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Pregnancy and the Kidney
1
Normal Pregnancy
1.1
Renal Adaptation
Normal pregnancy is associated with increases in glomerular filtration rate (GFR) of 40%–65% and renal plasma flow (RPF) of 50%–85% above nonpregnant levels during the first half of gestation. These increases are a result of reductions in both afferent and efferent arteriolar resistances without glomerular pressure change that have been demonstrated in micropuncture studies. Creatinine clearance has been found to be increased 25% by as early as the second week of gestation. In the final stages of pregnancy, RPF falls, while GFR is generally maintained throughout gestation. The rise in GFR results in a corresponding reduction in plasma concentration of creatinine and blood urea nitrogen (BUN). Average plasma creatinine during pregnancy is about 0.5 mg/dL and BUN 9 mg/dL, respectively, compared to prepregnancy average levels of approximately 0.8 and 13 mg/dL, respectively. This increase in GFR can also lead to the appearance of microalbuminuria in normal pregnancies, while women with preexisting proteinuric renal disease can expect to have a dramatic increase in proteinuria after the first trimester.
Accompanying the large rise in GFR is an increase in renal size by about 1 cm in length and 30% in volume, as well as dilation of the collecting systems. Physiologic hydronephrosis can be seen in up to 90% of pregnancies beginning in the first trimester and resolving after about 1 month postpartum. The etiology is attributed to the hormones that affect smooth muscle, such as progesterone, but primarily to mechanical compression by the gravid uterus, more pronounced on the right than the left because of dextrorotation of the uterus. Although typically asymptomatic, physiologic hydronephrosis can be a rare cause of acute renal failure (ARF) in pregnancy that is characterized by abdominal pain and severe hydronephrosis resulting in obstruction. More commonly, the physiologic dilation predisposes women to infection, which can range from asymptomatic bacteriuria to urosepsis.
Renal handling of electrolytes is also affected by the rise of GFR. The increase in urate clearance results in a decline of serum uric acid to as low as 2–3 mg/dL by the second trimester. In the third trimester, increased renal tubular absorption of urate accounts for the return to prepregnant serum uric acid concentrations by delivery. By week 8 of gestation, calcium excretion is found to be increased, likely from elevated circulating 1,25-dihydroxyvitamin D 3 , but this may be counteracted by a concomitant rise in excreted nephrocalcin, thought to be a crystalluria inhibitor. The overall incidence of nephrolithiasis is not increased compared to nonpregnant women of childbearing age, which might be attributable to the presence of a urinary inhibitory protein, physiologic dilation, and higher urine flow.
Diminished serum bicarbonate levels in pregnant women are commonly seen. This is not caused by a metabolic acidosis, but rather represents compensation for respiratory alkalosis, which is also reflected by a decline in arterial pCO 2 . Once compensation is achieved and steady state is again reached, urine pH returns to its usual acidity. Progesterone both increases the sensitivity of the respiratory center to CO 2 and stimulates the respiratory drive directly. As a result, pCO 2 drops to approximately 27–32 mmHg. This allows for a high-normal pO 2 to be sustained despite the 20%–33% increase in oxygen consumption in pregnancy.
Women without diabetes may experience mild glycosuria and aminoaciduria in a normal pregnancy because of increased GFR and therefore load of glucose and amino acids, as well as the decreased glucose absorption capacity of the kidneys reabsorption.
During the first trimester, plasma osmolality falls as a result of lowering of the osmotic threshold for thirst and secretion of antidiuretic hormone (ADH), shown to be induced by human chorionic gonadotropic hormone. The ability to excrete a water load is otherwise normal. As a result, mild hyponatremia is frequently observed at levels of 4–5 mEq/L below nonpregnant levels. In addition, circulating levels of vasopressinase, an enzyme that hydrolyzes arginine vasopressin, are increased during normal pregnancy. The gene product mediating placental vasopressinase activity was characterized as a novel placental leucine aminopeptidase that can also degrade other hormones such as oxytocin. Occasionally, the increase in vasopressinase can be very pronounced leading to diabetes insipidus. This syndrome of transient diabetes insipidus presents late in pregnancy and disappears after the delivery. The polyuria can be controlled by the administration of desamino-8- d -arginine vasopressin (DDAVP), which is not destroyed by vasopressinase.
The kidney in pregnancy preserves the ability to efficiently excrete a sodium load. However, sodium reabsorption is increased through activation of the renin-angiotensin-aldosterone system (RAAS), which offsets the additional renal loss of sodium from the rise in GFR and the natriuretic effect of other hormones, such as progesterone and atrial natriuretic peptide (ANP). This leads to a slow, gradual retention of sodium of about 900 mmol by term. Total body water, distributed among the fetus and the maternal extracellular and interstitial space, increases by 6–8 L. Because the increase in plasma volume is disproportionately greater than the increase in red cell mass, a physiologic fall in the hemoglobin concentration during pregnancy is commonly seen.
1.2
Cardiac and Vascular Adaptation in Pregnancy
One of the earliest physiological adaptations in pregnancy is decreased vascular resistance and increased arterial compliance. By as early as 6 weeks of gestation, even before placentation is complete, many of the major hemodynamic changes associated with pregnancy are already well underway: systemic vascular resistance drops, heart rate increases 15%–20%, mean arterial blood pressure decreases by about 10 mmHg, and cardiac output rises by approximately 20%, peaking at 50% above preconception level by the third trimester. As delivery approaches, these changes begin to revert.
The mechanisms underlying the significant hemodynamic changes in early pregnancy are incompletely understood; however, the fall in systemic vascular resistance that precedes full development of the fetal–placental unit appears to stem from the increase in not only uterine blood flow, but also in renal and other extrauterine blood flow. By the end of the first trimester, diminished response to the vasopressors angiotensin II, norepinephrine, and vasopressin, as well as increased production of vasodilators such as prostacyclin have been noted. Other hormones that also likely play a role in the systemic decrease in vascular tone include estrogen and progesterone.
In addition, during the first and second trimesters, as the placenta develops, “pseudovasculogenesis” takes place, whereby cytotrophoblasts, transforming from an epithelial to endothelial phenotype in the process of invading uterine spiral arteries to remodel the prepregnancy high-resistance, low-capacitance maternal arteries into large-caliber, high-capacitance vessels in anticipation of the requirements of the developing fetus and placenta. In the second and third trimesters, increasing uterine blood flow continues to play a part in persistent low systemic resistance.
Placental vascular development is complex and remains incompletely understood. The impact of angiogenic factors, such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt1), and the angiopoietin signaling pathway, both systemically and on the development of the placenta have yet to be fully elucidated, but it seems clear that imbalance of these factors can lead to defective placental vascular development, most notably, preeclampsia.
In contrast to other conditions of peripheral vasodilation, such as sepsis, cirrhosis, and high-output congestive heart failure that are not characterized by any change in RPF, pregnancy is marked by decreased renal vascular resistance and significantly increased RPF. The expectation that activation of the RAAS during pregnancy should lead to renal vasoconstriction therefore suggests the presence of a more dominant direct renal vasodilating factor. It has been proposed that the ovarian hormone relaxin plays this role in pregnancy. Relaxin is a 6-kDa peptide hormone isolated in the 1920s initially from pregnant serum and shown to relax the pelvic ligaments. It is secreted by the corpus luteum of the ovary and its release is stimulated by human chorionic gonadotropin (hCG). Studies in pregnant rats have indicated that relaxin mediates the renal vasodilation, glomerular hyperfiltration, and fall in plasma osmolality ( P osm ) of pregnancy. The mechanism is thought to be relaxin’s upregulation of matrix metalloproteinase 2, which in turn promotes cleavage of big endothelin (ET) into ET1-32. This then leads to nitric oxide (NO)-mediated vasodilation via endothelial ET-B receptors. More recently, relaxin infusions over 5 h in men and nonpregnant women resulted in a 50% increase in RPF without affecting GFR or peripheral blood pressure. No fall in P osm was noted; however, scleroderma patients treated with relaxin over several weeks did exhibit a small, but significant drop in P osm . Effects of relaxin have been tested in patients with congestive heart failure with beneficial effects and improvement in short-term mortality.
2
Preeclampsia and HELLP Syndrome
Preeclampsia is a pregnancy-associated hypertensive syndrome characterized by new-onset hypertension and proteinuria, often diagnosed in the third trimester, and is typically accompanied by edema and hyperuricemia. Clinical management still consists mainly of supportive measures, the only known definitive treatment being delivery of the fetus. The syndrome affects approximately 5% of pregnancies and continues to be a leading cause of maternal and neonatal morbidity and mortality, particularly in the developing world. The primary organs affected may be the liver (HELLP syndrome is the h emolysis, e levated l iver enzymes and l ow p latelet count syndrome); the brain (eclampsia); and the kidney (proteinuria and glomerular endotheliosis).
In the United States, preeclampsia and eclampsia represent 20% of pregnancy-related maternal mortality. Rates of severe preeclampsia have been increasing in the United States and age-period-cohort effects all contribute to these trends. Although increasing obesity may have partially driven these trends, changes in the diagnostic criteria may have also contributed to the age-period-cohort effects Worldwide, preeclampsia and eclampsia account for 10%–15% of the roughly 500,000 women who die annually in childbirth. The most common causes of maternal death are eclampsia, cerebral hemorrhage, renal failure, hepatic failure, and the HELLP syndrome. Worldwide, preeclampsia is associated with a perinatal and neonatal mortality rate of 10%. Neonatal death is usually caused by iatrogenic prematurity as a result of early delivery to preserve the health of the mother. The earlier preeclampsia presents in gestation, the higher the risk of neonatal mortality. Impaired uteroplacental blood flow or placental infarction can lead to fetal growth restriction. Less frequently seen are oligohydramnios and placental abruption. Despite significant recent advances in the understanding of its pathogenesis, the underlying etiology remains incompletely understood.
2.1
Epidemiology and Risk Factors
Preeclampsia has been described as a “disease of first pregnancies” and its incidence is highest among nulliparous women, who account for roughly 75% of cases of preeclampsia. Numerous risk factors for the development of preeclampsia have been identified. These include certain medical conditions, such as chronic hypertension, diabetes mellitus, renal disease, and hypercoagulable states, as well as settings of increased placental mass, such as molar and multiple gestation pregnancies. Women with a prior history of preeclampsia are also at increased risk. A recent systematic review and meta-analysis of cohort studies confirmed that those with prior preeclampsia had the greatest pooled relative risk (8.4, 7.1 to 9.9). Chronic hypertension ranked second, both in terms of its pooled rate (16.0%, 12.6%–19.7%) and pooled relative risk (5.1, 4.0–6.5) of preeclampsia. Pregestational diabetes (pooled rate 11.0%, 8.4%–13.8%; pooled relative risk 3.7, 3.1–4.3), prepregnancy body mass index (BMI) >30 (7.1%, 6.1%–8.2%; 2.8, 2.6–3.1), and use of assisted reproductive technology (6.2%, 4.7%–7.9%; 1.8, 1.6–2.1) were other prominent risk factors. Others that have been explored include genetic, nutritional, and environmental risk factors. Although preeclampsia is more common in first pregnancies, multigravidas who are pregnant with a new partner are also at a similarly elevated risk. Once thought to be related to immunoprotection by exposure to paternal antigens, it is now recognized that interpregnancy interval is likely the determinant of increased risk in this group.
Most cases occur without a family history; however, women who do have a first-degree relative with preeclampsia are at fourfold increased risk of severe preeclampsia, pointing to the influence of genetic factors on a woman’s susceptibility to preeclampsia. Both men and women who were products of a pregnancy complicated by preeclampsia are also more likely to have a child whose in utero course is complicated by preeclampsia. Genome-wide scanning of Icelandic, Finnish, and Dutch populations have revealed loci on chromosome 2p13, 2p25, and 12q, respectively, the last with a linkage to HELLP syndrome. A gene on chromosome 13 has also been suggested to raise susceptibility, since women with trisomy 13 fetuses have been found to have a higher incidence of preeclampsia. However, specific genetic mutations within these loci have not been identified.
Still other suspected risk factors that continue to be debated include infectious etiologies, racial/ethnic factors, thrombophilia, and teenage pregnancy. In women with early-onset preeclampsia, anti-CMV and anti-Chlamydia antibody (IgG) titers have been found to be increased, relative to normal controls and women with late-onset preeclampsia. The true role of infectious agents in the pathogenesis of preeclampsia has not been established.
As hypertension is a risk factor for preeclampsia, it has been suggested that the higher incidence of preeclampsia in black women seen in some studies stems from the increased rate of chronic hypertension in this subgroup. In general, African American women have also been noted to have a higher case-mortality rate, which could be attributed to more severe disease or inadequate prenatal care. Interestingly, Hispanic ethnicity, while associated with an increased risk of preeclampsia, appeared to have a decreased risk of gestational hypertension. Overall, it is difficult to determine racial differences in the incidence and severity of preeclampsia because of invariable confounding by socioeconomic and cultural factors.
Conflicting data currently exist on the association of preeclampsia with congenital or acquired thrombophilia. It is not surprising that data from the United States from 1979 to 1986 suggest that for every year past age 34, a woman’s risk for preeclampsia increases, but some studies have also pointed to teenage pregnancy as a risk factor for preeclampsia; however, a subsequent meta-analysis and systematic review did not support the latter.
2.2
Clinical Features and Pathophysiology
Preeclampsia is often a diagnostic challenge in the settings of proteinuric renal disease or chronic hypertension. It may be difficult to distinguish from other hypertensive disorders during pregnancy, such as gestational hypertension and chronic hypertension. Guidelines on the diagnosis of preeclampsia published by the American College of Obstetrics and Gynecology were recently updated in 2013 (see Table 18.1 ).
Table 18.1
Diagnostic Criteria for Preeclampsia
Adapted from Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013; 122 :1122–31.
| Diagnostic Criteria for Preeclampsia | |
| Hypertension |
Or
|
| And | |
| Proteinuria |
Or
|
| Or in the absence of proteinuria, new onset hypertension with the new onset of any of the following: | |
| Thrombocytopenia |
|
| Renal insufficiency |
|
| Impaired liver function |
|
| Pulmonary edema | |
| Cerebral or visual symptoms | |
| Diagnostic Criteria for Superimposed Preeclampsia | |
| Hypertension |
|
| Or | |
| Proteinuria |
|
2.2.1
Hypertension
Hypertension, as one of the criteria for the diagnosis of preeclampsia, is defined by ACOG as a systolic blood pressure of 140 mmHg or higher or a diastolic blood pressure of 90 mmHg or higher in two separate measurements at least 2 h apart, in a previously normotensive woman after 20 weeks of gestation. Blood pressure elevation in preeclampsia can vary considerably from mild, which may be treatable by bed rest alone, to severe, which may be resistant to multiple antihypertensive agents. When severe hypertension is accompanied by headache and visual disturbances as well, urgent delivery is indicated, as it may portend eclampsia.
In contrast to normal pregnancies, where peripheral vascular resistance and blood pressure are decreased, preeclampsia is marked by increased peripheral vascular resistance, which is the primary cause of the hypertension. The rises in peripheral vascular resistance and blood pressure seen in preeclampsia are thought to be mediated by a substantial increase in sympathetic vasoconstrictor activity. Results from a recent study suggested that this sympathetic overactivity may not be a secondary phenomenon of preeclampsia, but rather, a precursor of it. An exaggerated response to angiotensin II and other hypertensive stimuli has also been found in preeclamptic women. The hypertension seen in preeclampsia is distinctively characterized by suppression, rather than activation, of the renin–angiotensin–aldosterone system. Total plasma volume, however, is generally believed to be somewhat decreased. This perceived increase in effective circulating blood volume then leads to suppression of renin and aldosterone, as well as brain natriuretic peptide.
The perturbations of the balance of vasoactive substances are thought to reflect the contribution of endothelial dysfunction to the development of hypertension (reviewed later in the section on maternal endothelial function). Imbalances in these vasoactive substances that are predominantly synthesized by the vascular endothelium, including the vasoconstrictors norepinephrine, endothelin, and potentially thromboxane and placental endothelin 1 (ET-1), as well as the vasodilators, such as NO, appear to be responsible for the prominent vasoconstriction seen in preeclampsia.
Prostaglandin I 2 (PGI 2 , prostacyclin) is a circulating vasodilator produced chiefly by endothelial and smooth muscle cells and is increased in normal pregnancy. In women with preeclampsia, but not pregnant women with chronic hypertension, production of PGI 2 is reduced before the appearance of hypertension and proteinuria. Thromboxane A 2 (TXA 2 ) is a potent vasoconstrictor produced by endothelial cells, activated platelets, and macrophages. TXA 2 synthesis was noted to be higher in patients with coagulopathy and marked platelet activation. Studies examining the effect of aspirin on the incidence of preeclampsia via inhibition of platelet TXA 2 production have generally yielded conflicting data.
NO has generated interest because of its putative role in normal pregnancy as a vasodilator. In pregnant rats, its inhibition by NG-nitro- l -arginine methyl ester ( l -NAME), an exogenous nitric oxide synthase (NOS) inhibitor, induced some of the clinical characteristics of preeclampsia. Supplementation of l -arginine reversed the hypertension and proteinuria caused by infusion of l -NAME and decreased the extent of glomerular injury. Preeclampsia is characterized by decreased NO synthesis, and NO metabolites are inversely related to circulating angiogenic factors, molecules implicated in the pathogenesis of preeclampsia. Although levels of asymmetric dimethyl arginine, an endogenous inhibitor of NOS, are elevated in preeclampsia, its very low levels render it technically challenging to study and interpret. In addition, l -arginine supplementation has not been shown to be of significant benefit in preeclampsia.
2.2.2
Proteinuria
Although the urine dipstick method is frequently used to screen for proteinuria in routine prenatal monitoring, it has a high rate of false positives and false negatives in comparison to 24-h urine protein measurement. In the nonobstetric population, the urine-protein-to-creatinine ratio (in units of mg protein per mg creatinine) is commonly used to estimate 24-h protein excretion. A number of studies have also supported use of the urine-protein-to-creatinine ratio in pregnant women, given that it closely approximates the 24-h urinary protein excretion. In these studies, spot urine protein-to-creatinine ratios >0.3 mg/mg are highly (>90%) sensitive for detection of significant (>300 mg) proteinuria by 24 h collection in pregnant women in the third trimester.
The degree of proteinuria in preeclampsia can range widely, from minimal to nephrotic range; however, the degree of proteinuria is a poor predictor of adverse maternal and fetal outcomes and therefore not by itself an indication for urgent delivery. Among women with underlying proteinuria, other signs of preeclampsia such as elevated transaminases, thrombocytopenia, or cerebral signs/symptoms are more useful to diagnose superimposed preeclampsia. The proteinuria of preeclampsia is “nonselective” and thought to stem from loss of glomerular barrier charge selectivity. Postpartum, proteinuria generally resolves within 7–10 days, although it may persist for 3–6 months.
2.2.3
Uric Acid
A serum uric acid level greater than 5.5 mg/dL is a strong indicator of preeclampsia. The elevation of uric acid is attributed chiefly to decreased renal clearance and often precedes the onset of proteinuria and fall in GFR. In humans given infusions of vasoconstrictors, similar declines in uric acid clearance have been observed. Lowering serum uric acid with probenecid, however, does not appear to have any effect on the blood pressure in women with preeclampsia. The serum level of uric acid rises as preeclampsia progresses and correlates with its severity, as well as with adverse pregnancy outcome; a level greater than 7.8 mg/dL is associated with significant maternal morbidity. The degree of uric acid rise also correlates with the severity of proteinuria and renal pathological changes, and with fetal demise. Because the serum uric acid level in women with gestational hypertension similarly correlates with severity of disease and poor pregnancy outcomes, it is of limited clinical utility in distinguishing preeclampsia from other hypertensive disorders of pregnancy and/or as a clinical predictor of adverse outcomes. Meta-analysis of data from 18 studies including nearly 4000 women concluded that serum uric acid is a weak predictor of maternal and fetal complications in women with preeclampsia. Nevertheless, preeclampsia superimposed on chronic renal disease may be a clinical setting where serum uric acid could be useful, as the diagnostic criteria of new-onset hypertension and proteinuria may be difficult to apply. In such cases, a serum uric acid level that exceeds 5.5 mg/dL and stable renal function may suggest the diagnosis of preeclampsia.
2.2.4
Renal Changes and Pathology
In contrast to normal pregnancy, where GFR and RPF increase during early and midpregnancy, in preeclampsia, GFR and RPF are both decreased. Because of pregnancy’s overall effect of augmenting GFR, BUN, and serum creatinine often remain in the normal, nonpregnant range in preeclampsia despite the latter’s significant GFR-lowering effect. Although ARF can be seen in preeclampsia, it is more common for only proteinuria and renal sodium and water retention to manifest. Renal filtration fraction is lower in preeclamptics than in normal women in the third trimester of pregnancy. The fall in renal blood flow (RBF) is a consequence of high renal vascular resistance, chiefly from increased afferent arteriolar resistance. GFR declines because of the decreases in RBF and in the ultrafiltration coefficient (Kf), which is attributed to endotheliosis in the glomerular capillary bed.
The urinary sediment of preeclamptics is usually “bland” in preeclampsia, with no or few white and red blood cells, and cellular casts. Recent evidence reveals that “podocyturia,” the urinary excretion of glomerular visceral epithelial cells (podocytes) may be a novel way to distinguish women with preeclampsia from nonproteinuric, normotensive pregnant women. As a diagnostic, though not necessarily a predictive, marker, this remains to be validated by larger studies.
The unique appearance of glomerular endothelial cells in preeclampsia is termed “glomerular endotheliosis” and describes narrowed glomerular capillary lumen that are typically “bloodless,” enlarged glomeruli with generalized swelling, and vacuolization of endothelial cells ( Fig. 18.1 ). Glomerular cellularity may be slightly increased, and mesangial interposition may occur in severe cases or in the healing stages. Immunofluorescence may reveal deposits of fibrin and fibrinogen within the endothelial cells, particularly in biopsies done within 2 weeks postpartum. Electron microscopy shows loss of glomerular endothelial fenestrae, but with relative preservation of the podocyte foot processes. Glomerular subendothelial and occasional mesangial electron-dense deposits can also be seen. In contrast to other nephrotic diseases, where podocytes are damaged early in the disease, the primary focus of injury in preeclampsia is the endothelial cell. Other renal histological changes that have been described include atrophy of the macula densa and hyperplasia of the juxtaglomerular apparatus. It is now known that mild glomerular endotheliosis can be seen in nonpreeclamptic pregnant women. Indeed, up to 50% of patients with nonproteinuric pregnancy-induced hypertension exhibit mild glomerular endotheliosis, perhaps suggesting that pregnancy-induced hypertension may represent an early or mild form of preeclampsia, or even a phenomenon that occurs at term in all pregnancies. The glomerular enlargement and endothelial swelling generally resolve within 8 weeks postpartum, along with resolution of the proteinuria and hypertension. However, persistent renal damage can follow preeclampsia in the form of focal segmental glomerulosclerosis (FSGS) in 50% or more of cases.
2.2.5
Severe Preeclampsia and Eclampsia
Severe preeclampsia should prompt a consideration to terminate pregnancy, given the potential life-threatening nature of maternal morbidity. The clinical and laboratory findings that indicate severe disease include oliguria (less than 500 mL urine in 24 h, typically transient) and, uncommonly, ARF. Pulmonary edema is seen in 2%–3% of severe preeclampsia and can lead to respiratory failure. Elevated liver enzymes can occur alone or as part of the HELLP syndrome and may be associated with epigastric or right upper quadrant pain. Persistent headache or visual disturbances can portend seizures (eclampsia), seen in roughly 2% of cases of preeclampsia in the United States. Typically, but not invariably, eclampsia occurs in the presence of hypertension and proteinuria. Late postpartum eclampsia is a diagnostic challenge, accounts for up to one-third of cases, occasionally days to weeks after delivery, and is frequently seen by nonobstetricians in the emergency room setting. Magnetic resonance imaging (MRI) or computed tomography (CT) of the head usually reveals vasogenic edema and infarctions in subcortical white matter and adjacent gray matter of the parietooccipital lobes; however, radiological head imaging is not necessary if the diagnosis is otherwise clear. The cerebral edema of eclampsia predominantly involves the posterior, parieto-occipital lobes and is similar to images described in reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome characterized by headache, altered mental status, convulsions, and cortical blindness. Cerebral edema is thought to result primarily from endothelial dysfunction rather than from hypertension, as it appears to parallel markers of endothelial damage, rather than severity of hypertension. This is confirmed by autopsy findings of cerebral edema and intracerebral parenchymal hemorrhage in women who have died from eclampsia. Cerebral vasospasm, excitation of brain receptors, a hyperactive sympathetic nervous system, and hypertensive encephalopathy from cerebral overperfusion have all been associated with eclamptic seizures. Most of these women have been found to have cerebral overperfusion rather than ischemia. Interestingly, RPLS can be precipitated by acute blood pressure rises and treatment with antiangiogenic agents such as bevacizumab, a monoclonal antibody against VEGF and its receptors. These findings appear to align with the accumulating evidence on the role of antiangiogenic factors in the pathophysiology of preeclampsia/eclampsia.
2.2.6
HELLP Syndrome and Hematological Abnormalities
Although it can occur in the absence of proteinuria, the HELLP syndrome is generally considered to be a severe variant of preeclampsia. It develops in approximately 10%–20% of women with severe preeclampsia. The HELLP syndrome can be complicated by eclampsia (6% of cases), placental abruption (10%), ARF (5%), disseminated intravascular coagulation (DIC) (8%), and pulmonary edema (10%). Rarely, hepatic hemorrhage and rupture can occur, even after delivery of the fetus that is often associated with significant maternal and perinatal mortality.
The HELLP syndrome is a consumptive coagulopathy and thrombotic microangiopathy that shares many clinical and biological features with thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). In normal pregnancy, coagulation is enhanced because the circulating levels of all coagulation factors are increased, including those made in the liver and in the vascular endothelium. In preeclampsia, however, only factors that are synthesized by the vascular endothelium are elevated. These factors include prostacyclins (PGI 2 ), thrombomodulin, cellular fibronectin, PAI-1, and von Willebrand factor (vWF). Plasma concentrations of cellular fibronectin are increased weeks before the onset of hypertension. Exposure of cultured endothelial cells to serum from preeclamptic women results in greater cellular fibronectin and thrombomodulin release compared to serum from normotensive pregnant women. It was shown that the large vWF multimers (normally cleaved by the metalloproteinase ADAMTS13) that are highly reactive with platelets may be increased in women with the HELLP syndrome because of both endothelial activation and, similar to TTP, decreased ADAMTS13 levels. However, evidence for involvement of ADAMTS13 pathway in humans with HELLP syndrome is still lacking. Other markers of endothelial injury that have also been reported will be reviewed in the section on maternal endothelial function.
2.3
Long-Term Cardiovascular and Renal Outcomes
Although the symptoms of preeclampsia appear to remit completely following delivery of the fetus, many of these women ultimately develop cardiovascular and renal morbidity later. Women with a history of preeclampsia continue to have impaired endothelial-dependent vasorelaxation, as measured by brachial artery flow-mediated dilatation up to 3 years postpartum, implying that changes in the maternal endothelium may be long-standing. About 20% of women with preeclampsia are found to have hypertension or microalbuminuria on long-term follow-up. One study observed that development of subsequent ischemic heart disease was increased by 1.7-fold and hypertension by 2.4-fold in women with preeclampsia, which was confirmed by two large subsequent European studies. Women with preeclampsia and gestational hypertension have a roughly twofold increase in cardiovascular and cerebrovascular risk compared to age-matched controls. The rates of heart disease among women with preeclampsia complicated by preeclampsia with preterm birth or intrauterine growth restriction, and among those with severe or recurrent preeclampsia were increased by up to eightfold. Risks of chronic kidney disease and end-stage renal disease (ESRD) have also been found to be increased in women with recurrent preeclampsia or severe preterm preeclampsia.
Because preeclampsia and cardiovascular disease share many common risk factors, such as obesity, chronic hypertension, diabetes mellitus, renal disease, and the metabolic syndrome, it may well be the reason their risks are so closely linked. However, the increase in long-term cardiovascular mortality appears to be present even for women who develop preeclampsia without clear cardiovascular risk factors, raising the possibility that perhaps preeclampsia itself causes vascular damage and persistent endothelial dysfunction. Animal studies have revealed that preeclampsia itself may lead to persistent vascular injury that could substantially increase the risk of cardiovascular disease in the long term. Children who were products of pregnancies complicated by low birth weight with or without preeclampsia have been observed to have a higher incidence of subsequent hypertension, diabetes, cardiovascular disease, and chronic kidney disease.
2.4
Pathogenesis of Preeclampsia (See Fig. 18.2 )
2.4.1
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