Obstentrics_Williams

Obstentrics_Williams. The concept of vasospasm with preeclampsia has been advanced for a century (Volhard, 1918). Systemic endothelial activation causes vasospasm that elevates resistance to produce subsequent hypertension. Concurrently, systemic endothelial cell injury promotes interstitial leakage, and blood constituents, including platelets and ibrinogen, are deposited subendothelially. Endothelial junctional proteins are also disrupted, and the subendothelial region of resistance arteries undergoes ultrastructural change (Suzuki, 2003; Wang, 2002). The much larger venous circuit is similarly involved. With diminished blood low because of maldistribution from vasospasm and interstitial leakage, ischemia of the surrounding tissues can lead to necrosis, hemorrhage, and other end-organ disturbances characteristic of the syndrome. One important clinical correlate to this is the markedly attenuated blood volume seen in women with severe preeclampsia (Zeeman, 2009).


Obstentrics_Williams

Obstentrics_Williams. Injury to systemic endothelial cells is now a centerpiece of preeclampsia pathogenesis (Davidge, 2015). In this scheme, protein factor(s)-likely placental-are secreted into the maternal circulation and provoke activation and dysfunction of the systemic vascular endothelium. Many facets of the clinical syndrome of preeclampsia are thought to result from these widespread endothelial cell changes.


Obstentrics_Williams

Obstentrics_Williams. Intact endothelium has anticoagulant properties. lso, systemic endothelial cells, by releasing nitric oxide, blunt the response of vascular smooth muscle to agonists. Injured or activated endothelial cells may produce less nitric oxide and may secrete substances that promote coagulation and greater sensitivity to vasopressors. Further evidence of endothelial activation includes the characteristic changes in glomerular capillary endothelial morphology, greater capillary permeability, and elevated blood concentrations of substances associated with endothelial activation. Likely, multiple factors in the plasma of preeclamptic women combine to exert these vasoactive efects (Myers, 2007; Walsh, 2009).


Obstentrics_Williams

Obstentrics_Williams. As discussed in Chapter 4 (p. 63), pregnant women normally develop refractoriness to infused vasopressors (AbdulKarim, 1961). Women with early preeclampsia, however, have enhanced 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). Paradoxically, women who develop preterm preeclampsia have lower circulating levels of angiotensin II (Chase, 2017).


Obstentrics_Williams

Obstentrics_Williams. Several prostaglandins are thought to be central to preeclampsia syndrome pathophysiology. Specifically, the blunted pressor response seen in normal pregnancy is at least partially due to diminished vascular responsiveness mediated by endothelial prostaglandin synthesis. For example, compared with normal pregnancy, endothelial prostacyclin (PGI2) production is lower in preeclampsia. This action appears to be mediated by phospholipase A2 (Davidge, 2015). At the same time, thromboxane A2 secretion by platelets is increased, and the prostacyclin:thromboxane A2 ratio declines. The net result favors greater sensitivity to infused angiotensin II and, ultimately, vasoconstriction (Spitz, 1988). hese changes are apparent as early as 22 weeks' gestation in gravidas who later develop preeclampsia (Chavarria, 2003).


Obstentrics_Williams

Obstentrics_Williams. Nitric oxide is a potent vasodilator synthesized from I-arginine by endothelial cells. Inhibition of nitric oxide synthesis raises mean arterial pressure, lowers 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). he efects of nitric oxide production in preeclampsia are unclear. It appears that the syndrome is associated with decreased endothelial nitric oxide synthase expression, thus resulting in lower nitric oxide activity (Davidge, 2015).


Obstentrics_Williams

Obstentrics_Williams. Endothelins are 21-amino-acid pep tides and potent vasoconstrictors. Endothelin-1 (ET -1) is the primary isoform produced by human endothelium (Karumanchi, 2016b). Plasma ET-1 levels are elevated in normotensive pregnant women, but women with preeclampsia have even higher levels (Ajne, 2003). 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). And, in animal studies, sildenafil reduces ET-1 concentrations (Gillis, 2016).


Obstentrics_Williams

Obstentrics_Williams. Placental vasculogenesis is evident by 21 days after conception. The list of pro-and antiangiogenic substances involved in placental vascular development is extensive, and the families of vascular endothelial growth factor (VEGF) and angiopoietin are the most studied. Angiogenic imbalance describes excessive amounts of antiangiogenic factors, which are thought to be stimulated by worsening hypoxia at the uteroplacental interface. Trophoblast of women destined to develop preeclampsia overproduces at least two antiangiogenic pep tides that enter the maternal circulation (Karumanchi, 20 16a).


Obstentrics_Williams

Obstentrics_Williams. First, soluble ins-like yrosine kinase i {sFlt-i} is a receptor for VEGF. As depicted in Figure 40-3, elevated maternal sFlt-1 levels inactivate and reduce circulating free placental growth factor (PIGF) and VEGF concentrations, leading to endothelial dysfunction (Maynard, 2003). Importantly, sFlt-1 levels begin to rise in maternal serum months before preeclampsia is evident (Fig. 40-4). These high levels in the second trimester are associated with a doubling of the risk for preeclampsia (Haggerty, 2012). This divergence from normal levels appears to develop even sooner with early-onset preeclampsia (Vatten, 2012). These factors are also operative in pregnancies complicated by fetal-growth restriction (Herraiz, 2012).


Obstentrics_Williams

Obstentrics_Williams. A second antiangiogenic peptide, soluble endoglin (sEng), inhibits various transforming growth factor beta (TGF-3) isoforms from binding to endothelial receptors (see Fig. 40-3). Endoglin is one of these receptors. Decreased binding to endoglin diminishes endothelial nitric oxide-dependent vasodilatation. Serum levels of sEng also begin to rise months before clinical preeclampsia develops (Haggerty, 2012). Interestingly, metformin reduces antiangiogenic secretion from human tissues (Brownfoot, 2016). In one systematic review, third-trimester elevation of sFlt-1 levels and lower PIGF concentrations correlate with and soluble endoglin (sEng). preeclampsia development after 25 weeks' gestation (Widmer, 2007). Subsequently, Haggerty and coworkers (2012) reported that doubling of expressions of sFlt-1 and sEng increased the preeclampsia risk by 39 and 74 percent, respectively. The cause :J• :JE


Obstentrics_Williams

Obstentrics_Williams. FIGURE 40-4 Angiogenic and antiangiogenic factors in normotensive (N) and preeclamptic (PE) women across pregnancy. Both pairs of factors are significantly divergent by 23 to 26 weeks' gestation. sFlt = soluble fms-like tyrosine kinase 1; PIGF = placental growth factor. (Data from Myatt, 201o3.) of placental overproduction of anti angiogenic proteins remains an enigma. here is a racial-ethnic diference in their secretion (Yang, 2016). Concentrations of the soluble forms are not higher in fetal circulation or amnionic fluid of preeclamptic women, and their levels in maternal blood dissipate after delivery (Staf, 2007). Clinical research aims to employ antiangiogenic proteins in the prediction and diagnosis of preeclampsia. One preliminary report described therapeutic apheresis to reduce sFlt-1 levels (Thadhani, 2016).


Obstentrics_Williams

Obstentrics_Williams. Evidence for preeclampsia 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 lead to multiorgan involvement with a clinicl spectrum ranging from meager findings to one of cataclysmic deterioration. 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 overlap .


Obstentrics_Williams

Obstentrics_Williams. Cardiovascular disturbances are common with preeclampsia syndrome. hese are related to: (1) greater cardiac afterload caused by hypertension; (2) cardiac preload, which is reduced by a pathologically diminished volume expansion during pregnancy and which is increased by intravenous crystalloid or oncotic solutions; and (3) endothelial activation leading to interendothelial extravasation of intravascular fluid into the extracellular space and, importantly, into the lungs.


Obstentrics_Williams

Obstentrics_Williams. The cardiovascular aberrations of pregnancy-related hypertensive disorders vary depending on several modifiers. These factors include preeclampsia severity, hypertension severity, presence of underlying chronic disease, and the part of the clinical spectrum in which these are studied. In some women, these cardiovascular changes may precede hypertension (De Paco, 2008; Easterling, 1990; Khalil, 2012; Melchiorre, 2013). Nevertheless, with the clinical onset of preeclampsia, cardiac outpur declines, due at least in part to greater peripheral resistance. When assessing cardiac function in preeclampsia, consideration is given to echo cardiographic measures ofmyocardial function and to clinically relevant ventricular function. blood loss incurred at delivery. Anemia may also partially result from greater erythrocyte destruction as subsequently described.


Obstentrics_Williams

Obstentrics_Williams. blood loss incurred at delivery. Anemia may also partially result from greater erythrocyte destruction as subsequently described. The platelet count is routinely measured in women with any form of gestational hypertension. Decreased platelet concentra tions with eclampsia were described more than 100 years ago.


Obstentrics_Williams

Obstentrics_Williams. The frequency and intensity of thrombocytopenia vary and are dependent on the severity and duration of the preeclampsia syn drome (Heilmann, 2007; Hupuczi, 2007). Overt thrombocy topenia-deined by a platelet count < 100,000/�L-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 worsening thrombocytopenia usually ensues. Mter delivery, the platelet count may continue to decline for the irst day or so. It then usually rises progressively to reach a normal level within 3 to 5 days. As discussed later (p. 722), 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 attrib uted to one of the thrombotic microangiopathies discussed in Chapter 56 (p. 1088).


Obstentrics_Williams

Obstentrics_Williams. Chapter 56 (p. 1088). Myriad other platelet alterations are attributed to the preeclampsia syndrome. hese were reviewed by Kenny and coworkers (2015) and include platelet activation with increased .-degranulation producing �-thromboglobulin, factor 4, and enhanced clearance. Paradoxically, in most studies, in vitro platelet aggregation is reduced compared with the normal increase that is 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. Levels of platelet-bound and circulating platelet-bindable immunoglobulins are elevated, which suggests platelet surface alterations.


Obstentrics_Williams

Obstentrics_Williams. Abnormally low platelets do not develop in the fetuses or neonates born to preeclamptic women despite severe maternal thrombocytopenia (Kenny, 2015; Pritchard, 1987). Thus, maternal thrombocytopenia in a hypertensive woman is not a etal indication or cesarean delivery. Severe preeclampsia is frequently accompanied by hemolysis, which manifests as elevated serum lactate dehydrogenase levels and reduced haptoglobin levels. Other evidence comes from schizocytosis, spherocytosis, and reticulocytosis in peripheral blood (Cunningham, 1985; Pritchard, 1954, 1976). hese derangements result in part from microangiopathic hemoysis caused by endothelial disruption with platelet adherence and ibrin deposition. Cunningham and coworkers (1995) postulated that erythrocyte morphology was partially caused by serum lipid alterations. Related, substantively decreased longchain fatty acid content is found in erythrocytes of preeclamptic women (Mackay, 2012).


Obstentrics_Williams

Obstentrics_Williams. Mter early reports of hemolysis and thrombocytopenia with severe preeclampsia, descriptions were added of abnormally elevated serum liver transaminase levels that indicated hepatocellular necrosis (Chesley, 1978). Weinstein (1982) referred to this combination of events as the HELLP syndrome-and this term now is used worldwide. Also, facets of the HELLP syndrome are included in criteria that diferentiate severe from nonsevere preeclampsia (see Table 40-2). he HELLP syndrome is discussed further in that section (p. 722).


Obstentrics_Williams

Obstentrics_Williams. Subtle changes consistent with intravascular coagulation, and less often erythrocyte destruction, commonly are found with preeclampsia and especially eclampsia (Cunningham, 2015; Kenny, 2015). Some of these changes include elevated factor VIII consumption, increased levels of ibrinopeptides A and B and of D-dimers, and reduced levels of regulatory proteinsantithrombin III and proteins C and S. Coagulation aberrations generally are mild and are seldom clinically signiicant (Kenny, 2015; Pritchard, 1984). Unless placental abruption is comorbid, plasma ibrinogen levels do not difer remarkably from levels found in normal pregnancy. Fibrin degradation products such as D-dimers are minimally elevated. As preeclampsia worsens, so do abnormal indings with thromboelastography (Pisani-Conway, 2013). Despite these changes, routine laboratory assessments of coagulation, such as prothrombin time (PT), activated partial thromboplastin time (aPTT), and plasma ibrinogen level, are not required in the


Obstentrics_Williams

Obstentrics_Williams. Despite these changes, routine laboratory assessments of coagulation, such as prothrombin time (PT), activated partial thromboplastin time (aPTT), and plasma ibrinogen level, are not required in the management of pregnancy-associated hypertensive disorders.


Obstentrics_Williams

Obstentrics_Williams. Plasma levels of renin, angiotensin II, angiotensin 1-, aldosterone, deoxycorticosterone, and atrial natriuretic peptide (ANP) are substantively augmented during normal pregnancy. ANP is released during atrial wall stretching from blood volume expansion, and it responds to cardiac contractility (Chap. 4, p. 63). Levels of serum ANP rise in pregnancy, and its secretion is further enhanced in women with preeclampsia (Luft, 2009). Levels of its precursor-proatrial natriuretic peptide-are also increased in preeclampsia (Sugulle, 2012). Vasopressin levels are similar in nonpregnant, normally pregnant, and preeclamptic women even though the metabolic clearance is elevated in the latter two (Durr, 1999) .


Obstentrics_Williams

Obstentrics_Williams. In women with severe preeclampsia, the volume of extracellular luid, manifest as edema, is usually much greater than that in normal pregnant women. As discussed, the mechanism responsible for pathological luid retention is endothelial injury (Davidge, 2015). In addition to generalized edema and proteinuria, these women have reduced plasma oncotic pressure. his reduction creates a iltration imbalance and further displaces intravascular luid into the surrounding interstitium. Electrolyte concentrations do not difer appreciably in women with preeclampsia compared with those of normal pregnant women. Following an eclamptic convulsion, the serum pH and bicarbonate concentration are lowered due to lactic acidosis and compensatory respiratory loss of carbon dioxide. he intensity of acidosis relates to the amount of lactic acid producedmetabolic acidosis-and the rate at which carbon dioxide is exhaled-respiratory acidosis.


Obstentrics_Williams

Obstentrics_Williams. During normal pregnancy, renal blood flow and glomerular filtration rate rise appreciably (Chap. 4, p. 65). With preeclampsia, several reversible anatomical and pathophysiological changes ensue. Of clinical importance, renal perfusion and glomerular iltration are reduced. Levels that are much less than normal nonpregnant values are infrequent and are the consequence of severe disease. Most of the decrement in glomerular filtration is from higher renal aferent arteriolar resistance that may be elevated up to fivefold (Conrad, 2015; Comelis, 201r1). Morphological changes are characterized by glomerular endotheliosis, which blocks the barrier that allows filtration. Diminished iltration causes serum creatinine levels to rise to values seen in nonpregnant individuals, that is, 1 mg/ mL, and sometimes higher (Lindheimer, 2008a). Abnormal values usually begin to normalize 10 days or later after delivery (Comelis, 2011; Spaan, 2012a).


Obstentrics_Williams

Obstentrics_Williams. In most preeclamptic women, the urine sodium concentration is elevated. Urine osmolality rises, urine:plasma creatinine ratio is elevated, and fractional excretion of sodium is low, which all indicated that a prerenal mechanism is involved. Sodium-containing crystalloid infusion raises left ventricular illing 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 unless urine output is diminished from hemorrhage or luid loss from vomiting or fever.


Obstentrics_Williams

Obstentrics_Williams. Plasma uric acid concentration is typically elevated in preeclampsia. The elevation exceeds that attributable to 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 greater tubular reabsorption (Taufield, 1987). As shown in Table 40-1, detection of proteinuria helps to establish the diagnosis of preeclampsia. Abnormal protein excretion is empirically deined by 24-hour urinary excretion exceeding 300 mg; a urine protein:creatinine ratio �0.3; or persistent protein values of 30 mg/ dL (1 + dipstick) in random urine samples. 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 20r13 Task Force.


Obstentrics_Williams

Obstentrics_Williams. Problematically, the optimal method of establishing abnormal levels of either urine protein or albumin remains to be defined. For a 24-hour quantitative specimen, the "consensus" threshold value used is �300 mg/24 h (American College of Obstetricians and Gynecologists, 2013). Using a urinary protein excretion threshold of 165 mg in a 12-hour sample shows equivalent eicacy (Stout, 2015; Tun, 2012).


Obstentrics_Williams

Obstentrics_Williams. Determination of urinary protein:creatmme ratio may supplant the cumbersome 24-hour quantiication (Kyle, 2008; Morris, 2012). Chen and associates (2008) found that clean-catch and catheterized urine specimens correlate well. In one systematic review, random urine protein:creatinine ratios below 130 to 150 mg/ g, that is, 0.13 to 0.15, indicate a low likelihood of proteinuria exceeding 300 mg/ d (Papanna, 2008). Ratios <0.08 or > 1.19 have negative-or positive-predictive values of86 and 96 percent, respectively (Stout, 2013). However, midrange ratios, that is, 300 mg/g or 0.3, have poor sensitivity and specificity. Thus, many recommend that with midrange ratio values, 24-hour protein excretion should be quantified. With urine dipstick assessment, determinations depend on urine concentration and are notorious for false-positive and -negative results. hus, assessment may show a dipstick value of 1 + to 2+ from concentrated urine specimens from women who excrete < 300 mg/ d.


Obstentrics_Williams

Obstentrics_Williams. Importantly, 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 do not have proteinuria at presentation (Sibai, 2004). In one report, 17 percent of eclamptic women did not have proteinuria by the time of seizures (Zwart, 2008). Sheehan and Lynch (1973) frequently 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 capillay endotheliosis (Spargo, 1959). Endothelial cells are often so swollen that they block or partially block the capillary lumens (Fig. 40-7) (Hecht, 2017). Homogeneous subendothelial deposits of proteins and fibrin-like material are seen.


Obstentrics_Williams

Obstentrics_Williams. Endothelial swelling may result from angiogenic protein "withdrawal" caused by the complexing of free angiogenic proteins with a compatible circulating antiangiogenic protein receptor (see Fig. 40-3). The angiogenic proteins are crucial for podocyte health, and their inactivation leads to podocyte dysfunction and endothelial swelling (Conrad, 2015; Karumanchi, 2009). Also, eclampsia is characterized by greater excretion of these epithelial podocytes (Wagner, 2012; White, 2014).


Obstentrics_Williams

Obstentrics_Williams. Although mild degrees of acute kidney injury are encountered, clinically apparent acute tubular necrosis is almost invariably induced by comorbid hemorrhage with hypovolemia and hypotension (Chap. 41, p. 755). his is usually caused by severe obstetrical bleeding-especially placental abruption-coupled with inadequate blood replacement. Drakeley and coworkers (2002) described 72 women with preeclampsia and renal failure. Half had HELLP syndrome, and a third had placental abruption. In one review of 183 women with HELLP syndrome, 5 percent had kidney injury (Haddad, 2000). Of those with renal injury, half had placental abruption, and most had postpartum hemorrhage. Last, irreversible renal cortical necrosis develops rarely (Chap. 53, p. 1037).


Obstentrics_Williams

Obstentrics_Williams. Ofwomen with preeclampsia, serial echocardiographic studies document diastolic dysfunction in 40 to 45 percent (Guirguis, 2015; Melchiorre, 2012). With this dysfunction, ventricles do not properly relax and cannot ill properly. In some of these women, functional diferences persist up to 4 years after delivery (Evans, 2011; Orabona, 2017). Diastolic dysfunction stens from ventricular remodeling, which is judged to be an adaptive response to maintain normal contractility despite the increased afterload ofpreeclampsia. High levels ofantiangiogenic proteins may be contributory (Shahul, 2016). 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 (Wardhana, 2017). his is discussed further in Chapters 47 (p. 918) and 49 (p. 964).


Obstentrics_Williams

Obstentrics_Williams. Despite the relatively high frequency of diastolic dysfunction with preeclampsia, clinical cardiac function in most afected women is appropriate (Hibbard, 2015). In some preeclamptic women, cardiac troponin levels are slightly elevated, and amino-terminal pro-brain natriuretic peptide (Nt pro-BNP) levels are elevated with severe preeclampsia (Pergialiotis, 2016; Zachary, 2017). Importantly, both normally pregnant women and those with preeclampsia syndrome can have normal or slightly hyperdynamic ventricular function (Fig. 40-5). hus, both have a cardiac output that is appropriate for leftsided illing pressures. Filling pressures are dependent on the volume of intravenous fluids. Thus, aggressive hydration results in overtly hyperdynamic ventricular function. his is .J,


Obstentrics_Williams

Obstentrics_Williams. 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 cur e. Normal values are from Clark (1989), and those for eclampsia are from Hankins (1984). PCWP = pulmonary capillary wedge pressure; LVSWI = left ventricular stroke work index. accompanied by elevated pulmonary capillary wedge pressures, and pulmonary edema may develop despite normal ventricular function. This is because of an alveolar endothelial-epithelialrleak, and it is compounded by decreased oncotic pressure from a low serum albumin concentration. In sum, aggressive fluid administration to otherwise normal women with severe preeclampsia substantially elevates normal leftsided filling pressures and raises a physiologically normal cardiac output to hyperdynamic levels.


Obstentrics_Williams

Obstentrics_Williams. Hemoconcentration is a hallmark ofeclampsia. This concept was precisely quantiied by Zeeman and colleagues (2009), who expanded the prior observations of Pritchard and associates (1984). hey showed in eclamptic women that the normally expected pregnancy blood volume expansion is severely curtailed (Fig. 40-6). Women ofaverage size have a blood volume of 3000 mL, and during the last several weeks of a normal pregnancy, this averages 4500 mL. With eclampsia, however, much or all of the anticipated 1500 mL excess is lost. Such hemoconcentration results from generalized vasospasm that follows endothelial activation and leakage of plasma into the interstitial space. In women with preeclampsia, and depending on its severity, hemoconcentration is usually not as marked.


Obstentrics_Williams

Obstentrics_Williams. hese changes have substantial clinical consequences. Importantly, women with severe hemoconcentration are unduly sensitive to blood loss at delivery that otherwise may be considered normal. Vasospasm and endothelial leakage of plasma persist for a variable time ater delivery as the endothelium is restored to normalcy. u this takes place, vasoconstriction reverses, and s the blood volume reexpands, the hematocrit usully falls. Importanty} a substantive cause ofthisall in hematocrit} however} is usualy the :J0 FIGURE 40-6 Total blood volumes in normotensive women compared with those with eclampsia. The vertical extensions are one standard deviation from the mean. In eclamptic women, blood volume is minimally increased compared with a subsequent normotensive pregnancy. (Data from Zeeman, 2009.)


Obstentrics_Williams

Obstentrics_Williams. Liver involvement with preeclampsia may clinically display at least three manifestations. Narrow First, pain is considered a sign of interspace severe disease. It typically manifests by moderate-to-severe right upper quadrant or midepigasEndothelial tric pain and tenderness. Such swelling women usually have elevated serum aspartate transaminase (AST) or alanine transaminase (AL T) levels. In some cases, however, the amount of hepatic tissue involved with infarction may be surprisingly extensive yet still clinically insignificant (N elson, 2017). In our experiences, infarction may be worsened by FIGURE 40-7 Schematic showing glomerular capillary endotheliosis. The capillary of the normal hypotension from obstetrical glomerulus shown on the left has wide endothelial fenestrations, and the pedicels emanating hemorrhage, and it occasion from the podocytes are widely spaced (arrow). The illustration on the right is of a glomerulus with changes induced by the preeclampsia syndrome. The


Obstentrics_Williams

Obstentrics_Williams. pedicels emanating hemorrhage, and it occasion 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 fenes called shock liver (Alexander, trae narrowed, as are the pedicels that now abut each other.


Obstentrics_Williams

Obstentrics_Williams. 2009; Yoshihara, 2016). Second, elevations of serum • Liver AST and ALT levels are markers for severe preeclampsia. Values seldom exceed 500 U/L, but levels reaching more than 2000 The characteristic hepatic lesions with eclampsia are regions of U/L have been reported (Chap. 55, p. 1058). In general, serumperiportal hemorrhage in the liver periphery (Hecht, 2017). concentrations inversely follow platelet levels, and they bothHowever, lesions as extensive as those shown in Figure 40-8 are usually normalize within 3 days following delivery.


Obstentrics_Williams

Obstentrics_Williams. unusual. Sheehan and Lynch (1973) described that some degree As a third presentation, hemorrhagic infarction may extend of hepatic infarction accompanied hemorrhage in almost half of to form a hepatic hematoma. This in turn can extend to form women who died with eclampsia. hese findings corresponded a subcapsular hematoma that may rupture. Computed tomogwith reports during the 1960s that described elevated serum raphy (CT) scanning or magnetic resonance (MR) imaginghepatic transaminase levels. Along with the earlier observations greatly aids diagnosis (Fig. 40-9). Unruptured hematomasby Pritchard and associates (1954), who described hemolysis are probably more common than clinically suspected and areand thrombocytopenia with eclampsia, this constellation of more likely to be found with HELLP syndrome. Althoughhemolysis, hepatocellular necrosis, and thrombocytopenia was later termed HELLP syndrome.


Obstentrics_Williams

Obstentrics_Williams. FIGURE 40-8 Gross liver specimen from a woman with preeclampsia who died from aspiration Periportal hemorrhagic necrosis was seen microscopically. (Reproduced with permission from Cunningham FG: Liver disease complicating pregnancy. Williams Obstetrics, 19th ed. (Suppl 1), Norwalk, Appleton & Lange, 1993.) 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 flameshaped hemorrhages are seen at the hematoma interface (arrows).


Obstentrics_Williams

Obstentrics_Williams. FIGURE 40-11 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.) once considered a surgical condition, current management of a hepatic hematoma usually consists of observation unless bleeding is ongoing. In some cases, however, prompt surgical intervention or angiographic embolization may be lifesaving. In one review of 180 cases of hepatic hematoma or rupture, 94 percent of afected gravidas had HELLP syndrome, and in 90 percent of the total, the capsule had ruptured (Vigil-De Gracia, 2012). The maternal mortality rate was 22 percent, and the perinatal mortality rate was 31 percent. In rare cases, liver transplantation is necessary (Hunter, 1995; Wicke, 2004).


Obstentrics_Williams

Obstentrics_Williams. 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. However, the hallmark of acute fatty liver is significant liver dysfunction, and Table 55-1 (p. 1059) highlights these clinical diferences. Last, no convincing data link pancreatic involvement with preeclampsia syndrome (Sheehan, 1973). Thus, the occasional case of concurrent hemorrhagic pancreatitis is likely unrelated (Lynch, 2015; Swank, 2012). In our experiences from Parkland Hospital, amylase levels were seldom elevated in preeclamptic women (Nelson, 2014a).


Obstentrics_Williams

Obstentrics_Williams. There is no universally accepted strict deinition of HELLP syndrome, and thus its incidence varies by investigator. In the previously noted study of 183 women with HELLP syndrome, 40 percent had adverse outcomes, and two mothers died (Haddad, 2000). Complications included eclampsia in 6 percent, placental abruption-10 percent, acute kidney injury-5 percent, and pulmonary edema-10 percent. Stroke, hepatic hematoma, coagulopathy, acute respiratory distress syndrome, and sepsis were other serious complications.


Obstentrics_Williams

Obstentrics_Williams. Women with preeclampsia and HELLP syndrome typically have worse outcomes than preeclamptic women without the HELLP constellation (Kozic, 2011; Martin, 2012, 2013). In one review of693 women with HELLP syndrome, 10 percent had concurrent eclampsia (Keiser, 2011). Sep and associates (2009) described a significantly higher 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 diferences, it has been postulated that HELLP syndrome has a distinct pathogenesis (Reimer, 2013; Vaught, 2016). Headaches and visual symptoms are common with severe preeclampsia, and associated convulsions deine 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.


Obstentrics_Williams

Obstentrics_Williams. FIGURE 40-10 This autopsy brain slice shows a fatal hypertensive hemorrhage in a primigravida with eclampsia.


Obstentrics_Williams

Obstentrics_Williams. From early anatomical descriptions, brain pathology accounted for only about a third of fatal cases such as the one shown in Figure 40-10. In fact, most deaths were from pulmonary edema, nd brain lesions were coincidental. Thus, lthough 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). s shown in Figure 40-11, 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 micro infarcts and hemorrhages. Other frequently described major lesions include subcortical edema, multiple nonhemorrhagic areas of "sotening" throughout the brain, and hemorrhagic areas in the white matter (Hecht, 2017). here also may be hemorrhage in the basal ganglia or pons, sometimes with rupture into the ventricles.


Obstentrics_Williams

Obstentrics_Williams. 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 is a key in both. The first theory suggests that in response to acute and severe hypertension, cerebrovascular overregulation leads to vasospasm (Trommer, 1988). In this scheme, diminished cerebral blood low is hypothesized to result in ischemia, cytotoxic edema, and eventually tissue infarction. Little objective evidence supports this mechanism.


Obstentrics_Williams

Obstentrics_Williams. he 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. his leads to vasogenic edema. he recent description of a central nervous system lymphatic vasculature lends credibility to this theory (Louveau, 2015). he most likely mechanism is a combination of the two.


Obstentrics_Williams

Obstentrics_Williams. he most likely mechanism is a combination of the two. hus, a preeclampsia-associated interendothelial cell leak develops at blood pressure (hydraulic) levels much lower than those that usually cause vasogenic edema and is coupled with a loss of upper-limit autoregulation (Fugate, 2015; Zeeman, 2009). With imaging studies, these manifest as theposterior reversible encephalopathy syndrome (Fig. 40-12) (Fugate, 2015; Hinchey, 1996). he lesions of this syndrome principally involve the posterior brain-the occipital and parietal cortices. But, in at least a third of cases, other areas are involved (Edlow, 2013; Zeeman, 2004a). FIGURE 40-12 Cranial magnetic-resonance imaging in a nullipara with eclampsia. Multilobe T2-FLAIR high-signal lesions are apparent. FLAIR = fluid-attenuated inversion recovery. (Used with permission from Dr. Gerda Zeeman.)


Obstentrics_Williams

Obstentrics_Williams. Autoregulation is the mechanism by which cerebral blood flow sion pressure. Remember that cerebral perfusion pressure is the sure. In nonpregnant individuals, this autoregulation protects the brain from hyperperfusion when mean arterial pressures rise to as high as 160 mm Hg. hese 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 autoregu lation must be altered by pregnancy. Studies by Cipolla and colleagues (2007, 2009, 2015) have convincingly shown that autoregulation is unchanged across pregnancy in rodents. But, some investigators have provided evidence of impaired auto regulation in women with preeclampsia a anzarik, 2014; van Veen, 2013).


Obstentrics_Williams

Obstentrics_Williams. Veen, 2013). Zeeman and associates (2003) showed that cerebral blood flow during the irst two trimesters of normal pregnancy is similar to nonpregnant values. But during the last trimester, low significantly drops by 20 percent. his group also found greater cerebral blood low in this trimester in women with severe preeclampsia compared with that in normotensive pregnant women (Zeeman, 2004b). Taken together, these findings suggest that eclampsia occurs when cerebral hyperperfusion forces capillary luid interstitially because of endothelial damage. This leak leads to perivascular edema characteristic of the preeclampsia syndrome. Several neurological manifestations typiy the preeclampsia syndrome. Each signiies severe involvement and requires immediate attention.


Obstentrics_Williams

Obstentrics_Williams. Several neurological manifestations typiy the preeclampsia syndrome. Each signiies severe involvement and requires immediate attention. First, headache and scotomata are thought to arise from cerebrovascular hyperperusion that has a predilection for the occipital lobes. Up to 75 percent of women have headaches, and 20 to 30 percent have visual changes preceding eclamptic convulsions (Sibai, 2005; Zwart, 2008). 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 frequently improve ater magnesium sulfate infusion. Convulsions 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 suggests that extended seizures can cause signiicant brain injury and later brain dysfunction.


Obstentrics_Williams

Obstentrics_Williams. Blindness is rare with preeclampsia alone, but it complicates eclamptic convulsions in up to 15 percent of women (Cunningham, 1995). Blindness may develop up to a week or more following delivery (Chambers, 2004). There are at least two ypes of blindness, as discussed subsequently. 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 can result. Last, 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 in the inal section (p. 745).


Obstentrics_Williams

Obstentrics_Williams. Last, 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 in the inal section (p. 745). 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). These hypodense areas correspond to petechial hemorrhages and local edema. Edema of the occipital lobes or difuse cerebral edema may cause symptoms such as blindness, lethargy, and confusion (Cunningham, 2000). Widespread edema can appear as marked compression or even obliteration of the cerebral ventricles. Such women may develop signs of impending life-threatening trans tentorial herniation.


Obstentrics_Williams

Obstentrics_Williams. Several MR imaging acquisitions are used to study eclamptic women. Common findings are hyperintense T2lesions-namely, posterior reversible encephalopathy syndrome (PRES)-in the subcortical and cortical regions of the parietal and occipital lobes (see Fig. 40-12). Also, the basal ganglia, brainstem, and cerebellum are relatively commonly involved (Brewer, 2013; Zeeman, 2004a). Again, these lesions represent focal cerebral edema. Although these PRES lesions are almost universal in women with eclampsia, their incidence in women with preeclampsia approximates 20 percent (Mayama, 2016). Lesions are more likely in women who have severe disease and who have neurological symptoms. And although usully reversible, a fourth of these hyperintense lesions represent cerebral infarctions that have persistent indings (Loureiro, 2003; Zeeman, 2004a).


Obstentrics_Williams

Obstentrics_Williams. Scotomata, blurred vision, or diplopia are common with severe preeclampsia and eclampsia. hese 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 (Handor, 2014; Roos, 2012). Occipital blindness is also called amaurosis-from the Greek dimming. With imaging, afected women usually have evidence of extensive occipital lobe vasogenic edema. 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.


Obstentrics_Williams

Obstentrics_Williams. Blindness from retinal lesions is caused either by serous retinal detachment or rarely by retinal infarction, which is termed Purtscher retinopathy 40-13). Serous retinal detachment is usually unilateral and seldom causes total visual loss. In fact, asymptomatic serous retinal detachment is relatively common with preeclampsia (Saito, 1998). In most cases of eclampsiaassociated blindness, visual acuity subsequently improves. However, if blindness is caused by retinal artery occlusion, vision may be permanently impaired (Lara-Torre, 2002; Moseman, 2002; Roos, 2012). Clinical manifestations suggesting widespread cerebral edema are worrisome. During 13 years at Parkland Hospital, 10 of 175 women (6 percent) with eclampsia were diagnosed with


Obstentrics_Williams

Obstentrics_Williams. FIGURE 40-1 3 Purtscher retinopathy caused by choroidal ischemia and infarction in preeclampsia syndrome. Ophthalmoscopy shows scattered yellowish, opaque lesions of the retina (arrows). (Reproduced with permission from Lam OS, Chan W: Images in clinical medicine. Choroidal ischemia in preeclampsia. N Engl J Med 344(1o0):739,o2001o.) 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 acutey 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 indings of trans tentorial herniation, from which one died. Consideration is given for treatment with


Obstentrics_Williams

Obstentrics_Williams. is essential. In the 10 women with generalized edema, three became comatose and had imaging indings of trans tentorial herniation, from which one died. Consideration is given for treatment with mannitol or dexamethasone.


Obstentrics_Williams

Obstentrics_Williams. Compromised utero placental perfusion is almost certainly a major culprit in the greater perinatal morbidity and mortality rates seen with preeclampsia (Harmon, 2015). Defects in endovascular trophoblastic invasion with the preeclampsia syndrome were discussed earlier (p. 714). hus, measurement of uterine, intervillous, and placental blood low 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 eiuent, and the need for radioisotopes or invasive techniques.


Obstentrics_Williams

Obstentrics_Williams. Measurement of uterine artery blood low velocity has been used to estimate resistance to uteroplacental blood low (Chap. 17, p. 339). Vascular resistance is estimated by comparing arterial systolic and diastolic velocity waveforms. By the completion of placentation, impedance of uterine artery blood low 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. In some cases, but certainly not all, there was higher resistance (Fleischer, 1986; Trudinger, 1990).


Obstentrics_Williams

Obstentrics_Williams. Another Doppler waveform-uterine artery "notching"has been associated with elevated 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.


Obstentrics_Williams

Obstentrics_Williams. Resistance in uterine spiral arteries has also been measured. Impedance was higher in peripheral than in central vessels-a "ring-like" distribution (Matijevic, 1999). Mean resistance values were greater in all women with preeclampsia compared with those in normotensive controls. One study used MR imaging and other techniques to assess placental perfusion ex vivo in myometrial arteries removed from women with preeclampsia or fetal-growth restriction (Ong, 2003). 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 efect, fetal-growth restriction, is discussed in Chapter 44 (p. 847).


Obstentrics_Williams

Obstentrics_Williams. de Almeida Pimenta and colleagues (2014) assessed placental vascularity using a three-dimensional power Doppler histogram and described a placental vasculariy index. This index value was reduced in women with any pregnancy-associated hypertensive disorders-1l.1 percent compared with 15.2 percent in normal controls. Despite these indings, 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).


Obstentrics_Williams

Obstentrics_Williams. Various biological markers implicated in the preeclampsia syndrome have been measured to help predict its development. Although most have been evaluated in the irst half of pregnancy, some have been tested as predictors of severity in the third trimester (Chaiworapongsa, 2013; Lai, 2013; Mosimann, 2013). Others have been used to forecast recurrent preeclampsia (Demers, 2014; Eichelberger, 2015). Some of these tests are listed in Table 40-5, which is by no means all inclusive. Overall, these eforts have resulted in testing strategies with poor sensitivity and with poor positive-predictive values for preeclampsia (Conde-Agudelo, 2015; Odibo, 2013). Currenty, no screening tests or preecampsia are predictaby reliable, vali, and economical However, combinations of tests, some yet to be adequatelyevaluated, may be promising (Gallo, 2016; Olsen, 2012).


Obstentrics_Williams

Obstentrics_Williams. Most tests in this category are cumbersome, time consuming, and overall inaccurate. To evaluate blood pressure changes, three tests assess the blood pressure rise in response to a stimulus. In one, women at 28 to 32 weeks' gestation rest in the left lateral decubitus position and then roll to the supine position. With this rol-over test, increased blood pressure with this maneuver signifies a positive test. he isometric exercise TABLE 40-5. Predictive Tests for Development of the Preeclampsia Syndrome Roll-over test, isometric handgrip or cold pressor test, pressor response to aerobic exercise, angiotensin-II infusion, midtrimester mean arterial pressure, platelet angiotensin-II binding, renin, 24-hour ambulatory blood pressure monitoring, uterine artery r fetal transcranial Doppler velocimetry


Obstentrics_Williams

Obstentrics_Williams. Human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), estriol, pregnancy-associated protein A (PAPP A), inhibin A, activin A, placental protein 13, procalcitonin, corticotropinreleasing hormone, A disintegrin, ADAM-12, kisspeptin Serum uric acid, microalbuminuria, urinary calcium or kallikrein, microtransferrinuria, N-acetyl-3-glucosaminidase, cystatin C, podocyturia, podocalyxin Platelet count and activation, fibronectin, endothelial adhesion molecules, prostaglandins, prostacyclin, MMP-9, thromboxane, C-reactive protein, cytokines, endothelin, neurokinin B, homocysteine, lipids, insulin resistance, resistin, antiphospholipid antibodies, plasminogen activator-inhibitor (PAl), leptin, p-selectin, angiogenic and antiangiogenic factors such as placental growth factor (PIGF), vascular endothelial growth factor (VEGF), fms-like tyrosine kinase receptor-1 (sFlt-1), endoglin


Obstentrics_Williams

Obstentrics_Williams. Antithrombin-III(AT-3), atrial natriuretic peptide (ANP), 32-microglobulin, haptoglobin, transferrin, ferritin, 25-hydroxyvitamin 0, genetic markers, cell-free fetal DNA, serum and urine proteomics and metabolomic markers, hepatic aminotransferases ADAM 12 = ADAM metallopeptidase domain 12; MMP = matrix metalloproteinase. Adapted from Conde-Agudelo, 2015, Duckworth, 2016. test employs the same principle by squeezing a handball. The angiotensin 11 infusion test is performed by giving incrementally increasing doses intravenously, and the hypertensive response is quantiied. In an updated metaanalysis, sensitivities of all three tests were reported to range from 55 to 70 percent, and specificities approximated 85 percent (CondeAgudelo, 2015).


Obstentrics_Williams

Obstentrics_Williams. Uterine artey Doppler velocimety is posited to relect faulty trophoblastic invasion of the spiral arteries. his failure results in diminished placental perfusion and upstream greater uterine artery resistance. Increased uterine artery velocimetry determined by Doppler ultrasound in the first two trimesters might provide indirect evidence of this process and thus serve as a predictive test for preeclampsia (Dar, 2010; Groom, 2009). Elevated low resistance results in an abnormal vessel waveform represented by an exaggerated diastolic notch. hese indings have value for prediction of fetal-growth restriction but not preeclampsia (American College of Obstetricians and Gynecologists, 2015). Several low velocity waveforms have been investigated for preeclampsia prediction, however, none is suitable for clinical use (CondeAgudelo, 2015; Kleinrouweler, 2012; Myatt, 2012a).


Obstentrics_Williams

Obstentrics_Williams. Several serum analytes have been proposed to help predict preeclampsia (see Table 40-5). Newer ones are continually added. In general, none of these tests are clinically beneicial for hypertension prediction. Hyperuricemia likely results from reduced uric acid clearance from diminished glomerular filtration, increased tubular reabsorption, and decreased secretion. Cnossen and coworkers (2006) reported that its sensitivity to detect preeclampsia ranged from 0 to 55 percent, and speciicity was 77 to 95 percent. Isolated gestational proteinuria is a risk factor for preeclampsia Qayaballa, 2015; Morgan, 2016; Yamada, 2016). As a predictive test for preeclampsia, microalbuminuria has sensitivities that range from 7 to 90 percent and specificities that span 29 to 97 percent (Conde-Agudelo, 2015).


Obstentrics_Williams

Obstentrics_Williams. Endothelial activation and inflammation are major participants in the pathophysiology of the preeclampsia syndrome. As a result, compounds such as those listed in Table 40-5 are found to be elevated in circulating blood of afected women, and some have been assessed for their predictive value. First, ibronectins are high-molecular-weight glycoproteins released from endothelial cells and extracellular matrix following endothelial injury. However, in one systematic review, neither cellular nor total ibronectin levels were clinically useful to predict preeclampsia (Leeflang, 2007).


Obstentrics_Williams

Obstentrics_Williams. Thrombocytopenia and platelet dysfunction are integral features of preeclampsia. Platelet activation causes augmented destruction and lower concentrations. Mean platelet volume rises because of platelet immaturity (Kenny, 2015). Although markers of coagulation activation, described earlier (p. 719), are elevated, the substantive overlap with levels in normotensive pregnant women stultiies their predictive value. Markers of oxidative stress were also hoped to predict preeclampsia. Namely, associated higher levels of lipid peroxides coupled with decreased antioxidant activity raised this possibility. Other markers include iron, transferrin, and ferritin; resistin; hyperhomocysteinemia; blood lipids, including triglycerides, free fatty acids, and lipoproteins; and antioxidants such as ascorbic acid and vitamin E (Christiansen, 2015; CondeAgudelo, 2015; D'Anna, 2004; Mackay, 2012; Mignini, 2005). However, these have not been found to be predictive.


Obstentrics_Williams

Obstentrics_Williams. Last, an imbalance in antiangiogenic factors is linked to preeclampsia etiopathogenesis. For example, serum levels ofVEGF and PIGF begin to drop before clinical preeclampsia develops. And, recall from Figure 40-4 that at the same time, levels of some antiangiogenic factors, such as sFlt-1 and sEng, begin to rise (Karumanchi, 2016a; Maynard, 2008). With some of these factors, sensitivities for all cases of preeclampsia ranged from 30 to 50 percent, and specificity approximated 90 percent (Conde-Agudelo, 2015). heir predictive accuracy is higher for early-onset preeclampsia (Redman, 2015b; Tsiakkas, 2016). Determination of the sFlt-lIPIGF ratio in women admitted near 37 weeks' gestation to exclude preeclampsia was useful as a predictive factor (Baltajian, 2016; Zeisler, 2016a,b). These results suggest a clinical role for preeclampsia prediction, especially later in pregnancy (Ducworth, 2016; Gallo, 2016). They may also predict adverse pregnancy outcomes in women with lupus and comorbid


Obstentrics_Williams

Obstentrics_Williams. suggest a clinical role for preeclampsia prediction, especially later in pregnancy (Ducworth, 2016; Gallo, 2016). They may also predict adverse pregnancy outcomes in women with lupus and comorbid anti phospholipid antibodies (Kim, 2016).


Obstentrics_Williams

Obstentrics_Williams. As discussed in Chapter 13 (p. 273), cell-free DNA (cfDNA) can be detected in maternal plasma. It is hypothesized that cDNA is released in preeclampsia by accelerated apoptosis of cytotrophoblasts (DiFederico, 1999). One MFMU Network study found no correlation between total cfDNA levels and preeclampsia (Silver, 2017). Proteomic, metabolomic, and transcriptomic technologies can be employed to study serum and urinary proteins and cellular metabolites. These have opened new vistas for preeclampsia prediction, and preliminary studies indicate that these may become useful (Bahado-Singh, 2013; Carty, 2011; Ma, 2014; Myers, 2013). Various strategies used to prevent or modiy preeclampsia severity have been evaluated. Some are listed in Table 40-6. In general, none of these has been found to be convincingly and reproducibly efective.


Obstentrics_Williams

Obstentrics_Williams. Dietary "treatment" for preeclampsia has produced some interesting abuses (Chesley, 1978). A low-salt diet was one of the earliest research eforts to prevent preeclampsia (De Snoo, 1937). This was followed by years of inappropriate diuretic therapy. Although these practices were discarded, it ironically TABLE 40-6. Some Methods to Prevent Preeclampsia That Have Been Evaluated in Randomized Trials Dietary manipulation-low-salt diet, calcium or fish oil Exercise-physical activity, stretching Cardiovascular drugs-diuretics, antihypertensive drugs Antioxidants-ascorbic acid (vitamin C), a-tocopherol (vitamin E), vitamin D Antithrombotic drugs-low-dose aspirin, aspirin/ dipyridamole, aspirin + heparin, aspirin + ketanserin Modified from Staff, 2015. was not until relatively recently that the irst randomized trial was done and showed that a sodium-restricted diet was inefective in preventing preeclampsia (Knuist, 1998).


Obstentrics_Williams

Obstentrics_Williams. was not until relatively recently that the irst randomized trial was done and showed that a sodium-restricted diet was inefective in preventing preeclampsia (Knuist, 1998). Regular exercise during pregnancy is linked to a lower risk of developing preeclampsia (Barakat, 2016; Morris, 2017). Also, in one systematic review, a trend toward risk reduction with exercise was noted (Kasawara, 2012). Only a few studies have been randomized, and thus, more research is needed (Staf, 2015).


Obstentrics_Williams

Obstentrics_Williams. 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 signiicantly reduced relative risk-0.27-of developing preeclampsia. From two small randomized trials, prophylactic bed rest for 4 to 6 hours daily at home was successful in signiicantly lowering the incidence of preeclampsia in women with normal blood pressures (\1eher, 2006).


Obstentrics_Williams

Obstentrics_Williams. 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 low-risk nulliparas (Levine, 1997). Calcium supplementation did not prevent preeclampsia or pregnancy-associated hypertension. In one metaanalysis, increased calcium intake in high-risk women lowered the risk for preeclampsia (Patrelli, 2012). However, in aggregate, most of these trials have shown that unless women are calcium deficient, supplementation has no salutary efects (Sanchez-Ramos, 2017; Staf, 2015).


Obstentrics_Williams

Obstentrics_Williams. Cardioprotective aty acids found in some fatty fishes are plentiful in diets of Scandinavians and American Eskimos. Because supplementation with these fatty acids likely prevents inflammatory-mediated atherogenesis, it was posited that they might also prevent preeclampsia. Unfortunately, randomized trials conducted thus far have shown no such beneits from ish oil supplementation (Makrides, 2006; Olafsdottir, 2006; Zhou, 2012).


Obstentrics_Williams

Obstentrics_Williams. Because of the putative efects of sodium restriction for preeclampsia prevention, diuretic therapy became popular with the introduction of chlorothiazide in 1957 (Finnerty, 1958; Flowers, 1962). In one metaanalysis of nine randomized trials with more than 7000 pregnancies, women given diuretics had a lower incidence of edema and hypertension but not of preeclampsia (Churchill, 2007). Because women with chronic hypertension are at high risk for preeclampsia, several randomized trials have evaluated various antihypertensive drugs to reduce the incidence of superimposed preeclampsia (Chap. 50, p. 980). A critical analysis of these trials by Staf and coworkers (2015) failed to demonstrate benefits for this goal.


Obstentrics_Williams

Obstentrics_Williams. Data imply that an imbalance between oxidant and antioxidant activity plays a role in preeclampsia pathogenesis. Thus, naturally occurring antioxidants-vitamins C, D, and Emight reduce such oxidation. Several randomized studies have assessed antioxidant vitamin supplementation for women at high risk for preeclampsia (Poston, 2006; Rumbold, 2006; Villar, 2009). he Combined Antioxidant and Preeclampsia Prediction Studies (CAPPS) by the MFMU Network included almost 10,000 low-risk nulliparas (Roberts, 2010). None of these studies showed reduced preeclampsia rates in women provided vitamins C and E compared with those given placebo. Statins were proposed to prevent preeclampsia because they stimulate hemoxygenase-1 expression, which inhibits sFlt-1 release. Preliminary animal data suggest that statins may prevent hypertensive disorders of pregnancy (Lewis, 2017). The MFMU Network plans a randomized trial to test pravastatin for this purpose (Costantine, 2013, 2016).


Obstentrics_Williams

Obstentrics_Williams. Meormin inhibits hypoxic inducible actor 1. by lowering mitochondrial electron transport chain activity. It reduces sFlt-1 and sEng activity and thus has potential to prevent preeclampsia (Brownfoot, 2016). However, clinical studies are lacking. As noted earlier (p. 715), preeclampsia is characterized by vasospasm, endothelial cell dysfunction, and inlammation, as well as activation of platelets and the coagulation-hemostasis system. Other sequelae include placental infarction and spiral artery thrombosis (Nelson, 2014b). Thus, antithrombotic agents have been evaluated to reduce the incidence of preeclampsia. Low-molecular-weight heparin for prophylaxis has been studied in several randomized trials. Rodger and colleagues (2016) performed a metaanalysis using individual patient data from 963 women. The risk for recurrent preeclampsia, abruption, or fetal-growth restriction was similar in women receiving heparin or placebo.


Obstentrics_Williams

Obstentrics_Williams. Aspirin, in low oral doses of 50 to 150 mg daily, efectively inhibits platelet thromboxane A2 biosynthesis but has minimal efects on vascular prostacyclin production (Wallenburg, 1986). Still, several clinical trials have shown limited benefits in preeclampsia prevention. For example, a randomized trial from the MFMU Network found that risks for adverse outcomes were not significantly reduced with aspirin therapy (Caritis, 1998). Some combined reports, however, are more favorable. 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 preeclampsia, superimposed preeclampsia, preterm delivery, or any adverse pregnancy outcome was significantly decreased by 10 percent. Other metaanalyses report marginal benefits of low-dose aspirin for prevention of severe preeclampsia (Roberge, 2012; Villa, 2013). Recently, one randomized trial of more than


Obstentrics_Williams

Obstentrics_Williams. by 10 percent. Other metaanalyses report marginal benefits of low-dose aspirin for prevention of severe preeclampsia (Roberge, 2012; Villa, 2013). Recently, one randomized trial of more than 1600 women at high risk for preterm preeclampsia provided low-dose aspirin from 11 to 14 weeks' gestation until 36 weeks to prevent recurrence. The rate of preterm recurrence was 1.6 percent in the aspirin group compared with 4.3 percent in the placebo arm (Rolnik, 2017).


Obstentrics_Williams

Obstentrics_Williams. In recent dueling metaanalyses, Roberge and colleagues (2017) found that aspirin prophylaxis initiated before 16 weeks' gestation was associated with a signiicant risk reductionabout 60 percent-for preeclampsia and fetal-growth restriction. Moreover, they found a dose-response efect. At the same time, Meher and associates (2017) performed an individual participant data metaanalysis and reported a much lower-about 10 percent-risk reduction that was significant whether therapy was initiated before or after 16 weeks.


Obstentrics_Williams

Obstentrics_Williams. Meanwhile, the U.S. Preventive Services Task Force recommends low-dose aspirin prophylaxis for women at high risk for preeclampsia (Henderson, 2014). Because of this, the American College of Obstetricians and Gynecologists (2016b) issued a Practice Advisory that recommends low-dose aspirin be given between 12 and 28 weeks' gestation to help prevent preeclampsia in high-risk women. This includes those with a history of preeclampsia and those with twins, chronic hypertension, overt diabetes, renal disease, and autoimmune disorders. These results have also raised the question as to whether al pregnant women should be given aspirin (Mone, 2017). At this time, our answer is "no."


Obstentrics_Williams

Obstentrics_Williams. Low-dose aspirin coupled with heparin mmgates thrombotic sequelae in women with lupus anticoagulant (Chap. 59, p. 1145). Because of a similarly high prevalence of placental thrombotic lesions found with severe preeclampsia, trials have assessed the possible merits of such treatments for women with prior preeclampsia. In two randomized trials, women with a history of early-onset preeclampsia were given an aspirin therapy or an enoxaparin plus aspirin regimen (Groom, 2017; Haddad, 2016). Outcomes were similar. From their reviews, Sergis and associates (2006) reported better pregnancy outcomes in women with prior severe preeclampsia given low-molecularweight heparin plus low-dose aspirin compared with those given low-dose aspirin alone. Similar indings were reported by de Vries and coworkers (2012).


Obstentrics_Williams

Obstentrics_Williams. Pregnancy complicated by gestational hypertension is managed based on its severity, presence of preeclampsia, and gestational age. Preeclampsia cannot always be diagnosed definitively. hus, the Task Force (2013) 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 patholoy. Heightened surveillance permits more prompt recognition of ominous changes in blood pressure, critical laboratory findings, and clinical signs and symptoms (Macdonald-Wallis, 2015).


Obstentrics_Williams

Obstentrics_Williams. 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 a healthy newborn that 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 or succesul management is precise knowledge of etal age. • Early Diagnosis of Preeclampsia


Obstentrics_Williams

Obstentrics_Williams. • 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 eary developing preeclampsia is suspected during routine prenatal visits, are seen more frequenty. For many years at Parkland Hospital, 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 have, at minimum, returned for visits at 7 -day intervals. Outpatient surveillance is continued unless overt hypertension, proteinuria, headache, visual disturbances, or epigastric pain supervenes. 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. With hospitalization, a systematic evaluation is instituted to include:


Obstentrics_Williams

Obstentrics_Williams. With hospitalization, a systematic evaluation is instituted to include: Detailed examination, which is coupled with daily scrutiny for clinical indings such as headache, visual disturbances, epigastric pain, and rapid weight gain Quantification of proteinuria or urine protein:creatmme Blood pressure readings with an appropriate-size cuf every 4 hours, except between 2400 and 0600 unless previous readings are elevated Measurements of plasma or serum creatinine and hepatic transaminase levels and a hemogram that includes a platelet count. The frequency of testing is determined by hypertension severity. Although some recommend measurement of serum uric acid and lactate dehydrogenase levels and coagulation studies, their value has been questioned (CondeAgudelo, 2015; Thangaratinam, 2006). Evaluation of fetal size and well-being and amnionic luid volume, by either physical examination or sonography.


Obstentrics_Williams

Obstentrics_Williams. Evaluation of fetal size and well-being and amnionic luid volume, by either physical examination or sonography. 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 are included in the diet, and sodium and fluid intake are not limited or forced. In sum, goals of evaluation include early identification of preeclampsia or worsening of the syndrome and development of a management plan for timely delivery. Fortunately, many cases are suiciently 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 0/ al signs and symptoms, however, is uncommon until ater delivery. If severe preeclampsia is diagnosed using the criteria in Table 40-2, further management is subsequently described.


Obstentrics_Williams

Obstentrics_Williams. Termination o/pregnancy is the ony cure or preeclampsia. Head ache, visual disturbances, or epigastric pain are indicative that convulsions may be imminent, and oliguria is another ominous sign. Severe preeclampsia demands anticonvulsant and often antihypertensive therapy, followed by delivery. Treatment for eclampsia is identical. The prime objectives are to forestall con vulsions, to prevent intracranial hemorrhage and serious dam age to other vital organs, and to deliver a healthy newborn. his is true even when the cervix is unfavorable (T ajik, 2012). Labor induction is carried out, usually with preinduc tion cervical ripening with a prostaglandin or osmotic dilator (Chap. 26, p. 505).


Obstentrics_Williams

Obstentrics_Williams. Concerns stemming from 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 very-low-birthweight neonates. Others have reported similar observations (Alanis, 2008; Roland, 2017). However, whenever it appears that induction almost certainly will not succeed or attempts have failed, then cesarean delivery is indicated.


Obstentrics_Williams

Obstentrics_Williams. For a woman near term, with a soft, partially efaced cervix, even a milder degree of preeclampsia probably carries more risk to the mother and her fetus-newborn than does induction of labor (Tajik, 2012). A randomized trial of 756 women with mild preeclampsia supported delivery after 37 weeks' gestation (Koopmans, 2009).


Obstentrics_Williams

Obstentrics_Williams. When the fetus is preterm, the tendency is to temporize in the hope that additional weeks in utero will reduce the risk of neonatal death or serious morbidity from prematurity. 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 nonstress testing or biophysical proiles to assess fetal well-being (American College of Obstetricians and Gynecologists, 20 16a). Several tests can be used to provide evidence of lung maturity (Chap. 34, p. 638). An sFlt-lIPlGF ratio <38 is predictive of the short-term absence of preeclampsia, but this ratio testing is still investigational (Zeisler, 2016a,b). Also, women with higher ratios tend to have more adverse outcomes (Baltajian, 2016).


Obstentrics_Williams

Obstentrics_Williams. The decision to deliver late-preterm fetuses is less clear. Barton and coworkers (2011) reported excessive neonatal morbidity in women delivered before 38 weeks despite having stable, mild, nonprotein uric hypertension. The Netherlands study of 4316 newborns delivered, between 34°/7 and 36617 weeks also described substantive neonatal morbidity in these cases (Langenveld, 201l). Another Dutch study-HYPITAT-II-randomly assigned women with nonsevere hypertension between 34 and 37 weeks to immediate delivery or to expectant management (Broekhuijsen, 2015). Immediate delivery reduced the risks for adverse maternal outcomes-I. 1 versus 3.1 percent. However, it increased the risk for neonatal respiratory distress syndrome-5.7 versus 1. 7 percent. For women with mild-to-moderate stable hypertension is continued. During surveillance, reduced physical activity throughout much of the day, at least intuitively, seems beneicial. That said, complete bed rest is not recommended by the 2013


Obstentrics_Williams

Obstentrics_Williams. 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, it likely predisposes to thromboembolism (Knight, 2007). To reduce activity, several studies have addressed the beneits of inpatient care and outpatient management.


Obstentrics_Williams

Obstentrics_Williams. he 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 coworkers. Most hospitalized womenJJ have a beneficial response characterized by amelioration or improvement of hypertension. These women are not "cure, and neary 90 percent have recurrent hypertension bore or during labor. By 2016, more than 10,000 nulliparas with mild-to-moderate, early-onset hypertension during pregnancy had been managed successfully in this unit. Provider costsnot 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 neonate. Importantly, none of these women have


Obstentrics_Williams

Obstentrics_Williams. other than iron and folate supplements, and few essential laboratory tests are minimal compared with the cost of neonatal intensive care for a preterm neonate. Importantly, none of these women have sufered thromboembolic disease.


Obstentrics_Williams

Obstentrics_Williams. 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-tomoderate 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.


Obstentrics_Williams

Obstentrics_Williams. To assess this approach, 11r82 nulliparas with mild gestational hypertension-20 percent had proteinuria-were managed with home health care (Barton, 2002). 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 Day Unit 24 57 23 36 0 39.8 1n.1 3320 0 Usual Care 30 54 21 36.5 21 39 5.1 3340 0 Turnbull (2004) 374b Hospitalization 125 63 0 35.9 22 39 S.5 3330 3.S 0 Day Unit 249 62 0 36.2 22 39.7 7.2 3300 2.3 0 aExciuded women with proteinuria at study entry. blncluded women with sl+ proteinuria. BW = birthweight; EGA = estimated gestational age; HTN = hypertension; Parao= nulliparas; PMR = perinatal mortality rate; Prot = proteinuria; SGA = small for gestational age.


Obstentrics_Williams

Obstentrics_Williams. BW = birthweight; EGA = estimated gestational age; HTN = hypertension; Parao= nulliparas; PMR = perinatal mortality rate; Prot = proteinuria; SGA = small for gestational age. 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 births.


Obstentrics_Williams

Obstentrics_Williams. Several studies have compared continued hospitalization and outpatient care. In a pilot study from Parkland Hospital, 72 nulliparas with new-onset hypertension from 27 to 37 weeks were assigned either to continued hospitalization or to outpatient care (Horsager, 1995). he only significant diference was that women in the home care group developed severe preeclampsia significantly more frequently than hospitalized women42 versus 25 percent. In another trial, ater hospital evaluation, 218 women with mild gestational nonprotein uric hypertension were similarly divided (Crowther, 1992). As shown in Table 40-7, the mean hospital duration 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' gestation was increased twofold in the outpatient group. However, maternal and newborn outcomes were otherwise similar.


Obstentrics_Williams

Obstentrics_Williams. Another approach, popular in Europe, is day care (Milne, 2009). In one study, 54 women with hypertension after 26 weeks' gestation were assigned to either day care or routine outpatient management (see Table 40-7) (Tufnell, 1992). Progression to overt preeclampsia and labor inductions were signiicantly greater in the routine outpatient management group. In another, 395 women participated in either day care or inpatient management (Turnbull, 2004). Almost 95 percent had mild-to-moderate hypertension. Of enrolled women, 288 lacked proteinuria, and 86 had � 1 + proteinuria. There were no perinatal deaths, and none of the women developed eclampsia or HELLP syndrome. Costs for either scheme were not signiicantly diferent, and general satisfaction favored day care.


Obstentrics_Williams

Obstentrics_Williams. In sum, 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. hat said, the key to success is close surveillance and a conscientious patient with good home support. he use of antihypertensive drugs to prolong pregnancy or modiY perinatal outcomes in pregnancies complicated by various hypertensive disorders has been of considerable interest. Treatment for women with chronic hypertension complicating pregnancy is discussed in detail in Chapter 50 (p. 980).


Obstentrics_Williams

Obstentrics_Williams. Drug treatment for early mild preeclampsia has been disappointing (Table 40-8). Sibai and colleagues (1987a) reported that women given labetalol had significantly lower mean blood pressures. However, mean pregnancy prolongation, gestational age at delivery, and birthweight did not difer between groups. he cesarean delivery rate and the number of newborns admitted to special-care nurseries were also similar. The requency of growth-restricted neonates was doubled in women given labetalol-19 versus 9 percent. The three other studies listed in Table 40-8 compared labetalol or the calcium-channel blockers nifedipine and isradipine against placebo. Except for fewer episodes of severe hypertension, none of these studies showed any benefits from antihypertensive treatment (Magee, 2015). Similar conclusions were reached by Abalos and associates (2014), who reviewed 49 randomized trials of active antihypertensive therapy compared with either no treatment or placebo given to women with


Obstentrics_Williams

Obstentrics_Williams. Similar conclusions were reached by Abalos and associates (2014), who reviewed 49 randomized trials of active antihypertensive therapy compared with either no treatment or placebo given to women with mild-to-moderate gestational hypertension.


Obstentrics_Williams

Obstentrics_Williams. Up through the early 1990s, the prevailing\practice was that women with severe preeclampsia were usually delivered without delay. However, another approach for women with preterm severe preeclampsia has also been advocated. This approach calls for "conservative" or "expectant" management with the aA11 women had preeclampsia. blncludes postpartum hypertension. cp < .05 when study drug compared with placebo. HTN = hypertension; NS = not stated. 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


Obstentrics_Williams

Obstentrics_Williams. 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 irst 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 mortaliy rate was 87 percent. Although no mothers die, 13 su.ired placental abruption, 10 had eclampsia, three developed renal ailure, two had hypertensive encephalopathy, one had an intracerebral hemorrhage, and another had a ruptured hepatic hematoma.


Obstentrics_Williams

Obstentrics_Williams. Because of their early study, the Memphis group redeined criteria and performed a randomized trial of aggressive versus expectant 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 rom this tria. 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 for 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.


Obstentrics_Williams

Obstentrics_Williams. 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 syndromedeined as either one or two but not all three of the deining laboratory values. The third group included women who had severe preeclampsia without HELLP syndrome. Perinatal outyrcomes 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. Those with


Obstentrics_Williams

Obstentrics_Williams. 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. Those with fetal-growth restriction generally have shorter interval-to-delivery durations (McKinney, 2016).


Obstentrics_Williams

Obstentrics_Williams. 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. Serious complications in some of these and in later studies included placental abruption, HELLP syndrome, pulmonary edema, renal failure, and eclampsia (Table 40-9). Moreover, perinatal mortality rates averaged 90 per 1000 births. Fetal-growth restriction was common, and in the studies from The Netherlands, it was an astounding 94 percent (Ganzevoort, 2005a,b). Perinatal mortality rates are disproportionately high in these growth-restricted neonates, but maternal outcomes are not appreciably diferent (Haddad, 2007; Shear, 2005). 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 (VigilDe Gracia, 2013). The perinatal mortality


Obstentrics_Williams

Obstentrics_Williams. 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 (VigilDe Gracia, 2013). The perinatal mortality rate approximated


Obstentrics_Williams

Obstentrics_Williams. Ganzevoort (2005a, b) 216 11 1.8 18 3.6 NS 1.8 Bombrys (2009) 66 5 11 8 9 3 0 27 1.5 Abdel-Hady (2010) 211 12 3.3 7.6 0.9 6.6 0.9 NS 48 Vigil-De Gracia (2013) 131 10.3 7.6 14 1.5 4.5 0.8 22 8.7 Range 91n0 5-1n2 1.8-23 4.6-27 0.9-3.9 2.3-6.6 0.9-1n8 27-94 1.5-48 alncludes one maternal death. AKI = acute kidney injury; EGA = estimated gestational age; FGR = fetal-growth restriction; HELLP = hemolysis, elevated liver enzyme levels, low platelet count syndrome; NS = not stated; PMR = perinatal mortality rate; Pulm. = pulmonary. 9 percent in each group, the composite neonatal morbidity outcome was not improved 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. Expectant Management of Midtrimester Severe Preeclampsia


Obstentrics_Williams

Obstentrics_Williams. Expectant Management of Midtrimester Severe Preeclampsia Several small studies have focused on expectant management of severe preeclampsia syndrome bore 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 no neonates survived when delivered before 23 weeks, the Task Force (2013) recommends pregnancy termination in these cases. 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.


Obstentrics_Williams

Obstentrics_Williams. At least five observational studies of women with severe midtrimester preeclampsia who were managed expectantly have been published since 2005 (AbdelHady, 2010; Belghiti, 2011; Bombrys, Admit to L&D Contraindications to conservative management Eclampsia, pulmonary edema, HELLP syndrome Significant renal dysfunction, coagulopathy Frequent evaluation: vital signs, UOP Serial lab evaluation of re n.aI function and for HELLP syndrome Daily fetal assessment and evaluation of serial growth and amnionic fluid


Obstentrics_Williams

Obstentrics_Williams. Frequent evaluation: vital signs, UOP Serial lab evaluation of re n.aI function and for HELLP syndrome Daily fetal assessment and evaluation of serial growth and amnionic fluid FIGURE 40-14 Clinical management algorithm for severe preeclampsia at <34 weeks. HELLP = hemolysis, elevated liver enzyme levels, low platelet count; L&D = labor and delivery; MgS04= magnesium sulfate; UOP = urine output. (Adapted from the Society for 2008; Budden, 2006; Gaugler-Senden, Maternal-Fetal Medicine, 2011.) 2006). Maternal complications developed in 60 percent, and there was one maternal death. he perinatal mortality rate was 650 per 1000 births. At this time, no comparative studies attest to perinatal benefits of such expectant treatment versus early delivery in the face of serious maternal complications, which approach rates of 50 percent. We do not recommend such management.


Obstentrics_Williams

Obstentrics_Williams. 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 lower incidence of respiratory distress and improved fetal survival rates have been cited. hat said, only one randomized trial has evaluated corticosteroids given to hypertensive women for fetal lung maturation. his trial included 218 women with severe preeclampsia between 26 and 34 weeks' gestation who were randomly assigned to betamethasone or placebo administration (Amorim, 1999). Rates of neonatal complications that included respiratory distress, intraventricular hemorrhage, and death were reduced significantly when betamethasone was given compared with placebo. On the heaviy weighted negative side, there were two maternal deaths and 18 stillbirths. We add these indings to buttress our unenthusiastic acceptance of attempts to prolong gestation in many of these women (Alexander, 2015;


Obstentrics_Williams

Obstentrics_Williams. side, there were two maternal deaths and 18 stillbirths. We add these indings to buttress our unenthusiastic acceptance of attempts to prolong gestation in many of these women (Alexander, 2015; Bloom, 2003).


Obstentrics_Williams

Obstentrics_Williams. Taken in toto, these studies do not show overwhelming beneits compared with maternal risks for expectant management of severe preeclampsia in women with gestations from 24 to 32 weeks. Despite these caveats, the Society for MaternalFetal Medicine (201r1) has determined that such m�nagement is a reasonable alternative in selected women with severe preeclampsia before 34 weeks (Fig. 40-14). The Task Force (2013) supports this recommendation. As shown in Table 40-10, 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 rises with decreasing gestational age.


Obstentrics_Williams

Obstentrics_Williams. Our view is more conservative. Undoubtedly, the overriding reason to terminate pregnancies with severe preeclampsia is maternal safety. Indeed, it seems obvious that a delay to prolong gestation in women with severe preeclampsia may have serious maternal consequences (see Table 40-9). 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 by approximately 1 week. If undertaken, the caveats that mandate delivery shown in Table 40-10 should be strictly heeded. • Corticosteroids to Ameliorate HELLP Syndrome At least three randomized trials have evaluated the beneits of glucocorticoids given to improve the laboratory abnormalities TABLE 40-1 0. Indications for Delivery in Women Delivery ater Maternal Stabilization: Delay Delivery 48 hr If Possible: Thrombocytopenia < 1 OO,OOO/�L


Obstentrics_Williams

Obstentrics_Williams. TABLE 40-1 0. Indications for Delivery in Women Delivery ater Maternal Stabilization: Delay Delivery 48 hr If Possible: Thrombocytopenia < 1 OO,OOO/�L Hepatic transaminase levels twice upper limit of normal alnitial 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, 201n3.


Obstentrics_Williams

Obstentrics_Williams. associated with HELLP syndrome. First, Fonseca and associates (2005) randomly assigned 132 women with HELLP syndrome to either dexamethasone or placebo administration. Outcomes assessed included hospitalization length, recovery time of abnormal laboratory test results, resolution of clinical parameters, and complications that included acute renal fail ute, pulmonary edema, eclampsia, and death. None of these was signiicantly diferent between the two groups. In another study, 105 postpartum women with HELLP syndrome were assigned to dexamethasone or placebo treatment (Katz, 2008). Outcomes were analyzed similarly to the Fonseca study, and no advantage to dexamethasone was found (Fig. 40-15). In the third study, preeclamptic women were given either placebo or methylprednisolone if their platelet count was between 50,000 and 150,000/�L (Pourrat, 2016). No benefits were gained from corticosteroid therapy. Because of these indings, the 2013 Task Force does not recommend corticosteroid


Obstentrics_Williams

Obstentrics_Williams. platelet count was between 50,000 and 150,000/�L (Pourrat, 2016). No benefits were gained from corticosteroid therapy. Because of these indings, the 2013 Task Force does not recommend corticosteroid treatment for thrombocytopenia with HELLP syndrome.


Obstentrics_Williams

Obstentrics_Williams. In several preliminary studies, therapies have attempted to lower serum levels or mitigate the action of antiangiogenic factors. Some of these include therapeutic apheresis, done to lower sFlt-1 levels (Thadhani, 2016). Pravastatin has been given for preeclampsia prevention (Cleary, 2014). Sildenail citrate, a phosphodiesterase inhibitor, has been provided to promote vasodilation (Trapani, 2016; Vigil-De Gracia, 2016). In a recent randomized trial of 120 women with early-onset preeclampsia, an recombinant antithrombin infusion compared and occasionally anuria develops. There may be hemoglobinuria, but hemoglobinemia is rare. Often, facial and peripheral edema is pronounced, but it may be absent (Fig. 40-17). FIGURE 40-1 7 Severe edema in a young nullipara with antepartum preeclampsia. (Used with permission from Dr. Nidhi Shah.)


Obstentrics_Williams

Obstentrics_Williams. FIGURE 40-1 7 Severe edema in a young nullipara with antepartum preeclampsia. (Used with permission from Dr. Nidhi Shah.) As with severe preeclampsia, urinary output rises after delivery and is usually an early sign of improvement. With renal dysfunction, serum creatinine levels are serially 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, persisting and severe hypertension likely predicts underlying chronic vascular disease (Podymow, 2010).


Obstentrics_Williams

Obstentrics_Williams. In antepartum eclmpsia, labor may begin spontaneously shortly ater convulsions ensue and may progress rapidly. If the convulsions occur during labor, contractions may increase in frequency and intensity, and the duration oflabor may be shortened. Because of maternal hypoxemia and lactic acidemia caused by convulsions, fetal bradycardia oten follows a seixure (Fig. 40-18). he fetal heart rate usually recovers within 2 to 10 minutes (Ambia, 2018). If it persists more than about 10 minutes, another cause of bradycardia, such as placental abruption or imminent delivery, should be considered.