EARLY GESTOSIS. HYPERTENSIVE DISORDERS DURING PREGNANCY. PREECLAMPSIA, ECLAMPSIA.
prepared by Stelmakh O.
GESTOSIS OF PREGNANCY
GESTOSIS OF EARLY TERMS OF PREGNANCY
Ptyalism in pregnancy, or excessive salivation, is especially annoying for a small number of patients, sometimes approaching 1 liter production per day. Medical treatment with tincture of belladonna or atropine alter ptyalism only slightly so that reassurance of the time-limited nature of the problem is a mainstay of management.
At least 66 % of women experience nausea and 50 % emesis in the first trimester, with the frequency of these symptoms lessening as the second and third trimesters ensue. Classically, symptoms are predominantly present in the morning (“morning sickness”), but they may occur throughout the day and evening.
The genesis of pregnancy-induced nausea and vomiting is not clear. It may be that the hormonal changes of pregnancy are responsible. Chorionic gonadotropin, for instance, has been implicated on the basis that its levels are rather high at the same time that nausea and vomiting are most common.
Light, moderate and severe degrees of vomiting are distinguished.
Light degree of vomiting accompanying with 2-4 times per day episodes of vomiting after taking meals. general state of the woman is satisfactory, light tachycardia may be present.
Moderate degree of vomiting accompanying with 10 times and more per day episodes of vomiting which don’t from taking meals. Weight loss, ketosis, increased temperature are present.
Frequent small feedings and avoidance of foods that are unpleasant to the patient usually relieve symptoms to a manageable level. A variety of antiemetics can be prescribed if the above measures fail to provide adequate relief, but unfortunately, none is completely effective and all carry risks (Metoclopramide, Meclizine, Promethazine). Of historical interest is the compound medication Bendectin, a combination of the antihistamine doxylamine and vitamin B6 (pyrodoxine), which was reasonable effective as an antiemetic in pregnancy.
Severe degree of vomiting is also called as Hyperemesis gravidarum (intractable emesis during pregnancy) is a more severe form of nausea and vomiting, occurring in approximately 4 out of 1000 pregnancies.
Fortunately, hyperemesis gravidarum has become uncommon. This syndrome is defined as vomiting sufficiently pernicious to produce weight loss, dehydration, acidosis from starvation, alkalosis from loss of hydrochloric acid in vomitus, and hypokalemia. It appears to be related to high or rapidly rising serum levels of chorionic gonadotropin or estrogens. Goodwin and associates (1994) described significantly higher total as well as free b-subunits of chorionic gonadotropin concentrations in women with hyperemesis compared with asymptomatic controls. Hyperemesis may lead to transient hepatic dysfunction.
Dehydration is corrected as well as fluid and electrolyte deficits and acidosis or alkalosis. This requires appropriate amounts of sodium, potassium, chloride, lactate or bicarbonate, glucose, and water, all of which should be administered parenterally until vomiting has been controlled. Vomiting may be frequent and severe. Schwartz and Rossoff (1994) described a woman whose retching led to bilateral pneumothoraces and pneumomediastinum. A number of anti-emetics may be given to alleviate nausea and vomiting such as promethazine, prochlorperazine, and chlorpromazine. Nageotte and colleagues (1996) reported success with intravenous droperidol-diphenhydramine. For severe disease, metoclopramide may be given parenterally. This stimulates motility of the upper intestinal tract without stimulating gastric, biliary, or pancreatic secretions. Its anti-emetic properties apparently result from central antagonism of dopamine receptors. With persistent vomiting, appropriate steps should be taken to diagnose other diseases, such as gastroenteritis, cholecystitis, pancreatitis, hepatitis, peptic ulcer, pyelonephritis, and fatty liver of pregnancy.
In many instances, social and psychological factors contribute to the illness (Deuchar, 1995). With correction of these circumstances, the woman usually improves remarkably while hospitalized, only to relapse after discharge. Positive assistance with psychological and social problems is beneficial.
Godsey and Newman (1991) studied 140 women admitted for hyperemesis to the Medical University of South Carolina Hospital. In 27 percent of these women, multiple admissions were necessary. In some women with persistent and severe disease, parenteral nutrition is used (Levine and Esser, 1988). Enteral nutrition also has been successfully used after acute nausea and vomiting subside (Boyce, 1992).
firmed at surgery.
Rare forms of gestosis in pregnancy:
1. dermatosis gravidarum, clinic, diagnosis, treatment;
2. tetania gravidarum, clinic, diagnosis, treatment;
3. osteomalacia gravidarum, clinic, diagnosis, treatment;
4. acute fatty liver of pregnancy, clinic, diagnosis, differential diagnosis (viral hepatitis, cholestasis), treatment;
5. bronchial asthma of pregnancy, clinic, diagnosis, differential diagnosis, treatment.
Acute fatty liver of pregnancy is a rare complication of pregnancy, but its severity and maternal mortality rate of 30 % make its timely diagnosis and treatment of importance. It is usually occurs late in pregnancy in primagravidas and characterized by vague gastrointestinal symptoms becoming worse over several days’ time. Thereafter headache, mental confusion, and epigastric pain may ensue, and if untreated, there may be rapid development of coagulopathy, coma, multiple organ failute and death. Laboratory findings include an initial modest elevation in bilirubin and an elevation of transaminase levels. Treatment of this serious complication is correction of coagulopathy and electrolyte imbalances, cardiorespiratory support, and delivery as feasible by the vaginal route, if possible.
Fig.1 Fatty liver of pregnancy. Electron photomicrograph of two hepatocytes containing numerus microvesicular fat droplets (*). The nuclei (N) remain centered within the cells, unlike with the case of macrovesicular fat deposition. (Courtesy of Dr. Don Wheeler.)
Fig.2 Computerized tomograph in severely preeclamptic woman at term shows intrahepatic and subcapsular hemorrhage in right lobe of liver. (From Howard and Jones, 1993, with permission.)
ETIOLOGY, CLINICS, DIAGNOSIS AND TREATMENT OF PREGNANCY INDUCED HYPERTENSION
The term pregnancy-induced hypertension (PIH) has not been discarded, because the development of hypertension, especially in nulliparas, cannot be differentiated from transient hypertension except retrospectively. Therefore, the development of hypertension in a previously normotensive pregnant woman should and must be considered potentially dangerous to both her and her fetus. Thus, clinical situations should be designated pregnancy-induced hypertension and considered precursors to preeclampsia and eclampsia until after safe management of pregnancy. At this time, it may then be appropriate to reclassify the hypertension as transient.
1. primigravid status, new paternity;
2. family history of preeclampsia or eclampsia;
3. previous preeclampsia or eclampsia;
4. extremes of maternal age (younger than 20 y or older than 35 years of age);
5. preexisting hypertensive vascular, autoimmune, or renal disease;
6. preexisting renal, pulmonary, thyroid dysfunction;
7. Diabetes mellitus;
8. Multiple gestation;
9. Nonimmune or alloimmune fetal hydrops;
10. Hydatidiform Mole.
1. Generalized vasospasm.
4. Disseminated intravascular coagulopathy.
5. Metabolic impairment as result of hypoxia.
6.Organ dysfunction – renal, hepatic, cardiac and pulmonary, hematological, cerebral problems.
7. Placental dysfunction because the vasospastic changes.
Theories about the Cause of Pregnancy-induced Hypertension
Any satisfactory theory must account for the observation that pregnancy-induced or -aggravated hypertension is very much more likely to develop in the woman who (1) is exposed to chorionic villi for the first time; (2) is exposed to a superabundance of chorionic villi, as with twins or hydatidiform mole; (3) has preexisting vascular disease; or (4) is genetically predisposed to hypertension developing during pregnancy. Although chorionic villi are essential, they need not support a fetus or be located within the uterus.
The risk of pregnancy-induced hypertension is appreciably enhanced in circumstances where formation of blocking antibodies to antigenic sites on the placenta might be impaired. This may arise during immunosuppressive therapy to protect a renal transplant; where effective immunization by a previous pregnancy is lacking, as in first pregnancies; or where the number of antigenic sites provided by the placenta is unusually great compared with the amount of antibody, as with multiple fetuses (Beer, 1978). Strickland and associates (1986), however, provided data that do not support “immunization” by a previous pregnancy. They analyzed the outcomes of over 29,000 pregnancies at Parkland Hospital and reported that pregnancy-induced hypertension was decreased only slightly (22 versus 25 percent) in women who previously had aborted and were now having their first baby. The immunization concept is supported, however, by the observation that preeclampsia develops more frequently in multiparous women impregnated by a new consort (Feeney and Scott, 1980; Robillard and colleagues, 1994). Also, Dekker (1996) provided evidence that oral sex before pregnancy provided protection against preeclampsia. He hypothesized that “tolerization” to paternal antigens was operative.
Cooper and associates (1988) and Jagadeesan (1988) found no association of complement fractions C3, C3F, and CH50 with preeclampsia, and Hofmeyr and colleagues (1991) reported C4 concentrations to be reduced only in hypertensive pregnant women with proteinuria. Simon and co-workers (1988) reported no association of histocompatibility antigens HLA-A and -B with preeclampsia. They did report a higher incidence of recurrent hypertension in pregnancy in women with HLA-DR4 phenotypes, an observation consistent with an increased incidence of chronic hypertension and not preeclampsia. As cited previously, Hoff and associates (1992) found a maternal–fetal HLA-DR relationship with pregnancy-induced hypertension. Haeger and associates (1992) reported that complement, neutrophils, and macrophages are activated in women with severe preeclampsia. Despite such appealing theories, convincing proof of clinical significance is lacking.
Cooper and Liston (1979) examined the possibility that susceptibility to preeclampsia is dependent upon a single recessive gene. They calculated the expected first-pregnancy frequencies of daughters of women with eclampsia; daughters-in-law served as controls. The frequencies calculated by them and those actually observed by Chesley and co-workers (1968) in daughters and daughters-in-law of women with eclampsia are remarkably close. Subsequently, Chesley and Cooper (1986) concluded that the single-gene hypothesis fits well, but multifactorial inheritance cannot be excluded. Ward and associates (1993) reported that women carrying the angiotensinogen gene variant T235 had a higher incidence of pregnancy-induced hypertension. Morgan and colleagues (1995), however, could not confirm these findings. Although Arngrimsson and co-workers (1994) found no association between the renin gene and preeclampsia, Dizon-Townsend and colleagues (1996) found a higher incidence of factor V Leiden mutations in preeclamptic women.
Various dietary deficiencies have been suspected as a cause of preeclampsia; however, these hypotheses lack supportive data. For example, because pregnancy “depletes” a woman nutritionally, preeclampsia should be more common in multiparous women compared with nulliparas; but it is not. Moreover, various types of dietary supplementation do not decrease the frequency of hypertension. Finally, the incidence of hypertension is higher in obese women, and the incidence increases with prepregnancy weight (Sibai and co-workers, 1995a). Zlatnik and Burmeister (1983) provided convincing evidence that the incidence of preeclampsia is not related to the level of dietary protein.
Calcium deficiency has been implicated by some, and calcium supplementation appears to reduce the risk of preeclampsia (Carroli and colleagues, 1994). Belizán (1991), López-Jaramillo (1989), Sanchez-Ramos (1994b), and their associates reported that after midpregnancy, daily dietary supplementation with 2 g of elemental calcium significantly reduced the incidence of hyper-tension. Conversely, Sanchez-Ramos and co-workers (1995) found that severe preeclampsia was not prevented in women with mild preeclampsia who were treated with the 2-g dose. Certainly, decreased urinary excretion of calcium has been documented in preeclamptic and future hypertensive women (August and associates, 1992; Sanchez-Ramos and colleagues, 1991). What remains to be established is whether there is decreased dietary intake, altered calcium absorption, or intrinsic renal tubular dysfunction. Tolaymat and colleagues (1994) have provided evidence that calcium absorption is not impaired in preeclampsia. The apparent effectiveness of supplemental calcium may be explained by an overriding of impaired absorption or defective renal handling of calcium. Other possibilities exist, however, including changes in vasodilation and vascular reactivity mediated by increased prostacyclin or nitric oxide production (Gant and Gilstrap, 1990; López-Jaramillo and colleagues, 1990; St-Louis and Sicotte, 1992).
A wide variety of cellular and serum vasoactive factors likely play a role in the etiology or pathogenesis of pregnancy-induced hypertension. Endothelins are potent vasoconstrictors, and endothelin-1 is the only species produced by human endothelium (Mastrogiannis and co-workers, 1991). Plasma endothelin-1 is increased in normotensive laboring and nonlaboring women, and even higher levels have been reported in preeclamptic women (Clark, 1992; Mastrogiannis, 1991; Nova, 1991; Schiff, 1992; and their associates). Otani and colleagues (1991), however, did not observe increased plasma endothelin levels, and Barton and associates (1993) did not find increased urinary endothelin-1 levels in preeclamptic women.
Nitric oxide, previously termed endothelium-derived relaxing factor (EDRF), is synthesized by endothelial cells from L-arginine (Palmer and associates, 1988). It is a potent vasodilator whose absence or decreased concentration might play a role in the etiology of pregnancy-induced hypertension. Inhibition of nitric oxide has been shown to increase mean arterial pressure, decrease heart rate, and reverse the pregnancy-induced refractoriness to vasopressors in some animals. Equally important, it appears to maintain the normal low-pressure vasodilated state characteristic of fetoplacental perfusion in the sheep, guinea pig, and human (Chang and colleagues, 1992; Myatt and co-workers, 1992; Weiner and associates, 1992). Kupferminc and collaborators (1996) found no differences in circulating nitrite and nitrate levels in women with severe preeclampsia compared with normal controls. Morris and colleagues (1996) recently provided a scholarly review of these interactions.
Wang and colleagues (1991a,b) reported that normotensive pregnancies are characterized by progressive increases in the ratios of prostacyclin to thromboxane and vitamin E to lipid peroxides. They concluded that the vasodilating actions of prostacyclin and the antioxidant activity of vitamin E were favored progressively with advancing gestation. With increasing severity of preeclampsia, both ratios were progressively reversed. Thus, increased thromboxane resulted in increased vasospasm and platelet destruction, and increased lipid peroxides increased endothelial damage. Davidge and associates (1992), using a different assay, found similar findings in antioxidant activity in preeclamptic women.
Cigarette smoking has been reported to reduce the incidence of pregnancy-induced hypertension (Klonoff-Cohen and co-workers, 1993; Sibai and colleagues, 1995a). Smoking may stimulate a decrease in the specific activity of platelet-activating factor-acetylhydrolase. This enzyme is known to degrade platelet-activating factor, an extremely powerful vasodilator and platelet-aggregating factor (Miyaura and associates, 1992). The decrease in PAF-acetylhydrolase would lead to an increase in plasma platelet activating factor and vasodilation, a known effect of normal pregnancy (Maki and colleagues, 1993).
Evidence has accumulated for a pathogenic model of preeclampsia whereby an immunologically mediated deficiency in the trophoblast invasion of the placental bed spiral arteries leads to a poorly perfused fetoplacental unit. This results in the secretion of a factor (or factors) into the maternal circulation, which leads to “activation” of the vascular endothelium, with the clinical syndrome resulting from widespread changes in endothelial cell function (de Groot and colleagues, 1995; Friedman and associates, 1995; Roberts and Redman, 1993; Smárason and co-workers, 1996). Intact endothelium has anticoagulant properties and blunts the response of vascular smooth muscle to agonists. Damaged endothelium activates endothelial cells to promote coagulation, and increases sensitivity to vasopressor agents. Further evidence of endothelial activation in preeclampsia includes characteristic changes in glomerular capillary endothelial morphology, increased capillary permeability, and elevated blood levels of substances associated with endothelial cell activation (see the preceding section). Serum from preeclamptic women stimulates cultured endothelial cells to produce greater amounts of prostacyclin than sera from normotensive pregnant women.
The nature of the circulating factor(s) and the mechanism by which endothelium is activated are not known. Studies by Endresen and associates (1995) indicate that preeclamptic sera are not cytotoxic to endothelial cells. Baker and colleagues (1995) have shown that vascular endothelial growth factor (VEGF) levels are elevated in serum of preeclamptic women, and postulate that this may activate endothelial cells. Similarly, platelet-derived growth factor may be operative (Gurski and colleagues, 1996; Krueger and co-workers, 1996).
Pathophysiology of Preeclampsia–Eclampsia
Vasospasm is basic to the pathophysiology of preeclampsia–eclampsia. This concept, first advanced by Volhard (1918), is based upon direct observations of small blood vessels in the nail beds, ocular fundi, and bulbar conjunctivae, and it has been surmised from histological changes seen in various affected organs (Hinselmann, 1924; Landesman and co-workers, 1954). Vascular constriction causes resistance to blood flow and accounts for the development of arterial hypertension. It is likely that vasospasm itself also exerts a damaging effect on vessels. Moreover, angiotensin II causes endothelial cells to contract. These changes likely lead to endothelial cell damage and interendothelial cell leaks through which blood constituents, including platelets and fibrinogen, are deposited subendothelially (Brunner and Gavras, 1975). The vascular changes, together with local hypoxia of the surrounding tissues, presumably lead to hemorrhage, necrosis, and other end-organ disturbances that have been observed at times with severe preeclampsia. With this scheme, fibrin deposition is then likely to be prominent, as seen in fatal cases (McKay, 1965).
Increased Pressor Responses
Normally pregnant women develop refractoriness to infused vasopressors (Abdul-Karim and Assali, 1961). Increased vascular reactivity to pressors in women with early preeclampsia has been identified by Raab and co-workers (1956) and Talledo and associates (1968) using either norepinephrine or angiotensin II, and by Dieckmann and Michel (1937) and Browne (1946) using vasopressin. Gant and co-workers (1973) demonstrated that increased vascular sensitivity to angiotensin II clearly preceded the onset of pregnancy-induced hypertension. As shown in Figure 31–1 , nulliparas who remained normotensive were refractory to the pressor effect of infused angiotensin II, while women who subsequently became hypertensive lost this refractoriness weeks before the onset of hypertension. Of women who required more than 8 ng/kg per minute of angiotensin II to provoke a standardized pressor response between 28 and 32 weeks, 90 percent remained normotensive throughout pregnancy. Conversely, among normotensive nulliparas who required less than 8 ng/kg per minute at 28 to 32 weeks, 90 percent subsequently developed overt hypertension. Similar results from 231 women were subsequently reported by Öney and Kaulhausen (1982).
Supine Pressor Response
A hypertensive response induced by having the woman assume the supine position after lying laterally recumbent was demonstrated in some pregnant women by Gant and co-workers (1974b). The majority of nulliparous women at 28 to 32 weeks who had increased diastolic pressure of at least 20 mm Hg when the maneuver was performed later developed pregnancy-induced hypertension. Conversely, most women whose blood pressure did not become elevated when this was done remained normotensive. Although not all investigators have reported equally good predictive results (Dekker and Sibai, 1991), this so-called rollover test remains an effective screening test to identify asymptomatic women who will likely develop pregnancy-induced hypertension (O’Brien, 1990). Women who demonstrated a supine pressor response were also abnormally sensitive to infused angiotensin II, while those without a hypertensive response were normally refractory. The mechanism by which this maneuver incites a rise in blood pressure is not clear, but it is likely a manifestation of increased vascular responsitivity or sympathetic overactivity in those who will later develop pregnancy-induced hypertension (Sander and colleagues, 1995).
Women with underlying chronic hypertension have similar responses. An identically performed study of angiotensin II pressor responsiveness was conducted in women whose pregnancies were complicated by chronic hypertension (Gant and colleagues, 1977). Two groups were identified on the basis of clinical outcome and serial determinations of vascular reactivity to infused angiotensin II. All women were refractory to angiotensin II between 21 and 25 weeks; however, women who subsequently developed pregnancy-aggravated hypertension began to lose this refractoriness after 27 weeks.
It appears unlikely that the normally blunted pressor response to angiotensin II is due to down-regulation or decreased affinity of angiotensin II vascular smooth-muscle receptors (MacKanjee and associates, 1991). The metabolic clearance rate of angiotensin II is not altered in women with pregnancy-induced hypertension (Magness and co-workers, 1994). Other factors may be operative; for example, aldosterone secretion is increased strikingly in pregnant women. This is modulated by the effects of angiotensin II on the zona glomerulosa of the adrenal cortex. Based on the findings of a number of studies, it was concluded that the blunted pressor response was due principally to decreased vascular responsiveness mediated in part by vascular endothelial synthesis of prostaglandins or prostaglandin-like substances (Cunningham and associates, 1975; Gant and co-workers, 1974a). For example, refractoriness to angiotensin II in pregnant women is abolished by large doses of the prostaglandin synthase inhibitors (Everett and colleagues, 1978).
The exact mechanism by which prostaglandin(s) or related substances mediate vascular reactivity during pregnancy is unknown. Goodman and colleagues (1982) reported increased concentrations of vasodilating prostaglandins during normal pregnancy. Everett and colleagues (1978) demonstrated that large doses of indomethacin and aspirin increased vascular sensitivity to infused angiotensin II. They postulated that prostaglandin(s) synthesis was suppressed, returning the vascular system to a nonpregnant sensitive state. Sanchez-Ramos and colleagues (1987) documented a diminished vascular response within 2 hours of ingestion of 40 mg of aspirin likely due to a preferential suppression of the vasoconstrictor thromboxane.
Walsh (1985) showed that, compared with normal pregnancy, placental production of prostacyclin is decreased significantly and thromboxane A2 significantly increased in preeclampsia. Walsh (1988) reported that progesterone production is increased in vitro in placentas of preeclamptic pregnancies, and hypothesized that increased progesterone concentrations may inhibit prostacyclin production. Spitz and colleagues (1988) reported that 81 mg of aspirin given daily to future hypertensive women restored angiotensin II refractoriness by suppressing synthesis of thromboxane A2 by about 75 percent; however, prostacyclin synthesis was decreased by 20 percent and prostaglandin E2 by 30 percent. Thus, arachidonic acid, an essential fatty acid, is converted by cyclooxygenase into prostacyclin, prostaglandin E2, and thromboxane. In preeclamptic women, thromboxane is increased and prostacyclin and prostaglandin E2 are decreased, resulting in vasoconstriction and sensitivity to infused angiotensin II.
Low-dose aspirin therapy markedly decreases thromboxane production but only partially blocks prostacyclin and prostaglandin E2 production, allowing these two vasodilating prostanoids to restore refractoriness to infused angiotensin II.
Fig. Arachidonic acid (AA) may be converted into prostacyclin (PGI2), prostaglandin E2 (PGE2), and thromboxane A2 (TxA2). Low-dose aspirin therapy usually blocks thromboxane A2 production more than production of prostacyclin and prostaglandin E2.
Brown and associates (1990) reported similar findings in angiotensin II-sensitive women rendered refractory to angiotensin II by low-dose aspirin. In women remaining sensitive despite aspirin, however, all three prostaglandins were reduced significantly by low-dose aspirin. These observations indicate that vessel reactivity may be mediated through a delicate balance of production and metabolism of at least these three vasoactive prostaglandins. In this scheme, preeclampsia may follow inappropriately increased production or destruction of one prostaglandin, diminished synthesis or release of the other, or perhaps both.
The role of nitric oxide—endothelium-derived relaxing factor—or its endothelial loss is unclear. Withdrawal of nitric oxide from pregnant rats and guinea pigs results in the development of a clinical picture similar to preeclampsia (Conrad and Vernier, 1989; Weiner and associates, 1989). Nitric oxide appears to be important in the maintenance of a low fetal vascular resistance in the placental circulation (Chaudhuri and co-workers, 1991; Gude and co-workers, 1990; Myatt and associates, 1991). Decreased nitric oxide release or production has not been shown to develop prior to the onset of hypertension. Thus, the changes in nitric oxide concentrations in women with pregnancy-induced hypertension appear to be the consequence of hypertension and not the inciting event (Morris and colleagues, 1996).
At least two vasoconstrictor mechanisms may be operative in preeclamptic women in whom arachidonic acid is converted by cyclooxygenase into thromboxane A2 with an accompanying reduction of prostacyclin and prostaglandin E2 (Catella and associates, 1990; Fitzgerald and colleagues, 1990; Mitchell and Koenig, 1991; Tannirandorn and co-workers, 1991). This pathway is responsive to low-dose aspirin therapy. The second route is via the lipoxygenase pathway, which results in an increased placental production of 15-hydroxyeicosatetraenoic acid (15-HETE). This inhibits prostacyclin production, resulting in further vasoconstriction (Mitchell and Koenig, 1991). Biagi and co-workers (1990) also reported an increased lipoxygenase pathway activation in placentas from hypertensive women.
Maternal and Fetal Consequences of Preeclampsia–Eclampsia
Deterioration of function in a number of organs and systems, presumably as a consequence of vasospasm, has been identified in severe preeclampsia and eclampsia. For descriptive purposes, these effects are separated into maternal and fetal consequences; however, these aberrations often occur simultaneously. Although there are many possible maternal consequences of pregnancy-induced hypertension, for simplicity these effects are considered by analysis of cardiovascular, hematological, endocrine and metabolic, and regional blood flow changes with subsequent end-organ derangements. The major cause of fetal compromise occurs as a consequence of reduced uteroplacental perfusion.
Hemodynamic changes accompanying severe preeclampsia and eclampsia have been studied by a number of investigators. Key issues addressed include the cardiovascular status of these women before treatment, as well as volume expansion and pharmacological attempts to relieve vasospasm. Elucidation of the mechanisms that cause heart failure and pulmonary edema complicating the course of some women has also been pursued. In assessing cardiac function, four areas must be addressed:
(1) preload—end-diastolic pressure and chamber volume;
(2) afterload—intramyocardial systolic tension or resistance to ejection;
(3) contractile or inotropic state of the myocardium;
and (4) heart rate.
Variables that define cardiovascular status range from high cardiac output with low vascular resistance to low cardiac output with high vascular resistance. Similarly, left ventricular filling pressures, estimated by pulmonary capillary wedge pressure determination, range from low to pathologically high. At least three factors may explain these differences: (1) women with preeclampsia might present with a spectrum of cardiovascular findings dependent upon both severity and duration, (2) chronic underlying disease may modify the clinical presentation, or (3) therapeutic interventions may significantly alter these findings. It is likely that more than one of these is operative.
Cardiac function was hyperdynamic in all women, but filling pressures varied markedly.
Hemodynamic data obtained prior to active treatment of preeclampsia identified normal left ventricular filling pressures, high systemic vascular resistances, and hyperdynamic ventricular function. Benedetti (1980a), Hankins (1984), and their associates reported similar findings in women with severe preeclampsia or eclampsia who were being treated with magnesium sulfate, hydralazine, and intravenous crystalloid given at 75 to 100 mL/hour. Cardiac function in these women was appropriate, and the lower systemic vascular resistance was most likely due to hydralazine treatment.
Women similarly treated with magnesium sulfate and hydralazine plus aggressive intravenous therapy or volume expansion had the lowest systemic vascular resistances and highest cardiac outputs. A comparison of volume-restricted women with those hydrated aggressively shows hyperdynamic ventricular function in both groups, and two responses with respect to left ventricular stroke work index and pulmonary capillary wedge pressure . Fluid restriction resulted in wedge pressures of less than 10 mm Hg, and most were less than 5 mm Hg. Thus, hyperdynamic ventricular function was largely a result of low wedge pressures and not a result of augmented left ventricular stroke work index, which more directly measures myocardial contractility. By comparison, women given appreciably larger volumes of fluid commonly had pulmonary capillary wedge pressures that exceeded normal; however, ventricular function remained hyperdynamic because of increased cardiac output. Subsequently, Cotton and co-workers (1988) reported findings from 45 women with severe preeclampsia or eclampsia and described high systemic vascular resistance and hyperdynamic ventricular function in most. It is reasonable to conclude that aggressive fluid administration given to women with severe preeclampsia causes normal left-sided filling pressures to become substantively elevated, while increasing an already normal cardiac output to supranormal levels.
Easterling and colleagues (1990) provided evidence that preeclampsia is caused by high cardiac output. In their prospective longitudinal study of 179 nulliparas, they found that women who subsequently developed preeclampsia had elevated cardiac outputs throughout pregnancy. They challenged the concept of hypoperfusion as the hallmark of pathophysiology in preeclampsia. These intriguing results need to be corroborated.
Hemoconcentration in women with eclampsia was emphasized earlier by Dieckmann (1952). Pritchard and co-workers (1984) reported that in eclamptic women hypervolemia is usually absent . Women of average size should have a blood volume of nearly 5000 mL during the last several weeks of a normal pregnancy, compared with about 3500 mL when nonpregnant. With eclampsia, however, much or all of the anticipated 1500 mL of blood normally present late in pregnancy is absent. The virtual absence of an expanded blood volume is likely the consequence of generalized vasoconstriction made worse by increased vascular permeability. In women with preeclampsia, these differences are not as marked (Silver and Seebeck, 1996).
Dieckmann (1952) believed that clinical improvement was characterized by hemodilution, as reflected by a fall in hematocrit. An acute fall in hematocrit is more likely the consequence of blood loss at delivery in the absence of normal pregnancy hypervolemia; or occasionally it is the result of intense erythrocyte destruction, as described below.
In the absence of hemorrhage, the intravascular compartment in eclamptic women is usually not underfilled. Vasospasm has contracted the space to be filled; the reduction persists until after delivery when the vascular system typically dilates, blood volume increases, and hematocrit falls. The woman with eclampsia, therefore, is unduly sensitive to vigorous fluid therapy administered in an attempt to expand the contracted blood volume to normal pregnancy levels. She is sensitive as well to even normal blood loss at delivery.
Hematological abnormalities develop in some, but certainly not all, women who develop pregnancy-induced or -aggravated hypertension. These include thrombocytopenia, which at times may become so severe as to be life threatening; the level of some plasma clotting factors may be decreased; and erythrocytes may be so traumatized that they display bizarre shapes and undergo rapid hemolysis.
Hematological changes consistent with intravascular coagulation, and less often erythrocyte destruction, may complicate preeclampsia and especially eclampsia. Renewed interest in these changes has led to the concept by some investigators that disseminated intravascular coagulation is not only a characteristic feature of preeclampsia but also plays a dominant role in its pathogenesis.
Since the early description by Pritchard and co-workers (1954) of an eclamptic coagulopathy, we have found little evidence that it is common. Thrombocytopenia, infrequently severe, was the most common finding. Serum fibrin degradation products were elevated only occasionally. Nolan and associates (1993) found significant elevations of D-dimer fragment of fibrin degradation with preeclampsia; however, these were clinically insignificant. Unless some degree of placental abruption develops, plasma fibrinogen does not differ remarkably from levels found late in normal pregnancy. Similar results have been reported by Leduc and associates (1992). The thrombin time was somewhat prolonged in a third of the cases of eclampsia even when elevated levels of fibrin degradation products were not identified. The reason for this elevation is not known, but it has been attributed to hepatic derangements discussed subsequently. The coagulation changes just described are also identified in women with severe preeclampsia, but are certainly no more common. These observations in eclampsia are most consistent with the concept that coagulation changes are the consequence of preeclampsia–eclampsia, rather than the cause.
Maternal thrombocytopenia can be induced acutely by preeclampsia–eclampsia. After delivery, the platelet count will increase progressively to reach a normal level within a few days (Katz and associates, 1990; Romero and colleagues, 1989). The frequency and intensity of maternal thrombocytopenia vary in different studies, apparently dependent upon the intensity of the disease process, the length of delay between the onset of preeclampsia and delivery, and the frequency with which platelet counts are performed (Leduc and associates, 1992). Overt thrombocytopenia, defined by a platelet count less than 100,000/mL, is an ominous sign. It indicates severe disease and delivery is usually indicated because the platelet count most often continues to decrease.
The cause of the thrombocytopenia is not known. Platelet aggregation is increased in preeclamptic women (Torres and associates, 1996). Immunological processes or simply platelet deposition at sites of endothelial damage may be the cause (Pritchard and colleagues, 1976). Samuels and colleagues (1987) performed direct and indirect antiglobulin tests and found that platelet-bound and circulating platelet-bindable immunoglobulin were increased in preeclamptic women and their neonates. They interpreted these findings to suggest platelet surface alterations. Burrows and colleagues (1987) reported that platelets from preeclamptic women were more likely to have platelet-associated IgG, even if thrombocytopenia did not develop. Although they believed this mechanism implied an autoimmune process, IgG could also be bound to platelets damaged by any mechanism.
Kelton and colleagues (1985) showed that thrombocytopenia with preeclampsia was frequently associated with a prolonged bleeding time. This was true even with normal platelet levels. They attributed this to impaired thromboxane synthesis. Kilby and associates (1990) and Barr and colleagues (1989) found increased intracellular free calcium concentrations in platelets from preeclamptic women. Louden and colleagues (1991) interpret this and other evidence to mean that platelets from preeclamptic women are exhausted, that is, platelet aggregation and release are decreased.
The clinical significance of thrombocytopenia, in addition to the obvious impairment in coagulation, is that it reflects the severity of the pathological process. In general, the lower the platelet count, the greater are maternal and fetal morbidity and mortality (Leduc and co-workers, 1992; Verhaeghe and colleagues, 1991). The addition of elevated liver enzymes to this clinical picture is even more ominous. Weinstein (1982) referred to this combination of events as the HELLP syndrome—that is, hemolysis (H), elevated liver enzymes (EL), and low platelets (LP) (see “HELLP Syndrome” below ).
Thiagarajah and co-workers (1984) and Weinstein (1985) reported thrombocytopenia in neonates whose mothers had preeclampsia. Conversely, Pritchard and colleagues (1987), in a large clinical study, did not observe severe thrombocytopenia in the fetus or infant at or very soon after delivery. No cases of fetal or neonatal thrombocytopenia were identified, despite severe maternal thrombocytopenia. Thrombocytopenia did develop later in some of these infants after hypoxia, acidosis, and sepsis developed. Hence, maternal thrombocytopenia in hypertensive women is not a fetal indication for cesarean delivery.
Thrombocytopenia that accompanies severe preeclampsia and eclampsia may be accompanied by evidence of erythrocyte destruction characterized by hemolysis, schizocytosis, spherocytosis, reticulocytosis, hemoglobinuria, and occasionally hemoglobinemia (Pritchard and colleagues 1954, 1976). These derangements result in part from microangiopathic hemolysis, and human and animal studies are suggestive that intense vasospasm causes endothelial disruption, with platelet adherence and fibrin deposition. Cunningham and associates (1985) described erythrocyte morphological characteristics using scanning electron microscopy. Women with eclampsia, and to a lesser degree those with severe preeclampsia, demonstrated schizocytosis and echinocytosis but not spherocytosis when compared with normally pregnant women. Sanchez-Ramos and colleagues (1994a) described increased erythrocyte membrane fluidity in women with HELLP syndrome and postulated that these changes predispose to hemolysis.
Other Clotting Factors
A severe deficiency of any of the soluble coagulation factors is very uncommon in severe preeclampsia–eclampsia unless another event coexists that predisposes to consumptive coagulopathy, such as placental abruption or hepatic infarction.
Antithrombin III has been reported to be lower in women with preeclampsia compared with normally pregnant women and those with chronic hypertension (Chang and co-workers, 1992; Saleh and associates, 1987; Weiner and associates, 1985). Unfortunately, early hope that antithrombin III levels could be used to predict the future development of pregnancy-induced hypertension and separate chronic hypertensive women from those with preeclampsia has not proven to be true (Sen and colleagues, 1994). Fibronectin, a glycoprotein associated with vascular endothelial cell basement membrane, is elevated in women with preeclampsia (Brubaker, 1992; Saleh, 1988; Taylor, 1991; and their associates). Hsu and colleagues (1995) also reported that thrombomodulin was elevated with severe disease. Ballegeer and associates (1992) and Sen and co-workers (1994) reported that fibronectin and laminin were increased 4 weeks prior to hypertension. These observations are consistent with others that preeclampsia causes vascular endothelial injury with subsequent hematological aberrations. The clinical utility of serial antithrombin III or fibronectin measurements for the prediction, diagnosis, and management of preeclampsia awaits further evaluation.
Thrombin levels are elevated in normal and preeclamptic women. This is likely due to an enhanced inactivation of protein C by a1-antitrypsin, which is increased in preeclampsia but not chronic hypertension (De Boer and co-workers, 1989; Espaa and associates, 1991). This results in an increased level of activated protein C/a1-antitrypsin complex. Protein C inhibitor also appears to be decreased by kallikrein, which is increased as a consequence of activation of the intrinsic coagulation pathway.
Endocrine and Metabolic Changes
Plasma levels of renin, angiotensin II, and aldosterone are increased during normal pregnancy. Pregnancy-induced hypertension results in a decrease of these values toward the normal nonpregnant range (Weir and colleagues, 1973). With sodium retention, hypertension, or both, renin secretion by the juxtaglomerular apparatus decreases. Because renin catalyzes the conversion of angiotensinogen to angiotensin I (which is then transformed into angiotensin II by converting enzyme), angiotensin II levels decline, resulting in a decrease in aldosterone secretion. Despite this, women with preeclampsia avidly retain infused sodium (Brown and colleagues, 1988b).
Another potent mineralocorticoid, deoxycorticosterone (DOC), is increased strikingly in third-trimester plasma. Its increase is not from increased secretion by maternal adrenal glands but from conversion from plasma progesterone. Thus, it is not reduced by sodium retention or hypertension, and it may play a role in the pathogenesis or perpetuation of preeclampsia.
Antidiuretic hormone activity is normal or even low (Elias and colleagues, 1988). Plasma chorionic gonadotropin levels are elevated inconstantly; conversely, placental lactogen levels are reduced inconstantly.
Atrial natriuretic peptide is released upon atrial wall stretching from blood volume expansion. It is vasoactive and promotes sodium and water excretion likely by inhibiting aldosterone, renin activity, angiotensin II, and vasopressin. This peptide is increased in normal pregnancy. Atrial natriuretic peptide is increased substantively in women with preeclampsia. With volume expansion, there is an augmented release of the compound in preeclamptic compared with normotensive pregnant women. Increases in atrial natriuretic peptide following volume expansion result in comparable increases in cardiac output and decreases in peripheral vascular resistance in both normotensive and preeclamptic women (Nisell and associates, 1992). This observation may in part explain observations of a fall in peripheral vascular resistance following volume expansion in preeclamptic women.
Ouabain-like natriuretic factor is being studied in pregnancy because it is elevated in essential hypertension. It cross-reacts with some antidigoxin antibodies, and because of this, it also is called digoxin-like immunoreactive substance. The factor inhibits the sodium-potassium-ATPase pump, which causes increased peripheral vascular resistance. Ouabain-like natriuretic factor is increased in normal pregnancy. It is progressively more increased in women with pregnancy-induced hypertension alone, and even more increased in those with preeclampsia (Gregoire and colleagues, 1988; Kaminski and associates, 1991).
Fluid and Electrolyte Changes
Commonly, the volume of extracellular fluid in women with severe preeclampsia–eclampsia has expanded beyond the normally increased volume that characterizes pregnancy. The mechanism responsible for the pathological expansion is not clear. Edema is evident at a time when, paradoxically, aldosterone levels are reduced compared with the remarkably elevated levels of normal pregnancy. As discussed earlier, however, plasma deoxycorticosterone levels remain elevated, but they are not consistently greater than those in normotensive women. Electrolyte concentrations do not differ appreciably from those of normal pregnancy unless there has been vigorous diuretic therapy, sodium restriction, or administration of water with sufficient oxytocin to produce antidiuresis. Edema does not ensure a poor prognosis, and absence of edema does not ensure a favorable outcome.
Following an eclamptic convulsion, the bicarbonate concentration is lowered due to lactic acid acidosis and compensatory respiratory loss of carbon dioxide. The intensity of acidosis relates to the amount of lactic acid produced and its metabolic rate, as well as the rate at which carbon dioxide is exhaled.
During normal pregnancy, renal blood flow and glomerular filtration rate are increased appreciably. With development of preeclampsia, renal perfusion and glomerular filtration are reduced. Levels that are much below normal nonpregnant values are the consequence of severe disease. Plasma uric acid concentration is typically elevated, especially in women with more severe disease. The elevation exceeds the reduction in glomerular filtration rate and creatinine clearance that accompanies preeclampsia (Chesley and Williams, 1945). Despite this, plasma uric acid measurements are generally of little practical value for diagnosis, management, or prognosis.
In the majority of preeclamptic women, mild to moderately diminished glomerular filtration appears to result from a reduced plasma volume; thus, plasma creatinine seldom is below normal nonpregnant levels. In some cases of severe preeclampsia, however, renal involvement is profound, and plasma creatinine may be elevated two to three times over nonpregnant normal values. This is likely due to intrinsic renal changes caused by severe vasospasm (Pritchard and colleagues, 1984). Total renal perfusion does not appear to be reduced in preeclamptic women (Levine and associates, 1992). Lee and associates (1987) reported normal ventricular filling pressures in seven severely preeclamptic women with oliguria, and concluded that this was consistent with intrarenal vasospasm. In most, urine sodium concentration was elevated abnormally, suggesting an intrinsic renal etiology. Urine osmolality, urine–plasma creatinine ratio, and fractional excretion of sodium were also indicative that a prerenal mechanism was involved. Importantly, intensive intravenous fluid therapy was not indicated for these women with oliguria. When dopamine was infused into oliguric preeclamptic women, this renal vasodilator caused increased urine output, fractional sodium excretion, and free water clearance (Kirshon and co-workers, 1988).
Taufield and associates (1987) reported that preeclampsia is associated with diminished urinary excretion of calcium because of increased tubular reabsorption. This mechanism would explain the decreased calcium excretion in hypertensive and future hypertensive pregnant women.
After delivery, in the absence of underlying chronic renovascular disease, complete recovery of renal function usually can be anticipated. This would not be the case, of course, if renal cortical necrosis, an irreversible but rare lesion, develops (Sibai and associates, 1990c).
There should be some degree of proteinuria to establish the diagnosis of preeclampsia–eclampsia (Chesley, 1985). Because proteinuria develops late, however, some women may be delivered before it appears, and thus still have preeclampsia without proteinuria. Meyer and colleagues (1994) emphasized that 24-hour urine excretion should be measured. They found that a urinary dipstick of 1+ proteinuria or greater was predictive of at least 300 mg per 24 hours in 92 percent of cases. Conversely, trace or negative proteinuria had a negative predictive value of only 34 percent in hypertensive women. Urine dipstick values of 3+ to 4+ were positively predictive of severe preeclampsia in only 36 percent of cases.
Albuminuria is an incorrect term to describe proteinuria of preeclampsia. As with any other glomerulopathy, there is increased permeability to most large-molecular-weight proteins; thus, abnormal albumin excretion is accompanied by other proteins, such as hemoglobin, globulins, and transferrin. Normally, these large protein molecules are not filtered by the glomerulus, and their appearance in urine signifies a glomerulopathic process. Some of the smaller proteins that usually are filtered but reabsorbed are also detected in urine.
Changes identifiable by light and electron microscopy are commonly found in the kidney. Sheehan (1950) observed that the glomeruli were enlarged by about 20 percent. The capillary loops variably are dilated and contracted. The endothelial cells are swollen, and deposited within and beneath them are fibrils that have been mistaken for thickening of the basement membrane.
Most electron microscopical studies of renal biopsies are consistent with glomerular capillary endothelial swelling. These changes, accompanied by subendothelial deposits of protein material, were called glomerular capillary endotheliosis by Spargo and associates (1959). The endothelial cells are often so swollen that they block or partially block the capillary lumens. Homogeneous deposits of an electron-dense substance are found between basal lamina and endothelial cells and within the cells themselves. On the basis of immuno-fluorescent staining, Lichtig and co-workers (1975) identified deposited fibrinogen or its derivatives in 13 of 30 renal biopsy specimens from women with preeclampsia. The amount of fibrin was graded as more than a trace in only two. Kincaid-Smith (1991) found that these deposits disappear progressively in the first week postpartum. Petrucco and colleagues (1974) detected IgM, IgG, and sometimes complement in the glomeruli of preeclamptic women in proportion to disease severity.
The renal changes identified by electron microscopy have been advanced as being pathognomonic of preeclampsia. The uncertainties of clinical diagnosis are so great, however, as to preclude acceptance of such a one-to-one relation. The history of other alleged pathognomonic lesions in eclampsia engenders such skepticism. The subject was recently reviewed in detail by Gaber and colleagues (1994).
Renal tubular lesions are common in women with eclampsia, but what has been interpreted as degenerative changes may represent only an accumulation within cells of protein reabsorbed from the glomerular filtrate. The collecting tubules may appear obstructed by casts from derivatives of protein, including, at times, hemoglobin.
Acute renal failure from tubular necrosis may develop. Although this is more common in neglected cases, it is invariably induced by hypovolemic shock, usually associated with hemorrhage at delivery, for which adequate blood replacement is not given. Sibai and colleagues (1993b) reported that 7 percent of women with hemolysis, elevated liver enzymes, and thrombocytopenia—HELLP syndrome—developed acute renal failure. Moreover, half of these also had a placental abruption, and most had postpartum hemorrhages. Rarely, renal cortical necrosis develops when the major portion of the cortex of both kidneys undergoes necrosis. Both cause acute renal failure characterized clinically by oliguria or anuria and rapidly developing azotemia. Renal cortical necrosis is irreversible, and although it develops in nonpregnant women and in men, the lesion has most often been associated with pregnancy.
With severe preeclampsia, at times there are alterations in tests of hepatic function and integrity, including delayed excretion of bromosulfophthalein and elevation of serum aspartate aminotransferase levels (Combes and Adams, 1972). Severe hyperbilirubinemia is uncommon with preeclampsia (Pritchard and colleagues, 1976). Much of the increase in serum alkaline phosphatase is due to heat-stable alkaline phosphatase of placental origin. Oosterhof and co-workers (1994) described increased hepatic artery resistance using Doppler sonography in 37 women with preeclampsia.
Periportal hemorrhagic necrosis in the periphery of the liver lobule is the most likely reason for increased serum liver enzymes. In the past, this lesion was often identified at autopsy and was long considered to be the characteristic lesion of eclampsia. Such extensive lesions are seldom identified in nonfatal cases with liver biopsy (Barton and colleagues, 1992). Bleeding from these lesions may cause hepatic rupture or they may extend beneath the hepatic capsule and form a subcapsular hematoma. Such hemorrhages without rupture may be more common than previously suspected. Using computed tomography, Manas and colleagues (1985) showed that 5 of 7 women with preeclampsia and upper abdominal pain had hepatic hemorrhage. Prompt surgical intervention may be life saving. Smith and co-workers (1991) reviewed 28 cases of spontaneous hepatic rupture associated with preeclampsia and added seven cases of their own. The mortality rate was 30 percent, and they concluded that packing and drainage was superior to lobectomy. One such woman at Parkland Hospital survived after receiving blood and blood products from more than 200 donors. Hunter and co-workers (1995) described a similar woman in whom liver transplant was considered life saving.
It is not known precisely what effects preeclampsia has on cerebral blood flow. Evidence is consistent with vasospasm or with impairment of autoregulation with passive overdistension of cerebral arterioles. Morriss and colleagues (1997) used magnetic resonance angiography to measure cerebral artery flow in severely preeclamptic and eclamptic women. Although cerebral blood flow was not altered, these women had been given magnesium sulfate after their eclamptic seizures and before angiography was performed. Naidu and associates (1996) provided evidence that magnesium sulfate therapy relieves cerebral vasospasm.
Nonspecific electroencephalographic abnormalities can usually be demonstrated for some time after eclamptic convulsions. Sibai and colleagues (1985a) observed that 75 percent of 65 eclamptic women had abnormal electroencephalograms within 48 hours of seizures. Half of these abnormalities persisted past 1 week, but most were normal by 3 months. An increased incidence of electroencephalographic abnormalities has been described in family members of eclamptic women, a finding suggestive that some eclamptic women who convulse have an inherited predisposition to do so (Rosenbaum and Maltby, 1943).
The principal postmortem cerebral lesions are edema, hyperemia, focal anemia, thrombosis, and hemorrhage. Sheehan (1950) examined the brains of 48 eclamptic women very soon after death, and hemorrhages, ranging from petechiae to gross bleeding, were found in 56 percent. According to Sheehan, if the brain is examined within an hour after death, most often it is as firm as normal, and there is no obvious edema. Govan (1961) investigated the cause of death in 110 fatal cases of eclampsia and concluded that cerebral hemorrhage was responsible in 39. Small cerebral hemorrhagic lesions were also found in 85 percent of the 47 women who died of cardiorespiratory failure. A regular finding was fibrinoid changes in the walls of cerebral vessels. The lesions sometimes appeared to have been present for some time, as judged from the surrounding leukocytic response and hemosiderin-pigmented macrophages. These findings are consistent with the view that prodromal neurological symptoms and convulsions may be related to these lesions.
Using cranial computed tomography scanning, Brown and colleagues (1988a) found that nearly half of eclamptic women studied had abnormal findings. The most common findings were hypodense cortical areas, which corresponded to petechial hemorrhage and infarction sites reported at autopsy by Sheehan and Lynch (1973). Using magnetic resonance imaging, Morriss and colleagues (1997) confirmed remarkable changes, especially in the area of the posterior cerebral artery. These findings may provide an explanation of why some women with preeclampsia convulse but others do not. The brain, like the liver and kidney, may be more involved in some women than in others. Thus, the extent of ischemic and petechial subcortical lesions, further altered by an inherent seizure threshold, influences the incidence of eclampsia.
Although visual disturbances are common with severe preeclampsia, blindness, either alone or accompanying convulsions, is not. Some women with varying degrees of amaurosis are found to have radiographic evidence of extensive occipital lobe hypodensities; this is likely an exaggeration of the lesions described earlier and shown in Figure 31–9. Herzog and colleagues (1990) reported that magnetic resonance imaging was superior to computed tomography in identifying specific brain lesions responsible for this type of blindness. Over a 14-year period, we described 15 women with severe preeclampsia or eclampsia who also had blindness (Cunningham and associates, 1995). This persisted for 4 hours to 8 days, but in all it resolved completely.
Retinal artery vasospasm may be associated with visual disturbances. Fortuitously, Belfort and associates (1992) showed that a 6-g bolus of magnesium sulfate caused retinal artery vasodilation. Retinal detachment may also cause altered vision, although it is usually one sided and seldom causes total visual loss as in some women with cortical blindness. Surgical treatment is seldom indicated; prognosis is good, and vision usually returns to normal within a week.
It is rare for a woman with eclampsia not to awaken after a seizure. It is also rare for a woman with severe preeclampsia to become comatose without an antecedent seizure. Prognosis for these women is guarded. In two eclamptic women with coma that we have managed, extensive cerebral edema was documented by computed tomography. It does not appear that coma results from an extension of the ischemic and hemorrhagic lesions described above, because eclamptic women without coma have minimal cerebral edema (Brown and colleagues, 1988a; Morriss and associates, 1997). Because coma usually follows sudden and severe blood pressure elevations, it is more likely that this phenomenon represents an inability to autoregulate cerebral blood flow with severe acute hypertension; the result is generalized cerebral edema.
Coma may result from intracranial hemorrhage from a ruptured intracerebral vessel, an arteriovenous malformation, or a berry aneurysm. Sheehan and Lynch (1973) reported that 6 of 76 women with fatal eclampsia had massive white matter hemorrhage that caused coma and death. They also reported a high mortality rate with bleeding into the basal ganglia or pons. Treatment is the same as for any nonpregnant woman.
Compromised placental perfusion from vasospasm is almost certainly a major culprit in the genesis of increased perinatal morbidity and mortality associated with preeclampsia.
Attempts to measure human maternal placental blood flow have been hampered by several obstacles, including inaccessibility of the placenta, the complexity of its venous effluent, and the unsuitability of certain investigative techniques for humans. Despite formidable problems, Assali and associates (1953) and Metcalfe and co-workers (1955) measured uterine blood flow in pregnant women and obtained reasonably consistent results. Both groups used a nitrous oxide Fick principle method that required cannulation of a uterine vein. Total uterine perfusion was measured, rather than maternal placental blood flow. Uterine blood flow in normal-term pregnant women was approximately 500 to 700 mL/min.
Browne and Veall (1953) estimated changes in maternal placental flow through the use of a 24Na clearance technique. This method required needle insertion into the intervillous space. They, as well as Weis and associates (1958), observed that 24Na was cleared two to three times more rapidly in normotensive pregnant women than in preeclamptic women. This implied a two- to threefold decrease in uteroplacental perfusion in hypertensive women compared with normotensive controls.
The consistent results and conclusions obtained from these early studies continue to be supported by other methods of investigation. For instance, Brosens and associates (1972) reported that the mean diameter of myometrial spiral arterioles of 50 normal pregnant women was 500 mm. The same measurement in 36 women with preeclampsia was 200 mm.
Everett and colleagues (1980) presented evidence that the clearance rate of dehydroisoandrosterone sulfate through placental conversion to estradiol-17b was an accurate reflection of maternal placental perfusion. Fritz and colleagues (1985) reported that the technique paralleled uteroplacental perfusion in primates. Normally, as pregnancy advances, this measurement increases greatly. The placental clearance rate decreases before the onset of overt hypertension (Worley and associates, 1975). Finally, placental clearance is decreased in women given diuretics or hydralazine (Gant and co-workers, 1976).
Doppler measurement of blood velocity through uterine arteries has been used to estimate uteroplacental blood flow Vascular resistance is estimated by comparing arterial systolic and diastolic velocity waveforms. Fleischer and colleagues (1986) and Trudinger and associates (1990) reported increased systolic–diastolic ratio in uterine arteries of women with preeclampsia. Others have not confirmed this (Hanretty and colleagues, 1988). Absent end-diastolic flow or reversal of flow is associated with increased fetal morbidity and mortality in hypertensive women (Fairlie and co-workers, 1991; Kofinas and associates, 1990). Thaler and colleagues (1992) reported that the presence of a systolic or diastolic notch, or a combination of both, is associated with elevated resistance indexes in the uterine and umbilical vessels. Nifedipine therapy and epidural analgesia have been reported to decrease abnormally elevated systolic-diastolic ratios (Pirhonen, 1990; Puzey, 1991; Ramos-Santos, 1991; and their colleagues).
Ducey and associates (1987) described systolic– diastolic velocity ratios from both uterine and umbilical arteries in 136 pregnancies complicated by hypertension. Among 51 women considered to have preeclampsia, 20 percent had normal umbilical artery velocity ratios; 15 percent had normal umbilical but abnormal uterine artery ratios; and in 40 percent both ratios were abnormal. Atkinson and associates (1994b) showed that elevated umbilical artery S/D ratio is not a clinically useful predictor for preeclampsia in a low-risk population.
In our experiences, diminished uterine artery flow velocities are seldom encountered with uncomplicated preeclampsia. This is true even with severely elevated blood pressures. With associated fetal growth restriction, however, aberrant flow velocities are often seen in both umbilical and aortic vessels (Cameron and colleagues, 1988). In some reports, women were studied because of growth retardation. Thus, it appears that preeclampsia alone may not be associated with significant changes in the uterine artery systolic–diastolic ratio. Aberrations in fetal blood flow velocities detected in hypertensive pregnancies are much more likely if there is retarded fetal growth (Lowery and associates, 1990; Villar and colleagues, 1989a).
Histological Changes in the Placental Bed
Hertig (1945) identified in preeclamptic pregnancies a lesion of uteroplacental arteries characterized by prominent lipid-rich foam cells. Zeek and Assali (1950) termed this acute atherosis. Most investigators are now in accord that there is a lesion, but they do not agree on its precise nature. Classically, in normal pregnancy, spiral arteries are invaded by endovascular trophoblast. It seems that, in preeclampsia, decidual vessels, but not myometrial vessels, are invaded by endovascular trophoblasts. Using electron microscopical studies of arteries taken from the uteroplacental implantation site, De Wolf and co-workers (1980) reported that early preeclamptic changes included endothelial damage, insudation of plasma constituents into vessel walls, proliferation of myointimal cells, and medial necrosis. They also found that lipid accumulates first in myointimal cells and then in macrophages. Importantly, Meekins and associates (1994) showed that these changes are a continuum from normal pregnancies to those with severe preeclampsia.
Classification on pregnancy induced hypertension.
1. Hypertensive disorders during pregnancy.
2. Edema during pregnancy.
3. Proteinuria during pregnancy.
4. Mild preeclampsia.
5. Moderate preeclampsia.
6. Severe preeclampsia.
“Superimposed” hypertensive disorders develop on the underlying preexisting diseases, such as Diabetes Mellitus, Hypertensive disease, kidneys inflammatory diseases, thyroid and pulmonary dysfunction. They have such peculiarities as:
1. early beginning;
2. severe duration;
3. isolated symptoms only presenting (isolated proteinuria, edema, or hypertension);
4. presence of atypical clinical findings such as paresthesia, insomnia, hypersalivation.
Is defined as hypertension present before the twentieth week of gestation or beyond 6 weeks' postpartum.
Diagnosis of Coincidental (Chronic) Hypertension
All chronic hypertensive disorders, regardless of their cause, predispose to development of superimposed preeclampsia or eclampsia. These disorders can create difficult problems with diagnosis and management in women who are not seen until after midpregnancy. The diagnosis of coincidental or chronic underlying hypertension is suggested by (1) hypertension (140/90 mm Hg or greater) antecedent to pregnancy, (2) hypertension (140/90 mm Hg or greater) detected before 20 weeks (unless there is gestational trophoblastic disease), or (3) persistent hypertension long after delivery. Additional historical factors that help support the diagnosis are multiparity and hypertension complicating a previous pregnancy other than the first. There is also usually a strong family history.
The diagnosis of chronic hypertension may be difficult to make if the woman is not seen until the latter half of pregnancy. This is because blood pressure decreases during the second and early third trimesters in both normotensive and chronically hypertensive women. Thus, a woman with chronic vascular disease, who is seen for the first time at 20 weeks, will frequently have a normal blood pressure. During the third trimester, however, blood pressure returns to its former hypertensive level, presenting a diagnostic problem as to whether the hypertension is chronic or pregnancy induced.
There are many causes of underlying hypertension that are encountered during pregnancy are present in the Table .
UNDERLYING CHRONIC HYPERTENSIVE DISORDERS
Essential familial hypertension (hypertensive vascular disease)
Coarctation of the aorta
Glomerulonephritis (acute and chronic)
Chronic renal insufficiency
Essential hypertension is the cause of underlying vascular disease in more than 90 percent of pregnant women. McCartney (1964) studied renal biopsies from women with “clinical preeclampsia,” and found chronic glomerulonephritis in 20 percent of nulliparas and in nearly 70 percent of multiparas. Fisher and co-workers (1969), however, did not confirm this high prevalence of chronic glomerulonephritis.
Chronic hypertension causes morbidity whether or not a woman is pregnant. Specifically, chronic hypertension may lead to premature cardiovascular deterioration, resulting in cardiac decompensation and/or cerebrovascular accidents. Intrinsic renal damage may also result from chronic hypertensive disease. More commonly in young women, hypertension develops as a consequence of underlying renal parenchymal disease. Dangers specific to pregnancy complicated by chronic hypertension include the risk of pregnancy-aggravated hypertension, which may develop in as many as 20 percent of these women. Additionally, the risk of abruptio placentae is increased substantively. Moreover, the fetus of the woman with chronic hypertension is at increased risk for growth restriction and death.
Diagnosis of Pregnancy-aggravated Hypertension
Preexisting chronic hypertension worsens in some women, typically after 24 weeks. Such pregnancy-aggravated hypertension may be accompanied by proteinuria or pathological edema; the condition is then termed superimposed preeclampsia. Often, the onset of superimposed preeclampsia develops earlier in pregnancy than pure preeclampsia, and it tends to be quite severe and accompanied in many cases by fetal growth restriction.
The most common hazard faced by pregnant women with chronic hypertensive vascular disease is the superimposition of preeclampsia. The frequency of pregnancy-aggravated hypertension is difficult to specify precisely because the incidence varies with the diagnostic criteria employed. If the diagnosis is made only on the basis of (1) significant aggravation of the hypertension, (2) sustained proteinuria, and (3) generalized edema, the incidence will be relatively low because delivery is often accomplished before intense superimposed preeclampsia or eclampsia has developed. If, however, the diagnosis is made on the basis of a modest rise in blood pressure and minimal to modest proteinuria, the incidence will be much higher. For example, with mild chronic hypertension, the incidence of superimposed preeclampsia cited in the studies in Table 31–13 varied from 6 to 46 percent!
Pregnancy-aggravated hypertension typically becomes manifest by a sudden rise in blood pressure that almost always is complicated eventually by substantive proteinuria. Extreme hypertension—systolic pressure greater than 200 mm Hg and diastolic pressure of 130 mm Hg or more, oliguria, and impaired renal clearance may rapidly ensue; the retina may have extensive hemorrhages and cotton-wool exudates; and convulsions and coma are likely. Therefore, in its most severe form, the resultant syndrome is similar to hypertensive encephalopathy. With the development of superimposed preeclampsia or eclampsia, the outlook for both infant and mother is grave unless the pregnancy is terminated. The frequency of fetal growth restriction and preterm delivery is increased appreciably because of its relatively early onset in pregnancy, as well as the marked severity of the process itself. If the infant is born alive and survives the perinatal period, however, long-term prognosis is good.
The diagnosis requires documentation of chronic underlying hypertension. Pregnancy-aggravated hypertension is characterized by worsening hypertension, keeping in mind that both systolic and diastolic pressures normally rise as gestation increases.
Gestational hypertension - occurs after 20 weeks of pregnancy and doesn’t accompanies with proteinuria.
Hypertension - In pregnancy is generally defined as a diastolic blood pressure of 90 mm Hg or greater, as a systolic blood pressure at or above 140 mm Hg at two estimations with the interval 4 hours or 160/110 mm Hg at once.
Preeclampsia - Is defined as the development of hypertension with proteinuria or edema (or both).
Differential diagnosis of chronic hypertension and preeclampsia
Onset of hypertension
Before pregnancy and in the first 20 weeks of gestation
After 20 weeks of gestation
Duration of hypertension
Constant, lasts during 3 months after delivery
It disappears after 6 weeks or 3 months after delivery
Presence of hypertensive disease in the parents, family
35-40 years old
20-25 years old
Spasm of vessels, hemorrhages
Vasospasm, edema of retina
1. Symptoms and signs
The pregnant woman is usually unaware of the two most important signs of preeclampsia—hypertension and proteinuria. By the time symptoms develop such as headache, visual disturbances, or epigastric pain, the disorder is almost always severe. Hence, the importance of prenatal care in the early detection and management of preeclampsia is obvious.
1. Hypertension in pregnancy is generally defined as a diastolic blood pressure of 90 mm Hg or greater, as a systolic blood pressure at or above 140 mm Hg, or as an increase in the diastolic blood pressure of at least 15 mm Hg or in the systolic blood pressure of 30 mm Hg or more when compared to previous blood pressures.
2. Weight gain – a sudden increase in weight may precede the development of preeclampsia. Weight increase of about much more than 400 g per week is abnormal.
A sudden increase in weight may precede the development of preeclampsia, and indeed, excessive weight gain in some women is the first sign. A weight increase of about 1 pound per week is normal, but when weight gain exceeds more than 2 pounds in any given week, or 6 pounds in a month, developing preeclampsia should be suspected. The suddenness of excessive weight gain is characteristic of preeclampsia rather than an increase distributed throughout gestation. Such weight gain is due almost entirely to abnormal fluid retention and is usually demonstrable before visible signs of nondependent edema such as swollen eyelids and puffy fingers. In cases of fulminating preeclampsia or eclampsia, fluid retention may be extreme; and in these women, a weight gain of 10 or more pounds per week is not unusual
3. Edema - peripheral edema is common in pregnancy, especially in the lower extremities; however, persistent edema unresponsive to resting in the supine position is not normal, especially, when it also involves the upper extremities and face (Fig. 3)
4. Headache - is unusual in milder cases but frequent in more severe disease. It is often frontal but may be occipital, and it is resistant to relief from ordinary analgesics.
5. Abdominal pain – epigactric or right upper quadrant pain often is a symptom of severe preeclampsia and may be indicated of imminent convulsions. It may be the result of stretching of the hepatic capsule, possibly by edema and hemorrhage. Tenderness over the liver should be presented.
6. Visual disturbances – a spectrum of visual disturbances, ranging from slight blurring of vision to scotomas to partial or complete blindness, may accompany preeclampsia. These develop as a result of vasospasm, ischemia, andpetechial hemorrhages within the occipital cortex.
7. Hyperreflexia should be presented. The patellar and achilles deep tendom reflexes should be carefully elicited and noted this symptom. The demonstration of clonus at the ankle is especially worrisome.
8. Any history of loss of consciousness or seizures, even in the patient with a known seizure disorder, may be significant (Fig. 4)..
Assessment for proteinuria, edema, weight, hyperreflexia, headache, visual disturbances, epigastric pain is obligatory daily.
Fig. 3. A. Severe edema in a young primigravida with antepartum eclampsia and a markedly reduced blood volume compared with normal pregnancy. B. The same woman 3 days after delivery. The remarkable clearance of pedal edema, accompanied by diuresis and a 28-pound weight loss, was spontaneous and unprovoked by any diuretic therapy. (From Cunningham and Pritchard, 1984.)
Fig. 4 Hematoma of tongue from laceration during eclamptic convulsion. Thrombocytopenia may have contributed to the bleeding.
2. Laboratory findings.
Test or Procedure
Proteinuria is defined as 300 mg or more urinary protein during a 24-hour period or 30-100 mg per dL or more in at least two random urine specimens collected 6 hours or more apart
Hematocrit in complete blood count / every 2 days
It increasing may signify worsening vasocanstriction and decreased intravascular volume.
Platelet count / every 2 days
Thrombocytopenia and coagulopathy are associated with worsening PIH.
Coagulation profile (PT, PTT)
Fibrin split products
Liver function studies / weekly
Hepatocellular dysfunction is associated with worsening PIH
Serum creatinine / twice weekly
Decreased renal function is associated with worsening PIH.
24-hour urine for creatinine clearance / twice weekly
24- hour for total protein / twice weekly
Serum uric acid / twice weekly
Ultrasound for fetal growth / every 2 weeks
To assess for pregnancy-associated hypertension effects on the fetus, intrauterine growth restriction.
Amniotic fluid volume
Fetal movement record / daily
Chronic fetal distress.
Biophysical profile / twice weekly
Nonstress test / twice weekly
Assessment of different stages of PIH severity
Diastolic blood pressure
90-99 mm Hg
100-109 mm Hg
> 110 mm Hg
Proteinuria in 24-hour collection
< 0.3 g
< 0.3 - 5 g
> 5 g
Diuresis per hour
> 50 ml
> 40 ml
< 40 ml
Presence of edema
In lower extremities
In lower extremities, and abdominal wall
Number of thrombocytes
80 - 150. 000
36 – 38
39 – 42
< 75 mkmol/L
75 – 120 mkmol/L
> 120 mkmol/L
< 4,5 mmol/L
4,5 – 8 mmol/L
> 8 mkmol/L
Preeclampsia is classified as severe if there is a blood pressure greater than or equal to 170 mm Hg systolic or 110 mm Hg diastolic, marked proteinuria (generally > 5 g/24-hr urine collection, or 5 g/L or more on dipstick of a random urine), oliguria, weight gain exceeds more than 900 g in a week, cerebral or visual disturbances such as headache and scotomata, pulmonary edema or cyanosis, epigastric or right upper quadrant pain, evidence of hepatic dysfunction, or thrombocytopenia. These myriad changes illustrate the multisystem alterations associated with preeclampsia.
Complications of preeclapsia:
Maternal – placenta abruption, cerebral hemorrhage (Fig. 5), renal and liver insufficiency (Fig. 6), disseminated intravascular coagulopathy (Fig. 7), adrenal insufficiency, eclampsia.
Fetal – intrauterine growth retardation, fetal distress (Fig. 8), intranatal fetal death, infant morbodity and mortality.
ECLAMPSIA is characterized typically by those same abnormalities as severe preeclampsia with the addition of convulsions that are precipitated by pregnancy-induced hypertension. The seizures are grand mal and may appear during pregnancy, during labor, or postpartum.
Fig. 5 Computed tomographic scan of liver showing a subcapsular hematoma (arrow) along the right margin of the liver. (Reproduced, with permission, from Manas KJ, Welsh JD, Rankin RA, Miller DD. Hepatic hemorrhage without rupture in preeclampsia. N Engl J Med. 312:424-426, 1985. Copyright ©1985 Massachusetts Medical Society. All rights reserved.)
Fig. 6. Gross liver specimen from a woman with preeclampsia who died from severe acidosis and liver failure. Periportal hemorrhagic necrosis was seen microscopically. (From Cunningham, 1993.)
Fig. 7. Hypertensive hemorrhage with eclampsia.
Fig. 8 Fetal bradycardia developing in a woman with an intrapartum eclamptic convulsion. Bradycardia resolved and beat-to-beat variability returned after about 5 minutes following the seizure. (From Cantrell and Cunningham, 1994.)
- Persistent blood pressure greater than 140/90 mmHg before the 20th week of pregnancy
- Mild: over 140/90 mmHg
- Moderate: over 150/100 to 170/110 mmHg
- Severe: over 170/110 mmHg
- Hypertension initially diagnosed any time during pregnancy that persists for more than 12 weeks postpartum
B. Gestational hypertension (pregnancy-induced hypertension [PIH])
Definitions of hypertension based on incremental increases in blood pressure over baseline (e.g., diastolic blood pressure at 24 weeks that is 15 mmHg higher than a reading from before 20 weeks) are no longer used to diagnose PIH.
- Diagnostic criterion: onset of hypertension after 20 weeks' gestation
- Absolute blood pressure of 140/90 mmHg twice over 6 hours, without prior comparison
- Absolute mean arterial pressure of 105 mmHg without prior comparison
- Blood pressure returns to normal by 12 weeks postpartum
C. Preeclampsia: gestational hypertension with proteinuria
- Proteinuria is defined by:
- 30 mg/dL on dipstick (1+) on repeated samples or
- 300 mg on 24-hour urine collection
- Preeclampsia may be mild or severe (Table 16-1). Criteria for severe preeclampsia suggest end-organ involvement (Table 16-2). After a grand mal seizure, preeclampsia is termed eclampsia.
- HELLP syndrome (hemolysis, elevated liver enzymes, low platelets). This variant of severe preeclampsia develops in 10% of women with severe preeclampsia. However, approximately 10% of women with HELLP syndrome are normotensive, which is classified as atypical HELLP syndrome.
- Superimposed preeclampsia on chronic hypertension
- New-onset proteinuria after 20 weeks in a woman with chronic hypertension
- Sudden increase in proteinuria, edema, or blood pressure or a platelet count less than 100,000/mm3 in a woman with chronic hypertension and proteinuria before 20 weeks' gestation
TABLE 16-1 Hypertensive Disorders During Pregnancy: Indications of Severity
III. Chronic Hypertension
A. Effects on mother
- Mild chronic hypertension is unlikely to adversely affect pregnancy. Pregnancy is unlikely to hasten the progression of maternal hypertensive end-organ disease.
- Morbidity is increased over de novo preeclampsia.
B. Effects on fetus
- Abruptio placentae is four to eight times more likely in pregnancies complicated by chronic hypertension.
- When preeclampsia is superimposed on chronic hypertension, preeclampsia occurs earlier and is associated with more pronounced decreases in uteroplacental perfusion. Intrauterine growth retardation (IUGR) may result from decreased uteroplacental perfusion.
- However, IUGR is not more frequent in cases of mild chronic hypertension.
- When preeclampsia is superimposed on chronic hypertension, the incidence of IUGR is 30% to 40%.
- Prematurity is more common with severe chronic hypertension.
- Perinatal mortality approaches 25% in severe chronic hypertension.
TABLE 16-2 Criteria for Severe Preeclampsia
C. Antihypertensive management
- Treatment reduces the risk of maternal morbidity. Whether it reduces perinatal morbidity and mortality remains controversial.
- Existing antihypertensive therapy should be continued on diagnosis of pregnancy.
- Antihypertensive agents
- О±-Methyldopa is most used frequently and has been studied the most. There is no evidence of fetal or maternal adverse events.
- Labetalol (О±- and ОІ-blockade) is associated with a possible increase in growth restriction.
- Nifedipine has limited data, but it rapidly reduces blood pressure.
- ОІ-Antagonists have been associated with low birth weight.
- Angiotensin-converting enzyme inhibitors are contraindicated in pregnancy because of adverse effects on fetal renal function.
D. Antepartum management
- Baseline evaluation for end-organ disease
- Renal function tests
- Ophthalmologic examination
- Antihypertensive therapy is unlikely to benefit a pregnancy complicated by mild hypertension. It should be reserved for pregnancies complicated by moderate or severe hypertension (diastolic blood pressure more than 100 to 110 mmHg), where it reduces the incidence of cardiovascular and cerebrovascular events.
- Ultrasound should be used to determine specific gestational age. Serial ultrasound surveillance should be reserved for clinical suspicion of IUGR or superimposed preeclampsia.
- Nonstress testing and amniotic fluid assessment should be started at 32 to 34 weeks' gestation.
- Labor induction by 40 weeks' gestation can be considered.
IV. Preeclampsia: Epidemiology
A. Rate of occurrence
A Rate of occurrence: 7% of pregnancies, excluding first-trimester losses
B. Risk factors
- Pregnancy history. Primigravidas constitute 65% of cases.
- Multiple gestation: 30% incidence
- Gestational trophoblastic disease: 70% incidence
- Maternal age. Preeclampsia occurs at extremes of maternal age. However, the association with young age is confounded by the association with primigravidity. However, maternal age of more than 40 years is an independent risk factor.
- Family history. Evidence for a genetic contribution includes a 37% incidence in sisters and a 26% incidence in daughters. This pattern is consistent with a dominant gene with reduced penetrance.
- Obesity. Incidence is directly related to degree of obesity.
- Chronic hypertension. Preeclampsia occurs in approximately 25% of women with chronic hypertension.
V. Preeclampsia: Pathophysiology
A. Pathophysiologic changes
- Cardiovascular system
- Cardiac output remains normal, and increased total peripheral vascular resistance accounts for the hypertension.
- Preeclamptic endothelial cells generate less prostacyclin, a vasodilator, than normal endothelial cells. Less prostacyclin allows greater vascular sensitivity to angiotensin II, thus promoting vasospasm and increasing peripheral vascular resistance.
- Coagulation system
- Disseminated intravascular coagulation occurs in 10% of patients with preeclampsia.
- Because of endothelial damage, most of these patients have mild procoagulant consumption and elevated fibrin degradation products.
- Diffuse intravascular coagulation may arise from vascular damage sustained during vasospasm.
- Renal function
- Glomerular changes
- Glomerular filtration rate (GFR) is usually decreased in preeclampsia. Deceased renal plasma flow and glomeruloendotheliosis, which occludes the capillary lumen, account for the lower GFR.
- Protein leaks into urine. The glomerulus, which is normally impermeable to large proteins, becomes more permeable. In part, glomerular damage results from both vasospasm and endothelial damage. This leakage exceeds the tubules' ability to reabsorb proteins.
- Tubular changes, which affect the clearance of uric acid
- Uric acid is normally completely filtered at the glomerulus, secreted, and mostly reabsorbed by the proximal tubules.
- Uric acid clearance is 10% of creatinine clearance.
- Decreased uric acid clearance is observed prior to a GFR disturbance, suggesting a tubal etiology in which the mechanism remains unknown.
- Increased production by hypoxic tissues contributes to increased serum uric acid.
- Renin-angiotensin-aldosterone system
- Levels of the following components are increased:
- Plasma renin activity and plasma renin concentration
- Angiotensin II
- The theory that the renin-angiotensin system mediates the pathophysiologic alterations of preeclampsia is suggested by three factors:
- Potent vasoconstrictor effect of angiotensin II
- Stimulation of aldosterone by angiotensin II and consequent sodium retention
- The finding that large doses of angiotensin II can cause proteinuria
- It is possible that, despite decreased intravascular volume, preeclamptic vasoconstriction results in a physiologic perception of overfill, which suppresses renin release.
- Other signs of end-organ disease
- Visual disturbances result from papilledema and suggest cerebral involvement.
- Epigastric pain suggests hepatocellular dysfunction and edema and liver capsule distention.
- Intrauterine growth retardation and oligohydramnios suggest placental vasculopathy and uteroplacental insufficiency.
B. Pathologic findings
- Initially, arteriolar vasodilation results in hemorrhage into the hepatocellular columns. This condition is found on liver biopsy in 66% of patients with eclampsia.
- Hepatic infarction occurs later and is found on liver biopsy in 40% of patients with eclampsia.
- Glomerular endotheliosis is the characteristic renal lesion of preeclampsia.
- Endothelial cells enlarge and may occlude the capillary lumen.
- Podocytes are not altered.
- Changes are completely reversible with resolution of preeclampsia.
- Nonglomerular changes such as tubular alterations are less common.
- Placenta and placental site
- The syncytiotrophoblast is abnormal, containing areas of cell death and degeneration, syncytial knots, and decreased density of microvilli.
- Cytotrophoblastic cells proliferate in placental villi.
- Placental vascular pathology
- In normal pregnancy, the spiral artery endothelium, elastic lamina, and smooth muscle are replaced by trophoblast. This creates a low-resistance, high-flow system. These changes affect both the decidual and myometrial vessels.
- In preeclampsia, these changes do not uniformly occur or are limited to decidual vessels.
- These observations can be made on first-trimester abortion specimens, suggesting that pathologic change precedes the clinical presentation.
VI. Preeclampsia: Clinical Manifestations
A. Clinical signs
- Hypertension is required for diagnosis.
- Edema is related to sodium retention, not limited to dependent edema.
- Hyperreflexia is common.
B. Laboratory findings
- Renal function
- Hyperuricemia is likely caused by both altered renal function and increased production of uric acid.
- Increased serum creatinine is inversely correlated with creatinine clearance.
- Hematology findings
- Hemoconcentration as reflected by an increased hematocrit
- Hepatic findings. Increased transaminases, when associated with microangiopathic hemolysis and coagulopathy, suggest HELLP syndrome.
VII. Preeclampsia: Management
Delivery is the only known treatment. At term (37 weeks' gestation), delivery is recommended.
B. Route of delivery
- Vaginal delivery is preferable to cesarean delivery, which should be reserved for the usual obstetric indications.
- Cesarean delivery may be preferred in cases of severe preeclampsia remote from term with an unfavorable cervix.
- Some evidence suggests that preeclampsia may expedite cervical ripening and labor induction.
C. Antepartum treatment (before 37 weeks)
- Mild preeclampsia maybe managed expectantly using the following interventions. It is controversial whether in- or outpatient management is preferable.
- Bed rest
- Blood pressure and urinary protein monitoring
- Twice-weekly nonstress tests
- Laboratory surveillance
- Stable severe preeclampsia
- Before 24 weeks. Pregnancy termination should be offered.
- Before 32 weeks. Delivery is always a legitimate course of action, but expectant management with blood pressure control is an option.
- Presence of proteinuria or controllable hypertension does not require immediate delivery.
- After 32 weeks. Delivery is appropriate after documentation of fetal lung maturity.
- If fetal lung maturity is negative, antenatal steroids should be given before 34 weeks.
- Alternatively, steroids can be given to all patients between 32 and 34 weeks. Delivery may be effected 48 hours later without documenting fetal lung maturity.
- Unstable severe preeclampsia. Treatment at any gestational age involves prompt delivery.
D. Intrapartum management
- Seizure prophylaxis. Because there are no signs that accurately predict seizures, prophylaxis is most effective if all women with preeclampsia are treated.
- Magnesium sulfate is superior to other antiepileptic medications for preventing eclampsia-related seizures and seizure-related morbidity and mortality.
- An intravenous loading dose of 6 g is usually followed by a maintenance infusion of 2 to 4 g/hr.
- Patients must be monitored for signs of magnesium toxicity, such as hyporeflexia and respiratory depression.
- Magnesium toxicity may be confirmed by testing serum levels (Table 16-3). It can be reversed with 1 g of calcium gluconate.
- In instances in which magnesium sulfate cannot be used (e.g., myasthenia gravis, end-stage renal disease [because of impaired magnesium clearance]), phenytoin is safe.
- Antihypertensive therapy
- Persistent diastolic blood pressure of over 105 mmHg
- Isolated diastolic blood pressure of over 110 mmHg
- Pharmacologic agents
- Hydralazine (preferred agent) reduces afterload but compensates by increasing heart rate; therefore, uterine perfusion is not usually compromised.
- Labetalol does not reduce afterload.
- Invasive cardiac monitoring should be considered in the presence of oliguria or pulmonary edema.
- Type of anesthesia
- Epidural anesthesia is safe for patients with normal clotting ability and no thrombocytopenia. It can be used for either vaginal or cesarean deliveries.
- General anesthesia should be used with caution because the stimulation of intubation may exacerbate hypertension.
E. Postpartum management
- Magnesium sulfate should be continued for 24 hours but may be discontinued earlier in the presence of pronounced diuresis, because therapeutic levels are not likely attainable.
- Indications for acute antihypertensive therapy are the same as for the antepartum or intrapartum period.
- Women who continue to have hypertension but have a persistent diastolic blood pressure of less than 100 mmHg maybe discharged on oral therapy.
- Pregnancy-induced hypertension usually disappears completely by 2 weeks postpartum.
VIII. Preeclampsia: Prevention
There is no reliable method for preventing preeclampsia. Low-dose aspirin, calcium, antioxidants, low-sodium diet, and fish oil have all been shown to be ineffective.
Eclampsia is preeclampsia complicated by generalized tonic-clonic seizures. Pathophysiology of the convulsions is unknown.
- May occur before, during, or after labor and delivery
- May cause maternal death
- Consider cerebral imaging, especially if the seizures occur more than 24 hours postpartum
- Treatment includes magnesium sulfate to control seizures; antihypertensive therapy with hydralazine, labetalol, or nifedipine; prevention of aspiration and hypoxia; and delivery when the mother is stabilized
X. Preeclampsia: Prognosis
With timely delivery and magnesium sulfate, the maternal mortality rate should be virtually zero.
The risk is 40% for severe preeclampsia and increases with earlier diagnosis of the index case.
B. Future hypertension
Preeclampsia does not accelerate hypertension but seems to unmask existing, yet undiagnosed, chronic hypertension.
- Women with preeclampsia in a first pregnancy are no more likely to develop hypertension than controls.
- Multiparous women are more likely to develop hypertension, but this is confounded because preeclampsia is unlikely to develop de novo in multiparas. Many of these women had underlying hypertension.
MODERN METHODS OF PREVENTION AND TREATMENT OF PREGNANCY INDUCED HYPERTENSION
Prophylaxis and Early Treatment
Because women are usually asymptomatic and seldom notice the signs of incipient preeclampsia, its early detection demands careful observation at appropriate intervals, especially in women known to be predisposed to preeclampsia. Major predisposing factors are (1) nulliparity, (2) familial history of preeclampsia–eclampsia, (3) multiple fetuses, (4) diabetes, (5) chronic vascular disease, (6) renal disease, (7) hydatidiform mole, and (8) fetal hydrops.
Rapid weight gain any time during the latter half of pregnancy, or an upward trend in diastolic blood pressure, even while still in the normal range, is worrisome. Every woman should be examined at least weekly during the last month of pregnancy and every 2 weeks during the previous 2 months. At these visits, weight and blood pressure measurements are made. All women should be advised to report immediately any symptoms or signs of preeclampsia, such as headache, visual disturbances, epigastric distress, and puffiness of hands or face. The reporting of any such symptoms calls for an immediate examination to confirm or exclude preeclampsia.
Natriuretic drugs, such as chlorothiazide and its congeners, have been overused severely in the past. Although diuretics have been alleged to prevent preeclampsia, Collins and colleagues (1985) reviewed results of nine studies of more than 7000 women and concluded that perinatal mortality was not improved when diuretics were given. Furthermore, thiazides can induce serious sodium and potassium depletion, hemorrhagic pancreatitis, and severe neonatal thrombocytopenia. The failure of natriuretic drugs to prevent preeclampsia raises serious doubt about the efficacy of rigid dietary sodium restriction.
Wallenburg and co-workers (1986) reported their experiences with either 60 mg of aspirin or placebo to angiotensin-sensitive primigravid women at 28 weeks. The reduced incidence of preeclampsia in the treated group was attributed to selective suppression of thromboxane synthesis by platelets and sparing of endothelial prostacyclin production. In a group of high-risk women with prior bad pregnancy outcomes due to hypertension and placental insufficiency, Beaufils and colleagues (1985) reported that early prophylactic treatment with dipyridamole and aspirin reduced recurrences. Benigni and colleagues (1989) and Schiff and associates (1989) also reported salutary effects in high-risk women.
Spitz and colleagues (1988) reported that most angiotensin-sensitive women at high risk for developing preeclampsia could be rendered refractory to angiotensin by a 1-week course of daily 81-mg aspirin.
They confirmed that low-dose aspirin significantly decreased thromboxane synthesis. Prostacyclin and prostaglandin E2 synthesis were also decreased 20 to 30 percent by therapy. These same investigators reported that approximately 20 percent of angiotensin-sensitive pregnant women given low-dose aspirin did not become refractory to angiotensin, and all such women developed preeclampsia (Brown and associates, 1990). The nonresponders to low-dose aspirin had a significant fall in thromboxane levels, but they also had significant declines in prostacyclin and prostaglandin E2 levels.
Low-dose aspirin was not effective for women who already had mild pregnancy-induced hypertension (Schiff and associates, 1990); however, women with moderate hypertension improved. Magness and colleagues (1991) observed that less than 20 percent of women with early-onset pregnancy-induced hypertension failed to become normotensive with hospitalization. In the 20 percent who remained hypertensive after hospitalization, low-dose aspirin allowed prolongation of pregnancy compared with controls.
Low-dose aspirin may be effective in some women in preventing the development of pregnancy-induced hypertension and fetal growth restriction (Imperiale and Petrulis, 1991). Hauth and co-workers (1993) randomized 604 nulliparas to 60 mg aspirin or placebo beginning at 24 weeks. Only 1.7 percent of aspirin-treated women developed preeclampsia versus 5.6 percent of controls (P < 0.01). Studies from the National Institutes of Health sponsored Maternal–Fetal Medicine Network showed that aspirin prophylaxis significantly decreased preeclampsia to 4.6 percent compared with 6.3 percent in nontreated controls (Sibai and colleagues, 1993a). Overall, perinatal outcome was not improved, and women who took aspirin had significantly more placental abruptions, although Hauth and colleagues (1995) concluded that these abruptions were of no clinical importance.
In a study by the Royal College of Obstetricians and Gynecologists (CLASP, 1994), it was concluded that low-dose aspirin was ineffective to prevent preeclampsia. Similarly, the ECPPA Collaborative Group (1996), in a study from 12 Brazilian teaching hospitals, concluded that low-dose aspirin did not decrease the incidence of proteinuric preeclampsia in 1009 women randomized to aspirin or placebo. Both of these groups of investigators used Korotkoff IV sound for diastolic pressure, and this may overestimate diastolic pressure by 7 to 15 mm Hg (Brown and colleagues, 1994; Lindheimer and Katz, 1992; Shennan and co-workers, 1996). In their meta-analysis, the CLASP group concluded that low-dose aspirin reduced the incidence of preeclampsia by about 25 percent.
Currently, the salutary effects of low-dose aspirin therapy remain to be proven for most groups of women. The prevailing opinion is that normal women should not be treated, but selective treatment for certain high-risk groups is acceptable (Cunningham and Gant, 1989; Hauth and Cunningham, 1995; Royal College of Obstetricians and Gynecologists, 1996; Zuspan and Samuels, 1993).
Low-dose aspirin therapy appears to be safe for the fetus. Although most clinical trials have resulted in no apparent maternal risks, Brown and colleagues (1990) noted a rapid clinical deterioration if therapy was stopped suddenly.
The basic management objectives for any pregnancy complicated by pregnancy-induced hypertension are:
1. Termination of the pregnancy with the least possible trauma to the mother and the fetus.
2. Birth of the infant who subsequently thrives
3. Complete restoration of the health of the mother.
Hospitalization is considered for women with pregnancy-induced hypertension if there is a persistent or worsened elevation in blood pressure or development of proteinuria. With hospitalization, a systematic study should be instituted that includes the following:
1. A detailed medical examination followed by daily searches for development clinical findings such as headache, visual disturbances, epigastric pain, and rapid weight gain.
2. Admittance weight and every day thereafter.
3. Admittance analysis for proteinuria and at least every 2 days thereafter.
4. Blood pressure readings with an appropriate-size cuff every 4 hours, except between midnight and morning, unless the midnight pressure has increased.
5. Measurements of plasma creatinine, hematocrit, platelets, and serum liver enzymes, the frequency to be determined by the severity of hypertension.
6. Frequent evaluation of fetal size and amnionic fluid volume by the same experienced examiner and by serial sonography if remote from term.
If these observations lead to a diagnosis of severe preeclampsia, further management is the same as described for eclampsia.
Reduced physical activity throughout much of the day is beneficial. Ample, but not excessive, protein and calories should be included in the diet. Sodium and fluid intakes should not be limited or forced. Sedatives or tranquilizers have been used routinely by some; we do not recommend them. Further management depends upon (1) severity of preeclampsia, (2) duration of gestation; and (3) condition of the cervix. Fortunately, many cases prove to be sufficiently mild and near enough to term that they can be managed conservatively until labor commences spontaneously or until the cervix becomes favorable for labor induction. Complete abatement of all signs and symptoms, however, is uncommon until after delivery. Almost certainly, the underlying disease persists until after delivery!
1. Bed rest. Preferably with as much of the time as possible spent in a lateral decubitus position. In this position, cardiac function and uterine blood flow are maximized and maternal blood pressures in most cases are normalized. This improves uteroplacental function, allowing normal fetal growth and metabolism. ambulatory treatment has no place in the management of PIH; bed-rest throughout the greater part of the day is essential.
2. Sedative drugs for normalization of status of central nervous system:
1. Droperidol – 2 ml IM, Seduxen – 2 ml IM. These drugs should be combined with Droperidol – 0,25 % - 2ml IM or IV
3. Antihypertensive therapy eliminates vasospasm of macro- and microcirculation.
Antihypertensive drugs used in pregnancy:
1. spasmolytic agents – No-spani 2 % - 2-4 ml intramuscularly, Papaverine hydrochloride – 2 % - 2-4 ml IM, Plathyphillinum – 0,2 % - 2, 0 – twice a day, Dibasol – 1 % 2-4 ml IM or IV, Euphyllinum – 2,4 % 10, 0 IV;
2. Nifedipine – calcium-channel blocker – in the dose 10 mg po q 4-8 hours;
3. Labetalol – a- and b- adrenergic blockers – in the dose 20-50 mg IV q 3-6 hours;
4. Methyldopa – false neurotransmission, central nervous system effect;
5. Thiazide – decreased plasma volume and cardiac output.
If diastolic pressure is repeatedly above 110 mm Hg – Hydralazine is preferred agent because of its effectiveness and safety. An initial dose of 5 mg given as an intravenous bolus is increased by 5 to 10 mg every 20 minutes until suitable blood pressure is achieved. The goal of such therapy is to reduce the diastolic blood pressure to the 90-11 mm Hg range. Labetolol is a useful second-line drug for women whose hypertension is refractory to hydralazine.
Hydralazine is given intravenously whenever the diastolic blood pressure is 110 mm Hg or higher. It is administered in 5- to 10-mg doses at 15- to 20-minute intervals until a satisfactory response is achieved. A satisfactory response antepartum or intrapartum is defined as a decrease in diastolic blood pressure to 90 to 100 mm Hg, but not lower so that placental perfusion will not be compromised. Some recommend treatment of diastolic pressures over 100 mm Hg and some use 105 mm Hg as a cutoff (Cunningham and Lindheimer, 1992; Sibai, 1996).
Hydralazine so administered has proven remarkably effective, and importantly, cerebral hemorrhage has been avoided. At Parkland Hospital, approximately 8 percent of all women with pregnancy-induced hypertension are given hydralazine as described; this drug has been administered to more than 3500 women to control acute peripartum hypertension. Seldom was another antihypertensive agent needed because of poor response to hydralazine. In most European centers, hydralazine is also favored (Hutton and colleagues, 1992; Redman and Roberts, 1993).
The tendency to give a larger initial dose of hydralazine when the blood pressure is higher must be avoided. Figure 31–19 shows the mean arterial blood pressure responses to 5-mg hydralazine bolus doses. The response to even 5- to 10-mg doses cannot be predicted by the level of hypertension; thus we always give 5 mg as the initial dose. Hydralazine was injected more frequently than recommended in the protocol, and blood pressure decreased in less than 1 hour from 240–270/130–150 mm Hg to 110/80 mm Hg. Ominous fetal heart rate decelerations were evident when the pressure fell to 110/80 mm Hg, and the decelerations persisted until maternal blood pressure increased.
4. Magnesium Sulfate is used to arrest and prevent the convulsions of eclampsia without producing generalized central nervous system depression in either mother or the fetus. Magnesium sulfate may be given intramuscularly in the dose 25 % -5, 0 2-3 times a day or by continuos intravenous infusion in the dose 8 % - 200, 0 ml. It has spasmolytic, sedative, hypotensive and anticonvulsant effects.
Frequent evaluations of the patient's patellar reflex and respiration (> 14 respiratory act in a minute) are necessary to monitor for manifestations of toxic serum magnesium concentrations. In addition, because magnesium sulfate is excreted solely from the kidney, maintenance of urine output at > 30 ml/hr will avoid accumulation of the drug. Reversal of the effects of excessive magnesium concentrations is accomplished by the slow intravenous administration of 10% calcium gluconate along with oxygen supplementation and cardiorespiratory support if needed.
The maximal dose of magnesium during a day in the case of severe preeclampsia is 50-80 ml (12,5 – 80 gram).
Sheme of magnesium administration in the case of severe preeclampsia and eclampsia:
1) Intravenous administration of Magnesium Sulfate - 12 ml 25 % during 5 minutes. At the same time – intramuscularly administration of 4,5 – 6 g of Magnesium Sulfate in average dose 0,1 g per kg of patient’s weight. Than this dose is repeated each 6 hours intramuscularly. The general dose in 24 hour should be not exceed 24 gram. The course of treatment should be repeated after 12 hours.
2) Initial administration of 3 g IV and 4 g IM, followed by a 4,5-6 g every 4 hours maintenance dose.
3) administer 4-6 g of magnesium sulfate IV over 10-15 min, followed by a 2g/hour maintenance dose (American).
Magnesium sulfate is used to arrest and prevent convulsions due to eclampsia without producing generalized central nervous system depression in either the mother or the fetus-infant. Magnesium sulfate is not given to treat hypertension. Based on a number of studies that will be cited, as well as extensive clinical observations, magnesium most likely exerts a specific anticonvulsant action on the cerebral cortex. Typically, the mother stops convulsing after the initial administration of magnesium sulfate, and within an hour or two regains consciousness sufficiently to be oriented as to place and time.
Using these regimen, there has been no evidence of neonatal depression due to magnesium intoxication. In the unusual case in which the initial dose of 4 g intravenously plus 10 g intramuscularly has not arrested eclamptic convulsions, 2 g more, as a 20 percent solution, has been administered slowly intravenously. In a small woman, an additional 2 g dose may be used once, and twice if needed in a larger woman. In only 5 of 245 women with eclampsia was it necessary to use supplementary medication to control convulsions. The agent used was sodium amobarbital given slowly intravenously in doses up to 250 mg. Thiopental is also suitable. Maintenance magnesium sulfate therapy for eclampsia is continued intramuscularly every 4 hours for 24 hours after delivery. For eclampsia that develops postpartum, magnesium sulfate is administered for 24 hours after the onset of convulsions.
Parenterally administered magnesium is cleared almost totally by renal excretion, and magnesium intoxication is avoided by ensuring that before each dose (1) urine flow was at least 100 mL during the previous 4 hours, (2) the patellar reflex is present, and (3) there is no respiratory depression. Eclamptic convulsions are almost always prevented by plasma magnesium levels maintained at 4 to 7 mEq/L. As discussed below, loss of the patellar reflex begins with plasma levels of 8 to 10 mEq/L and, importantly, respiratory arrest occurs at levels of 12 mEq/L or more. Calcium gluconate, 1 g administered slowly intravenously, and oxygen usually suffice for treatment of respiratory depression. If respiratory arrest occurs, prompt tracheal intubation and ventilation are life saving.
Because magnesium is cleared almost exclusively by renal excretion, plasma magnesium concentration, using the doses described, will be excessive if glomerular filtration is decreased substantively. Renal function is estimated by measuring plasma creatinine, and whenever it is 1.3 mg/dL or higher, we give only half of the maintenance magnesium sulfate dose outlined in Table 31–11. Thus, the woman with eclampsia who has impaired renal function is given a loading dose of 4 g intravenously in addition to the 10 g intramuscular dose, to be followed by 2.5 g intramuscularly every 4 hours. Plasma magnesium levels are usually within the desired range of 4 to 7 mEq/L. Some prefer in these circumstances to give magnesium sulfate intravenously by continuous infusion. With either method, when there is renal insufficiency, plasma magnesium levels must be checked periodically.
Pharmacology and Toxicology of Magnesium Sulfate
Magnesium sulfate USP is MgSO4 · 7H2O and not MgSO4. When administered as described, the drug will practically always arrest eclamptic convulsions and prevent their recurrence. The initial intravenous infusion of 4 g is used to establish a prompt therapeutic level that is maintained by the nearly simultaneous intramuscular injection of 10 g of the compound, followed by 5 g intramuscularly every 4 hours, as long as there is no evidence of potentially dangerous hypermagnesemia. With this dosage schedule, therapeutically effective plasma levels of 4 to 7 mEq/L are achieved compared with pretreatment plasma levels of less than 2.0 mEq/L (Chesley and Tepper, 1957; Stone and Pritchard, 1970). Magnesium sulfate injected deeply into the upper outer quadrant of the buttocks, as described earlier, has not resulted in erratic absorption and consequent erratic plasma levels.
Sibai and co-workers (1984) performed a prospective study in which they compared continuous intravenous magnesium sulfate and intramuscular magnesium sulfate. There was no significant difference between mean magnesium levels observed after intramuscular magnesium sulfate and those observed following a maintenance intravenous infusion of 2 g/hr. However, the intramuscular regimen resulted in serum magnesium levels that were significantly higher than those obtained with a continuous intravenous maintenance dose of 1 g/hr. They concluded that there was no therapeutic advantage to the intravenous route of administration except for the avoidance of pain at the intramuscular injection site. When given intravenously, magnesium sulfate should be delivered by an infusion pump, and careful attention must be given to the solution concentration and the rate of delivery. Most recommend that 2 g/hr be given, to be followed by serial magnesium determinations to avoid toxicity.
Patellar reflexes disappear when the plasma magnesium level reaches 10 mEq/L, presumably because of a curariform action. This sign serves to warn of impending magnesium toxicity, because a further increase will lead to respiratory depression. Plasma cholinesterase activity is decreased substantively in preeclamptic women, but this is not altered further by magnesium therapy (Kambam and associates, 1988).
When plasma levels rise above 10 mEq/L, respiratory depression develops, and at 12 mEq/L or more, respiratory paralysis and arrest follow. Somjen and co-workers (1966) induced in themselves, by intravenous infusion, marked hypermagnesemia, achieving plasma levels up to 15 mEq/L. Predictably, at such high plasma levels, respiratory depression developed that necessitated mechanical ventilation, but depression of the sensorium was not dramatic as long as hypoxia was prevented. Treatment with calcium gluconate, 1 g intravenously, along with the withholding of magnesium sulfate usually reverses mild to moderate respiratory depression. Unfortunately, the effects of intravenously administered calcium may be short lived. For severe respiratory depression and arrest, prompt tracheal intubation and mechanical ventilation are life saving. Direct toxic effects on the myocardium from high levels of magnesium are uncommon. In humans, it appears that a major cause of cardiac dysfunction is due to hypoxia, the consequence of respiratory arrest, rather than a direct effect of magnesium. With appropriate ventilation, cardiac action is satisfactory even when plasma levels are exceedingly high (McCubbin and associates, 1981).
Parenterally injected magnesium is filtered through the glomerulus and variably reabsorbed by the tubule. As plasma magnesium concentration increases, more magnesium is filtered and less is reabsorbed. Nonetheless, when glomerular filtration is impaired, so is magnesium clearance. Therefore, an appreciably elevated plasma creatinine level indicates diminished renal capacity to excrete magnesium .
Acute cardiovascular effects of parenteral magnesium ion in women with severe preeclampsia have been studied by Cotton and associates (1984), who obtained data using pulmonary and radial artery catheterization. Following a 4-g intravenous dose given over 15 minutes, mean arterial blood pressure fell slightly, and this was accompanied by a 13 percent increase in cardiac index. Thus, magnesium decreased systemic vascular resistance and mean arterial pressure, and at the same time increased cardiac output, without evidence of myocardial depression. While they found that these effects dissipated within 15 minutes despite continuous magnesium infusion, Scardo and colleagues (1995) demonstrated an effect of at least 4 hours.
In monkeys with angiotensin-induced hypertension late in pregnancy, Harbert and co-workers (1969) demonstrated slightly increased uterine blood flow in response to the infusion of magnesium sulfate. At the same time, arterial blood pressure decreased minimally.
Watson and colleagues (1986) reported the effects of magnesium on cultured human umbilical vein endothelial cells. In concentrations similar to those achieved in plasma with therapeutic doses described above, magnesium stimulated prostacyclin release in a dose-dependent fashion. Plasma from women given magnesium sulfate therapy stimulated a two- to fivefold increase in prostacyclin production, compared with pretherapy plasma. Presumably also mediated by prostacyclin, magnesium enhanced platelet aggregation inhibition characteristic of endothelial cells. In contrast, O’Brien and colleagues (1990) questioned magnesium stimulation of prostacyclin because they could not identify an increased renal excretion of prostaglandin metabolites following magnesium therapy. Similarly, Hsu and associates (1996) observed that magnesium sulfate therapy had no effect on nitric oxide levels in preeclamptic women.
Cerebrospinal fluid magnesium levels are unchanged in untreated severely preeclamptic women when compared with normotensive controls (Fong and associates, 1995). Thurnau and colleagues (1987) showed that there was a small but highly significant increase in cerebrospinal fluid magnesium concentration after magnesium therapy for preeclampsia. The magnitude of the increase was directly proportional to the corresponding serum concentration. Borges and Gücer (1978) provided convincing evidence that the magnesium ion exerts an effect on the central nervous system much more specific than generalized depression. The degree of suppression increased as the plasma magnesium concentration increased, and decreased as it fell. Therefore, even though elevated concentrations of plasma magnesium inhibit acetylcholine release in response to motor nerve impulses, reduce motor end-plate sensitivity to acetylcholine, and decrease motor end-plate potential, these actions do not account for, nor should they necessarily be implicated in, the explanation of the beneficial effects of magnesium sulfate in controlling the convulsions of eclampsia.
Lipton and Rosenberg (1994) attribute anticonvulsant effects to neuronal calcium influx blocking through the glutamate channel. Cotton and associates (1992) induced seizure activity in the hippocampus region of rats because it is a region with a low seizure threshold and a high density of N-methyl-D-aspartate receptors. These receptors are linked to various models of epilepsy and can be blocked by magnesium. Because the hippocampal seizures could be blocked by magnesium, the investigators believed that this implicated the N-methyl-D-aspartate receptor in eclamptic seizures. Magnesium, therefore, has a central nervous system effect in blocking seizures.
Magnesium ions in relatively high concentration will depress myometrial contractility both in vivo and in vitro. With the regimen described and the plasma levels that have resulted, no evidence of myometrial depression has been observed beyond a transient decrease in activity during and immediately after the initial intravenous loading dose. Typically, as the cutaneous flushing from the intravenous dose disappeared, uterine activity returned to preinjection intensity.
Magnesium administered parenterally to the mother promptly crosses the placenta to achieve equilibrium in fetal serum and less so in amnionic fluid (Hallak and colleagues, 1993). With a single large intravenous dose, but not with smaller doses, magnesium sulfate may transiently cause a loss of fetal heart rate beat-to-beat variability (Pritchard, 1979). Atkinson and colleagues (1994a) reported a statistically significant but clinically insignificant decrease in short-term variability. They observed no changes in long-term variability or fetal heart rate acceleration. Others, however, have reported more profound reductions both in short- and long-term variability (Guzman and co-workers, 1993). Gray and colleagues (1994) reported that therapeutic magnesium sulfate for tocolysis did not alter the biophysical profile in 25 fetuses studied. The neonate may be depressed only if severe hypermagnesemia exists at delivery. We have not observed neonatal compromise after intramuscular therapy with magnesium sulfate (Cunningham and Pritchard, 1984), nor have Green and associates (1983).
More recently, Nelson and Grether (1995) described a possible protective effect of magnesium against cerebral palsy in very-low-birthweight infants. To the contrary, Kimberlin and colleagues (1996) found no improved neonatal outcome advantage of maternal magnesium sulfate tocolysis in infants born weighing less than 1000 g.
5. Normalization of blood reology because of hemoconcentration – Trental, Curantil, Komplamin.
6. Limited intravenous fluid therapy under control of blood volume, hematocrit, 24-hours diuresis. Primarily lactated Ringer’s containing 5 % dextrose – should be given at a rate of 60-125 ml per hour (not faster) unless there is unusual fluid loss from vomiting, diarrhea, or, more likely, excessive blood loss at delivery. Oliguria is common in severe preeclampsia and eclampsia, making it tempting to administer intravenous fluids more vigorously. However, the infusion of large volumes of fluid enhances the maldistribution of extracellular fluid and in that way increases the risk of pulmonary and cerebral edema.
Lactated Ringer solution is administered routinely at the rate of 60 mL/hr to no more than 125 mL/hr unless there was unusual fluid loss from vomiting, diarrhea, or diaphoresis, or more likely, excessive blood loss at delivery. Oliguria, common in cases of severe preeclampsia and eclampsia, coupled with the knowledge that maternal blood volume is very likely constricted compared with normal pregnancy, make it tempting to administer intravenous fluids more vigorously. The rationale for controlled, conservative fluid administration is that the typical eclamptic woman already has excessive extracellular fluid that is inappropriately distributed between the intravascular and extravascular spaces of the extracellular fluid compartment. Infusion of large fluid volumes could and does enhance the maldistribution of extracellular fluid and thereby appreciably increases the risk of pulmonary and cerebral edema (Benedetti and Quilligan, 1980b; Gedekoh and associates, 1981; Sibai and co-workers, 1987b).
For the patient with worsening preeclampsia or the patient who has severe preeclampsia or eclampsia, stabilization with magnesium sulfate, antihypertensive therapy as indicated, monitoring for maternal and fetal well-being, and delivery by induction or cesarean section are required. A 24-hour delay in delivery allow steroid administration to enhance fetal pulmonary maturity may be indicated in some cases.
7. Avoidance of Diuretics and Hyperosmotic Agents. Potent diuretics further compromise placental perfusion, because their immediate effects include further intravascular volume depletion, which most often is already reduced compared with normal pregnancy. Therefore, diuretics are not used to lower blood pressure, so as not to enhance the intensity of the maternal hemoconcentration and its adverse effects on the mother and fetus (Zondervan and associates, 1988).
Once delivery is accomplished, in almost all cases of severe preeclampsia and eclampsia there is a spontaneous diuresis that usually begins within 24 hours and results in the disappearance of excessive extravascular extracellular fluid over the next 3 to 4 days..
With infusion of hyperosmotic agents, the potential exists for an appreciable intravascular influx of fluid and, in turn, subsequent escape of intravascular fluid in the form of edema into vital organs, especially the lungs and brain. Moreover, an oncotically active agent that leaks through capillaries into lungs and brain promotes accumulation of edema at these sites. Most importantly, a sustained beneficial effect from their use has not been demonstrated. For all of these reasons, hyperosmotic agents have not been administered, and use of furosemide or similar drugs has been limited to the rare instances in which pulmonary edema was identified or strongly suspected.
PROTOCOL FOR TREATING ECLAMPSIA: Turn patient on her side, establish airways and administer oxygen, magnesial therapy. If convulsions are controlled and maternal condition is stable – delivery within 3 to 6 hours. Continue to administer magnesium for at least 24 hours after delivery or last convulsion.
Attention! In the case if severe preeclampsia and eclampsia a patient should be hospitalized in the single patient ward, three cathethers should be inserted obligatory:
1 – into central vein - v. subclavia for a fluid therapy and controling of central venous pressure;
2 – into urinary bladder for controling of diuresis per hour;
3 – transnasal catheterisation of stomach for prevention of Mendelson’s syndrome.
Parkland Hospital Eclampsia Regimen
In 1955 Pritchard initiated a standardized treatment regimen at Parkland Hospital, and this has been used since then to manage women with eclampsia. The carefully analyzed results of treatment of 245 cases of eclampsia, typically the severest form of pregnancy-induced or -aggravated hypertension, were reported by Pritchard and associates in 1984. The specific plan of management is summarized here.
1. Control of convulsions with magnesium sulfate, using an intravenously administered loading dose and periodic intramuscular injections standardized in dose and frequency of administration.
2. Intermittent intravenous injections of hydralazine to lower blood pressure whenever the dia-stolic pressure is 110 mm Hg or higher.
3. Avoidance of diuretics and hyperosmotic agents.
4. Limitation of intravenous fluid administration unless fluid loss is excessive.
DURATION OF TREATMENT AND DELIVERY
The timing and route of delivery for preeclamptic women are determined by gestational age, fetal condition, and maternal condition.
If the effect of treatment of mild and moderate preeclampsia is absent during 7-10 days, and in the case of severe preeclamsia – during 24-48 hours – a question about delivery should be discussed immediately.
Immediate delivery by cesarean section during or after an eclamptic seizure in eclampsia can be dangerous. The maternal condition usually can be stabilized within 5-6 hours. It is safe to proceed with definitive treatment, which is cesarean section.
Indications to preterm delivery in preeclampsia:
Laboratory findings: proteinuria more than 1g 24-hour collection, decreased level of serum creatinine, liver insufficiency, thrombocytopenia, abnormal nonstress test and biophysical profile, fatal growth retardation, diastolic blood pressure more than 100 mm Hg during 24 hours, diastolic blood pressure more than 110 mm Hg.
Maternal indications: HELLP-syndrome, eclampsia, pulmonary edema, heart insufficiency, coagulopathy, kidney dysfunction, cerebral symptoms, epigastrial pain.
Once anticonvulsant and antihypertensive therapy is established, attention is directed toward delivery. Induction of labor with amniotomy is often attempted, although cesarean delivery may be needed either if induction is unsuccessful or not possible or if maternal or fetal status is worsening. Epidural anesthesia is very effective in labor because of antihypertensive effect.
At delivery, blood loss must be closely monitored, because patients with preeclampsia or eclampsia have significantly reduced blood volumes. After delivery, patients are kept in the labor and delivery area for 24 hours for close observation of their clinical progress and further administration of magnesium sulfate to prevent postpartum eclamptic seizures. Approximately 25% of all preeclamptic patients who have eclamptic seizures have them before labor, approximately 50% during labor, and approximately 25% after delivery. Usually, the vasospastic process begins to reverse itself in the first 24 to 48 hours, as manifest by a brisk diuresis.
Indications to cesarean section in PIH are frequent convulsions that don’t eliminated by therapy, amaurosis, retinal detachment, unuria, severe eclampsia which is not eliminated by conservative treatment during 24-48 hours if the cervix is unfavorable, eclampsia combining with obstetric (breech presentation, contracted pelvis, macrosomic fetus, disseminated intravascular coagulopathy) or extragenital pathology.
MANAGEMENT OF THE ECLAMPTIC SEIZURE
The eclamptic seizure is a time of life-threatening risk for mother and fetus. Maternal risks include musculoskeletal injury (including biting the tongue), hypoxia, and aspiration. Maternal therapy consists of turning patient on her side, inserting a padded tongue blade, restraining gently as needed, providing oxygen, and gaining an intravenous (IV) access. Eclamptic seizures are usually self-limited so that medical therapy should be directed to the initiation of magnesium therapy to prevent further seizures rather than to anticonvulsant therapy with diazepam or similar drugs. Transient uterine hyperactivity for 2 to 15 minutes is associated with fetal heart rate (FHR) changes, including bradycardia or compensatory tachycardia, decreased beat-to-beat activity, and late decelerations. These are self-limited and not dangerous to the fetus unless they continue for 20 minutes or more. Delivery during this time imposes unnecessary risk for mother and fetus and should be avoided. If convulsions are controlled and maternal condition is stable, initiate induction or delivery within 3 to 6 hours is recommended.
HELLP syndrome is an extremely dangerous condition that can develop in pregnant women. It includes:
· EL: elevated liver enzymes
· LP: a low platelet count
Hemolysis refers to a breakdown of red blood cells. Specifically, red blood cells get broken down earlier than normal. Hemolysis can lead to anemia, a condition in which your blood does not have enough oxygen to supply your body.
Elevated liver enzymes indicate that your liver is functioning poorly. When liver cells are inflamed or injured, they leak abnormally high amounts of certain chemicals, including enzymes, into your blood.
Platelets are part of the blood that helps it clot. When they are low, you are at risk for excess bleeding.
HELLP syndrome usually occurs in the last trimester of pregnancy, before the 37th week. It is a major health concern because it can be fatal to both mother and unborn baby. Prompt treatment and delivery of the baby are generally required for the best outcome. However, about a third of HELLP cases occur after the baby is born in the first week after delivery (Padden, 1999).
The syndrome’s cause is unknown. Some experts believe it is related to preeclampsia, another pregnancy complication, which causes high blood pressure. There are certain factors that can also increase your chance of developing HELLP syndrome.
According to the National Institutes of Health, HELLP syndrome affects approximately one to two out of every 1,000 pregnant women. (NIH).
Preeclampsia is the greatest risk factor. This condition is marked by high blood pressure, and it occurs during the last trimester of pregnancy. However, not all pregnant women with preeclampsia will necessarily develop HELLP syndrome.
Other risk factors include:
· being over the age of 25
· being Caucasian
· having given birth previously
· being obese
· having a poor diet
· lack of exercise
· having diabetes
Having had HELLP syndrome during a previous pregnancy can also increase your risk. According to the American Pregnancy Association, your risk can increase by 19 to 25 percent in future pregnancies (APA, 2009).
HELLP symptoms are similar to flu-like symptoms. They may also seem to be “normal” side effects of pregnancy. Sadly, many women skip medical treatment because they misdiagnose themselves. It is important that if you have any flu-like symptoms during pregnancy that you have them checked by a professional to ensure that they are not indicative of serious health issues.
Some of the most common symptoms of HELLP syndrome are:
· feeling generally unwell or fatigued
You may also experience:
· swelling, especially in the hands or face
· excessive weight gain
· blurry vision or visual disturbances
· shoulder pain
· pain when breathing deeply
In rare cases, you may have:
Because HELLP has similar symptoms to the flu, a proper medical diagnosis is needed. Blood tests can determine platelet levels, as well as your red blood cell count (to check for hemolysis). A urine test can detect high liver enzymes. Your doctor may order a computed tomography (CT) scan to detect bleeding in your liver.
Patients may also exhibit marked physical signs. A doctor can feel for abdominal tenderness (which may indicate a liver problem) or an enlarged liver. Your doctor may also look for excess swelling.
Blood pressure readings are often high with HELLP syndrome. You may also have protein in your urine (proteinuria). Your doctor should test for this at each prenatal visit.
HELLP generally strikes before the 37th week of gestation. However, the best treatment is to deliver the baby. In many cases, the baby is born prematurely. Leaving the baby in the mother during HELLP may increase the health risks for both individuals.
Your treatment will depend on the severity of your condition and how near you are to your due date. If your HELLP syndrome symptoms are mild and/or your baby is less than 34 weeks, your doctor may recommend:
· bedrest (either at home or in the hospital)
· admission to the hospital
· blood transfusions to treat anemia and low platelets
· magnesium sulfate to prevent seizures
· antihypertensive medication to control blood pressure
· corticosteroid medication to help your baby’s lungs mature in case an early delivery is needed
Your doctor will also closely monitor your red blood cell, platelet, and liver enzyme levels to check for signs that your condition is worsening. Your baby’s health will also be watched closely. Your doctor may recommend fetal tests that measure movement, heart rate, stress, and blood flow.
If your doctor determines that your condition requires immediate delivery of your baby, you may be given medications to help induce labor. A cesarean section may be performed, but this may cause complications if you have blood clotting problems because your platelet count is low.
When treated early, most women recover from HELLP syndrome. Symptoms significantly improve post-delivery. According to the American Pregnancy Association, most symptoms and side effects have resolved two to three days after delivery (APA, 2009).
Perhaps the biggest concern is the condition’s effects on the baby. Because most babies are delivered early when mothers develop HELLP syndrome, there is a greater risk of complications from prematurity. Babies who are born before 37 weeks are carefully monitored in the hospital before being released to go home.
Early medical treatment is the key to help prevent further complications. However, some complications can arise during treatment efforts. Also, some symptoms of HELLP can affect you and your baby after delivery. Complications associated with HELLP syndrome include:
· blood clots
· kidney failure
· liver rupture
· lung failure (in mother and baby)
· fluid in the lungs
· renal failure
· excessive bleeding
· placental abruption (when the placenta detaches from the uterus before the baby is born)
The National Institutes of Health estimate that one in every four pregnant women develops serious complications during HELLP. This is most often due to delayed treatment (NIH, 2010).
HELLP syndrome is not preventable in many pregnant women because there is no one specific cause of the condition. However, if you have preeclampsia, then sticking to a healthy lifestyle may help prevent HELLP syndrome from developing. It is important to contact your doctor immediately if you suspect early symptoms of this condition.
HELLP, a syndrome characterized by hemolysis, elevated liver enzyme levels and a low platelet count, is an obstetric complication that is frequently misdiagnosed at initial presentation. Many investigators consider the syndrome to be a variant of preeclampsia, but it may be a separate entity. The pathogenesis of HELLP syndrome remains unclear. Early diagnosis is critical because the morbidity and mortality rates associated with the syndrome have been reported to be as high as 25 percent. Platelet count appears to be the most reliable indicator of the presence of HELLP syndrome. The D-dimer test may be a useful tool for the early identification of patients with preeclampsia who may develop severe HELLP syndrome. The mainstay of therapy is supportive management, including seizure prophylaxis and blood pressure control in patients with hypertension. Women remote from term should be considered for conservative management, whereas those at term should be delivered. Some patients require transfusion of blood products, and most benefit from corticosteroid therapy. Rarely, patients with refractory HELLP syndrome require plasmapheresis.
The acronym HELLP was coined in 1982 to describe a syndrome consisting of hemolysis, elevated liver enzyme levels and low platelet count.1 The syndrome has been considered a variant of preeclampsia, but it can occur on its own or in association with preeclampsia. Pregnancy-induced hypertension, preeclampsia and HELLP syndrome are related and overlap in their presentations. Because of the serious associated morbidity and mortality, family physicians who provide maternity care need to be aware of HELLP syndrome so that they can identify it early.
Etiology and Pathogenesis
The pathogenesis of HELLP syndrome is not well understood. The findings of this multisystem disease are attributed to abnormal vascular tone, vasospasm and coagulation defects.2 To date, no common precipitating factor has been found. The syndrome seems to be the final manifestation of some insult that leads to microvascular endothelial damage and intravascular platelet activation. With platelet activation, thromboxane A and serotonin are released, causing vasospasm, platelet agglutination and aggregation, and further endothelial damage.2 Thus begins a cascade that is only terminated with delivery.
The hemolysis in HELLP syndrome is a microangiopathic hemolytic anemia. Red blood cells become fragmented as they pass through small blood vessels with endothelial damage and fibrin deposits. The peripheral smear may reveal spherocytes, schistocytes, triangular cells and burr cells. The elevated liver enzyme levels in the syndrome are thought to be secondary to obstruction of hepatic blood flow by fibrin deposits in the sinusoids. This obstruction leads to periportal necrosis and, in severe cases, intrahepatic hemorrhage, subcapsular hematoma formation or hepatic rupture. The thrombocytopenia has been attributed to increased consumption and/or destruction of platelets.
Although some investigators speculate that disseminated intravascular coagulopathy (DIC) is the primary process in HELLP syndrome, most patients show no abnormalities on coagulation studies. Patients who develop DIC generally do so in the setting of well-developed HELLP syndrome. All patients with HELLP syndrome may have an underlying coagulopathy that is usually undetectable.
Epidemiology and Risk Factors
HELLP syndrome occurs in approximately 0.2 to 0.6 percent of all pregnancies.3 In comparison, preeclampsia occurs in 5 to 7 percent of pregnancies.3 Superimposed HELLP syndrome develops in 4 to 12 percent of women with preeclampsia or eclampsia.3 When preeclampsia is not present, diagnosis of the syndrome is often delayed.4
The risk factors for HELLP syndrome differ from those associated with preeclampsia (Table 1). The syndrome generally presents in the third trimester of pregnancy, although it occurs at less than 27 weeks of gestation in an estimated 11 percent of patients.5 The syndrome presents antepartum in 69 percent of patients and postpartum in 31 percent of patients.2 With postpartum presentation, the onset is typically within the first 48 hours after delivery; however, signs and symptoms may not become apparent until as long as seven days after delivery.
Comparison of Risk Factors for HELLP Syndrome and Preeclampsia
Maternal age greater than 25 years
Maternal age less than 20 years or greater than 45 years
Family history of preeclampsia
History of poor pregnancy outcome
Minimal prenatal care
HELLP = hemolysis, elevated liver enzyme levels and low platelet count.
The vague nature of the presenting complaints can make the diagnosis of HELLP syndrome frustrating to physicians. Approximately 90 percent of patients present with generalized malaise, 65 percent with epigastric pain, 30 percent with nausea and vomiting, and 31 percent with headache.3 Because early diagnosis of this syndrome is critical, any pregnant woman who presents with malaise or a viral-type illness in the third trimester should be evaluated with a complete blood cell count and liver function tests.6
The physical examination may be normal in patients with HELLP syndrome. However, right upper quadrant tenderness is present in as many as 90 percent of affected women.2 Edema is not a useful marker because swelling is a factor in up to 30 percent of normal pregnancies.3 Hypertension and proteinuria may be absent or mild. The differential diagnosis of HELLP syndrome includes acute fatty liver of pregnancy, thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.
Because of the variable nature of the clinical presentation, the diagnosis of HELLP syndrome is generally delayed for an average of eight days.7 Many woman with this syndrome are initially misdiagnosed with other disorders, such as cholecystitis, esophagitis, gastritis, hepatitis or idiopathic thrombocytopenia.3 In one retrospective chart review of patients with HELLP syndrome, only two of 14 patients entered the hospital with the correct diagnosis.7
The three chief abnormalities found in HELLP syndrome are hemolysis, elevated liver enzyme levels and a low platelet count. The hematocrit may be decreased or normal and is typically the last of the three abnormalities to appear. The finding of a decreased serum haptoglobin level may confirm ongoing hemolysis when the hematocrit is normal.8 The serum transaminase levels may be elevated to as high as 4,000 U per L, but milder elevations are typical. Platelet counts can drop to as low as 6,000 per mm3 (6 × 109 per L), but any platelet count less than 150 per mm3 (150 × 109 per L) warrants attention. Unless DIC is present, the prothrombin time, partial thromboplastin time and fibrinogen level are normal in patients with HELLP syndrome. In a patient with a plasma fibrinogen level of less than 300 mg per dL (3 g per L), DIC should be suspected, especially if other laboratory abnormalities are also present.
Proteinuria and an increased uric acid concentration are useful in diagnosing preeclampsia but not HELLP syndrome.9 The platelet count is the best indicator of the latter. Therefore, HELLP syndrome should be suspected in any patient who shows a significant drop in the platelet count during the antenatal period.10 A positive D-dimer test in the setting of preeclampsia has recently been reported to be predictive of patients who will develop HELLP syndrome.11 The D-dimer is a more sensitive indicator of subclinical coagulopathy and may be positive before coagulation studies are abnormal.
Two classification systems are used for HELLP syndrome. The first is based on the number of abnormalities that are present. In this system, patients are classified as having partial HELLP syndrome (one or two abnormalities) or full HELLP syndrome (all three abnormalities). Women with full HELLP syndrome are at higher risk for complications, including DIC, than women with the partial syndrome. Consequently, patients with the full syndrome should be considered for delivery within 48 hours, whereas those with partial HELLP syndrome may be candidates for more conservative management.12
Alternatively, HELLP syndrome can be classified on the basis of platelet count nadir: class I, less than 50,000 per mm3 (50 × 109 per L); class II, 50,000 to less than 100,000 per mm3 (50 to 100 × 109 per L); and class III, 100,000 to 150,000 per mm3 (100 to 150 × 109 per L).13 Patients with class I HELLP syndrome are at higher risk for maternal morbidity and mortality than patients with class 2 or 3 HELLP syndrome.5
Once the diagnosis of HELLP syndrome has been established, the best markers to follow are the maternal lactate dehydrogenase level and the maternal platelet count.14 Laboratory abnormalities typically worsen after delivery and peak at 24 to 48 hours postpartum.14 The peak lactate dehydrogenase level signals the beginning of recovery and subsequent normalization of the platelet count.14 The platelet count nadir is somewhat predictive for hemorrhagic complications. The incidence of hemorrhagic complications is higher when platelet counts are less than 40,000 per mm3 (40 × 109 per L).15 However, hepatic imaging and liver biopsy have shown that laboratory abnormalities do not correlate with the severity of HELLP syndrome.16,17 Therefore, patients with HELLP syndrome who complain of severe right upper quadrant pain, neck pain or shoulder pain should be considered for hepatic imaging regardless of the severity of the laboratory abnormalities, to assess for subcapsular hematoma or rupture.17
Prompt recognition of HELLP syndrome and timely initiation of therapy are vital to ensure the best outcome for mother and fetus. When the syndrome was first described, prompt delivery was recommended.1 Recent research suggests that morbidity and mortality do not increase when patients with HELLP are treated conservatively.18 The treatment approach should be based on the estimated gestational age and the condition of the mother and fetus (Figure 1).19
Management of HELLP Syndrome*
Patients with HELLP syndrome may be eligible for conservative management if hypertension is controlled at less than 160/110 mm Hg, oliguria responds to fluid management and elevated liver function values are not associated with right upper quadrant or epigastric pain. One study20 found that pregnancy was prolonged by an average of 15 days when conservative management (i.e., bed rest, fluids and close observation) was used in patients who were at less than 32 weeks of gestation. Maternal morbidity was not increased. For infants, the prolongation of pregnancy translated into less time in the neonatal intensive care unit, a decreased incidence of necrotizing enterocolitis and a decreased incidence of respiratory distress syndrome.20 Women treated conservatively should be managed in a tertiary care center that has a neonatal intensive care unit and a perinatologist available for consultation.
In the past, delivery in patients with HELLP syndrome was routinely accomplished by cesarean section. Patients with severe HELLP syndrome, superimposed DIC or a gestation of less than 32 weeks should be delivered by cesarean section. A trial of labor is appropriate in patients with mild to moderate HELLP syndrome who are stable, have a favorable cervix and are at 32 weeks of gestation or greater.2
Patients with HELLP syndrome should be routinely treated with corticosteroids. The antenatal administration of dexamethasone (Decadron) in a high dosage of 10 mg intravenously every 12 hours has been shown to markedly improve the laboratory abnormalities associated with HELLP syndrome.21 Patients treated with dexamethasone exhibit longer time to delivery; this facilitates maternal transfer to a tertiary care center and postnatal maturity of fetal lungs.
Steroids given antenatally do not prevent the typical worsening of laboratory abnormalities after delivery. However, laboratory abnormalities resolve more quickly in patients who continue to receive steroids postpartum.10 Corticosteroid therapy should be instituted in patients with HELLP syndrome who have a platelet count of less than 100,000 per mm3 (100 × 109 per L) and should be continued until liver function abnormalities are resolving and the platelet count is greater than 100,000 per mm3 (100 × 109 per L).
Patients with HELLP syndrome should be treated prophylactically with magnesium sulfate to prevent seizures, whether hypertension is present or not. A bolus of 4 to 6 g of magnesium sulfate as a 20 percent solution is given initially. This dose is followed by a maintenance infusion of 2 g per hour. The infusion should be titrated to urine output and magnesium level. Patients should be observed for signs and symptoms of magnesium toxicity. If toxicity occurs, 10 to 20 mL of 10 percent calcium gluconate should be given intravenously.
Antihypertensive therapy should be initiated if blood pressure is consistently greater than 160/110 mm Hg despite the use of magnesium sulfate. This reduces the risk of maternal cerebral hemorrhage, placental abruption and seizure. The goal is to maintain diastolic blood pressure between 90 and 100 mm Hg. The most commonly used antihypertensive agent has been hydralazine (Apresoline), which is given intravenously in small incremental doses of 2.5 to 5 mg (with 5 mg as the initial dose) every 15 to 20 minutes until the desired blood pressure is achieved. Labetolol (Normodyne) and nifedipine (Procardia) have also been used with success.
Because of reported potentiation of effect, care should be taken when nifedipine and magnesium sulfate are given concurrently.22 Diuretics may compromise placental perfusion and therefore are not used to control blood pressure in patients with HELLP syndrome. A hypertensive crisis may be treated with a continuous infusion of nitroglycerin or sodium nitroprusside (Nipride).
Between 38 and 93 percent of patients with HELLP syndrome receive some form of blood product.15 Patients with a platelet count greater than 40,000 per mm3 (40 × 109 per L) are unlikely to bleed. These patients do not require transfusion unless the platelet count drops to less than 20,000 per mm3 (20 × 109 per L). Patients who undergo cesarean section should be transfused if their platelet count is less than 50,000 per mm3 (50 × 109 per L). Prophylactic transfusion of platelets at delivery does not reduce the incidence of postpartum hemorrhage or hasten normalization of the platelet count.15 Patients with DIC should be given fresh frozen plasma and packed red blood cells.
The laboratory abnormalities in HELLP syndrome typically worsen after delivery and then begin to resolve by three to four days postpartum.14 Plasmapheresis has been successful in patients with severe laboratory abnormalities (i.e., a platelet count of less than 30,000 per mm3 [30 × 109 per L] and continued elevation of liver function values) who have required repeat transfusions to maintain their hematocrit at 72 hours postpartum. In these patients, plasmapheresis has resulted in an increase in the platelet count and a decrease in the lactate dehydrogenase level.23–25
Pain relief with intravenous narcotics and local anesthesia is acceptable but certainly not optimal for pain control. Epidural anesthesia has been controversial but is the technique of choice when it can be accomplished safely.26 Insertion of an epidural catheter is generally safe in patients with a platelet count greater than 100,000 per mm3 (100 × 109 per L), normal coagulation studies and a normal bleeding time.26 General anesthesia can be used when regional anesthesia is considered unsafe.
The mortality rate for women with HELLP syndrome is approximately 1.1 percent.5 From 1 to 25 percent of affected women develop serious complications such as DIC, placental abruption, adult respiratory distress syndrome, hepatorenal failure, pulmonary edema, subcapsular hematoma and hepatic rupture. A significant percentage of patients receive blood products.5
Infant morbidity and mortality rates range from 10 to 60 percent, depending on the severity of maternal disease.3 Infants affected by HELLP syndrome are more likely to experience intrauterine growth retardation and respiratory distress syndrome.27