Early Diagnosis and Evaluation

Traditionally, the frequency of prenatal visits is increased during the third trimester and this facilitates early detection of preeclampsia. Women with overt new-onset hypertension – 140/90 mm Hg or greater – are frequently admitted to the hospital for 2 to 3 days primarily to determine whether the rise in pressure is due to preeclampsia, and if so to evaluate its severity. Women with persistent severe disease are observed closely, and many are delivered. Conversely, women with apparently mild disease especially if remote from term may be carefully managed as outpatients.

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:

• 1.
  

  Detailed examination followed by daily scrutiny for clinical findings such as headache, visual disturbances, epigastric pain, and rapid weight gain.

  
  
• 2.
  

  Weight on admittance and daily thereafter.

  
  
• 3.
  

  Analysis for proteinuria on admittance and at least every 2 days thereafter.

  
  
• 4.
  

  Blood pressure readings in the sitting position with an appropriate-size cuff every 4 hours, except during normal sleeping hours.

  
  
• 5.
  

  Measurements of plasma or serum creatinine and liver enzymes, and hemogram to include platelet quantification. The frequency of testing is determined by the severity of hypertension. Some recommend measurement of serum uric acid and lactic acid dehydrogenase levels as well as coagulation studies, but some investigations have called into question the value of these tests.

  
  
• 6.
  

  Frequent evaluation of fetal size and well-being and amniotic fluid volume either clinically or using sonography.

Goals of such management include early identification of worsening preeclampsia and the development of a management plan for obstetrical care which includes a plan for timely delivery. If any of these observations leads to a diagnosis of severe preeclampsia, further management is the same as described subsequently for eclampsia.

Hospitalization Versus Outpatient Management

For women with non-severe stable hypertension – whether or not preeclampsia has been confirmed – continued surveillance either in hospital, or at home for reliable patients, or through a day-care unit is carried out. At least intuitively, reduced physical activity throughout much of the day seems beneficial, but absolute bed rest is unnecessary and it may predispose to venous thromboembolism. A number of observational studies as well as randomized trials have addressed the benefits of inpatient care as well as outpatient management to include day-care unit observation and these are subsequently discussed. Somewhat related, Abenhaim et al. conducted a retrospective cohort study of 677 women hospitalized for bed rest because of threatened preterm delivery. When outcomes of these women were compared with their general obstetrical population, bed rest was associated with a significantly reduced risk of developing preeclampsia – RR 0.27 (0.16–0.48). In a review of two small randomized trials totaling 106 women, prophylactic bed rest 4–6 hours daily at home in women at high risk of preeclampsia was successful in lowering the incidence of preeclampsia, but not gestational hypertension. These and other observations support the claim that restricted activity alters the underlying pathophysiology of the preeclampsia syndrome.

Many cases of new-onset hypertension, either with or without proteinuria, prove to be sufficiently mild and have an onset near enough to term that they can be managed conservatively until labor commences spontaneously or until the cervix becomes favorable for labor induction. Complete abatement of all signs and symptoms, however, is uncommon until after delivery. Almost certainly, the underlying disease persists until after delivery .

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 18 while the pharmacology and use during pregnancy of specific antihypertensive drugs are discussed in Chapter 19 .

Drug treatment for early mild preeclampsia has been disappointing, as shown in representative studies listed in Table 20.3 . Sibai et al. performed a randomized study to evaluate the effectiveness of labetalol and hospitalization compared with hospitalization alone. They evaluated 200 nulliparous women with preeclampsia diagnosed between 26 and 35 weeks. 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 birth weight. The cesarean delivery rates were similar, as were the numbers of infants admitted to special-care nurseries. It was problematic that growth-restricted infants were twice as frequent in women given labetalol compared with those treated by hospitalization alone – 19 versus 9% .

The three other studies listed in Table 20.3 were performed to compare the beta-blocking agent, labetalol, or calcium-channel blockers, nifedipine and isradipine, with placebo. In none of these studies were any benefits of antihypertensive treatment shown. Von Dadelszen et al. performed a meta-analysis that included the aforementioned trials for the purpose of determining the relation between fetal growth and antihypertensive therapy, and this is further analyzed in the systematic review undertaken in Chapter 19 . Von Dadelszen et al. concluded that treatment-induced decreases in maternal blood pressure may adversely affect fetal growth.

Abalos et al. performed a literature search for randomized trials of active antihypertensive therapy compared with either no treatment or placebo given to women with mild to moderate gestational hypertension. They included a total of 46 trials (4282 women) in their analysis, which is summarized in Table 20.4 . As seen, except for a halving of the risk of developing severe hypertension, active antihypertensive therapy had no beneficial effects. Importantly, fetal-growth restriction was not increased in the treated women. These issues are further discussed in Chapter 19 .

Indications for Delivery

Delivery is the only current cure known for preeclampsia. Headache, visual disturbances, or epigastric pain are indicative that convulsions may be imminent, and oliguria is another ominous sign. Most clinicians manage severe preeclampsia with prophylactic anticonvulsant magnesium sulfate infusion. Antihypertensive therapy is given to lower dangerously elevated blood pressure. 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 infant.

At term, delivery is typically indicated as opposed to the preterm gestation where temporizing measures are often employed. Exactly when to temporize versus facilitate delivery is not agreed upon, however, and this has not been well studied. The HYPITAT trial demonstrated improved maternal outcome with induction of women with mild preeclampsia beyond 37 weeks in a randomized controlled trial. Tavik et al. later published a secondary analysis from the same trial showing that this improvement in maternal outcome occurred with induction even if the cervix was unfavorable. For women with a late preterm gestation, the decision to deliver is not clear. Barton et al. reported excessive neonatal morbidity in women delivered before 38 weeks despite having stable, mild nonproteinuric hypertension. The Netherlands study of 4316 infants delivered between 34 ^0/7 and 36 ^6/7 weeks also described substantive neonatal morbidity. When the decision has been made to delay delivery because of prematurity, the hope is that a few more weeks in utero will reduce the risk of neonatal death or serious morbidity. Such a policy certainly is justified with non-severe hypertension. Assessments of fetal well-being and placental function are carried out, especially when there is hesitation to deliver the fetus preterm. Most investigators recommend frequent performance of various tests currently used to assess fetal well-being as described by the American College of Obstetricians and Gynecologists. These include the nonstress test or the biophysical profile . Measurement of the lecithin:sphingomyelin ratio in amniotic fluid will provide evidence of lung maturity in cases with unsure gestational dating.

With moderate or severe preeclampsia that does not improve after hospitalization, delivery is usually advisable for the welfare of both mother and fetus. Often labor is induced with intravenous oxytocin, usually along with cervical ripening techniques such as a prostaglandin or osmotic dilator. Whenever it appears that labor induction almost certainly will not succeed, or attempts at induction have failed, cesarean delivery is indicated. There is no evidence that failed efforts at induction followed by cesarean delivery are harmful to low-birthweight infants.

Delayed Delivery with Early-Onset Preeclampsia

In the past, all women with severe preeclampsia were usually delivered without delay. Over the past 25 years, a different approach for women with severe preeclampsia remote from term has been advocated. This calls for conservative or “expectant” management in a selected group of women with the aim of improving neonatal outcome without compromising the safety of the mother. Aspects of such conservative management always include careful daily – and usually more frequent – monitoring of the pregnancy in the hospital, with or without use of drugs to control hypertension.

Theoretically, antihypertensive therapy has potential application when preeclampsia severe enough to warrant termination of pregnancy develops before neonatal survival is likely. The caveat is that such management is controversial, and it may be catastrophic. In an early study, the Memphis group attempted to prolong pregnancy because of fetal immaturity in 60 women with severe preeclampsia diagnosed between 18 and 27 weeks. The total perinatal mortality rate was 87%, and although no mother 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 .

Later, the Memphis group redefined their study criteria and performed a randomized trial of expectant versus aggressive management of 95 women who had severe preeclampsia but with more advanced gestations of 28 to 32 weeks. 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 to control severe hypertension. Pregnancy was prolonged for a mean of 15.4 days in the expectant management group with an overall improvement in neonatal outcomes.

Following these experiences, expectant management became more commonly practiced but women with HELLP syndrome or growth-restricted fetuses were usually excluded. In a follow-up observational study, the Memphis group compared outcomes for 133 women with HELLP syndrome and infants delivered between 24 and 36 weeks with 136 women with severe preeclampsia but no HELLP criteria. Women with HELLP syndrome were subdivided into three study groups. The first group included those with hemolysis, elevated liver enzymes, and low platelets. The second included those with partial HELLP syndrome – this was defined as either one or two, but not three, of these laboratory findings. The third group included women who had severe preeclampsia without any of the accoutrements of the HELLP syndrome. Perinatal outcomes were similar in each group and this led the investigators to conclude that women with partial HELLP syndrome, as well as those with severe preeclampsia alone, could be managed expectantly. They also concluded that infant outcomes were related to gestational age rather than the hypertensive disorder per se.

Women in the Abramovici study were indeed severely hypertensive and had mean diastolic blood pressures of 110 mm Hg. The distinguishing feature between those with complete and those with partial HELLP syndrome appears to be the platelet count – the mean value was 52,000/μL in women with complete HELLP syndrome compared with 113,000/μL in those with partial HELLP syndrome. Gestational ages at delivery were about 2 weeks more advanced in women with severe preeclampsia alone compared with those with some degree of HELLP syndrome. Accordingly, neonatal outcomes, in terms of need for mechanical ventilation and neonatal death, were better in women with severe preeclampsia alone. Fetal-growth restriction was not related to the severity of maternal disease and was prevalent in all three groups. Maternal morbidity was not described. A most important observation was that the median elapsed time from admission to delivery was 0, 1, and 2 days for women with HELLP syndrome, partial HELLP syndrome, or severe preeclampsia, respectively. Later reports describing this cohort indicated that growth restriction adversely affected survival in infants from that institution.

Sibai and Barton reviewed most reports since the early 1990s of expectant management of women with severe preeclampsia with early onset from 24 to 34 weeks gestation. Some of these studies, as well as those published since 2005, are shown in Table 20.5 . While the average time gained ranged from 5 to 10 days, maternal morbidity was formidable and included placental abruption, HELLP syndrome, pulmonary edema, renal failure, and eclampsia. Moreover, perinatal mortality averaged from 15 to 480 per 1000. Fetal-growth restriction was common, and in the study from the Netherlands it was an astounding 94%. Perinatal mortality is disproportionately high in these growth-restricted infants, but maternal outcomes are not appreciably different from those in women without growth-restricted fetuses. Barber et al. provided a 10-year review of 3408 women with severe preeclampsia from 24 to 28 weeks who had been entered into the California vital statistics database. They found correlation between increased lengths of stay and increased rates of both maternal and neonatal morbidity.

Expectant Management of Midtrimester Severe Preeclampsia

A number of small studies have focused on expectant management of the severe preeclampsia syndrome before 28 weeks. In their review, Bombrys et al. found eight such studies, which included a total of nearly 200 women with severe preeclampsia from less than 24 to 26 completed weeks. Maternal complications were common and there were no infant survivors in those less than 23 weeks, and the authors recommend pregnancy termination for these. For those at 23 weeks, perinatal survival was 18% but morbidity was unknown. For those at 24–26 weeks, perinatal survival approaches 60%, and it averaged almost 90% for those at 26 weeks. Results from five studies published since 2005 are shown in Table 20.6 . Again, there are extraordinarily high maternal and perinatal morbidity and mortality rates in these extremely preterm pregnancies. At this time, there are inadequate contemporaneous comparative studies attesting to the perinatal benefits of such expectant treatment versus early delivery in the face of serious maternal complications that approach 50%. Thus, the caveat for detailed maternal counseling is repeated here. The 2013 Task Force supports these findings and recommended that a fetus that is<23 weeks gestation be considered previable and that women with severe preeclampsia be delivered.

Table 20.6

Maternal and Perinatal Outcomes with Expectant Management in Women with Midtrimester Severe Preeclampsia

Study	No.	Maternal Complications (%)	Perinatal Mortality (%)
Hall et al.	8	36	88
Gaugler-Senden et al.	26	65 *	82
Budden et al.	31	71	71
Bombrys et al.	46	38–64	43
Belghiti et al.	51	43	58
Weighted average	152	55	61

 

* One maternal death.

Glucocorticoids

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 have been cited. That said, we are aware of only one randomized trial of corticosteroids given to hypertensive women for fetal lung maturation. This trial included 218 women with severe preeclampsia between 26 and 34 weeks who were randomly assigned to be given betamethasone or placebo. Neonatal complications, including respiratory distress, intraventricular hemorrhage, and death, were decreased significantly when betamethasone was given compared with placebo. But 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.

Corticosteroids to Ameliorate HELLP Syndrome

Over 20 years ago, Thiagarajah et al. suggested that glucocorticoids might also play a role in treatment of the laboratory abnormalities associated with the HELLP syndrome. Subsequent investigators, however, reported less than salutary effects. Investigators at the University of Mississippi have been the staunchest advocates of corticosteroids to treat HELLP syndrome. Martin et al. reviewed outcomes of almost 500 such women. From 1994 to 2000, 90% were treated, and their outcomes considered more favorable than the cohort from 1985 to 1991, during which time only 16% were treated with steroids. Their randomized trial, while comparing two corticosteroid compounds, did not include a nontreated group. There have since been at least two prospective randomized studies designed to address this and they are summarized in Table 20.7 . Fonseca et al. from Cali, Columbia, randomized 132 women with HELLP syndrome to blinded treatment with either dexamethasone or placebo. Outcomes assessed included duration of hospitalization, time to recovery for abnormal laboratory tests, recovery of clinical parameters, and complications. None of these was statistically different between the two groups. In a similar blinded study Katz et al. randomized 105 postpartum women with HELLP syndrome to dexamethasone versus placebo. They analyzed outcomes similar to the Cali study and found no advantage to dexamethasone to hasten recovery ( Table 20.7 ). Shown in Fig. 20.1 are recovery times for platelet counts and serum AST and LDH levels in the Katz study. The responses are almost identical in women receiving the corticosteroid compared with those receiving placebo. The 2013 Task Force does not recommend use of corticosteroids to treat women with HELLP syndrome.

Table 20.7

Randomized Clinical Trials of Intravenous Dexamethasone Versus Placebo for Women with Severe Preeclampsia with HELLP Syndrome

Study	No.	Before Treatment a			Maternal Outcomes (%) a
		Platelets (10 /μL)	AST (U/L)	LDH (U/L)	ARF	Pulmonary Edema	Eclampsia	Death
Fonseca et al.	132 b
Dexamethasone	66	61±19	573±621	2124±1849	10	4.6	14	4.6
Placebo	66	58±21	492±579	2242±1671	13	1.5	15	1.5
Katz et al.	105 c
Dexamethasone	56	91±45	155±241	1103±1500	16.1	3.6	14	3.6
Placebo	49	95±57	240±371	1020±1282	24.5	10.2	25	4.1

 

HELLP=Hemolysis, Elevated Liver enzymes, Low Platelets; AST=aspartate transferase; LDH=lactate dehydrogenase; ARF=acute renal failure.

a All comparisons p >0.05.

b Includes 60 antepartum, 72 postpartum.

c All postpartum.

Serial laboratory values from initiation of therapy – dexamethasone versus placebo – in women with HELLP syndrome.

(From Katz et al. , with permission.)

Risks Versus Benefits – Recommendations

Taken in toto , these studies do not show overwhelming evidence of favorable risk-versus-benefits of expectant management of severe preeclampsia from 24 to 32 weeks. The Society of Maternal Fetal Medicine as well as the 2013 Task Force have determined that such management is a reasonable alternative in selected women with severe preeclampsia before 34 weeks. As shown in Table 20.8 , this type of management calls for in-hospital maternal and fetal surveillance with delivery prompted by evidence of worsening severe preeclampsia or maternal or fetal compromise. While attempts are made for vaginal delivery in most cases, the likelihood of cesarean delivery increases with decreasing gestational age.

Table 20.8

Indications for Delivery in Women with Severe Preeclampsia *

Maternal

Persistent severe headache or visual changes; eclampsia

Shortness of breath; chest tightness with rales and/or SaO 2 <94% breathing room air; pulmonary edema

Uncontrolled severe hypertension despite treatment

Oliguria<500 mL/24 hr or serum creatinine≥1.5 mg/dL

Persistent platelet counts<100,000/μL

Suspected abruption, progressive labor, and/or ruptured membranes

Fetal

Severe growth restriction –<5th percentile for EGA

Persistent severe oligohydramnios – AFI<5 cm

Biophysical profile≤4 done 6 hours apart

Reversed end-diastolic umbilical artery flow

Fetal death

 

AFI=amniotic fluid index.

From Sibai and Barton.

* Indications represent recommendations of the article’s authors and are not society guidelines.

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 20.8 . Notably, placental abruption develops in up to 20% and pulmonary edema in up to 4%. Moreover, there are substantive risks for eclampsia, cerebrovascular hemorrhage, and maternal death. These observations are especially pertinent when considered along with the absence of convincing evidence that perinatal outcomes are markedly improved by the average prolongation of pregnancy of about 1 week. If expectant management is undertaken, the caveats from the Society for Maternal Fetal Medicine and those shown in Table 20.8 should be strictly heeded. Thus, indications for delivery include worsening symptoms or hypertension; eclampsia, abruption, or pulmonary edema; renal dysfunction or oliguria; HELLP syndrome; fetal growth restriction, oligohydramnios, or other evidence of fetal compromise; and a gestational age of 34 weeks.