Pregnancy complicated by gestational hypertension is managed based on severity, gestational age, and presence of preeclampsia. With preeclampsia, management varies with the severity of endothelial cell injury and multiorgan dysfunction.
Preeclampsia cannot always be diagnosed definitively (Terminology and Diagnosis). Thus, the Task Force of the American College of Obstetricians and Gynecologists (2013b) recommends more frequent prenatal visits if preeclampsia is “suspected.” Increases in systolic and diastolic blood pressure can be either normal physiological changes or signs of developing pathology. Increased surveillance permits more prompt recognition of ominous changes in blood pressure, critical laboratory findings, and clinical signs and symptoms (Macdonald-Wallis, 2012).
The basic management objectives for any pregnancy complicated by preeclampsia are: (1) termination of pregnancy with the least possible trauma to mother and fetus, (2) birth of an infant who subsequently thrives, and (3) complete restoration of health to the mother. In many women with preeclampsia, especially those at or near term, all three objectives are served equally well by induction of labor. One of the most important clinical questions for successful management is precise knowledge of fetal age.
Early Diagnosis of Preeclampsia
Traditionally, the frequency of prenatal visits is increased during the third trimester, and this aids early detection of preeclampsia. Women without overt hypertension, but in whom early developing preeclampsia is suspected during routine prenatal visits, are seen more frequently. The protocol used successfully for many years at Parkland Hospital for women with new-onset diastolic blood pressures > 80 mm Hg but < 90 mm Hg or with sudden abnormal weight gain of more than 2 pounds per week includes, at minimum, return visits at 7-day intervals. Outpatient surveillance is continued unless overt hypertension, proteinuria, headache, visual disturbances, or epigastric discomfort supervene. Women with overt new-onset hypertension—either diastolic pressures ≥ 90 mm Hg or systolic pressures ≥ 140 mm Hg—are admitted to determine if the increase is due to preeclampsia, and if so, to evaluate its severity. Women with persistent severe disease are generally delivered, as discussed subsequently. Conversely, women with apparently mild disease can often be managed as outpatients, although there should be a low threshold for continued hospitalization for the nullipara, especially if there is proteinuria.
Hospitalization is considered at least initially for women with new-onset hypertension, especially if there is persistent or worsening hypertension or development of proteinuria. A systematic evaluation is instituted to include the following:
Detailed examination, which is followed by daily scrutiny for clinical findings such as headache, visual disturbances, epigastric pain, and rapid weight gain
Weight determined daily
Analysis for proteinuria or urine protein:creatinine ratio on admittance and at least every 2 days thereafter
Blood pressure readings in the sitting position with an appropriate-size cuff every 4 hours, except between 2400 and 0600 unless previous readings had become elevated
Measurements of plasma or serum creatinine and hepatic aminotransferase levels and a hemogram that includes platelet quantification. The frequency of testing is determined by hypertension severity. Some recommend measurement of serum uric acid and lactic acid dehydrogenase levels and coagulation studies. However, the value of these tests has been called into question (Cnossen, 2006; Conde-Agudelo, 2014; Thangaratinam, 2006).
Evaluation of fetal size and well-being and amnionic fluid volume, with either physical examination or sonography.
Goals of management include early identification of worsening preeclampsia and development of a management plan for timely delivery. If any of these observations lead to a diagnosis of severe preeclampsia as previously defined by the criteria in Table 40-2, further management is subsequently described.
Reduced physical activity throughout much of the day is likely beneficial, but as the 2013 Task Force concluded, absolute bed rest is not desirable. Ample protein and calories should be included in the diet, and sodium and fluid intake should not be limited or forced. Further management depends on: (1) preeclampsia severity, (2) gestational age, and (3) condition of the cervix.
Fortunately, many cases are sufficiently mild and near enough to term that they can be managed conservatively until labor commences spontaneously or until the cervix becomes favorable for labor induction. Complete abatement of all signs and symptoms, however, is uncommon until after delivery. Almost certainly, the underlying disease persists until delivery is accomplished.
Consideration for Delivery
Termination of pregnancy is the only cure for preeclampsia. Headache, visual disturbances, or epigastric pain are indicative that convulsions may be imminent, and oliguria is another ominous sign. Severe preeclampsia demands anticonvulsant and frequently antihypertensive therapy, followed by delivery. Treatment is identical to that described subsequently for eclampsia. The prime objectives are to forestall convulsions, to prevent intracranial hemorrhage and serious damage to other vital organs, and to deliver a healthy newborn.
When the fetus is preterm, the tendency is to temporize in the hope that a few more weeks in utero will reduce the risk of neonatal death or serious morbidity from prematurity. As discussed, such a policy certainly is justified in milder cases. Assessments of fetal well-being and placental function are performed, especially when the fetus is immature. Most recommend frequent performance of various tests to assess fetal well-being as described by the American College of Obstetricians and Gynecologists (2012a). These include the nonstress test or the biophysical profile (Chap. 17, Contraction Stress Testing and Acoustic Stimulation Tests). Measurement of the lecithin-sphingomyelin (L/S) ratio in amnionic fluid may provide evidence of lung maturity (Chap. 34, Amniocentesis for Fetal Lung Maturity).
With moderate or severe preeclampsia that does not improve after hospitalization, delivery is usually advisable for the welfare of both mother and fetus. This is true even when the cervix is unfavorable (Tajik, 2012). Labor induction is carried out, usually with preinduction cervical ripening from a prostaglandin or osmotic dilator (Chap. 26, Preinduction Cervical Ripening). Whenever it appears that induction almost certainly will not succeed or attempts have failed, then cesarean delivery is indicated.
For a woman near term, with a soft, partially effaced cervix, even milder degrees of preeclampsia probably carry more risk to the mother and her fetus-infant than does induction of labor (Tajik, 2012). The decision to deliver late-preterm fetuses is not clear. Barton and coworkers (2009) reported excessive neonatal morbidity in women delivered before 38 weeks despite having stable, mild, nonproteinuric hypertension. The Netherlands study of 4316 newborns delivered between 340/7 and 366/7 weeks also described substantive neonatal morbidity in these cases (Langenveld, 2011). Most of these deliveries were before 36 weeks, and the higher cesarean delivery rates were associated with more respiratory complications. Conversely, one randomized trial of 756 women with mild preeclampsia supported delivery after 37 weeks (Koopmans, 2009).
Elective Cesarean Delivery
Once severe preeclampsia is diagnosed, labor induction and vaginal delivery have traditionally been considered ideal. Temporization with an immature fetus is considered subsequently. Several concerns, including an unfavorable cervix, a perceived sense of urgency because of preeclampsia severity, and a need to coordinate neonatal intensive care, have led some to advocate cesarean delivery. Alexander and colleagues (1999) reviewed 278 singleton liveborn neonates weighing 750 to 1500 g delivered of women with severe preeclampsia at Parkland Hospital. In half of the women, labor was induced, and the remainder underwent cesarean delivery without labor. Induction was successful in accomplishing vaginal delivery in a third, and it was not harmful to the very-low-birthweight infants. Alanis and associates (2008) reported similar observations. The results of a systematic review also confirmed these conclusions (Le Ray, 2009).
Hospitalization versus Outpatient Management
For women with mild to moderate stable hypertension—whether or not preeclampsia has been confirmed—surveillance is continued in the hospital, at home for some reliable patients, or in a day-care unit. At least intuitively, reduced physical activity throughout much of the day seems beneficial. Several observational studies and randomized trials have addressed the benefits of inpatient care and outpatient management.
Somewhat related, Abenhaim and coworkers (2008) reported a retrospective cohort study of 677 nonhypertensive women hospitalized for bed rest because of threatened preterm delivery. When outcomes of these women were compared with those of the general obstetrical population, bed rest was associated with a significantly reduced relative risk—RR 0.27—of developing preeclampsia. In a review of two small randomized trials totaling 106 women at high risk for preeclampsia, prophylactic bed rest for 4 to 6 hours daily at home was successful in significantly lowering the incidence of preeclampsia but not gestational hypertension (Meher, 2006).
These and other observations support the claim that restricted activity alters the underlying pathophysiology of the preeclampsia syndrome. That said, complete bed rest is not recommended by the 2013 Task Force. First, this is pragmatically unachievable because of the severe restrictions it places on otherwise well women. Also, as discussed in Chapter 52 (Thrombophilias), it likely also predisposes to thromboembolism (Knight, 2007).
The concept of prolonged hospitalization for women with hypertension arose during the 1970s. At Parkland Hospital, an inpatient antepartum unit was established in 1973 by Dr. Peggy Whalley in large part to provide care for such women. Initial results from this unit were reported by Hauth (1976) and Gilstrap (1978) and their colleagues. Most hospitalized women have a beneficial response characterized by amelioration or improvement of hypertension. These women are not “cured,” and nearly 90 percent have recurrent hypertension before or during labor. By 2013, more than 10,000 nulliparas with mild to moderate early-onset hypertension during pregnancy had been managed successfully in this unit. Provider costs—not charges—for this relatively simple physical facility, modest nursing care, no drugs other than iron and folate supplements, and few essential laboratory tests are minimal compared with the cost of neonatal intensive care for a preterm infant. None of these women have suffered thromboembolic disease.
Many clinicians believe that further hospitalization is not warranted if hypertension abates within a few days, and this has legitimized third-party payers to deny hospitalization reimbursement. Consequently, many women with mild to moderate hypertension are managed at home. Outpatient management may continue as long as preeclampsia syndrome does not worsen and fetal jeopardy is not suspected. Sedentary activity throughout the greater part of the day is recommended. These women are instructed in detail to report symptoms. Home blood pressure and urine protein monitoring or frequent evaluations by a visiting nurse may prove beneficial. Caution is exercised regarding use of certain automated home blood pressure monitors (Lo, 2002; Ostchega, 2012).
In an observational study by Barton and associates (2002), 1182 nulliparas with mild gestational hypertension—20 percent had proteinuria—were managed with home health care. Their mean gestational ages were 32 to 33 weeks at enrollment and 36 to 37 weeks at delivery. Severe preeclampsia developed in approximately 20 percent, about 3 percent developed HELLP syndrome, and two women had eclampsia. Perinatal outcomes were generally good. In approximately 20 percent, there was fetal-growth restriction, and the perinatal mortality rate was 4.2 per 1000.
Several prospective studies have been designed to compare continued hospitalization with either home health care or a day-care unit. In a pilot study from Parkland Hospital, Horsager and colleagues (1995) randomly assigned 72 nulliparas with new-onset hypertension from 27 to 37 weeks either to continued hospitalization or to outpatient care. In all of these women, proteinuria had receded to less than 500 mg per day when they were randomized. Outpatient management included daily blood pressure monitoring by the patient or her family. Weight and dipstick spot urine protein determinations were evaluated three times weekly. A home health nurse visited twice weekly, and the women were seen weekly in the clinic. Perinatal outcomes were similar in each group. The only significant difference was that women in the home care group developed severe preeclampsia significantly more frequently than hospitalized women—42 versus 25 percent.
A larger randomized trial reported by Crowther and coworkers (1992) included 218 women with mild gestational nonproteinuric hypertension. After evaluation, half remained hospitalized, whereas the other half was managed as outpatients. As shown in Table 40-7, the mean duration of hospitalization was 22.2 days for women with inpatient management compared with only 6.5 days in the home-care group. Preterm delivery before 34 and before 37 weeks was increased twofold in the outpatient group, but maternal and infant outcomes otherwise were similar.
TABLE 40-7Randomized Clinical Trials Comparing Hospitalization versus Routine Care for Women with Mild Gestational Hypertension or Preeclampsia ||Download (.pdf) TABLE 40-7 Randomized Clinical Trials Comparing Hospitalization versus Routine Care for Women with Mild Gestational Hypertension or Preeclampsia
| ||Maternal Characteristics—Admission ||Maternal Characteristics—Delivery ||Perinatal Outcomes |
|Study Groups ||No. ||Para0 (%) ||Chronic HTN (%) ||EGA (wk) ||Prot (%) ||EGA (wk) ||< 37 wk (%) ||< 34 wk (%) ||Mean Hosp (d) ||Mean BW (g) ||SGA (%) ||PMR (%) |
|Crowther (1992) ||218a || || || || || || || || || || || |
| Hospitalization ||110 ||13 ||14 ||35.3 ||0 ||38.3 ||12 ||1.8 ||22.2 ||3080 ||14 ||0 |
| Outpatient ||108 ||13 ||17 ||34.6 ||0 ||38.2 ||22 ||3.7 ||6.5 ||3060 ||14 ||0 |
|Tuffnell (1992) ||54 || || || || || || || || || || || |
| Day Unit ||24 ||57 ||23 ||36 ||0 ||39.8 ||— ||— ||1.1 ||3320 ||— ||0 |
| Usual Care ||30 ||54 ||21 ||36.5 ||21 ||39 ||— ||— ||5.1 ||3340 ||— ||0 |
|Turnbull (2004) ||374b || || || || || || || || || || || |
| Hospitalization ||125 ||63 ||0 ||35.9 ||22 ||39 ||— ||— ||8.5 ||3330 ||3.8 ||0 |
| Day Unit ||249 ||62 ||0 ||36.2 ||22 ||39.7 ||— ||— ||7.2 ||3300 ||2.3 ||0 |
Another approach, popular in European countries, is day care (Milne, 2009). This approach has been evaluated by several investigators. In the study by Tuffnell and associates (1992), 54 women with hypertension after 26 weeks’ gestation were assigned to either day care or routine outpatient management (see Table 40-7). Progression to overt preeclampsia and labor inductions were significantly increased in the routine management group. Turnbull and coworkers (2004) enrolled 395 women who were randomly assigned to either day care or inpatient management (see Table 40-7). Almost 95 percent had mild to moderate hypertension. Of enrolled women, 288 were without proteinuria, and 86 had ≥ 1+ proteinuria. There were no perinatal deaths, and none of the women developed eclampsia or HELLP syndrome. Surprisingly, costs for either scheme were not significantly different. Perhaps not surprisingly, general satisfaction favored day care.
Summary of Hospitalization versus Outpatient Management
From the above, either inpatient or close outpatient management is appropriate for a woman with mild de novo hypertension, including those with nonsevere preeclampsia. Most of these studies were carried out in academic centers with dedicated management teams. That said, the key to success is close follow-up and a conscientious patient with good home support.
Antihypertensive Therapy for Mild to Moderate Hypertension
The use of antihypertensive drugs in attempts to prolong pregnancy or modify perinatal outcomes in pregnancies complicated by various types and severities of hypertensive disorders has been of considerable interest. Treatment for women with chronic hypertension complicating pregnancy is discussed in detail in Chapter 50 (Antihypertensive Drugs).
Drug treatment for early mild preeclampsia has been disappointing as shown in representative randomized trials listed in Table 40-8. Sibai and colleagues (1987a) evaluated the effectiveness of labetalol and hospitalization compared with hospitalization alone in 200 nulliparas with gestational hypertension from 26 to 35 weeks’ gestation. Although women given labetalol had significantly lower mean blood pressures, there were no differences between the groups in terms of mean pregnancy prolongation, gestational age at delivery, or birthweight. The cesarean delivery rates were similar, as were the number of infants admitted to special-care nurseries. The frequency of growth-restricted infants was doubled in women given labetalol—19 versus 9 percent. The three other studies listed in Table 40-8 were performed to compare labetalol or the calcium-channel blockers, nifedipine and isradipine, with placebo. Except for fewer episodes of severe hypertension, none of these studies showed any benefits of antihypertensive treatment. Moreover, there may have been treatment-induced adverse fetal growth (Von Dadelszen, 2002).
TABLE 40-8Randomized Placebo-Controlled Trials of Antihypertensive Therapy for Early Mild Gestational Hypertension ||Download (.pdf) TABLE 40-8 Randomized Placebo-Controlled Trials of Antihypertensive Therapy for Early Mild Gestational Hypertension
|Study ||Study Drug (No.) ||Pregnancy Prolonged(d) ||Severe HTNa(%) ||Cesarean Delivery (%) ||Placental Abruption (%) ||Mean Birthweight (g) ||Growth Restriction (%) ||Neonatal Deaths (No.) |
|Sibai (1987a)a |
|Labetalol (100) ||21.3 ||5 ||36 ||2 ||2205 ||19c ||1 |
| ||Placebo (100) ||20.1 ||15c ||32 ||0 ||2260 ||9 ||0 |
|Sibai (1992)b |
|Nifedipine (100) ||22.3 ||9 ||43 ||3 ||2405 ||8 ||0 |
| ||Placebo (100) ||22.5 ||18b ||35 ||2 ||2510 ||4 ||0 |
|Pickles (1992) |
|Labetalol (70) ||26.6 ||9 ||24 ||NS ||NS ||NS ||NS |
| ||Placebo (74) ||23.1 ||10 ||26 ||NS ||NS ||NS ||NS |
|Wide-Swensson (1995) ||Isradipine (54) ||23.1 ||22 ||26 ||NS ||NS ||NS ||0 |
| 111 outpatients ||Placebo (57) ||29.8 ||29 ||19 ||NS ||NS ||NS ||0 |
Abalos and associates (2007) reviewed 46 randomized trials of active antihypertensive therapy compared with either no treatment or placebo given to women with mild to moderate gestational hypertension. Except for a halving of the risk for developing severe hypertension, active antihypertensive therapy had no beneficial effects. They further reported that fetal-growth restriction was not increased in treated women. In this vein, it is also controversial whether β-blocking agents cause fetal-growth restriction if given for chronic hypertension (August, 2014; Umans, 2014). Thus, any salutary or adverse effects of antihypertensive therapy seem minimal at most.
Up through the early 1990s, it was the practice that all women with severe preeclampsia were delivered without delay. During the past 25 years, however, another approach for women with preterm severe preeclampsia has been advocated. This approach calls for “conservative” or “expectant” management with the aim of improving neonatal outcome without compromising maternal safety. Aspects of such management always include careful daily—and usually more frequent—inpatient monitoring of the mother and her fetus.
Expectant Management of Preterm Severe Preeclampsia
Theoretically, antihypertensive therapy has potential application when severe preeclampsia develops before intact neonatal survival is likely. Such management is controversial, and it may be dangerous. In one of the first studies, Sibai and the Memphis group (1985) attempted to prolong pregnancy because of fetal immaturity in 60 women with severe preeclampsia between 18 and 27 weeks. The results were disastrous. The perinatal mortality rate was 87 percent. Although no mothers died, 13 suffered placental abruption, 10 had eclampsia, three developed renal failure, two had hypertensive encephalopathy, and one each had an intracerebral hemorrhage and a ruptured hepatic hematoma.
Because of these catastrophic outcomes, the Memphis group redefined their study criteria and performed a randomized trial of expectant versus aggressive management for 95 women who had severe preeclampsia but with more advanced gestations of 28 to 32 weeks (Sibai, 1994). Women with HELLP syndrome were excluded from this trial. Aggressive management included glucocorticoid administration for fetal lung maturation followed by delivery in 48 hours. Expectantly managed women were observed at bed rest and given either labetalol or nifedipine orally if there was severe hypertension. In this study, pregnancy was prolonged for a mean of 15.4 days in the expectant management group. An overall improvement in neonatal outcomes was also reported.
Following these experiences, expectant management became more commonly practiced, but with the caveat that women with HELLP syndrome or growth-restricted fetuses were usually excluded. But in a subsequent follow-up observational study, the Memphis group compared outcomes in 133 preeclamptic women with and 136 without HELLP syndrome who presented between 24 and 36 weeks (Abramovici, 1999). Women were subdivided into three study groups. The first group included those with complete HELLP syndrome. The second group included women with partial HELLP syndrome—defined as either one or two but not all three of the defining laboratory findings. The third group included women who had severe preeclampsia without HELLP syndrome laboratory findings. Perinatal outcomes were similar in each group, and importantly, outcomes were not improved with procrastination. Despite this, the investigators concluded that women with partial HELLP syndrome and those with severe preeclampsia alone could be managed expectantly.
Sibai and Barton (2007b) reviewed expectant management of severe preeclampsia from 24 to 34 weeks. More than 1200 women were included, and although the average time gained ranged from 5 to 10 days, the maternal morbidity rates were formidable. As shown in Table 40-9, serious complications in some of these and in later studies included placental abruption, HELLP syndrome, pulmonary edema, renal failure, and eclampsia. Moreover, perinatal mortality rates averaged 90 per 1000. Fetal-growth restriction was common, and in the study from The Netherlands by Ganzevoort and associates (2005a,b), it was an astounding 94 percent. Perinatal mortality rates are disproportionately high in these growth-restricted infants, but maternal outcomes were not appreciably different from pregnancies in women without growth-restricted fetuses (Haddad, 2007; Shear, 2005).
TABLE 40-9Maternal and Perinatal Outcomes Reported Since 2005 with Expectant Management of Severe Preeclampsia from 24 to 34 Weeks ||Download (.pdf) TABLE 40-9 Maternal and Perinatal Outcomes Reported Since 2005 with Expectant Management of Severe Preeclampsia from 24 to 34 Weeks
The MEXPRE Latin Study was a multicenter trial that randomly assigned 267 women with severe preeclampsia at 28 to 32 weeks to prompt delivery or to expectant management (Vigil-De Gracia, 2013). The perinatal mortality rate approximated 9 percent in each group, and these investigators found no improvements in composite neonatal morbidity with expectant management. On the other hand, fetal-growth restriction—22 versus 9 percent—and placental abruption—7.6 versus 1.5 percent—were significantly higher in the group managed expectantly.
Barber and associates (2009) conducted a 10-year review of 3408 women with severe preeclampsia from 24 to 32 weeks. They found that increasing lengths of antepartum hospital stays were associated with slight but significantly increased rates of maternal and neonatal morbidity.
Expectant Management of Midtrimester Severe Preeclampsia
Several small studies have focused on expectant management of severe preeclampsia syndrome before 28 weeks. In their review, Bombrys and coworkers (2008) found eight such studies that included nearly 200 women with severe preeclampsia with an onset < 26 completed weeks. Maternal complications were common. Because there were no neonatal survivors in women presenting before 23 weeks, the Task Force of the American Collegeof Obstetricians and Gynecologists (2013b) recommends pregnancy termination. For women with slightly more advanced pregnancies, however, the decision is less clear. For example, at 23 weeks’ gestation, the perinatal survival rate was 18 percent, but long-term perinatal morbidity is yet unknown. For women with pregnancies at 24 to 26 weeks, perinatal survival approached 60 percent, and it averaged almost 90 percent for those at 26 weeks.
There have been at least five studies published since 2005 of women with severe midtrimester preeclampsia who were managed expectantly (Abdel-Hady, 2010; Belghiti, 2011; Bombrys, 2008; Budden, 2006; Gaugler-Senden, 2006). Maternal complications developed in 60 percent, and there was one death. Perinatal mortality was 65 percent. At this time, there are no comparative studies attesting to the perinatal benefits of such expectant treatment versus early delivery in the face of serious maternal complications that approach 50 percent.
Glucocorticoids for Lung Maturation
In attempts to enhance fetal lung maturation, glucocorticoids have been administered to women with severe hypertension who are remote from term. Treatment does not seem to worsen maternal hypertension, and a decrease in the incidence of respiratory distress and improved fetal survival has been cited. That said, there is only one randomized trial of corticosteroids given to hypertensive women for fetal lung maturation. This trial, by Amorim and colleagues (1999), included 218 women with severe preeclampsia between 26 and 34 weeks who were randomly assigned to betamethasone or placebo administration. Neonatal complications, including respiratory distress, intraventricular hemorrhage, and death, were decreased significantly when betamethasone was given compared with placebo. On the heavily weighted negative side, there were two maternal deaths and 18 stillbirths. We add these findings to buttress our unenthusiastic acceptance of attempts to prolong gestation in many of these women (Alexander, 2014; Bloom, 2003).
Corticosteroids to Ameliorate HELLP Syndrome
Almost 30 years ago, Thiagarajah and associates (1984) suggested that glucocorticoids might aid treatment of the laboratory abnormalities associated with HELLP syndrome. Subsequently, Tompkins (1999) and O’Brien (2002) and their colleagues reported less than salutary effects. Martin and coworkers (2003) reviewed observational outcomes of almost 500 such women treated at their institution and reported salutary results with treatment. Unfortunately, their subsequent randomized trial compared two corticosteroids and did not include a nontreated group (Isler, 2001).
Since these observational studies, at least two prospective randomized trials have addressed this question. Fonseca and associates (2005) randomly assigned 132 women with HELLP syndrome to either dexamethasone or placebo administration. Outcomes assessed included duration of hospitalization, recovery time of abnormal laboratory test results, resolution of clinical parameters, and complications that included acute renal failure, pulmonary edema, eclampsia, and death. None of these was significantly different between the two groups. In another randomized study, Katz and coworkers (2008) assigned 105 postpartum women with HELLP syndrome to treatment with dexamethasone or placebo. They analyzed outcomes similar to the Fonseca study and found no advantage to dexamethasone. Shown in Figure 40-16 are recovery times for platelet counts and serum aspartate aminotransferase (AST) levels. These times were almost identical in the two groups. For these reasons, the 2013 Task Force does not recommend corticosteroid treatment for thrombocytopenia with HELLP syndrome. A caveat is that in women with dangerously low platelet counts, corticosteroids might serve to increase platelets.
Recovery times for platelet counts and serum aspartate aminotransferase (AST) levels in women with HELLP syndrome assigned to receive treatment with dexamethasone or placebo. (Data from Katz, 2008.)
Expectant Managment—Risks versus Benefits—Recommendations
Taken in toto, these studies do not show overwhelming benefits compared with risks for expectant management of severe preeclampsia in those with gestations from 24 to 32 weeks. The Society for Maternal-Fetal Medicine (2011) has determined that such management is a reasonable alternative in selected women with severe preeclampsia before 34 weeks. The Task Force of the American College of Obstetricians and Gynecologists (2013b) supports this recommendation. As shown in Figure 40-17, such management calls for in-hospital maternal and fetal surveillance with delivery prompted by evidence for worsening severe preeclampsia or maternal or fetal compromise. Although attempts are made for vaginal delivery in most cases, the likelihood of cesarean delivery increases with decreasing gestational age.
Schematic clinical management algorithm for suspected severe preeclampsia at < 34 weeks. HELLP = hemolysis, elevated liver enzyme levels, low platelet count; L&D = labor and delivery; MgSO4 = magnesium sulfate; UOP = urine output. (Adapted from the Society for Maternal-Fetal Medicine, 2011.)
Our view is more conservative. Undoubtedly, the overriding reason to terminate pregnancies with severe preeclampsia is maternal safety. There are no data to suggest that expectant management is beneficial for the mother. Indeed, it seems obvious that a delay to prolong gestation in women with severe preeclampsia may have serious maternal consequences such as those shown in Table 40-9. Notably, placental abruption develops in up to 20 percent, and pulmonary edema in as many as 4 percent. Moreover, there are substantive risks for eclampsia, cerebrovascular hemorrhage, and especially maternal death. These observations are even more pertinent when considered with the absence of convincing evidence that perinatal outcomes are markedly improved by the average prolongation of pregnancy of about 1 week. If undertaken, the caveats that mandate delivery shown in Table 40-10 should be strictly heeded.
TABLE 40-10Indications for Delivery in Women < 34 Weeks’ Gestation Managed Expectantly ||Download (.pdf) TABLE 40-10 Indications for Delivery in Women < 34 Weeks’ Gestation Managed Expectantly
|Corticosteroid Therapy for Lung Maturationa and Delivery after Maternal Stabilization: |
| Uncontrolled severe hypertension |
| Eclampsia |
| Pulmonary edema |
| Placental abruption |
| Disseminated intravascular coagulation |
| Nonreassuring fetal status |
| Fetal demise |
|Corticosteroid Therapy for Lung Maturation—Delay Delivery 48 hr If Possible: |
| Preterm ruptured membranes or labor |
| Thrombocytopenia < 100,000/μL |
| Hepatic transaminase levels twice upper limit of normal |
| Fetal-growth restriction |
| Oligohydramnios |
| Reversed end-diastolic Doppler flow in umbilical artery |
| Worsening renal dysfunction |
Preeclampsia complicated by generalized tonic-clonic convulsions appreciably increases the risk to both mother and fetus. Mattar and Sibai (2000) described outcomes in 399 consecutive women with eclampsia from 1977 through 1998. Major maternal complications included placental abruption—10 percent, neurological deficits—7 percent, aspiration pneumonia—7 percent, pulmonary edema—5 percent, cardiopulmonary arrest—4 percent, and acute renal failure—4 percent. Moreover, 1 percent of these women died.
European maternity units also report excessive maternal and perinatal morbidity and mortality rates with eclampsia. In a report from Scandinavia, Andersgaard and associates (2006) described 232 women with eclampsia. Although there was but a single maternal death, a third of the women experienced major complications that included HELLP syndrome, renal failure, pulmonary edema, pulmonary embolism, and stroke. The United Kingdom Obstetric Surveillance System (UKOSS) audit reported by Knight (2007) described no maternal deaths in 214 eclamptic women, but five women experienced cerebral hemorrhage. In The Netherlands, there were three maternal deaths among 222 eclamptic women (Zwart, 2008). From Dublin, Akkawi and coworkers (2009) reported four maternal deaths among 247 eclamptic women (Akkawi, 2009). Data from Australia are similar (Thornton, 2013). Thus, in developed countries, the maternal mortality rate approximates 1 percent in women with eclampsia. In perspective, this is a thousand-fold increase above the overall maternal death rates for these countries.
Almost without exception—but at times unnoticed—preeclampsia precedes the onset of eclamptic convulsions. Depending on whether convulsions appear before, during, or after labor, eclampsia is designated as antepartum, intrapartum, or postpartum. Eclampsia is most common in the last trimester and becomes increasingly frequent as term approaches. In more recent years, the incidence of postpartum eclampsia has risen. This is presumably related to improved access to prenatal care, earlier detection of preeclampsia, and prophylactic use of magnesium sulfate (Chames, 2002). Importantly, other diagnoses should be considered in women with convulsions more than 48 hours postpartum or in women with focal neurological deficits, prolonged coma, or atypical eclampsia (Sibai, 2009, 2012).
Immediate Management of Seizure
Eclamptic seizures may be violent, and the woman must be protected, especially her airway. So forceful are the muscular movements that the woman may throw herself out of her bed, and if not protected, her tongue is bitten by the violent action of the jaws (Fig. 40-18). This phase, in which the muscles alternately contract and relax, may last approximately a minute. Gradually, the muscular movements become smaller and less frequent, and finally the woman lies motionless. After a seizure, the woman is postictal, but in some, a coma of variable duration ensues. When the convulsions are infrequent, the woman usually recovers some degree of consciousness after each attack. As the woman arouses, a semiconscious combative state may ensue. In severe cases, coma persists from one convulsion to another, and death may result. In rare instances, a single convulsion may be followed by coma from which the woman may never emerge. As a rule, however, death does not occur until after frequent convulsions. Finally and also rarely, convulsions continue unabated—status epilepticus—and require deep sedation and even general anesthesia to obviate anoxic encephalopathy.
Hematoma of tongue from laceration during an eclamptic convulsion. Thrombocytopenia may have contributed to the bleeding.
Respirations after an eclamptic convulsion are usually increased in rate and may reach 50 or more per minute in response to hypercarbia, lactic acidemia, and transient hypoxia. Cyanosis may be observed in severe cases. High fever is a grave sign as it likely emanates from cerebrovascular hemorrhage.
Proteinuria is usually, but not always, present as discussed on Indicators of Preeclampsia Severity. Urine output may be diminished appreciably, and occasionally anuria develops. There may be hemoglobinuria, but hemoglobinemia is observed rarely. Often, as shown in Figure 40-19, peripheral and facial edema is pronounced, but it may also be absent.
Severe edema in a young nullipara with antepartum preeclampsia. (Photograph contributed by Dr. Nidhi Shah.)
As with severe preeclampsia, an increase in urinary output after delivery is usually an early sign of improvement. If there is renal dysfunction, serum creatinine levels should be monitored. Proteinuria and edema ordinarily disappear within a week postpartum. In most cases, blood pressure returns to normal within a few days to 2 weeks after delivery (Berks, 2009). As subsequently discussed, the longer hypertension persists postpartum and the more severe it is, the more likely it is that the woman also has chronic vascular disease (Podymow, 2010).
In antepartum eclampsia, labor may begin spontaneously shortly after convulsions ensue and may progress rapidly. If the convulsions occur during labor, contractions may increase in frequency and intensity, and the duration of labor may be shortened. Because of maternal hypoxemia and lactic acidemia caused by convulsions, it is not unusual for fetal bradycardia to follow a seizure (Fig. 40-20). Bradycardia usually recovers within 3 to 5 minutes. If it persists more than about 10 minutes, however, then another cause such as placental abruption or imminent delivery must be considered.
Fetal heart rate tracing shows fetal bradycardia following an intrapartum eclamptic convulsion. Bradycardia resolved and beat-to-beat variability returned approximately 5 minutes following the seizure.
Pulmonary edema may follow shortly after eclamptic convulsions or up to several hours later. This usually is caused by aspiration pneumonitis from gastric-content inhalation during vomiting that frequently accompanies convulsions. In some women, pulmonary edema may be caused by ventricular failure from increased afterload that may result from severe hypertension and further aggravated by vigorous intravenous fluid administration (Dennis, 2012b). Such pulmonary edema from ventricular failure is more common in morbidly obese women and in those with previously unappreciated chronic hypertension.
Occasionally, sudden death occurs synchronously with an eclamptic convulsion, or it follows shortly thereafter. Most often in these cases, death results from a massive cerebral hemorrhage (see Fig. 40-11). Hemiplegia may result from sublethal hemorrhage. Cerebral hemorrhages are more likely in older women with underlying chronic hypertension as discussed on Management of Severe Hypertension. Rarely, they may be due to a ruptured cerebral berry aneurysm or arteriovenous malformation (Witlin, 1997a).
In approximately 10 percent of women, some degree of blindness follows a seizure. The causes of blindness or impaired vision are discussed on Neuroimaging Studies. Blindness with severe preeclampsia without convulsions is usually due to retinal detachment (Vigil-De Gracia, 2011). Conversely, blindness with eclampsia is almost always due to occipital lobe edema (Cunningham, 1995). In both instances, however, the prognosis for return to normal function is good and is usually complete within 1 to 2 weeks postpartum.
Up to 5 percent of women with eclampsia have substantively altered consciousness, including persistent coma, following a seizure. This is due to extensive cerebral edema, and transtentorial herniation may cause death as discussed on Neuroimaging Studies (Cunningham, 2000).
Rarely, eclampsia is followed by psychosis, and the woman becomes violent. This may last for several days to 2 weeks, but the prognosis for return to normal function is good, provided there was no preexisting mental illness. It is presumed to be similar to postpartum psychosis discussed in detail in Chapter 61 (Anxiety Disorders). Antipsychotic medications have proved effective in the few cases of posteclampsia psychosis treated at Parkland Hospital.
Generally, eclampsia is more likely to be diagnosed too frequently rather than overlooked. Epilepsy, encephalitis, meningitis, brain tumor, neurocysticercosis, amnionic fluid embolism, postdural puncture cephalgia, and ruptured cerebral aneurysm during late pregnancy and the puerperium may simulate eclampsia. Until other such causes are excluded, however, all pregnant women with convulsions should be considered to have eclampsia.
It has been long recognized that magnesium sulfate is highly effective in preventing convulsions in women with preeclampsia and in stopping them in those with eclampsia. In his review, Chesley (1978) cited observational data by Pritchard and colleagues (1955, 1975) from Parkland Hospital and from his own institution, Kings County Hospital in Brooklyn. At that time, most eclampsia regimens used in the United States adhered to a similar philosophy still in use today, the tenets of which include the following:
Control of convulsions using an intravenously administered loading dose of magnesium sulfate that is followed by a maintenance dose, usually intravenous, of magnesium sulfate
Intermittent administration of an antihypertensive medication to lower blood pressure whenever it is considered dangerously high
Avoidance of diuretics unless there is obvious pulmonary edema, limitation of intravenous fluid administration unless fluid loss is excessive, and avoidance of hyperosmotic agents
Delivery of the fetus to achieve a remission of preeclampsia.
Magnesium Sulfate to Control Convulsions
In more severe cases of preeclampsia and in eclampsia, magnesium sulfate administered parenterally is an effective anticonvulsant that avoids producing central nervous system depression in either the mother or the infant. It may be given intravenously by continuous infusion or intramuscularly by intermittent injection (Table 40-11). The dosages for severe preeclampsia are the same as for eclampsia. Because labor and delivery is a more likely time for convulsions to develop, women with preeclampsia-eclampsia usually are given magnesium sulfate during labor and for 24 hours postpartum.
TABLE 40-11Magnesium Sulfate Dosage Schedule for Severe Preeclampsia and Eclampsia ||Download (.pdf) TABLE 40-11 Magnesium Sulfate Dosage Schedule for Severe Preeclampsia and Eclampsia
|Continuous Intravenous (IV) Infusion |
|Give 4- to 6-g loading dose of magnesium sulfate diluted in 100 mL of IV fluid administered over 15–20 min |
|Begin 2 g/hr in 100 mL of IV maintenance infusion. Some recommend 1 g/hr |
|Monitor for magnesium toxicity: |
| Assess deep tendon reflexes periodically |
| Some measure serum magnesium level at 4–6 hr and adjust infusion to maintain levels between 4 and 7 mEq/L (4.8 to 8.4 mg/dL) |
| Measure serum magnesium levels if serum creatinine ≥ 1.0 mg/dL |
|Magnesium sulfate is discontinued 24 hr after delivery |
|Intermittent Intramuscular Injections |
|Give 4 g of magnesium sulfate (MgSO4·7H2O USP) as a 20% solution intravenously at a rate not to exceed 1 g/min |
|Follow promptly with 10 g of 50% magnesium sulfate solution, one half (5 g) injected deeply in the upper outer quadrant of each buttock through a 3-inch-long 20-gauge needle. (Addition of 1.0 mL of 2% lidocaine minimizes discomfort.) If convulsions persist after 15 min, give up to 2 g more intravenously as a 20% solution at a rate not to exceed 1 g/min. If the woman is large, up to 4 g may be given slowly |
|Every 4 hr thereafter, give 5 g of a 50% solution of magnesium sulfate injected deeply in the upper outer quadrant of alternate buttocks, but only after ensuring that: |
| The patellar reflex is present, |
| Respirations are not depressed, and |
| Urine output the previous 4 hr exceeded 100 mL |
|Magnesium sulfate is discontinued 24 hr after delivery |
Magnesium sulfate is almost universally administered intravenously. In most units, the intramuscular route has been abandoned. Of concern, magnesium sulfate solutions, although inexpensive to prepare, are not readily available in all parts of the developing world. And even when the solutions are available, the technology to infuse them may not be. Therefore, it should not be overlooked that the drug can be administered intramuscularly and that this route is as effective as intravenous administration (Salinger, 2013). In two reports from India, intramuscular regimens were nearly equivalent in preventing recurrent convulsions and maternal deaths in women with eclampsia (Chowdhury, 2009; Jana, 2013). These observations comport with earlier ones from Parkland Hospital as described by Pritchard and colleagues (1975, 1984).
Magnesium sulfate is not given to treat hypertension. Based on several studies cited subsequently and extensive clinical observations, magnesium most likely exerts a specific anticonvulsant action on the cerebral cortex. Typically, the mother stops convulsing after the initial 4-g loading dose. By an hour or two, she regains consciousness sufficiently to be oriented to place and time.
The magnesium sulfate dosages presented in Table 40-11 usually result in plasma magnesium levels illustrated in Figure 40-21. When magnesium sulfate is given to arrest eclamptic seizures, 10 to 15 percent of women will have a subsequent convulsion. If so, an additional 2-g dose of magnesium sulfate in a 20-percent solution is slowly administeredintravenously. In a small woman, this additional 2-g dose may be used once, but it can be given twice if needed in a larger woman. In only 5 of 245 women with eclampsia at Parkland Hospital was it necessary to use supplementary anticonvulsant medication to control convulsions (Pritchard, 1984). For these, an intravenous barbiturate is given slowly. Midazolam or lorazepam may be given in a small single dose, but prolonged use is avoided because it is associated with a higher mortality rate (Royal College of Obstetricians and Gynaecologists, 2006).
Comparison of serum magnesium levels in mEq/L following a 4-g intravenous loading dose of magnesium sulfate and then maintained by either an intramuscular or continuing infusion. Multiply by 1.2 to convert mEq/L to mg/dL. (Data from Sibai, 1984.)
Maintenance magnesium sulfate therapy is continued for 24 hours after delivery. For eclampsia that develops postpartum, magnesium sulfate is administered for 24 hours after the onset of convulsions. Ehrenberg and Mercer (2006) studied abbreviated postpartum magnesium administration in 200 women with mild preeclampsia. Of 101 women randomized to 12-hour treatment, seven had worsening preeclampsia, and treatment was extended to 24 hours. None of these 101 women and none of the other cohort of 95 given the 24-hour magnesium infusion developed eclampsia. This abbreviated regimen needs further study before being routinely administered for severe preeclampsia or eclampsia.
Pharmacology and Toxicology
Magnesium sulfate USP is MgSO4·7H2O and not simple MgSO4. It contains 8.12 mEq per 1 g. Parenterally administered magnesium is cleared almost totally by renal excretion, and magnesium intoxication is unusual when the glomerular filtration rate is normal or only slightly decreased. Adequate urine output usually correlates with preserved glomerular filtration rates. That said, magnesium excretion is not urine flow dependent, and urinary volume per unit time does not, per se, predict renal function. Thus, serum creatinine levels must be measured to detect a decreased glomerular filtration rate.
Eclamptic convulsions are almost always prevented or arrested by plasma magnesium levels maintained at 4 to 7 mEq/L, 4.8 to 8.4 mg/dL, or 2.0 to 3.5 mmol/L. Although laboratories typically report total magnesium levels, free or ionized magnesium is the active moiety for suppressing neuronal excitability. Taber and associates (2002) found poor correlation between total and ionized levels. Further studies are necessary to determine if either measurement provides a superior method for surveillance.
After a 4-g intravenous loading dose in nonobese women, magnesium levels observed with the intramuscular regimen and those observed with the maintenance infusion of 2 g/hr are similar (see Fig. 40-21). The obesity epidemic has affected these observations. Tudela and colleagues (2013) reported our observations from Parkland Hospital with magnesium administration to obese women. More than 60 percent of women whose body mass index (BMI) exceeded 30 kg/m2 and who were receiving the 2-g/hr dose had subtherapeutic levels at 4 hours. Thus, 40 percent of obese women would require 3 g/hr to maintain effective plasma levels. That said, currently most do not recommend routine magnesium level measurements (American College of Obstetricians and Gynecologists, 2013b; Royal College of Obstetricians and Gynaecologists, 2006).
Patellar reflexes disappear when the plasma magnesium level reaches 10 mEq/L—about 12 mg/dL—presumably because of a curariform action. This sign serves to warn of impending magnesium toxicity. When plasma levels rise above 10 mEq/L, breathing becomes weakened. At 12 mEq/L or higher levels, respiratory paralysis and respiratory arrest follow. Somjen and coworkers (1966) induced marked hypermagnesemia in themselves by intravenous infusion and achieved plasma levels up to 15 mEq/L. Predictably, at such high plasma levels, respiratory depression developed that necessitated mechanical ventilation, but depression of the sensorium was not dramatic as long as hypoxia was prevented.
Treatment with calcium gluconate or calcium chloride, 1 g intravenously, along with withholding further magnesium sulfate, usually reverses mild to moderate respiratory depression. One of these agents should be readily available whenever magnesium is being infused. Unfortunately, the effects of intravenously administered calcium may be short-lived if there is a steady-state toxic level. For severe respiratory depression and arrest, prompt tracheal intubation and mechanical ventilation are lifesaving. Direct toxic effects on the myocardium from high levels of magnesium are uncommon. It appears that cardiac dysfunction associated with magnesium is due to respiratory arrest and hypoxia. With appropriate ventilation, cardiac action is satisfactory even when plasma magnesium levels are exceedingly high (McCubbin, 1981; Morisaki, 2000).
Because magnesium is cleared almost exclusively by renal excretion, the dosages described will become excessive if glomerular filtration is substantially decreased. The initial 4-g loading dose of magnesium sulfate can be safely administered regardless of renal function. It is important to administer the standard loading dose and not to reduce it under the mistaken conception that diminished renal function requires it. This is because after distribution, a loading dose achieves the desired therapeutic level, and the infusion maintains the steady-state level. Thus, only the maintenance infusion rate should be altered with diminished glomerular filtration rate. Renal function is estimated by measuring plasma creatinine. Whenever plasma creatinine levels are > 1.0 mg/mL, serum magnesium levels are measured to guide the infusion rate. With severe renal dysfunction, only the loading dose of magnesium sulfate is required to produce a steady-state therapeutic level.
Acute cardiovascular effects of parenteral magnesium in women with severe preeclampsia have been studied using data obtained by pulmonary and radial artery catheterization. After a 4-g intravenous dose administered over 15 minutes, mean arterial pressure fell slightly, accompanied by a 13-percent increase in cardiac index (Cotton, 1986b). Thus, magnesium decreased systemic vascular resistance and mean arterial pressure. At the same time, it increased cardiac output without evidence of myocardial depression. These findings were coincidental with transient nausea and flushing, and the cardiovascular effects persisted for only 15 minutes despite continued magnesium infusion.
Thurnau and associates (1987) showed that there was a small but highly significant increase in total magnesium concentration in the cerebrospinal fluid with magnesium therapy. The magnitude of the increase was directly proportional to the corresponding serum concentration.
Magnesium is anticonvulsant and neuroprotective in several animal models. Some proposed mechanisms of action include: (1) reduced presynaptic release of the neurotransmitter glutamate, (2) blockade of glutamatergic N-methyl-d-aspartate (NMDA) receptors, (3) potentiation of adenosine action, (4) improved calcium buffering by mitochondria, and (5) blockage of calcium entry via voltage-gated channels (Arango, 2006; Wang, 2012a).
Relatively high serum magnesium concentrations depress myometrial contractility both in vivo and in vitro. With the regimen described and the plasma levels that result, no evidence of myometrial depression has been observed beyond a transient decrease in activity during and immediately after the initial intravenous loading dose. Leveno and associates (1998) compared outcomes in 480 nulliparous women given phenytoin for preeclampsia with outcomes in 425 preeclamptic women given magnesium sulfate. Magnesium did not significantly alter the need for oxytocin stimulation of labor, admission-to-delivery intervals, or route of delivery. Similar results have been reported by others (Atkinson, 1995; Szal, 1999; Witlin, 1997b).
The mechanisms by which magnesium might inhibit uterine contractility are not established. It is generally assumed, however, that these depend on its effects on intracellular calcium as discussed in detail in Chapter 21 (Phase 4 of Parturition: The Puerperium). Inhibition of uterine contractility is magnesium dose dependent, and serum levels of at least 8 to 10 mEq/L are necessary to inhibit uterine contractions (Watt-Morse, 1995). This likely explains why there are few if any uterine effects seen clinically when magnesium sulfate is given for preeclampsia. And as discussed in Chapter 42 (Ritodrine), magnesium is also not considered to be an effective tocolytic agent.
Fetal and Neonatal Effects
Magnesium administered parenterally promptly crosses the placenta to achieve equilibrium in fetal serum and less so in amnionic fluid (Hallak, 1993). Levels in amnionic fluid increase with duration of maternal infusion (Gortzak-Uzen, 2005). Current evidence supports the view that magnesium sulfate has small but significant effects on the fetal heart rate pattern—specifically beat-to-beat variability. Hallak and coworkers (1999) compared an infusion of magnesium sulfate with a saline infusion. These investigators reported that magnesium was associated with a small and clinically insignificant decrease in variability. Similarly, in a retrospective study, Duffy and associates (2012) reported a lower heart rate baseline that was within the normal range; decreased variability; and fewer prolonged decelerations. They noted no adverse outcomes.
Overall, maternal magnesium therapy appears safe for perinates. For example, a recent MFMU Network study of more than 1500 exposed preterm neonates found no association between the need for neonatal resuscitation and cord blood magnesium levels (Johnson, 2012). Still, there are a few neonatal adverse events associated with its use. In a Parkland Hospital study of 6654 mostly term exposed newborns, 6 percent had hypotonia (Abbassi-Ghanavati, 2012). In addition, exposed neonates had lower 1- and 5-minute Apgar scores, a higher intubation rate, and more admissions to the special care nursery. The study showed that neonatal depression occurs only if there is severe hypermagnesemia at delivery.
Observational studies have suggested a protective effect of magnesium against the development of cerebral palsy in very-low-birthweight infants (Nelson, 1995; Schendel, 1996). At least five randomized trials have also assessed neuroprotective effects in preterm newborns. These findings are discussed in detail in Chapter 42 (Magnesium Sulfate for Fetal Neuroprotection). Nguyen and colleagues (2013) expanded this possibility to include term newborn neuroprotection. They performed a Cochrane Database review to compare term neonatal outcomes with and without exposure to peripartum magnesium therapy and reported that there were insufficient data to draw conclusions.
Finally, as discussed in Chapter 42 (Ritodrine), long-term use of magnesium, given for several days for tocolysis, has been associated with neonatal osteopenia (American College of Obstetricians and Gynecologists, 2013c).
Maternal Safety and Efficacy of Magnesium Sulfate
The multinational Eclampsia Trial Collaborative Group study (1995) involved 1687 women with eclampsia randomly allocated to different anticonvulsant regimens. In one cohort, 453 women were randomly assigned to be given magnesium sulfate and compared with 452 given diazepam. In a second cohort, 388 eclamptic women were randomly assigned to be given magnesium sulfate and compared with 387 women given phenytoin. The results of these and other comparative studies that each enrolled at least 50 women are summarized in Table 40-12. In aggregate, magnesium sulfate therapy was associated with a significantly lower incidence of recurrent seizures compared with women given an alternative anticonvulsant—9.7 versus 23 percent. Importantly, the maternal death rate of 3.1 percent with magnesium sulfate was significantly lower than that of 4.9 percent for the other regimens.
TABLE 40-12Randomized Comparative Trials of Magnesium Sulfate with Another Anticonvulsant to Prevent Recurrent Eclamptic Convulsions ||Download (.pdf) TABLE 40-12 Randomized Comparative Trials of Magnesium Sulfate with Another Anticonvulsant to Prevent Recurrent Eclamptic Convulsions
| || ||Recurrent Seizures ||Maternal Deaths |
|Study ||Comparison Drug ||MgSO4 (%) ||Other Drug (%) ||RR (95% CI) ||MgSO4 (%) ||Other Drug (%) ||RR (95% CI) |
|Crowther (1990) ||Diazepam ||5/24 ||7/27 ||0.80 |
|1/24 ||0/27 || |
|Bhalla (1994) ||Lytic cocktail ||1/45 ||11/45 ||0.09 |
|0/45 ||2/45 || |
|Eclampsia Trial Collaborative Group (1995) ||Phenytoin |
|Totals || ||88/910 |
Magnesium safety and toxicity was recently reviewed by Smith and coworkers (2013). In more than 9500 treated women, the overall rate of absent patellar tendon reflexes was 1.6 percent; respiratory depression 1.3 percent; and calcium gluconate administration 0.2 percent. They reported only one maternal death due to magnesium toxicity. Our anecdotal experiences are similar—in the estimated 50 years of its use in more than 40,000 women, there has been only one maternal death from an overdose (Pritchard, 1984).
Management of Severe Hypertension
Dangerous hypertension can cause cerebrovascular hemorrhage and hypertensive encephalopathy, and it can trigger eclamptic convulsions in women with preeclampsia. Other complications include hypertensive afterload congestive heart failure and placental abruption (Clark, 2012).
Because of these sequelae, the National High Blood Pressure Education Program Working Group (2000) and the 2013 Task Force recommend treatment to lower systolic pressures to or below 160 mm Hg and diastolic pressures to or below 110 mm Hg. Martin and associates (2005) reported provocative observations that highlight the importance of treating systolic hypertension. They described 28 selected women with severe preeclampsia who suffered an associated stroke. Most of these were hemorrhagic strokes—93 percent—and all women had systolic pressures > 160 mm Hg before suffering their stroke. By contrast, only 20 percent of these same women had diastolic pressures > 110 mm Hg. It seems likely that at least half of serious hemorrhagic strokes associated with preeclampsia are in women with chronic hypertension (Cunningham, 2005). Long-standing hypertension results in development of Charcot-Bouchard aneurysms in the deep penetrating arteries of the lenticulostriate branch of the middle cerebral arteries. These vessels supply the basal ganglia, putamen, thalamus, and adjacent deep white matter, as well as the pons and deep cerebellum. These unique aneurysmal weakenings predispose these small arteries to rupture during sudden hypertensive episodes (Chap. 50, Pregnancy-Aggravated Hypertension or Superimposed Preeclampsia).
Several drugs are available to rapidly lower dangerously elevated blood pressure in women with the gestational hypertensive disorders. The three most commonly employed are hydralazine, labetalol, and nifedipine. For years, parenteral hydralazine was the only one of these three available. But when parenteral labetalol was later introduced, it was considered to be equally effective for obstetrical use. Orally administered nifedipine has since then gained some popularity as first-line treatment for severe gestational hypertension.
This is probably still the most commonly used antihypertensive agent in the United States for treatment of women with severe gestational hypertension. Hydralazine is administered intravenously with a 5-mg initial dose, and this is followed by 5- to 10-mg doses at 15- to 20-minute intervals until a satisfactory response is achieved (American College of Obstetricians and Gynecologists, 2012b). Some limit the total dose to 30 mg per treatment cycle (Sibai, 2003). The target response antepartum or intrapartum is a decrease in diastolic blood pressure to 90 to 110 mm Hg. Lower diastolic pressures risk compromised placental perfusion. Hydralazine has proven remarkably effective to prevent cerebral hemorrhage. Its onset of action can be as rapid as 10 minutes. Although repeated administration every 15 to 20 minutes may theoretically lead to undesirable hypotension, this has not been our experience when given in these 5- to 10-mg increments.
At Parkland Hospital, between 5 and 10 percent of all women with intrapartum hypertensive disorders are given a parenteral antihypertensive agent. Most often, we use hydralazine as described. We do not limit the total dose, and seldom has a second antihypertensive agent been needed. We estimate that nearly 6000 women have been so treated at Parkland during the past 50 years. Although less popular in Europe, hydralazine is used in some centers, according to the Royal College of Obstetricians and Gynaecologists (2006). A dissenting opinion for first-line intrapartum use of hydralazine was voiced by the Vancouver group after a systematic review (Magee, 2009). At the same time, however, Umans and coworkers (2014) concluded that objective outcome data did not support the use of one drug over another.
As with any antihypertensive agent, the tendency to give a larger initial dose of hydralazine if the blood pressure is higher must be avoided. The response to even 5- to 10-mg doses cannot be predicted by hypertension severity. Thus, our protocol is to always administer 5 mg as the initial dose. An adverse response to exceeding this initial dose is shown in Figure 40-22. This woman had chronic hypertension complicated by severe superimposed preeclampsia, and hydralazine was injected more frequently than recommended. Her blood pressure decreased in less than 1 hour from 240–270/130–150 mm Hg to 110/80 mm Hg, and fetal heart rate decelerations characteristic of uteroplacental insufficiency became evident. Decelerations persisted until her blood pressure was increased with rapid crystalloid infusion. In some cases, this fetal response to diminished uterine perfusion may be confused with placental abruption and may result in unnecessary and potentially dangerous emergent cesarean delivery.
Hydralazine was given at 5-minute intervals instead of 15-minute intervals. The mean arterial pressure decreased from 180 to 90 mm Hg within 1 hour and was associated with fetal bradycardia. Rapid crystalloid infusion raised the mean pressure to 115 mm Hg, and the fetus recovered.
This effective intravenous antihypertensive agent is an α1- and nonselective β-blocker. Some prefer its use over hydralazine because of fewer side effects (Sibai, 2003). At Parkland Hospital, we give 10 mg intravenously initially. If the blood pressure has not decreased to the desirable level in 10 minutes, then 20 mg is given. The next 10-minute incremental dose is 40 mg and is followed by another 40 mg if needed. If a salutary response is not achieved, then an 80-mg dose is given. Sibai (2003) recommends 20 to 40 mg every 10 to 15 minutes as needed and a maximum dose of 220 mg per treatment cycle. The American College of Obstetricians and Gynecologists (2012b) recommends starting with a 20-mg intravenous bolus. If not effective within 10 minutes, this is followed by 40 mg, then 80 mg every 10 minutes. Administration should not exceed a 220-mg total dose per treatment cycle.
Comparative studies of these two antihypertensive agents show equivalent results (Umans, 2014). In an older trial, Mabie and colleagues (1987) compared intravenous hydralazine with labetalol for blood pressure control in 60 peripartum women. Labetalol lowered blood pressure more rapidly, and associated tachycardia was minimal. However, hydralazine lowered mean arterial pressures to safe levels more effectively. In a later trial, Vigil-De Gracia and associates (2007) randomly assigned 200 severely hypertensive women intrapartum to be given either: (1) intravenous hydralazine—5 mg, which could be given every 20 minutes and repeated to a maximum of five doses, or (2) intravenous labetalol—20 mg initially, followed by 40 mg in 20 minutes and then 80 mg every 20 minutes if needed up to a maximum 300-mg dose. Maternal and neonatal outcomes were similar. Hydralazine caused significantly more maternal tachycardia and palpitations, whereas labetalol more frequently caused maternal hypotension and bradycardia. Both drugs have been associated with a reduced frequency of fetal heart rate accelerations (Cahill, 2013).
This calcium-channel blocking agent has become popular because of its efficacy for control of acute pregnancy-related hypertension. The NHBPEP Working Group (2000) and the Royal College of Obstetricians and Gynaecologists (2006) recommend a 10-mg initial oral dose to be repeated in 30 minutes if necessary. Nifedipine given sublingually is no longer recommended. Randomized trials that compared nifedipine with labetalol found neither drug definitively superior to the other. However, nifedipine lowered blood pressure more quickly (Scardo, 1999; Shekhar, 2013; Vermillion, 1999).
Other Antihypertensive Agents
A few other generally available antihypertensive agents have been tested in clinical trials but are not widely used (Umans, 2014). Belfort and associates (1990) administered the calcium antagonist verapamil by intravenous infusion at 5 to 10 mg per hour. Mean arterial pressure was lowered by 20 percent. Belfort and coworkers (1996, 2003) reported that nimodipine given either by continuous infusion or orally was effective to lower blood pressure in women with severe preeclampsia. Bolte and colleagues (1998, 2001) reported good results in preeclamptic women given intravenous ketanserin, a selective serotonergic (5HT2A) receptor blocker. Nitroprusside or nitroglycerine is recommended by some if there is not optimal response to first-line agents. With these latter two agents, fetal cyanide toxicity may develop after 4 hours. We have not had the need for either due to our consistent success with first-line treatment using hydralazine, labetalol, or a combination of the two given in succession, but never simultaneously.
There are experimental antihypertensive drugs that may become useful for preeclampsia treatment. One is calcitonin gene related peptide (CGRP), a 37-amino acid potent vasodilator. Another is antidigoxin antibody Fab (DIF) directed against endogenous digitalis-like factors, also called cardiotonic steroids (Bagrov, 2008; Lam, 2013).
Potent loop diuretics can further compromise placental perfusion. Immediate effects include depletion of intravascular volume, which most often is already reduced compared with that of normal pregnancy (Blood Volume). Therefore, before delivery, diuretics are not used to lower blood pressure (Zeeman, 2009; Zondervan, 1988). We limit antepartum use of furosemide or similar drugs solely to treatment of pulmonary edema.
Lactated Ringer solution is administered routinely at the rate of 60 mL to no more than 125 mL per hour unless there is unusual fluid loss from vomiting, diarrhea, or diaphoresis, or, more likely, excessive blood loss with delivery. Oliguria is common with severe preeclampsia. Thus, coupled with the knowledge that maternal blood volume is likely constricted compared with that of normal pregnancy, it is tempting to administer intravenous fluids more vigorously. But controlled, conservative fluid administration is preferred for the typical woman with severe preeclampsia who already has excessive extracellular fluid that is inappropriately distributed between intravascular and extravascular spaces. As discussed on Blood Volume, infusion of large fluid volumes enhances the maldistribution of extravascular fluid and thereby appreciably increases the risk of pulmonary and cerebral edema (Dennis, 2012a; Sciscione, 2003; Zinaman, 1985). For labor analgesia with neuraxial analgesia, crystalloid solutions are infused slowly in graded amounts (Chap. 25, Timing of Epidural Placement).
Women with severe preeclampsia-eclampsia who develop pulmonary edema most often do so postpartum (Cunningham, 1986, 2012; Zinaman, 1985). With pulmonary edema in the eclamptic woman, aspiration of gastric contents, which may be the result of convulsions, anesthesia, or oversedation, should be excluded. As discussed in Chapter 47 (Acute Pulmonary Edema), there are three common causes of pulmonary edema in women with severe preeclampsia syndrome—pulmonary capillary permeability edema, cardiogenic edema, or a combination of the two.
Some women with severe preeclampsia—especially if given vigorous fluid replacement—will have mild pulmonary congestion from permeability edema (see Fig. 40-6). This is caused by normal pregnancy changes magnified by the preeclampsia syndrome as discussed in Chapter 4 (Cardiovascular System). Importantly, plasma oncotic pressure decreases appreciably in normal term pregnancy because of decreased serum albumin concentration, and oncotic pressure falls even more with preeclampsia (Zinaman, 1985). And both increased extravascular fluid oncotic pressure and increased capillary permeability have been described in women with preeclampsia (Brown, 1989; Øian, 1986).
Invasive Hemodynamic Monitoring
Knowledge concerning cardiovascular and hemodynamic pathophysiological alterations associated with severe preeclampsia-eclampsia has accrued from studies done using invasive monitoring and a flow-directed pulmonary artery catheter (see Figs. 40-5 and 40-6). Clark and Dildy (2010) have reviewed such monitoring in obstetrics. Two conditions frequently cited as indications are preeclampsia associated with either oliguria or pulmonary edema. Somewhat ironically, it is usually vigorous treatment of the former that results in most cases of the latter. The American College of Obstetricians and Gynecologists (2013a) recommends against routine invasive monitoring. The College notes that such monitoring should be reserved for severely preeclamptic women with accompanying severe cardiac disease, renal disease, or both or in cases of refractory hypertension, oliguria, and pulmonary edema. An alternative noninvasive hemodynamic monitoring strategy has been evaluated in preliminary studies (Moroz, 2013).
Because the preeclampsia syndrome is associated with hemoconcentration, attempts to expand blood volume seem intuitively reasonable (Ganzevoort, 2004). This has led some to infuse various fluids, starch polymers, albumin concentrates, or combinations thereof to expand blood volume. There are, however, older observational studies that describe serious complications—especially pulmonary edema—with volume expansion (Benedetti, 1985; López-Llera, 1982; Sibai, 1987b). In general, these studies were not controlled or even comparative (Habek, 2006).
The Amsterdam randomized study reported by Ganzevoort and coworkers (2005a,b) was a well-designed investigation done to evaluate volume expansion. A total of 216 women with severe preeclampsia were enrolled between 24 and 34 weeks’ gestation. The study included women whose preeclampsia was complicated by HELLP syndrome, eclampsia, or fetal-growth restriction. All women were given magnesium sulfate to prevent eclampsia, betamethasone to promote fetal pulmonary maturity, ketanserine to control dangerous hypertension, and normal saline infusions restricted only to deliver medications. In the group randomly assigned to volume expansion, each woman was given 250 mL of 6-percent hydroxyethyl starch infused over 4 hours twice daily. Their maternal and perinatal outcomes were compared with a control group and are shown in Table 40-13. None of these outcomes was significantly different between the two groups. Importantly, serious maternal morbidity and a substantive perinatal mortality rate accompanied their “expectant” management (see Table 40-9).
TABLE 40-13Maternal and Perinatal Outcomes in a Randomized Trial of Plasma Volume Expansion versus Saline Infusion in 216 Women with Severe Preeclampsia between 24 and 34 Weeks ||Download (.pdf) TABLE 40-13 Maternal and Perinatal Outcomes in a Randomized Trial of Plasma Volume Expansion versus Saline Infusion in 216 Women with Severe Preeclampsia between 24 and 34 Weeks
|Outcomes ||Control Groupa (n = 105) ||Treatment Groupa (n = 111) |
|Maternal Outcomes (%) || || |
|Eclampsia (after enrollment) ||1.9 ||1.8 |
|HELLP (after enrollment) ||19.0 ||17.0 |
|Pulmonary edema ||2.9 ||4.5 |
|Placental abruption ||3.8 ||1.0 |
|Perinatal Outcomes || || |
|Fetal deaths (%) ||7 ||12 |
|Prolongation of pregnancy (mean) ||11.6 d ||6.7 d |
|EGA at death (mean) ||26.7 wk ||26.3 wk |
|Birthweight (mean) ||625 g ||640 g |
|Live births (%) ||93 ||88 |
|Prolongation of pregnancy (mean) ||10.5 d ||7.4 d |
|EGA at delivery (mean) ||31.6 wk ||31.4 wk |
|RDS (%) ||30 ||35 |
|Neonatal death (%) ||7.6 ||8.1 |
|Perinatal mortality rate (n per 1000) ||142/1000 ||207/1000 |
Neuroprophylaxis—Prevention of Seizures
There have been several randomized trials designed to test the efficacy of seizure prophylaxis for women with gestational hypertension, with or without proteinuria. In most of these, magnesium sulfate was compared with another anticonvulsant or with a placebo. In all studies, magnesium sulfate was reported to be superior to the comparator agent to prevent eclampsia. Four of the larger studies are summarized in Table 40-14. In the study from Parkland Hospital, Lucas and colleagues (1995) reported that magnesium sulfate therapy was superior to phenytoin to prevent eclamptic seizures in women with gestational hypertension and preeclampsia. Belfort and coworkers (2003) compared magnesium sulfate and nimodipine—a calcium-channel blocker with specific cerebral vasodilator activity—for eclampsia prevention. In this unblinded randomized trial involving 1650 women with severe preeclampsia, the rate of eclampsia was more than threefold higher for women allocated to the nimodipine group—2.6 versus 0.8 percent.
TABLE 40-14Randomized Comparative Trials of Prophylaxis with Magnesium Sulfate and Placebo or Another Anticonvulsant in Women with Gestational Hypertension ||Download (.pdf) TABLE 40-14 Randomized Comparative Trials of Prophylaxis with Magnesium Sulfate and Placebo or Another Anticonvulsant in Women with Gestational Hypertension
The largest comparative study was the entitled MAGnesium Sulfate for Prevention of Eclampsia and reported by the Magpie Trial Collaboration Group (2002). More than 10,000 women with severe preeclampsia from 33 countries were randomly allocated to treatment with magnesium sulfate or placebo. Women given magnesium had a 58-percent significantly lower risk of eclampsia than those given placebo. Smyth and associates (2009) provided follow-up data of infants born to these mothers given magnesium sulfate. At approximately 18 months, child behavior did not differ in those exposed compared with those not exposed to magnesium sulfate.
Who Should Be Given Magnesium Sulfate?
Magnesium will prevent proportionately more seizures in women with correspondingly worse disease. As previously discussed, however, severity is difficult to quantify, and thus it is difficult to decide which individual woman might benefit most from neuroprophylaxis. The 2013 Task Force recommends that women with either eclampsia or severe preeclampsia should be given magnesium sulfate prophylaxis. Again, criteria that establish “severity” are not totally uniform (see Table 40-2). At the same time, however, the 2013 Task Force suggests that all women with “mild” preeclampsia do not need magnesium sulfate neuroprophylaxis. The conundrum is whether or not to give neuroprophylaxis to any of these women with “nonsevere” gestational hypertension or preeclampsia (Alexander, 2006).
In many other countries, and principally following dissemination of the Magpie Trial Collaboration Group (2002) study results, magnesium sulfate is now recommended for women with severe preeclampsia. In some, however, debate continues concerning whether therapy should be reserved for women who have an eclamptic seizure. We are of the opinion that eclamptic seizures are dangerous for reasons discussed on HELLP Syndrome. Maternal mortality rates of up to 5 percent have been reported even in recent studies (Andersgaard, 2006; Benhamou, 2009; Moodley, 2010; Schutte, 2008; Zwart, 2008). Moreover, there are substantially increased perinatal mortality rates in both industrialized countries and underdeveloped ones (Abd El Aal, 2012; Knight, 2007; Ndaboine, 2012; Schutte, 2008; von Dadelszen, 2012). Finally, the possibility of adverse long-term neuropsychological and vision-related sequelae of eclampsia described by Aukes (2009, 2012), Postma (2009), Wiegman (2012), and their coworkers, which are discussed on Renal Sequelae, have raised additional concerns that eclamptic seizures are not “benign.”
Selective versus Universal Magnesium Sulfate Prophylaxis
There is uncertainty around which women with nonsevere gestational hypertension should be given magnesium sulfate neuroprophylaxis. An opportunity to address these questions was afforded by a change in our prophylaxis protocol for women delivering at Parkland Hospital. Before this time, Lucas and associates (1995) had found that the risk of eclampsia without magnesium prophylaxis was approximately 1 in 100 for women with mild preeclampsia. Up until 2000, all women with gestational hypertension were given magnesium prophylaxis intramuscularly as first described by Pritchard in 1955. After 2000, we instituted a standardized protocol for intravenously administered magnesium sulfate (Alexander, 2006). At the same time, we also changed our practice of universal seizure prophylaxis for all women with gestational hypertension to one of selective prophylaxis given only to women who met our criteria for severe gestational hypertension. These criteria, shown in Table 40-15, included women with ≥ 2+ proteinuria measured by dipstick in a catheterized urine specimen.
TABLE 40-15Selective versus Universal Magnesium Sulfate Prophylaxis: Parkland Hospital Criteria to Define Severity of Gestational Hypertension ||Download (.pdf) TABLE 40-15 Selective versus Universal Magnesium Sulfate Prophylaxis: Parkland Hospital Criteria to Define Severity of Gestational Hypertension
|In a woman with new-onset proteinuric hypertension, at least one of the following criteria is required: |
|Systolic BP ≥ 160 or diastolic BP ≥ 110 mm Hg |
|Proteinuria ≥ 2+ by dipstick in a catheterized urine specimen |
|Serum creatinine > 1.2 mg/dL |
|Platelet count < 100,000/μL |
|Aspartate aminotransferase (AST) elevated two times above upper limit of normal range |
|Persistent headache or scotomata |
|Persistent midepigastric or right-upper quadrant pain |
Following this protocol change, 60 percent of 6518 women with gestational hypertension during a 4½-year period were given magnesium sulfate neuroprophylaxis (Table 40-16). The remaining 40 percent with nonsevere hypertension were not treated, and of these, 27 women developed eclamptic seizures—1 in 92. The seizure rate was only 1 in 358 for 3935 women with criteria for severe disease who were given magnesium sulfate, and thus these cases were treatment failures. To assess morbidity, outcomes in 87 eclamptic women were compared with outcomes in all 6431 noneclamptic hypertensive women. Although most maternal outcomes were similar, almost a fourth of women with eclampsia who underwent emergent cesarean delivery required general anesthesia. This is a great concern because eclamptic women have laryngotracheal edema and are at a higher risk for failed intubation, gastric acid aspiration, and death (American College of Obstetricians and Gynecologists, 2013d). Neonatal outcomes were also a concern because the composite morbidity defined in Table 40-16 was significantly increased tenfold in eclamptic compared with noneclamptic women—12 versus 1 percent, respectively.
TABLE 40-16Selected Pregnancy Outcomes in 6518 Women with Gestational Hypertension According to Whether They Developed Eclampsia ||Download (.pdf) TABLE 40-16 Selected Pregnancy Outcomes in 6518 Women with Gestational Hypertension According to Whether They Developed Eclampsia
|Pregnancy Outcomes ||Eclampsia No. (%) ||Gest. HTNa No. (%) ||p value |
|Number ||87 ||6431 || |
|Maternal || || || |
|Cesarean delivery ||32 (37) ||2423 (38) ||0.86 |
|Placental abruption ||1 (1) ||72 (1) ||0.98 |
|General anesthesiab ||20 (23) ||270 (4) ||< 0.001 |
|Neonatal || || || |
|Composite morbidityc ||10 (12) ||240 (1) ||0.04 |
Thus, if one uses the Parkland criteria for nonsevere gestational hypertension, about 1 of 100 such women who are not given magnesium sulfate prophylaxis can be expected to have an eclamptic seizure. A fourth of these women likely will require emergent cesarean delivery with attendant maternal and perinatal morbidity and mortality from general anesthesia. From this, the major question regarding management of nonsevere gestational hypertension remains—whether it is acceptable to avoid unnecessary treatment of 99 women to risk eclampsia in one? The answer appears to be yes as suggested by the 2013 Task Force.
To avoid maternal risks from cesarean delivery, steps to effect vaginal delivery are used initially in women with eclampsia. Following a seizure, labor often ensues spontaneously or can be induced successfully even in women remote from term (Alanis, 2008). An immediate cure does not promptly follow delivery by any route, but serious morbidity is less common during the puerperium in women delivered vaginally.
Hemoconcentration or lack of normal pregnancy-induced hypervolemia is an almost predictable feature of severe preeclampsia-eclampsia as quantified by Zeeman and associates (2009) and shown in Figure 40-7. These women, who consequently lack normal pregnancy hypervolemia, are much less tolerant of even normal blood loss than are normotensive pregnant women. It is of great importance to recognize that an appreciable fall in blood pressure soon after delivery most often means excessive blood loss and not sudden resolution of vasospasm and endothelial damage. When oliguria follows delivery, the hematocrit should be evaluated frequently to help detect excessive blood loss. If identified, hemorrhage should be treated appropriately by careful crystalloid and blood transfusion.
During the past 20 years, the use of conduction analgesia for women with preeclampsia syndrome has proven ideal. Initial problems with this method included hypotension and diminished uterine perfusion caused by sympathetic blockade in these women with attenuated hypervolemia. But pulmonary edema was mitigated by techniques that used slow induction of epidural analgesia with dilute solutions of anesthetic agents to counter the need for rapid infusion of large volumes of crystalloid or colloid to correct maternal hypotension (Hogg, 1999; Wallace, 1995). Moreover, epidural blockade avoids general anesthesia, in which the stimulation of tracheal intubation may cause sudden severe hypertension. Such blood pressure increases, in turn, can cause pulmonary edema, cerebral edema, or intracranial hemorrhage. Finally, tracheal intubation may be particularly difficult and thus hazardous in women with airway edema due to preeclampsia (American College of Obstetricians and Gynecologists, 2013d).
At least three randomized studies have been performed to evaluate these methods of analgesia and anesthesia. Wallace and colleagues (1995) studied 80 women at Parkland Hospital with severe preeclampsia who were to undergo cesarean delivery. They had not been given labor epidural analgesia and were randomized to receive general anesthesia, epidural analgesia, or combined spinal-epidural analgesia. Their average preoperative blood pressures approximated 170/110 mm Hg, and all had proteinuria. Anesthetic and obstetrical management included antihypertensive drug therapy and limited intravenous fluids as previously described. Perinatal outcomes in each group were similar. Maternal hypotension resulting from regional analgesia was managed with judicious intravenous fluid administration. In women undergoing general anesthesia, maternal blood pressure was managed to avoid severe hypertension (Fig. 40-23). There were no serious maternal or fetal complications attributable to any of the three anesthetic methods. It was concluded that all three are acceptable for use in women with pregnancies complicated by severe preeclampsia if steps are taken to ensure a careful approach to the selected method.
Blood pressure effects of general anesthesia versus epidural or spinal–epidural analgesia for cesarean delivery in 80 women with severe preeclampsia. MAP = mean arterial pressure. Time posts (T): OR = operating room; IN = induction of anesthesia; T = tracheal intubation; IN5 = induction + 5 min; IN10 = induction + 10 min; IN20 = induction + 20 min; SKI = skin incision; D = delivery; SKC = skin closure; O = extubation. (From Wallace, 1995, with permission.)
Another randomized study included 70 women with severe preeclampsia receiving spinal analgesia versus general anesthesia (Dyer, 2003). All had a nonreassuring fetal heart rate tracing as the indication for cesarean delivery, and outcomes were equivalent. Dyer and coworkers (2008) later showed that decreased mean arterial blood pressure induced by epidural blockade could be effectively counteracted by phenylephrine infusion to maintain cardiac output.
In a study from the University of Alabama at Birmingham, Head and colleagues (2002) randomly assigned 116 women with severe preeclampsia to receive either epidural or patient-controlled intravenous meperidine analgesia during labor. Astandardized protocol limited intravenous fluids to 100 mL/hr. More women—9 percent—from the group assigned to epidural analgesia required ephedrine for hypotension. As expected, pain relief was superior in the epidural group, but maternal and neonatal complications were similar between groups. One woman in each group developed pulmonary edema.
It is important to emphasize that epidural analgesia is not to be considered treatment of preeclampsia. Lucas and associates (2001) studied 738 laboring women at Parkland Hospital who were 36 weeks or more and who had gestational hypertension of varying severity. Patients were randomly assigned to receive either epidural analgesia or patient-controlled intravenous meperidine analgesia. Maternal and neonatal outcomes were similar in the two study groups. However, as shown in Table 40-17, epidural analgesia resulted in a greater decrement of mean maternal arterial pressure compared with meperidine, but it was not superior in preventing recurrent severe hypertension later in labor.
TABLE 40-17Comparison of Cardiovascular Effects of Epidural versus Patient-Controlled Meperidine Analgesia During Labor in Women with Gestational Hypertension ||Download (.pdf) TABLE 40-17 Comparison of Cardiovascular Effects of Epidural versus Patient-Controlled Meperidine Analgesia During Labor in Women with Gestational Hypertension
| ||Labor Analgesia || |
|Hemodynamic Change ||Epidural (n = 372) ||Meperidine (n = 366) ||p value |
|Mean arterial pressure change (mean) ||–25 mm Hg ||–15 mm Hg ||< 0.001 |
|Ephedrine for hypotension (%) ||11% ||0 ||< 0.001 |
|Severe hypertension after analgesia (%) (BP ≥ 160/110 mm Hg) ||< 1% ||1% ||NS |
For these reasons, judicious fluid administration is essential in severely preeclamptic women who receive regional analgesia. Newsome and coworkers (1986) showed that vigorous crystalloid infusion with epidural blockade in women with severe preeclampsia caused elevation of pulmonary capillary wedge pressures (see Fig. 40-6). Aggressive volume replacement in these women increases their risk for pulmonary edema, especially in the first 72 hours postpartum (Clark, 1985; Cotton, 1986a). When pulmonary edema develops, there is also concern for development of cerebral edema. Finally, Heller and associates (1983) demonstrated that most cases of pharyngolaryngeal edema were related to aggressive volume therapy.
Persistent Severe Postpartum Hypertension
The potential problem of antihypertensive agents causing serious compromise of uteroplacental perfusion and thus of fetal well-being is obviated by delivery. Postpartum, if difficulty arises in controlling severe hypertension or if intravenous hydralazine or labetalol are being used repeatedly, then oral regimens can be given. Examples include labetalol or another β-blocker, nifedipine or another calcium-channel blocker, and possible addition of a thiazide diuretic. Persistent or refractory hypertension is likely due to mobilization of pathological interstitial fluid and redistribution into the intravenous compartment, underlying chronic hypertension, or usually both (Sibai, 2012; Tan, 2002). In women with chronic hypertension and left-ventricular hypertrophy, severe postpartum hypertension can cause pulmonary edema from cardiac failure (Cunningham, 1986, 2012; Sibai, 1987a).
Because persistence of severe hypertension corresponds to the onset and length of diuresis and extracellular fluid mobilization, it seems logical that furosemide-augmented diuresis might serve to hasten blood pressure control. To study this, Ascarelli and coworkers (2005) designed a randomized trial that included 264 postpartum preeclamptic women. After onset of spontaneous diuresis, patients were assigned to 20-mg oral furosemide given daily or no therapy. Women with mild disease had similar blood pressure control regardless of whether they received treatment or placebo. However, women with severe preeclampsia who were treated, compared with those receiving placebo, had a lower mean systolic blood pressure at 2 days—142 versus 153 mm Hg. They also required less frequently administered antihypertensive therapy during the remainder of hospitalization—14 versus 26 percent, respectively.
We have used a simple method to estimate excessive extracellular/interstitial fluid. The postpartum weight is compared with the most recent prenatal weight, either from the last clinic visit or on admission for delivery. On average, soon after delivery, maternal weight should be reduced by at least 10 to 15 pounds depending on infant and placental weight, amnionic fluid volume, and blood loss. Because of various interventions, especially intravenous crystalloid infusions given during operative vaginal or cesarean delivery, women with severe preeclampsia often have an immediate postpartum weight in excess of their last prenatal weight. If this weight increase is associated with severe persistent postpartum hypertension, then diuresis with intravenous furosemide is usually helpful in controlling blood pressure.
Martin and colleagues (1995) have described an atypical syndrome in which severe preeclampsia-eclampsia persists despite delivery. These investigators described 18 such women whom they encountered during a 10-year period. They advocate single or multiple plasma exchange for these women. In some cases, 3 L of plasma was exchanged three times—a 36- to 45-donor unit exposure for each patient—before a response was forthcoming. Others have described plasma exchange performed in postpartum women with HELLP syndrome (Förster, 2002; Obeidat, 2002). In all of these cases, however, the distinction between HELLP syndrome and thrombotic thrombocytopenic purpura or hemolytic uremic syndrome was not clear. As further discussed in Chapter 56 (Thrombotic Microangiopathies), in our experiences with more than 50,000 women with gestational hypertension among nearly 450,000 pregnancies cared for at Parkland Hospital through 2012, we have encountered very few women with persistent postpartum hypertension, thrombocytopenia, and renal dysfunction who were diagnosed as having a thrombotic microangiopathy (Dashe, 1998). These latter syndromes complicating pregnancy were reviewed by Martin (2008) and George (2013) and their colleagues, who conclude that a rapid diagnostic test for ADAMTS-13 enzyme activity might be helpful to differentiate most of these syndromes.
Reversible Cerebral Vasoconstriction Syndrome
This is another cause of persistent hypertension, “thunderclap” headaches, seizures, and central nervous system findings. It is a form of postpartum angiopathy. As shown in Figure 40-24, it is characterized by diffuse segmental constriction of cerebral arteries and may be associated with ischemic and hemorrhagic strokes. The reversible cerebral vasoconstriction syndrome has several inciting causes that include pregnancy, and particularly preeclampsia (Ducros, 2012). It is more common in women, and in some cases, vasoconstriction may be so severe as to cause cerebral ischemia and infarction. The appropriate management is not known at this time (Edlow, 2013).
Reversible cerebral vasoconstriction syndrome. Magnetic resonance angiography shows generalized vasoconstriction of the anterior and posterior cerebral circulation (arrows). (From Garcia-Reitboeck, 2013, with permission.)