levels between 4 and 7 mEq/L (4.8 to 8.4 mg/dL)
Measure serum magnesium levels if serum creatinine ≥ 1.0 mg/dL
Magnesium sulfate is discontinued 24 hr after delivery
Intermittent Intramuscular Injections
Give 4 g of magnesium sulfate (MgSO4·7H2O USP) as a 20% solution intravenously at a rate not to exceed 1 g/min
Follow promptly with 10 g of 50% magnesium sulfate solution, one half (5 g) injected deeply in the upper outer quadrant of each buttock through a 3-inch-long 20-gauge needle. (Addition of 1.0 mL of 2% lidocaine minimizes discomfort.) If convulsions persist after 15 min, give up to 2 g more intravenously as a 20% solution at a rate not to exceed 1 g/min. If the woman is large, up to 4 g may be given slowly
Every 4 hr thereafter, give 5 g of a 50% solution of magnesium sulfate injected deeply in the upper outer quadrant of
alternate buttocks, but only after ensuring that:
The patellar reflex is present,
Respirations are not depressed, and
Urine output the previous 4 hr exceeded 100 mL
Magnesium sulfate is discontinued 24 hr after delivery
Magnesium sulfate is almost universally administered intravenously. In most units, the intramuscular route has been abandoned. Of concern, magnesium sulfate solutions, although inexpensive to prepare, are not readily available in all parts of the developing world. And even when the solutions are available, the technology to infuse them may not be. Therefore, it should not be overlooked that the drug can be administered intramuscularly and that this route is as effective as intravenous administration (Salinger, 2013). In two reports from India, intramuscular regimens were nearly equivalent in preventing recurrent convulsions and maternal deaths in women with eclampsia (Chowdhury, 2009; Jana, 2013). These observations comport with earlier ones from Parkland Hospital as described by Pritchard and colleagues (1975, 1984).
Magnesium sulfate is not given to treat hypertension. Based on several studies cited subsequently and extensive clinical observations, magnesium most likely exerts a specific anticonvulsant action on the cerebral cortex. Typically, the mother stops convulsing after the initial 4-g loading dose. By an hour or two, she regains consciousness sufficiently to be oriented to place and time.
The magnesium sulfate dosages presented in Table 40-11 usually result in plasma magnesium levels illustrated in Figure 40-21. When magnesium sulfate is given to arrest eclamptic seizures, 10 to 15 percent of women will have a subsequent convulsion. If so, an additional 2-g dose of magnesium sulfate in a 20-percent solution is slowly administered intravenously. In a small woman, this additional 2-g dose may be used once, but it can be given twice if needed in a larger woman. In only 5 of 245 women with eclampsia at Parkland Hospital was it necessary to use supplementary anticonvulsant medication to control convulsions (Pritchard, 1984). For these, an intravenous barbiturate is given slowly. Midazolam or lorazepam may be given in a small single dose, but prolonged use is avoided because it is associated with a higher mortality rate (Royal College of Obstetricians and Gynaecologists, 2006).
FIGURE 40-21 Comparison of serum magnesium levels in mEq/L following a 4-g intravenous loading dose of magnesium sulfate and then maintained by either an intramuscular or continuing infusion. Multiply by 1.2 to convert mEq/L to mg/dL. (Data from Sibai, 1984.)
Maintenance magnesium sulfate therapy is continued for 24 hours after delivery. For eclampsia that develops postpartum, magnesium sulfate is administered for 24 hours after the onset of convulsions. Ehrenberg and Mercer (2006) studied abbreviated postpartum magnesium administration in 200 women with mild preeclampsia. Of 101 women randomized to 12-hour treatment, seven had worsening preeclampsia, and treatment was extended to 24 hours. None of these 101 women and none of the other cohort of 95 given the 24-hour magnesium infusion developed eclampsia. This abbreviated regimen needs further study before being routinely administered for severe preeclampsia or eclampsia.
Pharmacology and Toxicology. Magnesium sulfate USP is MgSO4·7H2O and not simple MgSO4. It contains 8.12 mEq per 1 g. Parenterally administered magnesium is cleared almost totally by renal excretion, and magnesium intoxication is unusual when the glomerular filtration rate is normal or only slightly decreased. Adequate urine output usually correlates with preserved glomerular filtration rates. That said, magnesium excretion is not urine flow dependent, and urinary volume per unit time does not, per se, predict renal function. Thus, serum creatinine levels must be measured to detect a decreased glomerular filtration rate.
Eclamptic convulsions are almost always prevented or arrested by plasma magnesium levels maintained at 4 to 7 mEq/L, 4.8 to 8.4 mg/dL, or 2.0 to 3.5 mmol/L. Although laboratories typically report totalmagnesium levels, free or ionized magnesium is the active moiety for suppressing neuronal excitability. Taber and associates (2002) found poor correlation between total and ionized levels. Further studies are necessary to determine if either measurement provides a superior method for surveillance.
After a 4-g intravenous loading dose in nonobese women, magnesium levels observed with the intramuscular regimen and those observed with the maintenance infusion of 2 g/hr are similar (see Fig. 40-21). The obesity epidemic has affected these observations. Tudela and colleagues (2013) reported our observations from Parkland Hospital with magnesium administration to obese women. More than 60 percent of women whose body mass index (BMI) exceeded 30 kg/m2 and who were receiving the 2-g/hr dose had subtherapeutic levels at 4 hours. Thus, 40 percent of obese women would require 3 g/hr to maintain effective plasma levels. That said, currently most do not recommend routine magnesium level measurements (American College of Obstetricians and Gynecologists, 2013b; Royal College of Obstetricians and Gynaecologists, 2006).
Patellar reflexes disappear when the plasma magnesium level reaches 10 mEq/L—about 12 mg/dL—presumably because of a curariform action. This sign serves to warn of impending magnesium toxicity. When plasma levels rise above 10 mEq/L, breathing becomes weakened. At 12 mEq/L or higher levels, respiratory paralysis and respiratory arrest follow. Somjen and coworkers (1966) induced marked hypermagnesemia in themselves by intravenous infusion and achieved plasma levels up to 15 mEq/L. Predictably, at such high plasma levels, respiratory depression developed that necessitated mechanical ventilation, but depression of the sensorium was not dramatic as long as hypoxia was prevented.
Treatment with calcium gluconate or calcium chloride, 1 g intravenously, along with withholding further magnesium sulfate, usually reverses mild to moderate respiratory depression. One of these agents should be readily available whenever magnesium is being infused. Unfortunately, the effects of intravenously administered calcium may be short-lived if there is a steady-state toxic level. For severe respiratory depression and arrest, prompt tracheal intubation and mechanical ventilation are lifesaving. Direct toxic effects on the myocardium from high levels of magnesium are uncommon. It appears that cardiac dysfunction associated with magnesium is due to respiratory arrest and hypoxia. With appropriate ventilation, cardiac action is satisfactory even when plasma magnesium levels are exceedingly high (McCubbin, 1981; Morisaki, 2000).
Because magnesium is cleared almost exclusively by renal excretion, the dosages described will become excessive if glomerular filtration is substantially decreased. The initial 4-g loading dose of magnesium sulfate can be safely administered regardless of renal function. It is important to administer the standard loading dose and not to reduce it under the mistaken conception that diminished renal function requires it. This is because after distribution, a loading dose achieves the desired therapeutic level, and the infusion maintains the steady-state level. Thus, only the maintenance infusion rate should be altered with diminished glomerular filtration rate. Renal function is estimated by measuring plasma creatinine. Whenever plasma creatinine levels are > 1.0 mg/mL, serum magnesium levels are measured to guide the infusion rate. With severe renal dysfunction, only the loading dose of magnesium sulfate is required to produce a steady-state therapeutic level.
Acute cardiovascular effects of parenteral magnesium in women with severe preeclampsia have been studied using data obtained by pulmonary and radial artery catheterization. After a 4-g intravenous dose administered over 15 minutes, mean arterial pressure fell slightly, accompanied by a 13-percent increase in cardiac index (Cotton, 1986b). Thus, magnesium decreased systemic vascular resistance and mean arterial pressure. At the same time, it increased cardiac output without evidence of myocardial depression. These findings were coincidental with transient nausea and flushing, and the cardiovascular effects persisted for only 15 minutes despite continued magnesium infusion.
Thurnau and associates (1987) showed that there was a small but highly significant increase in total magnesium concentration in the cerebrospinal fluid with magnesium therapy. The magnitude of the increase was directly proportional to the corresponding serum concentration.
Magnesium is anticonvulsant and neuroprotective in several animal models. Some proposed mechanisms of action include: (1) reduced presynaptic release of the neurotransmitter glutamate, (2) blockade of glutamatergic N-methyl-D-aspartate (NMDA) receptors, (3) potentiation of adenosine action, (4) improved calcium buffering by mitochondria, and (5) blockage of calcium entry via voltage-gated channels (Arango, 2006; Wang, 2012a).
Uterine Effects. Relatively high serum magnesium concentrations depress myometrial contractility both in vivo and in vitro. With the regimen described and the plasma levels that result, no evidence of myometrial depression has been observed beyond a transient decrease in activity during and immediately after the initial intravenous loading dose. Leveno and associates (1998) compared outcomes in 480 nulliparous women given phenytoin for preeclampsia with outcomes in 425 preeclamptic women given magnesium sulfate. Magnesium did not significantly alter the need for oxytocin stimulation of labor, admission-to-delivery intervals, or route of delivery. Similar results have been reported by others (Atkinson, 1995; Szal, 1999; Witlin, 1997b).
The mechanisms by which magnesium might inhibit uterine contractility are not established. It is generally assumed, however, that these depend on its effects on intracellular calcium as discussed in detail in Chapter 21 (p. 417). Inhibition of uterine contractility is magnesium dose dependent, and serum levels of at least 8 to 10 mEq/L are necessary to inhibit uterine contractions (Watt-Morse, 1995). This likely explains why there are few if any uterine effects seen clinically when magnesium sulfate is given for preeclampsia. And as discussed in Chapter 42 (p. 852), magnesium is also not considered to be an effective tocolytic agent.
Fetal and Neonatal Effects. Magnesium administered parenterally promptly crosses the placenta to achieve equilibrium in fetal serum and less so in amnionic fluid (Hallak, 1993). Levels in amnionic fluid increase with duration of maternal infusion (Gortzak-Uzen, 2005). Current evidence supports the view that magnesium sulfate has small but significant effects on the fetal heart rate pattern—specifically beat-to-beat variability. Hallak and coworkers (1999) compared an infusion of magnesium sulfate with a saline infusion. These investigators reported that magnesium was associated with a small and clinically insignificant decrease in variability. Similarly, in a retrospective study, Duffy and associates (2012) reported a lower heart rate baseline that was within the normal range; decreased variability; and fewer prolonged decelerations. They noted no adverse outcomes.
Overall, maternal magnesium therapy appears safe for perinates. For example, a recent MFMU Network study of more than 1500 exposed preterm neonates found no association between the need for neonatal resuscitation and cord blood magnesium levels (Johnson, 2012). Still, there are a few neonatal adverse events associated with its use. In a Parkland Hospital study of 6654 mostly term exposed newborns, 6 percent had hypotonia (Abbassi-Ghanavati, 2012). In addition, exposed neonates had lower 1- and 5-minute Apgar scores, a higher intubation rate, and more admissions to the special care nursery. The study showed that neonatal depression occurs only if there is severehypermagnesemia at delivery.
Observational studies have suggested a protective effect of magnesium against the development of cerebral palsy in very-low-birthweight infants (Nelson, 1995; Schendel, 1996). At least five randomized trials have also assessed neuroprotective effects in preterm newborns. These findings are discussed in detail in Chapter 42 (p. 854). Nguyen and colleagues (2013) expanded this possibility to include term newborn neuroprotection. They performed a Cochrane Database review to compare term neonatal outcomes with and without exposure to peripartum magnesium therapy and reported that there were insufficient data to draw conclusions.
Finally, as discussed in Chapter 42 (p. 852), long-term use of magnesium, given for several days for tocolysis, has been associated with neonatal osteopenia (American College of Obstetricians and Gynecologists, 2013c).
Maternal Safety and Efficacy of Magnesium Sulfate. The multinational Eclampsia Trial Collaborative Group study (1995) involved 1687 women with eclampsia randomly allocated to different anticonvulsant regimens. In one cohort, 453 women were randomly assigned to be given magnesium sulfate and compared with 452 given diazepam. In a second cohort, 388 eclamptic women were randomly assigned to be given magnesium sulfate and compared with 387 women given phenytoin. The results of these and other comparative studies that each enrolled at least 50 women are summarized in Table 40-12. In aggregate, magnesium sulfate therapy was associated with a significantly lower incidence of recurrent seizures compared with women given an alternative anticonvulsant—9.7 versus 23 percent. Importantly, the maternal death rate of 3.1 percent with magnesium sulfate was significantly lower than that of 4.9 percent for the other regimens.
TABLE 40-12. Randomized Comparative Trials of Magnesium Sulfate with Another Anticonvulsant to Prevent Recurrent Eclamptic Convulsions
Magnesium safety and toxicity was recently reviewed by Smith and coworkers (2013). In more than 9500 treated women, the overall rate of absent patellar tendon reflexes was 1.6 percent; respiratory depression 1.3 percent; and calcium gluconate administration 0.2 percent. They reported only one maternal death due to magnesium toxicity. Our anecdotal experiences are similar—in the estimated 50 years of its use in more than 40,000 women, there has been only one maternal death from an overdose (Pritchard, 1984).
Management of Severe Hypertension
Dangerous hypertension can cause cerebrovascular hemorrhage and hypertensive encephalopathy, and it can trigger eclamptic convulsions in women with preeclampsia. Other complications include hypertensive afterload congestive heart failure and placental abruption (Clark, 2012).
Because of these sequelae, the National High Blood Pressure Education Program Working Group (2000) and the 2013 Task Force recommend treatment to lower systolic pressures to or below 160 mm Hg and diastolic pressures to or below 110 mm Hg. Martin and associates (2005) reported provocative observations that highlight the importance of treating systolic hypertension. They described 28 selected women with severe preeclampsia who suffered an associated stroke. Most of these were hemorrhagic strokes—93 percent—and all women had systolic pressures > 160 mm Hg before suffering their stroke. By contrast, only 20 percent of these same women had diastolic pressures > 110 mm Hg. It seems likely that at least half of serious hemorrhagic strokes associated with preeclampsia are in women with chronic hypertension (Cunningham, 2005). Long-standing hypertension results in development of Charcot-Bouchard aneurysms in the deep penetrating arteries of the lenticulostriate branch of the middle cerebral arteries. These vessels supply the basal ganglia, putamen, thalamus, and adjacent deep white matter, as well as the pons and deep cerebellum. These unique aneurysmal weakenings predispose these small arteries to rupture during sudden hypertensive episodes (Chap. 50, p. 1007).
Several drugs are available to rapidly lower dangerously elevated blood pressure in women with the gestational hypertensive disorders. The three most commonly employed are hydralazine, labetalol, and nifedipine. For years, parenteral hydralazine was the only one of these three available. But when parenteral labetalol was later introduced, it was considered to be equally effective for obstetrical use. Orally administered nifedipine has since then gained some popularity as first-line treatment for severe gestational hypertension.
This is probably still the most commonly used antihypertensive agent in the United States for treatment of women with severe gestational hypertension. Hydralazine is administered intravenously with a 5-mg initial dose, and this is followed by 5- to 10-mg doses at 15- to 20-minute intervals until a satisfactory response is achieved (American College of Obstetricians and Gynecologists, 2012b). Some limit the total dose to 30 mg per treatment cycle (Sibai, 2003). The target response antepartum or intrapartum is a decrease in diastolic blood pressure to 90 to 110 mm Hg. Lower diastolic pressures risk compromised placental perfusion. Hydralazine has proven remarkably effective to prevent cerebral hemorrhage. Its onset of action can be as rapid as 10 minutes. Although repeated administration every 15 to 20 minutes may theoretically lead to undesirable hypotension, this has not been our experience when given in these 5- to 10-mg increments.
At Parkland Hospital, between 5 and 10 percent of all women with intrapartum hypertensive disorders are given a parenteral antihypertensive agent. Most often, we use hydralazine as described. We do not limit the total dose, and seldom has a second antihypertensive agent been needed. We estimate that nearly 6000 women have been so treated at Parkland during the past 50 years. Although less popular in Europe, hydralazine is used in some centers, according to the Royal College of Obstetricians and Gynaecologists (2006). A dissenting opinion for first-line intrapartum use of hydralazine was voiced by the Vancouver group after a systematic review (Magee, 2009). At the same time, however, Umans and coworkers (2014) concluded that objective outcome data did not support the use of one drug over another.
As with any antihypertensive agent, the tendency to give a larger initial dose of hydralazine if the blood pressure is higher must be avoided. The response to even 5- to 10-mg doses cannot be predicted by hypertension severity. Thus, our protocol is to always administer 5 mg as the initial dose. An adverse response to exceeding this initial dose is shown in Figure 40-22. This woman had chronic hypertension complicated by severe superimposed preeclampsia, and hydralazine was injected more frequently than recommended. Her blood pressure decreased in less than 1 hour from 240–270/130–150 mm Hg to 110/80 mm Hg, and fetal heart rate decelerations characteristic of uteroplacental insufficiency became evident. Decelerations persisted until her blood pressure was increased with rapid crystalloid infusion. In some cases, this fetal response to diminished uterine perfusion may be confused with placental abruption and may result in unnecessary and potentially dangerous emergent cesarean delivery.
FIGURE 40-22 Hydralazine was given at 5-minute intervals instead of 15-minute intervals. The mean arterial pressure decreased from 180 to 90 mm Hg within 1 hour and was associated with fetal bradycardia. Rapid crystalloid infusion raised the mean pressure to 115 mm Hg, and the fetus recovered.
This effective intravenous antihypertensive agent is an α1- and nonselective β-blocker. Some prefer its use over hydralazine because of fewer side effects (Sibai, 2003). At Parkland Hospital, we give 10 mg intravenously initially. If the blood pressure has not decreased to the desirable level in 10 minutes, then 20 mg is given. The next 10-minute incremental dose is 40 mg and is followed by another 40 mg if needed. If a salutary response is not achieved, then an 80-mg dose is given. Sibai (2003) recommends 20 to 40 mg every 10 to 15 minutes as needed and a maximum dose of 220 mg per treatment cycle. The American College of Obstetricians and Gynecologists (2012b) recommends starting with a 20-mg intravenous bolus. If not effective within 10 minutes, this is followed by 40 mg, then 80 mg every 10 minutes. Administration should not exceed a 220-mg total dose per treatment cycle.
Hydralazine versus Labetalol
Comparative studies of these two antihypertensive agents show equivalent results (Umans, 2014). In an older trial, Mabie and colleagues (1987) compared intravenous hydralazine with labetalol for blood pressure control in 60 peripartum women. Labetalol lowered blood pressure more rapidly, and associated tachycardia was minimal. However, hydralazine lowered mean arterial pressures to safe levels more effectively. In a later trial, Vigil-De Gracia and associates (2007) randomly assigned 200 severely hypertensive women intrapartum to be given either: (1) intravenous hydralazine—5 mg, which could be given every 20 minutes and repeated to a maximum of five doses, or (2) intravenous labetalol—20 mg initially, followed by 40 mg in 20 minutes and then 80 mg every 20 minutes if needed up to a maximum 300-mg dose. Maternal and neonatal outcomes were similar. Hydralazine caused significantly more maternal tachycardia and palpitations, whereas labetalol more frequently caused maternal hypotension and bradycardia. Both drugs have been associated with a reduced frequency of fetal heart rate accelerations (Cahill, 2013).
This calcium-channel blocking agent has become popular because of its efficacy for control of acute pregnancy-related hypertension. The NHBPEP Working Group (2000) and the Royal College of Obstetricians and Gynaecologists (2006) recommend a 10-mg initial oral dose to be repeated in 30 minutes if necessary. Nifedipine given sublingually is no longer recommended. Randomized trials that compared nifedipine with labetalol found neither drug definitively superior to the other. However, nifedipine lowered blood pressure more quickly (Scardo, 1999; Shekhar, 2013; Vermillion, 1999).
Other Antihypertensive Agents
A few other generally available antihypertensive agents have been tested in clinical trials but are not widely used (Umans, 2014). Belfort and associates (1990) administered the calcium antagonist verapamilby intravenous infusion at 5 to 10 mg per hour. Mean arterial pressure was lowered by 20 percent. Belfort and coworkers (1996, 2003) reported that nimodipine given either by continuous infusion or orally was effective to lower blood pressure in women with severe preeclampsia. Bolte and colleagues (1998, 2001) reported good results in preeclamptic women given intravenous ketanserin, a selective serotonergic (5HT2A) receptor blocker. Nitroprusside or nitroglycerine is recommended by some if there is not optimal response to first-line agents. With these latter two agents, fetal cyanide toxicity may develop after 4 hours. We have not had the need for either due to our consistent success with first-line treatment using hydralazine, labetalol, or a combination of the two given in succession, but never simultaneously.
There are experimental antihypertensive drugs that may become useful for preeclampsia treatment. One is calcitonin gene related peptide (CGRP), a 37-amino acid potent vasodilator. Another is antidigoxin antibody Fab (DIF)directed against endogenous digitalis-like factors, also called cardiotonic steroids (Bagrov, 2008; Lam, 2013).
Potent loop diuretics can further compromise placental perfusion. Immediate effects include depletion of intravascular volume, which most often is already reduced compared with that of normal pregnancy (p. 737). Therefore, before delivery, diuretics are not used to lower blood pressure (Zeeman, 2009; Zondervan, 1988). We limit antepartum use of furosemide or similar drugs solely to treatment of pulmonary edema.
Lactated Ringer solution is administered routinely at the rate of 60 mL to no more than 125 mL per hour unless there is unusual fluid loss from vomiting, diarrhea, or diaphoresis, or, more likely, excessive blood loss with delivery. Oliguria is common with severe preeclampsia. Thus, coupled with the knowledge that maternal blood volume is likely constricted compared with that of normal pregnancy, it is tempting to administer intravenous fluids more vigorously. But controlled, conservative fluid administration is preferred for the typical woman with severe preeclampsia who already has excessive extracellular fluid that is inappropriately distributed between intravascular and extravascular spaces. As discussed on page 737, infusion of large fluid volumes enhances the maldistribution of extravascular fluid and thereby appreciably increases the risk of pulmonary and cerebral edema (Dennis, 2012a; Sciscione, 2003; Zinaman, 1985). For labor analgesia with neuraxial analgesia, crystalloid solutions are infused slowly in graded amounts (Chap. 25, p. 516).
Women with severe preeclampsia-eclampsia who develop pulmonary edema most often do so postpartum (Cunningham, 1986, 2012; Zinaman, 1985). With pulmonary edema in the eclamptic woman, aspiration of gastric contents, which may be the result of convulsions, anesthesia, or oversedation, should be excluded. As discussed in Chapter 47 (p. 942), there are three common causes of pulmonary edema in women with severe preeclampsia syndrome—pulmonary capillary permeability edema, cardiogenic edema, or a combination of the two.
Some women with severe preeclampsia—especially if given vigorous fluid replacement—will have mild pulmonary congestion from permeability edema (see Fig. 40-6). This is caused by normal pregnancy changes magnified by the preeclampsia syndrome as discussed in Chapter 4 (p. 58). Importantly, plasma oncotic pressure decreases appreciably in normal term pregnancy because of decreased serum albumin concentration, and oncotic pressure falls even more with preeclampsia (Zinaman, 1985). And both increased extravascular fluid oncotic pressure and increased capillary permeability have been described in women with preeclampsia (Brown, 1989; Øian, 1986).
Invasive Hemodynamic Monitoring
Knowledge concerning cardiovascular and hemodynamic pathophysiological alterations associated with severe preeclampsia-eclampsia has accrued from studies done using invasive monitoring and a flow-directed pulmonary artery catheter (see Figs. 40-5 and 40-6). Clark and Dildy (2010) have reviewed such monitoring in obstetrics. Two conditions frequently cited as indications are preeclampsia associated with either oliguria or pulmonary edema. Somewhat ironically, it is usually vigorous treatment of the former that results in most cases of the latter. The American College of Obstetricians and Gynecologists (2013a) recommends against routine invasive monitoring. The College notes that such monitoring should be reserved for severely preeclamptic women with accompanying severe cardiac disease, renal disease, or both or in cases of refractory hypertension, oliguria, and pulmonary edema. An alternative noninvasive hemodynamic monitoring strategy has been evaluated in preliminary studies (Moroz, 2013).
Plasma Volume Expansion
Because the preeclampsia syndrome is associated with hemoconcentration, attempts to expand blood volume seem intuitively reasonable (Ganzevoort, 2004). This has led some to infuse various fluids, starch polymers, albumin concentrates, or combinations thereof to expand blood volume. There are, however, older observational studies that describe serious complications—especially pulmonary edema—with volume expansion (Benedetti, 1985; López-Llera, 1982; Sibai, 1987b). In general, these studies were not controlled or even comparative (Habek, 2006).
The Amsterdam randomized study reported by Ganzevoort and coworkers (2005a,b) was a well-designed investigation done to evaluate volume expansion. A total of 216 women with severe preeclampsia were enrolled between 24 and 34 weeks’ gestation. The study included women whose preeclampsia was complicated by HELLP syndrome, eclampsia, or fetal-growth restriction. All women were given magnesium sulfate to prevent eclampsia, betamethasone to promote fetal pulmonary maturity, ketanserine to control dangerous hypertension, and normal saline infusions restricted only to deliver medications. In the group randomly assigned to volume expansion, each woman was given 250 mL of 6-percent hydroxyethyl starch infused over 4 hours twice daily. Their maternal and perinatal outcomes were compared with a control group and are shown in Table 40-13. None of these outcomes was significantly different between the two groups. Importantly, serious maternal morbidity and a substantive perinatal mortality rate accompanied their “expectant” management (see Table 40-9).
TABLE 40-13. Maternal and Perinatal Outcomes in a Randomized Trial of Plasma Volume Expansion versus Saline Infusion in 216 Women with Severe Preeclampsia between 24 and 34 Weeks
Neuroprophylaxis—Prevention of Seizures
There have been several randomized trials designed to test the efficacy of seizure prophylaxis for women with gestational hypertension, with or without proteinuria. In most of these, magnesium sulfate was compared with another anticonvulsant or with a placebo. In all studies, magnesium sulfate was reported to be superior to the comparator agent to prevent eclampsia. Four of the larger studies are summarized in Table 40-14. In the study from Parkland Hospital, Lucas and colleagues (1995) reported that magnesium sulfate therapy was superior to phenytoin to prevent eclamptic seizures in women with gestational hypertension and preeclampsia. Belfort and coworkers (2003) compared magnesium sulfate and nimodipine—a calcium-channel blocker with specific cerebral vasodilator activity—for eclampsia prevention. In this unblinded randomized trial involving 1650 women with severe preeclampsia, the rate of eclampsia was more than threefold higher for women allocated to the nimodipine group—2.6 versus 0.8 percent.
TABLE 40-14. Randomized Comparative Trials of Prophylaxis with Magnesium Sulfate and Placebo or Another Anticonvulsant in Women with Gestational Hypertension
The largest comparative study was the entitled MAGnesium Sulfate for Prevention of Eclampsia and reported by the Magpie Trial Collaboration Group (2002). More than 10,000 women with severe preeclampsia from 33 countries were randomly allocated to treatment with magnesium sulfate or placebo. Women given magnesium had a 58-percent significantly lower risk of eclampsia than those given placebo. Smyth and associates (2009) provided follow-up data of infants born to these mothers given magnesium sulfate. At approximately 18 months, child behavior did not differ in those exposed compared with those not exposed to magnesium sulfate.
Who Should Be Given Magnesium Sulfate?
Magnesium will prevent proportionately more seizures in women with correspondingly worse disease. As previously discussed, however, severity is difficult to quantify, and thus it is difficult to decide which individual woman might benefit most from neuroprophylaxis. The 2013 Task Force recommends that women with either eclampsia or severe preeclampsia should be given magnesium sulfate prophylaxis. Again, criteria that establish “severity” are not totally uniform (see Table 40-2). At the same time, however, the 2013 Task Force suggests that all women with “mild” preeclampsia do not need magnesium sulfate neuroprophylaxis. The conundrum is whether or not to give neuroprophylaxis to any of these women with “nonsevere” gestational hypertension or preeclampsia (Alexander, 2006).
In many other countries, and principally following dissemination of the Magpie Trial Collaboration Group (2002) study results, magnesium sulfate is now recommended for women with severe preeclampsia. In some, however, debate continues concerning whether therapy should be reserved for women who have an eclamptic seizure. We are of the opinion that eclamptic seizures are dangerous for reasons discussed on page 742. Maternal mortality rates of up to 5 percent have been reported even in recent studies (Andersgaard, 2006; Benhamou, 2009; Moodley, 2010; Schutte, 2008; Zwart, 2008). Moreover, there are substantially increased perinatal mortality rates in both industrialized countries and underdeveloped ones (Abd El Aal, 2012; Knight, 2007; Ndaboine, 2012; Schutte, 2008; von Dadelszen, 2012). Finally, the possibility of adverse long-term neuropsychological and vision-related sequelae of eclampsia described by Aukes (2009, 2012), Postma (2009), Wiegman (2012), and their coworkers, which are discussed on page 770, have raised additional concerns that eclamptic seizures are not “benign.”
Selective versus Universal Magnesium Sulfate Prophylaxis
There is uncertainty around which women with nonsevere gestational hypertension should be given magnesium sulfate neuroprophylaxis. An opportunity to address these questions was afforded by a change in our prophylaxis protocol for women delivering at Parkland Hospital. Before this time, Lucas and associates (1995) had found that the risk of eclampsia without magnesium prophylaxis was approximately 1 in 100 for women with mild preeclampsia. Up until 2000, all women with gestational hypertension were given magnesium prophylaxis intramuscularly as first described by Pritchard in 1955. After 2000, we instituted a standardized protocol for intravenously administered magnesium sulfate (Alexander, 2006). At the same time, we also changed our practice of universal seizure prophylaxis for all women with gestational hypertension to one of selective prophylaxis given only to women who met our criteria for severe gestational hypertension. These criteria, shown in Table 40-15, included women with ≥ 2+ proteinuria measured by dipstick in a catheterized urine specimen.
TABLE 40-15. Selective versus Universal Magnesium Sulfate Prophylaxis: Parkland Hospital Criteria to Define Severity of Gestational Hypertension
In a woman with new-onset proteinuric hypertension, at least one of the following criteria is required:
Systolic BP ≥ 160 or diastolic BP ≥ 110 mm Hg
Proteinuria ≥ 2+ by dipstick in a catheterized urine specimen
Serum creatinine > 1.2 mg/dL
Platelet count < 100,000/μL
Aspartate aminotransferase (AST) elevated two times above upper limit of normal range
Persistent headache or scotomata
Persistent midepigastric or right-upper quadrant pain
BP = blood pressure.
Criteria based on those from National High Blood Pressure Education Program Working Group, 2000; American College of Obstetricians and Gynecologists, 2012b; cited by Alexander, 2006.
Following this protocol change, 60 percent of 6518 women with gestational hypertension during a 4½-year period were given magnesium sulfate neuroprophylaxis (Table 40-16). The remaining 40 percent with nonsevere hypertension were not treated, and of these, 27 women developed eclamptic seizures—1 in 92. The seizure rate was only 1 in 358 for 3935 women with criteria for severe disease who were given magnesium sulfate, and thus these cases were treatment failures. To assess morbidity, outcomes in 87 eclamptic women were compared with outcomes in all 6431 noneclamptic hypertensive women. Although most maternal outcomes were similar, almost a fourth of women with eclampsia who underwent emergent cesarean delivery required general anesthesia. This is a great concern because eclamptic women have laryngotracheal edema and are at a higher risk for failed intubation, gastric acid aspiration, and death (American College of Obstetricians and Gynecologists, 2013d). Neonatal outcomes were also a concern because the composite morbidity defined in Table 40-16 was significantly increased tenfold in eclamptic compared with noneclamptic women—12 versus 1 percent, respectively.
TABLE 40-16. Selected Pregnancy Outcomes in 6518 Women with Gestational Hypertension According to Whether They Developed Eclampsia
Thus, if one uses the Parkland criteria for nonsevere gestational hypertension, about 1 of 100 such women who are not given magnesium sulfate prophylaxis can be expected to have an eclamptic seizure. A fourth of these women likely will require emergent cesarean delivery with attendant maternal and perinatal morbidity and mortality from general anesthesia. From this, the major question regarding management of nonsevere gestational hypertension remains—whether it is acceptable to avoid unnecessary treatment of 99 women to risk eclampsia in one? The answer appears to be yes as suggested by the 2013 Task Force.
To avoid maternal risks from cesarean delivery, steps to effect vaginal delivery are used initially in women with eclampsia. Following a seizure, labor often ensues spontaneously or can be induced successfully even in women remote from term (Alanis, 2008). An immediate cure does not promptly follow delivery by any route, but serious morbidity is less common during the puerperium in women delivered vaginally.
Blood Loss at Delivery
Hemoconcentration or lack of normal pregnancy-induced hypervolemia is an almost predictable feature of severe preeclampsia-eclampsia as quantified by Zeeman and associates (2009) and shown in Figure 40-7. These women, who consequently lack normal pregnancy hypervolemia, are much less tolerant of even normal blood loss than are normotensive pregnant women. It is of great importance to recognize that an appreciable fall in blood pressure soon after delivery most often means excessive blood loss and not sudden resolution of vasospasm and endothelial damage. When oliguria follows delivery, the hematocrit should be evaluated frequently to help detect excessive blood loss. If identified, hemorrhage should be treated appropriately by careful crystalloid and blood transfusion.
Analgesia and Anesthesia
During the past 20 years, the use of conduction analgesia for women with preeclampsia syndrome has proven ideal. Initial problems with this method included hypotension and diminished uterine perfusion caused by sympathetic blockade in these women with attenuated hypervolemia. But pulmonary edema was mitigated by techniques that used slow induction of epidural analgesia with dilute solutions of anesthetic agents to counter the need for rapid infusion of large volumes of crystalloid or colloid to correct maternal hypotension (Hogg, 1999; Wallace, 1995). Moreover, epidural blockade avoids general anesthesia, in which the stimulation of tracheal intubation may cause sudden severe hypertension. Such blood pressure increases, in turn, can cause pulmonary edema, cerebral edema, or intracranial hemorrhage. Finally, tracheal intubation may be particularly difficult and thus hazardous in women with airway edema due to preeclampsia (American College of Obstetricians and Gynecologists, 2013d).
At least three randomized studies have been performed to evaluate these methods of analgesia and anesthesia. Wallace and colleagues (1995) studied 80 women at Parkland Hospital with severe preeclampsia who were to undergo cesarean delivery. They had not been given labor epidural analgesia and were randomized to receive general anesthesia, epidural analgesia, or combined spinal-epidural analgesia. Their average preoperative blood pressures approximated 170/110 mm Hg, and all had proteinuria. Anesthetic and obstetrical management included antihypertensive drug therapy and limited intravenous fluids as previously described. Perinatal outcomes in each group were similar. Maternal hypotension resulting from regional analgesia was managed with judicious intravenous fluid administration. In women undergoing general anesthesia, maternal blood pressure was managed to avoid severe hypertension (Fig. 40-23). There were no serious maternal or fetal complications attributable to any of the three anesthetic methods. It was concluded that all three are acceptable for use in women with pregnancies complicated by severe preeclampsia if steps are taken to ensure a careful approach to the selected method.
FIGURE 40-23 Blood pressure effects of general anesthesia versus epidural or spinal–epidural analgesia for cesarean delivery in 80 women with severe preeclampsia. MAP = mean arterial pressure. Time posts (T): OR = operating room; IN = induction of anesthesia; T = tracheal intubation; IN5 = induction + 5 min; IN10 = induction + 10 min; IN20 = induction + 20 min; SKI = skin incision; D = delivery; SKC = skin closure; O = extubation. (From Wallace, 1995, with permission.)
Another randomized study included 70 women with severe preeclampsia receiving spinal analgesia versus general anesthesia (Dyer, 2003). All had a nonreassuring fetal heart rate tracing as the indication for cesarean delivery, and outcomes were equivalent. Dyer and coworkers (2008) later showed that decreased mean arterial blood pressure induced by epidural blockade could be effectively counteracted by phenylephrine infusion to maintain cardiac output.
In a study from the University of Alabama at Birmingham, Head and colleagues (2002) randomly assigned 116 women with severe preeclampsia to receive either epidural or patient-controlled intravenous meperidine analgesia during labor. A standardized protocol limited intravenous fluids to 100 mL/hr. More women—9 percent—from the group assigned to epidural analgesia required ephedrine for hypotension. As expected, pain relief was superior in the epidural group, but maternal and neonatal complications were similar between groups. One woman in each group developed pulmonary edema.
It is important to emphasize that epidural analgesia is not to be considered treatment of preeclampsia. Lucas and associates (2001) studied 738 laboring women at Parkland Hospital who were 36 weeks or more and who had gestational hypertension of varying severity. Patients were randomly assigned to receive either epidural analgesia or patient-controlled intravenous meperidine analgesia. Maternal and neonatal outcomes were similar in the two study groups. However, as shown in Table 40-17, epidural analgesia resulted in a greater decrement of mean maternal arterial pressure compared with meperidine, but it was not superior in preventing recurrent severe hypertension later in labor.
TABLE 40-17. Comparison of Cardiovascular Effects of Epidural versus Patient-Controlled Meperidine Analgesia During Labor in Women with Gestational Hypertension
For these reasons, judicious fluid administration is essential in severely preeclamptic women who receive regional analgesia. Newsome and coworkers (1986) showed that vigorous crystalloid infusion with epidural blockade in women with severe preeclampsia caused elevation of pulmonary capillary wedge pressures (see Fig. 40-6). Aggressive volume replacement in these women increases their risk for pulmonary edema, especially in the first 72 hours postpartum (Clark, 1985; Cotton, 1986a). When pulmonary edema develops, there is also concern for development of cerebral edema. Finally, Heller and associates (1983) demonstrated that most cases of pharyngolaryngeal edema were related to aggressive volume therapy.
Persistent Severe Postpartum Hypertension
The potential problem of antihypertensive agents causing serious compromise of uteroplacental perfusion and thus of fetal well-being is obviated by delivery. Postpartum, if difficulty arises in controlling severe hypertension or if intravenous hydralazine or labetalol are being used repeatedly, then oral regimens can be given. Examples include labetalol or another β-blocker, nifedipine or another calcium-channel blocker, and possible addition of a thiazide diuretic. Persistent or refractory hypertension is likely due to mobilization of pathological interstitial fluid and redistribution into the intravenous compartment, underlying chronic hypertension, or usually both (Sibai, 2012; Tan, 2002). In women with chronic hypertension and left-ventricular hypertrophy, severe postpartum hypertension can cause pulmonary edema from cardiac failure (Cunningham, 1986, 2012; Sibai, 1987a).
Because persistence of severe hypertension corresponds to the onset and length of diuresis and extracellular fluid mobilization, it seems logical that furosemide-augmented diuresis might serve to hasten blood pressure control. To study this, Ascarelli and coworkers (2005) designed a randomized trial that included 264 postpartum preeclamptic women. After onset of spontaneous diuresis, patients were assigned to 20-mg oral furosemide given daily or no therapy. Women with mild disease had similar blood pressure control regardless of whether they received treatment or placebo. However, women with severe preeclampsia who were treated, compared with those receiving placebo, had a lower mean systolic blood pressure at 2 days—142 versus 153 mm Hg. They also required less frequently administered antihypertensive therapy during the remainder of hospitalization—14 versus 26 percent, respectively.
We have used a simple method to estimate excessive extracellular/interstitial fluid. The postpartum weight is compared with the most recent prenatal weight, either from the last clinic visit or on admission for delivery. On average, soon after delivery, maternal weight should be reduced by at least 10 to 15 pounds depending on infant and placental weight, amnionic fluid volume, and blood loss. Because of various interventions, especially intravenous crystalloid infusions given during operative vaginal or cesarean delivery, women with severe preeclampsia often have an immediate postpartum weight in excess of their last prenatal weight. If this weight increase is associated with severe persistent postpartum hypertension, then diuresis with intravenous furosemide is usually helpful in controlling blood pressure.
Martin and colleagues (1995) have described an atypical syndrome in which severe preeclampsia-eclampsia persists despite delivery. These investigators described 18 such women whom they encountered during a 10-year period. They advocate single or multiple plasma exchange for these women. In some cases, 3 L of plasma was exchanged three times—a 36- to 45-donor unit exposure for each patient—before a response was forthcoming. Others have described plasma exchange performed in postpartum women with HELLP syndrome (Förster, 2002; Obeidat, 2002). In all of these cases, however, the distinction between HELLP syndrome and thrombotic thrombocytopenic purpura or hemolytic uremic syndrome was not clear. As further discussed in Chapter 56 (p. 1116), in our experiences with more than 50,000 women with gestational hypertension among nearly 450,000 pregnancies cared for at Parkland Hospital through 2012, we have encountered very few women with persistent postpartum hypertension, thrombocytopenia, and renal dysfunction who were diagnosed as having a thrombotic microangiopathy (Dashe, 1998). These latter syndromes complicating pregnancy were reviewed by Martin (2008) and George (2013) and their colleagues, who conclude that a rapid diagnostic test for ADAMTS-13 enzyme activity might be helpful to differentiate most of these syndromes.
Reversible Cerebral Vasoconstriction Syndrome
This is another cause of persistent hypertension, “thunderclap” headaches, seizures, and central nervous system findings. It is a form of postpartum angiopathy. As shown in Figure 40-24, it is characterized by diffuse segmental constriction of cerebral arteries and may be associated with ischemic and hemorrhagic strokes. The reversible cerebral vasoconstriction syndrome has several inciting causes that include pregnancy, and particularly preeclampsia (Ducros, 2012). It is more common in women, and in some cases, vasoconstriction may be so severe as to cause cerebral ischemia and infarction. The appropriate management is not known at this time (Edlow, 2013).
FIGURE 40-24 Reversible cerebral vasoconstriction syndrome. Magnetic resonance angiography shows generalized vasoconstriction of the anterior and posterior cerebral circulation (arrows). (From Garcia-Reitboeck, 2013, with permission.)
COUNSELING FOR FUTURE PREGNANCIES
As discussed on page 732, defective remodeling of the spiral arteries in some placentations has been posited as the cause of at least one preeclampsia phenotype. Lack of deep placentation has been associated with preeclampsia, placental abruption, fetal-growth restriction, and preterm birth (Wikström, 2011). With this type of “overlap syndrome,” hypertensive disorders may serve as markers for subsequent preterm labor and fetal-growth restriction. For example, even in subsequent nonhypertensive pregnancies, women who had preterm preeclampsia are at increased risk for preterm birth (Connealy, 2013.)
In addition, women who have had either gestational hypertension or preeclampsia are at higher risk to develop hypertension in future pregnancies. Generally, the earlier preeclampsia is diagnosed during the index pregnancy, the greater the likelihood of recurrence. Sibai and colleagues (1986, 1991) found that nulliparas diagnosed with preeclampsia before 30 weeks have a recurrence risk as high as 40 percent during a subsequent pregnancy. In a prospective study of 500 women previously delivered for preeclampsia at 37 weeks, the recurrence rate in a subsequent gestation was 23 percent (Bramham, 2011). These investigators also found an increased risk during subsequent pregnancies for preterm delivery and fetal-growth restriction even if these women remained normotensive.
In a study from the Denmark Birth Registry, Lykke and coworkers (2009b) analyzed singleton births in more than 535,000 women who had a first and second delivery. Women whose first pregnancy was complicated by preeclampsia between 32 and 36 weeks had a significant twofold increased incidence of preeclampsia in their second pregnancy—25 versus 14 percent—compared with women who were normotensive during the first pregnancy. Analyzed from another view, they also found that preterm delivery and fetal-growth restriction in the first pregnancy significantly increased the risk for preeclampsia in the second pregnancy.
As probably expected, women with HELLP syndrome have a substantive risk for recurrence in subsequent pregnancies. In two studies the risk ranged from 5 to 26 percent, but the true recurrence risk likely lies between these two extremes (Habli, 2009; Sibai, 1995). Even if HELLP syndrome does not recur with subsequent pregnancies, there is a high incidence of preterm delivery, fetal-growth restriction, placental abruption, and cesarean delivery (Habli, 2009; Hnat, 2002).
Over the past 20 years, evidence has accrued that preeclampsia, like fetal-growth disorders and preterm birth, is a marker for subsequent cardiovascular morbidity and mortality. Thus, women with hypertension identified during pregnancy should be evaluated during the first several months postpartum and counseled regarding long-term risks. The Working Group concluded that hypertension attributable to pregnancy should resolve within 12 weeks of delivery (National High Blood Pressure Education Program, 2000). Persistence beyond this time is considered to be chronic hypertension (Chap. 50, p. 1000). The Magpie Trial Follow-Up Collaborative Group (2007) reported that 20 percent of 3375 preeclamptic women seen at a median of 26 months postpartum had hypertension. Importantly, even if hypertension does not persist in the short term, convincing evidence suggests that the risk for long-term cardiovascular morbidity is significantly increased in preeclamptic women.
Cardiovascular and Neurovascular Morbidity
With the advent of national databases, several studies confirm that any hypertension during pregnancy is a marker for an increased risk for morbidity and mortality in later life (American College of Obstetricians and Gynecologists, 2013c). In a case-control study from Iceland, Arnadottir and associates (2005) analyzed outcomes for 325 women who had hypertension complicating pregnancy and who were delivered from 1931 through 1947. At a median follow-up of 50 years, 60 percent of women with pregnancy-related hypertension compared with only 53 percent of controls had died. Compared with 629 normotensive pregnant controls, the prevalences of ischemic heart disease—24 versus 15 percent, and stroke—9.5 versus 6.5 percent, were significantly increased in the women who had gestational hypertension. In a Swedish population study of more than 400,000 nulliparas delivered between 1973 and 1982, Wikström and coworkers (2005) also found an increased incidence of ischemic heart disease in women with prior pregnancy-associated hypertension.
Lykke and associates (2009a) cited findings from a Danish registry of more than 780,000 nulliparous women. After a mean follow-up of almost 15 years, the incidence of chronic hypertension was significantly increased 5.2-fold in those who had gestational hypertension, 3.5-fold after mild preeclampsia, and 6.4-fold after severe preeclampsia. After two hypertensive pregnancies, there was a 5.9-fold increase in the incidence. Importantly, these investigators also reported a significant 3.5-fold increased risk for type 2 diabetes.
Bellamy and coworkers (2007) performed a systematic review and metaanalysis of long-term risks for cardiovascular disease in women with preeclampsia. As shown in Figure 40-25, the risks in later life were increased for hypertension, ischemic heart disease, stroke, venous thromboembolism, and all-cause mortality. As emphasized by several investigators, other cofactors or comorbidities are related to acquisition of these long-term adverse outcomes (Gastrich, 2012; Harskamp, 2007; Hermes, 2012; Spaan, 2012b). These include but are not limited to the metabolic syndrome, diabetes, obesity, dyslipidemia, and atherosclerosis. These conclusions are underscored by the findings of Berends and colleagues (2008), who confirmed shared constitutional risks for long-term vascular-related disorders in preeclamptic women and in their parents. Similar preliminary observations were reported by Smith (2009, 2012) and Stekkinger (2013) and their associates.
FIGURE 40-25 Long-term cardiovascular consequences of preeclampsia. All differences p ≤ .001. (Data from Bellamy, 2007.)
At least in some of these women, their hypertensive cardiovascular pathologies appear to have begun near the time of their own births. For example, individuals who are born preterm have increased ventricular mass later in life (Lewandowski, 2013). Women who have preeclampsia and who develop chronic hypertension later in life have an increased ventricular mass index before they become hypertensive (Ghossein-Doha, 2013). A similar phenomenon is associated with preterm birth and with fetal-growth disorders.
Preeclampsia appears to also be a marker for subsequent renal disease. In a preliminary study, the possibility was raised that persistent podocyturia might be a marker for such disease (Garrett, 2013). In a 40-year study of Norwegian birth and end-stage renal disease linked registries, although the absolute risk of renal failure was small, preeclampsia was associated with a fourfold increased risk (Vikse, 2008). Women with recurrent preeclampsia had an even greater risk. These data need to be considered in light of the findings that 15 to 20 percent of women with preeclampsia who undergo renal biopsy have evidence of chronic renal disease (Chesley, 1978). In another long-term follow-up study, Spaan and coworkers (2009) compared formerly preeclamptic women with a cohort of women who were normotensive at delivery. At 20 years following delivery, preeclamptic women were significantly more likely to be chronically hypertensive—55 versus 7 percent—compared with control women. They also had higher peripheral vascular and renovascular resistance and decreased renal blood flow. These data do not permit conclusions as to cause versus effect.
Until recently, eclamptic seizures were believed to have no significant long-term sequelae. Findings have now accrued, however, that this is not always the case. Recall that almost all eclamptic women have multifocal areas of perivascular edema, and about a fourth also have areas of cerebral infarction (Zeeman, 2004a).
A Dutch group has reported several long-term follow-up studies in women with severe preeclampsia and eclampsia (Aukes, 2007, 2009, 2012). These investigators found long-term persistence of brain white-matter lesions that were incurred during eclamptic convulsions (Aukes, 2009). When studied with MR imaging at a mean of 7 years, 40 percent of formerly eclamptic women had more numerous and larger aggregate white matter lesions compared with 17 percent of normotensive control women. These investigators later also observed these white-matter lesions in preeclamptic women without convulsions (Aukes, 2012). In studies designed to assess clinical relevance, Aukes and colleagues (2007) reported that formerly eclamptic women had subjectively impaired cognitive functioning. They also reported that women with multiple seizures had impaired sustained attention compared with normotensive controls (Postma, 2009). And recently, Wiegman and associates (2012) described that formerly eclamptic women at approximately 10 years had lower vision-related quality of life compared with control subjects. Because there were no studies done before these women suffered from preeclampsia or eclampsia, the investigators appropriately concluded that cause versus effect of these white-matter lesions remains unknown.
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