Brenner and Rector's The Kidney, 8th ed.

CHAPTER 44. Hypertension and Kidney Disease in Pregnancy

Sharon E. Maynard   S. Ananth Karumanchi   Ravi Thadhani

  

 

Physiologic Changes of Pregnancy, 1567

  

 

Preeclampsia and the HELLP Syndrome, 1569

  

 

Chronic Hypertension and Gestational Hypertension, 1582

  

 

Acute Kidney Injury in Pregnancy, 1585

Pregnancy is characterized by a myriad of physiologic changes, of which the emergence of a placenta and growing fetus is the most dramatic. Hypertension and/or renal disease occurring in the setting of pregnancy presents a unique set of clinical challenges. This chapter includes a detailed discussion of preeclampsia, a syndrome specific to pregnancy that remains one of the most enigmatic human disorders and continues to claim the lives of thousands of mothers and neonates yearly. Other causes of acute kidney injury (AKI) in pregnancy are discussed. The chapter reviews current data on epidemiology and management issues regarding chronic hypertension, chronic kidney disease (CKD), and kidney transplantation in the setting of pregnancy. Our hope is that this chapter offers the reader insights into our emerging understanding of the pathogenesis of preeclampsia and provides a sound basis for the management of pregnancy from a nephrologist's perspective.

PHYSIOLOGIC CHANGES OF PREGNANCY

Hemodynamic and Vascular Changes of Normal Pregnancy

Normal pregnancy is characterized by profound vascular and hemodynamic changes that reach far beyond the fetus and placenta ( Table 44-1 ). Early in pregnancy, Systemic vascular resistance (SVR) decreases and arterial compliance increases.[1] These changes are evident by 6 weeks' gestation, prior to the establishment of the uteroplacental circulation.[2] The decrease in SVR leads directly to several other cardiovascular changes. Mean arterial blood pressure falls by an average of 10 mm Hg below baseline by the second trimester ( Fig. 44-1 ). Sympathetic activity is increased, reflected in a 15% to 20% increase in heart rate.[3] The combination of increased heart rate and decreased afterload leads to a large increase in cardiac output in the early first trimester, which peaks at 50% above prepregnancy levels by the middle of the third trimester ( Fig. 44-2 ).

TABLE 44-1   -- Physiologic Changes in Pregnancy

Physiologic Variable

Change in Pregnancy

Hemodynamic parameters

Plasma volume

Rises by 30%–50% above baseline.

Blood pressure (BP)

Decreases by to about 10 mm Hg below prepregancy level; nadirs in second trimester. Gradual increase toward prepregnant levels by term.

Cardiac output

Rises 30%–50%.

Heart rate

Rises by 15–20 beats per minute (bpm).

Renal blood flow

Rises by 80% above baseline.

Glomerular filtration rate

150–200 ml/min (rises 40%–50% above baseline).

Serum chemistry and hematologic changes

Hemoglobin

Decreases by an average of 2 g/L (from 13 g/L to 11 g/L) owing to plasma volume expansion out of proportion to the increase in red blood cell mass.

Creatinine

Falls to 0.4–0.5 mg/dL.

Uric acid

Falls to a nadir of 2.0–3.0 mg/dL by 22–24 wk, then rises back to nonpregnant levels toward term.

pH

Increases slightly to 7.44.

PCO2

Decreases by about 10 mm Hg to an average of 27–32 mm Hg.

Calcium

Increased calcitriol stimulates increased intestinal calcium reabsorption and increased urinary calcium excretion.

Sodium

Falls by 4–5 mEq/L below nonpregnancy levels.

Osmolality

Falls to a new osmotic set point of about 270 mOsm/kg.

 

 

 

000848

000519

FIGURE 44-1  Changes in mean arterial pressure in normal gestation. Mean arterial blood pressure (MAP) according to gestational age in weeks in a large representative cohort of pregnant women followed longitudinally.  (Adapted from Thadhani R, Ecker JL, Kettyle E, et al: Pulse pressure and risk of preeclampsia: A prospective study. Obstet Gynecol 97(4):515–520, 2001.)

000519

 

 

000637

000519

FIGURE 44-2  Hemodynamic changes in pregnancy. Shown are the percent changes in heart rate, stroke volume, and cardiac output measured throughout pregnancy compared with prepregnancy values.  (Modified from Robson SC, Hunter S, Boys RJ, Dunlop W: Serial study of factors influencing changes in cardiac output during human pregnancy. Am J Physiol 256:H1060–1065, 1989.)

000519

 

 

The renin-aldosterone-angiotensin system is activated in pregnancy,[4] leading to renal salt and water retention. Increased renal interstitial compliance may also contribute to volume retention via an attenuation of the renal pressure natriuretic response.[5] Total body water increases by 6 to 8 L, leading to both plasma volume and interstitial volume expansion. Thus, most women have demonstrable clinical edema at some point during pregnancy. There is also cumulative retention of about 950 mmol of sodium distributed between the maternal extracellular compartments and the fetus.[6] The plasma volume increases out of proportion to the red blood cell mass, leading to mild physiologic anemia.[7] Plasma volume expansion is followed by increased atrial natriuretic peptide (ANP) secretion by the late first trimester.[2]

Renal Adaptation to Pregnancy

In pregnancy, the kidney length increases 1 to 1.5 cm and kidney volume increases by up to 30%.[8] There is physiologic dilatation of the urinary collecting system with hydronephrosis in up to 80% of women, usually more prominent on the right than on the left. These changes are likely due to mechanical compression of the ureters between the gravid uterus and the linea terminalis.[9] Estrogen, progesterone, and prostaglandins may also affect ureteral structure and peristalsis. Hydronephrosis of pregnancy is usually asymptomatic, but abdominal pain, and rarely, obstruction, can occur (see Obstructive Uropathy and Nephrolithiasis).

The glomerular filtration rate (GFR) increases by 40% to 65% as a result of an even larger increase in renal blood flow ( Fig. 44-3 ).[10] This increase occurs by the early second trimester and is maintained until the middle of the third trimester when renal blood flow begins to decline toward prepregnancy levels. The increase in GFR results in a physiologic decrease in circulating creatinine, blood urea nitrogen (BUN), and uric acid levels. Normal creatinine clearance in pregnancy rises to 150 to 200 mL/min, and average serum creatinine falls from 0.8 mg/dL to 0.5 to 0.6 mg/dL. Hence, a serum creatinine of 1.0 mg/dL, which would be considered normal in a nonpregnant individual, reflects renal impairment in a pregnant woman. Similarly, BUN falls from an average of 13 mg/dL in the nonpregnant state to approximately 8 to 10 mg/dL. Although proteinu-ria is not a feature of normal pregnancy, women with preexisting proteinuric renal disease have an exacerbation of proteinuria in the second and third trimesters, which is more exaggerated than that which would be expected from the increased GFR alone[11] (see below, Chronic Kidney Disease and Pregnancy).

000051

000519

FIGURE 44-3  Effect of pregnancy on glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Renal plasma flow rises out of proportion to the GFR, leading to a decrease in filtration fraction. Both peak at mid gestation at approximately 50% and 80% above prepregnancy levels, and fall slightly toward term.  (From Davison JM: Overview: Kidney function in pregnant women. Am J Kidney Dis 9:248, 1987.)

000519

 

 

Serum uric acid declines in early pregnancy because of the rise in GFR, reaching a nadir of 2.0 to 3.0 mg/dL by 22 to 24 weeks.[12] Thereafter, the uric acid level begins to rise, reaching nonpregnant levels by term. The late gestational rise in uric acid levels is attributed to increased renal tubular absorption of urate.

Pregnancy is characterized by several changes in renal tubular function. Owing to the large increase in GFR, glomerular tubular balance requires a concomitant increase in tubular solute reabsorption in order to avoid excessive renal losses. The kidney achieves this balance flawlessly, and sodium balance is maintained normally: Pregnant women have normal excretion of an exogenous solute load and appropriately conserve sodium when intake is restricted.[13]

The ability to excrete a water load is also normally maintained, albeit at a lower osmotic set-point. The osmotic threshold for stimulation of both antidiuretic hormone (ADH) release and thirst is decreased by a mechanism that appears to be mediated by human chorionic gonadotropin (hCG).[14] This results in mild hyponatremia: The serum sodium typically falls by 4 to 5 mEq/L below nonpregnancy levels. Animal studies suggest increased aquaporin 2 expression in collecting tubules may also contribute to this effect.[15]

Mild glucosuria and aminoaciduria can occur in normal pregnancy in the absence of hyperglycemia or renal disease. These are believed to be due to a combination of the increased filtered load of glucose and amino acids together with less efficient tubular reabsorption.

Respiratory Alkalosis of Pregnancy

Minute ventilation begins to rise by the end of the first trimester and continues to increase until term. Progesterone mediates this response by direct stimulation of respiratory drive and by increasing sensitivity of the respiratory center to CO2.[16] This results in a mild respiratory alkalosis—Pco2 falls to approximately 27 to 32 mm Hg—and a compensatory increase in renal excretion of bicarbonate. This large increase in minute ventilation allows maintenance of high-normal Po2 despite the 20% to 33% increase in oxygen consumption in pregnancy.

Mechanism of Vasodilation in Pregnancy

The mechanisms mediating the widespread pregnancy-induced decrease in vascular tone are not fully understood. The fall in SVR is only partially attributable to the presence of the low-resistance circulation in the pregnant uterus, as blood pressure and SVR are noted to fall before this system is well developed. Reduced vascular responsiveness to vasopressors such as angiotensin 2, norepinephrine, and vasopressin in pregnancy is well documented ( Fig. 44-4 ).[17] The mechanisms of this primary systemic vasodilatory response are not fully understood, but they likely reflect effects of several hormones and signaling pathways, including estrogen, progesterone, and prostaglandins.

000079

000519

FIGURE 44-4  Effect of pregnancy on sensitivity to the pressor effects of angiotensin II. The ordinate displays the dose of angiotensin II needed to raise diastolic blood pressure 20 mm Hg. In normal pregnancy (closed circles; N = 120), a higher dose was required than for nonpregnant women (dashed line). In women in whom preeclampsia ultimately developed (open circles; N = 72), insensitivity to angiotensin II was lost beginning in the mid-second trimester.  (From Gant NF, Daley GL, Chand S, et al: A study of angiotensin II pressor response throughout primigravid pregnancy. J Clinical Investig 52:2682–2689, 1973, by copyright permission of the American Society for Clinical Investigation.)

000519

 

 

Pregnancy differs fundamentally from other conditions of peripheral vasodilation, such as sepsis, cirrhosis, and high-output congestive heart failure, all of which are characterized by increased, rather than decreased, renal vascu-lar resistance. This suggests that, in pregnancy, there is a specific renal vasodilating effect that overrides vasoconstricting factors such as renin-angiotensin-aldosterone activation. Recent advances—mostly from studies of preg-nant rats—have suggested the hormone relaxin may central to this global vasodilatory response.[18] Relaxin is a 6-kDa peptide hormone first isolated from pregnant serum in the 1920s and noted to produce relaxation of the pelvic ligaments.[19] Relaxin is released predominantly from the corpus luteum and rises early in gestation in response to hCG. Relaxin facilitates increased endothelin and nitric oxide production in the renal circulation, leading to generalized renal vasodilation, decreased renal afferent and efferent arteriolar resistance, and a subsequent increase in renal blood flow and GFR.

The low-resistance, high-flow circulation of the fetoplacental unit also contributes to the low SVR characteristic of the second and third trimesters of pregnancy. During placental development, the high-resistance uterine arteries are transformed into larger-caliber capacitance vessels ( Fig. 44-5, upper panel ). This transformation appears to be driven by invasion of the maternal spiral arteries by fetal-derived cytotrophoblasts, which transform from an epithelial to an endothelial phenotype as they replace the endothelium of the maternal spiral arteries.[20] The mechanisms governing this process, termed pseudovasculogenesis, are still being elucidated. Angiogenic factors, such asvascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt1), and the angiopoiten receptors Tie-1 and Tie-2 have a complex spatial and temporal expression in developing placenta, and these factors may be involved in placental vascular development. [20] [21] Increased skin capillary density in pregnancy[22] suggests that angiogenic factors may be acting systemically as well as locally in the placenta. Dysregulation of these angiogenic factors may contribute to disorders of placental vasculogenesis, such as preeclampsia. This is more fully discussed under Pathogenesis of Preeclampsia.

000196

000519

FIGURE 44-5  Placentation in normal and preeclamptic pregnancies. In normal placental development, invasive cytotrophoblasts of fetal origin invade the maternal spiral arteries, transforming them from small-caliber resistance vessels to high-caliber capacitance vessels capable of providing placental perfusion adequate to sustain the growing fetus. During the process of vascular invasion, the cytotrophoblasts differentiate from an epithelial phenotype to an endothelial phenotype, a process referred to as pseudovasculogenesis or vascular mimicry (upper panel). In preeclampsia, cytotrophoblasts fail to adopt an invasive endothelial phenotype. Instead, invasion of the spiral arteries is shallow and they remain small-caliber resistance vessels (lower panel).  (From Lam C, Kim KH, Karumanchi SA: Circulating angiogenic factors in the pathogenesis and prediction of preeclampsia. Hypertension 46:1077–1085, 2005.)

000519

 

 

PREECLAMPSIA AND THE HELLP SYNDROME

Preeclampsia is systemic syndrome that is specific to pregnancy, characterized by the new onset of hypertension and proteinuria after 20 weeks' gestation. Preeclampsia affects approximately 3% to 5% of pregnancies worldwide.[23]Despite many advances in our understanding of the pathophysiology of preeclampsia, delivery of the neonate remains the only definitive treatment. Hence, preeclampsia is still a leading cause of preterm birth and consequent neonatal morbidity and mortality in the developed world. In developing countries, where access to safe, emergent delivery is less readily available, preeclampsia continues to claim the lives of over 60,000 mothers every year.[23]

Epidemiology and Risk Factors

The incidence of preeclampsia varies among populations. Most cases of preeclampsia occur in healthy nulliparous women in whom the incidence of preeclampsia has been reported as high as 7.5%.[24] Although classically a disorder of first pregnancies, multiparous women who are pregnant with a new partner appear to have an elevated preeclampsia risk similar to that of nulliparous women.[25] This effect may be due to increased interpregnancy interval rather than the change in partner per se.[26]

Although most cases of preeclampsia occur in the absence of a family history, the presence of preeclampsia in a first-degree relative increases a woman's risk of severe preeclampsia two- to fourfold,[27] suggesting a genetic contribution to the disease. Several large genomewide scans seeking a specific linkage to preeclampsia have been fairly discordant and disappointing, with significant logarithm of the odds (LOD) scores in isolated Finnish (2p25, 9p13)[28] and Icelandic (2p12)[29] populations. Specific genetic mutations consistent with these loci have remained elusive.

Several medical conditions are associated with increased preeclampsia risk, including chronic hypertension, diabetes mellitus, renal disease, and hypercoagulable states ( Table 44-2 ). Women with preeclampsia in a prior pregnancy have a high risk of preeclampsia in subsequent pregnancies. Conditions associated with increased placental mass, such as multifetal gestations and hyatidiform mole, are also associ ated with increased preeclampsia risk. Trisomy 13 is associated with a high risk of preeclampsia.[30] Although none of these risk factors is fully understood, they have provided insights into pathogenesis.


TABLE 44-2   -- Major Risk Factors for Preeclampsia

Risk Factor

OR or RR (95% CI)

Antiphospholipid antibody syndrome

9.7 (4.3–21.7)[31]

Renal disease

7.8 (2.2–28.2)[294]

Prior preeclampsia

7.2 (5.8–8.8)[31]

Systemic lupus erythematosis

5.7 (2.0–16.2)[295]

Nulliparity

5.4 (2.8–10.3)[296]

Chronic hypertension

3.8 (3.4–4.3)[297]

Diabetes mellitus

3.6 (2.5–5.0)[31]

High altitude

3.6 (1.1–11.9)[298]

Multiple gestations

3.5 (3.0–4.2)[299]

Strong family history of cardiovascular disease (heart disease or stroke in two or more first-degree relatives)

3.2 (1.4–7.7)[300]

Obesity

2.5 (1.7–3.7)[301]

Family history of preeclampsia in first-degree relative

2.3–2.6 (1.8–3.6)[27]

Advanced maternal age (>40 yr)

1.68 (1.23–2.29) for nulliparas
1.96 (1.34–2.87) for multiparas[31]

 

CI, confidence interval; OR, odds eatio; RR, relative risk.

 

 

 

Several putative risk factors remain controversial. Teen pregnancy has been identified as a risk factor in some studies, but this was not confirmed in a meta-analysis and systematic review.[31] Congenital or acquired thrombophilia is associated with preeclampsia in some [32] [33] but not all[34] studies. Racial differences in the incidence and severity of preeclampsia have been difficult to assess owing to confounding by socioeconomic and cultural factors. Although population-based studies have reported a higher rate of preeclampsia among African American women, these findings have not been confirmed in studies confined to healthy, nulliparous women. [35] [36] This suggests that the increased preeclampsia incidence noted in some studies may be attributable to the higher rate of chronic hypertension in African Americans, as chronic hypertension is itself a strong risk factor for preeclampsia (see Table 44-2 ).[37] African American women with preeclampsia also have a higher case-mortality rate,[38] which may be due to more severe disease or to deficiencies in prenatal care. In Hispanics, the incidence of preeclampsia appears to be increased, with a concomitant decrease in risk of gestational hypertension.[39]

The possibility that infectious agents contribute to preeclampsia risk has continued to have sporadic support. Both anti-cytomegalovirus (CMV) and anti-Chlamydia antibody (immunoglobulin G [IgG]) titers are increased in women with early-onset preeclampsia compared with women with late-onset preeclampsia and normal controls.[40] The association with Chlamydia is particularly interesting given its association with coronary and other vascular diseases, which share many common risk factors with preeclampsia. There are case reports of preeclampsia with parvovirus B19 infection.[41] Other viral infections, such as herpes simplex virus-2 (HSV-2) and Epstein-Barr virus (EBV), have been associated with a lower incidence of preeclampsia.[42] However, known infectious agents do not have a primary role in the majority of cases of preeclampsia.

Preeclampsia: Diagnosis and Clinical Features

The American College of Obstetrics and Gynecology published updated clinical criteria for the diagnosis of hypertensive disorders of pregnancy in 2002,[43] summarized in Table 44-3 . These guidelines help to distinguish preeclampsia, chronic hypertension in pregnancy, gestational hypertension, and chronic hypertension with superimposed preeclampsia. The diagnosis of preeclampsia in women with chronic hypertension and/or underlying proteinuric renal disease on clinical criteria alone remains challenging.


TABLE 44-3   -- Hypertensive Disorders of Pregnancy: Definitions and Classification

Preeclampsia

  

   

Hypertension: BP ≥140 mm Hg systolic or ≥90 mm Hg diastolic that occurs after 20 weeks' gestation in a woman with previously normal blood pressure, AND

  

   

Proteinuria: Excretion of ≥300 mg protein in a 24-hr urine specimen

Severe Preeclampsia

Preeclampsia with one or more of the following:

  

   

Systolic BP ≥160 mm Hg or diastolic BP ≥110 mm Hg on two occasions at least 6 hr apart while on bedrest

  

   

Proteinuria >5 g in a 24-hr urine specimen or dipstick proteinuria ≥3+ on two random urine samples at least 4 hr apart

  

   

Oliguria (<500 mL urine output over 24 hr)

  

   

Severe headache, mental status changes, or visual disturbances

  

   

Pulmonary edema or cyanosis

  

   

Epigastric or right-upper quadrant pain

  

   

Hepatocellular injury (transaminase elevation to at least twofold over normal levels)

  

   

Thrombocytopenia (<100,000 plts/mm3)

  

   

Fetal growth restriction

  

   

Cerebrovascular accident

Gestational hypertension

New-onset hypertension without proteinuria after 20 weeks' gestation

Chronic hypertension

Hypertension documented before the 20th wk of pregnancy[†]

Eclampsia

New-onset grand mal seizures during pregnancy or within 4 wk postpartum in a woman with preeclampsia

Preeclampsia superimposed on chronic hypertension

If proteinuria prior to 20 wk is absent:

  

   

New-onset proteinuria in a woman with chronic hypertension

 

If proteinuria prior to 20 wk is present, any of the following raise concern for superimposed preeclampsia:

  

   

A sudden increase in proteinuria

  

   

A sudden increase in hypertension

  

   

Thrombocytopenia

  

   

Increased in liver enzymes

Adapted from American College of Obstetricians and Gynecologists: ACOG Practice Bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Int J Gynaecol Obstet 77(1):67–75, 2002.

* Dipstick proteinuria (≥1+) or spot urine protein-to-creatinine ratio >0.3 are suggestive and should be followed-up with 24-hr urine collection.

 

Hypertension first noted after 20 wk that subsequently persists longer than 6 wk postpartum is retrospectively classified as chronic hypertension.

 

 

Hypertension

For the diagnosis of preeclampsia, hypertension is defined as a systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher after 20 weeks' gestation in a woman with previously normal blood pressure.[43] Hypertension should be confirmed by two separate measurements at least 2 hours apart. The severity of hypertension in preeclampsia can vary widely, from mild blood pressure elevations easily managed with bedrest alone to severe hypertension associated with headache and visual changes resistant to multiple medications. The latter situation can often herald seizures (eclampsia) and is an indication for urgent delivery. Medical management of hypertension in preeclampsia is discussed in the next section.

Proteinuria

The urine dipstick is widely used to screen for proteinuria during routine prenatal monitoring throughout pregnancy. However, the urine dipstick has a notoriously high rate of false positives (owing to the presence of blood, drugs, or a highly concentrated or alkaline urine sample) and false negatives (owing to low specific gravity, high acidity, or nonalbumin proteinuria) when compared with 24-hour urine protein measurement. A recent review found that the sensitivity and specificity of dipstick proteinuria (≤1+ level) was universally poor for the prediction of significant proteinuria (>300 mg) by 24-hour collection.[44] The urine protein-to-creatinine ratio (expressed in units of mg protein per mg creatinine) is widely used in the nonobstetric population to estimate of 24-hour protein excretion. Most studies comparing the spot urine protein-to-creatinine ratio in pregnant subjects suggest a strong correlation with 24-hour urinary protein excretion. [45] [46] [47] These studies suggest that a spot urine protein-to-creatinine ratio greater than 0.2 mg/mg is highly sensitive (>90%) for the detection of significant (>300 mg) proteinuria by 24-hour collection in pregnant women in the third trimester. Although not as widely utilized in the obstetrics community as it is among nephrologists, the urine protein-to-creatinine ratio is an excellent tool to estimate the degree of proteinuria in women with hypertension during pregnancy.

The degree of proteinuria in preeclampsia can range widely from minimal to nephrotic. In fact, women with gestational hypertension without proteinuria occasionally have other features of severe preeclampsia and should be treated as such. When proteinuria exceeds 5 g/day, the patient is classified as having severe preeclampsia (see Table 44-3 ). However, the degree of proteinuria does not appear to be an independent risk factor for adverse maternal or neonatal outcomes[48]; thus, heavy proteinuria alone is not an indication for urgent delivery.

Edema

Although edema was historically part of the diagnostic triad for preeclampsia, it is also recognized to be a feature of normal pregnancy, diminishing its usefulness as a specific pathologic sign. Still, the sudden onset of severe edema—especially edema of the hands and face—can be an important presenting symptom in this otherwise insidious disease and should prompt evaluation.

Uric Acid

Serum uric acid is elevated in preeclampsia, primarily as a result of enhanced tubular urate reabsorption. It has been suggested that hyperuricemia may contribute to the pathogenesis of preeclampsia by inducing endothelial dysfunction.[49] Serum uric acid levels are correlated with the presence and severity of preeclampsia and with adverse pregnancy outcomes,[50] even in gestational hypertension without proteinuria.[51] Unfortunately, uric acid is of limited clinical utility either in distinguishing preeclampsia from other hypertensive disorders of pregnancy or as a clinical predictor of adverse outcomes. [52] [53] A recent meta-analysis of almost 4000 women from 18 studies concluded that serum uric acid is a poor predictor of maternal and fetal complications in women with preeclampsia.[54] One clinical scenario in which serum uric acid may be useful is in the diagnosis of preeclampsia in women with CKD, in whom the usual diagnostic criteria of new-onset hypertension and proteinuria are often impossible to apply. In such patients, a serum uric acid level greater than 5.5 mg/dL in the presence of stable renal function can suggest superimposed preeclampsia.

Clinical Features of Severe Preeclampsia

Several clinical and laboratory findings suggest severe or progressive disease and should prompt consideration of pregnancy termination (see Table 44-3 ). Oliguria (<500 mL urine in 24 hr) is usually transient; AKI, although uncommon, can occur. Persistent headache or visual disturbances can be a prodrome to seizures. Pulmonary edema complicates 2% to 3% of severe preeclampsia[25] and can lead to respiratory failure. Epigastric or right upper quadrant pain may be associated with liver injury. Elevated liver enzymes can occur alone or as part of the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome (see later).

Eclampsia

Seizures complicate approximately 2% of preeclampsia cases in the United States.[55] Although eclampsia most often occurs in the setting of hypertension and proteinuria, it can occur without these warning signs. Up to one third of eclampsia occurs postpartum, sometimes days to weeks after delivery.[56] Late postpartum preeclampsia in particular is often a difficult and potentially missed diagnosis, often seen by nonobstetricians in the emergency room. Radiologic imaging by head computed tomography (CT) or magnetic resonance imaging (MRI) is usually not indicated when the diagnosis is apparent, but typically shows vasogenic edema, predominantly in the subcortical white matter of the parieto-occipital lobes (see Cerebral Changes).

HELLP Syndrome

HELLP is an acronym for the syndrome of hemolytic anemia, elevated liver enzymes, and low platelets. There remains considerable confusion and variability regarding the precise diagnostic criteria for the HELLP syndrome in the medical literature ( Table 44-4 ). The HELLP syndrome is generally considered to be a severe variant of preeclampsia, although it can occur in the absence of proteinuria. The HELLP syndrome is associated with increased maternal and neonatal adverse outcomes compared with preeclampsia alone, including eclampsia (affecting 6% of cases), placental abruption (10%), AKI (5%), disseminated intravascular coagulation (8%), pulmonary edema (10%),[57] and rarely, hepatic hemorrhage and rupture.[58]


TABLE 44-4   -- Comparison of Clinical and Laboratory Characteristics of HELLP, TTP/HUS, and AFLP

Clinical Feature

HUS/TTP

Preeclampsia/HELLP

AFLP

Hemolytic anemia

+++

++

±

Thrombocytopenia

+++

++

±

Coagulopathy

-

±

±

CNS symptoms

++

±

±

Liver disease

±

+++

+++

Renal failure

++

+

++

Hypertension

±

++

±

Proteinuria

±

++

±

Elevated AST

±

++

++

Elevated bilirubin

++

+

++

Anemia

++

+

±

Ammonia

Normal

Normal

High

Effect of delivery on disease

None

Recovery

Recovery

Management

Plasma exchange

Supportive care, delivery

Supportive care, delivery

Data derived from Allford SL, Hunt BJ, Rose P, Machin SJ: Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol 120(4):556–573, 2003; and Egerman RS, Sibai BM: Imitators of preeclampsia and eclampsia. Clin Obstet Gynecol 42(3):551–562, 1999.

AFLP, acute fatty liver of pregnancy; AST, aspartate transaminase; CNS, central nervous system; HELLP, hemolysis, elevated liver enzymes, and low platelets; TTP/HUS, hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura.

 

 

 

 

Maternal and Neonatal Mortality

Approximately 500,000 women die in childbirth each year worldwide,[59] and preeclampsia and eclampsia are estimated to account for 10% to 15% of these deaths.[60] In the United States, preeclampsia and eclampsia account for 20% of all pregnancy-related maternal mortality.[38] Maternal death is most often due to eclampsia, cerebral hemorrhage, kidney failure, hepatic failure, and the HELLP syndrome. Risk of death in preeclampsia is increased for women with little or no prenatal care, women of black race, those over age 35, and those with early-onset preeclampsia.[38] Adverse maternal outcomes can often be avoided with timely delivery; hence, in the developed world, the burden of morbidity and mortality falls on the neonate.

Worldwide, preeclampsia is associated with a perinatal and neonatal mortality rate of 10%[61]; as with maternal mortality, risk of neonatal mortality increases substantially for preeclampsia presenting earlier in gestation. Neonatal death is most commonly due to iatrogenic prematurity undertaken to preserve the health of the mother. In addition, intrauterine growth restriction (IUGR) can occur, likely as a result of impaired uteroplacental blood flow or placental infarction. Oligohydramnios and placental abruption are less common complications.

Postpartum Recovery

Generally, preeclampsia begins to remit soon after delivery of the fetus and placenta, and complete recovery is the rule. However, normalization of blood pressure and proteinuria often takes days to weeks.[62] Postpartum monitoring is important because eclampsia can occur after delivery.

Long-Term Cardiovascular and Renal Outcomes

Traditionally, women with preeclampsia have been re-assured that the syndrome remits completely after delivery, with no long-term consequences aside from increased preeclampsia risk in future pregnancies. Epidemiologic studies have tempered this claim. Approximately 20% of women with preeclampsia develop hypertension or microalbu-minuria with long-term follow-up.[63] Risk of subsequent cardiovascular and cerebrovascular disease is doubled in women with preeclampsia and gestational hypertension compared with age-matched controls. [64] [65] This increase in subsequent cardiovascular disease is present for both preeclampsia and gestational hypertension,[64] suggesting either common risk factors or a common pathophysiology in these two syndromes. Severe preeclampsia, recurrent preeclampsia, preeclampsia with preterm birth, and preeclampsia with IUGR are most strongly associated with adverse cardiovascular outcomes ( Fig. 44-6 ). Preeclampsia, especially in association with low neonatal birthweight, also carries an increased risk of later maternal kidney disease requiring a kidney biopsy.[66]

FIGURE 44-6  Preeclampsia increases risk for cardiovascular disease later in life. Kaplan-Meier plot of cumulative probability of survival without admission to hospital for ischemic heart disease or death from ischemic heart disease in women with and without a history of preeclampsia. (From Smith GC, Pell JP, Walsh D: Pregnancy complications and maternal risk of ischaemic heart disease: A retrospective cohort study of 129,290 births. Lancet 357:2002–2006, 2001.)



Preeclampsia and cardiovascular disease share many common risk factors, such as chronic hypertension, diabetes, obesity, kidney disease, and the metabolic syndrome. Still, the increase in long-term cardiovascular mortality holds even for women who develop preeclampsia in the absence of any overt vascular risk factors. Whether these observations result from vascular damage or persistent endothelial dysfunction caused by preeclampsia, or simply reflect the common risk factors shared by preeclampsia and cardiovascular disease, remains speculative.

Epidemiologic evidence suggests that low birth weight (with or without preeclampsia) is associated with the development of hypertension, diabetes, cardiovascular disease, and CKD in the offspring of affected pregnancies.[67] It has been hypothesized that this may be due to low nephron number.

Pathogenesis of Preeclampsia

The Role of the Placenta

Observational evidence suggests the placenta has a central role in preeclampsia. Preeclampsia occurs only in the presence of a placenta—although not necessarily a fetus, as in the case of hyatidiform mole—and almost always remits after its delivery. In a case of preeclampsia with extrauterine pregnancy, removal of the fetus alone was not sufficient; symptoms persisted until the placenta was delivered.[68] Severe preeclampsia is associated with pathologic evidence of placental hypoperfusion and ischemia. Findings include acute atherosis, a lesion of diffuse vascular obstruction, which includes fibrin deposition, intimal thickening, necrosis, atherosclerosis, and endothelial damage.[69]Infarcts, likely owing to occlusion of maternal spiral arteries, are also common. Although these findings are not universal, they appear to be correlated with severity of clinical disease.[70]

Abnormal uterine artery Doppler ultrasound, consistent with decreased uteroplacental perfusion, is observed before the clinical onset of preeclampsia.[71] Unfortunately, this finding is nonspecific, limiting its use as a routine screen-ing test if used alone.[72] The incidence of preeclampsia is increased two- to fourfold in women residing at high altitude, implying hypoxia may be a contributing factor.[73] Hypertension and proteinuria can be induced by constriction of uterine blood flow in pregnant primates and other mammals. These observations suggest placental ischemia may be an early event.

However, evidence for a causative role for placental ischemia alone remains circumstantial, and several observations call the hypothesis into question. For example, the animal models based on uterine hypoperfusion fail to induce several of the multiorgan features of preeclampsia, including seizures and glomerular endotheliosis, the hallmark renal pathologic finding. In most cases of preeclampsia, there is no evidence of growth restriction or fetal intolerance of labor, expected consequences of placental ischemia. Pregnant subjects with sickle cell disease, who often have pathologic evidence of placental ischemia and infarction, do not appear to have an increased risk for preeclampsia,[74]although not all studies confirm this observation.[75] It may be that the placental ischemic damage that accompanies late-stage preeclampsia may be a secondary event.

Placental Vascular Remodeling

Early in normal placental development, extravillous cytotrophoblasts invade the uterine spiral arteries of the decidua and myometrium (see Fig. 44-5 ). These invasive fetal cells replace the endothelial layer of the uterine vessels, transforming them from small resistance vessels to flaccid, high-caliber capacitance vessels.[76] This vascular transformation allows the increase in uterine blood flow needed to sustain the fetus through the pregnancy. In preeclampsia, this transformation is incomplete.[77] Cytotrophoblast invasion of the arteries is limited to the superficial decidua, and the myometrial segments remain narrow and undilated.[78] Zhou and co-workers[79] have shown that, in normal placental development, invasive cytotrophoblasts down-regulate the expression of adhesion molecules characteristic of their epithelial cell origin and adopt an endothelial cell-surface adhesion phenotype, a process dubbed pseudovasculogenesis. In preeclampsia, cytotrophoblasts do not undergo this switching of cell-surface integrins and adhesion molecules and fail to adequately invade the myometrial spiral arteries.

The factors that regulate this process are just beginning to be elucidated. Hypoxia-inducible factor-1 (HIF-1) activity is increased in preeclampsia, and HIF-1 target genes such as transforming growth factor-β3 (TGF-β3) may block cytotrophoblast invasion.[80] Invasive cytotrophoblasts express several angiogenic factors and receptors, also regulated by HIF, including VEGF, PlGF, and VEGF receptor-1 (VEGFR-1) Flt1; expression of these proteins by immunolocalization is altered in preeclampsia.[81] A genetic study recently identified polymorphisms in STOX1, a paternally imprinted gene and member of the winged helix gene family, in a Dutch preeclampsia cohort.[82] The authors hypothesized that loss-of-function mutations in this gene could result in defective polyploidization of extravillous trophoblast, leading to loss of cytotrophoblast invasion. More work is needed to uncover the molecular signals governing cytotrophoblast invasion early in placentation, defects in which may underlie the early stages of preeclampsia.

Maternal Endothelial Dysfunction

Although the origins of the preeclampsia syndrome appear to be placental, the target organ is the maternal endothelium. The clinical manifestations of preeclampsia reflect widespread endothelial dysfunction, resulting in vasoconstriction and end-organ ischemia. [83] [84] Incubation of endothelial cells with serum from women with preeclampsia results in endothelial dysfunction; hence, it has been hypothesized that factors present in maternal syndrome, likely originating in the placenta, are responsible for the manifestations of the disease ( Fig. 44-7 ).

FIGURE 44-7  Placental dysfunction and endothelial dysfunction in the pathogenesis of preeclampsia. Placental dysfunction, triggered by poorly understood mechanisms, which may include genetic, immunologic and environmental factors, plays an early and primary role in the development of preeclampsia. The diseased placenta in turn secretes a factor or factors into the maternal circulation, causing systemic endothelial cell dysfunction. Most of the manifestations of preeclampsia, including hypertension, proteinuria (glomerular endotheliosis), seizures (cerebral edema and/or vasospasm), and the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, can be attributed to vascular and endothelial effects.  (From Karumanchi SA, Maynard SE, Stillman IE, et al: Preeclampsia: A renal perspective. Kidney Int 67:2101–2113, 2005.)

 

 

Dozens of serum markers of endothelial activation are deranged in women with preeclampsia, including von Willebrand antigen, cellular fibronectin, soluble tissue factor, soluble E-selectin, platelet-derived growth factor, and endothelin.[84] C-reactive protein[85] and leptin[86] are increased early in gestation. There is evidence for oxidative stress and platelet activation.[87] Decreased production of prostacyclin, an endothelium-derived prostaglandin, occurs well before the onset of clinical symptoms.[88] Inflammation is often present; for example, there is neutrophil infiltration in the vascular smooth muscle of subcutaneous fat, with increased vascular smooth muscle expression of interleukin-8 (IL-8) and intercellular adhesion molecule 1 (ICAM-1).[89] Several of these aberrations occur well before the onset of symptoms, supporting the central role of endothelial dysfunction in the pathogenesis of preeclampsia.

Hemodynamic Changes

The decreases in peripheral vascular resistance and arterial blood pressure that occur during normal pregnancy are absent or reversed in preeclampsia. SVR is high and cardiac output is low when compared with those in normal pregnancies.[90] These changes are due to widespread vasoconstriction resulting from endothelial dysfunction. This hypothesis is supported by both in vivo and in vitro evidence. Women with preeclampsia have impaired endothelium-dependent vasorelaxation, which has been noted prospectively prior to onset of hypertension and proteinuria[91] and persists for years after the preeclampsia episode.[92] There is exaggerated sensitivity to vasopressors such as angiotensin II (Ang II) and norepinephrine (see Fig. 44-4 ).[84] Subtle increases in blood pressure and pulse pressure are present prior to the onset of overt hypertension and proteinuria, suggesting arterial compliance is decreased early in the course of the disease. [31] [93] Mechanisms underlying endothelial dysfunction are discussed in the next section.

Renal Changes

The pathologic swelling of glomerular endothelial cells in preeclampsia was first described in 1924.[94] Thirty years later, Spargo and colleagues[95] coined the term glomerular endotheliosis and characterized ultrastructural changes, including generalized swelling and vacuolization of the endothelial cells and loss of the capillary space ( Fig. 44-8 ). There are deposits of fibrinogen and fibrin within and under the endothelial cells, and electron microscopy shows loss of glomerular endothelial fenestrae.[96] The primary injury is specific to endothelial cells: The podocyte foot processes are intact early in the disease, a finding atypical of other nephrotic diseases. Changes in the afferent arteriole, including atrophy of the macula densa and hyperplasia of the juxtaglomerular apparatus, have also been described.[97] Although mild glomerular endotheliosis was once considered pathognomonic for preeclampsia, recent studies have shown that this also occurs in pregnancy without preeclampsia, especially in gestational hypertension.[98] This suggests the endothelial dysfunction of preeclampsia may in fact be an exaggeration of a process present near term in all pregnancies.

FIGURE 44-8  Glomerular endotheliosis. A, Human preeclamptic glomerulus, light microscopy (periodic acid-Schiff [PAS stain]). Renal biopsy findings of a 29-year-old woman with twin gestation and severe preeclampsia are shown. Patient's blood pressure was 170/112 mm Hg and random urine protein-to-creatinine ratio was 9.8. Note the “bloodless” appearance of the glomeruli and absent capillary lumen. Original magnification, 40×. B, Electron microscopy of glomerulus of the patient described in A. Note occlusion of capillary lumen cytoplasm and expansion of the subendothelial space with some electron-dense material. Podocyte cytoplasm shows protein resorption droplets and relatively intact foot processes. Original magnification, 1500×.  (Courtesy of IE Stillman.)



Both renal blood flow and GFR are low in preeclampsia as compared with normal pregnancy. Renal blood flow falls as a result of high renal vascular resistance, primarily owing to increased afferent arteriolar resistance. GFR falls as a result of both the fall in renal blood flow and a decrease in the ultrafiltration coefficient (Kf), attributed to endotheliosis in the glomerular capillary.[99] Although AKI can occur in preeclampsia, typically proteinuria (with a bland urinary sediment) and renal sodium and water retention are the only renal manifestations of disease.

Cerebral Changes

Cerebral edema and intracerebral parenchymal hemorrhage are common autopsy findings in women who died from eclampsia. The presence of cerebral edema in eclampsia correlates with markers of endothelial damage but not the severity of hypertension,[100] suggesting the edema is secondary to endothelial dysfunction rather than a direct result of blood pressure elevation. Findings on head CT and MRI are similar to those seen in hypertensive encephalopathy, with vasogenic cerebral edema and infarctions in the subcortical white matter and adjacent gray matter, predominantly in the parieto-occipital lobes.[56] A syndrome that includes these characteristic MRI changes, together with headache, seizures, altered mental status, and hypertension, has been described in patients with acute hypertensive encephalopathy in the setting of renal disease, eclampsia, or immunosuppression.[101] This syndrome, termed reversible posterior leukoencephalopathy, has subsequently been associated with the use of antiangiogenic agents for cancer therapy.[102] This supports the role of innate antiangiogenic factors in the pathophysiology of preeclampsia/eclampsia, as detailed later in this section.

The Renin-Angiotensin-Aldosterone System

In preeclampsia, plasma renin levels are suppressed relative to those in normal pregnancy as a secondary response to systemic vasoconstriction and hypertension. As noted in the prior section, preeclampsia is characterized by increased vascular responsiveness to Ang II and other vasoconstric-tive agents. Wallukat and associates[103] identified agonistic angiotensin-1 receptor (AT1) autoantibodies in women with preeclampsia. They hypothesized that these antibodies, which activate the AT1 receptor, may account for the increased Ang II sensitivity of preeclampsia. The same investigators later showed that these AT1 autoantibodies, like Ang II itself, stimulate endothelial cells to produce tissue factor, an early marker of endothelial dysfunction. Xia and co-workers[104] found AT1 autoantibodies decreased invasiveness of immor talized human trophoblasts in an in vitro invasion assay, suggesting these autoantibodies might contribute to defective placental pseudovasculogenesis as well. AT1 autoantibodies are not limited to pregnancy; they also appear to be increased in malignant renovascular hypertension and vascular rejection in nonpregnancy.[105] In addition, these antibodies have been identified in women with abnormal second trimester uterine artery Doppler studies who did not develop preeclampsia, suggesting this antibody may be a nonspecific response to placental hypoperfusion.[106]

The angiotensinogen T235 polymorphism, a common molecular variant associated with essential hypertension and microvascular disease, was associated with preeclampsia in U.S. and Japanese cohorts. [107] [108] Functional aspects of this mutation are unclear, however, and the association was not confirmed in a British population.[109] Work by Abdalla and colleagues[110] have suggested that heterodimerization of AT1 receptors with bradykinin 2 receptors may contribute to Ang II hypersensitivity in preeclampsia. This work remains to be validated in other studies.

Oxidative Stress

Oxidative stress, the presence of reactive oxygen species in excess of antioxidant buffering capacity, is a prominent feature of preeclampsia. Oxidative stress is known to damage proteins, cell membranes, and DNA and is a potential mediator of endothelial dysfunction. It has been hypothesized that, in preeclampsia, placental oxidative stress is transferred to the systemic circulation, resulting in oxidative damage to the maternal vascular endothelium.[111]However, the absence of any clinical benefit of antioxidant supplementation in the prevention of preeclampsia (see later) suggests that oxidative stress is likely to be a secondary phenomenon in pre-eclampsia and not a promising therapeutic target. Circulating placental cytotrophoblast debris and the accompanying inflammation have also been proposed as a pathogenic mechanism to explain the maternal endothelial dysfunction; however, causal evidence for this hypothesis is still lacking.[112]

Immunologic Intolerance

The possibility of immune maladaption remains an intriguing but unproven theory of the pathogenesis of preeclampsia. Normal placentation requires the development of immune tolerance between the fetus and the mother. The fact that preeclampsia occurs more often in first pregnancies or after a change in partners suggests an etiologic role for abnormal maternal immune response to paternally derived fetal antigens. This could result in failure of fetal cells to successfully invade the maternal vessels during placental vascular development.

Observational studies suggest that preeclampsia risk increases in cases of exposure to novel paternal antigens—not only in first pregnancies but also in pregnancies with a new partner[113] and with long interpregnancy interval.[26]Women using contraceptive methods that reduce exposure to sperm have increased preeclampsia incidence.[114] Women impregnated by intracytoplasmic sperm injection (ICSI) in which sperm were surgically obtained (i.e., the woman was never exposed to the partner's sperm in intercourse) had a threefold increased risk of preeclampsia compared with ICSI cases in which sperm were obtained by ejaculation.[115] Conversely, prior exposure to paternal antigens appears to be protective. The risk of preeclampsia is inversely proportional to the length of cohabitation,[116] and oral tolerization to paternal antigens by oral sex and swallowing is associated with decreased risk.[117] None of these clinical observations has yet provided insights into immunologic triggers or pathogenic links to the paternal syndrome.

It has also been observed that, although women with untreated human immunodeficiency virus (HIV) have a low rate of preeclampsia, treatment with effective antiretroviral therapy raises preeclampsia risk back to that of the general population or even higher.[118] This suggests that an intact immune system is required for the development of preeclampsia.

On a molecular level, human leukocyte antigen G (HLA-G) expression appears to be abnormal in preeclampsia. HLA-G is normally expressed by invasive extravillous cytotrophoblasts and may play a role in inducing immune tolerance at the maternal-fetal interface. In preeclampsia, HLA-G expression by cytotrophoblasts is reduced or absent,[119] and HLA-G protein concentrations are reduced in maternal serum and in placental tissue.[120] These alterations in HLA-G expression could contribute to the ineffective trophoblast invasion seen in preeclampsia.

Angiogenic Imbalance

Emerging evidence suggests that excess placental production of soluble fms-like tyrosine kinase-1, a truncated splice variant of the VEGF receptor Flt1, contributes to the pathogenesis of preeclampsia. sFlt1 antagonizes VEGF and PlGF by binding them in the circulation and preventing interaction with their endogenous receptors ( Fig. 44-9 ). sFlt1 is up-regulated in the placenta of women with preeclampsia, resulting in elevated circulating levels.[121] The increase in maternal circulating sFlt1 precedes the onset of clinical disease ( Fig. 44-10 ) [122] [123] [124] and is correlated with disease severity. [124] [125] In vitro effects of sFlt1 include vasoconstriction and endothelial dysfunction. Exogenous sFlt1 administered to pregnant rats produces a syndrome resembling preeclampsia, including hypertension, proteinuria, and glomerular endotheliosis.[121] This work has suggested sFlt1 may be an important mediator in preeclampsia.

FIGURE 44-9  Proposed mechanism of sFlt1-induced endothelial dysfunction. sFlt-1 protein, derived from alternative splicing of Flt-1, lacks the transmembrane and cytoplasmic domains, but still has the intact vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) binding extracellular domain. During normal pregnancy, VEGF and PlGF signal through the VEGF receptors (Flt-1) and maintain endothelial health. In preeclampsia, excess sFlt-1 binds to circulating VEGF and PlGF, thus impairing normal signaling of both VEGF and PlGF through their cell-surface receptors. Thus, excess sFlt-1 leads to maternal endothelial dysfunction.  (From Bdolah Y, Sukhatme VP, Karumanchi SA: Angiogenic imbalance in the pathophysiology of preeclampsia: Newer insights. Semin Nephrol 24:548–556, 2004.)

 

 

FIGURE 44-10  Concentrations of sFlt1 in preeclampsia and normal pregnancy. Shown are the mean serum sFlt-1 concentrations (±standard error of mean [SEM]) before and after onset of clinical preeclampsia according to the gestational age of the fetus. The P values given are for comparisons, after logarithmic transformation, with specimens from controls obtained during the same gestational-age interval. All specimens were obtained before labor and delivery.  (From Levine RJ, Maynard SE, Qian C, et al: Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683, 2004.)

 

 

Derangements in other angiogenic molecules have also been observed. Levels of endostatin, another antiangiogenic factor, are elevated in preeclampsia.[126] A naturally occurring soluble form of Flk (VEGFR-2), the other major VEGF receptor, has been identified in placenta.[127] Its role, if any, in placental vasculogenesis or preeclampsia remains unknown. More recently, circulating levels of yet another placental antiangiogenic protein, soluble endoglin, have been reported to be elevated in patients with preeclampsia. Soluble endoglin amplifies the vascular damage mediated by sFlt1 in pregnant rats, inducing a severe preeclampsia-like syndrome with features of the HELLP syndrome.[128] The precise role of soluble endoglin and its relationship with sFlt1 is currently being explored.

Further circumstantial evidence suggests interference with VEGF signaling could mediate endothelial dysfunction in preeclampsia. VEGF appears to be important in the stabilization of endothelial cells in mature blood vessels. VEGF is particularly important in the health of the fenestrated and sinusoidal endothelium found in the renal glomerulus, brain, and liver[129]—organs disproportionately affected in preeclampsia. VEGF is highly expressed by glomerular podocytes, and VEGFRs are present on glomerular endothelial cells.[130] In experimental glomerulonephritis, VEGF is necessary for glomerular capillary repair.[131] In a podocyte-specific VEGF knock-out mouse, heterozygosity for VEGF-A resulted in renal disease characterized by proteinuria and glomerular endotheliosis.[132] In antiangiogenesis cancer trials, VEGF antagonists produce proteinuria and hypertension in human subjects. [133] [134] This evidence suggests that VEGF deficiency induced by excess sFtl1 has the capacity to produce the characteristic renal lesion of preeclampsia.

Alterations in circulating sFlt1 have been noted in certain preeclampsia risk groups. Higher sFlt1 levels have been noted in first versus second pregnancies[135] and in twin versus singleton pregnancies, [136] [137] potentially accounting for the increased preeclampsia risk in these groups. Conversely, decreased levels of sFlt1 in smokers[138] may explain the protective effect of smoking in preeclampsia.[139] The Flt1 gene is located on chromosome 13q12, and it is interesting to note that trisomy 13 has long been associated with preeclampsia.[30]

Angiogenic factors are likely to be important in the regulation of placental vasculogenesis. VEGF ligands and receptors are highly expressed by placental tissue in the first trimester[140] sFlt1 decreases cytotrophoblast invasiveness in vitro.[81] Circulating sFlt1 levels are relatively low early in pregnancy and begin to rise in the third trimester. This may reflect a physiologic antiangiogenic shift in the placental milieu toward the end of pregnancy, corresponding to completion of the vasculogenic phase of placental growth. It is intuitive to hypothesize that placental vascular development might be regulated by a local balance between pro- and antiangiogenic factors and that excess antiangiogenic sFlt1 in early gestation could contribute to inadequate cytotrophoblast invasion in preeclampsia. By the third trimester, excess placental sFlt1 is detectable in the maternal circulation, producing end-organ effects. In this case, placental ischemia may not be causative but, rather, the earliest organ affected by this derangement of angiogenic balance.

In addition to angiogenic alterations, women who develop preeclampsia also have evidence of insulin resistance,[141] and women with pregestational or gestational diabetes mellitus have an increased risk for developing preeclampsia.[31] In accordance with this finding, in vitro models suggest insulin signaling and angiogenesis are intimately related at a molecular level,[142] and recent epidemiologic data find that evidence of altered angiogenesis and excess insulin resistance may be additive insults that lead to preeclampsia.[143] Furthermore, altered levels of biomarkers linked with angiogenesis and insulin resistance persist in the postpartum state,[144] possibly explaining the long-term cardiovascular risk in these women. Finally, it is also interesting to note that women with preeclampsia appear to have a decreased risk of malignancy, [65] [145] suggesting that the antiangiogenic milieu of preeclampsia may extend beyond pregnancy.

Screening

Although there is not yet any definitive therapeutic or preventive strategy for preeclampsia, clinical experience suggests that early detection, monitoring, and supportive care are beneficial to the patient and the fetus. For example, lack of adequate antenatal care is strongly associated with poor outcomes, including eclampsia and fetal death.[146] Risk assessment early in pregnancy is important to identify those who require close monitoring after 20 weeks. Women with first pregnancies or any of the risk factors in Table 44-2 should be assessed every 2 to 3 weeks during the third trimester for the development of hypertension, proteinuria, headache, visual disturbances, or epigastric pain.

Higher systolic and diastolic blood pressure at the initiation of prenatal care, even in the absence of overt hyperten sion, is associated with elevated risk for preeclampsia in healthy nulliparous women.[147] Unfortunately, these small elevations in midtrimester blood pressure are subtle and the positive predictive value as a screening test is low (especially given the relatively low prevalence), limiting routine clinical utility.

Presumably as a result of failed placental vascular remodeling, preeclampsia is associated with increased placental vascular resistance in the second trimester, as measured by uterine artery Doppler ultrasound.[148] Several studies have investigated the use of uterine artery Doppler for prediction of preeclampsia. Test performance varies widely among studies based on differences in populations studied, the gestational age at the time of measurement, the definition of an abnormal result, and the severity and timing of preeclampsia detected: Sensitivities and specificities range from 65% to 85%. Meta-analyses have concluded that uterine artery Doppler has limited diagnostic accuracy in predicting preeclampsia, IUGR, or perinatal death. [148] [149] Thus, screening for preeclampsia using uterine artery Doppler is not common medical practice, at least in the United States. Recent data suggest, however, there may be promise in combining uterine artery Doppler with serum markers.[150]

Of dozens of putative serum markers for preeclampsia, only a handful have been shown to be elevated prior to the onset of clinical disease, and none has yet proved to be an effective and useful screening test for preeclampsia. Cellular fibronectin, a marker of endothelial injury, has been reported to be elevated as early 9 to 12 weeks in one study[151]; however, other studies have failed to find a significant increase until after the onset of clinical disease.[152] Initially promising work regarding a pathogenic role for the neuropeptide neurokinin-B has not yet been borne out in follow-up studies.[153]

Alterations in circulating levels of angiogenic factors occur weeks prior to the onset of preeclampsia and may be useful for screening and/or diagnosis. Significant elevations in maternal sFlt1 are observed from midgestation onward[122] [154] and appear to rise 5 to 8 weeks prior to preeclampsia onset (see Fig. 44-10 ).[124] Maternal sFlt1 levels are particularly elevated in severe preeclampsia, early-onset preeclampsia, and preeclampsia complicated by a small-for-gestation infant. [124] [155] Serum levels of PlGF are lower in women who go on to develop preeclampsia from the first[156] or early second [124] [157] [158] trimester, although not all studies have confirmed these findings ( Fig. 44-11 ).[159]

FIGURE 44-11  Concentrations of PlGF in preeclampsia and normal pregnancy. Shown are the mean serum PlGF concentrations (±SEM) before and after onset of clinical preeclampsia according to the gestational age of the fetus. The P values given are for comparisons, after logarithmic transformation, with specimens from controls obtained during the same gestational-age interval. All specimens were obtained before labor and delivery.  (From Levine RJ, Maynard SE, Qian C, et al: Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683, 2004.)

 

 

Because PlGF passes into the urine, low urinary PlGF has been identified as a potential marker for preeclampsia. Urinary levels of PlGF are significantly lower in women who develop preeclampsia from the late second trimester[160]and may prove to be useful in screening and diagnosis of preeclampsia, especially in early-onset and severe preeclampsia.

Prevention

Strategies to prevent preeclampsia have been studied intently over the last 20 years. Unfortunately, no intervention to date has yet proved unequivocally effective.

Antiplatelet Agents

Because of prominent alterations in prostacyclin-thromboxane balance in preeclampsia, aspirin has been posited as a preventive strategy. Aspirin and other antiplatelet agents have been evaluated for the prevention of preeclampsia in dozens of trials, both in high-risk groups and in healthy nulliparous women. For women at high risk for preeclampsia, several small early trials suggested daily aspirin had a significant protective effect. Unfortunately, these initially promising findings were not confirmed in three large randomized, controlled trials, with a cumulative enrollment of 12,000 high-risk women. [161] [162] [163] All three studies found a small, nonsignifcant trend toward a lower incidence of preeclampsia in the aspirin-treated groups.

Two subsequent comprehensive meta-analyses of antiplatelet agents to prevent preeclampsia, which included over 32,000 women of varying risk status from 31 trials, suggested antiplatelet agents have a modest benefit, with a relative risk of preeclampsia of 0.81–0.90 for aspirin-treated patients. [164] [166] The magnitude of the relative protective effect did not appear to differ among risk groups, although the reduction in absolute risk is greatest in women at highest baseline risk. There remains concern that this finding may reflect publication bias (i.e., a small, early, positive trial is more likely to be published than a small, negative trial), or chance findings, since the largest trials in the analysis did not show a significant protective effect ( Fig. 44-12 ). Nevertheless, low-dose aspirin clearly appears to be safe: early concerns of an increased risk of post-partum hemorrhage have clearly been assuaged. Given the small but significant protective effect, aspirin prophylaxis should be considered as primary prevention for preeclampsia, especially in women at high baseline risk in whom the absolute risk reduction will be greatest.[164a]

FIGURE 44-12  Effect of antiplatelet drugs on preeclampsia in moderate- and high-risk women. Summary of studies of the effect of antiplatelet drugs on preeclampsia incidence. Subtotal indicates the results of a meta-analysis of all studies, suggesting a small but significant benefit. For both risk groups, the largest studies (N > 1000 for moderate-risk and N > 100 for high-risk women) did not show a statistically significant protective effect.  (From Duley L, Henderson-Smart D, Knight M, King J: Antiplatelet drugs for prevention of pre-eclampsia and its consequences: Systematic review. BMJ 322:329–333, 2001.)

 

 

Calcium

Several studies have examined the effectiveness of calcium supplementation to prevent preeclampsia. In a large U.S. cohort of healthy primiparous women, calcium supplementation did not reduce incidence of preeclampsia.[36] A recent meta-analysis of 11 trials, including 6634 women, reported a significant benefit only in populations with low baseline dietary calcium intake and women at high risk of gestational hypertension.[166] This was tested directly in a large randomized, placebo-controlled trial of calcium supplementation in over 8000 women with low baseline calcium intake (<600 mg/day).[167] Although there was no difference in the incidence of preeclampsia, the calcium group had a lower rate of eclampsia, gestational hypertension, preeclampsia complications, and neonatal mortality. Thus, calcium supplementation could be considered in women with low baseline calcium intake.

Antioxidants and Nutritional Interventions

Based on the hypothesis that oxidative stress may contribute to pathogenesis, it has been suggested that antioxidants may prevent preeclampsia.[168] Although an initial study suggested that vitamin C and vitamin E supplementation decreased preeclampsia among high-risk women (N = 283),[169] a larger trial (N = 2410) by the same group did not show a benefit and, in fact, suggested there may be an increase in low birth weight and other adverse neonatal outcomes in treated women.[170] A large Austrailian trial (N = 1877) failed to find a benefit of vitamin C and vitamin E supplementation in healthy nulliparous women.[171] An even larger trial (anticipated enrollment of 10,000 low-risk women) sponsored by the NIH Maternal-Fetal Medicine Units Network is ongoing; however, the current data do not support the routine use of antioxidants for the prevention of preeclampsia.

Nutritional interventions have generally not been found effective in decreasing preeclampsia risk. Protein and calorie restriction for obese pregnant women shows no reduction in the risk of preeclampsia or gestational hypertension and may increase the risk for IUGR, so this should be avoided.[172] Similarly, salt restriction is not effective in reducing preeclampsia or gestational hypertension.

Management and Treatment of Preeclampsia

Timing of Delivery

The timing of delivery in severe preeclampsia has been contentiously debated. In women presenting prior to 24 to 26 weeks, perinatal and neonatal mortality are extremely high (>80%) even with attempts to postpone delivery, and maternal complications are common. For this reason, termination is usually recommended in women with severe preeclampsia in the second trimester. In addition, the presence of non-reassuring fetal testing, suspected abruption placentae, thrombocytopenia, worsening liver and/or kidney function, and symptoms such as unremitting headache, visual changes, nausea, vomiting, or epigastric pain are generally considered indications for expedient delivery.

In preeclampsia presenting between 24 and 34 weeks' gestation without these severe signs and symptoms, postponing delivery may improve neonatal outcomes. The potential neonatal benefit needs to be balanced against the possibility of increased maternal morbidity as a result of delaying delivery. Two small randomized, controlled trials demonstrated that, in women presenting with severe preeclampsia between 28 and 32 weeks' gestation, expectant management (with delivery postponed 1-2 wk after presentation) resulted in decreased neonatal complications and decreased neonatal intensive care unit stay, with no significant increase in maternal complications. [174] [175] Most subsequent observational studies have confirmed that delivery can be safely and effectively postponed in women with severe preeclampsia, including those with HELLP syndrome and IUGR, with careful and intensive fetal and maternal monitoring. In addition, expectant management of preeclampsia appears to decrease subsequent respiratory disorders in childhood.[175]

There are no randomized, controlled trials to evaluate optimal mode of delivery in severe preeclampsia. Retrospective studies suggest maternal and neonatal outcomes are similar among women undergoing induction of labor with those undergoing cesarean section.[176]

Blood Pressure Management

Management of blood pressure in preeclampsia is substantially different from that in the nonpregnant population. Rather than seeking to minimize long-term cerebrovascular and cardiovascular complications, the goal of care is maximize the likelihood of successful delivery of a healthy infant while minimizing the chance of acute complications in the mother. Aggressive treatment of hypertension in pregnancy can compromise placental blood flow and fetal growth. Treatment of mild-to-moderate hypertension in pregnancy has not been shown to improve outcomes[177] and has been associated with increased risk of small-for-gestational-age infants ( Fig. 44-13 ).[178] Acutely, aggressive lowering of blood pressure can lead to fetal distress or demise, especially if placental perfusion is already compromised. Because of this, antihypertensive therapy for preeclampsia is usually withheld unless the blood pressure rises above 150 to 160 mm Hg systolic or 100 to 110 mm Hg diastolic, above which the risk of cerebral hemorrhage becomes significant.[43] In the next section, we review details regarding the use of specific antihypertensive agents for blood pressure management in pregnancy.

FIGURE 44-13  Treatment-induced fall in blood pressure is associated with lower mean birth weight. Results from a meta-analysis of 25 trials of antihypertensive therapy in pregnancy.  (From von Dadelszen P, Ornstein MP, Bull SB, et al: Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: A meta-analysis. Lancet 355:87–92, 2000.)



Magnesium and Seizure Prophylaxis

Magnesium has been widely used for the management and prevention of eclampsia for decades. Prior to the mid-1990s, evidence for its use was largely derived from clinical experience and from small uncontrolled studies. Over the last 10 years, magnesium has been proved to be superior to other agents in the prevention and treatment of seizures in preeclampsia, although not for the prevention of preeclampsia per se. In 1995, two randomized controlled trials in an international and a U.S. population showed magnesium sulfate superior to diazepam and phenytoin in reducing risk of seizures in women in preeclampsia/eclampsia. [180] [181] Subsequently, the Magpie study confirmed this benefit with a randomized, controlled trial of magnesium versus placebo for seizure prevention in over 10,000 women with preeclampsia from 33 countries, finding that magnesium decreased the incidence of eclamptic seizure by 50% (0.8% vs. 1.9%).[61] Unfortunately, use of magnesium is still distressingly low in many developing countries, and maternal mortality rates from eclampsia remain high.[181]

Magnesium is generally given intravenously as a bolus, followed by a continuous infusion. In the therapeutic range (5–9 mg/dL), magnesium sulfate slows neuromuscular conduction and depresses central nervous system irritability. Women receiving continuous infusions of magnesium should be monitored carefully for signs of toxicity, including loss of deep tendon reflexes, flushing, somnolence, muscle weakness, and decreased respiratory rate. Such monitoring is especially important in women with impaired renal function who have impaired urinary magnesium excretion.

Management of the HELLP Syndrome

The clinical course of the HELLP syndrome usually involves inexorable and often sudden and unpredictable deterioration. Given the high incidence of maternal complications, some authors recommend immediate delivery in all cases of confirmed HELLP. Among women in the 24- to 34-week gestational window whose clinical status appears relatively stable and with reassuring fetal status, expectant management is often a viable alternative. For many years, intravenous steroids have been suggested as an adjunct to usual management, based on retrospective and uncontrolled studies. A recent randomized, controlled trial showed no benefit to high-dose dexamethasone treatment in HELLP syndrome.[182] Post-hoc analysis suggested the subgroup with severe preeclampsia (platelet count <50,000) may have a shorter average platelet count recovery and shorter hospitalization with steroids, so further studies are required to evaluate the benefit in this population.

Based on pathophysiologic similarities to thrombotic thrombocytopenic purpura (TTP), there are reports of using plasmapheresis in the management of the HELLP syndrome. Data for the antepartum period are limited to a few case series with mixed results and no clear benefit.[183] Potential drawbacks include fetal compromise due to diminishment of already compromised placental blood flow. The litera-ture is more compelling for the use of plasmapheresis in the postpartum period, but controlled clinical trials are lacking.

Novel Therapies for Preeclampsia

Recent advances in our understanding of the pathophysiology of preeclampsia have revealed new potential therapeutic targets. Interfering with the production or signaling of sFlt1 may ameliorate the endothelial dysfunction of preeclampsia, allowing delivery to be more safely postponed. Phase I trials using recombinant VEGF-121 in the management of severe preeclampsia are currently being planned.

CHRONIC HYPERTENSION AND GESTATIONAL HYPERTENSION

The diagnosis of chronic hypertension in pregnancy is usually based on a documented history of hypertension prior to pregnancy or a blood pressure above 140/90 mm Hg prior to 20 weeks' gestation. Gestational hypertension, in contrast, is usually first noted after 20 weeks' gestation and, by definition, resolves after delivery. These diagnoses based on the timing of the first recorded blood pressure elevation can be subject to pitfalls, however. The physiologic dip in blood pressure in the second trimester, which nadirs at about 20 weeks' gestation (see Fig. 44-1 ), occurs in women with chronic hypertension and can mask the presence of underlying chronic hypertension early in pregnancy. In such cases, a woman with chronic hypertension may be inappropriately labeled as having gestational hypertension when the blood pressure rises in the third trimester. On the other hand, preeclampsia can occasionally present prior to 20 weeks' gestation; hence, preeclampsia should always be suspected in women presenting with new hypertension and proteinuria close to midgestation.

Chronic hypertension is present in 3% to 5% of pregnancies[184] and is more common with advanced maternal age, obesity, and black race.[185] Pregnant women with chronic hypertension have an increased risk of preeclampsia (21%–25%), premature delivery (33%–35%), IUGR (10%–15%), placental abruption (1%–3%), and perinatal mortality (4.5%). [187] [188] However, most adverse outcomes occur in women with severe hypertension (diastolic blood pressure >110 mm Hg) and those with preexisting cardiovascular and renal disease. Women with mild, uncomplicated chronic hypertension usually have obstetric outcomes comparable with those in the general obstetric population.[185] Both the duration and the severity of hypertension are correlated with perinatal morbidity and preeclampsia risk. [189] [190] The presence of baseline proteinuria increases the risk of preterm delivery and IUGR but not preeclampsia per se.[187]

The diagnosis of superimposed preeclampsia in chronic hypertension can be difficult. In the absence of underlying renal disease, the new onset of proteinuria (>300 mg/day), usually with worsening hypertension, is the most reliable sign of superimposed preeclampsia.[43] When proteinuria is present at baseline, the diagnosis requires a significant exacerbation hypertension (>30 mm Hg) over baseline levels, together with identification of other signs and symptoms of preeclampsia such as headache, visual changes, epigastric pain, and laboratory derangements such as hemoconcentration, elevated liver enzymes, and elevated uric acid.

Secondary Hypertension in Pregnancy

Prepregnancy evaluation of women with chronic hypertension should include consideration of secondary causes of hypertension such as renal artery stenosis, primary hyperaldosteronism, and pheochromocytoma. Renal artery stenosis due to fibromuscular dysplasia or, less often, atherosclerotic vascular disease occasionally presents in pregnancy and should be suspected when hypertension is severe and resistant to medical therapy. Diagnosis with magnetic resonance angiography (MRA) followed by successful angioplasty and stent placement in the second and third trimesters of pregnancy have been described.[190]

Although rare, pheochromocytoma can be devastating when it first presents during pregnancy. This syndrome is occasionally unmasked during labor and delivery, when fatal hypertensive crisis can be triggered by vaginal delivery, uterine contractions, and anesthesia.[191] Maternal and neonatal morbidity and mortality are much better when the diagnosis is made antepartum, with attentive and aggressive medical management. Surgical intervention is typically postponed until after delivery whenever possible.

Hypertension and hyperkalemia from primary hyperaldosteronism might be expected to improve during pregnancy, as progesterone antagonizes the effect of aldosterone on the renal tubule. However, such remission is not universal, and many women with primary hyperaldosteronism have a pregnancy-induced exacerbation of hypertension.[192] In the case of a functional adrenal adenoma, there are little data to favor either immediate surgical adrenalectomy or medical management until after delivery, although case reports have suggested success with both approaches. Although the use of spironolactone has been reported during pregnancy, theoretical risks to the fetus are significant and aldosterone antagonists should be avoided if possible.

A rare cause of early-onset hypertension is due to a mutation in the mineralocorticoid receptor. This results in inappropriate receptor activation by progesterone, and affected women develop a marked exacerbation of hypertension in pregnancy, but without proteinuria or other features of preeclampsia.[193]

Approach to Management of Chronic Hypertension in Pregnancy

Blood pressure control should be optimized prior to conception whenever possible, and women should be counseled regarding the risks of adverse pregnancy outcomes, including preeclampsia. Once pregnant, changes in antihypertensive agents may be appropriate (see later), and women should be followed closely as pregnancy progresses for signs of superimposed preeclampsia.

Management of Blood Pressure

When hypertension is severe (diastolic blood pressure >100 mm Hg), antihypertensive therapy is clearly indicated for the prevention of stroke and cardiovascular complications.[194] However, there is little evidence that treatment of mild-to-moderate hypertension has a clear benefit for either mother or fetus. Several clinical trials have evaluated the impact of antihypertensive therapy versus no treatment in such women, and these have been evaluated in three meta-analyses. [178] [185] [196] Although antihypertensive therapy lowered the risk of developing severe hypertension, there was no beneficial effect on the development of preeclampsia, neonatal death, preterm birth, small-for-gestational-age babies, or other adverse outcomes ( Fig. 44-14 ). In addition, aggressive treatment of mild-to-moderate hypertension in pregnancy may impair fetal growth. Treatment-induced falls in mean arterial pressure are associated with decreased birth weight and IUGR, presumably as a result of decreased uteroplacental perfusion (see Fig. 44-13 ).[178] Based on these data, current guidelines suggest that medical treatment should be initiated in women with newly diagnosed chronic hypertension in pregnancy only if there is evidence of end-organ damage (proteinuria, cardiomyopathy) or the blood pressure exceeds 150 to 160 mm Hg systolic or 100 to 110 mm Hg diastolic.[43] Similarly, in women already receiving chronic antihypertensive therapy prior to pregnancy, consideration could be given to tapering or discontinuing treatment unless blood pressures exceed these levels.

FIGURE 44-14  Effect of antihypertensive treatment vs. no treatment for mild chronic hypertension in pregnancy. Results from a meta-analysis of seven trials of the effect of antihypertensive treatment on maternal and perinatal outcomes.  (From Magee LA, Ornstein MP, von Dadelszen P: Forthnightly review: Management of hypertension in pregnancy. BMJ 318:1332–1336, 1999.)

 

 

Gestational Hypertension

Gestational hypertension is defined as the new onset of hypertension without proteinuria after 20 weeks' gestation that resolves postpartum. Gestational hypertension likely represents a mix of several underlying etiologies. A subset of women with gestational hypertension has previously existing essential hypertension that is undiagnosed. In such cases, if the woman presents for medical care during the second trimester nadir in blood pressure, she may be inappropriately presumed to be previously normotensive. In such a circumstance, the diagnosis of chronic hypertension is established postpartum, when blood pressure fails to return to normal.

Gestational hypertension progresses to overt preeclampsia in approximately 10% to 25% of cases.[196] When gestational hypertension is severe, it carries similar risks for adverse outcomes as preeclampsia, even in the absence of proteinuria.[197] A renal biopsy study suggests that a large proportion of women with gestational hypertension have renal glomerular endothelial damage. Hence, gestational hypertension may share the same pathophysiologic underpinnings as preeclampsia and should be monitored and treated as such.

In a subset of women with gestational hypertension, it may represent a temporary unmasking of an underlying predisposition toward chronic hypertension. Such women often present with a strong family history of chronic hypertension and develop hypertension in the third trimester with a low uric acid and no proteinuria. Although the hypertension often resolves after delivery, these women are at risk for the development of hypertension later in life.[198]

Management of Hypertension in Pregnancy

Choice of Agents

Recommendations for the use of antihypertensive agents in pregnancy are summarized in Table 44-5 . Methyldopa continues to be the first-line oral agent for the management of hypertension in pregnancy. Methyldopa is a centrally acting α2-adrenergic agonist now seldom used outside of pregnancy. Of all antihypertensive agents, it has the most extensive safety data and appears to have no adverse fetal effects. Drawbacks include a short half-life, sedation, and rare adverse effects include elevated liver enzymes and hemolytic anemia. Clonidine appears to be comparable with methyldopa in terms of mechanism and safety, but data are fewer.


TABLE 44-5   -- Safety of Antihypertensive Medications in Pregnancy

Drug

Advantages

Disadvantages

First-line agents: oral

Methyldopa

First-line, extensive safety data.

Short duration of action/bid or tid dosing.

Labetalol

Appears to be safe. Labetalol is preferred over other β-blockers owing to theoretical beneficial effect of α-blockade on uteroplacental blood flow.

Short duration of action/tid dosing.

Long-acting nifedipine

Appears to be safe. Available in a slow-release preparation, allowing once-daily dosing.

First-line agents: intravenous

Labetalol

Good safety data.

 

Nicardipine

Extensive safety data as a tocolytic during labor. Effective.

Second-line agents

Hydralazine (PO or IV)

Extensive clinical experience.

Increased risk of maternal hypotension and placental abruption when used acutely.

Metoprolol

Potential for once-daily dosing using long-acting formulation.

Safety data less extensive than for labetalol.

Verapamil, diltiazem

No evidence of adverse fetal effects.

Limited data.

Generally avoided

Diuretics

No clear evidence of adverse fetal effects.

Theoretically may impair pregnancy-associated expansion in plasma volume.

Atenolol

May impair fetal growth.

Nitroprusside

Risk of fetal cyanide poisoning if used for more than 4 hr.

Contraindicated

Angiotensin-converting enzyme (ACE) inhibitors

 

Multiple fetal anomalies, see text.

Angiotensin receptor antagonists

Similar risks as for ACE inhibitors.

 

 

 

β-Adrenergic antagonists have been used extensively in pregnancy and are effective without known teratogenicity or known adverse fetal effects. One possible exception is atenolol, which has been associated with IUGR.[199]Labetalol, which may result in better preservation of uteroplacental blood flow owing to its α-blocking action, has found widespread use and acceptance, as both an oral and an intravenous agent.[200]

Calcium channel blockers appear to be safe in pregnancy, and clinical experience with them is growing. Long-acting nifedipine is the most well-studied, and it appears to be safe and effective. [201] [202] Nondihydropyridine calcium channel blockers such as verapamil have also been used without apparent adverse effects. However, experience with these agents is more limited than some other classes.

Although diuretics are often avoided in preeclampsia, with the reasoning that circulating volume is already low, there is no evidence that diuretics are associated with adverse fetal or maternal outcomes. Similarly, diuretics are not considered first line in the management of chronic hypertension in pregnancy owing to the theoretical impact on the normal plasma volume expansion of pregnancy. When hypertension in pregnancy is complicated by pulmonary edema, diuretics are appropriate and effective.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are contraindicated in the second and third trimesters of pregnancy, as they have been found to produce renal dysfunction in the fetus, leading to renal dysgenesis, fetal oliguria and oligohydramnios, pulmonary hypoplasia, IUGF, and neonatal anuric AKI leading to death.[200] Although one small case series suggested a low incidence of adverse fetal effects in women who received ACE inhibitors in only the early first trimester,[202] fetal anomalies have been reported with exposure in all three trimesters.[203] Fewer data are available on the effects of angiotensin receptor blockers, but a case series strongly suggests fetal effects are similar to those of ACE inhibitors,[204] as would be expected on a theoretical basis.

Intravenous Agents for Urgent Blood Pressure Control

Severe hypertension in pregnancy occasionally requires inpatient management with intravenous agents. All intravenous medications commonly used for urgent control of severe hypertension are classified as pregnancy class C (lack of controlled studies in humans). Nevertheless, there is extensive clinical experience with several agents, which are widely used with no evidence of adverse effects. Options for intravenous use include labetalol, calcium channel blockers such as nicardipine, and hydralazine.

Intravenous labetalol, like oral labetalol, is safe and effective, with the major drawback being its short duration of action. Intravenous nicardipine has been used safely for tocolysis during premature labor, and recent reports suggest it is safe in treatment of hypertension as well.[205] The use of short-acting nifedipine is controversial owing to well-documented adverse effects in the nonpregnant population.

Hydralazine has been widely used as a first-line agent for severe hypertension in pregnancy. However, a recent meta-analysis of 21 trials comparing intravenous hydralazine to either labetalol or nifedipine for acute management of hypertension in pregnancy suggested an increased risk of maternal hypotension, maternal oliguria, placental abruption, and low Apgar scores with hydralazine.[206] Hence, hydralazine should probably be considered second line and its use limited when possible.

Nitroprusside carries risk of fetal cyanide poisoning if used for more than 4 hours and is generally avoided.

Antihypertensive Drugs in Breastfeeding

There are few well-designed studies of the safety of antihypertensive medications in breastfeeding women. In general, the agents that are considered safe during pregnancy remain so in breastfeeding. Methyldopa, if effective and well tolerated, should be considered first line. β-Blockers with high protein binding, such as labetalol and propranolol, are preferred over atenolol and metoprolol, which are concentrated in breastmilk.[200] Diuretics may decrease milk production and should be avoided.[200] ACE inhibitors are poorly excreted in breast milk and generally considered safe in lactating women.[207] Hence, in women with proteinuric renal disease, reinitiation of ACE inhibitors should be considered immedi ately after delivery. Finally, specific data on the pharmacokintetics of each medication should be used to guide mothers to time breastfeeding intervals before or well after peak breastmilk excretion to avoid significant exposure to the baby.

ACUTE KIDNEY INJURY IN PREGNANCY

The incidence of AKI in pregnancy in the developed world has fallen dramatically over the past 40 years.[208] This trend is due to a variety of factors, including improved availability of safe and legal abortion, more widespread and aggressive antibiotic use (both of which have decreased the incidence of septic abortion), and improvement in overall prenatal care.

The most common cause of AKI during pregnancy is prerenal azotemia owing to hyperemesis gravidarum or vomiting from acute pyelonephritis. Occasionally pregnancy-specific conditions such as preeclampsia, the HELLP syndrome, and acute fatty liver of pregnancy (AFLP) are complicated by AKI. Obstetric complications such as septic abortion and placental abruption are associated with severe acute tubular necrosis (ATN) and bilateral cortical necrosis. Obstructive uropathy is a rare cause of AKI in pregnancy.

Acute Tubular Necrosis and Bilateral Cortical Necrosis

ATN in pregnancy can be precipitated by a variety of factors. Volume depletion complicating hyperemesis gravidarum or uterine hemorrhage (owing to placental abruption, placenta previa, failure of the postpartum uterus to contract, or uterine lacerations and perforations) can lead to renal ischemia and subsequent ATN. AKI may also occur following intra-amniotic saline administration, amniotic fluid embolism, and diseases or accidents unrelated to pregnancy.

Bilateral cortical necrosis is a severe and often irreversible form of ATN that is associated with septic abortion and placental abruption. Septic abortion is an infection of the uterus and the surrounding tissues following any abortion, most commonly nonsterile illicit abortions. Septic abortion is now rare where safe therapeutic abortion is available, but it remains a serious clinical problem in countries where induced abortion is illegal and/or inaccessible. Women with septic abortion usually present with vaginal bleeding, lower abdominal pain, and fever hours to days after the attempted abortion. If untreated, progression to shock may be rapid, and patients can manifest a peculiar bronze color owing to hemolytic jaundice with cutaneous vasodilatation, cyanosis, and pallor. Renal failure, which complicates up to 73% of cases,[209] is often characterized by gross hematuria, flank pain, and oligoanuria. Other complications include acute respiratory distress syndrome, severe anemia, leukocytosis, severe thrombocytopenia, and disseminated intravascular coagulopathy. An abdominal x-ray may demonstrate air in the uterus or abdomen secondary to gas-forming organisms and/or perforation.

The bacteria associated with septic abortion are usually polymicrobial, derived from the normal flora of the vagina and endocervix, in addition to sexually transmitted pathogens. Clostridium wechii, Clostridium perfringens, Streptococcus pyogenes, and gram-negative organisms such as Escherica coli and Pseudomonas aeruginosa are all known pathogens. More recently, fatal toxic shock syndrome with Clostridium sordellii has been reported following medical termination of pregnancy using mifepristone (RU-486) and intravaginal misoprostol.[210] Pregnancy has long been known to confer a peculiar susceptibility to the vascular effects of gram-negative endotoxin (Shwartzman phenomenon). Perhaps because of the physiologic increase in procoagulant factors that occurs in normal pregnancy, the thrombotic microangiopathy and renal cortical necrosis that characterize septic shock—notably with gram-negative organisms—are particularly pronounced during pregnancy.

AKI with bilateral cortical necrosis in the last trimester of pregnancy can also be precipitated by placental abruption. Cortical necrosis can involve the entire renal cortex, often leading to irreversible renal failure, but more commonly, involvement is incomplete or patchy. In such cases, a protracted period of oligoanuria is followed by a variable return of renal function. The diagnosis of renal cortical necrosis can be usually be established by CT scan, which characteristically demonstrates hypodense areas in the renal cortex.

The treatment of ATN in pregnancy is supportive with prompt restoration of fluid volume deficits and, in later pregnancy, expedient delivery. No specific therapy is effective in acute cortical necrosis except for dialysis when needed. Both peritoneal and hemodialysis have been used during pregnancy; however, peritoneal dialysis carries the risk of impairing uteroplacental blood flow.[211] In patients with septicemia, death occurs rapidly in a small percentage of patients, but most respond to antibiotics and volume resuscitation. Survival is intimately linked with the management and recovery of AKI.[212]

Acute Kidney Failure and Thrombotic Microangiopathy

The presence of thrombotic microangiopathy and AKI in pregnancy is one of the most challenging differential diagnoses to face the nephrologist caring for pregnant patients. Five pregnancy syndromes share many clinical, laboratory, and pathologic features: preeclampsia/HELLP syndrome, TTP/hemolytic-uremic syndrome (HUS), AFLP, systemic lupus erythematosus (SLE) with the antiphospholipid antibody syndrome, and disseminated intravascular coagulation (usually complicating sepsis). Although it is difficult to establish clinical distinctions between these entities with certainty, the confluence of clinical clues can often establish a likely diagnosis (see Table 44-4 ).

Severe Preeclampsia

AKI is a rare complication of preeclampsia and is most frequently seen in the setting of coagulopathy, hepatic rupture, liver failure, or preexisting renal disease. When AKI occurs in the setting of preeclampsia, urgent delivery is indicated.

Acute Fatty Liver of Pregnancy

AFLP is a rare but potentially fatal complication of pregnancy, affecting about 1 in 10,000 pregnancies, with a 10% case fatality rate.[213] The clinical picture is dominated by liver failure, with elevated serum aminotransferase levels and hyperbilirubinemia. Severely affected patients have elevations in blood ammonia levels and hypoglycemia. Preeclampsia can also be present in up to half of cases. Hemolysis and thrombocytopenia are not prominent features, and the presence of these findings should suggest the diagnosis of HELLP syndrome or HUS/TTP (see Table 44-4 ). AKI in association with AFLP is seen mainly near term but can occur any time after midgestation.[214] The kidney lesion is mild and nonspecific, and the cause of renal failure is obscure. It may be due to hemodynamic changes akin to those seen in the hepatorenal syndrome or to a thrombotic microangiopathy.

Although liver biopsy is rarely undertaken clinically, AFLP is a pathologic diagnosis: Histologic changes include swollen hepatocytes filled with microvesicular fat and minimal hepatocellular necrosis. This histologic picture resembles that seen in Reye's syndrome and Jamaican vomiting sickness. A defect in mitochondrial fatty acid oxidation owing to mutations in the long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency has been recently hypothesized as a risk factor for the development of AFLP.[215]

Management of AFLP includes supportive care, comprising aggressive management of the coagulopathy, and prompt termination of the pregnancy. The syndrome typically remits postpartum with no residual hepatic or renal impairment, although it can recur in subsequent pregnancies.

Hemolytic-Uremic Syndrome/Thrombotic Thrombocytopenic Purpura

HUS/TTP is characterized by thrombocytopenia, hemolysis, and variable organ dysfunction including AKF.[216] Patients are believed to have TTP when neurologic symptoms dominate and HUS when renal failure is the dominant presenting feature. Pregnancy appears to be associated with an increased risk of both TTP (usually presenting prior to 24 wk) and HUS (typically occurring near term or postpartum),[217] and pregnancy can precipitate relapse in women with a history of TTP.[218] Deficiency in the von Willebrand factor cleaving protease (ADAMTS13) has been linked to the pathogenesis of TTP in nonpregnant states, but this has not been well studied in pregnancy. ADAMTS13 levels fall during the second and third trimesters, potentially contributing to the increased incidence of TTP in the latter half of pregnancy.[219]

The often challenging clinical distinction between HUS/TTP and preeclampsia/HELLP is important for patient management, because plasma exchange is beneficial in HUS/TTP but not in the HELLP syndrome. A history of preceding proteinuria, hypertension, and severe liver injury is more suggestive of the HELLP syndrome, whereas the presence of renal failure and severe hemolytic anemia is more typical of HUS/TTP (see Table 44-4 ). Although plasmapheresis for HUS/TTP in pregnancy and postpartum has not been evaluated in controlled studies, case series suggest it is safe and effective.[218] Termination of pregnancy does not appear to alter the course of HUS/TTP; thus, it is not generally recommended unless the fetus is compromised.

Obstructive Uropathy and Nephrolithiasis

AKI owing to bilateral ureteral obstruction is a rare complication of pregnancy. Because of the physiologic hydronephrosis of pregnancy (see Physiologic Changes of Pregnancy), the diagnosis of frank urinary obstruction can be challenging. If clinical suspicion is high (e.g., marked hydronephrosis, abdominal pain, elevated serum creatinine), a percutaneous nephrostomy may be needed as a diagnostic and therapeutic trial to confirm the diagnosis of obstructive uropathy. If present, obstruction can be managed with ureteral stenting.[220] Massive hematuria from the right ureter has been reported in the postpartum period, subsiding spontaneously following decompression of the partially obstructed right collecting system.[221]

Circulating levels of 1,25 dihydroxyvitamin D3 are increased during normal pregnancy, resulting in increased intestinal calcium absorption. Urinary excretion of calcium is also increased, leading to a tendency in some women to form kidney stones. Excessive intake of calcium supplements can lead to hypercalcemia and hypercalcuria. Although intestinal absorption and urinary excretion of calcium are increased, there is no evidence that the risk of nephrolithiasis is increased, possibly owing to a concomitant increase in urine flow and physiologic dilation of the urinary tract.

Calcium oxalate and calcium phosphate constitute the majority of the stones produced during pregnancy. As in nonpregnant patients, ureteral calculi in pregnancy produce flank pain and lower abdominal pain with hematuria. Premature labor is sometimes induced by the intense pain, and the risk of infection is increased. Ultrasonography is the preferred method to visualize obstruction and stones. The management of renal calculi is conservative with adequate hydration, analgesics, and antiemetics. Thiazide diuretics and allopurinol are contraindicated during pregnancy. Twenty-four-hour urine collection to quantify urinary calcium and uric acid excretion is recommended after delivery. Nephrolithiasis complicated by urinary tract infection should be treated with antibiotics for 3 to 5 weeks, followed by suppressive treatment after delivery, because the calculus may harbor a nidus of infection. Most stones pass spontaneously, but ureteral catheterization and placement of a ureteral stent may be needed. Lithotripsy is a relatively contraindicated during pregnancy owing to adverse effects on the fetus. However, extracorporeal shockwave lithotripsy has been used during the first 4 to 8 weeks of pregnancy without known adverse consequences to the fetus.[222]

Urinary Tract Infection

Infections of the urinary tract represent the most frequent renal problem encountered during gestation.[223] Although the prevalence of asymptomatic bacteriuria—which ranges between 2% and 10%—is similar to that in nonpregnant populations, it needs to be managed more aggressively for several reasons. Physiologic hydronephrosis predisposes pregnant women to ascending pyelonephritis in the setting of cystitis. Hence, whereas asymptomatic bacteriuria in the nonpregnant state is usually benign, untreated asymptomatic bacteriuria in pregnancy can progress to overt cystitis or acute pyelonephritis in up to 40% of patients.[224] Acute pyelonephritis is a serious complication during pregnancy, usually presenting between 20 and 28 weeks of gestation with fevers, loin pain, and dysuria. Sepsis resulting from pyelonephritis can progress to endotoxic shock, disseminated intravascular coagulation, and AKI. Asymptomatic bacteriuria has also been associated with an increased risk of premature delivery and low birth weight.[225] Treatment of asymptomatic bacteriuria during pregnancy has been shown to reduce these complications and improve perinatal morbidity and mortality.[226] Thus, early detection and treatment of asymptomatic bacteriuria are warranted.

The usual signs and symptoms of urinary tract infection can be unreliable in pregnancy. Dysuria and urinary frequency are common during the latter half of pregnancy in the absence of infection, owing to pressure on the bladder from the gravid uterus. Low-grade pyuria is often present because of contamination by vaginal secretions. The use of the urinary dipstick to screen for bacteriuria is associated with a high false-negative rate, and quantitative urine culture is preferred for screening. More than 105 bacteria/mL of a single species indicates significant bacteriuria. Screening for asymptomatic bacteriuria is recommended during the first prenatal visit and is repeated only in high-risk women such as those with a history of recurrent urinary infections or urinary tract anomalies.

If asymptomatic bacteriuria is found, prompt treatment is warranted (usually with a cephalosporin) for at least 3 to 7 days.[227] Treatment with a single dose of fosfomycin has also been used successfully. Trimethoprim-sulfa and tetracycline are contraindicated in early pregnancy because of their association with birth defects. A follow-up culture 2 weeks after treatment is necessary to ensure eradication of bacteriuria. Suppressive therapy with nitrofurantoin or cephalexin is recommended for those patients with bacteriuria that persists after two courses of therapy.[228] Prolonged suppressive treatment of bacteriuria has been shown to reduce the incidence of pyelonephritis.[229] Because of the high maternal morbidity and mortality associated with pyelonephritis, it is usually treated aggressively with hospitalization, intravenous antibiotics, and hydration.

Diabetes Insipidus of Pregnancy

For reasons that are obscure, circulating levels of vasopressinase, an enzyme that hydrolyzes arginine vasopressin, are increased during normal pregnancy. Occasionally, this increase is so pronounced that circulating ADH (arginine vasopressin) disappears, resulting in the polyuria and polydipsia of diabetes insipidus. This syndrome of transient diabetes insipidus presents during the second trimester and disappears after the delivery.[230] It is important to recognize this entity because affected women may become dangerously hypernatremic, especially with cesarean section using general anesthesia and/or water restriction in the delivery room. The polyuria can be controlled by the administration of desamino-8-d-arginine vasopressin (DDAVP), which is not destroyed by vasopressinase.

Chronic Kidney Disease and Pregnancy

Women who enter pregnancy with CKD are at increased risk for adverse maternal and fetal outcomes, including rapid decline of renal function and perinatal mortality. Although the frequency of live births now exceeds 90% in these women, the risk for preterm delivery, IUGR, perinatal mortality, and preeclampsia are significantly elevated. [232] [233] Therefore, the goals for any pregnancy in which a woman enters with CKD are to preserve maternal renal function during and after pregnancy and to ensure successful term delivery for the fetus.

The physiologic increase in renal blood flow and GFR characteristic of normal pregnancy is attenuated in chronic renal insufficiency.[232] The stress of greater renal blood flow during pregnancy may exacerbate renal damage in the setting of preexisting renal disease, similar to that in nonpregnant states in which the impaired kidney is more sensitive to such insults. Indeed, worsening of hypertension and proteinuria are common during pregnancy if these conditions exist prior to pregnancy,[233] and in concert with these observations, overall maternal and fetal prognosis correlates with the degree of hypertension, proteinuria, and renal insufficiency prior to conception.

Fortunately, there is good evidence to suggest that women with underlying kidney disease but only mild renal impairment, normal blood pressure, and no proteinuria have good maternal and fetal outcomes, with little risk for accelerated progression toward end-stage renal disease or preterm delivery. [233] [235] Although debate exists whether specific renal diseases are more commonly associated with aggressive decline postpartum, current consensus suggests the degree of renal insufficiency, rather than the underlying renal diagnosis, is the primary determinant of outcome. Women who become pregnant with a serum creatinine above 1.4 to 1.5 mg/dL are more likely to experience a decline in renal function than women with a comparable degree of renal dysfunction who do not become pregnant.[232] Initiating pregnancy with a serum creatinine greater than 2.0 mg/dL carries a high risk (>30%) for accelerated decline in renal function both during and after pregnancy.[231] Furthermore, among women with a serum creatinine above 2.5 mg/dL, over 70% experience preterm delivery and over 40% experience preeclampsia. [232] [234] Measures to predict which women will experience rapid decline postpartum do not exist, and terminating pregnancy does not reliably reverse the decline in renal function. Specific conditions including diabetic nephropathy and lupus nephritis are discussed later; however, regardless of cause of renal disease, the tenet that an elevated serum creatinine above 1.4 to 1.5 mg/dL puts women at increased risk for renal decline holds true.

Diabetic Nephropathy and Pregnancy

The incidence and prevalence of diabetes throughout the world is increasing, and with this has followed an increase in the incidence and prevalence of diabetic nephropathy. Currently, over 50% of patients with end-stage kidney disease have diabetes.[235] Although diabetes is less common among women of child-bearing age, the number of women entering pregnancy with diabetes is also rising.[236] Women with pregestational diabetes, with or without nephropathy, have a higher risk of adverse fetal and maternal outcomes during pregnancy as compared with nondiabetics. [238] [239] [240] For example, the risk of preeclampsia in women with pregestational diabetes is more than double that seen in the general population.[238] The presence of albuminuria confers an additional risk: Women with prepregnancy microalbuminuria are at increased risk for preeclampsia and preterm delivery.[240] Poor glycemic control before and during pregnancy has also been linked to preeclampsia and serious adverse fetal outcomes; hence, endocrinologic consultation before pregnancy is strongly advised. [242] [243]

Although it has been suggested that pregnancy negatively affects renal function in women with pregestational diabetes, pregnancy itself does not appear to adversely affect the progression of kidney disease if kidney function is normal or near normal at the onset.[243] The prognosis changes, however, if renal function is impaired at pregnancy onset. Compared with preconception measures, creatinine clearance is notably lower even within the first few months postpartum in women initiating pregnancy with impaired renal function.[244] In a study of 11 patients with diabetic nephropathy and serum creatinine higher than 1.4 mg/dL at pregnancy onset, more than 40% progressed to end-stage renal failure within 5 to 6 years after pregnancy.[245] Aggressive blood pressure control before and after pregnancy may attenuate the postpartum decline in renal function.[243] Nevertheless, inexorable decline in renal function following pregnancy is almost always the rule rather than the exception in women initiating pregnancy with diabetic nephropathy and impaired renal function. For this reason, women with diabetic nephropathy are strongly advised to postpone pregnancy until after renal transplantation, which improves fertility status and fetal outcomes and does not lead to impaired renal function if allograft function is normal.

ACE inhibitors and Ang II receptor blockers are contraindicated during pregnancy, and the inability to use these medications may contribute to the more rapid progression to renal failure in pregnant women with diabetic nephropathy and impaired renal function. Notably, these medications are toxic to the fetus if exposure occurs during the second or third trimester, leading to adverse outcomes including hypocalvaria (hypoplasia of the membrane bones of the skull), renal tubular dysplasia, and IUGR.[200] Whereas surveillance studies find little to no adverse fetal consequences among women taking ACE inhibitors in the first trimester. [201] [247] exencephaly and unilateral renal agenesis were found in a fetus of a mother who was taking an Ang II receptor blocker at conception.[247] Therefore, whereas preconception and postpartum (e.g., during breastfeeding) use of these medications appears to be safe, exposure during pregnancy, especially in the second or third trimester, is contraindicated.

The diabetic milieu during pregnancy may also subsequently affect metabolism and renal function in the offspring. [249] [250] For example, in a cross-sectional study of 503 Pima Indians with type 2 diabetes, the prevalence of albu minuria was significantly higher in the offspring of mothers with diabetes during pregnancy (58%) compared with offspring of mothers without evidence of diabetes during pregnancy (40%).[249] It is speculated that abnormal in utero exposure in the offspring of diabetic mothers leads to impaired nephrogenesis and reduced nephron mass, and this puts the offspring at higher risk for developing renal disease and hypertension in later life.

Lupus Nephritis and Pregnancy

SLE is one of the most common autoimmune diseases in women of childbearing age. During pregnancy, women with SLE are at increased risk for preterm birth, IUGR, spontaneous abortions, and preeclampsia. The presence of superimposed renal disease increases the risk of these complications even further. [251] [252] Over the past two decades, improvements in disease management and perinatal monitoring have led to a decrease in pregnancy loss and preterm deliveries.[252] Outcomes, however, still appear to be poor in developing countries.[253] With careful planning, monitoring, and management, the majority of patients with SLE—especially those with normal baseline renal function—can complete pregnancy without serious maternal or fetal complications.[254]

Although there remains a longstanding debate about whether pregnancy itself induces a lupus flare, it is clear that active disease, compromised renal function, hypertension, or proteinuria at conception is associated with an increased risk of adverse fetal (e.g., fetal loss and preterm delivery) and maternal (e.g., preeclampsia, renal deterioration) outcomes. [256] [257] [258] Specific subsets of women with SLE are at especially high risk. For example, women with SLE and antiphospholipid antibodies have an increased risk of thrombosis, fetal loss, and preeclampsia.[258] Proliferative (World Health Organizatin [WHO] class III or IV) lupus nephritis is associated with a higher risk of preeclampsia and lower birth weights than mesangial (WHO class II) or membranous (WHO class V) lupus nephritis.[259] Women with lupus should postpone pregnancy until lupus activity is quiescent and immunosuppressives are minimized.[256] Importantly, prophylactic therapy with steroids does not appear to prevent a lupus flare during pregnancy[260]; however, immunosuppressives (e.g., steroids, azathioprine) have been used to manage lupus flares during pregnancy in the hope of extending pregnancy duration.[261]

Pregnant women with a history of lupus nephritis are at risk both for a flare of their underlying renal disease and for preeclampsia. Unfortunately, both syndromes share the common presenting symptoms of hypertension and proteinuria; hence, distinguishing the two can be a clinical challenge.[262] In addition, women with proteinuric renal disease of any etiology usually have an increase in proteinuria as pregnancy continues owing to increased GFR (see Renal Adaptation to Pregnancy), further clouding the differential diagnosis. The distinction between preeclampsia and lupus flare is critical, however, especially in women presenting prior to 37 weeks' gestation because the treatments differ. For a lupus nephritis flare, steroids and azathioprine may quell the disease, allowing pregnancy to continue, whereas for preeclampsia, induction of delivery is the definitive treatment. Even in the medical literature reports of preeclampsia in the setting of lupus renal disease are prone to misclassification, because the diagnosis of preeclampsia is often based on blood pressure elevation and development of proteinuria[50] and not on renal biopsy or specific serologic testing. Alterations in components of the complement cascade (e.g., reductions in C3, C4, CH50) have been used to identify pregnant women with a lupus flare and to distinguish lupus flare from preeclampsia.[263] Unfortunately, low complement levels and the presence of hematuria are neither sensitive nor specific for a lupus nephritis flare. [263] [265] An active urinary sediment is common in lupus nephritis, whereas the sediment in preeclampsia is typically bland. Nonetheless, distinguishing lupus flare from preeclampsia remains a challenge and requires frequent clinical assessment by a multidisciplinary team. Often, a renal biopsy is required. Although data on the safety of renal biopsy during pregnancy are limited, clinical experience suggests that it is safe if undertaken prior to about 30 weeks' gestation. Later in gestation, kidney biopsy is technically difficult as the gravid uterus makes the requisite prone position difficult. On the horizon, novel serologic tests for preeclampsia based on angiogenic factors may aid clinical decision making, especially during the critical time period before term [50] [263] (see Screening, earlier).

Pregnancy in Chronic Dialysis

End-stage kidney disease is characterized by severe hypothalamic-pituitary-gonadal dysfunction that is reversed by transplantation but not by dialysis. Women of child-bearing age on dialysis have menstrual disturbances, anovulation, and infertility.[265] Animal studies suggest that uremia impairs fertility via aberrant neuroendocrine regulation of hypothalamic gonadotropin-releasing hormone (GnRH) secretion.[266] Gonadal function is impaired in men as well, who can experience testicular atrophy, hypospermatogenesis, infertility, and impotence.

Conception on dialysis is unusual but not impossible. Hence, adequate contraception remains important in women of child-bearing age who do not wish to become pregnant. Although in a recent report, United States Renal Data Systems (USRDS) investigators found that pregnancy and live birth rates over the past decade have increased in young women (<30 yr of age) receiving dialysis,[267] the literature on pregnancy in dialysis patients remains dominated by case reports and small, single-center case series. Two surveys provide some insight into epidemiology. A 1994 survey of 206 U.S. dialysis units reported that 1.5% of 1281 women of child-bearing age became pregnant over a 2-year period while on hemodialysis.[268] This finding was confirmed in a 1998 survey of 930 dialysis units, which reported 2% of 6230 women of child-bearing age became pregnant over a 4-year period.[269] In both studies, approximately half of pregnancies resulted in successful delivery of a live infant, although the majority (84% in the 1994 study) were premature. Two case series of pregnancies in the setting of chronic hemodialysis with optimal care have reported somewhat higher neonatal survival (70%–75%). [271] [272] Adverse fetal outcomes are most often due to preterm labor, premature rupture of membranes, polyhydramnios, and IUGR.

When pregnancy does occur in a woman on chronic hemodialysis, significant changes in management are required. Current guidelines recommend increasing the weekly dialysis dose to 20 or more hours per week, as this has been associated with improved neonatal outcomes and longer gestations. [270] [273] This is often most realistically attained by daily nocturnal dialysis. Management of volume status is challenging because the dry weight increases throughout pregnancy, and hypovolemia needs to be vigilantly avoided. Medications must be carefully reviewed to avoid drugs toxic to the fetus, such as ACE inhibitors. Erythropoeitin dosing should be adjusted to approximate the physiologic anemia of pregnancy (10–11 g/L), as high hematocrit has been associated with adverse fetal outcomes. Exacerbation of hypertension is common, although the incidence of preeclampsia is difficult to ascertain owing to the inability to apply standard diagnostic criteria. Close monitoring of fetal well-being in collaboration with an obstetrician is essential after 24 weeks' gestation because early fetal distress is common. Data on pregnancy outcomes in peritoneal dialysis are even more limited but appear to be similar to those seen in hemodialysis patients.[269]

Pregnancy in the Renal Transplant Patient

Although women with end-stage renal disease on dialysis are typically infertile, successful kidney transplantation results in a return to normal hormonal function and fertility within 6 months in approximately 90% of women of child-bearing age.[273] Over 14,000 pregnancies in renal allograft recipients have been documented since 1958 ( Fig. 44-15 ).[274] Although the majority of pregnancies following kidney transplant lead to excellent outcomes for both mother and fetus, such pregnancies are not without risk and require close monitoring and collaboration between the nephrologist and the obstetrician. [276] [277] The goals of care in these patients are to optimize maternal health, including graft function and detection and management of hypertensive disorders of pregnancy, and maximize the possibility of a healthy newborn.

FIGURE 44-15  Pregnancies in kidney transplant recipients worldwide. The circles represent the numbers of pregnancies reported worldwide in kidney transplant recipients during the indicated year. The numbers include therapeutic terminations, spontaneous abortions, ectopic pregnancies, and stillbirths. The squares represent the numbers of transplant recipients reported to have been pregnant during that year, again including all outcomes. The triangles represent the numbers of pregnancies beyond the first trimester reported in the literature during the indicated year. The data are from the National Transplantation Pregnancy Registry in the United States, the European Dialysis and Transplant Association Registry, and the UK Transplant Pregnancy Registry.  (From McKay DB, Josephson MA: Pregnancy in recipients of solid organs—Effects on mother and child. N Engl J Med 354:1281–1293, 2006.)

 

 

Fetal and Neonatal Outcomes

Most data on pregnancy outcomes in transplant patients are derived from voluntary registries, case reports, and single-center retrospective studies. Three major registries, the U.S. National Pregnancy Transplantation Registry (NPTR),[277] the European Dialysis and Transplant Association Registry,[278] and the UK Transplant Pregnancy Registry[279] have documented pregnancy outcomes on over 2000 pregnancies in women with solid organ transplants. Statistics on the major complications of pregnancy are remarkably consistent. Approximately 22% of pregnancies among renal transplant recipients end in the first trimester, 13% due to miscarriage and the remainder due to elective termination.[277] For pregnancies that continue, more than 90% result in a successful outcome for both mother and fetus; however, there is a substantial risk of low birth weight (25%–50%) and/or preterm delivery (30%–50%). [278] [281] Ectopic pregnancy appears to be slightly increased, especially in pregnancies that occur soon after transplant, but the rate remains below 1%. The rate of structural birth defects is no higher than the general population. Vaginal delivery is safe, and cesarean section should be performed only for obstetric indications.

Timing of Pregnancy after Transplantation

Several factors need to be considered in the decision of how long to wait after transplant before attempting pregnancy. Pregnancy within the first 6 to 12 months following transplantation is undesirable for several reasons. The risk of acute rejection is relatively high, immunosuppressant medications are at higher dosages, and risk of infection is greatest.[274] Traditionally, it has been recommended that women wait approximately 2 years after transplant prior to attempting conception.[281] However, many women who have undergone renal transplantation are of advanced maternal age; hence, delaying pregnancy may lead to age-related decreases in fertility. The American Society of Transplantation currently suggests that for women on stable, low doses of immunosuppressive agents, with normal renal function, and with no prior rejection episodes, conception could be safely considered as early as 1 year post-transplant.[274]

Effect of Pregnancy on Renal Allograft Function

Pregnancy itself does not appear to adversely affect graft function in transplant recipients, provided baseline graft function is normal and significant hypertension is not present.[281] In general, when pregnancy occurs 1 to 2 years after transplant, the rejection rate is similar to that seen in nonpregnant controls (3%–4%).[277] When moderate renal insufficiency is present (serum creatinine >1.5–1.7 mg/dL), pregnancy does carry a risk of progressive renal dysfunction[282] as well as an increased risk of a small-for-gestational-age infant and of preeclampsia.[283]

Only two small case-control studies have reported long-term (>10-yr) graft function after pregnancy. Whereas one study suggested that 10-year graft survival may be diminished in transplant recipients who become pregnant compared with controls who did not become pregnant,[284] the second reported no significant difference.[285] Further studies reporting long-term outcomes in the era of calcineurin inhibitors are needed.

Owing to ongoing immunosuppression, transplant recipients are at risk for infections that have implications for the fetus, including CMV, HSV, and toxoplasmosis. The rate of bacterial urinary tract infections is increased (≈13%–40%),[282] but these are usually treatable and uncomplicated.

The most common complication of pregnancy in transplant recipients is hypertension, which affects between 30% and 75% of pregnancies among transplant recipients. [278] [287] Hypertension is likely due to a combination of underlying medical conditions and the use of calcineurin inhibitors. Preeclampsia complicates 25% to 30% of pregnancies in renal transplant patients, [278] [281] [283] and diagnosis is often challenging owing to the frequent presence of hypertension and/or proteinuria at baseline. The American Society of Transplantation recommends that hypertension in pregnant renal transplant recipients should be managed aggressively, with target blood pressure close to normal—a goal that differs from somewhat higher blood pressure goals in women with hypertension in pregnancy in the absence of a transplant. [201] [275] Agents of choice (see Table 44-5 ) include methyldopa, nonselective β-adrenergic antagoinists (i.e., labetalol), and calcium channel blockers. ACE inhibitors are contraindicated in all but the early first trimester, and even then should be avoided. Details about the use of these agents in pregnancy are discussed in greater detail in Management of Hypertension in Pregnancy above.

Management of Immunosuppressive Therapy in Pregnancy

The U.S. Food and Drug Administration classifies drugs as pregnancy category A (no risk in controlled studies), B (no evidence of risk in humans), C (risks cannot be ruled out), D (positive evidence of risk), and X (contraindicated). Because controlled studies on developmental toxicity owing to immunosuppressive agents cannot be performed for ethical reasons, most immunosuppressive agents fall within the C class. Nevertheless, a significant amount of published data can inform decisions to use some of these agents safely in pregnancy ( Table 44-6 ).


TABLE 44-6   -- Immunosuppressive Medications in Pregnancy

Drug

Recommendations

Predinisone

Safe chronically at low-to-moderate doses (5–10 mg/day).

Safe acutely at high doses.

Cyclosporine

Extensive clinical data suggest safe at low-to-moderate clinical doses.

Animal data suggest adverse fetal effects at high doses.

Changes in absorption and metabolism require close monitoring of levels and frequent dose adjustments in pregnancy.

Tacrolimus

Similar to that of cyclosporine, although somewhat less data available.

Sirolimus

Contraindicated in pregnancy: teratogenic in animal studies.

Azathioprine

Considered safe at dosages < 2 mg/kg/day

Mycophenylate mofetil

Contraindicated in pregnancy: teratogenic in animal and human studies.

OKT-3

Case reports of successful use for induction in unsuspected pregnancy and for acute rejection, but data are limited.

Antithymocyte globulin, dacilizumab, basiliximab

No data.

 

 

 

Cyclosporine (or tacrolimus) and steroids, with or without azathioprine, form the basis of immunosuppression during pregnancy. Corticosteroids at low-to-moderate doses (5–10 mg/day) are safe, and prednisone is classified as pregnancy class B.[287] Stress-dose steroids are needed at the time of delivery and for 24 to 48 hours after delivery. Azathioprine is generally considered safe at dosages less than 2 mg/kg/day, although higher doses are associated with congenital anomalies, immunosuppression, and IUGR and, thus, should be avoided if possible.[281]

Although high doses of both cyclosporine and tacrolimus are associated with fetal resorption in animal studies, both animal and human data suggest that lower doses of calcinurin inhibitors are safe in pregnancy. [288] [289]Experience with tacrolimus is more limited than that for cyclosporine, but growing. [289] [290] Clinical data have not demonstrated an increased incidence of congenital malformations, with the possible exception of low birth weight.[287] Owing to decreased gastrointestinal absorption, increased volume of distribution, and increased GFR, levels of cyclosporine and tacrolimus can fluctuate significantly in pregnancy, with concomitant risk of acute rejection. Hence, close monitoring of blood levels with dosing adjustment is required to maintain optimal levels.[288]

Sirolimus is contraindicated in pregnancy because it is teratogenic in rats at doses used clinically.[287] The risk of fetal malformations is highest at 30 to 71 days' gestation, so there is a window to stop sirolimus if pregnancy is detected early. Nevertheless, sirolimus should be discontinued preemptively in women of child-bearing age who are not using contraception.

Mycophenolate mofetil (MMF) is associated with developmental toxicity, malformations, and intrauterine death in animal studies at therapeutic dosages. Human data are limited to isolated case reports but suggest MMF may be associated with spontaneous abortions and with major fetal malformations,[290] especially in combination with cyclosporine.[287] Hence MMF, like sirolimus, should be avoided in pregnancy. For a more detailed discussion of data on effects of these agents on neonatal immunologic function and long-term outcomes, the reader is referred to an excellent review by McKay and associates.[276]

Management of Acute Rejection in Pregnancy

The incidence of acute rejection during pregnancy is similar to that in the nonpregnant population [278] [282]; however, the diagnosis of acute rejection during pregnancy can be difficult. Acute rejection should be suspected if fever, oliguria, graft tenderness, or deterioration in renal function is noted. Biopsy of the renal graft should be performed to confirm the diagnosis prior to initiation of treatment. Although high-dose steroids have been associated with fetal malformations and maternal infections, this remains a mainstay of treatment of acute rejection during pregnancy. [282] [292] Little data are available on the safety of agents such as OKT-3, antithymocyte globulin, dacilizumab, and basiliximab in pregnancy (see Table 44-6 ).[287] The NPTR reported five cases of OKT-3 use during pregnancy, with four surviving infants.[277] Polyclonal and monoclonal antibodies would be expected to cross the placenta, but fetal effects are largely unknown.

Breastfeeding and Immunosuppressive Agents

Owing to lack of definitive data, breastfeeding is generally discouraged in women taking immunosuppressive drugs. Studies on transfer of calcineurin inhibitors to the babies of breastfeeding mothers are inconsistent, with some studies reporting undetectable levels, [288] [293] and others reporting high neonatal blood concentrations.[293] Theoretically, MMF should be safe in breastfeeding because the active metabolite secreted in breast milk, methylmalonic acid (MMA), is not gastrointestinal bioavailable; however, human evidence of safety is lacking. Nevertheless, breastfeeding among transplant recipients remains controversial.[276]

References

1. Poppas A, Shroff SG, Korcarz CE, et al: Serial assessment of the cardiovascular system in normal pregnancy. Role of arterial compliance and pulsatile arterial load.  Circulation  1997; 95(10):2407-2415.

2. Chapman AB, Abraham WT, Zamudio S, et al: Temporal relationships between hormonal and hemodynamic changes in early human pregnancy.  Kidney Int  1998; 54(6):2056-2063.

3. Desai DK, Moodley J, Naidoo DP: Echocardiographic assessment of cardiovascular hemodynamics in normal pregnancy.  Obstet Gynecol  2004; 104(1):20-29.

4. Elsheikh A, Creatsas G, Mastorakos G, et al: The renin-aldosterone system during normal and hypertensive pregnancy.  Arch Gynecol Obstet  2001; 264(4):182-185.

5. Khraibi AA: Renal interstitial hydrostatic pressure and sodium excretion in hypertension and pregnancy.  J Hypertens Suppl  2002; 20(3):S21-S27.

6. Davison JM: Edema in pregnancy.  Kidney Int Suppl  1997; 59:S90-S96.

7. Sifakis S, Pharmakides G: Anemia in pregnancy.  Ann N Y Acad Sci  2000; 900:125-136.

8. Bailey RR, Rolleston GL: Kidney length and ureteric dilatation in the puerperium.  J Obstet Gynaecol Br Commonw  1971; 78(1):55-61.

9. Rasmussen PE, Nielsen FR: Hydronephrosis during pregnancy: A literature survey.  Eur J Obstet Gynecol Reprod Biol  1988; 27(3):249-259.

10. Dunlop W: Serial changes in renal haemodynamics during normal human pregnancy.  BJOG  1981; 88(1):1-9.

11. Gordon M, Landon MB, Samuels P, et al: Perinatal outcome and long-term follow-up associated with modern management of diabetic nephropathy.  Obstet Gynecol  1996; 87(3):401-409.

12. Lind T, Godfrey KA, Otun H, Philips PR: Changes in serum uric acid concentrations during normal pregnancy.  BJOG  1984; 91(2):128-132.

13. Chesley LC, Valenti C, Rein H: Excretion of sodium loads by nonpregnant and pregnant normal, hypertensive and pre-eclamptic women.  Metabolism  1958; 7(5):575-588.

14. Davison JM, Shiells EA, Philips PR, Lindheimer MD: Influence of humoral and volume factors on altered osmoregulation of normal human pregnancy.  Am J Physiol  1990; 258(4 pt 2):F900-F907.

15. Ohara M, Martin PY, Xu DL, et al: Upregulation of aquaporin 2 water channel expression in pregnant rats.  J Clin Invest  1998; 101(5):1076-1083.

16. Rizk NW, Lapinsky SE: The lungs in obstetric and gynecologic disease.   In: Mason RJ, Murray JF, Broaddus VC, Nadel JA, ed. Murray and Nadel's Textbook of Respiratory Medicine,  Philadelphia: Elsevier; 2005.

17. Gant NF, Chand S, Whalley PJ, MacDonald PC: The nature of pressor responsiveness to angiotensin II in human pregnancy.  Obstet Gynecol  1974; 43(6):854.

18. Conrad KP, Jeyabalan A, Danielson LA, et al: Role of relaxin in maternal renal vasodilation of pregnancy.  Ann N Y Acad Sci  2005; 1041:147-154.

19. Sherwood OD: An “old hand's” perspective of Relaxin 2004's place along the relaxin trail.  Ann N Y Acad Sci  2005; 1041:xxix-xxxv.

20. Zhou Y, Genbacev O, Fisher SJ: The human placenta remodels the uterus by using a combination of molecules that govern vasculogenesis or leukocyte extravasation.  Ann N Y Acad Sci  2003; 995:73-83.

21. Kayisli UA, Cayli S, Seval Y, et al: Spatial and temporal distribution of tie-1 and tie-2 during very early development of the human placenta.  Placenta  2006; 27:648-659.

22. Hasan KM, Manyonda IT, Ng FS, et al: Skin capillary density changes in normal pregnancy and pre-eclampsia.  J Hypertens  2002; 20(12):2439-2443.

23. World Health Organization : World Health Report: Make every mother and child count,  Geneva, WHO, 2005.

24. Hauth JC, Ewell MG, Levine RJ, et al: Pregnancy outcomes in healthy nulliparas who developed hypertension. Calcium for Preeclampsia Prevention Study Group.  Obstet Gynecol  2000; 95(1):24-28.

25. Tuffnell DJ, Jankowicz D, Lindow SW, et al: Outcomes of severe pre-eclampsia/eclampsia in Yorkshire 1999/2003.  BJOG  2005; 112(7):875-880.

26. Skjaerven R, Wilcox AJ, Lie RT: The interval between pregnancies and the risk of preeclampsia.  N Engl J Med  2002; 346(1):33-38.

27. Carr DB, Epplein M, Johnson CO, et al: A sister's risk: Family history as a predictor of preeclampsia.  Am J Obstet Gynecol  2005; 193(3, suppl 1):965-972.

28. Laivuori H, Lahermo P, Ollikainen V, et al: Susceptibility loci for preeclampsia on chromosomes 2p25 and 9p13 in Finnish families.  Am J Hum Genet  2003; 72(1):168-177.

29. Arngrimsson R, Sigurardottir S, Frigge ML, et al: A genome-wide scan reveals a maternal susceptibility locus for pre-eclampsia on chromosome 2p13.  Hum Mol Genet  1999; 8(9):1799-1805.

30. Tuohy JF, James DK: Pre-eclampsia and trisomy 13.  BJOG  1992; 99(11):891-894.

31. Duckitt K, Harrington D: Risk factors for pre-eclampsia at antenatal booking: Systematic review of controlled studies.  BMJ  2005; 330(7491):565.

32. Roque H, Paidas MJ, Funai EF, et al: Maternal thrombophilias are not associated with early pregnancy loss.  Thromb Haemost  2004; 91(2):290-295.

33. Rasmussen A, Ravn P: High frequency of congenital thrombophilia in women with pathological pregnancies?.  Acta Obstet Gynecol Scand  2004; 83(9):808-817.

34. Kujovich JL: Thrombophilia and pregnancy complications.  Am J Obstet Gynecol  2004; 191(2):412-424.

35. Sibai BM, Caritis SN, Thom E, et al: Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.  N Engl J Med  1993; 329(17):1213-1218.

36. Levine RJ, Hauth JC, Curet LB, et al: Trial of calcium to prevent preeclampsia.  N Engl J Med  1997; 337(2):69-76.

37. Samadi AR, Mayberry RM, Zaidi AA, et al: Maternal hypertension and associated pregnancy complications among African-American and other women in the United States.  Obstet Gynecol  1996; 87(4):557-563.

38. Mackay APM, Berg CJMM, Atrash HKMM: Pregnancy-related mortality from preeclampsia and eclampsia.  Obstet Gynecol  2001; 97(4):533-538.

39. Wolf M, Shah A, Jimenez-Kimble R, et al: Differential risk of hypertensive disorders of pregnancy among Hispanic women.  J Am Soc Nephrol  2004; 15(5):1330-1338.

40. von Dadelszen P, Magee LA, Krajden M, et al: Levels of antibodies against cytomegalovirus and Chlamydophila pneumoniae are increased in early onset pre-eclampsia.  BJOG  2003; 110(8):725-730.

41. Yeh SP, Chiu CF, Lee CC, et al: Evidence of parvovirus B19 infection in patients of pre-eclampsia and eclampsia with dyserythropoietic anaemia.  Br J Haematol  2004; 126(3):428-433.

42. Trogstad LI, Eskild A, Bruu AL, et al: Is preeclampsia an infectious disease?.  Acta Obstet Gynecol Scand  2001; 80(11):1036-1038.

43. American College of Obstetricians and Gynecologists : ACOG Practice Bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002.  Int J Gynaecol Obstet  2002; 77(1):67-75.

44. Waugh JJ, Clark TJ, Divakaran TG, et al: Accuracy of urinalysis dipstick techniques in predicting significant proteinuria in pregnancy.  Obstet Gynecol  2004; 103(4):769-777.

45. Neithardt AB, Dooley SL, Borensztajn J: Prediction of 24-hour protein excretion in pregnancy with a single voided urine protein-to-creatinine ratio.  Am J Obstet Gynecol  2002; 186(5):883-886.

46. Rodriguez-Thompson D, Lieberman ES: Use of a random urinary protein-to-creatinine ratio for the diagnosis of significant proteinuria during pregnancy.  Am J Obstet Gynecol  2001; 185(4):808-811.

47. Yamasmit W, Chaithongwongwatthana S, Charoenvidhya D, et al: Random urinary protein-to-creatinine ratio for prediction of significant proteinuria in women with preeclampsia.  J Matern Fetal Neonatal Med  2004; 16(5):275-279.

48. Hall DR, Odendaal HJ, Steyn DW, Grove D: Urinary protein excretion and expectant management of early onset, severe pre-eclampsia.  Int J Gynaecol Obstet  2002; 77(1):1-6.

49. Khosla UM, Zharikov S, Finch JL, et al: Hyperuricemia induces endothelial dysfunction.  Kidney Int  2005; 67(5):1739-1742.

50. Thadhani RI, Johnson RJ, Karumanchi SA: Hypertension during pregnancy: A disorder begging for pathophysiological support.  Hypertension  2005; 46(6):1250-1251.

51. Roberts JM, Bodnar LM, Lain KY, et al: Uric acid is as important as proteinuria in identifying fetal risk in women with gestational hypertension.  Hypertension  2005; 46(6):1263-1269.

52. Lim KH, Friedman SA, Ecker JL, et al: The clinical utility of serum uric acid measurements in hypertensive diseases of pregnancy.  Am J Obstet Gynecol  1998; 178(5):1067-1071.

53. Lam C, Lim KH, Kang DH, Karumanchi SA: Uric acid and preeclampsia.  Semin Nephrol  2005; 25(1):56-60.

54. Thangaratinam S, Ismail K, Sharp S, et al: Accuracy of serum uric acid in predicting complications of pre-eclampsia: A systematic review.  BJOG  2006; 113(4):369-378.

55. Saftlas AF, Olson DR, Franks AL, et al: Epidemiology of preeclampsia and eclampsia in the United States, 1979-1986.  Am J Obstet Gynecol  1990; 163(2):460-465.

56. Sibai BM: Diagnosis, prevention, and management of eclampsia.  Obstet Gynecol  2005; 105(2):402-410.

57. Haddad B, Barton JR, Livingston JC, et al: Risk factors for adverse maternal outcomes among women with HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome.  Am J Obstet Gynecol  2000; 183(2):444-448.

58. Sheikh RA, Yasmeen S, Pauly MP, Riegler JL: Spontaneous intrahepatic hemorrhage and hepatic rupture in the HELLP syndrome: Four cases and a review.  J Clin Gastroenterol  1999; 28(4):323-328.

59. Hill K, AbouZhar C, Wardlaw T: Estimates of maternal mortality for 1995.  Bull World Health Organ  2001; 79(3):182-193.

60. Duley L: Maternal mortality associated with hypertensive disorders of pregnancy in Africa, Asia, Latin America and the Caribbean.  BJOG  1992; 99(7):547-553.

61. Altman D, Carroli G, Duley L, et al: Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: Arandomised placebo-controlled trial.  Lancet  2002; 359(9321):1877-1890.

62. Ferrazzani S, De Carolis S, Pomini F, et al: The duration of hypertension in the puerperium of preeclamptic women: Relationship with renal impairment and week of delivery.  Am J Obstet Gynecol  1994; 171(2):506-512.

63. Nisell H, Lintu H, Lunell NO, et al: Blood pressure and renal function seven years after pregnancy complicated by hypertension.  BJOG  1995; 102(11):876-881.

64. Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA: Cardiovascular health after maternal placental syndromes (CHAMPS): Population-based retrospective cohort study.  Lancet  2005; 366(9499):1797-1803.

65. Irgens HU, Reisaeter L, Irgens LM, Lie RT: Long term mortality of mothers and fathers after pre-eclampsia: Population based cohort study.  BMJ  2001; 323(7323):1213-1217.

66. Vikse BE, Irgens LM, Bostad L, Iversen BM: Adverse perinatal outcome and later kidney biopsy in the mother.  J Am Soc Nephrol  2006; 17(3):837-845.

67. Zandi-Nejad K, Luyckx VA, Brenner BM: Adult hypertension and kidney disease: The role of fetal programming.  Hypertension  2006; 47(3):502-508.

68. Shembrey MA, Noble AD: An instructive case of abdominal pregnancy.  Aust N Z J Obstet Gynaecol  1995; 35(2):220-221.

69. Hertig AT: Vascular pathology in the hypertensive albuminuric toxemias of pregnancy.  Clinics  1945; 4:602-614.

70. Salafia CM, Pezzullo JC, Ghidini A, et al: Clinical correlations of patterns of placental pathology in preterm pre-eclampsia.  Placenta  1998; 19(1):67-72.

71. Bower S, Schuchter K, Campbell S: Doppler ultrasound screening as part of routine antenatal scanning: Prediction of pre-eclampsia and intrauterine growth retardation.  BJOG  1993; 100(11):989-994.

72. North RA, Ferrier C, Long D, et al: Uterine artery Doppler flow velocity waveforms in the second trimester for the prediction of preeclampsia and fetal growth retardation.  Obstet Gynecol  1994; 83(3):378-386.

73. Palmer SK, Moore LG, Young D, et al: Altered blood pressure course during normal pregnancy and increased preeclampsia at high altitude (3100 meters) in Colorado.  Am J Obstet Gynecol  1999; 180(5):1161-1168.

74. Stamilio DM, Sehdev HM, Macones GA: Pregnant women with the sickle cell trait are not at increased risk for developing preeclampsia.  Am J Perinatol  2003; 20(1):41-48.

75. Larrabee KD, Monga M: Women with sickle cell trait are at increased risk for preeclampsia.  Am J Obstet Gynecol  1997; 177(2):425-428.

76. De Wolf F, De Wolf-Peeters C, Brosens I, Robertson WB: The human placental bed: Electron microscopic study of trophoblastic invasion of spiral arteries.  Am J Obstet Gynecol  1980; 137(1):58-70.

77. Robertson WB, Brosens I, Dixon HG: The pathological response of the vessels of the placental bed to hypertensive pregnancy.  J Pathol Bacteriol  1967; 93(2):581-592.

78. Meekins JW, Pijnenborg R, Hanssens M, et al: A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies.  BJOG  1994; 101(8):669-674.

79. Zhou Y, Fisher SJ, Janatpour M, et al: Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion?.  J Clin Invest  1997; 99(9):2139-2151.

80. Caniggia I, Mostachfi H, Winter J, et al: Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFbeta(3).  J Clin Invest  2000; 105(5):577-587.

81. Zhou Y, McMaster M, Woo K, et al: Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome.  Am J Pathol  2002; 160(4):1405-1423.

82. van Dijk M, Mulders J, Poutsma A, et al: Maternal segregation of the Dutch preeclampsia locus at 10q22 with a new member of the winged helix gene family.  Nat Genet  2005; 37(5):514-519.

83. Ferris TF: Pregnancy, preeclampsia, and the endothelial cell.  N Engl J Med  1991; 325(20):1439-1440.

84. Roberts JM, Taylor RN, Musci TJ, et al: Preeclampsia: An endothelial cell disorder.  Am J Obstet Gynecol  1989; 161(5):1200-1204.

85. Qiu C, Luthy DA, Zhang C, et al: A prospective study of maternal serum C-reactive protein concentrations and risk of preeclampsia.  Am J Hypertens  2004; 17(2):154-160.

86. Chappell LC, Seed PT, Briley A, et al: A longitudinal study of biochemical variables in women at risk of preeclampsia.  Am J Obstet Gynecol  2002; 187(1):127-136.

87. Davidge ST: Oxidative stress and altered endothelial cell function in preeclampsia.  Semin Reprod Endocrinol  1998; 16(1):65-73.

88. Mills JL, DerSimonian R, Raymond E, et al: Prostacyclin and thromboxane changes predating clinical onset of preeclampsia: A multicenter prospective study.  JAMA  1999; 282(4):356-362.

89. Leik CE, Walsh SW: Neutrophils infiltrate resistance-sized vessels of subcutaneous fat in women with preeclampsia.  Hypertension  2004; 44(1):72-77.

90. Visser W, Wallenburg HC: Central hemodynamic observations in untreated preeclamptic patients.  Hypertension  1991; 17(6 pt 2):1072-1077.

91. Khan F, Belch JJ, MacLeod M, Mires G: Changes in endothelial function precede the clinical disease in women in whom preeclampsia develops.  Hypertension  2005; 46(5):1123-1128.

92. Chambers JC, Fusi L, Malik IS, et al: Association of maternal endothelial dysfunction with preeclampsia.  JAMA  2001; 285(12):1607-1612.

93. Thadhani R, Ecker JL, Kettyle E, et al: Pulse pressure and risk of preeclampsia: A prospective study.  Obstet Gynecol  2001; 97(4):515-520.

94. Mayer C: Changes in the endothelium during eclampsia and their signficance.  Klin Wochenschr  1924; H27:

95. Spargo BH, McCartney C, Winemiller R: Glomerular capillary endotheliosis in toxemia of pregnancy.  Arch Pathol  1959; 13:593-599.

96. Lafayette RA, Malik T, Druzin M, et al: The dynamics of glomerular filtration after Caesarean section.  J Am Soc Nephrol  1999; 10(7):1561-1565.

97. Govan AD: Renal changes in eclampsia.  J Pathol Bacteriol  1954; 67(2):311-322.

98. Strevens H, Wide-Swensson D, Hansen A, et al: Glomerular endotheliosis in normal pregnancy and pre-eclampsia.  B J Obstet Gynaecol  2003; 110(9):831-836.

99. Moran P, Baylis PH, Lindheimer MD, Davison JM: Glomerular ultrafiltration in normal and preeclamptic pegnancy.  J Am Soc Nephrol  2003; 14(3):648-652.

100. Schwartz RB, Feske SK, Polak JF, et al: Preeclampsia-eclampsia: Clinical and neuroradiographic correlates and insights into the pathogenesis of hypertensive encephalopathy.  Radiology  2000; 217(2):371-376.

101. Hinchey J, Chaves C, Appignani B, et al: A reversible posterior leukoencephalopathy syndrome.  N Engl J Med  1996; 334(8):494-500.

102. Ozcan C, Wong SJ, Hari P: Reversible posterior leukoencephalopathy syndrome and bevacizumab.  N Engl J Med  2006; 354(9):980-982.discussion 982

103. Wallukat G, Homuth V, Fischer T, et al: Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor.  J Clin Invest  1999; 103(7):945-952.

104. Xia Y, Wen H, Bobst S, et al: Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human trophoblast cells.  J Soc Gynecol Investig  2003; 10(2):82-93.

105. Fu ML, Herlitz H, Schulze W, et al: Autoantibodies against the angiotensin receptor (AT1) in patients with hypertension.  J Hypertens  2000; 18(7):945-953.

106. Walther T, Wallukat G, Jank A, et al: Angiotensin II type 1 receptor agonistic antibodies reflect fundamental slterations in the uteroplacental vasculature.  Hypertension  2005; 46(6):1275-1279.

107. Ward K, Hata A, Jeunemaitre X, et al: A molecular variant of angiotensinogen associated with preeclampsia.[see comment].  Nat Genet  1993; 4(1):59-61.

108. Kobashi G, Shido K, Hata A, et al: Multivariate analysis of genetic and acquired factors; T235 variant of the angiotensinogen gene is a potent independent risk factor for preeclampsia.  Semin Thromb Hemost  2001; 27(2):143-147.

109. Morgan L, Crawshaw S, Baker PN, et al: Maternal and fetal angiotensinogen gene allele sharing in pre-eclampsia.  BJOG  1999; 106(3):244-251.

110. Abdalla S, Lother H, el Massiery A, Quitterer U: Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness.[see comment].  Nat Med  2001; 7(9):1003-1009.

111. Roberts JM, Hubel CA: Is oxidative stress the link in the two-stage model of pre-eclampsia? [comment].  Lancet  1999; 354(9181):788-789.

112. Redman CW, Sargent IL: Latest advances in understanding preeclampsia.  Science  2005; 308(5728):1592-1594.

113. Tubbergen P, Lachmeijer AMA, Althuisius SM, et al: Change in paternity: A risk factor for preeclampsia in multiparous women?.  J Reprod Immunol  1999; 45(1):81-88.

114. Klonoff-Cohen HS, Savitz DA, Cefalo RC, McCann MF: An epidemiologic study of contraception and preeclampsia.  JAMA  1989; 262(22):3143-3147.

115. Wang JX, Knottnerus A-M, Schuit G, et al: Surgically obtained sperm, and risk of gestational hypertension and pre-eclampsia.  Lancet  2002; 359(9307):673-674.

116. Robillard P-Y, Perianin J, Janky E, et al: Association of pregnancy-induced hypertension with duration of sexual cohabitation before conception.  Lancet  1994; 344(8928):973-975.

117. Koelman CA, Coumans AB, Nijman HW, et al: Correlation between oral sex and a low incidence of preeclampsia: A role for soluble HLA in seminal fluid?.  J Reprod Immunol  2000; 46(2):155-166.

118. Suy A, Martinez E, Coll O, et al: Increased risk of pre-eclampsia and fetal death in HIV-infected pregnant women receiving highly active antiretroviral therapy.  AIDS  2006; 20(1):59-66.

119. Goldman-Wohl DS, Ariel I, Greenfield C, et al: Lack of human leukocyte antigen-G expression in extravillous trophoblasts is associated with pre-eclampsia.  Mol Hum Reprod  2000; 6(1):88-95.

120. Yie SM, Li LH, Li YM, Librach C: HLA-G protein concentrations in maternal serum and placental tissue are decreased in preeclampsia.  Am J Obstet Gynecol  2004; 191(2):525-529.

121. Maynard SE, Min JY, Merchan J, et al: Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.  J Clin Invest  2003; 111(5):649-658.

122. Wathen KA, Tuutti E, Stenman UH, et al: Maternal serum-soluble vascular endothelial growth factor receptor-1 in early pregnancy ending in preeclampsia or intrauterine growth retardation.  J Clin Endocrinol Metab  2006; 91(1):180-184.

123. McKeeman GC, Ardill JES, Caldwell CM, et al: Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop.  Am J Obstet Gynecol  2004; 191(4):1240-1246.

124. Levine RJ, Maynard SE, Qian C, et al: Circulating angiogenic factors and the risk of preeclampsia.  N Engl J Med  2004; 350(7):672-683.

125. Chaiworapongsa T, Romero R, Espinoza J, et al: Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Young Investigator Award.  Am J Obstet Gynecol  2004; 190(6):1541-1547.discussion 7-50

126. Hirtenlehner K, Pollheimer J, Lichtenberger C, et al: Elevated serum concentrations of the angiogenesis inhibitor endostatin in preeclamptic women.  J Soc Gynecol Investig  2003; 10(7):412-417.

127. Ebos JML, Bocci G, Man S, et al: A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma.  Mol Cancer Res  2004; 2(6):315-326.

128. Venkatesha S, Karumanchi SA: Soluble endoglin contributes to the pathogenesis of preeclampsia.  Nat Med  2006; 12:642-649.

129. Esser S, Wolburg K, Wolburg H, et al: Vascular endothelial growth factor induces endothelial fenestrations in vitro.  J Cell Biol  1998; 140(4):947-959.

130. Simon M, Rockl W, Hornig C, et al: Receptors of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in fetal and adult human kidney: Localization and [125I]VEGF binding sites.  J Am Soc Nephrol  1998; 9(6):1032-1044.

131. Masuda Y, Shimizu A, Mori T, et al: Vascular endothelial growth factor enhances glomerular capillary repair and accelerates resolution of experimentally induced glomerulonephritis.  Am J Pathol  2001; 159(2):599-608.

132. Eremina V, Sood M, Haigh J, et al: Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases.  J Clin Invest  2003; 111(5):707-716.

133. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer.  J Clin Oncol  2003; 21(1):60-65.

134. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.  N Engl J Med  2003; 349(5):427-434.

135. Wolf M, Shah A, Lam C, et al: Circulating levels of the antiangiogenic marker sFLT-1 are increased in first versus second pregnancies.  Am J Obstet Gynecol  2005; 193(1):16-22.

136. Bdolah Y, Lam C, Rajakumar A, et al: Preeclamspia in twin pregnancies: Hypoxia or bigger placental mass?.  J Soc Gynecol Investig  2006; 12:A670.

137.   Maynard SE, Moore-Simas T, Solitro M, et al: Circulating soluble fms-like tyrosine kinase-1 (sFlt1) is increased in twin vs. singleton pregnancies. Abstract. Annual Meeting of the National Society for the Study of Hypertension in Pregnancy, 2005. Wheeling, WV, 2005.

138. Belgore FM, Lip GY, Blann AD: Vascular endothelial growth factor and its receptor, Flt-1, in smokers and non-smokers.  Br J Biomed Sci  2000; 57(3):207-213.

139. Lain KY, Wilson JW, Crombleholme WR, et al: Smoking during pregnancy is associated with alterations in markers of endothelial function.  Am J Obstet Gynecol  2003; 189(4):1196-1201.

140. Yancopoulos GD, Davis S, Gale NW, et al: Vascular-specific growth factors and blood vessel formation.  Nature  2000; 407(6801):242-248.

141. Wolf M, Sandler L, Munoz K, et al: First trimester insulin resistance and subsequent preeclampsia: A prospective study.  J Clin Endocrinol Metab  2002; 87(4):1563-1568.

142. Vicent D, Ilany J, Kondo T, et al: The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance.  J Clin Invest  2003; 111(9):1373-1380.

143. Thadhani R, Ecker JL, Mutter WP, et al: Insulin resistance and alterations in angiogenesis: Additive insults that may lead to preeclampsia.  Hypertension  2004; 43(5):988-992.

144. Wolf M, Hubel CA, Lam C, et al: Preeclampsia and future cardiovascular disease: Potential role of altered angiogenesis and insulin resistance.  J Clin Endocrinol Metab  2004; 89(12):6239-6243.

145. Vatten LJ, Romundstad PR, Trichopoulos D, Skjaerven R: Pre-eclampsia in pregnancy and subsequent risk for breast cancer.  Br J Cancer  2002; 87(9):971-973.

146. Abi-Said D, Annegers JF, Combs-Cantrell D, et al: Case-control study of the risk factors for eclampsia.  Am J Epidemiol  1995; 142(4):437-441.

147. Sibai BM, Gordon T, Thom E, et al: Risk factors for preeclampsia in healthy nulliparous women: A prospective multicenter study. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.  Am J Obstet Gynecol  1995; 172(2 pt 1):642-648.

148. Chien PF, Arnott N, Gordon A, et al: How useful is uterine artery Doppler flow velocimetry in the prediction of pre-eclampsia, intrauterine growth retardation and perinatal death? An overview.  B J Obstet Gynaecol  2000; 107(2):196-208.

149. Conde-Agudelo A, Villar J, Lindheimer M: World Health Organization systematic review of screening tests for preeclampsia.  Obstet Gynecol  2004; 104(6):1367-1391.

150. Parra M, Rodrigo R, Barja P, et al: Screening test for preeclampsia through assessment of uteroplacental blood flow and biochemical markers of oxidative stress and endothelial dysfunction.  Am J Obstet Gynecol  2005; 193(4):1486-1491.

151. Chavarria ME, Lara-Gonzalez L, Gonzalez-Gleason A, et al: Maternal plasma cellular fibronectin concentrations in normal and preeclamptic pregnancies: A longitudinal study for early prediction of preeclampsia.  Am J Obstet Gynecol  2002; 187(3):595-601.

152. Islami D, Shoukir Y, Dupont P, et al: Is cellular fibronectin a biological marker for pre-eclampsia?.  Eur J Obstet Gynecol Reprod Biol  2001; 97(1):40-45.

153. Page NM, Woods RJ, Gardiner SM, et al: Excessive placental secretion of neurokinin B during the third trimester causes pre-eclampsia.  Nature  2000; 405(6788):797-800.

154. Park CW, Park JS, Shim SS, et al: An elevated maternal plasma, but not amniotic fluid, soluble fms-like tyrosine kinase-1 (sFlt-1) at the time of mid-trimester genetic amniocentesis is a risk factor for preeclampsia.  Am J Obstet Gynecol  2005; 193(3 pt 2):984-989.

155. Powers RW, Roberts JM, Cooper KM, et al: Maternal serum soluble fms-like tyrosine kinase 1 concentrations are not increased in early pregnancy and decrease more slowly postpartum in women who develop preeclampsia.  Am J Obstet Gynecol  2005; 193(1):185-191.

156. Thadhani R, Mutter WP, Wolf M, et al: First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia.  J Clin Endocrinol Metab  2004; 89(2):770-775.

157. Taylor RN, Grimwood J, Taylor RS, et al: Longitudinal serum concentrations of placental growth factor: Evidence for abnormal placental angiogenesis in pathologic pregnancies.  Am J Obstet Gynecol  2003; 188(1):177-182.

158. Polliotti BM, Fry AG, Saller DN, et al: Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia.  Obstet Gynecol  2003; 101(6):1266-1274.

159. Livingston JC, Haddad B, Gorski LA, et al: Placenta growth factor is not an early marker for the development of severe preeclampsia.  Am J Obstet Gynecol  2001; 184(6):1218-1220.

160. Levine RJ, Thadhani R, Qian C, et al: Urinary placental growth factor and risk of preeclampsia.  JAMA  2005; 293(1):77-85.

161. Low-dose aspirin in prevention and treatment of intrauterine growth retardation and pregnancy-induced hypertension. Italian Study of Aspirin in Pregnancy.  Lancet  1993; 341(8842):396-400.

162. Caritis S, Sibai B, Hauth J, et al: Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.  N Engl J Med  1998; 338(11):701-705.

163. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group: CLASP: A randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women.  Lancet  1994; 343(8898):619-629.

164.   Duley L, Henderson-Smart DJ, Meher S, King JF: Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD004659.

164a. Askie LM, Duley L, Henderson-Smart DJ, Steward LA: Antiplatelet agents for prevention of pre-eclampsia: A meta-analysis of individual patient data.  Lancet  2007; 369:1791-1798.

165. Subtil D, Goeusse P, Puech F, et al: Aspirin (100 mg) used for prevention of pre-eclampsia in nulliparous women: The Essai Regional Aspirine Mere-Enfant study (Part 1).  B J Obstet Gynaecol  2003; 110(5):475-484.

166. Atallah AN, Hofmeyr GJ, Duley L: Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems.  The Conchrane Library, Issue 1,  Chichester, UK, John Wiley & Sons, 2004.

167.   Hofmeyr GJ, Atallah AN, Duley L: Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD001059.

168. Roberts JM, Speer P: Antioxidant therapy to prevent preeclampsia.  Semin Nephrol  2004; 24(6):557-564.

169. Chappell LC, Seed PT, Briley AL, et al: Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: A randomised trial.  Lancet  1999; 354(9181):810-816.

170. Poston L, Briley AL, Seed PT, et al: Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): Randomised placebo-controlled trial.  Lancet  2006; 367(9517):1145-1154.

171. Rumbold AR, Crowther CA, Haslam RR, et al: Vitamins C and E and the risks of preeclampsia and perinatal complications.  N Engl J Med  2006; 354(17):1796-1806.

172. Villar J, Abalos E, Nardin JM, et al: Strategies to prevent and treat preeclampsia: Evidence from randomized controlled trials.  Semin Nephrol  2004; 24(6):607-615.

173. Odendaal HJ, Pattinson RC, Bam R, et al: Aggressive or expectant management for patients with severe preeclampsia between 28-34 weeks' gestation: A randomized controlled trial.  Obstet Gynecol  1990; 76(6):1070-1075.

174. Sibai BM, Mercer BM, Schiff E, Friedman SA: Aggressive versus expectant management of severe preeclampsia at 28 to 32 weeks' gestation: A randomized controlled trial.  Am J Obstet Gynecol  1994; 171(3):818-822.

175. Withagen MIJ, Wallenburg HCS, Steegers EAP, et al: Morbidity and development in childhood of infants born after temporising treatment of early onset pre-eclampsia.  BJOG  2005; 112(7):910-914.

176. Coppage KH, Polzin WJ: Severe preeclampsia and delivery outcomes: Is immediate cesarean delivery beneficial?.  Am J Obstet Gynecol  2002; 186(5):921-923.

177.   Abalos E, Duley L, Steyn DW, Henderson-Smart DJ: Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev (2):CD002252, 2001.

178. von Dadelszen P, Ornstein M, Bull S, et al: Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: A meta-analysis.  Lancet  2000; 355(9198):87-92.

179. Collaborative Eclampsia Trial: Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial.  Lancet  1995; 345(8963):1455-1463.

180. Lucas MJ, Leveno KJ, Cunningham FG: A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia.  N Engl J Med  1995; 333(4):201-206.

181. Sevene E, Lewin S, Mariano A, et al: System and market failures: The unavailability of magnesium sulphate for the treatment of eclampsia and pre-eclampsia in Mozambique and Zimbabwe.  BMJ  2005; 331(7519):765-769.

182. Fonseca JE, Mendez F, Catano C, Arias F: Dexamethasone treatment does not improve the outcome of women with HELLP syndrome: A double-blind, placebo-controlled, randomized clinical trial.  Am J Obstet Gynecol  2005; 193(5):1591-1598.

183. Saphier CJ, Repke JT: Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome: A review of diagnosis and management.  Semin Perinatol  1998; 22(2):118-133.

184. Magee LA, Ornstein MP, von Dadelszen P: Fortnightly review: Management of hypertension in pregnancy.  BMJ  1999; 318(7194):1332-1336.

185. Sibai BM: Treatment of hypertension in pregnant women.  N Engl J Med  1996; 335(4):257-265.

186. ACOG Practice Bulletin : Chronic hypertension in pregnancy. ACOG Committee on Practice Bulletins.  Obstet Gynecol  2001; 98(1; suppl):177-185.

187. Sibai BM, Lindheimer M, Hauth J, et al: Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.  N Engl J Med  1998; 339(10):667-671.

188. August P, Helseth G, Cook EF, Sison C: A prediction model for superimposed preeclampsia in women with chronic hypertension during pregnancy.  Am J Obstet Gynecol  2004; 191(5):1666-1672.

189. McCowan LM, Buist RG, North RA, Gamble G: Perinatal morbidity in chronic hypertension.  BJOG  1996; 103(2):123-129.

190. Hayashida M, Watanabe N, Imamura H, et al: Congenital solitary kidney with renovascular hypertension diagnosed by means of captopril-enhanced renography and magnetic resonance angiography.  Int Heart J  2005; 46(2):347-353.

191. Del Giudice A, Bisceglia M, D'Errico M, et al: Extra-adrenal functional paraganglioma (phaeochromocytoma) associated with renal-artery stenosis in a pregnant woman.  Nephrol Dial Transplant  1998; 13(11):2920-2923.

192. Wyckoff JA, Seely EW, Hurwitz S, et al: Glucocorticoid-remediable aldosteronism and pregnancy.  Hypertension  2000; 35(2):668-672.

193. Geller DS, Farhi A, Pinkerton N, et al: Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy.  Science  2000; 289(5476):119-123.

194. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.  Am J Obstet Gynecol  2000; 183(1):S1-S22.

195. Ferrer RL, Sibai BM, Mulrow CD, et al: Management of mild chronic hypertension during pregnancy: A review.  Obstet Gynecol  2000; 96(5 pt 2):849-860.

196. Saudan P, Brown MA, Buddle ML, Jones M: Does gestational hypertension become pre-eclampsia?.  BJOG  1998; 105(11):1177-1184.

197. Buchbinder A, Sibai BM, Caritis S, et al: Adverse perinatal outcomes are significantly higher in severe gestational hypertension than in mild preeclampsia.  Am J Obstet Gynecol  2002; 186(1):66-71.

198. Marin R, Gorostidi M, Portal CG, et al: Long-term prognosis of hypertension in pregnancy.  Hypertens Pregnancy  2000; 19(2):199-209.

199.   Magee LA, Duley L: Oral beta-blockers for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev (3):CD002863, 2003.

200. Podymow T, August P, Umans JG: Antihypertensive therapy in pregnancy.  Semin Nephrol  2004; 24(6):616-625.

201. Bortolus R, Ricci E, Chatenoud L, Parazzini F: Nifedipine administered in pregnancy: Effect on the development of children at 18 months.  BJOG  2000; 107(6):792-794.

202. Lip GY, Churchill D, Beevers M, et al: Angiotensin-converting-enzyme inhibitors in early pregnancy.  Lancet  1997; 350(9089):1446-1447.

203. Shotan A, Widerhorn J, Hurst A, Elkayam U: Risks of angiotensin-converting enzyme inhibition during pregnancy: Experimental and clinical evidence, potential mechanisms, and recommendations for use.  Am J Med  1994; 96(5):451-456.

204. Serreau R, Luton D, Macher MA, et al: Developmental toxicity of the angiotensin II type 1 receptor antagonists during human pregnancy: A report of 10 cases.  BJOG  2005; 112(6):710-712.

205. Hanff LM, Vulto AG, Bartels PA, et al: Intravenous use of the calcium-channel blocker nicardipine as second-line treatment in severe, early-onset pre-eclamptic patients.  J Hypertens  2005; 23(12):2319-2326.

206. Magee LA, Cham C, Waterman EJ, et al: Hydralazine for treatment of severe hypertension in pregnancy: Meta-analysis.  BMJ  2003; 327(7421):955-960.

207. Beardmore KS, Morris JM, Gallery ED: Excretion of antihypertensive medication into human breast milk: A systematic review.  Hypertens Pregnancy  2002; 21(1):85-95.

208. Stratta P, Besso L, Canavese C, et al: Is pregnancy-related acute renal failure a disappearing clinical entity?.  Ren Fail  1996; 18(4):575-584.

209. Finkielman JD, De Feo FD, Heller PG, Afessa B: The clinical course of patients with septic abortion admitted to an intensive care unit.  Intensive Care Med  2004; 30(6):1097-1102.

210. Clostridium sordellii toxic shock syndrome after medical abortion with mifepristone and intravaginal misoprostol—United States and Canada, 2001-2005.  MMWR Morb Mortal Wkly Rep  2005; 54(29):724.

211. Holley JL, Reddy SS: Pregnancy in dialysis patients: A review of outcomes, complications, and management.  Semin Dial  2003; 16(5):384-388.

212. Gammill HS, Jeyabalan A: Acute renal failure in pregnancy.  Crit Care Med  2005; 33(10 suppl):S372-S384.

213. Pereira SP, O'Donohue J, Wendon J, Williams R: Maternal and perinatal outcome in severe pregnancy-related liver disease.  Hepatology  1997; 26(5):1258-1262.

214. Fesenmeier MF, Coppage KH, Lambers DS, et al: Acute fatty liver of pregnancy in 3 tertiary care centers.  Am J Obstet Gynecol  2005; 192(5):1416-1419.

215. Ibdah JA, Bennett MJ, Rinaldo P, et al: A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women.  N Engl J Med  1999; 340(22):1723-1731.

216. Vesely SK, Li X, McMinn JR, et al: Pregnancy outcomes after recovery from thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.  Transfusion  2004; 44(8):1149-1158.

217. George JN: The association of pregnancy with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.  Curr Opin Hematol  2003; 10(5):339-344.

218. Allford SL, Hunt BJ, Rose P, Machin SJ: Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias.  Br J Haematol  2003; 120(4):556-573.

219. Mannucci PM, Canciani MT, Forza I, et al: Changes in health and disease of the metalloprotease that cleaves von Willebrand factor.  Blood  2001; 98(9):2730-2735.

220. Eckford SD, Gingell JC: Ureteric obstruction in pregnancy—Diagnosis and management.  Br J Obstet Gynaecol  1991; 98(11):1137-1140.

221. Bui HT, Avjioglu E, Clarke A, Ellis D: Severe post-partum haemorrhage of the right kidney.  Aust N Z J Obstet Gynaecol  2003; 43(3):243-245.

222. Carringer M, Swartz R, Johansson JE: Management of ureteric calculi during pregnancy by ureteroscopy and laser lithotripsy.  Br J Urol  1996; 77(1):17-20.

223. Millar LK, Cox SM: Urinary tract infections complicating pregnancy.  Infect Dis Clin North Am  1997; 11(1):13-26.

224. Hill JB, Sheffield JS, McIntire DD, Wendel Jr GD: Acute pyelonephritis in pregnancy.  Obstet Gynecol  2005; 105(1):18-23.

225. Naeye RL: Causes of the excessive rates of perinatal mortality and prematurity in pregnancies complicated by maternal urinary-tract infections.  N Engl J Med  1979; 300(15):819-823.

226.   Smaill F: Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database Syst Rev (2):CD000490, 2001.

227.   Villar J, Lydon-Rochelle MT, Gulmezoglu AM, Roganti A: Duration of treatment for asymptomatic bacteriuria during pregnancy. Cochrane Database Syst Rev (2):CD000491, 2000.

228. Vercaigne LM, Zhanel GG: Recommended treatment for urinary tract infection in pregnancy.  Ann Pharmacother  1994; 28(2):248-251.

229. Gratacos E, Torres PJ, Vila J, et al: Screening and treatment of asymptomatic bacteriuria in pregnancy prevent pyelonephritis.  J Infect Dis  1994; 169(6):1390-1392.

230. Lindheimer MD: Unraveling the mysteries of preeclampsia.  Am J Obstet Gynecol  2005; 193(1):3-4.

231. Jones DC, Hayslett JP: Outcome of pregnancy in women with moderate or severe renal insufficiency.  N Engl J Med  1996; 335(4):226-232.

232. Hou S: Pregnancy in chronic renal insufficiency and end-stage renal disease.  Am J Kidney Dis  1999; 33(2):235-252.

233. Sanders CL, Lucas MJ: Renal disease in pregnancy.  Obstet Gynecol Clin North Am  2001; 28(3):593-600.vii

234. Jungers P, Houillier P, Forget D, et al: Influence of pregnancy on the course of primary chronic glomerulonephritis.  Lancet  1995; 346(8983):1122-1124.

235. U.S. Renal Data System: USRDS 2004 Annual Data Report,  Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2004.

236. Dunne F: Type 2 diabetes and pregnancy.  Semin Fetal Neonatal Med  2005; 10(4):333-339.

237. Dunne F, Brydon P, Smith K, Gee H: Pregnancy in women with type 2 diabetes: 12 years outcome data 1990-2002.  Diabet Med  2003; 20(9):734-738.

238. Sibai BM, Caritis S, Hauth J, et al: Risks of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes mellitus. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.  Am J Obstet Gynecol  2000; 182(2):364-369.

239. Clausen TD, Mathiesen E, Ekbom P, et al: Poor pregnancy outcome in women with type 2 diabetes.  Diabetes Care  2005; 28(2):323-328.

240. Ekbom P: Pre-pregnancy microalbuminuria predicts pre-eclampsia in insulin-dependent diabetes mellitus. Copenhagen Pre-eclampsia in Diabetic Pregnancy Study Group.  Lancet  1999; 353(9150):377.

241. Hiilesmaa V, Suhonen L, Teramo K: Glycaemic control is associated with pre-eclampsia but not with pregnancy-induced hypertension in women with type I diabetes mellitus.  Diabetologia  2000; 43(12):1534-1539.

242. Suhonen L, Hiilesmaa V, Teramo K: Glycaemic control during early pregnancy and fetal malformations in women with type I diabetes mellitus.  Diabetologia  2000; 43(1):79-82.

243. Rossing K, Jacobsen P, Hommel E, et al: Pregnancy and progression of diabetic nephropathy.  Diabetologia  2002; 45(1):36-41.

244. Biesenbach G, Grafinger P, Stoger H, Zazgornik J: How pregnancy influences renal function in nephropathic type 1 diabetic women depends on their pre-conceptional creatinine clearance.  J Nephrol  1999; 12(1):41-46.

245. Purdy LP, Hantsch CE, Molitch ME, et al: Effect of pregnancy on renal function in patients with moderate-to-severe diabetic renal insufficiency.  Diabetes Care  1996; 19(10):1067-1074.

246. Postmarketing surveillance for angiotensin-converting enzyme inhibitor use during the first trimester of pregnancy—United States, Canada, and Israel, 1987-1995.  MMWR Morb Mortal Wkly Rep  1997; 46(11):240-242.

247. Boix E, Zapater P, Pico A, Moreno O: Teratogenicity with angiotensin II receptor antagonists in pregnancy.  J Endocrinol Invest  2005; 28(11):1029-1031.

248. Biesenbach G, Grafinger P, Zazgornik J, Helmut S: Perinatal complications and three-year follow-up of infants of diabetic mothers with diabetic nephropathy stage IV.  Ren Fail  2000; 22(5):573-580.

249. Nelson RG, Morgenstern H, Bennett PH: Intrauterine diabetes exposure and the risk of renal disease in diabetic Pima Indians.  Diabetes  1998; 47(9):1489-1493.

250. Rahman P, Gladman DD, Urowitz MB: Clinical predictors of fetal outcome in systemic lupus erythematosus.  J Rheumatol  1998; 25(8):1526-1530.

251. Khamashta MA, Hughes GR: Pregnancy in systemic lupus erythematosus.  Curr Opin Rheumatol  1996; 8(5):424-429.

252. Clark CA, Spitzer KA, Laskin CA: Decrease in pregnancy loss rates in patients with systemic lupus erythematosus over a 40-year period.  J Rheumatol  2005; 32(9):1709-1712.

253. Chandran V, Aggarwal A, Misra R: Active disease during pregnancy is associated with poor foetal outcome in Indian patients with systemic lupus erythematosus.  Rheumatol Int  2005; 26(2):152-156.

254. Erkan D, Sammaritano L: New insights into pregnancy-related complications in systemic lupus erythematosus.  Curr Rheumatol Rep  2003; 5(5):357-363.

255. Soubassi L, Haidopoulos D, Sindos M, et al: Pregnancy outcome in women with pre-existing lupus nephritis.  J Obstet Gynaecol  2004; 24(6):630-634.

256. Moroni G, Ponticelli C: Pregnancy after lupus nephritis.  Lupus  2005; 14(1):89-94.

257. Dhar JP, Essenmacher LM, Ager JW, Sokol RJ: Pregnancy outcomes before and after a diagnosis of systemic lupus erythematosus.  Am J Obstet Gynecol  2005; 193(4):1444-1455.

258. Ruiz-Irastorza G, Khamashta MA: Management of thrombosis in antiphospholipid syndrome and systemic lupus erythematosus in pregnancy.  Ann N Y Acad Sci  2005; 1051:606-612.

259. Carmona F, Font J, Moga I, et al: Class III-IV proliferative lupus nephritis and pregnancy: A study of 42 cases.  Am J Reprod Immunol  2005; 53(4):182-188.

260. Khamashta MA, Ruiz-Irastorza G, Hughes GR: Systemic lupus erythematosus flares during pregnancy.  Rheum Dis Clin North Am  1997; 23(1):15-30.

261. Kart Koseoglu H, Yucel AE, Kunefeci G, et al: Cyclophosphamide therapy in a serious case of lupus nephritis during pregnancy.  Lupus  2001; 10(11):818-820.

262. Williams Jr WW, Ecker JL, Thadhani RI, Rahemtullah A: Case records of the Massachusetts General Hospital. Case 38-2005. A 29-year-old pregnant woman with the nephrotic syndrome and hypertension.  N Engl J Med  2005; 353(24):2590-2600.

263. Buyon JP, Tamerius J, Ordorica S, et al: Activation of the alternative complement pathway accompanies disease flares in systemic lupus erythematosus during pregnancy.  Arthritis Rheum  1992; 35(1):55-61.

264. Case Records of the Massachusetts General Hospital: Weekly clinicopathological exercises. Case 30-1998. A 30-year-old woman with increasing hypertension and proteinuria.  N Engl J Med  1998; 339(13):906-913.

265. Leavey SF, Weitzel WF: Endocrine abnormalities in chronic renal failure.  Endocrinol Metab Clin North Am  2002; 31(1):107-119.

266. Handelsman DJ, Dong Q: Hypothalamo-pituitary gonadal axis in chronic renal failure.  Endocrinol Metab Clin North Am  1993; 22(1):145-161.

267. USRDS 2005 Annual Report: Atlas of End-Stage Renal Disease in the United States,  Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005.

268. Hou SH: Frequency and outcome of pregnancy in women on dialysis.  Am J Kidney Dis  1994; 23(1):60-63.

269. Okundaye I, Abrinko P, Hou S: Registry of pregnancy in dialysis patients.  Am J Kidney Dis  1998; 31(5):766-773.

270. Romao Jr JE, Luders C, Kahhale S, et al: Pregnancy in women on chronic dialysis. A single-center experience with 17 cases.  Nephron  1998; 78(4):416-422.

271. Chao AS, Huang JY, Lien R, et al: Pregnancy in women who undergo long-term hemodialysis.  Am J Obstet Gynecol  2002; 187(1):152-156.

272. Hou S: Pregnancy in dialysis patients: Where do we go from here?.  Semin Dial  2003; 16(5):376-378.

273. Lessan-Pezeshki M, Ghazizadeh S, Khatami MR, et al: Fertility and contraceptive issues after kidney transplantation in women.  Transplant Proc  2004; 36(5):1405-1406.

274. McKay DB, Josephson MA, Armenti VT, et al: Reproduction and transplantation: Report on the AST Consensus Conference on Reproductive Issues and Transplantation.  Am J Transplant  2005; 5(7):1592-1599.

275. Hou S: Pregnancy in renal transplant recipients.  Adv Ren Replace Ther  2003; 10(1):40-47.

276. McKay DB, Josephson MA: Pregnancy in recipients of solid organs—Effects on mother and child.  N Engl J Med  2006; 354(12):1281-1293.

277. Armenti VT, Radomski JS, Moritz MJ, et al: Report from the National Transplantation Pregnancy Registry: Outcomes of pregnancy after transplantation.   In: Cecka JM, Terasaki PI, ed. Clinical Transplants 2004,  Los Angeles: UCLA Immunogenetics Center; 2004:103-114.

278. Rizzoni G, Ehrich JH, Broyer M, et al: Successful pregnancies in women on renal replacement therapy: Report from the EDTA Registry.  Nephrol Dial Transplant  1992; 7(4):279-287.

279. Davison JM, Redman CW: Pregnancy post-transplant: The establishment of a UK registry.  BJOG  1997; 104(10):1106-1107.

280. Gutierrez MJ, Acebedo-Ribo M, Garcia-Donaire JA, et al: Pregnancy in renal transplant recipients.  Transplant Proc  2005; 37(9):3721-3722.

281. European Renal Association-European Dialysis and Transplant Association Guidelines : Pregnancy in renal transplant recipients.  Nephrol Dial Transplant  2002; 17(S4):50-55.

282. Galdo T, Gonzalez F, Espinoza M, et al: Impact of pregnancy on the function of transplanted kidneys.  Transplant Proc  2005; 37(3):1577-1579.

283. Thompson BC, Kingdon EJ, Tuck SM, et al: Pregnancy in renal transplant recipients: The Royal Free Hospital experience.  QJM  2003; 96(11):837-844.

284. Salmela KT, Kyllonen LE, Holmberg C, Gronhagen-Riska C: Impaired renal function after pregnancy in renal transplant recipients.  Transplantation  1993; 56(6):1372-1375.

285. Sturgiss SN, Davison JM: Effect of pregnancy on the long-term function of renal allografts: An update.  Am J Kidney Dis  1995; 26(1):54-56.

286. Al-Khader AA, Al G, Basri N, et al: Pregnancies in renal transplant recipients—With a focus on the maternal issues.  Ann Transplant  2004; 9(3):62-64.

287. Danesi R, Del Tacca M: Teratogenesis and immunosuppressive treatment.  Transplant Proc  2004; 36(3):705-707.

288. Garcia-Donaire JA, Acevedo M, Gutierrez MJ, et al: Tacrolimus as basic immunosuppression in pregnancy after renal transplantation. A single-center experience.  Transplant Proc  2005; 37(9):3754-3755.

289. Kainz A, Harabacz I, Cowlrick IS, et al: Review of the course and outcome of 100 pregnancies in 84 women treated with tacrolimus.  Transplantation  2000; 70(12):1718-1721.

290. Le Ray C, Coulomb A, Elefant E, et al: Mycophenolate mofetil in pregnancy after renal transplantation: A case of major fetal malformations.  Obstet Gynecol  2004; 103(5):1091-1094.

291. Mastrobattista JM, Katz AR: Pregnancy after organ transplant.  Obstet Gynecol Clin North Am  2004; 31(2):415-428.vii

292. Munoz-Flores-Thiagarajan KD, Easterling T, Davis C, Bond EF: Breast-feeding by a cyclosporine-treated mother.  Obstet Gynecol  2001; 97(5):816-818.

293. Moretti ME, Sgro M, Johnson DW, et al: Cyclosporine excretion into breast milk.  Transplantation  2003; 75(12):2144-2146.

294. Mostello D, Catlin TK, Roman L, et al: Preeclampsia in the parous woman: Who is at risk?.  Am J Obstet Gynecol  2002; 187(2):425-429.

295. Wolfberg AJ, Lee-Parritz A, Peller AJ, Lieberman ES: Association of rheumatologic disease with preeclampsia.  Obstet Gynecol  2004; 103(6):1190-1193.

296. Eskenazi B, Fenster L, Sidney S: A multivariate analysis of risk factors for preeclampsia.  JAMA  1991; 266(2):237-241.

297. Zetterstrom K, Lindeberg SN, Haglund B, Hanson U: Maternal complications in women with chronic hypertension: A population-based cohort study.  Acta Obstet Gynecol Scand  2005; 84(5):419-424.

298. Palmer SK, Moore LG, Young D, et al: Altered blood pressure course during normal pregnancy and increased preeclampsia at high altitude (3100 meters) in Colorado.  Am J Obstet Gynecol  1999; 180(5):1161-1168.

299. Krotz S, Fajardo J, Ghandi S, et al: Hypertensive disease in twin pregnancies: A review.  Twin Res  2002; 5(1):8-14.

300. Ness RB, Markovic N, Bass D, et al: Family history of hypertension, heart disease, and stroke among women who develop hypertension in pregnancy.  Obstet Gynecol  2003; 102(6):1366-1371.

301. Weiss JL, Malone FD, Emig D, et al: Obesity, obstetric complications and cesarean delivery rate—A population-based screening study.  Am J Obstet Gynecol  2004; 190(4):1091-1097.

302. Egerman RS, Sibai BM: Imitators of preeclampsia and eclampsia.  Clin Obstet Gynecol  1999; 42(3):551-562.