This condition is caused by a partial or complete blockage of the urethra. The urethra is the tube that allows the bladder to empty into the amniotic space, making it possible for the baby’s urine to maintain normal amniotic fluid levels.
What is fetal bladder obstruction (lower urinary tract obstruction, LUTO)?
Fetal urine produced by the fetal kidneys travels down the urinary tract (ureters, bladder, urethra) before exiting into the amniotic cavity (bag of waters) when the baby urinates. Occasionally, there is a blockage along the urinary tract that prevents the urine from following its normal path. If the obstruction is at the level of the exit of urine from the bladder, it is called “Fetal bladder outlet obstruction”, also known as “Lower urinary tract obstruction, or LUTO.
What are the causes of LUTO?
Obstruction of the urinary tract below the fetal bladder can have different causes. The most common cause in boys is a condition called “Posterior urethral valves”, or PUV, affecting 50-75% of cases. The word “posterior” comes from the location of the valves, in the back or the urethra (the anterior portion of the urethra is closer to the tip of the penis, the posterior portion of the urethra is closer to the bladder). The valves result from lack abnormal location of primitive urinary structures or from lack of reabsorption of tissue that normally separates the posterior from the anterior portion of the urethra during embryological development. PUV has been classified into Types I, II and III. In type I, there is a slit in the valve, through which the urine can still exit, although at the expense of increased bladder pressure. In this case, the valves function like a windsock, whereby urine may not exit easily from the bladder, but passage of a catheter after birth from the urethra into the bladder is not impeded. Type III PUV consists of diaphragm that blocks entirely the exit of urine from the bladder. Type II PUV has been debated, may represent a pinhole defect in the an absolute blockage, with no communication between the posterior and the anterior urethra. Other causes of LUTO include prune-belly syndrome (lax abdominal muscles associated with a lax bladder and urinary tract structures and narrowing of the urethra), urethral atresia (lack of communication between the anterior and posterior portions of the urethra), anterior urethral valves (blockage in the portion of the urethral closer to the tip of the penis), and obstructive ureterocele (see below). In girls, a complex malformation of the lower urinary tract, genital tract and GI tract called “cloaca” may be particularly prevalent. Distension of the urinary tract may also be due to non-obstructive causes such as megalourethra (distended urethra in boys due to absence of a muscle layer in the penis) and megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) (a genetic defect that affects the muscles of the lower GI tract and urinary tract).
Can the cause of LUTO be genetic?
Most cases of LUTO are sporadic (occur by chance) and are not associated with a genetic abnormality. However, LUTO can be seen in fetuses with chromosomal abnormalities (trisomy-21, trisomy-13, 47, XXY) in approximately 10% of cases. Specific gene disorders may also be associated with LUTO, despite having a normal karyotype. The assessment of fetuses with LUTO therefore involves ruling out both chromosomal and genetic abnormalities.
How is LUTO diagnosed?
Obstruction of the urinary tract can be diagnosed with ultrasound. Typically, the obstruction is present from early on during the development of the fetus. Because fetal urine begins to be produced in the latter part of the first trimester, a distended bladder can be seen even at the 11-13 6/7 scan. Most patients can be diagnosed before 20 weeks by ultrasound, by noting a distended fetal bladder. Blockage below the level of the bladder at the level of the posterior urethra can also show a distended posterior urethra, which on ultrasound appears like a “key-hole sign”. Blockage of the bladder may also produce distension of the ureters (hydroureters) and of the collecting area of the kidneys (pyelectasis or hydronephrosis, depending on the degree of distension). Thus, for example, a fetus affected by LUTO from PUV may show hydronephrosis, hydroureters, a distended bladder (megacystis) and a “key-hole sign.” However, obstruction of the bladder does not necessarily produce hydroureters or hydronephrosis. So the absence of hydronephrosis or hydroureters does not eliminate the diagnosis of LUTO.
If the bladder obstruction is complete, the amniotic fluid will decrease progressively, until there is virtually no fluid around the baby (anhydramnios). If the obstruction is incomplete, there may be variable degrees of decreased fluid (oligohydramnios). In some cases, the bladder is distended, but the amniotic fluid volume is normal. These cases may represent a “lazy” bladder due to different genetic conditions, and may not carry the same adverse effects as with complete bladder obstruction. In other cases, it represents type I PUVs, with incomplete obstruction of the urethra. The distinction between these two entities (“lazy bladder” vs. type I PUV) both of which may present with a distended bladder and normal amniotic fluid volume, may not be easily done by ultrasound, except that in PUVs a “key-hole sign” is more likely to be present than in a “lazy bladder” condition.
What are the consequences of LUTO?
Urinary consequences. Blockage of the exit of urine into the amniotic cavity below the bladder causes the bladder to become distended. This can be diagnosed with ultrasound by noting an excessively large bladder. Sometimes the bladder muscle (the bladder is mostly muscle) is weak, and the bladder distends massively, reaching the chest of the fetus. At other times, the bladder muscle is strong and, as it tries to overcome the obstruction, becomes thickened, such that the bladder distension is less marked. The blockage increases the pressure within the urinary tract, which may damage the fetal kidneys to a variable degree, including total kidney damage (renal dysplasia).
Pulmonary consequences of LUTO. The fetal lungs are also affected by LUTO. Because the fetus cannot urinate, the amniotic cavity (bag of waters) dries up and the baby no longer has the cushioning of fluid around its body. The fetal lungs therefore become compressed by the reduced space, such that their development can be affected or totally arrested. Because the fetus does not need its lungs to live while in the womb, the adverse effect is not seen before birth. However, when the baby is born, it needs its lungs to breathe. If the lungs did not develop in the womb because of the lack of fluid around the baby, the baby may not be able to deliver enough oxygen to its body and not survive.
Can obstruction of the urinary tract occur elsewhere?
Obstruction at other levels of the urinary tract (for example, at the level of the junction of the kidneys with the ureters or at the junction of the ureters and the bladder) may also occur. In most cases, the obstruction does not affect both sides (right and left). Therefore, obstruction of only one side still allows urine produced on the other side to exit into the amniotic cavity. Bilateral obstruction (obstruction of both sides) prevents normal exit of urine form the urinary tract, resulting in oligohydramnios or anhydramnios. Occasionally, obstruction of one ureter can block the urethra (obstructive ureterocele). This is typically the result of the presence of a “third” ureter, arising from rogue kidney tissue that is not normally communicated with the rest of the urinary tract. In those cases, the obstruction, although coming from only one side, behaves in the same way as any other form of LUTO.
What is the prognosis of fetuses diagnosed with LUTO?
The prognosis of fetuses affected by LUTO will depend both on the effect of LUTO on the fetal kidneys and lungs as well as on the underlying cause. For example, regardless of the cause, if the blockage causes complete damage of the kidneys and anhydramnios, the baby may not survive either from lack of kidney function or from respiratory failure. On the other hand, if damage to the kidneys is not complete and lung development is not impaired, the ultimate outcome may depend more on the underlying disease. Untreated antenatally, LUTO may result in neonatal death in approximately 90% of cases.
Can LUTO be treated before birth?
Because the likelihood of neonatal death is so high in fetuses affected with LUTO, investigators sought to find ways to treat fetuses affected with LUTO since the early 1980’s by deriving the fetal urine into the amniotic fluid bypassing the obstruction. Under ultrasound guidance, a shunt (“double pig-tail plastic tubing, catheter) was placed with one of the pigtails inside the fetal bladder and the other pigtail outside in the fetal skin (shunt between the bladder – vesico – and the amniotic fluid, or vesicoamniotic shunt, VAS). With this treatment, approximately 50% of fetuses could survive, although the quality of the function of the kidneys varied in the different cases. Unfortunately, the shunt would malfunction in up to 60% of patients, which required repeating the procedure as many times during the pregnancy as necessary to keep the bladder drained. Because of the high failure rate of the VAS procedure, some investigators proposed performing open fetal surgery to surgically connect the fetal bladder with the fetal skin. This approach never gained support given the extremely invasive nature of the procedure and the potential adverse consequences to the mother. Despite the shortcomings, a recent study showed that VAS is still a better option than no treatment. Therefore, efforts are aimed at improving the performance of VAS procedures.
Can all fetuses affected with LUTO offered antenatal treatment?
Treatment of fetuses with LUTO can be offered if the intervention is likely to make a difference. If the fetus has another underlying condition (for example a genetic abnormality) or if the kidney damage has already occurred (which is irreversible), treatment will not change the prognosis and therefore should be withheld. Therefore, to offer antenatal treatment, assessment of possible genetic causes and evaluation of the function of the fetal kidneys is first performed.
How can possible genetic causes of LUTO and function of the kidneys both be assessed in the womb?
Non-invasive methods: Ultrasound. Ultrasound may reveal other birth defects in the fetus that may suggest the presence of a chromosomal abnormality. For example, fetuses with trisomy-18 or 13 are likely to show cardiac and limb anomalies. Fetuses with trisomy-21 may also show cardiac anomalies, but in much lower rate than other chromosomal aberrations. Ultrasound may also help assess the functional status of the kidneys. If complete damage of the kidneys has occurred, the kidneys may show small bright bubbly structures on the surface and be smaller (renal dysplasia). If the kidneys only appear bright (hyperechogenic) or if there is hydronephrosis (dilatation of the collecting chamber of the kidney) ultrasound may not be able to differentiate if the kidney function is permanently damaged or not. For this, invasive testing is necessary.
Invasive methods: Genetic testing. Assessment of the genetic makeup of the fetus can be achieved from cells obtained from either fetal blood, amniotic fluid or fetal urine (in order of preference). Fetal blood may be obtained by performing a cordocentesis, whereby a needle is inserted under ultrasound guidance into the umbilical cord. Technically, this method may prove more challenging, given the small size of the umbilical cord in early gestational ages. A sample of amniotic fluid may be obtained in those cases in which there is still fluid present in the amniotic cavity. In cases of anhydramnios (total absence of amniotic fluid) an amniocentesis can obviously not be performed. A sample of urine may be obtained by inserting a needle in the fetal bladder under ultrasound guidance. This procedure is called vesicocentesis. Although the cells in the fetal urine may be difficult to grow for genetic analysis, the large volume of urine that is usually obtained during vesicocentesis increases the chance of having enough cells for the assessment. However, the lab may be unable to process cells obtained from fetal urine, such that other methods of obtaining fetal cells must be considered. Genetic testing may also be performed by obtaining a sample of the placenta. This is particularly useful in patients with an anterior placenta, in which the placenta may be in the same path as the one needed to perform the vesicocentesis. I such cases, the vesicocentesis is performed first, followed by sampling of the placenta as the needle is being removed from the uterus.
Assessment of fetal kidney function with vesicocentesis.
The fetal kidneys filter the fetal blood and remove impurities, which make up the fetal urine, while retaining electrolytes and other essential elements. The function of the fetal kidneys matures progressively during the pregnancy, particularly after 16-18 weeks. Damage to the fetal kidneys from LUTO affects their filtering function, such that, electrolytes and essential elements are lost into the urine. Thus, damaged kidneys are “salt-wasting”, and the fetal urine has a higher concentration than normal of certain elements. The elements that are tested in fetal urine obtained from a vesicocentesis and their normal cut-off values are the following:
Some authors have questioned the utility of these biochemical elements in assessing the function of the fetal kidneys. However, the analysis has included fetuses treated unsuccessfully in utero, which may not accurately reflect the predictive value of these analytes.
Assessment of fetal kidney function via cordocentesis. The function of the fetal kidneys can also be assessed by determining the blood level of a specific substance, β2-microglobulin. This protein is particularly interesting in that it is produced by the fetus but does not cross the placenta. Therefore, its assessment in fetal blood reflects only the fetal environment. Ordinarily, the fetal kidney filters all of the β2-microglobulin present in fetal blood. Therefore, impairment of the function of the fetal kidney by LUTO leads to an elevation of the level of β2-microglobulin fetal blood. An elevation of the level of β2-microglobulin in fetal blood has been correlated with renal damage demonstrable in analysis of fetal renal tissue. A value of beta 2 mg greater than 5 mg/L in fetal blood is suggestive of significant renal damage and poor postnatal prognosis.
What are the management alternatives for patients diagnosed antenatally with LUTO?
Patients diagnosed with LUTO are faced with difficult choices:
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