Pre‐eclampsia is a multi‐system disorder characterized by the new onset of hypertension and proteinuria and/or end‐organ dysfunction after 20 weeks in a patient who was previously noted to be normotensive. Patients diagnosed with this condition are at increased risk for maternal and/or fetal mortality or serious morbidity. Patients often present with symptoms of persistent headaches, visual changes, peripheral edema of upper and lower extremities, and possible right upper quadrant pain. Current criteria for the diagnosis of pre‐eclampsia involves the association of sustained hypertensive blood pressure associated with thrombocytopenia, altered liver function, the new development of renal insufficiency, pulmonary edema, or new onset cerebral or visual changes. Pre‐eclampsia can be diagnosis with and without severe features and terminology such as “mild pre‐eclampsia” should no longer be used in clinical practice (Table 25.1). It is important to note that recent American College of Obstetricians and Gynecologists (ACOG) criteria [1] for the diagnosis of severe disease has removed proteinuria as an essential feature. Additionally, other notable changes include that fact that they have removed proteinuria >5 g day⁻¹ and fetal growth restriction as criteria for the diagnosis of severe disease. Finally, oliguria is no longer used as a factor indicative of severe pre‐eclampsia.

The prevalence of pre‐eclampsia in the United States is about 3.4%, but 1.5‐fold to 2‐fold higher in first pregnancies. The age‐period‐cohort analysis showed a strong age effect, with women at the extremes of maternal age having the greatest risk of pre‐eclampsia [2]. Late onset disease (≥34 weeks) is more prevalent than early onset disease (<34 weeks) in one population‐based study: 2.7% versus 0.3%, respectively). Also, as expected in this dataset it was noted that women with early‐onset and late‐onset pre‐eclampsia have significantly higher rates of specific maternal morbidity compared with women without early‐onset and late‐onset disease. Maternal death rates were higher among women with early‐onset (42.1/100 000 deliveries) and late‐onset pre‐eclampsia (11.2/100 000) compared with women without pre‐eclampsia (4.2/100 000) [3]. Along with hemorrhage, cardiovascular conditions, and thromboembolism, pre‐eclampsia in one of the four leading causes of maternal death in the United States [4]. Women with pre‐eclampsia are at increased risk for developing multiple life threatening complications including but not limited to: eclampsia, coagulopathy, placental abruption, hemorrhage, acute kidney damage, liver failure, hepatic capsular rupture, pulmonary edema and cardiovascular collapse, and cerebral hemorrhage. Atypical presentation of pre‐eclampsia includes: onset of symptoms prior to 20 weeks gestation, hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome patients (i.e. HELLP is an acronym that refers to a syndrome characterized by Hemolysis with a microangiopathic blood smear, Elevated Liver enzymes, and a Low Platelet count), or delayed postpartum onset after 48 hours postpartum. Pre‐eclampsia prior to 20 weeks gestation is often due to a molar gestation (i.e. complete or partial) or associated with a preexisting medical condition (e.g. lupus nephritis, thrombotic thrombocytopenic purpura, hemolytic‐uremic syndrome, antiphospholipid syndrome, acute fatty liver of pregnancy). The precise criteria for HELLP are necessary for predicting maternal complication and current ACOG guidelines have adopted the Tennessee classification [5]. It requires the presence of all of the following criteria to diagnose HELLP: (i) microangiopathic hemolytic anemia with characteristic schistocytes (also called helmet cells) on blood smear. Other signs suggestive of hemolysis include an elevated indirect bilirubin level and a low serum haptoglobin concentration (≤25 mg dl⁻¹); (ii) platelet count ≤100 000 cells/microl, (iii) total bilirubin ≥1.2 mg dl⁻¹ (20.52 μmol l⁻¹); and (iv) serum aspartate aminotransferase (AST) >2 times upper limit of normal for local laboratory (usually >70 international units l⁻¹). Alanine aminotransferase (ALT) levels may be used instead of, or in addition to, AST levels. An advantage of the AST is that it is a single test that reflects both hepatocellular necrosis and red cell hemolysis. Hypertension (blood pressure ≥140/90 mmHg) and/or proteinuria are present in approximately 85% of cases, but they may be absent in women with otherwise severe HELLP syndrome [6]. The most common definition for delayed postpartum pre‐eclampsia can be defined as signs and symptoms of the disease often leading to readmission greater than two days but prior to six weeks after delivery. In a recent retrospective cohort study of patients who were discharged and later readmitted with the diagnosis of delayed postpartum pre‐eclampsia (more than two days to six weeks or less after delivery) the authors noted that 96 (63.2%) patients had no antecedent diagnosis of hypertensive disease in the current pregnancy. Twenty‐two patients (14.5%) developed postpartum eclampsia, and more than 90% of these patients presented within seven days after discharge from the hospital. The most common presenting symptom was headache in 105 (69.1%) patients. This study highlights the fact that education about the possibility of delayed postpartum pre‐eclampsia and eclampsia should occur after delivery, whether or not patients develop hypertensive disease before discharge from the hospital [7].

In a recent meta‐analysis of patients with prior history of pre‐eclampsia it was noted that data showed that 20.7% of patients developed hypertensive disorder in a subsequent pregnancy. Recurrence manifested as pre‐eclampsia in 13.8% of the studies (95% confidence interval (CI),13.6–14.1%), gestational hypertension in 8.6% of the studies (95% CI, 8.4–8.8%) and HELLPs syndrome in 0.2% of the studies (95% CI, 0.16–0.25%). Recurrence increased with decreasing gestational age at delivery in the index pregnancy. If the hypertensive disorder of pregnancy recurred, in general it was milder, regarding maximum diastolic blood pressure, proteinuria, the use of oral antihypertensive and anticonvulsive medication, the delivery of a small‐for‐gestational‐age child, premature delivery, and perinatal death [8]. Women with pregnancies complicated by either pre‐eclampsia, growth restriction, preterm delivery, abruptio placentae, and/or stillbirth can all be sequelae of impaired placental function are at increased risk of developing one of the other disorders in future pregnancies. It is interesting to note that early onset pre‐eclampsia is more likely to be associated with one of these adverse events in a subsequent pregnancy, even if normotensive, than late onset pre‐eclampsia [9]. Most available evidence does not support an association between inherited thrombophilia and pre‐eclampsia and screening for these conditions is not advised at this time [10, 11]. However, based upon the Sydney criteria for the diagnosis of Antiphospholipid Antibody Syndrome, screening for antiphospholipid antibodies is reasonable in the setting of ≥1 preterm deliveries of a morphologically normal infant before 34 weeks of gestation due to severe pre‐eclampsia, eclampsia, or features consistent with placental insufficiency. The three main types of antiphospholipid antibodies (aPL) of concern to obstetricians are lupus anticoagulants (LAs), anticardiolipin antibodies (aCL), and anti‐beta‐2‐glycoprotein‐1 antibodies. Other antibody specificities have been proposed, but have not proven to be predictive in clinical studies [12]. No test performed in early pregnancy performs clinically well enough for selecting women who are likely to develop pre‐eclampsia in current practice. Low‐dose aspirin (60–81 mg) daily is the only drug for which there is some evidence of benefit in reducing the risk of pre‐eclampsia when administered throughout the second and third trimesters to women at high risk for developing the disease. For women at low risk for development of pre‐eclampsia, available evidence does not support use of low‐dose aspirin for prevention of pre‐eclampsia, but a modest (approximately 10%) reduction in the risk of pre‐eclampsia and its sequelae (growth restriction, preterm birth) is possible for women at moderate to high risk of developing the disease. US Preventive Services Task Force (USPSTF) criteria for high risk include: Previous pregnancy with pre‐eclampsia, especially early onset and with an adverse outcome, multifetal gestation, chronic hypertension, Type 1 or 2 diabetes mellitus, renal disease, autoimmune disease (antiphospholipid syndrome, systemic lupus erythematosus) USPSTF criteria for moderate risk include: nulliparity, obesity (BMI >30 kg m⁻²), family history of pre‐eclampsia in mother or sister, age ≥35 years, sociodemographic characteristics (African‐American, low socioeconomic level), personal risk factors (e.g. history of low birthweight or small for gestational age (SGA), previous adverse pregnancy outcome, >10 year pregnancy interval) [13]. Treatment is begun at 12 weeks of gestation, however, adverse effects from earlier initiation (e.g. preconception) have not been reported.

Gestational hypertension (aka pregnancy induced hypertension) has been defined as hypertension without proteinuria or other signs/symptoms of pre‐eclampsia that develops after 20 weeks of gestation. This state does not persist after 12 weeks postpartum and is regarded as a transient state. While this diagnosis may often be benign with usually a high successful pregnancy outcome, this entity can worsen to severe blood pressure elevations or even progress to fulfill criteria for pre‐eclampsia. Therefore, even when blood pressure elevations are noted to be mild enhanced surveillance is indicated. Ten to 50% of women initially diagnosed with gestational hypertension go on to develop pre‐eclampsia in one to five weeks [14]. Clinical risk factors associated with increased risk for progression include: diagnosis prior to 34 weeks gestation, mean systolic blood pressure of >135 mmHg on 24 hour blood pressure monitoring, abnormal uterine artery Doppler velocimetry, and/or elevated uric acid levels >5.2 mg dl⁻¹ [15, 16]. Management of women with preterm gestational hypertension is controversial as it balances maternal and fetal morbidities. The HYPITAT‐II trial from the Netherlands attempted to address this question by randomly assigning 703 women with non‐severe hypertensive disorders of pregnancy at 34–36^6/7 weeks to delivery within 24 hours of diagnosis(n = 352) or to expectant management (n = 351) with delivery at 37 weeks or upon development of features of severe pre‐eclampsia. The composite adverse maternal outcome (thromboembolic complications, HELLP syndrome, eclampsia, placental abruption) occurred in four (1.1%) of 352 women allocated to immediate delivery versus 11 (3.1%) of 351 women allocated to expectant monitoring (relative risk [RR] 0.36, 95% CI 0.12–1.11; p = 0.069). However, immediate delivery resulted in more cases of neonatal respiratory distress syndrome (5.7% versus 1.7%) [17]. Based upon this data and others we advise close monitoring of pregnancies with non‐severe gestational hypertension and manage these patients expectantly as outpatient and deliver them when their clinical situation deteriorates or at term as consistent with ACOG guidelines [18]. Recently, the Antenatal Late Preterm Steroids (ALPSs) Trial randomly assigned women at 34–36^5/7 weeks of gestation at high risk for late preterm birth to receive a first course of antenatal betamethasone or placebo and found that the frequency of a composite outcome of neonatal respiratory problems was reduced in the betamethasone group [19]. Based on these data, we believe offering a first course of antenatal corticosteroids to patients diagnosed with gestational hypertension between 34 and 37 weeks may be considered and should be individualized based on severity of blood pressure and other comorbidities. We generally perform twice weekly antepartum visits with antenatal testing, our preferred test of choice is the sonographic portion of the biophysical profile with reflex nonstress test (NST) testing as indicated [20]. We instruct patients to promptly report any symptoms suggestive of pre‐eclampsia (headache, visual changes, epigastric, or right upper quadrant pain). We also review signs suggestive of possible fetal impairment, such as decreased fetal movement and vaginal bleeding, and signs of preterm labor. Women may maintain most of their normal physical activities but advise against exercise. We do not prescribe antihypertensive drugs for treatment of gestational hypertension unless hypertension is severe (systolic >160 mmHg or diastolic >110 mmHg) at which point these patients are generally hospitalized and delivered if >34 weeks. For those pregnancies <34 weeks administration of antenatal steroids, and in the hospital monitoring is a reasonable approach. Patients who develop pre‐eclampsia or have abnormal results on antepartum fetal testing are managed according to usual standards for these pregnancy complications. Additionally, this condition may also be a harbinger for future development of chronic hypertension in the nonpregnant state later on in life, and therefore is a useful marker for follow‐up and preventative medicine decisions.

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