PREGNANCY-INDUCED URINARY TRACT CHANGES
URINARY TRACT INFECTIONS
PREGNANCY AFTER RENAL TRANSPLANTATION
POLYCYSTIC KIDNEY DISEASE
CHRONIC RENAL DISEASE
ACUTE KIDNEY INJURY
LOWER URINARY TRACT LESIONS
Renal and urinary tract disorders are commonly encountered in pregnancy. Some precede pregnancy—one example being nephrolithiasis. In some women, pregnancy-induced changes may predispose to development or worsening of urinary tract disorders—an example is the markedly increased risk for pyelonephritis. Finally, there may be renal pathology unique to pregnancy such as preeclampsia. With good prenatal care, however, most women with these disorders will likely have no long-term sequelae.
PREGNANCY-INDUCED URINARY TRACT CHANGES
Significant changes in both structure and function that take place in the urinary tract during normal pregnancy are discussed in Chapter 4 (p. 63). The kidneys become larger, and as shown in Figure 53-1, dilatation of the renal calyces and ureters can be striking. Some dilatation develops before 14 weeks and likely is due to progesterone-induced relaxation of the muscularis. More marked dilatation is apparent beginning in midpregnancy because of ureteral compression, especially on the right side (Faúndes, 1998). There is also some vesicoureteral reflux during pregnancy. An important consequence of these physiological changes is an increased risk of upper urinary infection, and occasionally erroneous interpretation of studies done to evaluate obstruction.
FIGURE 53-1 The 50th, 75th, and 90th percentiles for maternal renal caliceal diameters measured using sonography in 1395 pregnant women from 4 to 42 weeks. (Redrawn from Faúndes, 1998.)
Evidence of functional renal hypertrophy becomes apparent very soon after conception. Glomeruli are larger, although cell numbers do not increase (Strevens, 2003). Pregnancy-induced intrarenal vasodilatation—both afferent and efferent resistance decreases—leads to increased effective renal plasma flow and glomerular filtration (Helal, 2012; Hussein, 2014). By 12 weeks’ gestation, the glomerular filtration rate is already increased 20 percent above nonpregnant values (Hladunewich, 2004). Ultimately, plasma flow and glomerular filtration increase by 40 and 65 percent, respectively. Consequently, serum concentrations of creatinine and urea decrease substantively across pregnancy, and values within a nonpregnant normal range may be abnormal for pregnancy (Appendix, p. 1289). Other alterations include those related to maintaining normal acid-base homeostasis, osmoregulation, and fluid and electrolyte retention.
Assessment of Renal Function During Pregnancy
The urinalysis is essentially unchanged during pregnancy, except for occasional glucosuria. Although protein excretion normally is increased, it seldom reaches levels that are detected by usual screening methods. As discussed in Chapter 4 (p. 65), Higby and colleagues (1994) reported 24-hour protein excretion to be 115 mg with a 95-percent confidence level of 260 mg/day. There were no significant differences by trimester. Albumin constitutes only a small part of total protein excretion and ranges from 5 to 30 mg/day. From their review, Airoldi and Weinstein (2007) concluded that proteinuria must exceed 300 mg/day to be considered abnormal. Many consider 500 mg/day to be important with gestational hypertension. Quantification of urinary albumin-to-creatinine ratio (ACR) in a spot urine sample—ideally from a first-morning void—is helpful in estimating a 24-hour albumin excretion rate (AER), in which ACR (mg/g) approximates AER (mg/24 h). Some laboratories measure total proteins instead of albumin.
Stehman-Breen and associates (2002) found that 3 percent of 4589 nulliparas had idiopathic hematuria, defined as 1+ or greater blood on urine dipstick when screened before 20 weeks. They also reported that these women had a twofold risk of developing preeclampsia. In another study of 1000 women screened during pregnancy, Brown and coworkers (2005) reported a 15-percent incidence of dipstick hematuria. Most women had trace levels of hematuria, and the false-positive rate was 40 percent.
If the serum creatinine level in pregnancy persistently exceeds 0.9 mg/dL (75 μmol/L), then intrinsic renal disease should be suspected. In these cases, some determine the creatinine clearance as an estimate of the glomerular filtration rate. Sonography provides imaging of renal size, relative consistency, and elements of obstruction (see Fig. 53-1). Full-sequence intravenous pyelography is not done routinely, but injection of contrast media with one or two abdominal radiographs may be indicated by the clinical situation (Chap. 46, p. 931). The usual clinical indications for cystoscopy are followed. There is an approximate 5-percent complication rate of ureteroscopy done for stone removal during pregnancy (Johnson, 2012; Semins, 2009). Magnetic resonance (MR) imaging of renal masses has been shown to have excellent results (Putra, 2009).
Although renal biopsy is relatively safely performed during pregnancy, it usually is postponed unless results may change therapy. From a review of 243 biopsies in pregnant women, the incidence of complications was 7 percent—this compares with 1 percent in postpartum women (Piccoli, 2013). Lindheimer and colleagues (2007a) recommend its consideration for rapid deterioration of renal function with no obvious cause or for symptomatic nephrotic syndrome. We and others have found biopsy helpful in selected cases to direct management (Chen, 2001; Piccoli, 2013). Strevens and associates (2003) performed renal biopsy in 12 normal pregnant volunteers and reported that five had slight to moderate glomerular endotheliosis. In contrast, all 27 women with proteinuric hypertension had endotheliosis, and in all but one, it was moderate to severe.
Pregnancy after Unilateral Nephrectomy
After removal of one kidney, and if the remaining kidney is normal, there is hypertrophy of renal function. In addition, with pregnancy, the surviving kidney undergoes further hypertrophy of function (Fig. 53-2). Because of this, women with one normal kidney most often have no difficulty in pregnancy (Baylis, 1991). Thorough functional evaluation of the remaining kidney is essential. Finally, there are no long-term adverse consequences of kidney donation done before pregnancy (Ibrahim, 2009).
FIGURE 53-2 Increased glomerular filtration rate in early pregnancy in normal women, those stable after unilateral nephrectomy, and those with a successful renal transplant. (Data from Newcastle-upon-Tyne, 1974–2006, courtesy of Dr. John Davison.)
URINARY TRACT INFECTIONS
These are the most common bacterial infections during pregnancy. Although asymptomatic bacteriuria is the most common, symptomatic infection includes cystitis, or it may involve the renal calyces, pelvis, and parenchyma—pyelonephritis.
Organisms that cause urinary infections are those from the normal perineal flora. Approximately 90 percent of Escherichia coli strains that cause nonobstructive pyelonephritis have adhesins such as P- and S-fimbriae. These are cell-surface protein structures that enhance bacterial adherence and thereby, virulence (Foxman, 2010; Hooton, 2012). These adhesins promote binding to vaginal and uroepithelial cells through expression of the PapG gene that encodes the P-fimbriae tip and by production of toxins and other virulence factors (Spurbeck, 2011).
Data suggest that pregnant women have more severe sequelae from urosepsis. The T-helper cell—Th1/Th2 ratio—reversal of normal pregnancy is discussed in Chapter 4 (p. 56). There are also various perturbations of cytokine expression that have been reported (Chaemsaithong, 2013). And maternal deaths have been attributed to E coli bearing Dr+ and P adhesins (Sledzińska, 2011). But even if pregnancy itself does not enhance these virulence factors, urinary stasis, vesicoureteral reflux, and diabetes predispose to symptomatic upper urinary infections (Czaja, 2009; Twickler, 1994).
In the puerperium, there are several risk factors that predispose a woman to urinary infections. Bladder sensitivity to intravesical fluid tension is often decreased as a consequence of labor trauma or conduction analgesia (Chap. 36, p. 676). Sensation of bladder distention can also be diminished by discomfort caused by an episiotomy, periurethral lacerations, or vaginal wall hematomas. Normal postpartum diuresis may worsen bladder overdistention, and catheterization to relieve retention commonly leads to urinary infection. Postpartum pyelonephritis is treated in the same manner as antepartum renal infections (McDonnold, 2012).
This refers to persistent, actively multiplying bacteria within the urinary tract in asymptomatic women. Its prevalence in nonpregnant women is 5 to 6 percent and depends on parity, race, and socioeconomic status (Hooton, 2000). The highest incidence is in African-American multiparas with sickle-cell trait, and the lowest incidence is in affluent white women of low parity. Asymptomatic infection is also more common in diabetics (Schneeberger, 2014). Because in most women there is recurrent or persistent bacteriuria, it frequently is discovered during prenatal care. The incidence during pregnancy is similar to that in nonpregnant women and varies from 2 to 7 percent.
Bacteriuria is typically present at the first prenatal visit. An initial positive urine culture result prompts treatment, after which, fewer than 1 percent of women develop a urinary tract infection (Whalley, 1967). A clean-voided specimen containing more than 100,000 organisms/mL is diagnostic. It may be prudent to treat when lower concentrations are identified, because pyelonephritis develops in some women despite colony counts of only 20,000 to 50,000 organisms/mL (Lucas, 1993).
If asymptomatic bacteriuria is not treated, approximately 25 percent of infected women will develop symptomatic infection during pregnancy. Eradication of bacteriuria with antimicrobial agents prevents most of these. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2012), as well as a U.S. Preventive Services Task Force (2008), recommend screening for bacteriuria at the first prenatal visit (Chap. 9, p. 174). Standard urine cultures may not be cost effective when the prevalence is low. However, less expensive screening tests such as the leukocyte esterase-nitrite dipstick are when the prevalence is 2 percent or less (Rouse, 1995). Because of a high prevalence—5 to 8 percent—at Parkland Hospital, culture screening is done in most women. Susceptibility determination is not necessary because initial treatment is empirical (Hooton, 2012). Also, a dipstick culture technique has excellent positive- and negative-predictive values (Mignini, 2009). With this, a special agar-coated dipstick is first placed into urine and then also serves as the culture plate.
In some, but not all studies, covert bacteriuria has been associated with preterm or low-birthweight infants (Kass, 1962). It is even more controversial whether eradication of bacteriuria decreases these complications. Evaluating a cohort of 25,746 mother-infant pairs, Schieve and coworkers (1994) reported urinary tract infection to be associated with increased risks for low-birthweight infants, preterm delivery, pregnancy-associated hypertension, and anemia. These findings vary from those of Gilstrap and colleagues (1981b) and Whalley (1967). In most studies, asymptomatic infection is not evaluated separately from acute renal infection (Banhidy, 2007). A Cochrane database review by Vasquez and Abalos (2011) found that benefits of treatment for asymptomatic bacteria are limited to the reduction of the incidence of pyelonephritis.
Bacteriuria responds to empirical treatment with any of several antimicrobial regimens listed in Table 53-1. Although selection can be based on in vitro susceptibilities, in our extensive experience, empirical oral treatment for 10 days with nitrofurantoin macrocrystals, 100 mg at bedtime, is usually effective. Lumbiganon and associates (2009) reported satisfactory results with a 7-day oral course of nitrofurantoin, 100 mg given twice daily. Single-dose antimicrobial therapy has also been used with success for bacteriuria. The important caveat is that, regardless of regimen given, the recurrence rate is approximately 30 percent. This may indicate covert upper tract infection and the need for longer therapy.
TABLE 53-1. Oral Antimicrobial Agents Used for Treatment of Pregnant Women with Asymptomatic Bacteriuria
Amoxicillin, 3 g
Ampicillin, 2 g
Cephalosporin, 2 g
Nitrofurantoin, 200 mg
Trimethoprim-sulfamethoxazole, 320/1600 mg
Amoxicillin, 500 mg three times daily
Ampicillin, 250 mg four times daily
Cephalosporin, 250 mg four times daily
Ciprofloxacin, 250 mg twice daily
Levofloxacin, 250 or 500 mg daily
Nitrofurantoin, 50 to 100 mg four times daily or 100 mg twice daily
Trimethoprim-sulfamethoxazole, 160/800 mg two times daily
Nitrofurantoin, 100 mg four times daily for 10 days
Nitrofurantoin, 100 mg twice daily for 5 to 7 days
Nitrofurantoin, 100 mg at bedtime for 10 days
Nitrofurantoin, 100 mg four times daily for 21 days
Suppression for bacterial persistence or recurrence
Nitrofurantoin, 100 mg at bedtime for pregnancy remainder
Periodic surveillance is necessary to prevent recurrent urinary infections (Schneeberger, 2012). For recurrent bacteriuria, we have had success with nitrofurantoin, 100 mg orally at bedtime for 21 days (Lucas, 1994). For women with persistent or frequent bacteriuria recurrences, suppressive therapy for the remainder of pregnancy can be given. We routinely use nitrofurantoin, 100 mg orally at bedtime. This drug may rarely cause an acute pulmonary reaction that dissipates on its withdrawal (Boggess, 1996).
Cystitis and Urethritis
Lower urinary infection during pregnancy may develop without antecedent covert bacteriuria (Harris, 1981). Cystitis is characterized by dysuria, urgency, and frequency, but with few associated systemic findings. Pyuria and bacteriuria are usually found. Microscopic hematuria is common, and occasionally there is gross hematuria from hemorrhagic cystitis (Fakhoury, 1994). Although cystitis is usually uncomplicated, the upper urinary tract may become involved by ascending infection. Almost 40 percent of pregnant women with acute pyelonephritis have preceding symptoms of lower tract infection (Gilstrap, 1981a).
Women with cystitis respond readily to any of several regimens. Most of the three-day regimens listed in Table 53-1 are usually 90-percent effective (Fihn, 2003). Single-dose therapy is less effective, and if it is used, concomitant pyelonephritis must be confidently excluded.
Lower urinary tract symptoms with pyuria accompanied by a sterile urine culture may be from urethritis caused by Chlamydia trachomatis. Mucopurulent cervicitis usually coexists, and azithromycin therapy is effective. (Chap. 65, p. 1270)
Renal infection is the most common serious medical complication of pregnancy. In a study of the 2006 Nationwide Inpatient Sample by Jolley and coworkers (2012), there were nearly 29,000 hospitalizations for acute pyelonephritis. Rates were highest for adolescents at 17.5 per 1000 and for Hispanic women at 10.1 per 1000. In another study of more than 70,000 pregnancies in a managed care organization, Gazmararian and colleagues (2002) reported that 3.5 percent of antepartum admissions were for urinary infections. The potential seriousness is underscored by the observations of Snyder and associates (2013) that pyelonephritis was the leading cause of septic shock during pregnancy. And in a 2-year audit of admissions to the Parkland Hospital Obstetrical Intensive Care Unit, 12 percent of antepartum admissions were for sepsis syndrome caused by pyelonephritis (Zeeman, 2003). There is also concern that urosepsis may be related to an increased incidence of cerebral palsy in preterm infants (Jacobsson, 2002). Fortunately, there appear to be no serious long-term maternal sequelae (Raz, 2003).
Renal infection develops more frequently in the second trimester, and nulliparity and young age are associated risk factors (Hill, 2005). Pyelonephritis is unilateral and right-sided in more than half of cases, and it is bilateral in a fourth. There is usually a rather abrupt onset with fever, shaking chills, and aching pain in one or both lumbar regions. Anorexia, nausea, and vomiting may worsen dehydration. Tenderness usually can be elicited by percussion in one or both costovertebral angles. The urinary sediment contains many leukocytes, frequently in clumps, and numerous bacteria. Bacteremia is demonstrated in 15 to 20 percent of these women. E coli is isolated from urine or blood in 70 to 80 percent of infections, Klebsiella pneumoniae in 3 to 5 percent, Enterobacter or Proteus species in 3 to 5 percent, and gram-positive organisms, including group B Streptococcus and S aureus, in up to 10 percent of cases (Hill, 2005; Wing, 2000). The differential diagnosis includes, among others, labor, chorioamnionitis, appendicitis, placental abruption, or infarcted leiomyoma. Evidence of the sepsis syndrome is common, and this is discussed in detail in Chapter 47 (p. 946).
Plasma creatinine is monitored because early studies reported that 20 percent of pregnant women developed renal dysfunction. More recent findings, however, show this to be only 5 percent if aggressive fluid resuscitation is provided (Hill, 2005). Follow-up studies have demonstrated that this endotoxin-induced damage is reversible in the long term. Varying degrees of respiratory insufficiency from endotoxin-induced alveolar injury are manifest in up to 10 percent of women and may result in frank pulmonary edema (Cunningham, 1987; Sheffield, 2005; Snyder, 2013). In some cases, pulmonary injury may be so severe that it causes acute respiratory distress syndrome (ARDS) (Fig. 53-3).
FIGURE 53-3 A series of anterior-posterior projection chest radiographs of improving acute respiratory distress syndrome (ARDS) in a second-trimester pregnant woman with severe pyelonephritis. A. An extensive infiltrative process and complete obliteration of the diaphragm (white arrows) is seen. B. Improved aeration of lung fields bilaterally is noted as pleural disease resolves (arrows). C. Markedly improved visualization of the lungs fields with residual platelike atelectasis and normal appearance of the diaphragm.
Uterine activity from endotoxin is common and is related to fever severity (Graham, 1993). In the study by Millar and coworkers (2003), women with pyelonephritis averaged 5 contractions per hour at admission, and this decreased to 2 per hour within 6 hours of intravenous fluid and antimicrobial administration. As discussed in Chapter 47 (p. 942), ·-agonist therapy for tocolysis increases the likelihood of respiratory insufficiency from permeability edema because of the sodium- and fluid-retaining properties of those agents (Lamont, 2000). The incidence of pulmonary edema in women with pyelonephritis who were given ·-agonists was reported to be 8 percent—a fourfold increase over that expected (Towers, 1991).
Endotoxin-induced hemolysis is common, and approximately a third of patients with pyelonephritis develop anemia (Cox, 1991). With recovery, hemoglobin regeneration is normal because acute infection does not affect erythropoietin production (Cavenee, 1994).
One scheme for management of acute pyelonephritis is shown in Table 53-2. Although we routinely obtain urine and blood cultures, prospective trials show them to be of limited clinical utility (Wing, 2000). Intravenous hydration to ensure adequate urinary output is the cornerstone of treatment. Antimicrobials are also begun promptly with the caveat that they may initially worsen endotoxemia from bacterial lysis. Ongoing surveillance for worsening of sepsis syndrome is monitored by serial determinations of urinary output, blood pressure, pulse, temperature, and oxygen saturation. High fever should be lowered with a cooling blanket or acetaminophen. This is especially important in early pregnancy because of possible teratogenic effects of hyperthermia (Chap. 14, p. 284).
TABLE 53-2. Management of the Pregnant Woman with Acute Pyelonephritis
Obtain urine and blood cultures
Evaluate hemogram, serum creatinine, and electrolytes
Monitor vital signs frequently, including urinary output—consider indwelling catheter
Establish urinary output ≥ 50 mL/hr with intravenous crystalloid solution
Administer intravenous antimicrobial therapy (see text)
Obtain chest radiograph if there is dyspnea or tachypnea
Repeat hematology and chemistry studies in 48 hours
Change to oral antimicrobials when afebrile
Discharge when afebrile 24 hours, consider antimicrobial therapy for 7 to 10 days
Repeat urine culture 1 to 2 weeks after antimicrobial therapy completed
Modified from Lucas, 1994; Sheffield, 2005.
Antimicrobial therapy usually is empirical, and ampicillin plus gentamicin; cefazolin or ceftriaxone; or an extended-spectrum antibiotic were all 95-percent effective in randomized trials (Sanchez-Ramos, 1995; Wing, 1998, 2000). Fewer than half of E coli strains are sensitive to ampicillin in vitro, but cephalosporins and gentamicin generally have excellent activity. Serum creatinine is monitored if nephrotoxic drugs are given. Initial treatment at Parkland Hospital is ampicillin plus gentamicin. Some recommend suitable substitutes if bacterial studies show in vitro resistance. With any of the regimens discussed, response is usually prompt, and 95 percent of women are afebrile by 72 hours (Hill, 2005; Sheffield, 2005; Wing, 2000). After discharge, most recommend oral therapy for a total of 7 to 14 days (Hooton, 2012).
Persistent Infection. Generally, intravenous hydration and antimicrobial therapy are followed by stepwise defervescence of approximately 1°F per day. With persistent spiking fever or lack of clinical improvement by 48 to 72 hours, urinary tract obstruction or another complication or both are considered. Renal sonography is recommended to search for obstruction manifest by abnormal ureteral or pyelocaliceal dilatation (Seidman, 1998). Although most women with continuing infection have no evidence of obstruction, some are found to have calculi. Although renal sonography will detect hydronephrosis, stones are not always seen in pregnancy (Butler, 2000; Maikranz, 1987). If stones are strongly suspected despite a nondiagnostic sonographic examination, a plain abdominal radiograph will identify nearly 90 percent. Another option is the modified one-shot intravenous pyelogram—a single radiograph obtained 30 minutes after contrast injection—which usually provides adequate imaging (Butler, 2000).
In some women, MR imaging may disclose the cause of persistent infection (Spencer, 2004). Even without urinary obstruction, persistent infection can be due to an intrarenal or perinephric abscess or phlegmon (Cox, 1988; Rafi, 2012). Obstruction relief is important, and one method is cystoscopic placement of a double-J ureteral stent (Rodriguez, 1988). Because these stents are usually left in place until after delivery, they frequently become encrusted and require replacement. We have found that percutaneous nephrostomy is preferable because the stents are more easily replaced. Finally, surgical removal of stones may be required in some women (p. 1057).
Outpatient Management of Pyelonephritis. Outpatient management is an option for nonpregnant women with uncomplicated pyelonephritis (Hooton, 2012). Wing and associates (1999) have described outpatient management in 92 pregnant women who were first given in-hospital intramuscular ceftriaxone, two 1-g doses 24 hours apart. At this point, one third of the group was considered suitable for outpatient therapy, and these women were randomized either to discharge and oral antimicrobials or to continued hospitalization with intravenous therapy. A third of the outpatient management group was unable to adhere to the treatment regimen and was admitted. These findings suggest that outpatient management is applicable to very few pregnant women.
Recurrent infection—either covert or symptomatic—is common and develops in 30 to 40 percent of women following completion of treatment for pyelonephritis (Cunningham, 1973). Unless other measures are taken to ensure urine sterility, nitrofurantoin, 100 mg orally at bedtime given for the remainder of the pregnancy, reduces bacteriuria recurrence (Van Dorsten, 1987).
Vesicoureteral reflux in early childhood can cause recurrent urinary tract infections, and thus, subsequent chronic interstitial nephritis was attributed to chronic pyelonephritis. Moreover, it was also found that high-pressure sterile reflux impaired normal renal growth. Combined, this leads to patchy interstitial scarring, tubular atrophy, and loss of nephron mass and is termed reflux nephropathy. In adults, long-term complications include hypertension, which may be severe if there is demonstrable renal damage (Diamond, 2012; Köhler, 2003).
Perhaps half of women with reflux nephropathy were treated during childhood for renal infections. Of these, many also had surgical correction of reflux as children, and these commonly have bacteriuria when pregnant (Mor, 2003). In the other half of women with reflux nephropathy, there is no clear history of recurrent cystitis, acute pyelonephritis, or obstructive disease (Diamond, 2012). Reports describing 939 pregnancies in 379 women with reflux nephropathy indicate that impaired renal function and bilateral renal scarring were associated with increased maternal complications (El-Khatib, 1994; Jungers, 1996; Köhler, 2003). Chronic renal disease and pregnancy outcome is discussed further on page 1061.
Kidney stones develop in 7 percent of women during their lifetime with an average age of onset in the third decade (Asplin, 2012). Calcium salts make up approximately 80 percent of stones, and up to half of affected women have polygenic familial idiopathic hypercalciuria (Worcester, 2010). Hyperparathyroidism should be excluded. Although calcium oxalate stones in young nonpregnant women are most common, most stones in pregnancy—65 to 75 percent—are calcium phosphate or hydroxyapatite (Ross, 2008; Tan, 2013). Patients who have a stone typically form another stone every 2 to 3 years.
Contrary to past teachings, a low-calcium diet promotes stone formation. Prevention of recurrences with hydration and a diet low in sodium and protein is currently recommended (Asplin, 2012). Thiazide diuretics also diminish stone formation. In general, obstruction, infection, intractable pain, and heavy bleeding are indications for stone removal. Removal by a flexible basket via cystoscopy, although used less often than in the past, is still a reasonable consideration for pregnant women. In nonpregnant patients, stone destruction by lithotripsy is preferred to surgical therapy in most cases. There is limited information on the use of these procedures during pregnancy, and they are not generally recommended.
Stone Disease During Pregnancy
The incidence of stone disease complicating pregnancy has been reported with widespread variability. At the low end, Butler and colleagues (2000) found the incidence to be 0.3 admissions per 1000 pregnancies in more than 186,000 deliveries at Parkland Hospital. In an Israeli population-based study, the incidence in nearly 220,000 pregnancies was 0.8 per 1000 (Rosenberg, 2011). In a population-based study from Washington state, Swartz and coworkers (2007) reported an incidence of 1.7 per 1000 pregnancies. Bladder stones are rare, but recurrent infection and labor obstructed by stones have been reported (Ait Benkaddour, 2006; Ruan, 2011).
Data are conflicting whether women with kidney stones have an increased risk for low-birthweight and preterm infants. The case-control study by Swartz and colleagues (2007) of 2239 women with nephrolithiasis reported excessive preterm delivery—10.6 versus 6.4 percent—compared with normal controls. The more recent nationwide population-based case-control study from Taiwan also reported 20- to 40-percent increases in low-birthweight and preterm births (Chung, 2013). To the contrary, a case-control study from Hungary reported that pregnancy outcomes, including preterm delivery, were similar in women with stones and normal controls (Banhidy, 2007). Comparable conclusions were drawn from the Israeli population-based study noted earlier (Rosenberg, 2011).
There is some evidence that pregnant women may have fewer symptoms with stone passage because of urinary tract dilatation (Hendricks, 1991; Tan, 2013). That said, more than 90 percent of pregnant women with nephrolithiasis present with pain. Gross hematuria is less common than in nonpregnant women and was reported to be a presenting symptom in 23 percent of women described by Butler and associates (2000). In another study, however, Lewis and coworkers (2003) found that only 2 percent had hematuria. Sonography is usually selected to visualize stones, but as discussed above, many are not detected because hydronephrosis may obscure findings (McAleer, 2004). If there is abnormal dilatation without stone visualization, then the one-shot pyelogram may be useful. Transabdominal color Doppler sonography to detect presence or absence of ureteral “jets” of urine into the bladder has been used to exclude obstruction (Asrat, 1998).
Helical computed tomography (CT) scanning is the imaging method of choice for nonpregnant individuals, however, it is avoided during pregnancy if possible (Brown, 2010). If it is used, the slices can be tailored as needed (Chap. 46, p. 934). For pregnant women, White and colleagues (2007) recommend unenhanced helical CT and cite an average fetal radiation dose to be 7 mGy. These exigencies have led some to recommend MR imaging as the second-line test following nondiagnostic sonography (Masselli, 2013).
Treatment depends on symptoms and gestational age (Semins, 2013). Intravenous hydration and analgesics are given. In half of women with symptomatic stones, infection will be identified, and this is treated vigorously. Although calculi infrequently cause symptomatic obstruction during pregnancy, persistent pyelonephritis should prompt a search for obstruction due to nephrolithiasis.
Approximately 65 to 80 percent of symptomatic women will have improvement with conservative therapy, and the stone usually passes spontaneously (Tan, 2013). Others require an invasive procedure such as ureteral stenting, ureteroscopy, percutaneous nephrostomy, transurethral laser lithotripsy, or basket extraction (Butler, 2000; Semins, 2010). The need for fluoroscopy limits the utility of percutaneous nephrolithotomy (Toth, 2005). In the case-control study cited above by Swartz and associates (2007), there were 623 procedures performed in 2239 symptomatic pregnant women, but less than 2 percent required surgical exploration.
As noted earlier, extracorporeal shock-wave lithotripsy is contraindicated in pregnancy. Watterson and coworkers (2002) described successful transurethral holmium:YAG laser lithotripsy in nine of 10 women. Semins and Matlaga (2010) found that ureteroscopic removal is also safe in pregnancy.
PREGNANCY AFTER RENAL TRANSPLANTATION
In 2013, there were approximately 97,000 registrants on the waiting list for renal transplantations through the Organ Procurement and Transplantation Network—OPTN (2013). The 1-year graft survival rate is 95 percent for grafts from living donors and 89 percent from deceased donors (Carpenter, 2008). Survival rates approximately doubled between 1988 and 1996, due in large part to the introduction of cyclosporine and muromonab-CD3 (OKT3 monoclonal antibody) to prevent and treat organ rejection. Since then, mycophenolate mofetil and tacrolimus have further reduced acute rejection episodes, however, the former is considered teratogenic (Briggs, 2011). In the report from the National Transplant Pregnancy Registry, 23 percent of fetuses exposed to mycophenolate had birth defects (Coscia, 2010). Importantly, resumption of renal function after transplantation promptly restores fertility in reproductive-aged women (Hladunewich, 2011; Lessan-Pezeshki, 2004). More than half of transplant recipients reported that they were not counseled regarding contraception (French, 2013).
Coscia and coworkers (2010) reviewed the outcomes of 2000 pregnancies in transplant recipients as reported to the National Transplantation Pregnancy Registry. Most were treated with cyclosporine and tacrolimus, and approximately 75 percent of pregnancies resulted in a live birth. Similar outcomes were described for the Australian and New Zealand Transplant Registry by Wyld and associates (2013). Bramham and colleagues (2013) identified 105 pregnancies in renal transplant recipients and the United Kingdom Obstetric Surveillance System (UKOSS). Excluding nine abortions, there was only one perinatal death and 97 living children. Half were delivered before 37 weeks’ gestation, but only 9 percent before 32 weeks. Half were born weighing < 2500 g, and a fourth were growth restricted. Importantly, the incidence of fetal malformations was not increased, except in those who took mycophenolate mofetil (Coscia, 2010). Twin pregnancy has also been described following renal transplantation (Gizzo, 2014).
The incidence of preeclampsia is high in all transplant recipients (Brosens, 2013). In the UK National Cohort Study reported by Bramham and associates (2013), the incidence of preeclampsia was 22 percent. From their review, Josephson and McKay (2011) cite an incidence of a third of pregnancies but question the validity of this frequency. Importantly, in some cases, rejection is difficult to distinguish from preeclampsia. That said, the incidence of rejection episodes approximates only 2 percent (Bramham, 2013). Viral infections—especially polyomavirus hominis 1, also called BK virus, infections—are frequent. Also, gestational diabetes is found in approximately 5 percent. Both are likely related to immunosuppression therapy. Similar outcomes have been reported by several other investigators (Al Duraihimh, 2008; Cruz Lemini, 2007; Ghafari, 2008; Gutierrez, 2005).
Lindheimer (2007a) and Josephson (2011) and their coworkers recommend that women who have undergone transplantation satisfy several requisites before attempting pregnancy. First, women should be in good general health for at least 1 to 2 years after transplantation. Also, there should be stable renal function without severe renal insufficiency—serum creatinine < 2 mg/dL and preferably < 1.5 mg/dL—and < 500 mg/day proteinuria. Evidence for graft rejection should be absent for 6 months, and pyelocalyceal distention by urography should not be apparent. Moreover, hypertension should be absent or well controlled. And last, no teratogenic drugs are being given, and drug therapy is reduced to maintenance levels.
Cyclosporine or tacrolimus is given routinely to renal transplantation recipients (Jain, 2004). Cyclosporine blood levels decline during pregnancy, although this was not reported to be associated with rejection episodes (Thomas, 1997). Unfortunately, these agents are nephrotoxic and also may cause renal hypertension. In fact, they likely contribute substantively to chronic renal disease that develops in 10 to 20 percent of patients with nonrenal solid-organ transplantation (Goes, 2007).
Concern persists regarding the possible late effects in offspring subjected to immunosuppressive therapy in utero. These include malignancy, germ cell dysfunction, and malformations in the children of the offspring. In addition, cyclosporine is secreted in breast milk, and in at least one instance, it produced therapeutic serum levels in the nursing child (Moretti, 2003).
Finally, although pregnancy-induced renal hyperfiltration theoretically may impair long-term graft survival, Sturgiss and Davison (1995) found no evidence for this in a case-control study of 34 allograft recipients followed for a mean of 15 years.
Close surveillance is necessary. Covert bacteriuria is treated, and if it is recurrent, suppressive treatment is given for the remainder of the pregnancy. Serial hepatic enzyme concentrations and blood counts are monitored for toxic effects of azathioprine and cyclosporine. Some recommend measurement of serum cyclosporine levels. Gestational diabetes is more common if corticosteroids are taken, and overt diabetes must be excluded with glucose tolerance testing done at approximately 26 weeks’ gestation. Surveillance for opportunistic infections from herpesvirus, cytomegalovirus, and toxoplasmosis is important because these infections are common. Some recommend surveillance for BK virus in women known to be infected (Josephson, 2011). Treatment is problematic.
Renal function is monitored, and as shown in Figure 53-2, the glomerular filtration rate usually increases 20 to 25 percent. If a significant rise in the serum creatinine level is detected, then its cause must be determined. Possibilities include acute rejection, cyclosporine toxicity, preeclampsia, infection, and urinary tract obstruction. Evidence of pyelonephritis or graft rejection should prompt admission for aggressive management. Imaging studies and kidney biopsy may be indicated. The woman is carefully monitored for development or worsening of underlying hypertension, and especially superimposed preeclampsia. Management of hypertension during pregnancy is the same as for patients without a transplant.
Because of increased incidences of fetal-growth restriction and preterm delivery, vigilant fetal surveillance is indicated (Chaps. 42, p. 842 and 44, p. 880). Although cesarean delivery is reserved for obstetrical indications, occasionally the transplanted kidney obstructs labor. In all women with a renal transplant, the cesarean delivery rate exceeds 60 percent (Bramham, 2013; Rocha, 2013).
POLYCYSTIC KIDNEY DISEASE
This usually autosomally dominant systemic disease primarily affects the kidneys. Its basic pathophysiology is one of a ciliopathy (Hildebrandt, 2011). The disease is found in 1 in 800 live births and causes approximately 5 to 10 percent of end-stage renal disease in the United States (Bargman, 2012). Although genetically heterogeneous, almost 85 percent of cases are due to PKD1 gene mutations on chromosome 16, and the other 15 percent to PKD2mutations on chromosome 4 (Salant, 2012). Prenatal diagnosis is available if the mutation has been identified in a family member or if linkage has been established in the family.
Renal complications are more common in men than in women, and symptoms usually appear in the third or fourth decade. Flank pain, hematuria, proteinuria, abdominal masses, and associated calculi and infection are common findings. Hypertension develops in 75 percent, and progression to renal failure is a major problem. Superimposed acute renal failure may also develop from infection or obstruction from ureteral angulation by cyst displacement.
Other organs are commonly involved. Hepatic involvement is more common and more aggressive in women than in men (Chapman, 2003). Asymptomatic hepatic cysts coexist in a third of patients with polycystic kidneys. Approximately 10 percent of patients with polycystic kidney disease die from rupture of an associated intracranial berry aneurysm. Up to a fourth of patients have cardiac valvular lesions, with mitral valve prolapse and mitral, aortic, and tricuspid valvular incompetence.
The prognosis for pregnancy in women with polycystic kidney disease depends on the degree of associated hypertension and renal insufficiency. Urinary tract infections are common. Chapman and coworkers (1994) compared pregnancy outcomes in 235 affected women who had 605 pregnancies with those of 108 unaffected family members who had 244 pregnancies. Composite perinatal complication rates were similar—33 versus 26 percent—but hypertension, including preeclampsia, was more common in women with polycystic kidneys. Pregnancy does not seem to accelerate the natural disease course (Lindheimer, 2007b).
The glomerulus and its capillaries are subject to numerous and various conditions and agents that can lead to acute and chronic diseases. Glomerular damage can be caused by several agents such as toxins or infections or from systemic disorders such as hypertension or diabetes. It may also be idiopathic. When there is capillary inflammation, the process is termed glomerulonephritis, and in many of these cases, an autoimmune process is involved. Glomerular disease or glomerulonephritis may result from a single stimulus such as that following group A streptococcal infections. However, it may be a manifestation of a multisystem disease such as systemic lupus erythematosus or diabetes (Sethi, 2012).
Persistent glomerulonephritis eventually leads to renal functional decline. Progression is variable and often does not become apparent until chronic renal insufficiency is diagnosed as discussed on page 1060. Lewis and Neilsen (2012) group glomerular injuries into six syndromes based on clinical patterns (Table 53-3). Some underlying disorders—examples include infections, vasculitides, and diabetes—can result in one clinical pattern in different individuals. Finally, within each of these categories, there are disorders encountered in young women, and thus, these may antedate or first manifest during pregnancy.
TABLE 53-3. Patterns of Clinical Glomerulonephritis
Acute Nephritic Syndromes: poststreptococcal, infective endocarditis, SLE, antiglomerular basement membrane disease, IgA nephropathy, ANCA vasculitis, Henoch-Schönlein purpura, cryoglobulinemia, membranoproliferative and mesangioproliferative glomerulonephritis
Pulmonary-Renal Syndromes: Goodpasture, ANCA vasculitis, Henoch-Schönlein purpura, cryoglobulinemia
Nephrotic Syndromes: minimal change disease, focal segmental glomerulosclerosis, membranous glomerulonephritis, diabetes, amyloidosis, others
Basement Membrane Syndromes: anti-GBM disease, others
Glomerular Vascular Syndromes: atherosclerosis, chronic hypertension, sickle-cell disease, thrombotic microangiopathies, antiphospholipid antibody syndrome, ANCA vasculitis, others
Infectious Disease-Associated Syndromes: poststreptococcal, infective endocarditis, HIV, HBV, HCV, syphilis, others
ANCA = antineutrophilic cytoplasmic antibodies; anti-GBM = anti-glomerular basement membrane; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IgA = immunoglobulin A; SLE = systemic lupus erythematosus.
Adapted from Lewis, 2012.
Acute Nephritic Syndromes
Acute glomerulonephritis may result from any of several causes (see Table 53-3). The clinical presentation usually includes hypertension, hematuria, red-cell casts, pyuria, and proteinuria. Varying degrees of renal insufficiency and salt and water retention result in edema, hypertension, and circulatory congestion (Lewis, 2012). The prognosis and treatment of nephritic syndromes depends on their etiology. Some recede spontaneously or with treatment. However, in some patients, rapidly progressive glomerulonephritis leads to end-stage renal failure, whereas in others, chronic glomerulonephritis develops with slowly progressive renal disease.
The prototype is acute poststreptococcal glomerulonephritis, which is historically interesting because it was confused with eclampsia until the mid-1800s. IgA nephropathy, also known as Berger disease, is the most common form of acute glomerulonephritis worldwide (Wyatt, 2013). The isolated form occurs sporadically, and it may be related to Henoch-Schönlein purpura as the systemic form (Donadio, 2002). Isolated nephritis may be due to antiglomerular basement membrane (GBM) antibodies. These may also involve the lungs to manifest as a pulmonary-renal syndrome with alveolar hemorrhage, which is termed Goodpasture syndrome (Bazari, 2012; Vasilou, 2005).
Acute nephritic syndromes during pregnancy can be difficult to differentiate from severe preeclampsia or eclampsia. One example is systemic lupus erythematosus with a flare during the second half of pregnancy (Bramham, 2012; Zhao, 2013). In some cases, renal biopsy may be necessary to determine etiology as well as to direct management (Lindheimer, 2007a; Ramin, 2006). This is discussed further in Chapter 59 (p. 1170).
Whatever the underlying etiology, acute glomerulonephritis has profound effects on pregnancy outcome. In an older study, Packham and coworkers (1989) described 395 pregnancies in 238 women with primaryglomerulonephritis diagnosed before pregnancy. The most common lesions on biopsy were membranous glomerulonephritis, IgA glomerulonephritis, and diffuse mesangial glomerulonephritis. Although most of these women had normal renal function, half developed hypertension, a fourth were delivered preterm, and the perinatal mortality rate after 28 weeks’ gestation was 80 per 1000. As expected, the worst perinatal outcomes were in women with impaired renal function, early or severe hypertension, and nephrotic-range proteinuria.
Similar outcomes have been reported for pregnancies in women with IgA nephropathy. From their review of more than 300 such pregnancies, Lindheimer and colleagues (2000) concluded that pregnancy outcome was related to the degree of renal insufficiency and hypertension. Ronkainen and associates (2006) followed a cohort of children with IgA nephritis for an average of 19 years. They described 22 pregnancies of which half were complicated by hypertension and a third were delivered preterm.
Heavy proteinuria is the hallmark of the nephrotic syndromes, which may be caused by several primary and secondary kidney disorders. These can cause immunological- or toxic-mediated injury with glomerular capillary wall breakdown that allows excessive filtration of plasma proteins. In addition to heavy urine protein excretion, the syndrome is characterized by hypoalbuminemia, hypercholesterolemia, and edema. There frequently is hypertension, and along with albumin nephrotoxicity, renal insufficiency eventually develops.
Some of the more common causes of the nephrotic syndrome are shown in Table 53-4. In most cases, renal biopsy will disclose microscopic abnormalities that may help direct treatment, which depends on etiology. Edema is problematic, especially during pregnancy (Jakobi, 1995). Normal amounts of dietary protein of high biological value are encouraged—indeed, high-protein diets increase proteinuria. The incidence of thromboembolism is increased and varies with the severity of hypertension, proteinuria, and renal insufficiency (Stratta, 2006). Although both arterial and venous thromboses may develop, renal vein thrombosis is particularly worrisome. The value, if any, of prophylactic anticoagulation is unclear. Some cases of nephrosis from primary glomerular disease respond to glucocorticosteroids and other immunosuppressants or cytotoxic drug therapy. In most of those cases caused by infection or drugs, proteinuria recedes when the underlying cause is corrected.
TABLE 53-4. Causes of the Nephrotic Syndrome in Adults and Percentage of Attributable Cases
Minimal change disease (MCD) (10–15%): primary idiopathic (most cases), drug-induced (NSAIDs), allergies, viral infections
Focal segmental glomerulosclerosis (FSGS) (35%): viruses, hypertension, reflux nephropathy, sickle-cell disease
Membranous glomerulonephritis (30%): idiopathic (most cases), malignancy, infection, connective-tissue diseases
Diabetic nephropathy: most common cause of ESRD
ESRD = end-stage renal disease; NSAIDs = nonsteroidal antiinflammatory drugs.
Adapted from Lewis, 2012.
Maternal and perinatal outcomes in women with the nephrotic syndromes depend on its underlying cause and severity. Whenever possible, these should be ascertained, and renal biopsy may be indicated to determine if there is a treatment-responsive etiology. Half of women with nephrotic-range proteinuria will have rise in daily protein excretion as pregnancy progresses (Packham, 1989). In women with nephrosis cared for at Parkland Hospital, we reported that two thirds had protein excretion that exceeded 3 g/day (Stettler, 1992). At the same time, however, if these women had only mild degrees of renal dysfunction, they had normally augmented glomerular filtration across pregnancy (Cunningham, 1990).
Management of edema during pregnancy can be particularly challenging as it is intensified by normally increasing hydrostatic pressure in the lower extremities. In some women, massive vulvar edema may develop as described by Jakobi and coworkers (1995) in diabetic women. Massive vulvar edema associated with the nephrotic syndrome caused by secondary syphilis is shown in Figure 53-4. Another major problem is that up to half of these women have chronic hypertension that may require treatment (Chap. 50, p. 1005). In these, as well as in previously normotensive women, preeclampsia is common and often develops early in pregnancy.
FIGURE 53-4 Massive vulvar edema in a pregnant woman with the nephrotic syndrome due to secondary syphilis. (Photograph contributed by Dr. George Wendel, Jr.)
Most women with nephrotic syndromes who do not have severe hypertension or renal insufficiency will have successful pregnancy outcomes. Conversely, if there is renal insufficiency, moderate to severe hypertension, or both, the prognosis is much worse. Our experiences from women with 65 pregnancies cared for at Parkland Hospital noted that there are frequent complications (Stettler, 1992). Protein excretion during pregnancy averaged 4 g daily, and a third of the women had classic nephrotic syndrome. There was some degree of renal insufficiency in 75 percent, chronic hypertension in 40 percent, and persistent anemia in 25 percent. Importantly, preeclampsia developed in 60 percent, and 45 percent had preterm deliveries. Even so, after excluding abortions, 53 of 57 infants were born alive. Stratta and associates (2006) reported fetal-growth restriction in a third of these women.
Women identified to have nephrotic syndromes either before or during pregnancy are at risk for serious long-term adverse outcomes. In women cared for at Parkland Hospital cited in the report above, all 21 women who subsequently underwent renal biopsy had abnormal histological findings (Stettler, 1992). At least 20 percent of women followed for 10 years progressed to end-stage renal failure. Similarly, Chen and colleagues (2001) reported short-term outcomes in 15 women with nephrotic syndromes in whom they had performed renal biopsy during pregnancy. By 2 years, three of these women had died, three had developed chronic renal failure, and two had progressed to end-stage renal disease. In the report by Imbasciati and coworkers (2007), women whose serum creatinine level was > 1.4 mg/dL and whose 24-hour protein excretion exceeded 1 g/day had the shortest renal survival times following pregnancy.
CHRONIC RENAL DISEASE
This describes a pathophysiological process that can progress to end-stage renal disease. The National Kidney Foundation describes six stages of chronic kidney disease defined by decreasing glomerular filtration rate (GFR). It progresses from stage 0—GFR > 90 mL/min/1.73 m2 to stage 5—GFR < 15 mL/min/1.73 m2. There are a number of diseases that result in progressively declining renal function, and many result from one of the glomerular diseases that were discussed earlier. Those that most commonly lead to end-stage disease requiring dialysis and kidney transplantation and their approximate percentages include: diabetes, 33 percent; hypertension, 25 percent; glomerulonephritis, 20 percent; and polycystic kidney disease, 15 percent (Abboud, 2010; Bargman, 2012).
Most reproductive-aged women with these diseases have varying degrees of renal insufficiency, proteinuria, or both. To counsel regarding fertility and pregnancy outcome, the degree of renal functional impairment and of associated hypertension are assessed. Successful pregnancy outcome in general may be more related to these two factors than to the specific underlying renal disorder. A general prognosis can be estimated by considering women with chronic renal disease in arbitrary categories of renal function (Davison, 2011). These include normal or mild impairment—defined as a serum creatinine < 1.5 mg/dL; moderate impairment—defined as a serum creatinine 1.5 to 3.0 mg/dL; and severe renal insufficiency—defined as a serum creatinine > 3.0 mg/dL. Although some have suggested adopting the classification of the National Kidney Foundation, others recommend using the older categories (Davison, 2011; Piccoli, 2010a, 2011). Thus, the obstetrician must be familiar with both.
Pregnancy and Chronic Renal Disease
Most women have relatively mild renal insufficiency, and its severity along with any underlying hypertension is prognostic of pregnancy outcome. Renal disease with comorbidities secondary to a systemic disorder—for example, diabetes or systemic lupus erythematosus—portends a worse prognosis (Davison, 2011; Fischer, 2004). For all women with chronic renal disease, the incidences of hypertension and preeclampsia, preterm and growth-restricted infants, and other problems are high. Despite these, the National High Blood Pressure Education Program Working Group (2000) has concluded that the prognosis has substantively improved since the 1980s. This has subsequently been verified by several reviews (Davison, 2011; Nevis, 2011; Ramin, 2006).
Loss of renal tissue is associated with compensatory intrarenal vasodilation and hypertrophy of the surviving nephrons. The resultant hyperperfusion and hyperfiltration eventually damage surviving nephrons to cause nephrosclerosis and worsening renal function. With mild renal insufficiency, pregnancy causes greater augmentation of renal plasma flow and glomerular filtration (Baylis, 2003; Helal, 2012). With progressively declining renal function, there is little, if any, augmented renal plasma flow. In one study, only half of women with moderate renal insufficiency demonstrated pregnancy-augmented glomerular filtration, and women with severe disease had no increase (Cunningham, 1990).
Importantly, chronic renal insufficiency also curtails normal pregnancy-induced hypervolemia. Blood volume expansion during pregnancy is related to disease severity and correlates inversely with serum creatinine concentration. As shown in Figure 53-5, women with mild to moderate renal dysfunction have normal blood volume expansion that averages 55 percent. With severe renal insufficiency, however, volume expansion averages only 25 percent, which is similar to that seen with hemoconcentration from eclampsia. In addition, these women have variable degrees of chronic anemia due to intrinsic renal disease.
FIGURE 53-5 Blood volume expansion in 44 normally pregnant women at term compared with 29 who had eclampsia; 10 with moderate chronic renal insufficiency (CRI)—serum creatinine 1.5 to 2.9 mg/dL; and four with severe CRI—serum creatinine ≥ 3.0 mg/dL. (Data from Zeeman, 2009; Cunningham, 1990.)
Renal Disease with Preserved Function
In some women, although glomerular disease has not yet caused renal dysfunction, there is still an increased incidence of pregnancy complications. As shown in Table 53-5, these complications are less frequent than in cohorts of women with moderate and severe renal insufficiency. Two studies illustrate this. In one, Surian and colleagues (1984) described outcomes in 123 pregnancies in women with biopsy-proven glomerular disease. Although only a few of these women had renal dysfunction, 40 percent developed obstetrical or renal complications. In another study, Packham and coworkers (1989) described outcomes in 395 pregnancies in women with preexisting glomerulonephritis and minimal renal insufficiency. Impaired renal function developed in 15 percent of these women during pregnancy, and 60 percent had worsening proteinuria. Only 12 percent had antecedent chronic hypertension, however, more than half of the 395 pregnancies were complicated by hypertension. The perinatal mortality rate was 140 per 1000, but even without early-onset or severe hypertension or nephrotic-range proteinuria, the rate was 50 per 1000. Importantly, in 5 percent, worsening renal function was permanent.
TABLE 53-5. Complications (%) Associated with Chronic Renal Disease During Pregnancy
Chronic Renal Insufficiency
As indicated, pregnancy complication rates are greater in women with chronic kidney disease who also have renal insufficiency compared with women with preserved renal function. Furthermore, adverse outcomes are generally directly related to the degree of renal impairment. Of the more recent reports shown in Table 53-5, outcomes of women with moderate versus severe renal insufficiency are usually not separated. That said, Piccoli and associates (2010a) described 91 pregnancies complicated by stage 1 chronic kidney disease. Primarily because of hypertension, 33 percent were delivered preterm, and 13 percent had fetal-growth restriction. Alsuwaida and colleagues (2011) reported similar observations.
Other investigators have described pregnancies complicated by moderate or severe renal insufficiency (Cunningham, 1990; Imbasciati, 2007; Jones, 1996). Despite a high incidence of chronic hypertension, anemia, preeclampsia, preterm delivery, and fetal-growth restriction, perinatal outcomes were generally acceptable. As shown in Figure 53-6, fetal growth is frequently impaired and related to renal dysfunction severity.
FIGURE 53-6 Birthweight percentiles of infants born to 29 women at Parkland Hospital with mild to moderate renal insufficiency—serum creatinine 1.4–2.4 mg/dL (black points) and severe renal insufficiency—serum creatinine ≥ 2.5 mg/dL (red points). (Data from Cunningham, 1990; Stettler, 1992. Growth curves are those reported by Alexander, 1996.)
There are several important aspects of prenatal care for women with chronic renal disease. Frequent monitoring of blood pressure is paramount, and serum creatinine levels and 24-hour protein excretion are quantified as indicated. Bacteriuria is treated to decrease the risk of pyelonephritis and further nephron loss. Protein-restricted diets are not recommended (Lindheimer, 2000; Ruggenenti, 2001). In some women with anemia from chronic renal insufficiency, a response is seen with recombinant erythropoietin. However, hypertension is a common side effect. Serial sonography is performed to follow fetal growth (Chap. 44, p. 880). The differentiation between worsening hypertension and superimposed preeclampsia is problematic. Preliminary data indicate that the angiogenic biomarkers placental growth factor (PlGF) and its soluble receptor (sFlt-1) may be useful to separate chronic from gestational hypertension. This is described in Chapter 40 (p. 747).
In some women, pregnancy may accelerate chronic renal disease progression by increasing hyperfiltration and glomerular pressure to worsen nephrosclerosis (Baylis, 2003; Helal, 2012). Women with more severe renal insufficiency have increased susceptibility. For example, Jungers and associates (1995) reported few long-term pregnancy-related adverse effects in 360 women with chronic glomerulonephritis and antecedent normal renal function. In women with severe chronic renal insufficiency, however, renal insufficiency may become worse during pregnancy (Abe, 1991; Jones, 1996). In the study by Imbasciati and coworkers (2007), worsening renal function was more likely in women who had a serum creatinine ≥ 1.4 mg/dL and > 1 g/day protein excretion.
As noted, progression is common for many women with chronic renal disorders. At 1 year after pregnancy, Jones and Hayslett (1996) reported that 10 percent of the women had developed end-stage renal failure—stage 5 chronic kidney disease. In a study from Parkland Hospital, we found that 20 percent of pregnant women with moderate to severe insufficiency had developed end-stage renal failure by a mean of 4 years (Cunningham, 1990). Similar findings in women with a median follow-up of 3 years were described by Imbasciati and colleagues (2007). By this time, end-stage disease was apparent in 30 percent of women whose serum creatinine was ≥ 1.4 mg/dL and who had proteinuria > 1 g/day. Chronic proteinuria is also a marker for subsequent development of renal failure. In another report from Parkland Hospital, we found that 20 percent of women with chronic proteinuria discovered during pregnancy progressed to end-stage renal failure within several years (Stettler, 1992).
Dialysis During Pregnancy
Significantly impaired renal function is accompanied by subfertility that may be corrected with chronic renal replacement therapy—either hemodialysis or peritoneal dialysis (Hladunewich, 2011; Shahir, 2013). Not unexpectedly, these pregnancies can be complicated. Chou and associates (2008) reviewed 131 cases reported since 1990. They found that mean fetal birthweight was higher in women who conceived while undergoing dialysis—1530 g versus 1245 g in women who conceived before starting dialysis. This was also true for 77 pregnancies reported to the Australian and New Zealand Dialysis and Transplantation Registry (Jesudason, 2014). Similar outcomes from several reports since 1999 are shown in Table 53-6.
TABLE 53-6. Pregnancy Outcomes in 156 Women Undergoing Dialysis During Pregnancy
These reports described similar outcomes with either hemodialysis or peritoneal dialysis. Thus, for the woman already undergoing either method, it seems reasonable to continue that method with consideration for its increasing frequency. In the woman who has never been dialyzed, the threshold for initiation during pregnancy is unclear. Lindheimer and colleagues (2007a) recommend initiation when serum creatinine levels are between 5 and 7 mg/dL. Because it is imperative to avoid abrupt volume changes that cause hypotension, dialysis frequency may be extended to five to six times weekly (Reddy, 2007).
Hladunewich and coworkers (2011) recommend attention to certain protocols that include replacement of substances lost through dialysis. Multivitamin doses are doubled, and calcium and iron salts are provided along with sufficient dietary protein and calories. Chronic anemia is treated with erythropoietin. To meet pregnancy changes, extra calcium is added to the dialysate along with less bicarbonate.
Maternal complications are common and include severe hypertension, placental abruption, heart failure, and sepsis. Piccoli and associates (2010b) reviewed reported outcomes in 90 pregnancies in 78 women. They found that these studies were heterogeneous for definitions; types of dialysis, frequency, and prescription; and perinatal outcomes. Although they were encouraged by their findings, they described high incidences of maternal hypertension and anemia, preterm and growth-restricted infants, stillbirths, and hydramnios.
ACUTE KIDNEY INJURY
Previously termed acute renal failure, acute kidney injury is now used to describe sudden impairment of kidney function with retention of nitrogenous and other waste products normally excreted by the kidneys (American Society of Nephrology, 2005; Waikar, 2012). Acute kidney injury has become less common today. For example, in a 6-year period the overall incidence at the Mayo Clinic was 0.4 percent (Gurrieri, 2012). Although the incidence of acute kidney injury in pregnancy has decreased substantially, it still occasionally causes significant obstetrical morbidity, and women who require acute dialysis have increased mortality rates (Kuklina, 2009; Singri, 2003). Outcomes are available from four older studies comprising a total of 266 women with renal failure (Drakeley, 2002; Nzerue, 1998; Sibai, 1990; Turney, 1989). Approximately 70 percent had preeclampsia, 50 percent had obstetrical hemorrhage, and 30 percent had a placental abruption. Almost 20 percent required dialysis, and the maternal mortality rate in these was approximately 15 percent.
Obstetrical cases of acute kidney injury that require dialysis have become less common today. That said, acute renal ischemia is still commonly associated with severe preeclampsia and hemorrhage (Gurrieri, 2012). Particularly contributory are HELLP syndrome and placental abruption (Audibert, 1996; Drakely, 2002). Septicemia is another common comorbidity, especially in resource-poor countries (Acharya, 2013; Srinil, 2011; Zeeman, 2003). Acute kidney injury is also common in women with acute fatty liver of pregnancy (Sibai, 2007). Nelson and colleagues (2013) reported some degree of renal insufficiency in virtually all of 52 such women cared for at Parkland Hospital (Chap. 55, p. 1087). Another woman from Parkland Hospital developed acute kidney injury from dehydration caused by severe hyperemesis gravidarum at 15 weeks (Hill, 2002). Her serum creatinine level peaked at 10.7 mg/dL, and she required hemodialysis for 5 days. Other causes that are discussed further in Chapter 56 (p. 1116) include thrombotic microcoagulopathies (Ganesan, 2011).
Diagnosis and Management
In most women, renal failure develops postpartum, thus management is usually not complicated by fetal considerations. An acute increase in serum creatinine is most often due to renal ischemia (Abuelo, 2007). Oliguria is an important sign of acutely impaired renal function. In obstetrical cases, both prerenal and intrarenal factors are commonly operative. For example, with total placental abruption, severe hypovolemia is common from massive hemorrhage, and frequently associated preeclampsia causes preexistent renal ischemia.
When azotemia is evident and severe oliguria persists, some form of renal replacement treatment is indicated, and hemofiltration or dialysis is initiated before marked deterioration occurs. Hemodynamic measurements are normalized. Medication dose adjustments are imperative, and magnesium sulfate is a prominent example (Singri, 2003; Waikar, 2012). Early dialysis appears to reduce the mortality rate appreciably and may enhance the extent of renal function recovery. With time, renal function usually returns to normal or near normal.
Acute kidney injury in obstetrics is most often due to acute blood loss, especially that associated with preeclampsia. Thus, it may often be prevented by the following means:
1. Prompt and vigorous volume replacement with crystalloid solutions and blood in instances of massive hemorrhage, such as in placental abruption, placenta previa, uterine rupture, and postpartum uterine atony (Chap. 41, p. 814).
2. Delivery or termination of pregnancies complicated by severe preeclampsia or eclampsia, and careful blood transfusion if loss is more than average (Chap. 40, p. 766).
3. Close observation for early signs of sepsis syndrome and shock in women with pyelonephritis, septic abortion, chorioamnionitis, or sepsis from other pelvic infections (Chap. 47, p. 946).
4. Avoidance of loop diuretics to treat oliguria before ensuring that blood volume and cardiac output are adequate for renal perfusion.
5. Judicious use of vasoconstrictor drugs to treat hypotension, and only after it has been determined that pathological vasodilatation is the cause.
Irreversible ischemic renal failure caused by acute cortical necrosis has become exceedingly uncommon in obstetrics. Before widespread availability of dialysis, it complicated a fourth of obstetrical renal failure cases (Grünfeld, 1987; Turney, 1989). Most cases followed placental abruption, preeclampsia-eclampsia, and endotoxin-induced shock. Once common with septic abortion, this is a rare cause in this country today (Lim, 2011; Srinil, 2011). Histologically, the lesion appears to result from thrombosis of segments of the renal vascular system. The lesions may be focal, patchy, confluent, or gross. Clinically, renal cortical necrosis follows the course of acute renal failure, and its differentiation from acute tubular necrosis is not possible during the early phase. The prognosis depends on the extent of the necrosis. Recovery of function is variable, and stable renal insufficiency may result (Lindheimer, 2007a).
Obstructive Renal Failure
Rarely, bilateral ureteral compression by a very large pregnant uterus is greatly exaggerated. Resultant ureteral obstruction in turn, may cause severe oliguria and azotemia. An extreme example is shown in Figure 53-7. Brandes and Fritsche (1991) reviewed 13 cases that were the consequence of a markedly overdistended uterus. They described a woman with twins who developed anuria and a serum creatinine level of 12.2 mg/dL at 34 weeks’ gestation. After amniotomy, urine flow resumed at 500 mL/hr and was followed by a rapid decline in serum creatinine levels to normal range. Eckford and Gingell (1991) described 10 women in whom ureteral obstruction was relieved by stenting. The stents were left in place for a mean of 15.5 weeks and removed 4 to 6 weeks postpartum. Sadan and coworkers (1994) reported a similar experience in eight such women who underwent stent placement at a mean of 29 weeks for moderate to severe hydronephrosis. The stents remained in situ for a mean of 9 weeks, during which time renal function remained normal.
FIGURE 53-7 A. Magnetic resonance image in a coronal plane of a pregnant woman with unilateral hydronephrosis caused by ureteral obstruction. The serum creatinine was 8 mg/dL and decreased to 0.8 mg/dL after a percutaneous nephrostomy tube was placed. B. Left kidney (arrow) and associated hydronephrosis (asterisk) are again noted in this axial plane image.
We have observed this phenomenon on several occasions (Satin, 1993). Partial ureteral obstruction may be accompanied by fluid retention and significant hypertension. When the obstructive uropathy is relieved, diuresis ensues and hypertension dissipates. In one woman with massive hydramnios (9.4 L) and an anencephalic fetus, amniocentesis and removal of some of the amnionic fluid was followed promptly by diuresis, a decline in the plasma creatinine concentration, and improvement of hypertension. In our experience, women with previous urinary tract surgery for reflux are more likely to have such obstructions.
LOWER GENITAL TRACT LESIONS
Infrequently complicating pregnancy, this type of diverticulum is thought to originate from an enlarging paraurethral gland abscess that ruptures into the urethral lumen. As infection clears, the remaining dilated diverticular sac and its ostium into the urethra persist. Urine collecting within and dribbling from the sac, pain, palpable mass, and recurrent urinary infections may be associated findings. In general, a diverticulum is managed expectantly during pregnancy. Rarely, drainage may be necessary, or surgery required (Iyer, 2013). If additional antepartum evaluation is needed, MR imaging is preferred for its superior soft tissue resolution and ability to define complex diverticula (Dwarkasing, 2011; Pathi, 2013).
Genital Tract Fistulas
Fistulas found during pregnancy likely existed previously, but in rare cases, they form during pregnancy. In developed countries, vesicovaginal fistula following a McDonald cerclage has been reported (Massengill, 2012). These fistulas may also form with prolonged obstructed labor that is more commonly seen in resource-poor countries. In these cases, the genital tract is compressed between the fetal head and bony pelvis. Brief pressure is not significant, but prolonged pressure leads to tissue necrosis with subsequent fistula formation (Wall, 2012). Vesicouterine fistulas that developed after prior cesarean delivery have been described (DiMarco, 2012; Manjunatha, 2012). Rarely, vesicocervical fistula may follow cesarean delivery or may form if the anterior cervical lip is compressed against the symphysis pubis (Dudderidge, 2005).
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