Pregnancy-Related Hypertension

Chronic Hypertension

Chronic hypertension is defined by ACOG as persistent blood pressures greater than 140/90 mm Hg diagnosed before pregnancy or before 20 weeks’ gestation. The diagnosis can also be based on hypertension that is observed for the first time during pregnancy and persists beyond the 84th day after birth.

Gestational Hypertension

Gestational hypertension is defined as new-onset blood pressure elevations after 20 weeks’ gestation in the absence of proteinuria. This provisional diagnosis includes women without preeclampsia and those who will develop preeclampsia who have not yet exhibited proteinuria. Because gestational hypertension may predate the onset of preeclampsia, women with newly elevated blood pressures after 20 weeks’ gestation should be monitored closely for preeclampsia. If blood pressures do not normalize postpartum (typically within 6 weeks), the diagnosis should be changed to chronic hypertension.

Preeclampsia, Eclampsia, And Hellp

Preeclampsia is defined as new-onset blood pressure elevations accompanied by proteinuria or other signs (see later) in pregnancy. It is a pregnancy-specific disease that typically occurs after 20 weeks’ gestation. The diagnosis includes at least two measurements at least four hours apart of systolic pressures greater than or equal to 140 mm Hg or diastolic pressures greater than or equal to 90 mm Hg. An incremental rise of blood pressure by 30 mm Hg systolic or 15 mm Hg diastolic is no longer included in the diagnostic criteria because there is not an increased risk for adverse outcomes in this cohort of patients. ^,

Proteinuria is defined by the presence of 300 mg of protein or more in a 24-hour urine specimen or if the ratio of protein to creatinine in a single voided urine sample exceeds 0.3 (as measured in mg/dL). A 24-hour urine specimen is preferable for diagnosis because of the discrepancy between random protein determinations and 24-hour urine protein measurements in preeclampsia. ^, A qualitative dipstick reading of 2+ (30 mg/dL) is suggestive of proteinuria but should only be used for diagnosis when quantitative methods are not readily available because of both false-positive and false-negative readings. ^, In the absence of proteinuria, preeclampsia may be diagnosed when hypertension is associated with thrombocytopenia (platelet count <100,000/μL), elevated liver enzymes (transaminases greater than twice the upper limit of normal concentration), new onset renal insufficiency (serum creatinine >1.1 mg/dL in the absence of other renal disease), pulmonary edema, or new-onset cerebral or visual disturbances.

Preeclampsia occurs as a spectrum that is divided into those with or without severe features. ACOG recommends abandoning the term mild for those without severe features; preeclampsia is associated with an increased risk for morbidity and mortality even in the absence of severe features. The diagnosis of preeclampsia with severe features is made for any of the following criteria :

• Blood pressure of 160 mm Hg systolic or higher or 110 mm Hg diastolic or higher on two occasions at least 4 hours apart (unless antihypertensive therapy is initiated)

• New-onset cerebral or visual disturbances

• Pulmonary edema

• Persistent epigastric or right upper quadrant pain unresponsive to medication and not accounted for by alternative diagnoses

• Impaired liver function as indicated by abnormally elevated blood concentrations of liver enzymes (twice normal concentrations)

• Thrombocytopenia (platelet count <100,000/μL)

• Progressive renal insufficiency (serum creatinine concentration >1.1 mg/dL in the absence of other renal disease)

Of note, fetal growth restriction and proteinuria greater than 5 g are no longer criteria for preeclampsia with severe features. New-onset proteinuria is no longer a criterion for preeclampsia with severe features because massive proteinuria (>5 g) does not alter pregnancy outcome in women diagnosed with preeclampsia. ^, Additionally, as management of most cases of preeclampsia with fetal growth restriction is similar regardless of mild or severe features, the ACOG Task Force removed fetal growth restriction as a criterion for preeclampsia with severe features.

Edema occurs in too many normal pregnant women to be discriminant and has been abandoned as a marker for preeclampsia by most classification schemes. ^, Edema of the hands and face occurs in 10% to 15% of normotensive women in pregnancy, but this finding can be massive in severe preeclampsia ( Fig. 45.1 ).

Eclampsia is the occurrence of new-onset seizures that cannot be attributed to other causes in a woman with preeclampsia. HELLP syndrome ( h emolysis, e levated l iver enzymes, and l ow p latelets) is thought to be a variant of preeclampsia. Hypertension and proteinuria may not occur with this condition. Although management for HELLP syndrome is similar to that for preeclampsia, some differences suggest that these two conditions may be separate entities. For example, women with HELLP syndrome tend to be older, White, and multiparous compared to women with preeclampsia. The characteristic pathophysiologic changes in the renin-angiotensin system in women with preeclampsia do not occur in those with HELLP syndrome. Still, the progression of HELLP syndrome and its termination with delivery argue for a management strategy similar to that for preeclampsia with severe features as recommended by the ACOG Task Force.

Preeclampsia Superimposed On Chronic Hypertension

Preeclampsia can occur in women with underlying chronic hypertension, a diagnosis that is associated with worse maternal and fetal prognoses than either condition alone. The distinction between superimposed preeclampsia and worsening chronic hypertension frequently tests the skills of the clinician. For clinical management, the principles of high sensitivity and unavoidable overdiagnosis are accepted, especially with advancing gestational age. The diagnosis of superimposed preeclampsia is often suspected based on the new onset of proteinuria after 20 weeks’ gestation. It is likely to occur in women with preexisting proteinuria who display a sudden increase in blood pressure or proteinuria. The diagnosis may be made more easily when these women display objective evidence of involvement of other organ systems, including thrombocytopenia (platelet count <100,000/mm ³ ), elevated levels of liver transaminases, and worsening renal function or symptoms of right upper quadrant pain, pulmonary edema, or severe headache.

Problems With Diagnosis And Classification

The normal physiologic trends of blood pressure measurements during pregnancy prove problematic for classification schemes. Blood pressure usually decreases early in pregnancy by an average of 7 mm Hg for systolic and diastolic readings, reaching a nadir at approximately 22 weeks’ gestation ( Fig. 45.2 ). Although women with chronic hypertension also experience lower blood pressures compared with normotensive women, their blood pressure remains higher, reaches a nadir later, and returns to baseline later than in normotensive women. ^, The early decline and subsequent return of blood pressure to prepregnant levels in late gestation may erroneously satisfy criteria for a diagnosis of preeclampsia in women with chronic hypertension. This physiologic pattern of blood pressures can be particularly troublesome in women who do not seek care outside of pregnancy and therefore may not carry a diagnosis of chronic hypertension.

The diagnosis of chronic hypertension based on the failure of blood pressure to return to normal by 6–12 weeks after delivery can also be erroneous. For example, in a long-range prospective study, Chesley showed that many women who remained hypertensive 6 weeks after the birth were normotensive at long-term follow-up.

Diagnosis of hypertensive disorders is further clouded by the fact that neither proteinuria nor hypertension is specific for preeclampsia. Renal biopsy specimens highlight these diagnostic difficulties ( Table 45.1 ). Of 62 women with a diagnosis of preeclampsia, 70% had a glomerular lesion thought to be characteristic of the disorder, but 24% had evidence of chronic renal disease. Of 152 subjects with chronic hypertension and a presumed diagnosis of superimposed preeclampsia, only 3% had characteristic glomerular lesions, and 43% had evidence of preexisting renal disease. Additionally, although endotheliosis has been considered pathognomic of preeclampsia, in a study including renal biopsy of 12 healthy controls and 8 women with gestational hypertension, mild endotheliosis was identified in 5 of the healthy controls and all of the women with gestational hypertension.

The clinical spectrum of preeclampsia is variable. Rather than beginning with eclampsia or severe preeclampsia, the disease typically begins without severe features and progresses at a variable rate. In most cases, this progression is slow, and the disorder remains without severe features until delivery. In others, particularly at early gestational ages, the disease can progress rapidly, presenting with or developing severe features over days to weeks (or hours in fulminant cases). A study conducted within the International Network of Obstetric Survey Systems demonstrated that 42% to 43% of eclamptic women had a preceding diagnosis of preeclampsia, and 30% to 50% had no evidence of severe hypertension preceding their eclamptic seizure. For purposes of clinical management, overdiagnosis is accepted because prevention of the serious complications of preeclampsia and eclampsia requires high sensitivity and early treatment, especially as gestational age progresses. Studies of preeclampsia are necessarily confounded by inclusion of women diagnosed as preeclamptic who have another cardiovascular or renal disorder.

Epidemiology Of Preeclampsia And Eclampsia

The incidence of hypertensive disorders of pregnancy (gestational hypertension, preeclampsia, and eclampsia) is approximately 85 per 1000 deliveries in the United States and demonstrates significant variation by state.

Based on a meta-analysis of risk factors for preeclampsia, nulliparity accounts for the greatest population attributable fraction for preeclampsia at 32.3% (95% CI, 27.4% to 37.0%). Some risk factors for preeclampsia, including age, race, and underlying medical conditions, are similar in nulliparous and parous women. Additional risk factors include prior preeclampsia, antiphospholipid syndrome, in vitro fertilization, and family history of preeclampsia ( Table 45.2 ).

The impression that preeclampsia is more common among women of lower socioeconomic status may be confounded by the relationship of preeclampsia to age, race, and parity. Several studies have shown no relationship between preeclampsia and socioeconomic status. In contrast, eclampsia is clearly more common in women of lower socioeconomic status, ^{, ,} a finding that is likely related to the limited availability of quality obstetric care for indigent women.

Preeclampsia has been linked to the extremes of childbearing age. This relationship has been demonstrated in older women regardless of parity, ^{, ,} but the relation to young maternal age is lost after controlling for parity.

The relationship between preeclampsia and race is confounded by a relatively higher prevalence of chronic hypertension in African Americans. A modest association between preeclampsia and African-American race has been identified in some studies, with stronger associations often seen in studies that include more severe forms of preeclampsia. One study showed that Black race was a significant risk factor only in nulliparous women (odds ratio [OR] = 12.3; 95% confidence interval [CI], 1.6 to 100.8), but two large studies of nulliparous women showed no association between race and preeclampsia after controlling for other risk factors. ^, Maternal non-White race appears to be related more to severity than the incidence of disease.

Several medical disorders may predispose women to preeclampsia. Chronic hypertension is a well-recognized risk factor, and 25% of women with chronic hypertension subsequently develop preeclampsia during pregnancy. ^, Chronic renal failure with ^, or without diabetes mellitus is another important risk factor.

Pregestational diabetes mellitus is independently associated with an increased risk for preeclampsia, particularly in the setting of diabetic microvascular disease. ^, Studies suggest a 20% risk for the disease overall in diabetic patients. ^, The risk varies according to disease severity, with an 11% to 16% risk with White’s class B diabetes, a 21% to 23% risk with class C diabetes, a 35% to 40% risk with class D diabetes, and up to 70% risk with classes F and R diabetes. ^{, ,}

Connective tissue disorders such as systemic lupus erythematosis ^, and antiphospholipid syndrome are risk factors for preeclampsia. In systemic lupus erythematosis, the risk is particularly elevated in the setting of hypertension or lupus nephropathy. ^, While antiphospholipid syndrome is a strong risk factor for preeclampsia, the utility of routine testing for APS antibodies in women with prior early-onset severe preeclampsia is debatable. ^,

Obesity increases the risk for preeclampsia by approximately threefold, and the strength of this relationship increases with the magnitude of obesity. ^{, ,} A linear relationship between prepregnancy body mass index (BMI) and the frequency of preeclampsia can be seen even in women of normal weight. This relationship is likely related to increased insulin resistance, in concordance with the increased frequency of preeclampsia in women with gestational diabetes. Obesity is a major attributable risk factor for preeclampsia in places like the United States, where 35% to 50% of women of reproductive age are obese, and is associated with up to one-third of cases.

Certain conditions of pregnancy also increase the risk for preeclampsia. For example, the disease occurs in 70% of women with large, rapidly growing hydatidiform moles. Preeclampsia often occurs at an early gestational age in these patients, and the diagnosis of a molar pregnancy should be suspected when preeclampsia is diagnosed before 20 weeks’ gestation.

Preeclampsia is associated with multifetal gestations, particularly in multiparous women. ^, The incidence appears to increase with each additional fetus, occurring in 6.7% of twin, 12.7% of triplet, 20% of quadruplet, and 19.6% of quintuplet pregnancies. The disease process may be apparent earlier and may be more severe in women with multiple gestations.

The mirror syndrome, a variant of preeclampsia in which the mother’s peripheral edema mirrors fetal hydrops, occurs in pregnancies complicated by hydrops fetalis. It can be seen with both immune and nonimmune hydrops and occurred in 9 of 11 affected pregnancies in one small series. This condition can manifest early in pregnancy with severe signs and symptoms of preeclampsia, including massive proteinuria and severe blood pressure elevations. Based on several case reports, the current theory of mirror syndrome is that the hydropic placenta expresses antiangiogenic factors (e.g., soluble FMS-like tyrosine kinase-1 [sFLT1]), similar to preeclampsia. Despite this severity, eclampsia is a rare complication, and signs and symptoms of preeclampsia may resolve with treatment of the underlying disease process or delivery.

Clinical Presentation

Women with preeclampsia may present with a wide variety of signs and symptoms that range from mild to life-threatening. The fetus may likewise be minimally affected or may be severely compromised. An understanding of the pathophysiology of the disorder provides insight into the diverse clinical presentations.

Pathologic Changes In Preeclampsia

Pathologic changes in organs and tissues provide strong evidence that preeclampsia is not merely an unmasking of essential hypertension or a variant of malignant hypertension. Evidence suggests that poor tissue perfusion, not blood pressure elevations, is the primary pathogenetic component driving the disease process.

Brain

Imaging with computed tomography (CT) and magnetic resonance imaging (MRI) demonstrates cerebral edema in some women with severe preeclampsia or eclampsia. ^, Posterior reversible encephalopathy syndrome (PRES), a vasogenic and parietooccipital cerebral edema that is typically reversible, may be diagnosed in women with preeclampsia-eclampsia ( Fig. 45.3 ). Noninvasive studies of cerebral blood flow and resistance suggest that vascular barotrauma and loss of cerebral vascular autoregulation contribute to the pathogenesis of cerebral vascular pathology in this disease. Although preeclampsia-eclampsia has traditionally been thought to not have long-term neurologic consequences, women with preeclampsia have more white matter lesions on neuroimaging and are more likely to report cognitive dysfunction when compared with women who have normotensive pregnancies. Consistent with imaging studies, autopsies in eclamptic women show that the parenchymal injury was white-matter predominant and ranged from mild edema to extensive white matter necrosis.

Liver

Gross lesions of the liver are visible in 60% of women with eclampsia, and one-third of the remaining patients have evidence of microscopic abnormalities. Two temporally and etiologically distinct hepatic lesions have been described. Initially, hemorrhage into the hepatic cellular columns occurs because of vasodilation of arterioles, with dislocation and deformation of hepatocytes in their stromal sleeves ( Fig. 45.4 ). Later, intense vasospasm causes hepatic infarction, ranging from small to large areas beginning near the sinusoids and extending toward the portal vessels ( Fig. 45.5 ). Hemorrhagic changes are present in 66% and necrotic changes in 40% of eclamptic women and in about one-half as many preeclamptic women. Hyalinization and thrombosis of hepatic vessels have been cited as evidence of DIC but could be the result of hemorrhage. Similar changes have been described in women with abruptio placentae. ^,

Kidney

Unique glomerular, tubular, and arteriolar changes have been described with preeclampsia. The glomerular lesion is considered by some to be pathognomonic of preeclampsia, but identical changes may be seen in isolated placental abruption.

Glomerular changes seen by light microscopy include decreased glomerular size, protrusion of the glomerular tuft into the proximal tubule, decreased diameter of the capillary lumen, and increased cytoplasmic volume within endothelial-mesangial cells ( Fig. 45.6 ). Electron microscopy suggests that the primary pathologic change occurs in endothelial cells, which are greatly increased in size and can occlude the capillary lumen, a phenomenon known as glomerular capillary endotheliosis ( Fig. 45.7 ).

Characteristic glomerular changes occur in 70% of primiparas but in only 14% of multiparas who are diagnosed with preeclampsia. Glomerular lesions become increasingly common as certainty regarding the diagnosis of preeclampsia increases, and the magnitude of the lesions increases as the clinical condition becomes more severe. These changes are more consistently correlated with proteinuria than with hypertension. The glomerular alterations resolve within 5 to 10 weeks after delivery.

Nonglomerular renal changes occur with preeclampsia, including dilation of proximal tubules with thinning of the epithelium, tubular necrosis, enlargement of the juxtaglomerular apparatus, and hyaline deposition in renal tubules. Fat deposition has been associated with prolonged, heavy proteinuria, and necrosis of the loop of Henle may be seen with hyperuricemia. Thickening of renal arterioles may be visualized, particularly in women with preexisting hypertension, a finding that is likely related to the preexisting disease process because it does not regress after delivery.

Vascular Changes in the Placental Site

Figs. 45.8 and 45.9 depict the characteristic changes seen in the placenta during normal pregnancy. Spiral arteries increase greatly in diameter, endothelium is replaced by trophoblast, and the internal elastic lamina and smooth muscle of the media are replaced by trophoblast and an amorphous matrix containing fibrin (see Fig. 45.8 ). These changes initially occur in the decidual portion of the spiral arteries and then extend into the myometrium as pregnancy advances, sometimes involving the distal portion of the uterine radial artery. The basal arteries are not affected. These morphologic changes in the vasculature are considered to be a direct or humoral reaction to trophoblast that results in increased perfusion of the placental site.

In women with preeclampsia, these normal physiologic changes may not occur or are limited to the decidual portion of the spiral arteries. Myometrial segments of these vessels retain the nonpregnant component of intima and smooth muscle, and the diameter of these arteries is about 40% that of vessels in a normal pregnancy. Spiral arterioles may become necrotic, with components of the normal vessel wall replaced by amorphous material and foam cells, a change called acute atherosis ( Fig. 45.10 ). This lesion is best seen in basal arteries but is also present in the decidual and myometrial vessels. Acute atherosis can progress to frank vessel obliteration, a finding that corresponds to areas of placental infarction. These changes may also be seen in other conditions of pregnancy, including fetal growth restriction, diabetes mellitus, and preterm labor. Abnormal invasion alone may not cause preeclampsia.

These placental changes are seen in one of seven primiparous women at the time of first-trimester abortion, ^, suggesting that disordered placentation precedes the clinical presentation of preeclampsia. The disease process resembles that seen with rejection of transplanted kidneys, suggesting an immunologic cause. This immunologic theory is consistent with the finding of complement deposition within these decidual vessels.

Vascular remodeling of spiral arteries depends on normal trophoblastic invasion. Expression of implantation-related adhesion molecules and receptors is abnormal in preeclampsia. Although the trophoblast lining decidual vessels normally begin to express molecules usually present only on endothelium, this phenomenon does not occur in preeclampsia. These changes are potentially driven by decidually produced cytokines and local oxygen tension. ^, Alterations in interactions between specific molecules on trophoblasts and maternal decidual cells may also contribute to abnormal invasion.

Pathophysiologic Changes In Preeclampsia

Preeclampsia can cause changes in virtually all organ systems, but several organ systems are consistently and characteristically involved.

Cardiovascular Changes

Blood pressure is the product of cardiac output and systemic vascular resistance (SVR). The cardiac output normally increases by up to 50% in pregnancy, but blood pressure remains largely unchanged, indicating that SVR must be decreased. A reduction in blood pressure is common in the first half of pregnancy, reaching a nadir at approximately 22 weeks’ gestation (see Fig. 45.2 ). Some women who ultimately develop preeclampsia demonstrate a higher cardiac output before clinically evident disease, but output falls to prepregnancy levels with the onset of clinical preeclampsia. Increased SVR must therefore be the mechanism driving the increase in blood pressure seen with preeclampsia.

Arteriolar narrowing occurs in preeclampsia, a phenomenon that can be seen in vessels of the retina, kidney, nail bed, and conjunctiva. Measurements of forearm blood flow indicate higher resistance in preeclampsia compared with normal pregnant women. ^, The cause of this increased resistance remains unclear, but it is unlikely to be determined by the autonomic nervous system. Whereas normal pregnant women are exquisitely sensitive to interruption of autonomic neurotransmission by ganglionic blockade and high spinal anesthesia, preeclamptic women are less sensitive.

Humoral factors have been implicated in the process of arteriolar narrowing (i.e., toxemia), but later results are inconsistent with this theory, showing minimal changes in catecholamine levels. Although levels of endothelin 1, a vasoconstrictor produced by endothelial cells, are increased in the blood of preeclamptic women, they still occur in concentrations much lower than those necessary to stimulate vascular smooth muscle contraction in vitro.

A more compelling explanation for the vasospasm of preeclampsia is that of an increased response to normal concentrations of endogenous pressors. Women with preeclampsia have a higher sensitivity to all endogenous pressors tested, including vasopressin, epinephrine, norepinephrine, and angiotensin II. For example, administration of vasopressin can elicit marked blood pressure elevation, oliguria, and seizures in some preeclamptic patients. The relationship between norepinephrine administration and blood pressure elevation is depicted in Fig. 45.11 .

The most striking difference is seen in the sensitivity of the preeclamptic woman to angiotensin II. Normal pregnant women are less sensitive to angiotensin II than nonpregnant women, requiring approximately 2.5 times as much angiotensin II to raise blood pressure by a similar increment. In contrast, preeclamptic women are much more sensitive to angiotensin II than are normal pregnant or nonpregnant women ( Fig. 45.12 ), a finding that may be observed weeks before the development of elevated blood pressure ( Fig. 45.13 ). Significant differences in sensitivity between women who later become hypertensive and those who remain normotensive have been observed as early as 14 weeks. However, a large British study did not confirm this classic finding, perhaps reflecting the heterogeneity of preeclampsia.

Another theory suggests that arteriolar narrowing in preeclampsia is related to a decrease in circulating or local vasodilator substances, rather than an increase in circulating pressors. This attractive hypothesis, however, is not consistent with the unchanged sensitivities to norepinephrine, epinephrine, and vasopressin in normal pregnancy.