Figure 4: Polyacrylamide electrophoresis of polymerase
chain reaction products derived from oligonucleotide primers bracketing
the location of the D-F-508 mutation. The left and right outside
lanes contain size standards. The second and third lanes (from the
left) and the third and fourth lanes are products derived from controls
that are heterozygous and homozygous (respectively) for the mutation.
The fifth and sixth lanes are products derived from the fetal DNA,
while the seventh and eighth are from a normal control. Note that
the fetal products have a migration and distribution identical to that of the homozygous (affected) control.
The neonatal course was marked by necrotizing enterocolitis, which was medically treated. The infant progressed to oral feedings and was discharged home in stable condition, but the child was subsequently lost to follow-up.
Meconium peritonitis is a rare condition. Among neonates, the frequency is given as 1 in 35,000. Since some cases occurring in utero may resolve or may be clinically inapparent at delivery, the actual frequency may be higher1. The diagnosis was reported by radiography in 19442. Prenatal sonographic diagnosis was first described in 1980, and subsequently, a number of additional cases have been described, including several in which meconium pseudocysts were identified3-7. All of the cases were diagnosed after 24 weeks" gestation.
Meconium peritonitis occurs when in utero bowel perforation from any cause results in leakage of meconium into the peritoneal cavity. A remarkable case in which leakage was actually observed during an ultrasound examination was recently reported4; these authors described the flowing meconium to have "a high affinity to the surface of the liver and to the part of the umbilical vein which passed freely through the ascitesâ€. A sterile inflammatory reaction follows meconium contamination of the peritoneal cavity. In some cases, calcification results; in others, pseudocyst formation follows.
The causes of meconium peritonitis include bowel obstruction due to stricture, atresia, volvulus, intussusception, and meconium plug syndrome from cystic fibrosis8. In cases diagnosed after delivery, cystic fibrosis is the most frequent cause and is present in 40% of cases1.
Cystic fibrosis is an autosomal recessive disorder that affects multiple organs. The molecular defect is still not well understood, but it produces a dysfunction of the exocrine glands, resulting in excessive sodium and chloride excretion in sweat glands and from other epithelial surfaces9. In cystic fibrosis, the viscosity of mucus secreted by the intestinal tract is markedly increased. It clings to the intestinal wall and is difficult to move. Inspissated and impacted meconium can fill the intestine, particularly the distal ileum. This produces intestinal obstruction - "meconium ileusâ€.
Perforation of the intestine in utero is uncommon even in cystic fibrosis. Ninety percent of babies with meconium ileus have cystic fibrosis; 10-15% of babies with cystic fibrosis present with meconium ileus10.
The differential diagnosis at the time of prenatal sonographic evaluation includes other causes of ascites. Acites with intra-abdominal calcification also raises the possibility of congenital infection with cytomegalovirus or toxoplasmosis. Meconium pseudocyst must be differentiated from other intra-abdominal cysts and masses, including ovarian, urachal, mesenteric, omental, and retroperitoneal cysts, hematometrocolpos, and the extremely rare intra-abdominal tumors11.
Association with cystic fibrosis
In their review of 19 cases reported between 1980 and 1987, and seven newly diagnosed cases, Foster and associates7 noted that the rate of cystic fibrosis in cases diagnosed in utero was lower than that in postnatal series. They also made the observation that cases with calcification were unlikely to be of cystic fibrosis: "To date, no infant with sonographically detectable peritoneal calcification has proved to have cystic fibrosis, although such cases will undoubtedly be reported in futureâ€ 7.
The first step in evaluation of the fetus with ascites and suspected meconium peritonitis is a careful survey of other aspects of fetal anatomy. If no other anomalies are identified, and the fetus is not hydropic, testing of maternal blood for antibodies to red cell determinants, cytomegalovirus, and toxoplasmosis is indicated. DNA testing now affords the possibility of making the rapid and firm diagnosis of cystic fibrosis in utero in the majority of patients of Northern European ancestry.
Cystic fibrosis trait is localized on the long arm of chromosome 7. The cystic fibrosis gene codes for a protein called cystic fibrosis transmembrane regulator (CFTR). It inserts into the cell membrane and is believed to function as an anion pump regulator. The most common gene mutation results in a deletion of phenylalanine amino acid 508, within one of the ATP binding sites. This mutation, D-F-508, accounts for approximately 70% of all cystic fibrosis genes in Caucasians in North America. There are more than 50 less common mutations of the gene which account for the remainder of cystic fibrosis cases. D-F-508 allele testing can be performed from specimens obtained by chorionic villus sampling, amniocentesis, or fetal or neonatal blood12-15.
There is a paucity of information regarding the natural history of meconium peritonitis, with or without pseudocyst formation, diagnosed in utero. Therapy is empiric. Since some cases improve and may even resolve in utero, most authors recommend expectant management, unless the fetus develops rapidly progressive ascites or other signs of compromise8.
In the neonate with meconium peritonitis, the perforation may either have sealed off completely in utero, may seal off in the neonatal period, or may require surgical repair. Prior to labor, meconium is sterile, so that perforation does not translate into bacterial contamination. However, this can occur after delivery. Treatment consists of elimination of the obstructing meconium and evaluation of the gastrointestinal tract for continued leakage; continued leakage would be an indication for surgical repair.
Necrotizing enterocolitis, to our knowledge, has not been previously reported in meconium ileus, perforation in meconium ileus or in perforation in cystic fibrosis. The occurrence of necrotizing enterocolitis, however, is consistent with the risk factors of compromised intestinal function and prematurity.
1. Foster M, Nyberg D, Mahony B, et al: Meconium peritonitis: prenatal sonographic findings and their clinical significance. Radiology 165:661-5, 1987.
2. Neuhauser EBD: The roentgen diagnosis of fetal meconium peritonitis. AJR 51:421, 1944.
3. Fleischer A, Davis R, Campbell L: Sonographic detection of a meconium-containing mass in a fetus: a case report. JCU 11:103-5, 1983.
4. Chalubinski K., Deutinger J., Bernaschek G. Meconium peritonitis: extrusion of meconium and different sonographical appearances in relation to the stage of the disease. Prenat Diagn 12:631-6, 1992.
5. Lauler J, Cradock T. Meconium pseudocyst: prenatal sonographic and antenatal radiologic correlation. J Ultrasound Med 1:333-5, 1982.
6. McGahan J, Hanson F. Meconium peritonitis with accompanying pseudocyst: prenatal sonographic diagnosis. Radiology 148:125-6, 1983.
7. Fleischer A, David R, Campbell L. Sonographic detection of a meconium-containing mass in a fetus: a case report. JCU 11:103-5, 1983.
8. Romero R, Pilu G, Jeanty P, et al: Prenatal diagnosis of congenital anomalies. Norwalk: Appleton & Lange pp 243-245 1986
9. Behrman RE, ed. Cystic fibrosis. Nelson Textbook of Pediatrics, 14th Edition. Philadelphia: W.B. Saunders Co. 1992 pp 1106-1116.
10. Behrman RE, ed. Meconium ileus in cystic fibrosis. Nelson Textbook of Pediatrics, 14th Edition Philadelphia: W.B. Saunders Co, 1992 pp 475-6.
11. Nyberg DA. Intra-abdominal abnormalities. In:Nyberg DA, Mahony BS, Pretorius DH; eds. Diagnostic ultrasound of fetal anomalies: text and atlas. Chicago: Yearbook Medical Publishers, 342394, 1990.
12. Karem BS, Rommens JM, Buchanan JA, et al: Identification of the cystic fibrosis gene: genetic analysis. Science 245:1073-80, 1989.
13. Rommens JM, Kerem BS, Greer W, et al: Rapid non-radioactive detection of the major CF mutation. Am J Hum Genet 46:395-6, 1990.
14. Karem E, Lynch A. Screening for cystic fibrosis: Ethical and social issues. Am Rev Respir Dis 143:457-6, 1991.
15. Tizzano EF, Buchwald M. Cystic fibrosis: Beyond the gene to therapy. J Pediatr 120:337-49, 1992.