Posterior urethral valves (PUVs) are the most common cause of bladder outlet obstruction in males.
PUVs account for 10% of all urologic anomalies detected by prenatal ultrasound.
PUVs have a broad range of severity from completely asymptomatic to complete obstruction, oligohydramnios, pulmonary hypoplasia, and renal dysplasia.
Oligohydramnios due to a PUV, if untreated, is associated with nearly uniform neonatal mortality due to pulmonary hypoplasia.
Sonographic prognostic criteria predicting poor outcome include presence of subcortical cysts and increased echogenicity of the kidneys, which are associated with renal dysplasia.
Fetal urine electrolytes (Na <100, Cl <90, Osm <210, β2-microglobulin <6) are associated with preserved renal function and favorable prognosis with treatment.
Fetal urine electrolytes are only valid for fetuses at 20 weeks of gestation or later.
Treatment options include vesicoamniotic shunt placement, fetoscopic ablation of PUV, and open fetal surgery for vesicostomy.
Fifty percent of successfully treated fetuses with PUV develop growth failure and chronic renal failure requiring dialysis and/or transplantation.
Unlike obstruction of the urinary tract at other levels, bladder outlet obstruction has the potential to affect the development of the whole urinary tract as well as the lungs. In males, the most common cause of bladder outlet obstruction is posterior urethral valves (PUVs) (Atwell, 1983). In contrast, in females the most common cause of bladder outlet obstruction is urethral atresia. As in many other congenital anomalies, there is a broad range of severity, with bladder outlet obstruction ranging from completely asymptomatic to the infant who presents at delivery with respiratory insufficiency due to pulmonary hypoplasia caused by long-standing oligohydramnios and renal failure from renal dysplasia.
PUVs are thought to be embryologically derived from mullerian duct remnants or remnants of the cloacal membrane dating back to between the 7th and 11th weeks of gestation (Dewan et al., 1992, 1995). Young et al. (1919) described a classification scheme for PUVs. In type I, the valves are sail-like leaflets that arise from the crista-urethralis distal to the verumontanum. These valves may cover only the lower half of the urethra or may encircle the urethra and cause complete obstruction. Type II valves are nonobstructing folds of the superficial muscle and mucosa that extend from the verumontanum to the bladder neck (Cuckow, 1998). Type III valves usually cause a diaphragm-like obstruction at the level of the verumontanum, but can be seen at the level of the anterior urethra distal to the external urethral sphincter (Hendren, 1971).
The characteristic prenatal presentation of bladder outlet obstruction is that of a dilated bladder and bilateral hydroureteronephrosis. The severity of prenatal bladder outlet obstruction ranges from mild to severe as is seen postnatally. At the better end of the spectrum, the fetus may have obstructive uropathy with preservation of amniotic fluid volume, minimal changes in the bladder and ureters, and no dysplastic changes in the kidneys. At the severe end of the spectrum are fetuses with profound oligohydramnios, distended bladder, and ureters with cystic dysplastic changes in the kidneys. The longstanding oligohydramnios results in pulmonary hypoplasia, which leads to severe respiratory insufficiency at birth and is a leading cause of death during the neonatal period. Fetuses with obstructive uropathy can also have other associated nongenitourinary anomalies, chromosomal abnormalities, and deformations related to oligohydramnios, emphasizing the importance of careful prenatal evaluation. In cases of isolated bladder outlet obstruction due to PUVs, vesicoamniotic shunting may be lifesaving.
The figures reported for the incidence of bladder outlet obstruction vary widely, reflecting the spectrum of severity seen in obstructive uropathy. In PUVs, the most common cause, the range in severity extends from fetuses presenting with oligohydramnios, renal dysplasia, and pulmonary hypoplasia to asymptomatic octogenarians noted to have PUVs at the time of cytoscopy for benign prostatic hypertrophy. The incidence of PUVs has been reported to be between 1 in 5000 and 1 in 25,000 births (Atwell, 1983). PUVs account for 10% of all urologic anomalies detected by prenatal ultrasound, which occur as frequently as 1 in 800 livebirths (Thomas and Gordon, 1989;Hutton et al., 1994). Prenatal ultrasound picks up 50% of new cases of PUVs, suggesting an incidence of 1 in 4000 livebirths (Cuckow, 1998). Recently, there has been increased awareness of PUVs, and Richmond and Atkins reported an increase in apparent prevalence from 1.9 per 10,000 births to 2.4 per 10,000 births (Richmond and Atkins, 2005). This estimate does not take into account cases of intrauterine fetal death, loss to pregnancy termination, stillbirths, or the asymptomatic cases that present later in life with voiding difficulty (Hendren, 1971; Pieretti, 1993).
Urinary tract obstruction at the level of the bladder outlet is usually due to PUVs in male fetuses and urethral atresia in females. The cardinal features of bladder outlet obstruction include marked and persistent dilation of the urinary bladder with a thickened, often trabeculated, bladder wall (Glick et al., 1984; Mahony et al., 1985). The posterior urethra is dilated in urethral obstruction due to PUVs. This dilated proximal urethra resembles a keyhole, extending from the bladder toward the fetal perineum (Figure 82-1). The dilated bladder can become quite large, filling both fetal pelvis and abdomen. The mural thickness of the normal bladder is quite thin and bladder wall thickness greater than 2 mm is pathologic. In cases of severe bladder outlet obstruction, the nondilated bladder (either following bladder tap or spontaneous voiding) can be as thick as 10 to 15 mm (Mahony, 1994). Often, severe bladder outlet obstruction will result in ureterectasis and caliectasis due to vesicoureteral reflux induced by high intravesical pressure. However, the absence of these features does not preclude the diagnosis of bladder outlet obstruction because only 40% of fetuses will demonstrate ureterectasis and pyelectasis in bladder outlet obstruction (Mahony, 1994). In high-grade bladder outlet obstruction, the urinary bladder may spontaneously decompress through rupture of the urinary tract, resulting in either fetal urinary ascites or perinephric urinoma (Callen et al., 1983; Mahony et al., 1984). The end-stage effects of early gestation high-grade bladder outlet obstruction is often bilateral renal dysplasia. This may be sonographically evident from markedly increased renal parenchymal echogenicity and, most specifically, from the presence of subcortical cysts (Mahony et al., 1984; Crombleholme et al., 1991). Paradoxically, the lack of caliectasis in the otherwise obstructed urinary tract may suggest the presence of renal dysplasia and reflects the lack of urine production by severely damaged kidneys. Oligohydramnios is indicative of high-grade obstruction and, if long-standing, may result in deformations including Potter facies and clubfeet.
The upper panel shows four MRI images of the same fetus. The panel at the left shows a small perinephric urinoma (small yellow arrow). The second panel shows the dilated bladder and posterior urethra. The third panel shows in coronal section the dilated urethra and hydronephrosis and calyceal dilatation. The blue arrow points out the dilated posterior urethra. The panel on the right shows the very dilated bladder with thickened walls.
Lower panel demonstrates characteristic findings on ultrasound in posterior urethral valves in a fetus at 21 weeks of gestation. The left panel shows the dilated thick-walled bladder in sagittal plane. The middle panel shows the hydronephrotic kidney with calyceal dilatation. The right panel demonstrates the dilated tortuous ureter. (Courtesy of Pramod Reddy, MD, Pediatric Urology, Fetal Care Center of Cincinnati)
Fetal MRI has been found to be a useful adjunctive imaging modality in the evaluation of the fetus with obstructive uropathy (Caire et al., 2003). MRI may be more sensitive in defining subcortical cysts, suggesting renal dysplasia. In addition, fetal MRI may provide anatomic detail on pelvic structures not available with ultrasound, particularly in the setting of bladder outlet obstruction presenting prior to 16 weeks of gestation. In these early cases, persistent cloaca may be more clearly diagnosed by MRI than by ultrasound alone.
The functional capacity of the fetal kidney affected by obstructive uropathy depends on the extent and severity of renal dysplasia caused by the obstruction. The dysplastic fetal kidney is characterized by the presence of disorganized metanephric structures surrounded by fibrous tissue which, in addition, may have cortical cysts (Rubenstein et al., 1961; Beck, 1971; Potter, 1972;Risdon, 1975; Bernstein, 1976). More than 90% of dysplastic kidneys with cortical cysts are associated with obstruction during nephrogenesis (Rubenstein et al., 1961; Bernstein, 1976). Detection of cortical cysts sonographically implies the presence of severe renal dysplasia and irreversible renal damage, excluding the patient from intervention. A normal kidney will display an echotexture similar to that of the liver, with an internal architecture showing a differentiation between cortex and medulla. The medulla containing tubules and fluid will appear darker. A dysplastic kidney, however, will show no internal architecture and may display an increased echogenicity due to a disruption in the normal renal histology. Renal dysplasia may be associated with cystic formation with the parenchyma (Harrison et al., 1982a; Risdon, 1975). Features of multicystic dysplasia of the kidney (MCDK) include the presence of multiple noncommunicating cysts of variable sizes, interfaces between the cysts (presence of echogenic areas within the renal parenchyma), nonmedial location of the largest cyst, and absence of an organized parenchyma (see Chapter 78) (Fong et al., 1986; Kleiner et al., 1986). Multicystic dysplasia of the kidney is most often seen unilaterally and is associated with a high incidence of contralateral urologic anomalies that will warrant postnatal evaluation by a pediatric urologist (Thomas, 1990). Cystic dysplasia should not be confused with severe hydronephrosis.
Mahony et al. (1984) studied the kidneys of 49 fetuses with obstructive uropathy and found that the presence of cortical cysts had a positive predictive value of 100% for the presence of renal dysplasia. Sonography was also 100% specific as no fetus without dysplasia had detectable cortical cysts. The presence of cortical cysts reliably predicts the presence of renal dysplasia and irreversible renal damage, but the absence of cortical cysts cannot ensure the absence of renal dysplasia. Of the kidneys without cortical cysts in the study by Mahony et al., only 44% were free of dysplastic changes. Renal dysplasia may be present without cysts, or the diameter of the cysts may be below the resolution of ultrasound. Technical factors may also limit the ability of the sonographer to adequately image the fetal kidneys, including shadowing from the adjacent spine and oligohydramnios, which often accompanies obstructive uropathy.
In the dysplastic kidney, there is abundant fibrous tissue that may increase the echogenicity of the renal parenchyma. It has been suggested that increased echogenicity at the renal cortex may be a sign of renal dysplasia. However, when this sonographic sign was evaluated, it was shown to be less specific and to have a lower positive predictive value than the presence of cortical cysts (Mahony et al., 1985). The evaluation of renal echogenicity is also a more subjective assessment with inherent interobserver variability, which further limits its utility.
Ultrasonographic examination of the fetal kidneys may provide prognostic information if cortical cysts and increased echogenicity are detected, but is less specific in their absence (Mahony et al., 1985; Crombleholme et al., 1991). Similarly, the volume of amniotic fluid is not a useful prognostic indicator except at the extremes (Harrison et al., 1981a, 1982a, 1987; Glick et al., 1985). Zaccara et al. found that amniotic fluid index remains a reliable predictor of renal function in cases of obstructive uropathy (Zaccara et al., 2005). Preserved amniotic fluid almost always predicts normal renal function at long-term evaluation. Fetuses with bilateral hydronephrosis and normal amniotic fluid may not require intervention. Similarly, fetuses with bilateral hydronephrosis, severe oligohydramnios, and severely dysplastic renal cortex as seen on ultrasound are unlikely to benefit from in utero therapy. It is for the fetuses between these two extremes that prognostic criteria are most important. Assessment of residual fetal renal function by indirect methods such as ultrasound determination of bladder filling and emptying or furosemide stimulation of urine production have not proven reliable (Campbell et al., 1973; Wladimiroff, 1975; Chamberlain et al., 1985). A more sensitive means of assessing fetal renal function is essential for the appropriate selection of fetuses with obstructive uropathy for treatment.
An evaluation of the fetal urinary tract should include an assessment of the overall growth and development of the fetus, amniotic fluid index, gender, renal parenchymal appearance, extent of dilatation of the collecting system, unilateral or bilateral involvement, and bladder size, thickness, and emptying (Cendron et al., 1994). Because of the increased incidence of associated malformations, the fetus should be scanned for extrarenal anomalies. Serial sonographic evaluation is also essential to evaluate for progression of these sonographic features.
The sex of the fetus will help narrow the differential diagnosis. Sonographic demonstration of male external genitalia in the setting of bladder outlet obstruction strongly suggests the diagnosis of PUVs. In a female fetus, one should consider the diagnosis of urethral atresia, persistent cloaca, caudal regression anomaly, or megacystis-microcolon–intestinal hypoperistalsis syndrome (Table 82-1). An unusual cause of bladder outlet obstruction that can occur in either sex is prolapse of an ectopic ureterocele from a duplex collecting system. In distinguishing urethral atresia in a female fetus, the oligohydramnios is profound and long standing. Particularly when diagnosed prior to 16 weeks of gestation, a dilated “bladder” on ultrasound should raise the possibility of persistent cloaca. The presence of a persistent cloaca may be suspected from the anatomy of the “bladder” and the presence of debris in the cloaca from the intestinal communication. Intraluminal calcifications within bowel loops suggest a communication between intestinal and genitourinary tracts. Caudal regression should be evident from images of the fetal spine. In the megacystis-microcolon–intestinal hypoperistalsis syndrome, the bladder is very dilated but with a thin wall even after decompression, as opposed to the pressure-induced hypertrophy observed in bladder outlet obstruction from PUVs. This is a rare, usually lethal, anomaly in which 80% of affected fetuses are females (Winter and Knowles, 1986). Other features that are clues to this diagnosis include small-bowel dilation, a microcolon with malrotation, and polyhydramnios in the third trimester (Stramm et al., 1991). This is inherited as an autosomal recessive condition and therefore has implications for future pregnancies.
Table 82-1Causes of Bilateral Hydronephrosis ||Download (.pdf) Table 82-1 Causes of Bilateral Hydronephrosis
|Supravesical obstruction |
|Infravesical obstruction |
|Vesicoureteral reflux (bilateral, usually high-grade) |
|Prune belly syndrome |
|Megacystis-microcolon–hypoperistalsis syndrome |
ANTENATAL NATURAL HISTORY
A thorough understanding of the pathophysiology of fetal obstructive uropathy and its sequelae in the developing fetus is essential in formulating a rational approach to clinical management. It is important to understand why obstructive uropathy results in pulmonary hypoplasia, renal dysplasia, and associated malformations and whether or not these changes can be reversed by decompression in utero.
Obstruction of the urethra during the latter half of gestation results in dilatation and hypertrophy of the bladder and megaureter and bilateral hydronephrosis. But obstruction that starts this late in gestation does not usually produce the dysplastic changes in the renal parenchyma seen in human fetuses. Some have argued that dysplasia is caused by an abnormal interaction between the ureteric bud and the metanephric mesenchyme and is only incidentally associated with obstruction. Experiments in a fetal chick in which ureteric buds were denuded of metanephric mesenchyme formed primitive ducts, suggesting that in the chick, dysplasia may be due to nonobstructive causes. These studies have questionable relevance to the pathogenesis in higher animals and humans.
The proponents of obstruction-induced dysplasia argue that after 8 to 10 weeks of gestation, when the kidney begins to make urine, obstruction results in back pressure into the developing nephrons. Potter demonstrated that the collecting tubules of the nephrogenic kidney are straight and short and may be more susceptible to injury from back pressure than the mature nephron. Chevalier (1993) confirmed that early in development, renal injury from ureteral obstruction occurs more frequently than in the adult kidney. It follows that in order to preserve renal function in the face of an obstruction, early recognition and prompt decompression may be necessary. Early obstruction will cause the development of dysplastic changes in the kidney, but further impairment in renal function may occur not so much as a result of nephron loss from a pressure-mediated mechanism, but by a vasoconstrictive effect mediated by an overactivation of the renin–angiotensin system (Chevalier, 1993).
In humans, oligohydramnios, because of obstructive uropathy, renal agenesis, or prolonged amniotic fluid leak, results in severe pulmonary hypoplasia (Kemper and Mueller-Wiefel, 2007). The lungs of infants affected by obstructive uropathy show decreased airway branches from segmental bronchi, reflecting compromised development during the first half of gestation (pseudoglandular stage, 5 to 16 weeks). Although the lung made hypoplastic by compression during the pseudoglandular stage would not be expected to develop new airway branches, it would retain the capacity to make new alveoli and intra-acinar arteries. To evaluate the effect of obstructive uropathy on pulmonary development in an early gestation model, Adzick et al. (1987) performed bilateral ureteral ligation at 60 days of gestation, during the pseudoglandular stage of lung development (60–80 days of gestation), on lambs. Morphometric analysis of the lungs at birth revealed significant reduction of lung volume, radial alveolar count, and mean linear intercept (an indicator of airspace size) in the lambs with bilateral ureteral ligation as compared with the controls (Adzick et al., 1987). In addition, muscularization of the intra-acinar arteries was greater in lambs with bilateral ureteral ligation, indicating increased peripheral pulmonary arteriolar muscularization. These morphometric findings were the same as those in human infants who died from oligohydramnios-induced pulmonary hypoplasia from obstructive uropathy (Potter, 1972; Hislop et al., 1979). These experimental models replicated both the renal dysplastic changes and the pulmonary hypoplasia that are observed in human fetuses who die from severe obstructive uropathy and oligohydramnios.
The mechanism by which oligohydramnios causes pulmonary hypoplasia is uncertain. Several possible contributing factors include the small uterine cavity, which causes thoracic compression and limited intrathoracic space. Fetal breathing movements may be limited by uterine compression of the fetal chest and abdomen. Fetal respiration is thought to be an important factor in lung growth (Wigglesworth and Desai, 1982). Ablation of fetal breathing by cord transection, curare-induced paralysis, or damping fetal breathing movements by thoracoplasty—all result in pulmonary hypoplasia (Liggins et al., 1979; Wigglesworth and Desai, 1979; Moessinger, 1983). Oligohydramnios may also increase the loss of lung fluid, with decreased lung fluid volume within the airway (Lanman et al., 1971). Chronic fetal tracheal drainage of lung fluid results in pulmonary hypoplasia. The amniotic fluid may also act as a hydraulic stent. Increases in amniotic pressure are transmitted to the fluid in the fetal airway and prevent increases in transthoracic pressure, which might restrict lung growth from chest compression. Another possibility is the loss of a growth factor produced by the kidneys (Lanman et al., 1971).
These studies form the basis for in utero intervention to decompress the urinary tract and restore amniotic fluid dynamics to prevent neonatal death due to pulmonary hypoplasia and renal dysplasia.
A fetus with suspected bladder outlet obstruction should undergo a detailed sonographic survey to detect nongenitourinary anomalies. In particular, sonographic features of trisomies 13, 18, and 21 should be ruled out because chromosomal abnormalities can be seen in bladder outlet obstruction in as many as 12% of cases (Crombleholme et al., 1991; Cusick et al., 1995). Deformations due to oligohydramnios such as clubfoot and Potter facies should be ruled out. A sonographic evaluation of the urinary tract should include the sex of the fetus, amniotic fluid volume, presence or absence of ascites, and a detailed examination of the urinary tract itself. Not only the presence of the keyhole sign, but the size of the bladder and evidence of bladder wall hypertrophy should be noted. The presence or absence of an ureterocele should be sought, and the bladder should be observed during voiding for evidence of vesicoureteral reflux. The degree of ureteral dilation, hydronephrosis, and/or caliectasis may increase with voiding in the presence of vesicoureteral reflux. All fetuses with bladder outlet obstruction should have a genetic consultation and should consider amniocentesis. Echocardiography should be performed to rule out structural heart disease. In less severe cases of bladder outlet obstruction, in which amniotic fluid volume is preserved, there should be no adverse effects on pulmonary development and the site, timing, and mode of delivery should be unaffected. In severe cases in which oligohydramnios has occurred, either a decision should be made not to aggressively resuscitate the infant, or the baby should be delivered in a tertiary care setting. In the case of severe long-standing bladder outlet obstruction associated with oligohydramnios and renal dysplasia, there should be no intervention for nonreassuring fetal testing or attempts at resuscitation because these infants have severe pulmonary hypoplasia and renal dysplasia that are incompatible with life. Prenatal consultation with pediatric specialists in urology, nephrology, and neonatology may be helpful in counseling parents about the options for treatment and long-term outcome. The approach to the fetus with bladder outlet obstruction is outlined in the algorithm in Figure 82-2.
Algorithm for prenatal and perinatol management of the fetus with bladder outlet obstruction. VA, vesicoamniotic; GU, genitourinary; FETURP, fetoscopic transuterine release of posterior urethral valves; PUBS, percutaneous umbilical blood sampling. (Lim FY, Crombleholme TM. In: Mattei P, ed. Surgical Directives: Pediatric Surgery. 2nd ed. In Press.)
It is important to stress that the appearance of the fetus with bladder outlet obstruction may evolve during gestation. The fetus with complete or high-grade bladder outlet obstruction associated with oligohydramnios may spontaneously evolve with development of less-severe outlet obstruction and restoration of amniotic fluid volume. Conversely, the fetus with high-grade partial bladder outlet obstruction but preserved amniotic fluid volume may progress during pregnancy, with the kidneys becoming more echogenic and demonstrating subcortical cysts consistent with the development of dysplasia. Serial sonographic surveillance should be a part of a prenatal management plan of all fetuses with bladder outlet obstruction.
During the past decades, much has been learned about the natural history of obstructive uropathy, and the pathophysiology has been replicated in animal models (Glick et al., 1984; Harrison et al., 1985, 1987; Nakayama et al., 1986; Bronshtein et al., 1990; Crombleholme et al., 1988b, 1991; Mandell et al., 1992; D'Alton and DeCherney, 1993). It has been demonstrated experimentally that bladder decompression in utero can prevent the progression of dysplastic changes seen in obstructive uropathy (Glick et al., 1983, 1984). There are those who question whether animal models accurately replicate the pathophysiology in humans (Berman and Maizels, 1982; Lissauer et al., 2007). A major problem in management is the proper selection of fetuses with bilateral hydronephrosis who might be candidates for intervention, i.e., fetuses with obstruction severe enough to compromise renal and pulmonary development, but not so severe that renal damage is irreversible even if the obstruction is relieved. Several methods have been suggested to assess the functional capacity of the kidneys in a fetus with obstructive uropathy, including the sonographic appearance of the kidneys, amniotic fluid volume, and various fetal urine electrolytes and proteins.
In the 13th week of gestation, the fetus begins to make urine, which is best characterized as an ultrafiltrate of fetal serum (McCance and Widdowson, 1953; Alexander and Nixon, 1961; McGrory, 1972; Mellor and Slatter, 1972; Hill and Lumbers, 1988). The urine is hypotonic because of selective tubular resorption of Na and Cl in excess of free water (Glick et al., 1985). The urine composition normally becomes progressively hypotonic between 16 and 21 weeks and may become even slightly more hypotonic late in gestation as a result of tubular maturation and increased fetal glomerular filtration rate (Glick et al., 1985; Nicolini et al., 1992). Glick et al. (1985) observed that fetuses with congenital hydronephrosis and normal renal function after birth had hypotonic urine but those with poor function produced urine that was isotonic. Similar observations were made in fetuses with hydronephrosis but good renal and pulmonary function was evaluated postnatally by Weinstein and McFaydon and their colleagues (Weinstein et al., 1982; McFaydon et al., 1983).
It is uncertain why the fetus produces isotonic urine in the presence of long-standing obstruction. It has been suggested that dysplastic changes may alter tubular function sufficiently to prevent the resorption of Na and Cl. Rappaport et al. (1960) suggested that the stagnant urine may equilibrate with serum. The fluid aspirated from the fetus with severe obstructive uropathy may also present fluid produced by bladder urothelium.
In order to develop more sensitive fetal renal function tests, Glick et al. (1985) used bladder catheterization to evaluate 20 fetuses with obstructive uropathy. The fetuses who subsequently had a poor outcome were all “salt wasters” and those who had a good outcome had hypotonic urine. On the basis of this study, prognostic criteria for renal function in congenital hydronephrosis were proposed (Table 82-2). These results were questioned by other groups, who reported that these prognostic criteria did not accurately predict the renal function at birth. Wilkins et al. (1987) reported results using these prognostic criteria in nine cases of fetal obstructive uropathy. The criteria were accurate in predicting a poor outcome, as all four patients died and three of these four had evidence of renal dysplasia. In the fetuses with a predicted good prognosis, four of the five had poor renal function and the only patient with a good outcome underwent in utero decompression with a vesicoamniotic shunt.
Table 82-2Prognostic Criteria in Obstructive Uropathy ||Download (.pdf) Table 82-2 Prognostic Criteria in Obstructive Uropathy
|Prognostic Criteria in Obstructive Uropathy |
|Sonography ||No Cortical Cyst, Normal Echogenicity |
|Na ||<100 mEq per liter |
|Cl ||<90 mEq per liter |
|Osm ||<210 mEq per liter |
|Ca ||< 2 mmol per liter |
|PO4 ||< 2 mmol per liter |
|β2 -microglobulin ||< 2 mg per liter |
The reports questioning the utility of fetal urine electrolyte levels as prognostic criteria prompted a reevaluation in a series of 40 fetuses with bilateral hydronephrosis. Crombleholme et al. (1991) retrospectively assigned fetuses to a good prognostic group only if they had a Na < 100, Cl <90, osmolarity <210, and there was no sonographic evidence of dysplasia (Figure 82-3). Fetuses were assigned to a poor-prognosis group if even one of these criteria was not met. There was a statistically significant difference in survival in the good versus the poor-prognosis group (81% vs. 12.5%) even after excluding pregnancy terminations (87% vs. 30%). These prognostic criteria were intended as a means to select fetuses for in utero intervention. They accurately select the fetuses that have sufficient renal function to have a favorable outcome if decompressed in utero. If the fetal obstruction is unrelieved, however, the renal function is likely to deteriorate despite a favorable prognostic profile. Fetal obstructive uropathy is a dynamic process, and experimental studies in fetal lambs have demonstrated that the severity of renal damage from obstruction depends on the timing, duration, and severity of the obstruction (Harrison et al., 1981a, 1983; Glick et al., 1983, 1984). The fetal urine electrolytes obtained at 20 to 24 weeks of gestation may only reflect the renal function at the time they are assayed. In fact, Nicolini et al. (1992) have demonstrated by serial fetal bladder aspirations the worsening urinary electrolyte profile and renal function in fetuses with obstructive uropathy in which the obstruction was untreated. In the report from Wilkins et al. (1987), the fetuses in the favorable group had unrelieved obstruction and progression in their renal deterioration. The one fetus that was successfully decompressed in utero had a good outcome.
Algorithm for the postnatal evaluation of fetal hydronephrosis. MCDK, multicystic dysplastic kidney; VUR, vesicoureteral reflux; VCUG, voiding cystourethrography; F/U PRN, follow up as needed.
These prognostic criteria for in utero intervention in obstructive uropathy have become widely used and are being more appropriately applied as selection criteria for intervention. However, Nicolini et al. (1992) have pointed out that one potential problem with these criteria is that they fail to take into account the gestational age of the fetus and that threshold values were established in fetuses with obstructive uropathy and not normal fetuses. The effect of gestational age on fetal urine electrolytes is most marked prior to 21 weeks of gestation, becoming progressively more hypotonic and then remaining relatively stable throughout the remainder of gestation. The criteria proposed by Glick et al. (1985) were selected to establish the threshold for a poor prognosis as 2 SD from the mean value of the patients with a good prognosis. This does skew the criteria toward including potentially compromised fetuses into the good-prognosis group. But as the results reported by Crombleholme et al. (1991) confirm, this has not resulted in the treatment of fetuses with irrevocably compromised renal function. In fact, overly stringent selection criteria for intervention as proposed by Nicolini et al. (1992) may exclude many potentially salvageable fetuses from treatment. There are, however, no established fetal urine electrolyte parameters for fetuses less than 20 weeks of gestation.
In addition to the use of fetal urine Na, Cl, and osmolarity, other groups have suggested the addition of urine Ca2+, PO4, and β 2-microglobulin to assess fetal renal function. Nicolini et al. (1992) studied fetal urine creatinine, urea, and electrolytes, notably Ca2+, Na, and PO4 in a group of 24 fetuses with obstructive uropathy and 26 normal controls. They found that the urinary Ca2+ and Na were significantly higher in fetuses with renal dysplasia as compared with those with lower urinary tract obstruction but normal renal histology or normal clinical outcome. Urinary Ca2+ levels were found to be the most sensitive (100%) indicator of renal dysplasia but lacked specificity (60%). Urinary Na was slightly less sensitive (87%) but was found to be the most specific (80%). Urinary PO4, creatinine, and urea were not significantly different in fetuses with dysplastic kidneys versus those without dysplasia.
The predictive value of fetal urine electrolytes in bladder outlet obstruction has been found to be enhanced by serial bladder taps (Johnson et al., 1995). Johnson et al. have recommended complete bladder drainage at 24-hour intervals for a minimum of three taps to best establish a clear pattern of increasing or decreasing urinary hypertonicity. While values clearly in the normal range on initial bladder tap may not require additional bladder taps to establish a prognosis, a fetus with elevated values may show a clear trend of improving electrolyte values with sequential taps. The sequential taps are thought to clear stagnant urine that may not accurately reflect renal function (Qureshi et al., 1996).
It has been observed that obstructive uropathy due to PUVs has a long natural history (Parkhouse et al., 1988; Harrison and Adzick, 1991). Renal failure may not develop for years in a newborn with PUVs. A fetus with obstructive uropathy, a favorable prognostic profile, and normal amniotic fluid is currently not considered a candidate for in utero decompression. A small number of fetuses diagnosed with hydronephrosis were observed to have findings consistent with obstructive uropathy, a favorable prognostic profile, and normal amounts of amniotic fluid, but progressive renal insufficiency subsequently developed during infancy despite good renal function initially. We, thus, have lacked criteria that allow us to identify a fetus with obstructive uropathy and a good prognostic profile that, despite the presence of normal amniotic fluid volume, is at risk for ongoing renal damage. Muller et al. (1993) reported the use of fetal urinary β 2-microglobulin as a predictor of postnatal renal function at 1 year of age. They reported that 17 of 40 patients with normal amniotic fluid volume and a good prognostic profile had a creatinine level of >0.56 mg/L at 1 year of age. This value was selected as the threshold since it was 2 SD from the mean creatinine of normal 1-year-old infants. In this group of patients, the β 2-microglobulin was found to be significantly elevated as compared with patients with the same prognostic profile but with a creatinine of <0.56 mg/L at 1 year of age. β 2-Microglobulin may allow us to identify fetuses at risk for renal damage by unrelieved obstruction even though their amniotic fluid has not diminished.
Our current approach to in utero treatment for obstructive uropathy is to intervene in fetuses with a good prognostic profile only for decreasing amniotic fluid or frank oligohydramnios (Crombleholme et al., 1991; Cendron et al., 1994) (see Figure 82-3). Fetal therapy of obstructive uropathy up to now has been aimed at restoration of amniotic fluid volume to allow pulmonary development, averting neonatal death from pulmonary hypoplasia. The potential utility of β 2-microglobulin is that it may allow us to select for in utero therapy among fetuses with a good prognostic profile those at risk for ongoing renal damage. The goal of this treatment would be preservation of renal function as opposed to prevention of pulmonary hypoplasia. This would significantly expand the indications for fetal intervention in obstructive uropathy. However, this report is preliminary, and longer follow-up of these children as well as confirmation by other investigators will be necessary to define the role of fetal intervention in the setting of an elevated urinary β 2-microglobulin in fetuses with good prognostic profiles and normal amniotic fluid volume.
One major question that is difficult to address in fetal treatment of obstructive uropathy is assessing the efficacy of prenatal decompression. In a report of a large experience with vesicoamniotic shunts at a single institution, Johnson et al. (1995) described the outcome in 55 fetuses that underwent shunt placement. Unfortunately, this was a heterogeneous group of patients with good- and poor-prognosis patients with a range of diagnoses including PUVs, prune belly, urethral atresia, and a variety of other anomalies. In the group with PUVs, the postnatal survival was 60%. Of note is that the incidence of an elevated nadir creatinine level > 1 mg/dL in the first year of life was 33%. Coplen et al. (1996) in a review of prenatal intervention for lower urinary tract obstruction from five reported series found an overall survival rate of only 48% and a catheter-related complication rate of 45%. In the report by Crombleholme et al. (1991), in both the good-prognosis and poor-prognosis groups, survival was greater in fetuses who were decompressed in utero as opposed to those who were not decompressed. In the group of 10 fetuses with a poor prognosis, 3 were electively terminated, 4 neonatal deaths were from pulmonary hypoplasia or renal dysplasia, and 3 had survived. All three survivors had restoration of normal amniotic fluid levels, but renal failure developed in two of the three survivors and they have since undergone renal transplantation. Among the 14 patients with no intervention, there were no survivors (11 terminations and 3 neonatal deaths from pulmonary hypoplasia).
In the good-prognosis group of nine fetuses, one was electively terminated, and there were no deaths, leaving eight neonatal survivors. One infant died at 9 months of age from unrelated causes, with normal renal function. Of the seven patients in the good-prognosis group who were not treated, five survived and two died after birth. Renal failure later developed in two of the survivors. The incidence of oligohydramnios in the good-prognosis group was 7 out of 16. All six patients with oligohydramnios who had fetal intervention survived. One patient with oligohydramnios that was untreated died at birth from pulmonary hypoplasia.
When in utero intervention restores amniotic fluid volume, neonatal death from pulmonary hypoplasia is averted. When oligohydramnios develops during the canalicular stage of lung development (16–24 weeks) the fetus usually has pulmonary hypoplasia precluding survival. In the group of fetuses reported by Crombleholme et al. (1991), there was a preponderance of oligohydramnios in the poor-prognosis group (23 of 24 as compared with 7 of 16 in the good-prognosis group). Fetuses from the good-prognosis group appear to survive as a result of fetal treatment in the face of variable rates of oligohydramnios. In the good-prognosis group, six of the seven fetuses with oligohydramnios had intervention and all six survived with normal renal function. However, the seventh patient with oligohydramnios, who was not treated, died at birth from pulmonary hypoplasia. Uncorrected oligohydramnios was associated with a 100% neonatal mortality. Normal or restored amniotic fluid volume was associated with a 94% survival (Crombleholme et al., 1991).
In utero decompression appears to prevent neonatal death from pulmonary hypoplasia, but the effect on renal function is less clear. The development of postnatal renal failure in two infants who were not treated because amniotic fluid volume remained normal raises a question about treating obstructed fetuses before oligohydramnios develops. Because renal development or maldevelopment is complete at birth, relief of obstruction in infancy or childhood may not prevent the progression to end-stage renal failure (Warshaw et al., 1982).
The severity of renal dysplasia at birth depends on the timing and severity of obstruction before birth (Glick et al., 1984; Adzick et al., 1987). Experimental work suggests that relief of obstruction during the most active phase of nephrogenesis (20–30 weeks of gestation) may obviate further damage and allow normal nephrogenesis to proceed (Bronshtein et al., 1990; Patten et al., 1990; Thomas, 1990; Blyth et al., 1993). One fetus in this series evaluated at 18 weeks of gestation had a favorable prognostic profile, but because the amniotic fluid level was normal, it was not a candidate for intervention. While the sonographic appearance of the kidneys was normal at 18 weeks of gestation, postnatal sonography suggested renal dysplasia and development of chronic renal insufficiency.
The maternal morbidity of vesicoamniotic shunts was minimal, but there was a high incidence of chorioamnionitis, in 3 of 21 procedures. However, all cases of chorioamnionitis were early in this particular study experience, before the routine use of prophylactic antibiotics and during a period when long-term (4–16 hours) bladder catheterization rather than aspiration was used for fetal urine sampling (Glick et al., 1985; Crombleholme et al., 1991). Among the five open cases of fetal surgery, there was no fetal morbidity or mortality, but preterm labor was observed in each mother requiring aggressive tocolytic therapy (Crombleholme et al., 1988a).
Harrison et al. (1981a, 1981b) first proposed the concept of in utero decompression in a report of poor outcome in 13 fetuses with obstructive uropathy. This same group subsequently reported the first case of vesicoamniotic shunting for obstructive uropathy using a “Harrison” double pig-tail catheter. Other groups quickly followed suit, and in a 1986 report of the International Fetal Surgery Registry, 62 fetuses had been treated by percutaneous vesicoamniotic shunts (Manning et al., 1986). The overall survival was only 48%; the survival rate was 76% in cases due to PUVs. The procedure-related mortality rate in the registry was 3%. There were several problems with this early experience with vesicoamniotic shunts. Many fetuses were treated inappropriately prior to the development of selection criteria. Secondly, many cases were assessed by indwelling fetal bladder catheters for several hours, which along with the lack of prophylactic antibiotics, predisposed to chorioamnionitis. In addition, as noted by Glick et al. (1985), multiple shunt insertions are often necessary because of shunt occlusion, or dislodgment. Iatrogenic “gastroschisis” has also been reported when trocars used for insertion lacerated the abdominal wall during placement of vesicoamniotic shunts (Manning et al., 1986) (Figure 82-4). Rodeck has reported experience with the KCH catheter, which appears to function better than the Harrison catheter (Rodeck et al., 1988). The utility of vesicoamniotic shunts is limited, however, by the brief duration of decompression, risk of infection, catheter obstruction or dislodgment, fetal injury during placement, and potentially inadequate decompression of the fetal urinary tract. These factors make vesicoamniotic shunting inappropriate for early gestation decompression of the urinary tract. It is not clear that vesicoamniotic shunting has any benefit beyond restoring amniotic fluid volume. Both the Harrison catheter as well as the KCH catheter have a small diameter and are relatively long. According to Poiseuilles's law, very high intravesical pressures are necessary to force urine through the shunt from the bladder to the amniotic cavity. In most cases of high-grade bladder outlet obstruction, there is incompetence of the vesicoureteral junction and intravesical pressure is transmitted to the developing kidney. Despite restoring amniotic fluid volume, vesicoamniotic shunts do not completely decompress the genitourinary tract and do not protect the developing kidneys. This view is consistent with the poor long-term renal outcomes of fetuses successfully treated by vesicoamniotic shunting. Freedman et al., found that 50% of successfully treated fetuses had severely compromised growth and 55% had renal insufficiency or chronic renal failure requiring dialysis or transplantation (Freedman et al., 1999). Biard et al., reported similar growth problems but slightly better renal outcomes in PUV versus urethral atresia. Another underappreciated complication of vesicoamniotic shunts is subsequent severe bladder dysfunction, which may be sufficiently severe to preclude kidney transplantation (Biard et al., 2005).
Newborn with iatrogenic gastroschisis due to herniation of viscera through the abdominal wall defect created by attempted vesicoamniotic shunt placement. (Courtesy of Burton Harris, MD)
The presence of oligohydramnios in the second-trimester fetus with bilateral hydronephrosis due to bladder outlet obstruction is uniformly fatal if untreated (Glick et al., 1985; Crombleholme et al., 1991). Complete decompression of the genitourinary tract and elimination of high intravesical pressure can only be achieved by vesicostomy. Vesicoamniotic shunts are inadequate to completely decompress the genitourinary tract and protect the bladder and kidneys from high intravesical pressures, and Harrison et al. have reported their experience with open fetal surgery in eight cases (Crombleholme et al., 1988a, 1991; Harrison et al., 1991). Six of the eight treated were delivered by cesarean section at 32 to 35 weeks of gestation. Four of the six had restoration of amniotic fluid levels by the procedure and had no evidence of pulmonary hypoplasia. The other two fetuses died postnatally of severe pulmonary hypoplasia because of persistent oligohydramnios due to renal dysplasia. They displayed long-standing oligohydramnios prior to treatment and suffered pulmonary hypoplasia despite intervention. These cases would be excluded from treatment by current selection criteria. There were two stillbirths; one pregnancy was terminated (by parental request) because of cloacal anomaly and the other when the mother discontinued tocolytic therapy. Three of the four survivors have had no evidence of renal insufficiency during follow-up of up to 8 years. Progressive renal insufficiency developed in the fourth patient, requiring renal transplantation at 5 years of age; the child was doing well 4 years after transplantation.
Recently, Crombleholme et al. have reintroduced open fetal surgery for vesicostomy in bladder outlet obstruction due to PUVs (T. M. Crombleholme, personal oral communication, 2010) (Figure 82-5). Preliminary experience with this approach suggests that open vesicostomy successfully decompresses the genitourinary tract and preserves renal function and bladder function. No maternal complications have occurred in these patients. However, prematurity with deliveries from 29 to 35 weeks of gestation have been observed. Long-term follow-up will be necessary to accurately assess renal function and bladder function. Open fetal surgery for fetal vesicostomy to relieve bladder outlet obstruction is technically feasible and has been successful in restoring amniotic fluid dynamics and preventing death from pulmonary hypoplasia. However, this is achieved at potentially significant risk to mother and fetus in the form of preterm labor precipitated by hysterotomy. Fetal cystoscopic treatment of bladder outlet obstruction offers the appeal of a minimally invasive approach that can be performed under local anesthesia (Quintero et al., 1998; Agarwal et al., 1999). Fetal cystoscopy can be used to disrupt the valves by hydroablation, guide-wire passage, or laser ablation (Quintero et al., 1995a, 1995b, 2000; Welsh et al., 2003). Clifton et al., have recently reported success with antegrade passage of a transurethral stent, not only restoring amniotic fluid but with normal renal function out to 2 years (Clifton et al., 2008). A limitation of all fetoscopic approaches is the angulation of the posterior urethra, which increases at 20 weeks of gestation, making this approach technically more difficult.
Intraoperative photograph taken during open fetal surgery for vesicostomy creation in a 19-week gestation fetus with bladder outlet obstruction due to posterior urethral valves.
It has been recognized that there is a paucity of high-quality evidence to inform counseling and decision-making regarding fetal therapy (Clark et al., 2003). As a result, a randomized controlled trial of percutaneous shunting in lower urinary tract obstruction (PLUTO trial) is underway (funded by Wellbeing for Women). Even if shunting proves not to be efficacious, other interventions such as fetoscopic techniques and open fetal surgery will still need to be evaluated. (Lissauer et al., 2007).
A team approach is extremely helpful to inform the parents and to help them understand and cope with the diagnosis and understand the postnatal evaluation (see Figure 82-2).
Any newborn with a prenatal diagnosis of hydronephrosis should undergo a physical examination at birth. Monitoring of the urinary output within the first 24 to 48 hours is unreliable. Failure to void during the first 2 days after birth may reflect normal fluid shifts or may be the first sign of a significant urologic anomaly. In the neonate who does not void within the first 48 hours, the differential diagnosis of anuria includes obstructive uropathy, renal failure, urogenic bladder, and the effects of maternal medication. However, most patients with an obstructive process will void, albeit with a weak stream, within the first 2 days of life. Serum electrolytes, blood urea nitrogen, and creatinine levels measured within the first day of life are a reflection of maternal renal function via placental exchange. It is best to wait for 24 hours to measure these levels. The most helpful test in the initial evaluation of the newborn with prenatally diagnosed hydronephrosis is ultrasonography of the abdomen including a scan of the bladder. Timing of the ultrasonography depends on the degree of prenatal hydronephrosis. If severe dilatation of the renal pelvis has been detected antenatally, then early ultrasound evaluation should be performed so as to permit early intervention. Otherwise, ultrasound examination can be postponed for 3 to 7 days in order to let the diuresis that occurs during the first 48 hours of life to resolve (Arant, 1992). If the initial postnatal renal ultrasound is normal, the evaluation should be pursued, with a repeat ultrasound in 3 to 4 weeks. There is a high incidence (50%) of additional lesions, such as ureteropelvic junction obstruction (UPJ) and vesicoureteral reflux, diagnosed in neonates with antenatal diagnosis of hydronephrosis that have a normal upper urinary tract at the time of the first ultrasound (Detjer and Gibbons, 1989).
Mild cases of hydronephrosis can be watched and may warrant only one or two ultrasounds during the postnatal period (see Figure 82-2). It is rare for mild dilatation of the upper urinary tract to progress. In cases in which other findings are seen (such as cortical thinning, upper tract dilatation, and a normal bladder) voiding cystorurethrography (VCUG) should be performed. If there is reflux, then a renal scan with 99 technetium diethylenetriaminepentaacetic acid (DTPA) or mercaptoacetyltriglycine (MAG-3) will be helpful in documenting function within each kidney. If no evidence of reflux is noted by VCUG, then a MAG-3 scan with furosemide should be obtained to evaluate possible UPJ obstruction. If UPJ obstruction is noted, treatment is determined by the severity of the obstruction. In severe UPJ obstruction, in which a kidney shows 35% or less function, pyeloplasty should be performed. In cases in which mild-to-moderate obstruction is noted and the kidney has more than 35% function, observation alone may be indicated, with repeat ultrasonography in 3 months. A repeat renal scan will help to assess changes in renal function. As stated earlier, there is growing evidence to suggest that a mild degree of UPJ obstruction may resolve and may not warrant surgical intervention (see Chapter 81).
If prenatal ultrasound reveals a multicystic dysplastic kidney, a VCUG and renal scan should be obtained. These studies confirm the lack of function in the affected kidney and rule out any abnormalities in the contralateral kidney (Flack and Bellinger, 1993).
Surgical intervention at birth is required in cases when a severe obstruction will jeopardize renal function. This applies most often to cases of PUVs, obstructing ureterocele, and severe UPJ obstruction affecting a solitary kidney. Emergency surgical treatment is seldom warranted. Reconstruction of the urinary tract should not be attempted until the newborn has stabilized from a medical standpoint and has been fully evaluated. Drainage of the urinary tract can provide decompression by placement of either a urethral catheter, suprapubic catheter, or a nephrostomy tube until definitive repair of the urinary tract can be accomplished.
PUVs and obstructing ureterocele are amenable to early endoscopic treatment but may require further surgical intervention once the child has stabilized and grown. In the presence of a solitary kidney, every attempt should be made to ensure adequate drainage so as to not further jeopardize renal function.
Reports in the urologic literature in the late 1970s and early 1980s reviewing experience with PUVs in newborns were notable for the lack of respiratory problems encountered. In contrast, Nakayama et al. (1986) reported 11 cases of PUVs, clinically evident at birth, in which five of the infants died. Three died within hours of birth as a result of respiratory insufficiency and two survived their respiratory insufficiency only to die from renal failure within 3 weeks. Of the six survivors, four had severe respiratory problems requiring prolonged ventilatory support. In addition to the two infants who died early from renal failure, three others developed renal failure despite urinary diversion. Only two of the patients in this series had normal renal function after reconstruction of their urinary tracts.
Clinical experience suggests that the pulmonary and renal consequences of bladder obstruction will vary with the severity of the obstruction. The degree of obstruction will determine the volume of amniotic fluid, the extent of pulmonary hypoplasia, and the dysplastic effects of obstruction on the developing kidney. High-grade bladder outlet obstruction causes megacystis, bilateral hydronephrosis, and oligohydramnios, which results in pulmonary hypoplasia and postnatal respiratory insufficiency. In addition to pulmonary hypoplasia and renal dysplasia, fetal urethral obstruction produces a wide variety of deformations, including Potter facies, limb abnormalities such as clubfoot and hip dislocation, and abnormal abdominal wall muscular development (prune belly). Less severe obstruction may permit enough urine output to allow sufficient pulmonary development for survival. Despite adequate pulmonary development for survival, partial high-grade obstruction may result in renal dysplasia, bladder dysfunction, and irreversible renal failure. Milder forms of obstruction may have normal pulmonary development and mild renal insufficiency or normal renal function. This broad spectrum of severity of fetal obstructive uropathy presents a diagnostic and therapeutic challenge: which cases are severe enough to warrant prenatal intervention, which should be delivered early to prevent ongoing renal damage, and which are best managed postnatally at term?
Freedman et al. (1987) have reported on the long-term outcome of 14 patients who underwent vesicoamniotic shunting for obstructive uropathy. This was a mixed group of patients, with seven cases of prune belly, four cases of PUVs, and one case each of urethral atresia, megacystis–microcolon syndrome, and bilateral vesicoureteral reflux. Growth was observed to be below the 5th percentile in 7 and below the 25th percentile in 12. Four of the patients required ventilatory support at birth; two required it for up to a month. Two children had reactive airway disease and four had chronic bronchitis. Eight of the fourteen void spontaneously, four catheterize in addition to voiding, and the remaining two catheterize only. Bladder augmentation was required in three of the four patients with PUVs. Renal function was normal in six, renal insufficiency in three, and the remaining five had end-stage renal disease and had undergone renal transplantation. Biard et al., reported only slightly better outcomes in the setting of PUVs (Biard et al., 2005).
Sexual function may be impaired because of a much higher incidence of undescended testes, impaired ejaculatory mechanism, and effects of renal failure on potency. The incidence of undescended testes is 12% in patients with PUVs as compared with 0.8% in the normal population (Kruegar et al., 1980). Woodhouse et al. (1989) reported that half of 21 adult patients aged 19 to 37 years with PUVs had dry, slow, or retrograde ejaculations. In addition, one patient had poor erections and another was impotent as a result of renal failure and dialysis. Despite these problems, semen analysis revealed all to be potentially fertile, and 3 of the 21 had fathered children.
GENETICS AND RECURRENCE RISK
In most cases, bladder outlet obstruction due to PUVs is a sporadic event, with no risk of recurrence. However, if associated with chromosomal abnormality, there may be an increased risk of having an affected fetus, depending on the nature of the abnormality. The megacystis–microcolon–intestinal hypoperistalsis syndrome is a rare cause of bladder outlet obstruction that may be difficult to distinguish from other causes. This is an important distinction, as this syndrome has an autosomal recessive inheritance pattern with a 25% risk of affecting a subsequent pregnancy.
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