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Among the many physiologic changes that occur in normal pregnancy, few are as profound as those affecting the urinary system.1 These healthy alterations and various diagnostic pitfalls for the unwary clini-cian are discussed in Chapter 7. Improvements in our knowledge about gestational physiology in antenatal care generally, technology for fetal surveillance, and neonatology services have meant better care and out-comes for women with renal problems and their newborns.2,3 With this is mind, this chapter focuses on urinary tract infection (UTI), acute and chronic renal disease in pregnancy, and the management of preg-nant women on dialysis or with renal allografts.

Urinary Tract InfectionThe incidence of asymptomatic bacteriuria (i.e., signifi cant growth of a uropathogen in the absence of symptoms) is 2% to 10%, which is the same during pregnancy as it is in sexually active nonpregnant women.4 However, the structural and immunologic changes to the urothelium of the renal tracts during pregnancy5 make it more likely that a lower UTI will ascend to cause acute pyelonephritis.4,5 During pregnancy, 12.5% to 30% of women with untreated asymptomatic bacteriuria develop acute pyelonephritis,4,6-8 a serious infection with signifi cant morbidity for the mother and fetus.

Diagnosis of Urinary Tract InfectionsDuring pregnancy, symptoms suggesting a UTI are dysuria and offen-sive-smelling urine. Others usually associated with a UTI are urinary frequency, nocturia, urge incontinence, and strangury (i.e., the urge to pass urine having just done so), but these symptoms are also found in healthy pregnant women.

Microscopy and culture of a freshly voided midstream urine sample allow quantifi cation of pyuria (i.e., leukocytes in the urine) and growth of a urinary pathogen. A bacterial UTI is the most common cause of pyuria and is considered signifi cant if microscopy of a sample of unspun midstream urine reveals more than 10 leukocytes per micro-liter. Urine culture is conventionally recognized as signifi cant if there is growth of more than 105 colony-forming units per milliliter (CFU/mL) of a single recognized uropathogen, in association with pyuria.9 Low counts of bacteriuria10 (24 to 104 CFU/mL) may still be signifi cant if symptomatic women have a high fl uid intake or are infected with a slow-growing organism. If left untreated, most symptomatic women with low-count bacteriuria will have 105 CFU/mL 2 days later.9 During pregnancy, the most common uropathogens are bowel commensals,

Escherichia coli (70% to 80%), Klebsiella, Proteus, Enterobacter, and Staphylococcus saprophyticus.

If urine from a symptomatic pregnant woman is cloudy and posi-tive on dipstick testing for nitrite (produced by most uropathogens) and leukocyte esterase (produced by white blood cells), a UTI is likely and empiric treatment can be started.9 These urine sticks are not sensi-tive enough to be used for screening for asymptomatic bacteriuria in early pregnancy,10 and microscopy and culture of a clean catch mid-stream urine sample is necessary. Hematuria and proteinuria are unre-liable indicators of a UTI, but they are important signs of renal disease (discussed later).

Asymptomatic Bacteriuria

Maternal and Fetal RisksDuring pregnancy, untreated asymptomatic bacteriuria will develop into acute pyelonephritis in up to 30% of women, but if treated, less than 1% of pregnant women develop pyelonephritis.4,6,7 A systematic review of 14 studies confi rmed that antibiotic treatment of asymptom-atic bacteriuria signifi cantly reduced the incidence of pyelonephritis compared with placebo or no treatment (odds ratio [OR], 0.25; 95% confi dence interval [CI], 0.14 to 0.48).11 After successful treatment of asymptomatic bacteriuria, monthly screening of midstream urine is necessary, because about 30% of women will have a relapse of bacte-riuria, making them vulnerable to acute pyelonephritis again.4

Asymptomatic bacteriuria has been associated with an increased risk of preterm delivery and low birth weight.12 Treatment of asymp-tomatic bacteriuria has been shown to reduce the incidence of low-birth-weight infants (OR, 0.66; 95% CI, 0.49 to 0.89)11 but have no effect on preterm delivery.6 It has been suggested that the underlying renal pathology, which is commonly associated with bacteriuria, is responsible for poor pregnancy outcomes.6 Additional good-quality studies are needed to settle this issue.

Management of Asymptomatic BacteriuriaContrary to much published advice, not all pregnant women need to be screened for asymptomatic bacteriuria. There are two main reasons. First, the prevalence of asymptomatic bacteriuria varies between populations, and where it is low (<2.5%), it is hard to justify the cost-effectiveness of screening. In populations in which the prevalence of asymptomatic bacteriuria is more than 5%, the case for screening is much stronger.7 Second, approximately 1% to 2% of the 90% to 98% of asymptomatic women who test negative for bacteriuria in the fi rst

Chapter 44

Renal DisordersDavid J. Williams, PhD, and John M. Davison, MD

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906 CHAPTER 44 Renal Disorders

trimester will develop a symptomatic UTI.8,13 This means that one third of all women who develop a UTI in late pregnancy would have been missed on fi rst-trimester screening.8,13 Women at increased risk for pyelonephritis or renal impairment should be screened for asymp-tomatic bacteriuria every 4 to 6 weeks throughout pregnancy.

Treatment of Urinary Tract InfectionsThere is no consensus about the optimal treatment of asymptomatic bacteriuria14 or the empiric treatment of symptomatic UTIs in preg-nancy.15 Most urinary infections during pregnancy (approximately 75%) are caused by E. coli, which is usually sensitive to nitrofurantoin (89%), trimethoprim with or without sulfamethoxazole (87%), ampi-cillin (72%), or cephalosporins.16,17 Until well-structured trials are done, the most cost-effective treatment for asymptomatic bacteriuria or a fi rst episode of cystitis is nitrofurantoin monohydrate macrocrys-tals (100 mg twice daily for 3 days) or trimethoprim (200 mg twice daily for 3 days).17 Nitrofurantoin should be avoided after the onset of labor in patients with glucose-6-phosphate dehydrogenase defi ciency, although no well-documented cases of hemolysis in neonates have been recorded,18 and trimethoprim should be avoided in the fi rst tri-mester because it is a folic acid antagonist associated with an increased risk of neural tube defect.19

Screening for recurrent infections should begin 1 week after com-pletion of initial treatment and then be done every 4 to 6 weeks for the remainder of pregnancy. Recurrent infections or a fi rst infection in a pregnant woman at high risk for pyelonephritis should be treated with a 7- to 10-day course of an antibiotic that refl ects antibacterial sensitivities.17 Women who have had two episodes of asymptomatic bacteriuria or cystitis should be considered for low-dose antibiotic prophylaxis—guided by the sensitivities of the most recent infective organism—for the remainder of pregnancy and until 4 to 6 weeks after birth.20 Suitable regimens for long-term antibiotic prophylaxis include nitrofurantoin (50 to 100 mg each night), amoxicillin (250 mg each night), cephalexin (125 to 250 mg each night), or trimethoprim (100 to 150 mg each night).20 These women should also be investigated for structural abnormalities of the renal tracts or renal calculus using ultrasonography.

Acute PyelonephritisThe same uropathogens that cause asymptomatic bacteriuria and cystitis are responsible for acute pyelonephritis.21 The prevalence of asymptomatic bacteriuria in a pregnant population dictates the inci-dence of acute pyelonephritis. Screening and treating a high-risk popu-lation for asymptomatic bacteriuria reduces the incidence of acute pyelonephritis to less than 1%.8,11 Unless acute pyelonephritis is treated promptly, there is considerable maternal and fetal morbidity.21

Maternal Symptoms and SignsMost women with acute pyelonephritis present in the second or third trimester.21 More than 80% of women present with backache, fever, rigors and costovertebral angle tenderness, and about one half have lower urinary tract symptoms, nausea, and vomiting.21 Bacteremia occurs in 15% to 20% of pregnant women with acute pyelonephritis,21 and a small proportion of these women will develop septic shock and increased capillary leak, leading to pulmonary edema.22 It is important, however, to differentiate the hypotension due to reduced intravascular volume (i.e., fever, nausea, and vomiting) from that caused by septic shock. Women with pyelonephritis at risk for serious complications are those who present with the highest fever (>39.4 °C) and tachycardia

(>110 beats/min) at 20 weeks’ gestation or later and who have received tocolytic agents and injudicious fl uid replacement.23

Fetal RisksAcute pyelonephritis can trigger uterine contractions and preterm labor.24 Antibiotic treatment of pyelonephritis reduces uterine activity, but patients with recurrent infection or marked uterine activity are at increased risk for preterm labor.24 Because uterine activity often occurs in the absence of cervical change and because tocolysis with β-mimet-ics aggravates the cardiovascular response to endotoxemia,23 tocolytic therapy should be used with care and only in those with cervical changes.25

Management of Acute PyelonephritisWomen suspected of acute pyelonephritis from their history, symp-toms, and signs should be admitted to the hospital. Laboratory tests should include a full blood cell count, serum creatinine concentration, levels of electrolytes, and urine culture. If there are systemic symptoms or septic shock, a blood culture may be useful. Pregnant women with pyelonephritis and septic shock need intensive care. For these women, assessment of the state of hydration is critical and often requires invasive hemodynamic monitoring with a central venous pressure line. This can optimize fl uid balance, aiming for a urine output greater than 30mL/hr to minimize renal impairment and reduce the risk of pulmonary edema. Intravenous antibiotics should be started empirically (discussed later) until the sensitivities of blood and urine cultures are known. These women often have transient renal impairment, thrombocytopenia, and hemolysis, suggesting that the alveolar capillary endothelium is damaged by endotoxin.22 A blood fi lm and lactate dehydrogenase concentration can be used to diagnose hemolysis.

Trials investigating the outpatient management of pyelonephritis in pregnancy have identifi ed a group of women who can be managed at home.25 These women should be less than 24 weeks’ gestation, be relatively healthy, and understand the importance of compliance. They should have an initial period of observation in the hospital to demon-strate an ability to take oral fl uids and receive intramuscular cefurox-ime or ceftriaxone. After satisfactory laboratory tests, they can go home and are seen again within 24 hours for a second intramuscular dose of cephalosporin. They then start a 10-day course of oral cephalexin (500 mg four times daily) or appropriate antibiotic with regular out-patient follow-up.24 Following this regimen, 90% of women will improve as outpatients, and 10% will require hospital admission because of sepsis or recurrent pyelonephritis. Women with acute pyelonephritis who are beyond 24 weeks’ gestation should be admitted for at least 24 hours to observe the maternal condition as described earlier and to monitor uterine activity and the fetal heart rate.25

Gram-negative bacteria causing pyelonephritis in pregnancy are often resistant to ampicillin,26 and intravenous cefuroxime (750 mg to 1.5 gm, depending on severity of condition, every 8 hours) is an effec-tive fi rst choice until culture sensitivities are known.15 Women allergic to β-lactam antibiotics can be given intravenous gentamicin (1.5 mg/kg every 8 hours) for the initial treatment of acute pyelonephritis. A single-dose regimen (7 mg/kg every 24 hours) should be avoided during pregnancy to reduce the very small risk of cranial nerve VIII damage to the fetus.17 Serum concentrations of gentamicin should be measured and dose adjustments made according to identifi ed levels. Intravenous antibiotics should be continued until the patient has been afebrile for 24 hours. Oral antibiotics should then be given for 7 to 10 days, according to bacterial sensitivities, or if not available, as if for symptomatic lower UTI.17

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907CHAPTER 44 Renal Disorders

Failure of these measures to improve the maternal clinical condition within 48 to 72 hours suggests an underlying structural abnormality. Ultrasonography is an easy but inconclusive way of excluding stones. If clinical suspicion is high, a plain abdominal radiograph can identify 90% of renal stones, and a one-shot intravenous urogram (IVU) at 20 to 30 minutes can identify the remainder.25 The risk to the fetus from radiation of one or two radiographs is minimal, especially when compared with the clinical benefi t of identifying an obstructed, nonfunctioning kidney. Urinary tract obstruction can also be detected using magnetic resonance urography, especially during the second and third trimesters.27

After one episode of pyelonephritis, pregnant women should have monthly urine cultures to screen for a recurrence.25 The risk of recur-rent pyelonephritis can be reduced with antimicrobial prophylaxis chosen according to the sensitivities of initial bacterial infection20,28 or with nitrofurantoin (100 mg every night) continued until 4 to 6 weeks after delivery.25

Acute Renal Failure in PregnancyAcute renal failure has become a rare but serious complication of pregnancy. In early pregnancy, acute renal failure is associated with septic abortion (a complication largely confi ned to the developing world) and dehydration related to hyperemesis gravidarum. Around the time of delivery, acute renal failure is most commonly caused by gestational syndromes such as preeclampsia and abruptio placentae (Table 44-1). However, pregnancy is a prothrombotic state that is asso-ciated with heightened infl ammation29 and major changes to the vas-cular endothelium,30 particularly the glomerular capillary endothelium.31 These physiologic changes predispose pregnant women to acute glo-merular capillary thrombosis. Whereas nonpregnant patients who suffer an acute prerenal insult (e.g., hemorrhage, dehydration, septic shock) may develop transient acute tubular necrosis if inadequately treated, the same prerenal insult in pregnancy is more likely to develop into renal cortical necrosis with permanent renal impairment. This is even more likely to occur if a prerenal insult coexists with a pregnancy-related condition that induces a consumptive coagulopathy or endo-thelial damage (e.g., preeclampsia).

Management is aimed at identifi cation and correction of the pre-cipitating insult and optimal fl uid resuscitation, which is best guided by monitoring the central venous pressure and pulmonary artery wedge pressure. If oliguria persists despite euvolemia with deteriorat-ing renal function or fl uid overload, fl uid restriction followed by renal replacement therapy is indicated.

Preeclampsia

Preeclampsia and the KidneyPreeclampsia rarely causes acute renal failure severe enough to require dialysis.32 In a cohort of South African women with severe preeclamp-sia and renal impairment, 7 (10%) of 72 required temporary dialysis, and none developed chronic renal failure.32 All women with severe preeclampsia who needed dialysis had hemorrhage, which often was caused by abruptio placentae.32 Preeclampsia causing mild transient renal impairment (serum creatinine up to 125 μmol/L or 1.41 mg/dL) is common, but with appropriate management, there should be com-plete recovery of renal function.

Women with preexisting renal disease are more vulnerable to pre-eclampsia, especially when it is associated with chronic hypertension33 (see Chapter 35). A meta-analysis of trials investigating the effective-ness of low-dose aspirin (50 to 150 mg/day) in pregnant women with moderate to severe renal disease revealed a signifi cant reduction in the risk of preeclampsia and perinatal death.34

Conversely, 2% to 5% of women with preeclampsia are later found to have underlying renal disease,35 but if preeclampsia is severe, up to 20% of women will have chronic kidney disease (CKD).36 Women who have had preeclampsia should therefore be checked for persistent postpartum hypertension and proteinuria. Gestational hypertension usually resolves within 3 months of delivery, but severe proteinuria due to preeclampsia can take up to 12 months to disappear. Women who have had preeclampsia are more likely to have persistent microalbu-minuria compatible with microvascular disease and are at increased risk for cardiovascular disease in later life.37,38

Women who develop high levels of proteinuria (>10 g/24 hr) tend to have earlier-onset preeclampsia and deliver at an earlier gestational age compared with preeclamptic women who have less marked pro-teinuria (<5 g/24 hr).39 After correction for prematurity, however, massive proteinuria (>10 g/24 hr) has no signifi cant effect on neonatal outcome.39 Increasing proteinuria is not therefore an indication for delivery. We suggest that pregnant women who develop a proteinuria level of more than 1 to 3 g in 24 hours accompanied by other maternal risk factors for thrombosis should be considered for thromboprophy-laxis with enoxaparin (40 mg SC each day) or Fragmin (5000 units SC each day).

The diagnosis of preeclampsia is diffi cult if there is chronic hyper-tension and preexisting proteinuria, especially because these two parameters become increasingly marked in late pregnancy. Hyperuri-cemia and intrauterine growth restriction are common features of preeclampsia and chronic renal impairment, but the presence of increased levels of hepatic transaminases and thrombocytopenia support a diagnosis of preeclampsia.40

Preeclampsia: Management of Renal

Impairment and Fluid BalanceThe cure for severe preeclampsia is delivery of the infant and placenta. Delivery may halt the general progression of preeclampsia, but post-partum maternal renal function usually deteriorates before improv-ing.32 It is advisable to recommend delivery for women who have preeclampsia and an increase in the serum creatinine concentration from about 70 μmol/L (0.79 mg/dL) to more than 120 μmol/L (1.36 mg/dL) to prevent ongoing renal impairment.

Fluid balance is critical to the management of acute renal failure during pregnancy. Too little intravascular fl uid leads to prerenal failure, which is especially damaging to chronically impaired kidneys, whereas too much fl uid risks pulmonary edema, adult respiratory distress syn-

TABLE 44-1 CAUSES OF ACUTE RENAL FAILURE IN PREGNANCY

Most common causes Severe preeclampsiaPlacental abruption

Causes in early pregnancy Septic abortionHyperemesis gravidarumOvarian hyperstimulation syndrome

Rare causes Amniotic fl uid embolusHemolytic uremic syndrome/

thrombotic thrombocytopenic purpura

Acute fatty liver of pregnancyAcute obstruction of renal tracts

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drome, and maternal death.41 Transient oliguria (<100 mL over 4 hours) is a common observation in the fi rst 24 hours after a healthy pregnancy. If a preeclamptic woman is not obviously hypovolemic and has a serum urea level of 5 mmol/L or less and serum creatinine level of 90 μmol/L or less, repeated fl uid challenges to increase urine output are unneces-sary and increase the maternal risk of pulmonary edema. Women with severe preeclampsia and renal impairment (i.e., serum creatinine level of more than 120 μmol/L or 1.36 mg/dL) should have their fl uid balance guided by a central venous pressure catheter or, when available, a pul-monary artery fl otation catheter on a high-dependency unit familiar with this equipment.42 The rate of fl uid replacement should take account of central venous fi lling pressure, pulmonary wedge pressure, hourly urine output, and insensible loses. After the patient is euvolemic, the rate of intravenous fl uid replacement should equal the previous hours’ urine output plus insensible losses; this is usually 30 mL/hr if the patient is afebrile. The amount of intravenous fl uid replacement can be reduced after the mother can take oral fl uid and her renal impairment starts to improve. Intravenous fl uid regimens that stick to a fi xed hourly replace-ment can lead to fl uid overload in oliguric women and to reduced intravascular volume in those having a diuresis. Fluid replacement should include blood to replace blood loses and then isotonic sodium chloride or compound sodium lactate (i.e., Hartmann’s solution). Dex-trose solutions are hypotonic and lead to maternal hyponatremia (5% dextrose contains only 30 mmol/L of NaCl, compared with 150 mmol/L of NaCl in a 0.9% sodium chloride solution).

Low-dose “renal” dopamine infusion (3 μg/kg/min) was previously used to increase renal blood fl ow in people with acute renal failure, but it is no longer thought to be benefi cial. It is recommended that once hypovolemia has been corrected, as judged by the central venous pres-sure or pulmonary wedge pressure, preeclamptic women with oliguria (<200 mL/12 hr) and a serum urea level higher than 14 mmol/L (39 mg/dL) and serum creatinine level higher than 500 mmol/L (5.65 mg/dL) may benefi t from a furosemide infusion (5 mg/hr) in an effort to prevent fl uid overload and hemodialysis.43

After acute tubular necrosis is established with oliguria and a rising serum creatinine level despite adequate intravascular volume and blood pressure, fl uid intake should be restricted to avoid fl uid over-load. In these circumstances, dialysis is indicated. There are no good studies that have followed up women with acute renal failure related to preeclampsia, but those with the most severe renal impairment will undoubtedly be left with a degree of permanent renal impairment that may not manifest until later life.32

Hypertension due to preeclampsia is caused by vasoconstriction around a reduced plasma volume.40 For this reason and despite the lack of evidence from randomized trials, women with severe preeclampsia often receive plasma volume expansion before therapeutic vasodila-tion. Unless there are signs of pulmonary edema (i.e., basal crackles and PO2 < 95% on air), 500 mL of colloid or crystalloid given over 30 to 60 minutes or 250 mL per hour until the pulmonary wedge pressure is 10 to 12 mm Hg can improve maternal and fetal well-being in cases of severe preeclampsia.45,46 A vasodilator given alone can cause pro-found hypotension that may threaten maternal renal, cerebral, and uteroplacental blood fl ow.

Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic PurpuraHemolytic uremic syndrome (HUS) and thrombotic thrombocytope-nic purpura (TTP) are similar syndromes (designated HUS/TTP).

They are characterized by microangiopathic hemolytic anemia and thrombocytopenia. The congenital and acquired forms of HUS/TTP are more common in late pregnancy.46 Women with HUS/TTP develop platelet thrombi attached to von Willebrand factor multimers in end-organ microvessels. This typically results in a multiorgan disorder with abdominal ischemia and renal or neurologic impairment.47 A plasma metalloprotease (ADAMTS13), which normally cleaves von Willebrand factor multimers to prevent microthrombi, is defi cient in some women with congenital HUS/TTP,48 and antibodies that neutralize ADAMTS13 have been found in women with acquired HUS/TTP.49

HUS/TTP is more common in women (approximately 70% of cases) and more common in association with pregnancy (approxi-mately 13% of cases).46 During pregnancy, the levels of ADAMTS13 fall progressively.50 This may explain why women with a congenital defi ciency of ADAMTS13 or with other risk factors for thrombosis (e.g., obesity, thrombophilia) are predisposed to peripartum HUS/TTP.

Hemolytic Uremic Syndrome, Thrombotic

Thrombocytopenic Purpura, and PreeclampsiaPreeclampsia shares many similarities with HUS/TTP. Both syndromes occur most frequently in the third trimester or immediately after delivery. It is, however, important to differentiate them, because management is different. Women with HUS/TTP often present with gastrointestinal or neurologic abnormalities,46 and they are more likely to have severe renal impairment, hemolysis, and thrombocytopenia compared with women who have preeclampsia. Because disseminated intravascular coagulation (DIC) is rare in HUS/TTP, the prothrombin time and kaolin clotting time are usually normal.47 Women with preeclampsia are also more likely to have elevated levels of hepatic transaminases, heavy proteinuria, and abnormal clotting compared with women with HUS/TTP.40 However, in many women, the distinction between preeclampsia and HUS/TTP can be determined only by the course of the illness after delivery,51 but acute renal failure due to preeclampsia usually becomes transiently worse before improving.32

Management of Hemolytic Uremic Syndrome

and Thrombotic Thrombocytopenic PurpuraMaternal survival from HUS/TTP greatly improved since treatment with plasmapheresis (i.e., infusion of fresh plasma and removal of old plasma).52 Until recently, it was unclear why plasmapheresis worked, but the discovery of antibodies to ADAMTS13 (removed with old plasma) and a congenital defi ciency of ADAMTS13 (replenished with infusion of fresh plasma) gives reason to this process. However, severe defi ciency of ADAMTS13, which is not a routine laboratory measure-ment, is not present in all cases of HUS/TTP, and plasmapheresis is effective in pregnant women who have milder defi ciencies of ADAMTS13.53

Steroids are often added to the plasma exchange regimen and are a rationale choice for acquired HUS/TTP with an autoimmune pathol-ogy, but there are no randomized, controlled trials of their use. Anti-platelet regimens with aspirin and dipyridamole may also be benefi cial in conjunction with plasma exchange.54 Conversely, administration of platelets to thrombocytopenic patients with HUS/TTP can result in a precipitous decline in clinical status.

Acute Renal Cortical NecrosisIn the developed world, acute renal cortical necrosis (ARCN) has become a rare complication of pregnancy. The reduced incidence of

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septic abortion and improved management of peripartum obstetric emergencies have prevented prerenal impairment developing into acute tubular necrosis and then renal cortical necrosis. In the develop-ing world, however, obstetric emergencies are still responsible for most cases of ARCN.55 Acute renal failure after septic abortion or peripar-tum obstetric emergencies developed into ARCN in 20% of women after a prolonged period of acute tubular necrosis.56

ARCN is most commonly caused by abruption of the placenta with hemorrhage, amniotic fl uid embolus, and sepsis associated with DIC.57 After hemorrhage or sepsis with hypotension, prerenal failure without adequate resuscitation leads to acute tubular necrosis. If anuria persists for longer than a week, ARCN should be suspected. A defi nitive diag-nosis can be made with renal biopsy, but it is often missed because of the patchy nature of cortical necrosis. Selective renal angiography can confi rm the diagnosis, but it introduces another nephrotoxic agent and is usually unnecessary. Because of the serious nature of the precipitat-ing illness and the limited availability of renal replacement therapy in the developing world, the maternal mortality rate is still high.56

For women who survive the acute illness, renal function usually returns slowly over the next 6 to 24 months. Long-term renal function depends on the extent of cortical necrosis, which is often incomplete. Hyperfi ltration through remnant glomeruli usually leads to a subse-quent progressive decline in renal function.

Acute Fatty Liver of PregnancyAcute fatty liver of pregnancy (AFLP) causes reversible peripartum liver and renal impairment in 1 of 5000 to 10,000 pregnancies.58 The diagnosis is based on clinical and laboratory fi ndings of impaired liver, renal function, and clotting function, rather than on histologic or radiologic evidence of a fatty liver.58 Women with AFLP usually present with nausea, vomiting, and abdominal cramps. Impaired renal func-tion and reduced plasma antithrombin levels are early fi ndings of AFLP that may precede liver dysfunction.58 In established cases of AFLP, depressed function of the liver with prolonged prothrombin time, hypoglycemia, and DIC are more markedly abnormal than levels of liver transaminases, which may only be moderately elevated.58 In a series of 28 women with AFLP, other ubiquitous laboratory fi ndings at the time of delivery were elevated levels of serum total bilirubin (mean, 7.5 mg/dL), serum creatinine (mean, 205 mmol/L or 2.3 mg/dL), and uric acid (mean, 11 mg/dL).58

A recessively inherited fetal inborn error of mitochondrial fatty acid oxidation may explain up to 20% of AFLP cases.59 Mitochondrial fatty acid oxidation is important for normal renal and liver function and may therefore explain the dual vulnerability of these organs in women with AFLP.

In women with AFLP, maternal renal impairment is aggravated by hypotension from hemorrhage, which is most likely to follow an emer-gency operative delivery.58,60 The combination of renal dysfunction, hemorrhage, and DIC resulting from liver failure during pregnancy or after delivery requires intensive care with a multidisciplinary team of hepatologists, nephrologists, intensive care specialists, and obstetri-cians. Management is supportive and aimed at maintaining adequate fl uid balance for renal perfusion, replacing blood, correcting the coag-ulopathy with fresh frozen plasma and possibly with antithrombin concentrate and fresh platelets. Hypoglycemia should be corrected with 10% dextrose solutions. Temporary dialysis may be necessary, but with good supportive care, recovery of normal renal and liver function is usual.58 Perinatal survival in association with AFLP is improving, but it depends on the early recognition of the maternal condition, close fetal surveillance, timely delivery, and excellent neonatal care.

Nephrotoxic Drugs during PregnancyNonsteroidal anti-infl ammatory drugs (NSAIDs), including the more selective cyclooxygenase-2 (COX-2) inhibitors, when given to the mother in the peripartum period, reduce renal blood fl ow and have been associated with acute renal impairment in the mother and fetus.61 Women with reduced intravascular volume, especially with preexisting renal impairment, are particularly vulnerable and should be prescribed NSAIDs with caution. Aminoglycosides are also nephrotoxic and should be prescribed with care and attention to drug plasma levels in women with mild renal impairment.

Acute Renal Obstruction in PregnancyThe renal tracts may be obstructed during pregnancy by renal calculi (discussed later), congenital renal tract abnormalities, or a gestational overdistention syndrome. Women born with congenital obstructive uropathies at the pelviureteral junction (PUJ) or vesicoureteric junc-tion (VUJ) are at increased risk of urine outfl ow obstruction in the second half of pregnancy, even if they have had surgical correction in childhood.62 Congenital abnormalities of the lower urinary tracts, including the bladder and urethra, are varied and usually require extensive surgical correction in childhood. During pregnancy, these women are at increased risk for recurrent urine infections and, less commonly, for outfl ow obstruction requiring temporary nephrostomy or a ureteric stent.63

Women with a single kidney and urologic abnormalities are par-ticularly vulnerable to develop post-renal failure in relation to gesta-tional obstruction of their solitary kidney. An incomplete obstruction can cause renal impairment with an apparently good urine output. High backpressures compress and damage the renal medulla, leading to a loss of renal concentrating ability and production of dilute urine that is passed through an incomplete obstruction. It is also important for the obstetrician to remember that a congenitally single kidney is often associated with other abnormalities of the genital tracts, such as a unicornuate uterus.64

During pregnancy, the renal tracts can rarely and spontaneously become grossly overdistended. If untreated, overdistention occasion-ally can lead to rupture of the kidney or renal tracts.65 Women with overdistention of the renal tracts initially present with severe loin pain, most commonly on the right side and radiating to the lower abdomen. The pain is positional and inconstant; it is characteristically relieved by lying on the opposite side and tucking the knees up to the chest. A palpable tender fl ank mass may suggest renal tract rupture.65 Rupture of the kidney almost always occurs in a previously diseased kidney, usually in association with a benign hamartoma or renal abscess.65 Urinalysis can reveal gross or microscopic hematuria. A renal ultra-sound can detect a hydronephrotic kidney with a grossly dilated pelvicaliceal system. Occasionally, a urinoma is evident around the kidney, indicating rupture of the renal pelvis that can sometimes seal spontaneously.

The pain from the overdistention syndrome varies from mild to very severe. Women with mild symptoms can usually be managed with advice on positional relief and regular analgesia. Women with severe unremitting pain, hematuria, and grossly distended renal tracts on ultrasound in the absence of structural or infected masses usually have immediate pain relief after decompression of the system with a ureteric stent or nephrostomy. Rupture of the kidney necessi-tates immediate surgery and almost invariably an emergency nephrectomy.65

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Chronic Kidney DiseaseNormal Pregnancy and Renal AssessmentThe glomerular fi ltration rate (GFR), measured as 24-hour creatinine clearance, increases by more than 50% shortly after conception. Serum creatinine (and urea nitrogen levels, which average 70 μmol/L (0.8 mg/dL) and 5 mmol/L (13 mg/dL), respectively, in nonpregnant women, decrease to mean values of 50 μmol/L (0.6 mg/dL) and 3 mmol/L (9 mg/dL) in pregnant women. Near term, a 15% to 20% decrement in GFR occurs, which affects serum creatinine levels minimally.

Serum creatinine values of 80 μmol/L (0.9 mg/dL) and urea nitro-gen of 6 mmol/L (14 mg/dL), which are acceptable in nonpregnant subjects, are suspect in pregnant women. However, the physician should use caution in assessing renal function by serum creatinine levels alone, because the creatinine is fi ltered and secreted by the kidney, and the ratio of creatinine to inulin clearance normally falls to between 1.1 and 1.2. As renal disease progresses, a greater portion of urinary creatinine is formed as a result of secretion (clearance ratios rise to between 1.4 and 1.6 when the serum creatinine level is 1.4). The GFR may be overestimated by 50%.

Formulas (e.g., the Cockroft-Gault formula) that use serum creati-nine in relation to age, height, and weight to calculate GFR should not be used in pregnancy because weight or body size does not refl ect kidney size. The use of estimated GFR (eGFR) from the Modifi cation of Diet in Renal Disease (MDRD) formula, whereby the serum creati-nine value is adjusted for age, gender, and race, cannot be recom-mended for use in pregnancy because it signifi cantly underestimates the GFR.66 Ideally, evaluation of renal function in pregnancy should be based on the clearance of creatinine rather than its serum concentra-tion. Creatinine levels may increase by up to 12 μmol/L (0.15 mg/dL) shortly after ingestion of cooked meat (because cooking converts pre-formed creatine into creatinine), and the timing of the blood sample during a clearance period must take into account meals and their content.

Renal Dysfunction and Preconception CounselingCKD is often clinically and biochemically silent until renal impair-ment is advanced. Symptoms are unusual until GFR declines to less than 25% of normal, and more than 50% of renal function can be lost before the serum creatinine level rises above 120 μmol/L (1.36 mg/dL). However, women who become pregnant with a serum creatinine level above 125 μmol/L (1.4 mg/dL) are at increased risk for an accelerated decline in renal function and poor pregnancy outcome.67-70

CKD is universally classifi ed into fi ve stages according to the level of renal function (i.e., GFR) (Table 44-2). CKD stages 3 through 5 (GFR < 60 mL/min) affect approximately 1 in 250 women of child-bearing age (20 to 39 years),71 but due to reduced fertility and an increased rate of early miscarriage, pregnancy in these women is less common. Studies of CKD in pregnancy have mostly classifi ed women on the basis of serum creatinine values, but we estimate that approxi-mately 1 of 750 pregnancies are complicated by CKD stages 3, 4, or 5.72,73 Some women are discovered to have CKD for the fi rst time during pregnancy. Approximately 20% of women who develop early preeclampsia (≤30 weeks’ gestation), especially those with heavy pro-teinuria, have previously unrecognized CKD.74

Women with CKD are less able to make the renal adaptations characteristic of and essential to healthy pregnancy. Their inability to boost renal hormones often leads to normochromic normocytic anemia, reduced plasma volume expansion, and vitamin D defi -ciency.75,76 The gestational rise in GFR is impaired in women with moderate renal impairment and usually absent in those with a serum creatinine level higher than 200 μmol/L (2.26 mg/dL).68,77,78 If pre-eclampsia develops there is often a mild deterioration in renal func-tion, but the addition of a prerenal insult, such as signifi cant peripartum hemorrhage, can seriously threaten maternal renal function.

Renal Dysfunction and the Impact of Pregnancy

Mild Renal Impairment: Chronic Kidney Disease

Stages 1 and 2

Most women with CKD who become pregnant have mild renal dys-function, and pregnancy usually succeeds without affecting renal prog-nosis. However, complications such as preeclampsia, intrauterine fetal growth restriction, and preterm birth are more common (Table 44-3).69,68

A case-controlled study of 360 women with primary glomerulone-phritis and only mild pre-pregnancy renal dysfunction (serum creati-nine level less than 110 μmol/L), minimal proteinuria (<1 g/24 hr), and absent or well-controlled hypertension, showed that pregnancy had little or no adverse effect on long-term (up to 25 years) maternal renal function.79 The situation is quite different for women who have moderate to severe renal impairment (CKD stages 3, 4, or 5).

Moderate to Severe Renal Impairment: Chronic

Kidney Disease Stages 3 through 5Small, mainly uncontrolled, retrospective studies have shown that women with the worst pre-pregnancy renal function are at greatest risk for an accelerated decline in renal function caused by pregnancy (see Table 44-3). Proteinuria and hypertension add to this risk.68,70,77,80,81 One retrospective series of women with CKD (87 pregnancies) found that those with initially moderate renal impairment (serum creatinine level of 124 to 168 mmol/L or 1.4 to 1.9 mg/dL) had a 40% risk of a pregnancy-related decline in renal function, which persisted after delivery in about one half of those affected, whereas 13 (65%) of 20 women with severe renal impairment (i.e., serum creatinine level higher than 177 mmol/L or 2.0 mg/dL) had a decline in renal function

TABLE 44-2 STAGES OF CHRONIC KIDNEY DISEASE

Stage Description GFR*

1 Kidney damage with normal or increased GFR

≥90

2 Kidney damage with mildly decreased GFR

60-89

3 Moderately decreased GFR 30-594 Severely decreased GFR 15-295 Kidney failure <15 or dialysis

*Glomerular fi ltration rate (GFR) reported as mL/min/1.73 m2.

From the National Kidney Foundation: K/DOQI clinical practice

guidelines for chronic kidney disease: Evaluation, classifi cation and

stratifi cation. Am J Kidney Dis 39(Suppl 1):S1-S266, 2002.

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during the third trimester that persisted in almost all and deteriorated to end-stage renal failure in 7 (35%) of 20.67,82

The fi rst prospective study to assess the rate of decline of maternal renal function before and after pregnancy in 49 women with pre-preg-nancy CKD stages 3 to 5 confi rmed these earlier observations.70 Spe-cifi cally, women with a pre-pregnancy eGFR less than 40 mL/min/1.73 m2 and proteinuria level of more than 1 g in 24 hours, but not either factor alone, showed an accelerated decline in renal function after their preg-nancy compared with before pregnancy. Chronic hypertension, which predisposes women to preeclampsia, may explain why those with milder renal dysfunction also have a gestational decline in renal func-tion. This risk is reduced when hypertension is controlled.

Impact of Chronic Kidney Disease on Perinatal OutcomeMaternal hypertension, proteinuria, and recurrent urinary infection often coexist in women with CKD, and it is diffi cult to apportion the contribution that each factor makes to a poor pregnancy outcome. It appears, however, that each factor is individually and cumulatively detrimental to fetal outcome.67,70,76,77 Although women with severe renal impairment have the greatest diffi culty conceiving, the highest rate of miscarriage, and poorest fetal outcome, there is a spectrum of poor outcomes, including preeclampsia, fetal growth restriction, preterm delivery, and perinatal death, correlating with the level of renal dysfunction.68,69,70,78,83

Preconception CounselingInitiating and sustaining pregnancy are related to the degree of func-tional impairment. Fertility is diminished as renal function falls. When the preconception serum creatinine level exceeds 280 μmol/L (3 mg/L), corresponding to a GFR of less than 25 mL/min, normal pregnancy is unusual; however, successes have been documented in women with moderate to severe disease, including some treated with dialysis because of accelerated maternal renal deterioration.84

Ideally, pregnancy is probably best restricted to women with pre-conception serum creatinine levels below 180 μmol/L (2 mg/dL) and a diastolic blood pressure of 90 mm Hg or less. If the patient has hypertension requiring more than one drug for control, prognosis becomes substantially poorer. Some clinicians extend this limit to 250 μmol/L (2.8 mg/dL), whereas others believe it should be no higher than 140 μmol/L (1.5 mg/dL). Whatever level is used, we reiterate that degrees of impairment not causing symptoms or disrupt-ing homeostasis in nonpregnant individuals can still jeopardize preg-nancy. Clinical complications such as hypertension, proteinuria,

and infection increase the risk of complications at all levels of renal impairment.

A question should be asked: Is pregnancy advisable? If a woman with chronic renal disease wishes to have a family, the sooner she starts, the better. In some of these patients, renal function continues to decline with time. Women are not always counseled before conception. A patient with suspected or known renal disease may present already pregnant, and the question then becomes whether to continue the pregnancy.

Ideally, all women with CKD should be made aware of the risks pregnancy may have on their own long-term renal function and preg-nancy outcome before they conceive. Folic acid (400 mg daily) should be given as usual around conception until at least 12 weeks’ gestation. Low-dose aspirin (50 to 150 mg/day) should be started in early preg-nancy to reduce risk of preeclampsia and improve perinatal outcome.34 Regular drugs should be reviewed so that fetotoxic drugs (e.g., angio-tensin-converting enzyme [ACE] inhibitors, angiotensin II receptor blockers) can be stopped as soon as pregnancy is confi rmed.85

There are reports of women with severe chronic renal failure having successful pregnancies managed without dialysis.86 In one woman, the serum creatinine level was 700 μmol/L (8 mg/dL) at the time of spon-taneous delivery.87 Dialysis has also been instituted prophylactically during pregnancy to increase the chances of a successful outcome.88 Nevertheless, we believe that these women should not take additional health risks. The aim should be to preserve what little renal function remains and to achieve renal rehabilitation by dialysis and transplanta-tion, after which the question of pregnancy can be considered if appropriate.

The literature that forms the basis of our views is primarily retro-spective. Most patients described had only mild dysfunction, and women with greater dysfunctional disease were limited in number. Confi rmation of any preconception guidelines requires defi nitive observational trials that must be prospective.

Antenatal Strategy and Decision Making

Patients should be seen at least at 2-week intervals or less until 32 weeks’ gestation, after which assessment should be weekly. Routine serial antenatal observations should be supplemented with the following:

1. Assessment of renal function using serum creatinine levels and protein excretion using the protein to creatinine ratio on a spot urine sample on approximately a monthly basis

TABLE 44-3 PRE-PREGNANCY RENAL FUNCTION IN CHRONIC RENAL DISEASE WITH ESTIMATES FOR PREGNANCY OUTCOME (>24 WEEKS) AND IMPACT ON MATERNAL RENAL FUNCTION

Serum Creatinine

Level

mmol/L (mg/dL)IUGR

(%)

Preterm Delivery

(%)

Preeclampsia

(%)

Loss of Renal Function*

Perinatal Deaths

(%)

Pregnancy

(%)

Persists after Delivery

(%)

ESRF in 1 Year

(%)

<125 (<1.4) 25 30 22 1 2 — —125-180 (1.4-2.0) 40 60 40 5 40 20 2>180 (>2.0) 65 >95 60 10 70 50 35

*Estimates are based on literature from 1985 to 2007, with all pregnancies attaining at least 24 weeks’ gestation.

ESRF, end-stage renal function; IUGR, intrauterine growth restriction.

Data from references 67-70, 72, 77, 78, 83, 165-169.

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2. Careful monitoring of blood pressure for early detection of hyper-tension and treatment to keep blood pressure at 140/90 mm Hg or less

3. Early detection of superimposed preeclampsia, with checks of blood urea nitrogen, full blood cell count, liver function tests, blood pres-sure, and proteinuria

4. Biophysical assessment of fetal size, development, and well-being5. Early detection of asymptomatic bacteriuria or confi rmation of

UTI every month

Renal FunctionIf renal function deteriorates, reversible causes should be sought, such as a UTI, subtle dehydration, or electrolyte imbalance, which is occa-sionally precipitated by inadvertent diuretic therapy. Near term, a 15% to 20% decrement in function, which affects serum creatinine levels minimally, is permissible. Failure to detect a reversible cause of a sig-nifi cant decrement is reason to end the pregnancy by elective delivery. When proteinuria occurs and persists but blood pressure is normal and renal function is preserved, the pregnancy can be allowed to continue.

Blood PressureMost of the specifi c risks of hypertension appear to be mediated through superimposed preeclampsia. There is still controversy about the incidence of preeclampsia in women with preexisting renal disease. The diagnosis cannot be made with certainty on clinical grounds alone because hypertension and proteinuria may be manifestations of the underlying renal disease. Treatment of hypertension in pregnancy is considered in Chapter 35.

High blood pressure in the presence of an underlying kidney dis-order is treated more aggressively than are other hypertensive compli-cations of pregnancy. This is done because such actions preserve function longer. Although diastolic levels of 100 mm Hg or less may be permissible in many pregnant women with underlying essential hypertension, a diastolic goal of 90 mm Hg or less should be set for patients with renal disease.

Fetal Surveillance and Timing of DeliverySerial assessment of fetal well-being is essential because renal disease can be associated with intrauterine growth restriction, and when com-plications do arise, the judicious moment for intervention is infl uenced by fetal status. Current technology should minimize the risk of intra-uterine fetal death and neonatal morbidity and mortality. Regardless of gestational age, most infants weighing 1500 g or more are better off in a special care nursery than in a hostile intrauterine environment. Deliberate preterm delivery may be necessary if renal function deterio-rates substantially or for the usual maternal and fetal causes, such as uncontrollable hypertension, and signs adduced by monitoring of fetal jeopardy.

Renal BiopsyPercutaneous renal biopsy is usually avoided in pregnancy because the plethoric kidney appears to be more prone to bleeding, especially in hypertensive pregnant women.89 Renal biopsy, although not usually required for the diagnosis and management of preeclampsia, may be indicated if there is reason to suspect a renal lesion that could be suc-cessfully treated, especially in early pregnancy and up to 32 weeks’ gestation, whilst permitting the pregnancy to continue.

Postpartum CareIt can take up to 3 months (occasionally longer) for the physiologic changes of pregnancy to disappear. During that time, close monitoring

of fl uid balance, renal function, and blood pressure and a further review of drug therapy are necessary. Breastfeeding should be encour-aged in women with CKD, but is sometimes not possible for those with severe CKD. Information is still lacking on whether some immunosup-pressive drugs appear in breast milk, but prednisolone, azathioprine, and ACE inhibitors are barely detectable in breast milk. Women who have heavy proteinuria associated with preeclampsia should be fol-lowed until the proteinuria disappears or a diagnosis of renal disease is made.

Problems Associated with Specifi c Kidney DiseasesIn 1991, Imbasciati and Ponticelli90 reviewed outcomes for more than 1000 patients with a variety of specifi c disorders, which were usually documented by kidney biopsy. In this review and in other editorials,3 therapeutic abortions were excluded from calculation of pregnancy success rates and the discussion of the underlying factors.

Acute and Chronic GlomerulonephritisThe acute form of glomerulonephritis is a rare complication of preg-nancy, and it can be mistaken for preeclampsia. For patients with chronic glomerulonephritis, one view warns of aggravation because of the hypercoagulable state accompanying pregnancy, with patients more prone to superimposed preeclampsia or hypertensive crises earlier in pregnancy. The consensus, however, is that if renal func-tion is stable and hypertension is absent, most pregnancies are suc-cessful.76 In a review of 906 pregnancies in 557 women, these generalizations were endorsed90 and several specifi c issues were highlighted:

� Complications developed more frequently in women who already had some dysfunction or hypertension in early pregnancy.

� De novo hypertension or worsening of preexisting hypertension occurred in 25% of pregnancies but usually reverted after delivery, suggesting superimposed preeclampsia, a diagnosis that is not easy to confi rm in this group of patients.

� In 10% of pregnancies, hypertension persisted after delivery, especially in patients with focal and segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and IgA nephropathy.

� Higher rates of fetal loss observed in these women can be accounted for by the greater prevalence of severe hypertension and renal insuffi ciency.

Other, smaller series have endorsed these points. For example, preg-nancy is well tolerated without effect on the course of the disease if blood pressure is normal and the GFR is higher than 70 mL/minute before conception.76,91 With hypertension, the rate of live births is reduced if hypertension exists before pregnancy or is not well con-trolled during gestation.

Hereditary nephritis, an uncommon disorder, may fi rst manifest or become exacerbated during pregnancy, but most gestations succeed. One variant of hereditary nephritis involves disordered platelet mor-phology and function. In these cases, pregnancy has been successful but was sometimes complicated by bleeding problems, especially at delivery.

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Chronic PyelonephritisChronic pyelonephritis (i.e., tubulointerstitial disease) in pregnancy may be infectious or noninfectious. The prognosis in pregnancy is similar to that for patients with glomerular disease; the outcome is best for patients with adequate renal function and normal blood pressure. Compared with nonpregnant women, pregnant women have a higher frequency of symptomatic infections, but these patients may have a more benign antenatal course than do women with glomerular disease.

Refl ux NephropathyThe term refl ux nephropathy is used to describe renal morphologic and functional changes that relate to past (and usually present) vesicoure-teric refl ux, which often is complicated by recurrent infection. Opin-ions were once controversial, but with preserved renal function and no hypertension, fetal and maternal outcomes appear to be excellent.77 For these patients, vigilance is still necessary to detect and treat UTIs (28% to 65%), with many physicians advocating prophylactic antibiotics. Unfortunately, refl ux nephropathy is often associated with hyperten-sion and moderate or severe renal dysfunction by the time these patients reach childbearing age, and such a scenario adversely affects pregnancy outcome. Specifi c obstetric concerns about affected patients include severe intrauterine growth restriction and the risk of sudden, rapid worsening of hypertension and renal function with accelerated progression to renal failure.92

UrolithiasisThe prevalence of urolithiasis in pregnancy is 0.03% to 0.35%.93 Renal and ureteric calculi cause nonuterine abdominal pain severe enough to necessitate hospital admission during pregnancy. Most calculi are calcium oxalate (the more benign type), but occasionally, the more malicious struvite stones (e.g., staghorn) are seen. Uric acid and cystine are much less common.

Management should be conservative initially, with adequate hydra-tion, appropriate antibiotic therapy, and pain relief with systemic anal-gesics. Most women pass their stones spontaneously. The use of continuous segmental (T11 to L2) epidural block has been advocated, as in nonpregnant patients with ureteric colic, and it may favorably infl uence spontaneous passage of the stones. With good pain relief, patients micturate without diffi culty, move without assistance, and are less at risk for thromboembolic problems than if they are drowsy, nauseated, and bedridden with pain.

When there are complications that may require surgical interven-tion, pregnancy should not be a deterrent to limited IVU, even though the clinician may be reluctant to consider radiologic investigation. Specifi c clinical criteria should be met before a limited IVU is under-taken: microscopic hematuria, recurrent urinary tract symptoms, and sterile urine culture when pyelonephritis is suspected. The presence of two of these criteria indicates a diagnosis of calculi in 60% of women.94

Magnetic resonance urography can be used to avoid radiation exposure.95 Another approach involves the cystoscopic placement of an intraureteral tube, or stent, between the bladder and kidney under local anesthesia.96 The stent retains its position because it has a pigtail or J-like curve at each end (double-J), and it can be changed every 8 weeks to prevent encrustation. Early empiric use for presumed stone obstruc-tion in pregnant women with fl ank pain is recommended by some, especially when hydration, analgesia, and antibiotics do not resolve

pain or fever, and when the pregnancy is over, the usual x-ray evalua-tion is obtained and standard management resumed.97

Sonographically guided percutaneous nephrostomy is another effective and safe method of treating gravidas with ureteric colic or symptomatic obstructive hydronephrosis. The procedure is rapid, requires minimal anesthesia, and is preferable to retrograde stenting or more invasive surgery.

In patients with cystinuria, assiduous maintenance of high fl uid intake is the mainstay of management. Although D-penicillamine appears relatively safe, it should be used only for severe cases, such as when urinary cystine excretion is known to be very high.98

Autosomal Dominant Polycystic Kidney DiseaseAutosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disorder, but it may remain undetected during pregnancy. Careful questioning for a history of familial problems and the use of ultrasonography may lead to earlier detection. Patients do well when functional impairment is minimal and hypertension is absent, as is often the case in childbearing years.99 They do, however, have an increased incidence of hypertension late in preg-nancy and a higher rate of perinatal mortality compared with that in pregnancies of sisters unaffected by this autosomal dominant disease.

Women with advanced renal failure are best advised against preg-nancy, although use of prophylactic dialysis has been advocated, despite lack of controlled studies, for this type of patient.100 If one or the other prospective parent has evidence of polycystic renal disease, the couple may seek genetic counseling. There is a 50% chance of transmitting the disease to the offspring, which is caused by two identifi ed genes: PKD1 (85%) and PKD2 (15%). DNA probe techniques can make the diagnosis of ADPKD, but a signifi cant number of ADPKD mutations are caused by multiple amino acid substitutions, which need to be interpreted with caution.101

Diabetic NephropathyBecause many patients have had diabetes since childhood, they probably already have microscopic changes in the kidneys.102 During pregnancy, diabetic women have an increased prevalence of covert bacteriuria (and may be more susceptible to symptomatic UTI), peripheral edema, and preeclampsia.84

Most women with diabetic nephropathy who become pregnant still have good renal function and demonstrate normal GFR increments (with perhaps signifi cant proteinuria), and pregnancy does not accel-erate renal deterioration.103 There is, however, a report of diabetic women with moderate renal dysfunction (serum creatinine level above 125 μmol/L or ≤1.4 mg/dL) whose renal function permanently deteri-orated in pregnancy compared with the changes before and after-ward.104 Such changes occurred despite good metabolic control and might have been related to hypertension, which often accelerates in the third trimester regardless of intensifi ed treatment.105 However, there were no controls for this study. The condition of diabetic patients with creatinine levels above 1.4 mg/dL who do not become pregnant often progresses rapidly to further renal failure.

Hypertension should be treated more intensively in diabetics. As with other renal disorders during pregnancy, we believe that more aggressive antihypertensive therapy is a reasonable objective. These patients often are treated with “renoprotecting” ACE inhibitors or angiotensin receptor blockers prescribed before conception, but

Ch044-X4224.indd 913 8/26/2008 4:09:21 PM


these drugs should be stopped as soon as possible after conception to avoid teratogenic effects that become evident after 6 weeks’ gestation.85

Systemic Lupus ErythematosusSystemic lupus erythematosus (SLE) is a relatively common disease and has a predilection for women of childbearing age. Its coincidence with pregnancy poses complex clinical problems because of the pro-found disturbance of the immunologic system, multiorgan involve-ment, and complicated immunology of pregnancy itself.84 The outcome of pregnancy for women with SLE is variable and to some extent unpredictable, so careful monitoring, especially for those women with lupus nephritis, is required (see Chapter 51).

Decisions regarding the status of the disease and the importance of having a child to the patient and her partner should be made on an individual basis. Most pregnancies succeed, especially when the mater-nal disease has been in complete clinical remission for 6 months before conception, even if there were marked pathologic changes in the origi-nal renal biopsy and heavy proteinuria in the early stages of the disease.106 Continued signs of disease activity or increasing renal dys-function reduces the likelihood of an uncomplicated pregnancy and the clinical course thereafter.

The effects of gestation on SLE activity and on the course of lupus nephritis have long been debated. Taking into account extrarenal man-ifestations and renal changes, at least 50% of women show some change in clinical status, often called a lupus fl are.107 Some increments in proteinuria or blood pressure may result from preeclampsia. Women with lupus nephritis and renal insuffi ciency (serum creatinine level higher than 125 μmol/L or 1.4 mg/dL) that antedates pregnancy have worse outcomes.

Lupus nephritis may sometimes become manifest during preg-nancy, and when accompanied by hypertension and renal dysfunction, it may be mistaken for preeclampsia. Some patients experience relapse, occasionally severely in the puerperium; therefore, some clinicians prescribe or increase immunosuppression at this time.108 It is our prac-tice to increase immunosuppression only if there are signs of increased disease activity.

SLE serum contains an array of autoantibodies (i.e., lupus serum factor) against nucleic acids, nucleoproteins, cell-surface antigens, and phospholipids. Antiphospholipid antibodies exert a complicated effect on the coagulation system.109 This led to the defi nition of a lupus anticoagulant, which is found in 5% to 10% of patients with SLE (see Chapter 40). Because treatment with low-molecular-weight heparin and aspirin may lead to successful pregnancies, it is important to screen for lupus anticoagulant in women with SLE and especially in those with a history of recurrent intrauterine death or thrombotic episodes to identify this particular cohort.

Periarteritis NodosaIn contrast to lupus nephritis, the outcome of pregnancy in women with renal involvement as a result of periarteritis nodosa is very poor, largely because of the associated hypertension, which frequently is malignant. Many cases in the literature have involved maternal demise. However, this dismal prognosis is based primarily on selected anec-dotal studies, and a few successful pregnancies have been reported. Still, until more data are available (perhaps through a registry), con-sideration of early therapeutic termination must be made in the best interests of maternal health.

Systemic SclerosisScleroderma is a term that includes a heterogeneous group of limited and systemic conditions causing hardening of the skin. Systemic scle-rosis implies involvement of skin and other sites, particularly certain internal organs. Renal involvement is thought to occur in about 60% of these patients, usually within 3 to 4 years of diagnosis. Manifestation may take one of three forms: sudden onset of malignant hypertension, rapidly progressive renal failure, or slowly increasing azotemia.110

The combination of systemic sclerosis and pregnancy is unusual because the disease occurs most often in the fourth and fi fth decades, and affected patients are usually infertile. When it has its onset in pregnancy, there is a greater tendency for deterioration. Patients with scleroderma and no evidence of renal involvement before conception have developed severe kidney disease during gestation. There are also instances in which pregnancy has been uneventful and successful, but marked reactivation occurred unexpectedly in the puerperium. Most maternal deaths involve rapidly progressive scleroderma with severe pulmonary complications, infections, hypertension, and renal failure.

The extent of systemic involvement is probably more important than the duration of the disease, and limited, mild disease carries a better prognosis. Sclerosis usually spares the abdominal wall skin, but there is one report of hydronephrosis, presumed to have been caused by thickened skin and decreased abdominal wall compliance, in a twin pregnancy complicated by polyhydramnios.111

Wegener GranulomatosisInformation on the outcome of pregnancy in women with Wegener granulomatosis is scarce. Proteinuria (with or without hypertension) is common, and reports have described complicated and uneventful pregnancies.112 Experience with cyclophosphamide (Cytoxan) in preg-nancy is limited, and the risks to the embryo and fetus must be weighed in relation to the course of the disease if such therapy were to be with-held from the mother.

Previous Urinary Tract SurgeryPermanent urinary diversion is still used in the management of patients with congenital lower urinary tract defects, but its use for neurogenic bladder has declined since the introduction of self-catheterization. The most common complication of pregnancy is urinary infection. Premature labor occurs in 20%, and the use of prophylactic antibiotics throughout pregnancy may reduce its incidence. Decline in renal func-tion may occur, invariably related to infection or intermittent obstruc-tion, or both. With an ileal conduit, elevation and compression by the expanding uterus can cause outfl ow obstruction, whereas with a ure-terosigmoid anastomosis, actual ureteral obstruction may occur. The changes usually reverse after delivery.

The mode of delivery is dictated by obstetric factors. Abnormal presentation accounts for a cesarean section rate of 25%. Vaginal deliv-ery is safe, but because the continence of a ureterosigmoid anastomosis depends on an intact anal sphincter, this area must be protected with a mediolateral episiotomy.

During the past decade, urinary tract reconstruction by means of augmentation cystoplasty, with or without artifi cial genitourinary sphincter, has become more common. Deterioration of renal function and urinary tract obstruction or infection can occur at any time in pregnancy. Delivery by cesarean section is recommended for these

Ch044-X4224.indd 914 8/26/2008 4:09:21 PM


gravidas because of the potential for disruption of the continence mechanism.

Solitary KidneySome patients have a congenital absence of one kidney or marked unilateral renal hypoplasia. Most, however, have had a previous nephrectomy because of pyelonephritis (with abscess or hydronephro-sis), unilateral tuberculosis, congenital abnormalities, or a tumor. It is important to know the indication for and the time elapsed since the nephrectomy. In patients with an infectious or a structural renal problem, sequential pre-pregnancy investigation is needed to detect any persistent infection.

It makes no difference whether the right or left kidney remains, as long as it is located in the normal anatomic position. If function is normal and stable, women with this problem seem to tolerate preg-nancy well despite the superimposition of GFR increments on already hyperfi ltering nephrons. Single kidneys are most often associated with the rare instances of acute renal failure as a result of obstruction during pregnancy.

Ectopic kidneys (usually pelvic) are more vulnerable to infection and are associated with decreased fetal salvage, probably because of associated malformations of the urogenital tract. If infection occurs in a solitary kidney during pregnancy and does not quickly respond to antibiotics, termination may have to be considered for preservation of renal function.

Nephrotic SyndromeThe most common cause of nephrotic syndrome in late pregnancy is preeclampsia. Other causes include proliferative or membranoprolif-erative glomerulonephritis, lipid nephrosis, lupus nephritis, hereditary nephritis, diabetic nephropathy, renal vein thrombosis, and amyloido-sis. Some of these conditions do not respond to steroids and may even be aggravated by them; this emphasizes the importance of a tissue diagnosis before steroid therapy is begun.113

If renal function is adequate and hypertension is absent, there should be few complications during pregnancy and good fetal outcome. However, physiologic changes occurring during gestation may mimic aggravation or exacerbation of disease. Increments in renal hemody-namics and increases in renal vein pressure may enhance protein excretion during pregnancy. Serum albumin levels usually decrease by 0.5 to 1.0 g/dL during normal pregnancy, and further decreases due to nephrotic syndrome may enhance the tendency toward fl uid retention. Care must be taken with the use of diuretics to treat edema because reduced intravascular volume may reduce uteroplacental perfusion or aggravate the increased tendency to thrombotic episodes.

Human Immunodefi ciency Virus—Associated NephropathyDuring the past 25 years, there have been increasing numbers of reports about a nephrotic syndrome and severe renal impairment in patients infected with the human immunodefi ciency virus (HIV).114 The condition is characterized by severe proteinuria, by bright echogenic kidneys, and often by rapid progression to end-stage renal disease. The distinctive features seen on histologic evaluation of renal biopsy are a collapsing glomerulosclerosis, visceral epithelial cell hypertrophy, and cystic tubular degenerative changes.114 The

incidence of this HIV-associated nephropathy appears to be increas-ing, particularly in the African-American population and in cases of intravenous drug abuse. Although few cases of this nephropathy have been reported in pregnant women, with the rising incidence of acquired immunodefi ciency syndrome (AIDS), especially among black African women, this form of renal disease should be considered in HIV-infected patients presenting with severe proteinuria.

Factors Affecting Prognosis

Effects of Specifi c Disorders on Fetal OutcomeThe problems associated with the specifi c disorders discussed in this section are summarized in Table 44-4. In general, we suggest that pre-served renal function and the absence of hypertension before concep-tion predict successful fetal outcome and few maternal complications, regardless of the nature of the disorder. These conclusions often are based on poorly controlled, retrospective data, underscoring the need for registries and for prospectively acquired data; there is only one such study.70

Effect of Pregnancy on Renal Disease/

Remote PrognosisPregnancy does not adversely affect the natural history of the renal lesion if kidney dysfunction is minimal and hypertension is absent at conception, with the exception of certain collagen disorders. An impor-tant factor in remote prognosis is the sclerotic effect that hyperfi ltra-tion might already have had in the residual (intact) glomeruli of kidneys of patients with renal insuffi ciency. Further progressive loss of renal function can ensue in pregnancy, but this is not the case in animals when pregnancy is superimposed on experimental glomerulonephritis.115

The superimposition of pregnancy hyperfi ltration on the com-pensatory changes already present in a single kidney may lessen the lifespan of the kidney. The crux of this hypothesis is the implication that increases in glomerular pressure or glomerular plasma fl ow cause sclerosis within the glomerulus and that in pregnancy further physiologic hyperfi ltration augments the damage. In health, it seems unlikely that there are long-term renal sequelae.115 More human and animal research is needed because patients with renal disease can have unpredicted, accelerated, and irreversible renal decline in pregnancy or immediately afterward, and the mechanisms are unknown.

Hemodialysis Patients and PregnancyIt has been several decades since the fi rst description of conception and successful delivery in a patient on chronic hemodialysis, and additional case reports and registry data have been published since then.116-119 Any optimism must be tempered by the thought that clinicians are reluc-tant to publish failures or disasters, and consequently, the true inci-dence of unsuccessful pregnancies in women on dialysis cannot be determined. The high surgical abortion rate in these patients, although decreased from 40% in 1989 to 18% today, still indicates that those who become pregnant do so accidentally, probably because they are unaware that pregnancy is a possibility.

Ch044-X4224.indd 915 8/26/2008 4:09:22 PM


Counseling and Early Pregnancy AssessmentDespite irregular or absent menstruation and impaired infertility, women on dialysis should use contraception if they wish to avoid pregnancy.120 The introduction of recombinant human erythro-poietin (rHuEPO) for the treatment of women with renal failure appears to be associated in some cases with return of normal menses (and ovulation), probably because of improved overall health.121

There are substantial arguments against pregnancy, not least of which are the risks to the patient (e.g., severe hypertension, cardiac failure, maternal death) and the fact that even when therapeutic ter-mination of pregnancy is excluded, there is at the very best only a 40% to 50% likelihood of a successful outcome.122 If only data since the late 1990s are considered, fetal survival seems to be improving, although maternal risk remains formidable (Table 44-5).116

Early diagnosis of pregnancy is diffi cult. A missed period is usually ignored. The mistake the clinician may make is failure to consider the possibility of pregnancy, and many of these patients have not been given contraception counseling. Resistance to rHuEPO or progression of anemia (i.e., hematocrit decrease by 8% of pre-pregnancy levels) can be a useful clue to early diagnosis of pregnancy. Urine pregnancy tests are unreliable, and defi nitive diagnosis and estimation of gestational age are best accomplished by sonar technology.

Antenatal Strategy and Decision MakingFor a successful outcome, scrupulous attention must be paid to blood pressure control, fl uid balance, increased hours of dialysis, and provi-sion of good nutrition. Excellent publications should be consulted for more details.116,123-127

TABLE 44-4 CHRONIC RENAL DISEASE AND PREGNANCY

Renal Disease Effects

Chronic glomerulonephritis and focal glomerular sclerosis (FGS)

Incidence of high blood pressure late in gestation is increased, but there usually is no adverse effect if renal function is preserved and hypertension is absent before gestation. Some disagree, believing coagulation changes in pregnancy exacerbate disease, especially immunoglobulin A (IgA) nephropathy, membranoproliferative glomerulonephritis, and FGS.

IgA nephropathy Some cite risks of sudden escalating or uncontrolled hypertension and renal deterioration. Most fi nd good outcomes when renal function is preserved.

Chronic pyelonephritis (infectious tubulointerstitial disease)

Bacteriuria occurs in pregnancy and may lead to exacerbation.

Refl ux nephropathy In the past, some emphasized risks of sudden escalating hypertension and worsening of renal function. Consensus now is that results are satisfactory when preconception function is only mildly affected and hypertension is absent. Vigilant screening for urinary tract infections is necessary.

Urolithiasis Ureteral dilatation and stasis do not seem to affect natural history, but infections can become more frequent. Stents have been successfully placed, and sonographically controlled ureterostomy has been performed during gestation.

Polycystic kidney disease Functional impairment and hypertension are usually minimal in childbearing years.Diabetic nephropathy There are no adverse effects of the renal lesion. Frequencies of infections, edema, and preeclampsia

increase.Systemic lupus erythematosus Prognosis is most favorable if disease is in remission 6 or more months before conception. Some

authorities increase steroid dosage in the immediate postpartum period.Periarteritis nodosa Fetal prognosis is poor. Disease is associated with maternal death. Therapeutic abortion should be

considered.Scleroderma For onset during pregnancy, there can be rapid overall deterioration. Reactivation of quiescent

scleroderma can occur during pregnancy and after delivery.Previous urologic surgery Depending on the original reason for surgery, there may be other malformations of the urogenital tract.

Urinary tract infection is common during pregnancy, and renal function may undergo reversible decrease. No signifi cant obstructive problem, but cesarean section may be necessary in case of abnormal presentation or to avoid disruption of the continence mechanism if artifi cial sphincters or neourethras are present.

After nephrectomy, solitary and pelvic kidney

Pregnancy is well tolerated. Condition may be associated with other malformations of the urogenital tract. Dystocia rarely occurs with a pelvic kidney.

TABLE 44-5 ESTIMATES FOR PREGNANCY COMPLICATIONS AND OUTCOMES IN DIALYSIS PATIENTS

Complication or Outcome Incidence or Timing*

Polyhydramnios 40%Intrauterine growth restriction 90%Preterm delivery 85%Average gestational age at delivery 33 wkHypertension/preeclampsia (Severe)

70%15%

Surviving infant Conceived on dialysis 50% Conceived before dialysis 75%

*Estimates are based on literature from 1992 to 2007, with all

pregnancies attaining at least 24 weeks’ gestation.

Data from references 2, 88, 121, 123-127, 163, 164.

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Dialysis PolicySome patients show apparent increments in GFR even though the level of renal function is too poor to sustain life without hemodialysis, whereas other women remain completely anuric.128 Women with some residual renal function and satisfactory daily urine volumes, in whom dialysis control is easier, are more likely to become pregnant and to sustain pregnancy.

Management of dialysis during pregnancy should mimic the physi-ologic changes of healthy pregnancy as closely as possible. This aim can be capsulated in seven points:

1. Maintain serum urea at less than 20 mmol/L (60 mg/dL), although some would argue lower (e.g., 15 mmol/L [<45 mg/dL]). This is likely to necessitate almost daily dialysis from the end of the fi rst trimester

2. Avoid hypotension during dialysis, which could be damaging to the fetus. In late pregnancy, the gravid uterus and the supine posture may aggravate this by decreasing venous return.

3. Ensure good control of blood pressure, but consider excess fl uid as a cause of hypertension.

4. Ensure minimal fl uctuations in fl uid balance, and limit volume changes.

5. Scrutinize carefully for preterm labor, because dialysis or uterine contractions with or without signifi cant changes in fetal hemody-namics are associated.127

6. Watch calcium levels closely, and avoid hypercalcemia.7. Limit interdialysis weight gain to about 1 kg until late pregnancy.

After midpregnancy, the physician should take the classic 0.5 kg/wk weight gain into account when considering dry weight. This means at least a 50% increase in hours and frequency of dialysis. Frequent dialysis renders dietary management and control of weight gain much easier.

In one report from Saudi Arabia of 27 pregnancies in 22 women, only 10 went beyond 28 weeks’ gestation, and 8 of these were successful.124 Comparing the pregnancies that ended before 28 weeks with those that went beyond, the researchers found no signifi cant dif-ferences in blood pressure, hemoglobin, creatinine levels, type of dialy-sate, obstetric history, or duration on hemodialysis, but the dialysis hours were signifi cantly longer for the successful group.

Intensifi ed Anemia ManagementPatients with severe renal insuffi ciency are usually anemic. This anemia is aggravated further in pregnancy, and increased erythropoietin therapy and even blood transfusion may be needed, especially before delivery. Caution is necessary because erythropoietin therapy or trans-fusion may exacerbate hypertension and impair the ability to control circulatory overload, even with extra dialysis. Fluctuations in blood volume can be minimized if packed red cells are transfused during dialysis.

It appears that genetically engineered erythropoietin (rHuEPO) is well tolerated in pregnancy.121,130 The theoretical risks of hypertension alluded to previously and thrombotic complications have not been cited. Invariably, rHuEPO requirements to maintain a target hemato-crit of 30% increase until delivery131 may attain 300 IU/kg/wk.126 No adverse effects have been identifi ed in neonates in whom normal hematologic indices and erythropoietin concentrations for gestational age suggest that rHuEPO does not have signifi cant transplacental effects.

Unnecessary blood sampling should be avoided when there is anemia or a lack of venipuncture sites. The protocol for various tests

usually performed in a particular unit should be followed strictly, with no more blood removed per venipuncture than is absolutely necessary.

HypertensionBecause patients with hypertension may have abnormal lipid profi les and possibly accelerated atherogenesis, it is diffi cult to predict the car-diovascular capacity to tolerate pregnancy. Diabetic women receiving dialysis who have become pregnant are those in whom cardiovascular problems are most evident. In these and other women with renal disease, a normotensive state at conception is reassuring. Unfortu-nately, blood pressure tends to be labile, and hypertension is a common problem, although it may be possible to help control it by dialysis.

Ensuring Good Maternal NutritionDespite more frequent dialysis, relatively free dietary intake should be discouraged. A daily oral intake of 70 g of protein, 1500 mg of calcium, 50 mM of potassium, and 80 mM of sodium is advised, with supple-ments of dialyzable vitamins, particularly folic acid. Vitamin D supplementation can be diffi cult to judge in patients who have had parathyroidectomy. In addition, the placenta produces hydroxyvitamin D, which is one reason why oral supplementation may have to be cur-tailed. All of this poses risks for fetal nutrition in addition to the fact that the exact impact of the uremic environment is diffi cult to assess. The use of parenteral nutrition supplementation in pregnancy in these gravidas has been advocated.132

Fetal Surveillance and Timing of DeliveryWhat has been said with regard to chronic renal disease applies here as well. Cesarean section should be necessary only for purely obstetric reasons. It could be argued that elective cesarean section in all cases may minimize potential problems during labor. Preterm labor is generally the rule and may commence during hemodialysis.133 The role of cesarean section in this situation needs to be carefully considered.

Peritoneal Dialysis Patients and Pregnancy

Since 1976, continuous ambulatory peritoneal dialysis (CAPD) and continuous cycling peritoneal dialysis have been used more frequently in the management of patients with all forms of renal insuffi ciency. Several features of peritoneal dialysis make it an attractive approach for the management of renal failure in pregnancy:

� Maintenance of a more stable environment for the fetus in terms of fl uid and electrolyte concentrations

� Avoidance of episodes of abrupt hypotension, a frequent occurrence during hemodialysis, which can cause fetal distress

� Continuous allowance for extracellular fl uid volume control so that blood pressure control is augmented

� Better blood sugar control in patients with diabetes mellitus with the use of intraperitoneal insulin

Nevertheless, there appears to be no differences in outcome because of mode of renal replacement therapy (i.e., hemodialysis versus peri-toneal dialysis), and there may even be greater infertility in patients receiving CAPD.88,116 Peritoneal dialysis may not be able to keep up with the physiologic changes of pregnancy to the same extent as daily hemodialysis.

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Peritonitis, which can be a severe complication of CAPD, accounts for most therapy failures in nonpregnant populations. Peritonitis superimposed on a pregnancy can present a confusing diagnostic picture and a whole series of treatment problems.

Renal Transplant Patients and PregnancyAfter transplantation, renal and endocrine functions return rapidly, and normal sexual activity can ensue.134 About 1 in 50 women of childbearing age with a functioning renal transplant becomes preg-nant. Of the conceptions, 40% do not go beyond the initial trimester because of spontaneous or therapeutic abortion. More than 90% of pregnancies that continue past the fi rst trimester end successfully (Table 44-6).75

Allografting has been performed when the surgeons were unaware that the recipient was in early pregnancy.135 Obstetric success in such cases does not negate the importance of contraception counseling for all patients with renal failure and the exclusion of pregnancy before transplantation.

Counseling and Early Pregnancy AssessmentA woman should be counseled from the time the various treatments for renal failure and the potential for optimal rehabilitation are dis-cussed. Information regarding potential reproductive capacity must be included. Even after transplantation, stress will still be a major factor in everyday life, which will always have a baseline of uncertainty. Couples who want a child should be encouraged to discuss all the implications, including the harsh realities of maternal prospects of survival.136

Preconception GuidelinesIndividual centers have their own guidelines.137,138 For most, a wait of 12 to 18 months after transplantation is advised. This has turned out to be good advice, because by then, the patient will have recovered from the major surgery and any sequelae, graft function will have stabilized, and immunosuppression is likely to be at maintenance levels. If func-tion is well maintained at 24 months, there also is a high probability of allograft survival at 5 years.

A suitable set of guidelines is given here, but the criteria are only relative:

1. Good general health for 12 to 18 months after transplantation, with comorbid factors under control

2. Stature compatible with good obstetric outcome3. No or minimal proteinuria.4. Absence of or well-controlled hypertension5. No evidence of graft rejection6. Absence of pelvicalyceal distention on a recent IVU or renal

ultrasound7. Stable renal function with a serum creatinine level of 180 μmol/L

(2 mg/dL) or less and preferably less than 125 μmol/L (1.4 mg/dL)139,140

8. Drug therapy reduced to maintenance levels for prednisone (≤15 mg/day), azathioprine (≤2 mg/kg/day), cyclosporine (≤5 mg/kg/day), and tacrolimus (≤0.1 to 0.2 mg/kg/day)

Experience with newer immunosuppressive drugs (e.g., mycophe-nolate mofetil, sirolimus) is minimal, and current advice is to avoid their use in pregnancy unless stopping them would seriously endanger maternal health. Further information is keenly awaited about out-comes with the use of newer agents.

Pregnancy in the female transplant population and its ethical dilemmas have been comprehensively discussed in several publica-tions, particularly those from a Consensus Conference on Reproduc-tive Issues and Transplantation.138,141,142 These issues do apply to all women with potentially serious medical conditions and their partners who want to become parents.

Ectopic PregnancyEctopic pregnancy occurs in at least 0.5% of all conceptions. The diagnosis can be diffi cult because irregular bleeding and amenorrhea accompany deteriorating renal function or even an intrauterine preg-nancy. Patients who have had previous urologic surgery, peritoneal dialysis, and pelvic infl ammatory disease are at higher risk for ectopic pregnancy because of pelvic adhesions. Intrauterine contraceptive devices have a higher failure rate in immunosuppressed women. The main clinical problem is that symptoms of genuine pelvic pathology are erroneously attributed to the transplant.

Antenatal Strategy and Decision MakingPatients must be monitored as high-risk cases by an obstetrician and an experienced transplantation nephrologist. Management requires attention to serial assessment of renal function, diagnosis and treat-

TABLE 44-6 PRE-PREGNANCY RENAL FUNCTION IN RENAL TRANSPLANT RECIPIENTS WITH ESTIMATES FOR PREGNANCY OUTCOME (>24 WEEKS) AND IMPACT ON MATERNAL RENAL FUNCTION

Serum Creatinine

Level

mmol/L (mg/dL)IUGR

(%)

Preterm Delivery

(%)

Preeclampsia

(%)

Loss of Renal Function*

Perinatal Deaths

(%)

Pregnancy

(%)

Persists after Delivery

(%)

ESRF in 1 year

(%)

<125 (<1.4) 30 35 24 3 15 4 —125-160 (1.4-1.85) 50 70 45 7 20 7 10>160 (>1.85) 60 90 60 12 45 35 70

*Estimates are based on literature from 1991 to 2007, with all pregnancies attaining at least 24 weeks’ gestation.

ESRF, end-stage renal function; IUGR, intrauterine growth restriction.

Data from references 139, 140, 145, 148, 158, 166, 170-177.

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ment of rejection, blood pressure control, early diagnosis or prevention of anemia, treatment of any infection, and meticulous assessment of fetal well-being.

Antenatal visits should be at least at every 2 weeks up to 32 weeks and weekly thereafter. The following tests should be undertaken monthly:

Complete blood cell count, including plateletsBlood urea nitrogenCreatinine levelElectrolyte levelsUrate levelsTwenty-four-hour creatinine clearance and protein excretionMidstream urine specimens for microscopy and culture

Liver function tests, plasma protein, and calcium and phosphate levels should be checked at 6-week intervals. Tests for cytomegalovirus and herpesvirus should be performed during each trimester if the initial fi ndings are negative (see Chapter 38). Although immunosup-pressive therapy is usually maintained at pre-pregnancy levels, adjust-ments may be needed if there are decreases in the maternal white blood cell and platelet counts. Hematinic agents should be prescribed if the various hematologic indices show defi ciency.

Allograft FunctionSerial data on renal function are needed to supplement routine ante-natal observations (discussed earlier). The anatomic changes and the increased and then sustained GFR characteristic of early pregnancy are evident, even though the allograft is ectopic, denervated, potentially damaged by previous ischemia, and immunologically different from both recipient and fetus. The better the pre-pregnancy GFR, the greater the increment in pregnancy, and graft gender has no signifi cant effect on the hyperfi ltration response.143 Transient reductions in GFR can occur during the third trimester and usually do not represent a dete-riorating situation with permanent impairment. In 15% of patients, signifi cant renal functional impairment develops during pregnancy and may persist after delivery. Because a gradual decline in function is common in nonpregnant patients, it is diffi cult to delineate a specifi c effect of pregnancy.

Subclinical chronic rejection with declining renal function may occur after an episode of acute rejection or if immunosuppression becomes suboptimal. Whether cyclosporine is more nephrotoxic in pregnancy compared with the blunting of augmentation in GFR in the nonpregnant patient is unknown. We recommend keeping cyclospo-rine and tacrolimus levels at the lower end of the therapeutic range during pregnancy, which usually necessitates a small rise in drug dose. Increases in proteinuria, often to abnormal levels, occur near term in 40% of patients; this regresses after delivery and, in the absence of hypertension, is not signifi cant.

Allograft RejectionSerious rejection episodes occur in 6% of pregnant allograft recipients. Although this incidence of rejection is no greater than that expected for nonpregnant transplant patients, it is unusual because it has been assumed that the privileged immunologic state of pregnancy could be benefi cial. Rejection can occur in the puerperium and may be caused by return to a normal immune state (despite immunosuppression) or possibly by a rebound effect from the altered immunoresponsiveness of pregnancy.

Chronic rejection may be a problem in all recipients, having a pro-gressive subclinical course. Whether a pregnancy infl uences the course

of subclinical chronic rejection is unknown. No factors consistently predict which patients will experience allograft rejection during preg-nancy. Some have hypothesized a nonimmune contribution to chronic graft failure because of the damaging effect of hyperfi ltration through remnant nephrons, which is perhaps even exacerbated during preg-nancy. From the clinical viewpoint, several points are important. Because rejection is diffi cult to diagnose, when any of the clinical hallmarks are present (e.g., fever, oliguria, deteriorating renal function, renal enlargement, tenderness), the diagnosis should be considered. Although ultrasonography may prove helpful in the nonpregnant setting, in the pregnant state, without renal biopsy, rejection cannot be distinguished from acute pyelonephritis, recurrent glomerulopathy, possibly severe preeclampsia, and even cyclosporine nephrotoxicity. Renal biopsy is indicated before aggressive anti-rejection therapy is instigated.

ImmunosuppressionImmunosuppressive therapy is usually maintained at pre-pregnancy levels, but adjustments may be needed if the maternal leukocyte or platelet count decreases.144,145 When white blood cell counts are main-tained within physiologic limits for pregnancy, the neonate usually is born with a normal blood count. Azathioprine liver toxicity has been seen occasionally during pregnancy, and it responds to dose reduction. The National Transplantation Pregnancy Registry (NTPR), maintained by Vincent T. Armenti at Thomas Jefferson University in Philadelphia, is accruing data.146,147

Numerous adverse effects are attributed to cyclosporine in non-pregnant transplant recipients, including renal toxicity, hepatic dys-function, chronic hypertension, tremor, convulsions, diabetogenic effects, hemolytic uremic syndrome, and neoplasia. In pregnancy, some of the maternal adaptations that normally occur may theoretically be blunted or abolished by cyclosporine, especially plasma volume expansion and renal hemodynamic augmentation. Data suggest that patients treated with cyclosporine have more hypertension (≈70%) and smaller infants (20% to 50%), but it is still too early for defi nitive conclusions.140,148

Newer agents such as mycophenolate mofetil (MMF/CellCept) and lymphocyte immune globulin (Atgam) are being prescribed more frequently for transplant recipients,149 but there is little information about these agents in pregnancy. Orthodione (OKT3) is an IgG that crosses the placenta, but data are limited.150 Some of the agents were originally considered to have a rescue role only for kidney and kidney-pancreas transplantations, but they are being used as primary immunosuppressants.149

Hypertension and PreeclampsiaAt least 50% of patients have signifi cant hypertension requiring medi-cation before pregnancy (see Chapter 35). All medications should be reviewed. The appearance of hypertension or worsening of chronic hypertension in the third trimester, its relationship to deteriorating renal function, and the possibility of chronic underlying pathology and preeclampsia are diagnostic problems. Escalating hypertension, particularly before 28 weeks’ gestation, is associated with adverse perinatal outcome,151 which may be linked to covert cardiovascular changes that accompany or are aggravated by chronic hypertension. Preeclampsia is diagnosed clinically in about 30% of pregnancies with transplants.

InfectionsPatients should be carefully monitored for all types of infection throughout pregnancy. Prophylactic antibiotics must be given before

Ch044-X4224.indd 919 8/26/2008 4:09:22 PM


any surgical procedure, however trivial. The various viral infections that may be involved in these patients are discussed in Chapter 38.

Diabetes MellitusPregnancies are increasingly reported in women whose renal failure was caused by juvenile onset type 1 diabetes mellitus. Pregnancy com-plications occur with at least twice the frequency seen in the nondia-betic patient, and this may result from the presence of generalized cardiovascular pathology, which is part of the metabolic risk factor syndrome.152 Successful pregnancies are increasingly reported after confi rmed pancreas-kidney allografting.

Fetal Surveillance and Timing of DeliveryThe points given for chronic renal disease are equally applicable to transplantation patients. Preterm delivery is common (45% to 60%) because of intervention for obstetric reasons and the common occur-rence of preterm labor or preterm rupture of membranes. Preterm labor frequently is associated with poor renal function.144 However, gestational age is the crucial confounding variable associated with renal dysfunction and hypertension, and it needs adjusting when assessing infl uence on birth weight.

Vaginal delivery should be the aim, and there usually is no mechani-cal injury to the transplant. Unless there are specifi c obstetric prob-lems, spontaneous onset of labor can be awaited.153

Management during LaborCareful monitoring of maternal fl uid balance, cardiovascular status, and temperature is essential, and aseptic technique is important for every procedure. Surgical induction of labor (i.e., amniotomy) and episiotomy warrant antibiotic coverage. Pain relief is conducted as for healthy women. Augmentation of steroids is necessary to cover delivery.

Role of Cesarean SectionThe kidney does not usually obstruct the birth canal. Cesarean section is necessary for the usual obstetric reasons. Several factors are impor-tant when choosing the delivery route. Transplant recipients may have pelvic osteodystrophy related to previous renal failure (and dialysis) or prolonged steroid therapy, particularly before puberty. Antenatal diag-nosis of these problems is important and permits the planning of elective cesarean delivery.

If there is a question of disproportion or kidney compression, simultaneous IVU and x-ray pelvimetry can be performed (with limi-tation of the IVU to one to three fi lms) at 36 weeks’ gestation. When a cesarean section is performed, a lower segment approach is usually feasible, although previous urologic surgery or peritonitis may make this diffi cult.

Pediatric Management

Immediate ProblemsMore than 50% of liveborn infants have no neonatal problems. Preterm delivery is common (45% to 60%), small-for-gestational-age (SGA) infants are delivered in 30% to 50% of cases, and the two factors occa-sionally coexist. Although management is the same as in neonates of other mothers, some specifi c problems exist. Adrenocortical insuf-fi ciency due to the maternal steroid therapy potentially increases the risk of overwhelming neonatal infection. There are anecdotal data associating tacrolimus with oligoanuria and hypokalemia in the neonate.133

BreastfeedingThere are substantial benefi ts to breastfeeding. It could be argued that because the infant has been exposed to immunosuppressive agents and their metabolites in pregnancy, breastfeeding should not be allowed. Little is known, however, about the quantities of these agents and their metabolites in breast milk and whether the levels are biologically trivial or substantial. Cyclosporine levels in breast milk are usually greater than those in a simultaneously taken blood sample. Until the many uncertainties are resolved, breastfeeding should not be encouraged or perhaps limited to 1 month in the fi rst instance and the neonate moni-tored for healthy growth and well-being after that time. Azathioprine does not appear in breast milk,154 but cyclosporine and tacrolimus do.155

Long-Term AssessmentAzathioprine can cause abnormalities in the chromosomes of leuko-cytes, which may take almost 2 years to disappear spontaneously. The sequelae could be eventual development of malignant tumors in affected offspring, autoimmune complications, or abnormalities in the reproductive performance in the next generation.145 There are some worrisome animal data. For instance, fertility problems affect the female offspring of mice that have received low doses of 6-mercapto-purine, the major metabolite of azathioprine (equivalent to 3 mg/kg). These offspring subsequently proved to be sterile; if they conceived, they had smaller litters and more dead fetuses than did unexposed dams, with the inference that exposure in utero may not affect other-wise normal females until they attempt childbearing.156 The long-term sequelae of in utero exposure to the newer immunosuppressants are unknown. However, to date, information about general progress in early childhood has been good.157

Maternal Follow-up after PregnancyThe ultimate measure of transplant success is the long-term survival of the patient and the graft. Because it is only 30 years since this pro-cedure became widely employed in the management of end-stage renal failure, few long-term data from suffi ciently large series exist from which to draw conclusions. The long-term results for renal transplan-tation come from a period when many aspects of management would be unacceptable by current standards. Average survival fi gures for large numbers of patients worldwide indicate that about 90% of recipients of kidneys from related living donors are alive 5 years after transplanta-tion. With cadaver kidneys, the fi gure is approximately 60%. If renal function was normal 2 years after transplantation, the survival rate increased to about 80%. This is why women are counseled to wait 1 to 2 years before considering a pregnancy, although the emerging view is that 1 year is suffi cient.138,141

A major concern is that the mother may not survive or remain well enough to rear the child she bears. Pregnancy occasionally and some-times unpredictably causes irreversible declines in renal function. However, the consensus is that pregnancy has no effect on graft func-tion or survival provided graft function before pregnancy is satisfac-tory (ideally, a serum creatinine level less than 125 μmol/L or 1.4 mg/dL).140,158 Repeated pregnancies do not adversely affect graft function or fetal development, provided that renal function is well preserved at the time of conception.159,160 If the pre-pregnancy serum creatinine level is higher than 150 μmol/L (1.8 mg/dL) and there is drug-treated hypertension during pregnancy, there is poorer graft sur-vival after pregnancy.140

Many women choose parenthood in an effort to reestablish a normal life and possibly in defi ance of the sometimes negative atti-

Ch044-X4224.indd 920 8/26/2008 4:09:22 PM


tudes of the medical establishment. More long-term studies are needed to assess this area, especially with the advent of newer immunosup-pressive drugs, so that counseling can be based on recorded experience rather than clinical anecdote.

ContraceptionIt is unwise to offer the option of sterilization at the time of transplan-tation; this decision should not take place at that time. Oral contracep-tives may cause or aggravate hypertension or thromboembolism and can produce subtle changes in the immune system, but this does not necessarily contraindicate their use.

An intrauterine contraceptive device (IUD) may aggravate men-strual problems, which may obscure signs and symptoms of abnor-malities of early pregnancy, such as threatened abortion and ectopic pregnancy. The increased risk of pelvic infection associated with the IUD in an immunosuppressed patient makes this method worrisome. Because insertion or replacement of an IUD can be associated with bacteremia of vaginal origin, antibiotic coverage is essential at this time. The effi cacy of the IUD may be reduced by immunosuppres-sive and anti-infl ammatory agents, possibly because of modifi cation of the leukocyte response. Careful counseling and follow-up are essential.

Gynecologic ProblemsThere is a danger that symptoms resulting from genuine pelvic pathol-ogy may be erroneously attributed to the transplant because of its location near the pelvis. Patients may be at slightly higher risk for ectopic pregnancy because of pelvic adhesions resulting from previous urologic surgery, pelvic infl ammatory disease, or the overzealous use of IUDs. Diagnosis can be overlooked because irregular bleeding and amenorrhea may be associated with deteriorating renal function and intrauterine pregnancy.

Transplant recipients receiving immunosuppressive therapy have a malignancy rate estimated to be 100 times greater than normal, and the female genital tract is no exception.161 This association is probably related to factors such as loss of immune surveillance, chronic immu-nosuppression allowing tumor proliferation, and prolonged antigenic stimulation of the reticuloendothelial system. Regular gynecologic assessment is essential. Management should be on conventional lines, with the outcome unlikely to be infl uenced by stopping or reducing immunosuppression.

SummaryChanges in the urinary tract during normal pregnancy are so marked that norms in the nonpregnant state cannot be used for obstetric management. Awareness of all gestational alterations is essential if kidney problems in pregnancy are to be suspected or detected and then handled correctly.

Lower urinary infections are no more common in pregnancy com-pared with sexually active nonpregnant women, but lower UTIs are more likely to ascend to cause pyelonephritis. Asymptomatic bacteri-uria should be screened for every 4 to 6 weeks in women who have renal disease and treated. If there is more than one UTI, low-dose antibiotic prophylaxis should be given for the remainder of the preg-nancy and until 6 weeks after delivery.

Most women with mild and moderate renal disease tolerate preg-nancy well and have a successful obstetric outcome without adverse effect on the natural history of the underlying renal lesion. Crucial determinants are renal functional status at conception, the presence or

absence of hypertension, and the type of renal disease. There have been disagreements regarding pregnancy outcome in the presence of focal glomerular sclerosis, IgA nephropathy, mesangioproliferative glomeru-lonephritis, and refl ux disease, although the evidence seems to favor the importance of renal function before pregnancy. Patients with certain collagen disorders (especially periarteritis nodosa and sclero-derma) do poorly. In general, prognosis is good if renal dysfunction is minimal and hypertension is absent.

Pregnancy in women receiving dialysis treatment can be excessively complicated. Increased frequency and duration of dialysis are needed to increase the likelihood of a successful pregnancy outcome. There is high fetal wastage at all stages of pregnancy, but especially in the fi rst trimester. In the absence of severe maternal problems, the hazards of pregnancy in renal transplant recipients are minimal, and successful obstetric outcome is the rule.

The key to management of acute renal failure in pregnancy is to identify the cause of renal impairment and treat it. This often necessi-tates premature delivery in favor of maternal health.

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