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General Considerations
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Hypertension is the most common medical disorder of pregnancy and complicates a reported 6–10% of pregnancies. Of four million women giving birth in the United States each year, an estimated 240,000 are affected by hypertension. Hypertension and preeclampsia can cause serious maternal and fetal problems and account for ˜15% of maternal deaths in the United States. Worldwide, preeclampsia causes at least 63,000 maternal deaths yearly.
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There are four major hypertensive disorders in pregnancy: (1) Chronic hypertension, (2) preeclampsia, which is pregnancy-induced hypertension associated with proteinuria, (3) preeclampsia superimposed on chronic hypertension, and (4) gestational hypertension. All four types may lead to maternal and perinatal complications, although preeclampsia with severe hypertension is associated with the highest maternal and fetal risks. The diagnosis essentially depends on the gestational age at presentation of hypertension and the presence or absence of proteinuria (Figure 43–4).
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Chronic hypertension is blood pressure (BP) >140/90 mm Hg that either predates pregnancy or presents earlier than 20 weeks of pregnancy. It is not associated with proteinuria and complicates approximately 3% of pregnancies.
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Preeclampsia–Eclampsia
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Preeclampsia, a pregnancy-specific syndrome that develops in the latter half of pregnancy (after 20 weeks) in 5–6% of all pregnant women, and is characterized by increased BP (>140/90 mm Hg) and new onset proteinuria (>0.3 g daily) in a woman who had normal BP before 20 weeks. Eclampsia is the occurrence of seizures that cannot be attributed to other causes and complicates approximately 3% of preeclamptic women.
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A severe variant of preeclampsia that features hemolysis, elevated liver enzymes, and low platelets (the HELLP syndrome) occurs in 1 in 1000 pregnancies.
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Preeclampsia Superimposed on Chronic Hypertension
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Women with chronic hypertension are at increased risk for the development of superimposed preeclampsia, which complicates 25% of chronic hypertensive pregnancies (versus 5% of nonhypertensive pregnancies). The diagnosis of superimposed preeclampsia is made if proteinuria develops for the first time after 20 weeks in association with an (even higher) increase in BP. In women with both hypertension and proteinuria before 20 weeks of gestation (for example, patients with diabetic nephropathy and proteinuria), superimposed preeclampsia is diagnosed (1) when there is a sudden increase in proteinuria or a sudden increase in BP in the latter half of pregnancy in a woman whose hypertension had previously been well controlled or (2) as part of the HELLP syndrome when there is new onset thrombocytopenia with hemolysis and elevated levels of alanine aminotransferase or aspartate aminotransferase.
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Gestational Hypertension
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Gestational hypertension, seen in 6% of pregnancies, develops in the latter half of pregnancy and is not associated with features of preeclampsia (eg, proteinuria). Some women may ultimately develop signs of preeclampsia, so the final diagnosis can only be made postpartum.
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Differential Diagnosis
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The prevalence of hypertension in premenopausal women is close to 25% and increases with age. Approximately 2–5% of pregnancies are complicated by chronic hypertension. Preexisting hypertension may be more common, particularly in industrialized urban areas where women often postpone child bearing to later years.
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If hypertension was clearly documented before conception, the diagnosis of chronic hypertension in pregnancy is straightforward (Figure 43–4). Chronic hypertension is also the most likely diagnosis when hypertension (and no proteinuria) is present before 20 weeks of gestation. In normotensive patients, BP falls in early pregnancy. Systolic pressure changes little, whereas diastolic pressure falls by ˜10 mm Hg within 13–20 weeks, with a nadir at 24 weeks, and then rises again to prepregnancy levels in the third trimester (weeks 28–40) (Figure 43–5). This physiologic fall may be even more exaggerated in women with chronic hypertension, and difficulties in diagnosis arise when pregnant women with undiagnosed chronic hypertension are seen for the first time in the second trimester, during the time of the physiologic decrease in BP. In this circumstance, women may appear normotensive (when it is really the physiologic decrease in BP); later they are inaccurately diagnosed with gestational hypertension or preeclampsia when BP rises to prepregnancy levels in the third trimester. In such cases the diagnosis of preeclampsia is ruled out by the absence of proteinuria (greater than “trace” on dipstick is abnormal) and the absence of other classic laboratory abnormalities of preeclampsia or HELLP syndrome such as uric acid greater than 5.5 mg/dL (325 μmol/L), elevated liver function tests, and decreased platelets.
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White-coat hypertension (elevated office BP with normal BP outside the medical setting) may be seen in up to 29% of women without preexisting hypertension. A noninvasive 24-hour blood pressure monitor can distinguish white-coat hypertension from true hypertension in the pregnant patient. White-coat hypertension does not appear to predispose paatients to preeclampsia.
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Women who present with hypertension before gestational week 20 likely have chronic hypertension. Young women may have secondary hypertension (eg, renal disease, renovascular hypertension, primary aldosteronism, Cushing's syndrome, pheochromocytoma). When secondary hypertension is suspected, noninvasive evaluation may be appropriate (Figure 43–6). For example, if proteinuria is documented in early pregnancy, noninvasive evaluation for renal disease is indicated. This might include 24-hour urinary protein excretion, creatinine clearance, renal ultrasound, and serologic testing to rule out systemic lupus erythematosus if there are suggestive symptoms. Another form of secondary hypertension that should be considered is pheochromocytoma, which although rare is associated with a high rate of morbidity and mortality during pregnancy. This entity should be considered in women with severe hypertension, especially when associated with symptoms such as headache, palpitations, pallor, and sweats. Significant hypokalemia (potassium <3.2 mEq/L) may be a sign of primary aldosteronism.
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Baseline laboratory tests including uric acid, platelets, liver function tests, urea, creatinine, and 24-hour urine for protein should be performed in women with early pregnancy hypertension, as this is helpful in determining the clinical significance of later increases in BP accompanied by abnormal laboratory tests.
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Distinguishing between chronic hypertension (that is first noted in pregnancy) and gestational hypertension is not possible until after delivery. In some instances, women with undocumented hypertension before pregnancy will have normal BP throughout their entire pregnancy, only to return to prepregnancy hypertensive levels in the postpartum period; this accounts for the mysterious cases of isolated postpartum hypertension.
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Management of the pregnant woman with chronic hypertension begins before conception to establish the diagnosis and to rule out forms of secondary hypertension such as renal disease and renovascular hypertension (Figure 43–7). Patients who have had hypertension for longer than 5 years, older women, and women with chronic illnesses such as diabetes may be evaluated for target organ damage such as left ventricular hypertrophy, fundoscopic changes, azotemia, and cardiac disease. Ideally, medications should be adjusted before pregnancy, and medications with deleterious fetal effects, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), can be assessed. Preconception is also the time to discuss the risks posed by pregnancy. Women should be informed of the likelihood of a favorable outcome if they have chronic hypertension, but should be apprised of the risks of superimposed preeclampsia and fetal complications. Patient education regarding these issues helps to increase compliance and may improve outcome, and frequent visits will increase the likelihood of detecting preeclampsia and other complications before they become life threatening.
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Nonpharmacologic Management
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Treatment of hypertension in the gravid patient represents a departure from guidelines for treastment of nonpregnant hypertensive women. Patients are not advised to exercise vigorously as the concern is that women with chronic hypertension are at risk for preeclampsia, a condition characterized by decreased uteroplacental blood flow that vigorous exercise may further compromise. Of note, women who work outside the home had both higher blood pressure and an increased risk of preeclampsia in one study. Decreased work hours and more rest may theoretically increase placental blood flow and decrease BP.
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Excessive weight loss during pregnancy is not advisable, even in obese women. Salt restriction is an important component of the management of many nonpregnant hypertensive individuals, but extremely low sodium intake (<2 g sodium) is not advisable during pregnancy. Calcium supplementation in excess of the recommended dietary allowance has not been shown to reduce the incidence of superimposed preeclampsia; however, in the developing world, in women with low dietary intake, calcium supplementation may prevent preeclampsia.
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Pharmacologic Management
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In nonpregnant adults, control of BP can decrease the long-term incidence of cardiovascular disease and mortality. During the 9 months of pregnancy, however, untreated mild to moderate hypertension is unlikely to lead to adverse maternal outcomes. An important issue for women with chronic hypertension is the prevention of preeclampsia; however, there is little evidence that the treatment of mild to moderate hypertension in pregnancy reduces the incidence of superimposed preeclampsia.
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The appropriate level of BP in a pregnant woman with hypertension is consensus rather than evidence based. International guidelines vary concerning both the thresholds for starting treatment and the targeted BP goals. Recommendations here are in accord with those of the National High Blood Pressure Education Programs' (NHBEP) working Group Report on High Blood Pressure in pregnancy. When maternal BP reaches levels ≥150/90–95 mm Hg, treatment should be instituted to avoid hypertensive vascular damage, with BP generally targeted to 140/90 mm Hg.
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As BP normally drops in the first two trimesters of pregnancy, including women with chronic hypertension, clinicians can consider discontinuing antihypertensive drugs and monitoring. Therapy can then be initiated at a BP of ≥150/90 mm Hg for otherwise healthy pregnant women with mild to moderate hypertension, regardless of type. A wide variety of reasonable agents are available for use (Table 43–4). The Food and Drug Administration classification of drugs in pregnancy designates most antihypertensive medications as category C, indicating that the drug should be given only if potential benefits justify potential risks to the fetus. This category cannot be interpreted as no risk, and is so broad that it is not clinically useful. The most recent evidence assessing the risks and benefits of drugs useful in treating hypertension in pregnancy will be reviewed. These medications have the longest history of safe use in pregnancy; however, they are rarely used in the nonpregnant population due to side effects or inconvenient dosing.
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Central Adrenergic Agonists
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Methyldopa remains the drug of first choice for treatment of hypertension in pregnancy; it has not been found to be teratogenic after a 40-year history of use. In treated patients it has been found to be useful in decreasing the occurrence of severe hypertension and hospital admissions compared with untreated patients. Birth weight and development in the first year as well as development to the age of 7 years were similar in children exposed to methyldopa compared to children in the placebo group. Methyldopa is metabolized to α-methylnorepinephrine and replaces norepinephrine to decrease sympathetic tone centrally. The adverse effects are due to its action at the brainstem and include decreased mental alertness, impaired sleep, and decreased salivation leading to xerostomia. It can cause elevated liver enzymes in 5% of patients, with hepatitis or hepatic necrosis rarely reported. It has been associated with Coombs' positivity without (except rarely) hemolytic anemia as well as a positive antinuclear antibody (ANA).
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Clonidine is another α2-adrenergic agonist comparable to methyldopa, although it is not used in preference to methyldopa given the proven safety of the latter. There is a greater potential for rebound hypertension when this drug is abruptly discontinued, and its use is reserved for individuals who cannot tolerate the other medications.
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β-Adrenoceptor Blockers
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β-Adrenoceptor blockers have been studied extensively in pregnancy and none has been associated with teratogenicity. Individual agents are not distinguishable with the exception of atenolol, which has been associated with decreased fetal weight compared to placebo. Oral and parenteral β-blockade have been associated with neonatal bradycardia, which was not clinically significant for the most part.
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Maternal outcomes have been found to improve with the use of β-blockers, which control maternal BP and decrease both the incidence of severe hypertension and the rate of admission to hospital prior to delivery. They have been compared and found to be equivalent to methyldopa in 15 trials. Adverse effects due to β-blockade include fatigue, lethargy, exercise intolerance, sleep disturbance, and bronchoconstriction in patients with asthma.
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Labetalol, a nonselective β-blocker with vascular α1-receptor blocking capabilities, has gained wide acceptance for use in pregnancy. When administered orally in patients with chronic hypertension, it is as safe and effective as methyldopa. Parenterally it is used to treat severe hypertension, and when compared to hydralazine has been associated with a lower incidence of maternal hypotension and other side effects.
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Calcium Channel Blockers
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Calcium channel blockers have been used to treat chronic hypertension, mild preeclampsia, and urgent hypertension in preeclampsia. Orally administered nifedipine and verapamil do not appear to pose teratogenic risk to fetuses exposed in the first trimester. Maternal side effects of the calcium channel blockers include palpitations, peripheral edema, headaches, and facial flushing. Most investigators have focused on the use of nifedipine, although there are reports on nicardipine, isradipine, felodipine, and verapamil as well; amlodipine is still unstudied in pregnancy.
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A concern with the use of calcium antagonists for control of BP in preeclampsia is the concomitant use of magnesium sulfate to prevent seizures; drug interactions with nifedipine and magnesium sulfate have been reported to cause neuromuscular blockade, myocardial depression, or circulatory collapse, although in practice these medications are commonly used together and the actual risk appears to be low.
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Although diuretics are widely used in the treatment of nonpregnant hypertensive patients, obstetricians are reluctant to use diuretics because of a concern that they will interfere with the physiologic volume expansion of normal pregnancy. However, in a meta-analysis of trials involving >7000 subjects diuretics appeared to prevent preeclampsia. While volume contraction might be expected to limit fetal growth, data have not supported this concern. Of note, mild volume contraction with diuretic therapy may lead to hyperuricemia, and in so doing may invalidate serum uric acid levels as a laboratory marker in the diagnosis of superimposed preeclampsia.
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Diuretics are commonly prescribed in essential hypertension prior to conception and, given their apparent safety, the NHBEP Working Group on High Blood Pressure in Pregnancy concluded that they may be continued through gestation or used in combination with other agents, especially for women deemed likely to have salt-sensitive hypertension. Hydrochlorothiazide may be continued; utilization of low doses, no more than 25 mg daily, can minimize the side effects of impaired glucose tolerance and hypokalemia. Spironolactone is not recommended due to theoretic antiandrogen effects during fetal development.
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Hydralazine is effective orally, intramuscularly, or intravenously; parenteral administration is useful for rapid control of severe hypertension. Adverse effects, mostly due to excessive vasodilation or sympathetic activation, include headache, nausea, flushing, or palpitations. In rare cases, chronic use can lead to a pyridoxine-responsive polyneuropathy or to a drug-induced lupus syndrome.
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Hydralazine has been used in all trimesters of pregnancy and is not associated with teratogenicity. It has been widely used for chronic hypertension in the second and third trimesters, but use has been supplanted by agents with more favorable side effect profiles. For acute severe hypertension later in pregnancy, intravenous hydralazine has been associated with more maternal and perinatal adverse effects than intravenous labetalol or oral nifedipine, such as maternal hypotension, oliguria, cesarean sections, placental abruptions, and APGAR scores <7. Furthermore, the common side effects such as headache, nausea, and vomiting mimic the symptoms of deteriorating preeclampsia. A recent meta-analysis of the use of intravenous hydralazine for severe hypertension in pregnancy does not support its use first line, and suggests that parenteral labetalol or oral nifedipine may be preferable.
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Nitroprusside is seldom used in pregnancy; it is used only as a last resort in cases of life-threatening hypertension with heart failure. Adverse effects include excessive vasodilation and syncope in the mother and a risk of cyanide toxicity in the fetus.
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Isosorbide dinitrate has been investigated in a small study of gestational hypertensive and preeclamptic patients. It was found to lower BP but not cerebral perfusion, thus decreasing the risk for ischemia and infarction when BP is lowered.
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Serotonin2 Receptor Blockers
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Ketanserin is a selective S2 receptor-blocking drug that appears to be safe and useful in the treatment of chronic hypertension in pregnancy, preeclampsia, and HELLP syndrome. Ketanserin is used in Australia and South Africa, but has not been approved by the Food and Drug Administration for use in the United States.
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Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Antagonists
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ACEIs and angiotensin receptor agents are contraindicated in pregnancy due to toxicity associated with reduced perfusion of the fetal kidneys; their use is associated with a fetopathy similar to that observed in Potter's syndrome, ie, bilateral renal agenesis, oligohydramnios due to fetal oliguria, calvarial hypoplasia, pulmonary hypoplasia, intrauterine growth retardation, and neonatal anuric renal failure leading to death. Use of ARBs in pregnancy has also caused fetal demise amid the same pathogenic features.
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The available evidence on first trimester exposure to ACEIs is not consistent with high teratogenic risk, although a small risk cannot be ruled out. Most cases of malformations have been associated with second or third trimester use. As such, inadvertent first trimester drug exposure is not considered to be an indication for elective termination of the pregnancy. Of note, many women at risk for hypertension during pregnancy, particularly those with underlying diabetes mellitus, may benefit from use of ACEIs prior to conception. Since all cases of ACEI-associated fetopathy or renal failure occurred with drug use in the latter two trimesters, it seems reasonable to use these drugs when appropriate and to counsel women to switch to alternate agents either while attempting to conceive or as soon as the pregnancy is diagnosed.
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Clinical Features and Diagnosis
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Preeclampsia is the development of hypertension in association with new-onset proteinuria (>0.3 g daily), edema, and hyperuricemia after 20 weeks of gestation. Edema alone has been abandoned as a marker of preeclampsia because it is present in too many normal pregnant women to be a specific indicator of disease. Mild preeclampsia can be distinguished from severe preeclampsia: features of severe preeclampsia include severe hypertension (systolic pressure greater than 160/110 mm Hg on two occasions), eclampsia (seizures), pulmonary edema, cortical blindness, proteinuria >5 g/24 hours, renal failure or oliguria (<500 mL/24 hours), hepatocellular injury (serum transaminase levels ≥2 × normal), thrombocytopenia (<100,000 platelets/mm3), coagulopathy, or HELLP syndrome.
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Important findings on physical examination in addition to elevated BP include hyperreflexia, generalized edema, and vasospasm on fundoscopic examination.
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It is important to determine which women are at increased risk for preeclampsia, because such individuals need to be followed more closely during pregnancy. Those at increased risk for preeclampsia include women with chronic hypertension, women who had early (before 34 weeks of gestation) or severe preeclampsia in a previous pregnancy, and women with diabetes, collagen vascular disease, renovascular disease, renal parenchymal disease, or a multifetal pregnancy, or women who were the product of a pregnancy complicated by preeclampsia (Table 43–5). Such women should have a baseline laboratory evaluation performed early in gestation. Recommended tests that are helpful to compare and to discriminate preeclampsia from chronic or transient hypertension later in pregnancy include hematocrit, hemoglobin, platelet count, serum creatinine, uric acid, alanine aminotransferase, and aspartate aminotransferase. If qualitative dipstick proteinuria is documented, a 24-hour urine collection should be performed for the determination of protein and creatinine clearance. There is an extensive literature reporting the ability of various clinical signs or laboratory tests to predict, early in pregnancy, which patients will later develop preeclampsia. While many of these tests reflect important pathophysiologic features of preeclampsia, none is considered sensitive or specific enough to use at this time.
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Strategies to prevent preeclampsia, including sodium restriction, diuretics, high protein diets, low dose aspirin, calcium supplementation, fish oil, magnesium, antioxidants, and antihypertensive medication, have been largely ineffective. Baby aspirin is a relatively benign drug that is still used in select cases, although in large meta analyses its utility appears uncertain.
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The pathophysiology of preeclampsia can be divided into two stages: Alterations in placental perfusion and the maternal syndrome. Abnormalities begin in the vascular supply of the developing placenta, leading to placental ischemia and production of vasculogenic substances, which upon reaching the maternal circulation produce the maternal clinical syndrome. There is evidence for the importance of the placenta in the pathogenesis of preeclampsia, which can develop without a fetus in the case of molar pregnancies (a rapidly growing placenta with trophoblastic tissue) and in multiple gestations (increased placental mass).
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There is an increased incidence of preeclampsia in women with medical conditions associated with microvascular disease such as hypertension, diabetes, and collagen vascular disease, as the impaired placental perfusion leading to ischemia may be the common starting point of this disease.
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Impaired placental perfusion appears to cause the release of “factors” into the maternal circulation. Angiogenic proteins such as placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), which are both required for normal angiogenesis and endothelial function in pregnancy, are reduced in women with preeclampsia. Recent studies report elevated maternal serum levels of a protein that appears to scavenge these factors and induce endothelial dysfunction: sFlt-1, a soluble fms-like tyrosine kinase. This molecule functions to neutralize VEGF and PlGF. In experimental studies, increased serum levels of sFlt-1 and reduced levels of PlGF have been found to predict the development of preeclampsia in humans. The mechanism for the upregulation of sFlt-1 and whether normalization of VEGF and PlGF levels might halt progression of preeclampsia are yet unknown.
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High BP in preeclampsia is due mainly to a reversal of the vasodilation of normal pregnancy, replaced by a marked increase in peripheral vascular resistance. Preeclamptic patients do not develop overt hypertension until late gestation (after week 20, and usually not until the third trimester-weeks 28–40), but vasoconstrictor influences may be present much earlier. For instance, longitudinal and epidemiologic surveys show that women destined to develop preeclampsia have slightly higher “normal” blood pressure (eg, diastolic levels >70 mm Hg) as early as the second trimester.
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BP in preeclampsia is characteristically labile, and there is a reversal of the normal circadian rhythm, with BP levels often being higher at night. These changes should be kept in mind when evaluating a woman with preeclampsia, because two observers may obtain different readings, reflecting lability and not measurement error. In addition, increases in peripheral vascular resistance and BP that characterize preeclampsia have been found to be mediated by an increase in sympathetic vasoconstrictor activity, which reverts to normal after delivery. These observations lend mechanistic support to the use of methyldopa and labetalol.
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Most cases of preeclampsia present close to term. They are managed by obstetricians with an approach that includes bed rest, consideration of the use of antihypertensive medications, and delivery of the fetus, followed by seizure prophylaxis with magnesium sulfate. Although there are no proven strategies for the prevention of preeclampsia, early diagnosis is important to avoid severe complications. When early signs of preeclampsia are detected, hospitalization should be strongly considered to permit close monitoring of the patient. If preeclampsia is diagnosed early, bed rest and close monitoring of maternal and fetal conditions may enable prolongation of pregnancy and improve maternal and fetal outcomes.
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Lowering BP does not cure preeclampsia but may prolong the pregnancy, because uncontrolled hypertension is frequently an indication for delivery. In a woman with preeclampsia it prevents the maternal cerebrovascular and cardiovascular complications that result from elevated BP. There is a consensus that severe hypertension, defined as >160/110 mm Hg, requires treatment because these women are at increased risk of intracerebral hemorrhage and because lowering BP leads to a decrease in maternal death. Women with hypertensive encephalopathy, hemorrhage, or eclampsia (seizures) require treatment with parenteral agents to lower mean arterial pressure (two-thirds diastolic + one-third systolic BP) by 25% over minutes to hours, and then to further lower BP to ≤160/100 mm Hg over subsequent hours. In women with preeclampsia, treatment of acute severe hypertension should be initiated at lower doses, as these patients may be intravascularly volume depleted and are at increased risk for hypotension. The parenteral medications used to treat acute hypertension in women with preeclampsia are listed in Table 43–6. If delivery is not anticipated immediately (within 24–48 hours) antihypertensive therapy should be considered when diastolic BP reaches 100 mm Hg; in this instance, oral agents are appropriate.
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Maternal factors that may signal the time for delivery in preeclampsia include gestational age over 38 weeks, platelet count <100 × 103, progressive deterioration in liver and renal function, suspected abruptio placenta, and uncontrolled severe hypertension despite medication. Fetal factors include fetal growth restriction, nonreassuring fetal testing results, and oligohydramnios.
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Renal function is usually well preserved, and because relative oliguria is often a manifestation of renal vasoconstriction rather than impaired glomerular filtration rate it is not advisable to “push fluids” in such circumstances to increase urine output. Aggressive hydration of women with preeclampsia may result in acute pulmonary edema, a rare manifestation that may develop when abundant intravenous fluids are administered or on the backdrop of preexisting coronary disease. Decreased urinary output will usually resolve within 24 hours of delivery and will not be associated with acute tubular necrosis.
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Some, although not all women develop considerable peripheral edema in association with preeclampsia. The mechanisms are likely a combination of hypoalbuminemia, increased renal sodium reabsorption, and local tissue factors such as increased capillary permeability. Despite the presence of edema, plasma volume is reduced in most cases, presumably as a consequence of vasoconstriction as opposed to underfilling of the arterial circulation. In view of the reduced plasma volume, there is a reluctance to administer diuretic therapy to women with preeclampsia, even when edema is present, because diuretics may further reduce plasma volume and potentially compromise uteroplacental perfusion. However, in the postpartum period, edema may become considerably worse due to administration of intravenous fluids during surgery. Moreover, hypertension may be worse in the first postpartum week, and tends to reach its maximum by the fifth postpartum day. Thus, on occasion, it may be necessary to administer small doses of diuretics when edema becomes marked and causes discomfort, particularly when BP is elevated.
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Seizures are generally preceded with complaints of headache. The contribution of uncontrolled hypertension to the eclamptic seizure has been disputed. Some have argued that eclampsia is a manifestation of hypertensive encephalopathy, while others cite data indicating that many women who seize have BP levels that are only mildly elevated. However, uncontrolled hypertension may lower the seizure threshold, and although the treatment of hypertension does not necessarily prevent eclamptic seizures, BP levels should be maintained in a “safe” range of 130–150/80–100 mm Hg. Most of the cases of intracerebral hemorrhage and death due to eclampsia have occurred in women with preexisting hypertension and uncontrolled BP. Antihypertensive therapy should be combined with intravenous magnesium sulfate in the postpartum period, because it is the anticonvulsant of choice to prevent eclamptic seizures. Reversible posterior leukencephalopathy (transient cortical blindness) resolves with BP management as above.
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The liver may be involved in severe cases of preeclampsia, usually in association with hemolysis and thrombocytopenia (the HELLP syndrome). The HELLP syndrome is associated with a poor prognosis and is usually an indication for urgent delivery. Women with liver involvement may develop epigastric or right upper quadrant pain resulting from hepatocellular necrosis, edema, and ischemia leading to stretching of the Glisson capsule. Periportal hemorrhagic necrosis in the periphery of the liver lobule results in elevations in liver enzymes. On rare occasions, there may be bleeding from these lesions, and hepatic rupture is a fatal complication of preeclampsia if not recognized early and treated aggressively with supportive therapy and surgery. The consultant should be familiar with these complications of preeclampsia and should recognize the potential severity of the development of epigastric, chest, or abdominal pain in a woman with preeclampsia.
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Obstetric Issues: Fetal Monitoring and Delivery
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Once preeclampsia is diagnosed, monitoring of the fetusis indicated to identify fetal distress, which, if present, would be an indication for urgent delivery. One of the most difficult management issues in preeclampsia is the timing of delivery in cases in which fetal maturity is questionable. Delivery is always appropriate therapy for the mother. However, delivery is not indicated for a preterm fetus with no evidence of fetal compromise in a woman with only mild preeclampsia. Important decisions are based on whether the fetus is more likely to survive without significant neonatal complications in utero or in the nursery and whether maternal safety will be jeopardized by the postponement of delivery.
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Delivery is always indicated when preeclampsia develops at term and should be strongly considered in women who have severe preeclampsia beyond 32–34 weeks of gestation. In women with preeclampsia remote from term (23–32 weeks) prolongation of pregnancy is possible in only a select group of women with easily controlled hypertension, no evidence of fetal distress, and no indication of serious maternal disease (headache, abdominal pain, and signs of the HELLP syndrome).
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Hypertension frequently persists after delivery in women with antenatal hypertension or preeclampsia, and BP may be labile in the weeks postpartum. BP may increase even higher if patients are treated with nonsteroidal anti-inflammatory agents. The goals of treatment are to prevent severe hypertension (and its consequences of cerebral hemorrhage and eclampsia). Antihypertensive treatment given antenatally should be reordered postpartum and then discontinued in days to weeks after BP normalizes. If BP was normal prior to conception, then normalization is likely to return after 2–12 weeks. Hypertension that persists beyond that may represent previously undiagnosed chronic hypertension or secondary hypertension and should be evaluated and followed.
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Evaluation should also be considered postpartum for patients who developed preeclampsia early (at less than 34 weeks of gestation), who had severe preeclampsia, who had a recurrence of this condition, or who continue to have persistent proteinuria. In these cases, renal disease, secondary hypertension, and thrombophilias (eg, factor V Leiden) may be evaluated.
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Counseling for future pregnancies requires consideration of different recurrence rates for preeclampsia depending on the pathogenesis and population. The earlier in gestation, the higher the risk of recurrence; before week 30, recurrence may be as high as 40%. If preeclampsia has developed in a nulliparous woman close to term (ie, after 36 weeks), the risk of recurrence is thought to be 10%. Patients who had HELLP syndrome appear to have a high risk of subsequent obstetric complications, with preeclampsia occurring in 55%; however, the rate of recurrent HELLP appears to be low, only 6%.
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Hypertensive diseases of pregnancy have been associated with the risk of hypertension and stroke later in life. In one study, gestational hypertension was associated with a relative risk (RR) of 3.72 for later hypertension, and preeclampsia with a RR of 3.98 for later hypertension and 3.59 for stroke. Preeclampsia is also a risk factor for coronary disease when studied retrospectively. These associations serve to increase awareness for the need to monitor patients for future hypertensive and cardiovascular disorders.
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In general, antihypertensive drugs that are bound to plasma protein are not transferred to breast milk. Lipid-soluble drugs achieve concentrations higher than water-soluble drugs. Neonatal exposure to methyldopa, labetalol, captopril, and nifedipine via nursing is low, and these medications are considered safe in breastfeeding. Atenolol and metoprolol are concentrated in breast milk, possibly to levels that could affect the infant, and are not recommended. Finally, although the concentration of diuretics in breast milk is usually low, these agents may reduce milk production due to mild volume contraction and may interfere with the ability to successfully breast feed.
Levine RJ et al: Urinary placental growth factor and risk of preeclampsia. JAMA 2005;293(1):77.
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Sibai BM: Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol 2004;103(5 Pt 1):981.