Hypertensive Disorders of Pregnancy

PREECLAMPSIA/ECLAMPSIA

Preeclampsia is a syndrome unique to pregnancy, characterized by the new onset of hypertension and proteinuria in the latter half of gestation. Preeclampsia is classically considered to be a disease affecting the first pregnancy, but it also occurs in multiparas, especially if there are predisposing risk factors such as twins, diabetes mellitus, chronic hypertension, or a change in husband/partner. When it arises in the early second trimester (14 to 20 weeks), a hydatidiform mole or choriocarcinoma should be considered.

The following two criteria are essential for the diagnosis of preeclampsia: (1) the development of hypertension (systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg), in a woman whose blood pressures were previously normal, after the 20th week of pregnancy; (2) the development of new-onset proteinuria after the 20th week of gestation. Proteinuria is defined as more than or equal to 0.3 g protein in a timed 24-hour urine collection. This usually correlates with a urinalysis report of 30 mg/dL (1+ on dipstick) or greater on a clean-catch urine sample.

In the past, a 30-mm Hg rise in systolic blood pressure or a 15-mm Hg rise in diastolic pressure was considered a sign of preeclampsia. Because of the previously described physiologic rise in blood pressure during the third trimester and the frequent lack of accurate prepregnant blood pressures for use as a baseline, this rise is no longer considered diagnostic if the blood pressure remains under 140/90 mm Hg. Despite this, rising blood pressures should be of concern because they may precede the development of the full preeclampsia syndrome. Similarly, preeclampsia is often preceded by, or associated with, the development of generalized edema. Dependent edema (edema of the lower extremities) is very common in normal pregnancies. Hand and facial edema are more likely to be associated with preeclampsia, but if unaccompanied by hypertension and proteinuria, they are not diagnostic of the preeclampsia syndrome.

Preeclampsia is divided into mild and severe forms, depending on the severity of the hypertension, the amount of proteinuria, and the degree to which other organ systems are affected. Box 14-2 lists specific criteria for the diagnosis of severe preeclampsia. If any of the symptoms, signs, or laboratory abnormalities listed in Box 14-2 is present in a woman with preeclampsia, it is very likely that she has severe disease, which is associated with much greater maternal and perinatal morbidity.

A variant of severe preeclampsia with particularly high morbidity is the HELLP syndrome. This syndrome occurs in preeclamptic women with evidence of hemolysis, elevated liver enzymes, and low platelets (thrombocytopenia). In contrast to more typical presentations of preeclampsia, the patient with HELLP syndrome is more likely to be multiparous, older than 25 years, and at less than 36 weeks’ gestation. Hypertension may be initially absent in 20% of the patients, whereas 30% will have mild elevations in blood pressure, and 50% will have severe elevations.

ECLAMPSIA

Eclampsia is the presence of tonic-clonic seizures in a woman with preeclampsia that cannot be attributed to other causes. Patients with severe preeclampsia are at the greatest risk for developing seizures, but the seizures can occur in so-called mild preeclamptic patients. Eclamptic seizures can also occur before the development of classic signs of preeclampsia. There is a wide range in the reported frequency and timing of eclamptic seizures. Clinical practices, including the use of magnesium sulfate intrapartum and postpartum for seizure prophylaxis in women with preeclampsia, as well as the timely recognition and delivery of women with severe preeclampsia, undoubtedly influence these numbers. In a recent review of this subject, 38% to 53% of eclamptic seizures occurred before labor, 18% to 36% occurred during labor, and 11% to 44% occurred after delivery (usually within the first 24 to 48 hours postpartum). When evaluating atypical cases of eclampsia (i.e., more than 48 hours postpartum or previous evidence of only mild disease) it is important to consider other causes of seizures such as underlying seizure disorder, hypertensive encephalopathy, metabolic abnormalities including hypoglycemia and hyponatremia, and CNS hemorrhage, thrombosis, mass, or infection.

CHRONIC HYPERTENSION

The diagnosis of chronic hypertension requires at least one of the following: known hypertension before pregnancy, development of hypertension before 20 weeks’ gestation, or, in cases in which hypertension is first noted during pregnancy, persistence of elevated blood pressures greater than 12 weeks’ postpartum.

Most pregnant women with chronic hypertension have essential hypertension, but a small percentage have secondary hypertension due to renal, vascular, endocrine, or behavioral causes (e.g., methamphetamine and cocaine use). Most of these conditions can be suspected on the basis of a thorough history and physical examination. Certain endocrine disorders, in particular hyperthyroidism, may present for the first time during pregnancy. Depending on the associated symptoms, signs, and response to medication, a workup to determine the etiology of the hypertension may be indicated. It is not uncommon for the physiologic stress of pregnancy to cause subclinical vascular or renal disease to become manifest. In these situations, it may be very difficult to differentiate between preeclampsia and an aggravated chronic hypertensive condition. Sometimes only careful follow-up postpartum will indicate the correct diagnosis.

CHRONIC HYPERTENSION WITH SUPERIMPOSED PREECLAMPSIA

Preeclampsia may become superimposed on chronic hypertensive disease. Superimposed preeclampsia can be very difficult to distinguish from poorly controlled chronic hypertension, especially if the woman is not seen until after the 20th week of gestation, but the two conditions are managed differently. In general, superimposed preeclampsia carries a worse prognosis than does either condition alone.

The diagnosis of superimposed preeclampsia should be reserved for those women with chronic hypertension who develop new-onset proteinuria (≥0.3 g in a 24-hour collection) after the 20th week of gestation. In pregnant women with preexisting hypertension and proteinuria, the diagnosis of superimposed preeclampsia should be considered if they experience sudden significant increases in blood pressure or proteinuria or any of the other signs and symptoms consistent with severe preeclampsia listed in Box 14-2, including thrombocytopenia or abnormally elevated liver enzymes.

GESTATIONAL HYPERTENSION

The diagnosis of gestational hypertension is made if hypertension without proteinuria first appears after 20 weeks’ gestation or within 48 to 72 hours after delivery and resolves by 12 weeks postpartum. It is extremely difficult to differentiate this condition from the early stages of preeclampsia. A significant percentage of women with apparent gestational hypertension go on to develop proteinuria and the full preeclampsia syndrome at a later stage in pregnancy. Others have previously unrecognized chronic hypertension. The diagnosis of gestational hypertension can only be made in retrospect, if the pregnancy has been completed without the development of proteinuria and if the blood pressure has returned to normal before the 12th week postpartum.

ETIOLOGY

Preeclampsia is called a “disease of theories,” because genetic, immunologic, vascular, hormonal, nutritional, and behavioral factors have all been proposed as causes. No single, definitive “cause” has been identified, and the origins of the disease are considered to be multifactorial. Because of the resolution of the preeclampsia after delivery, most attention has been focused on the placenta and the uterine-placental-fetal interface.

Placental ischemia, or hypoxia, appears to be central to the development of the disease and has been attributed to failure of the cytotrophoblasts to adequately invade the uterine spiral arteries and establish the low-resistance uteroplacental circulation characteristic of normal pregnancy. Placental ischemia could also be due to underlying maternal vascular disease such as might occur in chronic hypertension, or to immunologically mediated placental vascular damage (see Chapter 6). Alternatively, ischemia could be caused by increased metabolic demand in the setting of a multiple gestation or a large singleton fetus.

It is postulated that uteroplacental ischemia results in oxidative stress leading to the production and release of toxins that enter the circulation and cause widespread inflammation, endothelial dysfunction, and activation of the coagulation system. The nature of these toxins has not yet been identified but may involve production of reactive oxygen and reactive nitrogen species. This is supported by the observation that preeclampsia is increased in pregnant women with underlying conditions such as obesity and diabetes that are associated with chronic inflammation and dyslipidemia. A hypoxic placenta may also shed microparticles derived from apoptosis of syncytiotrophoblasts, which can then lead to widespread endothelial injury. Antiangiogenic factors have also been shown to cause systemic hypertension, vascular injury, and activation of the coagulation system. Preeclamptic women have an imbalance in angiogenic and antiangiogenic proteins. Circulating levels of the proangiogenic proteins vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are decreased, whereas levels of the antiangiogenic proteins soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin are markedly increased. In animal models, overexpression of sFlt1 results in a preeclampsia-like syndrome.

Endothelial dysfunction leads to an imbalance between different classes of locally produced vasoconstrictors and vasodilators. Preeclampsia is associated with a disturbance in prostaglandin production, with a decrease in the ratio of the vasodilators prostaglandin E₂ (PGE₂) and prostacyclin to the vasoconstrictor PGF series and thromboxanes. Endothelial changes also appear to involve a relative deficiency in the production of nitric oxide, a vasodilator and inhibitor of platelet aggregation, along with increased production of endothelin-I. Endothelin-I is an extremely potent vasoconstrictor and activator of platelets. This shift in the production of locally acting vasoactive substances could enhance vasoconstriction in response to circulating pressor hormones.

The net effect of these processes would be widespread vasoconstriction leading to hypoxic and ischemic damage in different vascular beds, systemic hypertension, the HELLP syndrome (see later) or DIC, and worsening placental ischemia. The relative severity of the signs and symptoms of preeclampsia in any given individual would vary on the basis of which specific organ systems were most affected.

PATHOPHYSIOLOGY

Although the cause of preeclampsia is unknown, one of the primary underlying pathophysiologic abnormalities is generalized vasospasm. Cardiac output in untreated pregnant patients with preeclampsia is not significantly different from that of normal subjects in the last trimester of pregnancy, but systemic vascular resistance is significantly elevated.

Renal blood flow and glomerular filtration rate (GFR) are significantly lower