Genetics and Prenatal Diagnosis in Pediatric Surgery
Friday, March 6, 2009
Serious malformations occur in 1.5% of all births. For half of these children the etiology is unknown; the other half have a documented genetic or teratogenic cause. The importance of prenatal diagnosis lies in its ability to give parents several options. If there are malformations or conditions incompatible with life, the pregnancy can be terminated. If the malformation is correctable at term, surgery can take place after delivery. For some malformations, progressive adverse effects in utero may warrant consideration of early delivery or fetal surgery.
Modern obstetric care includes close monitoring during pregnancy and various prenatal screening-tests, such as alpha-fetoprotein screening and prenatal ultrasonography. Fetal ultrasonography is routinely performed around the 18th gestational week. Occasionally, there are indications for more invasive screening tests, such as chorionic villus sampling, amniocentesis, fetoscopy, fetal sampling, and percutaneous umbilical blood sampling.
Early detection of congenital defects in utero allows for both parental counseling and referral to a perinatal center where further investigation of the condition can be undertaken and monitoring of the high-risk pregnancy can be done. The perinatal center should advise when, where and how delivery will take place. Appropriate centers must have a skilled neonatal intensive care facility and pediatric surgical expertise.
Prenatal Diagnostic Studies and Tests
Chorionic Villus Sampling (CVS)
CVS allows biopsy of fetal cells for chromosomal, enzymatic or DNA analysis in the first trimester (9-12 weeks gestation). Cells are obtained by direct biopsy of chorion, either transcervically or transabdominally, preferably under ultrasound guidance The major disadvantage of this procedure is the associated 3% increased rate of spontaneous abortion. CVS is the preferred prenatal diagnostic test for many high risk conditions (i.e., cystic fibrosis, sickle cell disease, Duchenne’s dystrophy, etc.)
Alpha-Fetoprotein (AFP) Screening
AFP is one of the major proteins in fetal serum. Screening should be offered to women at 16-18 weeks of gestation. AFP in maternal serum is of fetal origin. Increased levels of AFP are found in fetuses with neural tube defects, anencephaly, Turner’s syndrome, omphalocele, sacrococcygeal teratoma, intestinal obstruction and missed abortion. Low AFP levels are observed in intrauterine growth retardation, Trisomy 18, Trisomy 21, and other conditions. However, a normal AFP level does not rule out trisomy. Women with a maternal age exceeding 35 years are at high risk for having babies with Downs Syndrome. Consequently, this group and indeed most pregnant women are now offered assay for both AFP and human chorionic gonadotropin (hCG). Human chorionic gonadotropin levels are frequently elevated in fetuses with Trisomy 21.
Amniocentesis
Amniocentesis involves sampling and analysis of amniotic fluid to detect presence of metabolic disorders and chromosomal defects. Amniocentesis can be safely performed between 12-18 weeks gestation and usually takes 14 days to obtain results. The safety of this procedure is somewhat better than CVS. The risk of miscarriage following amniocentesis is less than 1%.
Fetoscopy and Fetal Sampling
When appropriate, these procedures are performed between 15 and 21 weeks of gestation. Analysis of fetal blood can reveal many conditions including Wiskott-Aldrich syndrome, hemophilia A and B, hemoglobinopathies, alpha 1-antitrypsin deficiency, and chronic granulomatous disease. Conditions in which the genetic defect is not expressed in the amniotic fluid can be discovered by sampling from the skin and liver. Fibroblastic cell culture can be performed to reveal mosaicism. The risk of miscarriage is around 5%.
Percutaneous Umbilical Blood Sampling
Percutaneous aspiration of umbilical cord blood can be safely performed under ultrasound guidance. The blood samples can reveal hematologic abnormalities including isoimmunization. This procedure is usually done between 18 and 20 weeks of gestation. The risk of miscarriage is about 2%. Results of analysis are usually available within 2-3 days.
Prenatal Ultrasound
Sonography is the most important method of fetal screening. It is useful to determine gestational age of the fetus, single or multiple births, the amniotic fluid volume, growth in high risk pregnancies, and a significant number of fetal anomalies. Ultrasonography is the best noninvasive method for determining both functional and anatomic abnormalities in the fetus. Evaluation of amniotic fluid volume is most important. When performed in the 4th month of gestation, the finding of normal amounts of amniotic fluid suggests normal swallowing and renal function. A finding of reduced amniotic fluid volume, or no fluid at all, is a sign of impaired renal function, such as obstruction, multicystic kidneys or renal agenesis. Too much amniotic fluid (more than 2000 ml = polyhydramnios) suggests impaired fetal swallowing (neurologic abnormality, anencephali), proximal alimentary tract obstruction, or compression of the esophagus due to diaphragmatic hernia or congenital lung malformation.
Although a single ultrasound study can provide a wealth of information, serial studies over time can provide even more. Functional evaluation of kidney, heart, and lungs is considerably more accurate with repeated exams.
The heart and the great vessels are easily visualized with ultrasonography or fetal echocardiography. The dynamic function can be evaluated. The four chambers and the two great vessels should be visualized and allows the diagnosis of anomalies such as tetralogy of Fallot, tricuspid atresia, hypoplastic left heart, aortic valve stenosis/ atresia and double outlet right ventricle.
Cerebral malformations, encephaloceles, and hydrocephalus are readily identified by prenatal ultrasound. Intraabdominal structures like hepatic neoplasms (hemangioma), neuroblastoma, enteric duplications and atresias of the gut can also be detected. The differentiation of omphalocele and gastroschisis is especially important because the prognosis in omphalocele is so much worse, compared to gastroschisis, because of the serious associated anomalies and chromosomal defects.
Indications for Prenatal Diagnosis
General Risk Factors
Maternal age more than 35 years (increased risk for fetal chromosomal abnormality). Elevated or reduced serum AFP Increased serum hCG.
Specific Risk Factors
Previous still birth or neonatal death. Previous child with a structural defect or chromosomal abnormality. Structural abnormality in any of the parents. Balanced translocation in any of the parents. Inherited disorders (i.e., cystic fibrosis, metabolic disorders, sex-linked disorders) Medical disease in the mother (i.e., diabetes mellitus) Exposure to teratogens (i.e., ionizing radiation, anticonvulsant medicine, alcohol, etc.) Infections (i.e., rubella, toxoplasmosis, cytomegalovirus)
Treatment of the Fetus
Hydrops fetalis can occur secondary to isoimmunization induced hemolysis. Prenatal treatment of this condition may include erythrocyte transfusion in utero. Transplacental treatment can be administered for cardiac arrhythmias (especially supraventricular tachycardia) leading to hydrops. The most common prenatal treatment used for the fetus is steroid (i.e., glucocorticoid ) administration to increase pulmonary surfactant in the lungs of the preterm infants.
Fetal Surgery
The indication for fetal surgery is malformations that interfere with fetal organ development, which if alleviated would allow normal organogenesis. Pioneering work is now carried out in a few centers for highly selected cases; however, these procedures involve significant risks for both the mother and the fetus (i.e., infection, premature labor, etc.).
Although no large series have proven any long term benefits, work continues (and should continue at a few centers with close supervision) on the use of fetal surgery for:
Modern obstetric care includes close monitoring during pregnancy and various prenatal screening-tests, such as alpha-fetoprotein screening and prenatal ultrasonography. Fetal ultrasonography is routinely performed around the 18th gestational week. Occasionally, there are indications for more invasive screening tests, such as chorionic villus sampling, amniocentesis, fetoscopy, fetal sampling, and percutaneous umbilical blood sampling.
Early detection of congenital defects in utero allows for both parental counseling and referral to a perinatal center where further investigation of the condition can be undertaken and monitoring of the high-risk pregnancy can be done. The perinatal center should advise when, where and how delivery will take place. Appropriate centers must have a skilled neonatal intensive care facility and pediatric surgical expertise.
Prenatal Diagnostic Studies and Tests
Chorionic Villus Sampling (CVS)
CVS allows biopsy of fetal cells for chromosomal, enzymatic or DNA analysis in the first trimester (9-12 weeks gestation). Cells are obtained by direct biopsy of chorion, either transcervically or transabdominally, preferably under ultrasound guidance The major disadvantage of this procedure is the associated 3% increased rate of spontaneous abortion. CVS is the preferred prenatal diagnostic test for many high risk conditions (i.e., cystic fibrosis, sickle cell disease, Duchenne’s dystrophy, etc.)
Alpha-Fetoprotein (AFP) Screening
AFP is one of the major proteins in fetal serum. Screening should be offered to women at 16-18 weeks of gestation. AFP in maternal serum is of fetal origin. Increased levels of AFP are found in fetuses with neural tube defects, anencephaly, Turner’s syndrome, omphalocele, sacrococcygeal teratoma, intestinal obstruction and missed abortion. Low AFP levels are observed in intrauterine growth retardation, Trisomy 18, Trisomy 21, and other conditions. However, a normal AFP level does not rule out trisomy. Women with a maternal age exceeding 35 years are at high risk for having babies with Downs Syndrome. Consequently, this group and indeed most pregnant women are now offered assay for both AFP and human chorionic gonadotropin (hCG). Human chorionic gonadotropin levels are frequently elevated in fetuses with Trisomy 21.
Amniocentesis
Amniocentesis involves sampling and analysis of amniotic fluid to detect presence of metabolic disorders and chromosomal defects. Amniocentesis can be safely performed between 12-18 weeks gestation and usually takes 14 days to obtain results. The safety of this procedure is somewhat better than CVS. The risk of miscarriage following amniocentesis is less than 1%.
Fetoscopy and Fetal Sampling
When appropriate, these procedures are performed between 15 and 21 weeks of gestation. Analysis of fetal blood can reveal many conditions including Wiskott-Aldrich syndrome, hemophilia A and B, hemoglobinopathies, alpha 1-antitrypsin deficiency, and chronic granulomatous disease. Conditions in which the genetic defect is not expressed in the amniotic fluid can be discovered by sampling from the skin and liver. Fibroblastic cell culture can be performed to reveal mosaicism. The risk of miscarriage is around 5%.
Percutaneous Umbilical Blood Sampling
Percutaneous aspiration of umbilical cord blood can be safely performed under ultrasound guidance. The blood samples can reveal hematologic abnormalities including isoimmunization. This procedure is usually done between 18 and 20 weeks of gestation. The risk of miscarriage is about 2%. Results of analysis are usually available within 2-3 days.
Prenatal Ultrasound
Sonography is the most important method of fetal screening. It is useful to determine gestational age of the fetus, single or multiple births, the amniotic fluid volume, growth in high risk pregnancies, and a significant number of fetal anomalies. Ultrasonography is the best noninvasive method for determining both functional and anatomic abnormalities in the fetus. Evaluation of amniotic fluid volume is most important. When performed in the 4th month of gestation, the finding of normal amounts of amniotic fluid suggests normal swallowing and renal function. A finding of reduced amniotic fluid volume, or no fluid at all, is a sign of impaired renal function, such as obstruction, multicystic kidneys or renal agenesis. Too much amniotic fluid (more than 2000 ml = polyhydramnios) suggests impaired fetal swallowing (neurologic abnormality, anencephali), proximal alimentary tract obstruction, or compression of the esophagus due to diaphragmatic hernia or congenital lung malformation.
Although a single ultrasound study can provide a wealth of information, serial studies over time can provide even more. Functional evaluation of kidney, heart, and lungs is considerably more accurate with repeated exams.
The heart and the great vessels are easily visualized with ultrasonography or fetal echocardiography. The dynamic function can be evaluated. The four chambers and the two great vessels should be visualized and allows the diagnosis of anomalies such as tetralogy of Fallot, tricuspid atresia, hypoplastic left heart, aortic valve stenosis/ atresia and double outlet right ventricle.
Cerebral malformations, encephaloceles, and hydrocephalus are readily identified by prenatal ultrasound. Intraabdominal structures like hepatic neoplasms (hemangioma), neuroblastoma, enteric duplications and atresias of the gut can also be detected. The differentiation of omphalocele and gastroschisis is especially important because the prognosis in omphalocele is so much worse, compared to gastroschisis, because of the serious associated anomalies and chromosomal defects.
Indications for Prenatal Diagnosis
General Risk Factors
Maternal age more than 35 years (increased risk for fetal chromosomal abnormality). Elevated or reduced serum AFP Increased serum hCG.
Specific Risk Factors
Previous still birth or neonatal death. Previous child with a structural defect or chromosomal abnormality. Structural abnormality in any of the parents. Balanced translocation in any of the parents. Inherited disorders (i.e., cystic fibrosis, metabolic disorders, sex-linked disorders) Medical disease in the mother (i.e., diabetes mellitus) Exposure to teratogens (i.e., ionizing radiation, anticonvulsant medicine, alcohol, etc.) Infections (i.e., rubella, toxoplasmosis, cytomegalovirus)
Treatment of the Fetus
Hydrops fetalis can occur secondary to isoimmunization induced hemolysis. Prenatal treatment of this condition may include erythrocyte transfusion in utero. Transplacental treatment can be administered for cardiac arrhythmias (especially supraventricular tachycardia) leading to hydrops. The most common prenatal treatment used for the fetus is steroid (i.e., glucocorticoid ) administration to increase pulmonary surfactant in the lungs of the preterm infants.
Fetal Surgery
The indication for fetal surgery is malformations that interfere with fetal organ development, which if alleviated would allow normal organogenesis. Pioneering work is now carried out in a few centers for highly selected cases; however, these procedures involve significant risks for both the mother and the fetus (i.e., infection, premature labor, etc.).
Although no large series have proven any long term benefits, work continues (and should continue at a few centers with close supervision) on the use of fetal surgery for:
- vesicoamniotic shunt for severe bilateral hydronephrosis with pulmonary hypoplasia
- congenital diaphragmatic hernia with prenatal prosthetic patch repair or tracheal plugging
- lobectomy for congenital cystic adenomatoid malformation
- thoracoamniotic shunt for fetal chylothorax
- ventriculoamniotic shunt for severe obstructive hydrocephalus
- resection of sacrococcygeal teratoma to prevent cardiac failure secondary to arteriovenous fistula
- correction of critical aortic stenosis to prevent severe left ventricular hypoplasia
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