Address correspondence to Luanna Lettieri, MD, University of Connecticut Health Center, Department Obstetrics and Gynecology, Division Maternal-Fetal Medicine, 263 Farmington Avenue, Room C-2165, Farmington, CT 06030 Ph: 203-679-3267; Fax: 203-679-1271

Synonyms: Cystic fibrosis, mucoviscidosis, fibrocystic disease of pancreas.

Definition: Autosomal recessive disorder involving the dysfunction of all exocrine glands.

Prevalence: 5:10,000 caucasian live births; gene frequency among caucasian: 2%, carrier rate: 4%, less frequent among blacks and asians. M1:F1.

Etiology: Mutation in the long arm of chromosome 7.

Pathogenesis: Abnormal mucous secretion, particularly in the lungs and gastrointestinal system due to deficiency of the transport mechanism of chloride. Electrolyte abnormalities are common.

Associated anomalies: Meconium ileus is present at birth in 10-15%.

Differential diagnosis: Non-immune hydrops, ascites secondary to small bowel obstruction and perforation, urinary ascites, congenital intrauterine viral infection (e.g. CMV), upper lymphatic obstruction.

Prognosis: 50% survival to mid - 20"s.

Recurrence risk: 25% for each subsequent child.

Management: Prenatal: Prenatal diagnosis by gene mapping and linkage is possible¹. Postnatal: Comprehensive management plan including aggressive use of antibiotics, chest physiotherapy and nutritional supplementation including pancreatic enzymes.

MESH Cystic Fibrosis BDE 0237 MIM 219700 POS 3792 ICD9 2770 CDC 277.010

Introduction

Cystic fibrosis is the most common lethal genetic disorder affecting caucasians. Gastrointestinal complications are common, often occur in utero, and their manifestations (i.e., meconium ileus and meconium peritonitis) can be identified sonographically. We report the prenatal manifestations of cystic fibrosis in both fetuses of a twin pregnancy. To our knowledge, this is the earliest example (13 weeks gestation) of meconium peritonitis secondary to cystic fibrosis discovered in utero.

Case report

A 30-year-old caucasian woman with a twin pregnancy conceived by intrauterine insemination with donor sperm was referred to our antenatal evaluation unit. Ascites in twin B had been initially detected at 13 weeks gestation. Her medical and family history were negative.

At our initial ultrasound examination, measurements of both fetuses confirmed the gestational age. Twin A appeared structurally normal but had polyhydramnios. Twin B had minimal ascites and an abdominal cyst with calcifications along the peritoneum and small bowel (fig. 1, Table 1).

There was no evidence of skin edema or pleural or pericardial effusion. Oligohydramnios was present. These findings suggested meconium peritonitis with a meconium pseudocyst versus an intrauterine congenital infection. A monochorionic gestation was suspected because of identical sex, single placenta and thin dividing membrane. An amniocentesis was performed for amniotic fluid alpha-fetoprotein, chromosomes and cytomegalovirus (CMV). Both fetuses had normal amniotic fluid alpha FP and normal female karyotype. Maternal TORCH titers and amniotic fluid CMV cultures were negative.

By 22 weeks gestation, twin A had oligohydramnios with no other apparent pathology. Twin B now had polyhydramnios with significant ascites and a rim of calcifications along the peritoneal edge. Small bowel calcifications were also present. A 32% discordance was noted between the estimated fetal weight (EFW) of the twins, raising the possibility of a twin-twin transfusion syndrome.

Due to concerns that the ascites could cause sufficient compression of the lung tissue to result in pulmonary hypoplasia, a paracentesis was performed on twin B. Eighty milliliters of amber fluid were removed (fig 2-3).

Because of the ultrasound picture of meconium peritonitis, coupled with normal chromosomes and negative results for congenital infection, cystic fibrosis was suspected despite the negative family history. A sample of the ascitic fluid was sent for cystic fibrosis testing. The cystic fibrosis screen was positive with 2 different mutations present: DF508 and G542X. Subsequent testing of amniotic fluid from twin A also indicated that she had cystic fibrosis. Due to increasing ascites and polyhydramnios, a repeat therapeutic paracentesis with removal of 60 cc"s of ascitic fluid and a therapeutic amniocentesis with removal of 80 cc"s of amniotic fluid were performed on twin B at 25 weeks (fig. 4-5).

By 28 weeks gestation, twin A began to have areas of increased echogenicity in the abdominal cavity consistent with a meconium ileus. The amniotic fluid volume was normal at this point. Twin B had decreasing ascites with peritoneal–small bowel calcifications and normal amniotic fluid.

At 30 weeks, twin A exhibited a dilated stomach bubble, intraabdominal echogenicities and normal amniotic fluid (fig 6).

Twin B had only a small amount of ascites, normal amniotic fluid and peritoneal calcifications. The estimated fetal weight discordance was 27%. At 33 weeks gestation the discordance was 23%. Twin A had polyhydramnios and multiple loops of dilated small bowel that were initially suggestive of a double-bubble sign (duodenal atresia). Twin B no longer had ascites, but did have dilated loops of bowel and severe oligohydramnios.

Table 1: Clinical and sonographic evolution

Postnatal course

Twin A weighed 1460g with Apgars of 8 and 8. She was clinically diagnosed with duodenal atresia and underwent corrective surgery, at which time a proximal jejunal atresia was found and repaired. The intestinal atresia was felt to be secondary to the cystic fibrosis. Twin B weighed 1780g with Apgars of 8 and 9 and had radiographic confirmation of a small bowel obstruction. Conservative therapy with enemas did not relieve the obstruction. Therefore, an exploratory laparotomy was performed which revealed a bowel perforation in addition to a small bowel obstruction and signs of a long-standing peritonitis. Hematologic studies were consistent with a twin-twin transfusion syndrome. Histologic examination of the placenta revealed a diamniotic, monochorionic placentation and multiple vascular anastomoses indicative of a twin-twin transfusion syndrome.

Discussion

Prevalence

Cystic fibrosis, an autosomal recessive disorder of abnormal mucous secretion, is the most common lethal genetic disorder in caucasians, with a carrier rate of 4%. Most of the newly diagnosed patients, however, do not have an affected relative and therefore are not known to be at risk.

Diagnosis

Fetal gastrointestinal complications, in particular meconium ileus and meconium peritonitis, are the earliest manifestations of cystic fibrosis². These gastrointestinal complications can be detected by ultrasound, thus suggesting the diagnosis of cystic fibrosis, even in the absence of a positive family history.

In our case, twin B developed a meconium ileus early in the second trimester with subsequent perforation and development of meconium peritonitis which was observed on ultrasound at 13 weeks gestation. Meconium ileus has most often been reported in the literature as being diagnosed after 26 weeks gestation, although Papp reported a case at 15 weeks². Meconium peritonitis secondary to cystic fibrosis has not been previously reported as early as 13 weeks³. Interestingly, twin A was diagnosed with cystic fibrosis before she developed sonographically identifiable signs of meconium ileus.

Complications

Neonates with cystic fibrosis often present with signs of a bowel obstruction.

Meconium ileus, a form of bowel obstruction caused by the abnormally thick and tenacious meconium characteristic of cystic fibrosis, occurs in 10-15% of patients with cystic fibrosis⁴. Conversely, almost all patients with meconium ileus have cystic fibrosis. Meconium ileus is the third most common cause of neonatal bowel obstruction, with atresia and malrotation being first and second, respectively. The meconium in cystic fibrosis patients contains less water and more protein than normal and therefore tends to become impacted in the distal ileum, resulting in a dilated ileum with a normal jejunum and an empty colon. The characteristic ultrasound findings include dilated bowel with echogenic meconium. Polyhydramnios often occurs. Due to the decreased water content, the meconium in cystic fibrosis is unusually echogenic. However, echogenic abdominal masses in fetuses prior to 20 weeks gestation may represent a normal variant in small bowel appearance^5. Persistence of the echogenicities, however, is pathologic and may imply gastrointestinal pathology. It has been suggested that virtually all fetuses with cystic fibrosis develop meconium ileus with varying degrees of severity and duration⁶. The diagnosis is usually made after 26 weeks gestation, and 50% will develop other gastrointestinal complications such as volvulus, atresia, bowel perforation or meconium peritonitis.

Meconium peritonitis is a chemical peritonitis resulting from intraperitoneal leakage of meconium and digestive enzymes secondary to a bowel perforation in utero. In contrast to meconium ileus, only 25-40% of meconium peritonitis is secondary to cystic fibrosis⁷. Foster et al⁸ however reviewed 19 cases of meconium peritonitis prenatally detected and found that only 10% of the patients actually had cystic fibrosis. They concluded, therefore, that prenatally diagnosed cases of meconium peritonitis may be less frequently associated with cystic fibrosis than previously suggested. The peritonitis is sterile but causes an intense inflammatory reaction which can actually seal the perforation spontaneously. As the inflammation progresses, calcifications begin to occur. The ultrasound findings are variable and depend, in part, on the extent of the perforation and the resultant inflammation. Typical ultrasound findings include peritoneal calcifications (most common), meconium pseudocyst, ascites, bowel dilatation and polyhydramnios. The peritoneal calcifications are usually linear and occur at the peritoneal edge.

The meconium pseudocyst is actually a walled-off mass surrounded by a rim of calcification which can be visualized by ultrasound. The development of ascites is due to the intense inflammation, and bowel dilatation is the result of the obstructive process. Polyhydramnios presumably occurs secondary to impaired fetal swallowing.

Prenatal diagnosis

The cystic fibrosis gene and its major mutations have recently been identified. Prior to this identification, prenatal diagnosis was made by DNA analysis with either haplotype or linkage analysis or by intestinal microvillar enzyme activity. The major cystic fibrosis mutation is the DF508 which accounts for 76% of the mutations known to occur in North American caucasian cystic fibrosis patients. At least 130 additional mutations have been identified. Most centers screen between 6-12 of the most frequent mutations, and these identify approximately 85% of cystic fibrosis cases in caucasians. It is important to realize that at least 15% of caucasian and a higher percentage of noncaucasian cystic fibrosis patients will not be identified by gene mutation and therefore will need further testing with alternative methods. Linkage analysis of tightly linked markers, in addition to haplotype analysis can also be utilized. Analysis of intestinal microvillar enzymes in the amniotic fluid can be used for diagnosis. Reduced levels of intestinal enzyme activity are found in cystic fibrosis patients⁶. Low levels can also be found in patients with a chromosomal abnormality and rarely, in normal patients. The enzyme activity is gestational age dependent and the reliability of the test is optimal at 17-18 weeks gestation. The false positive rate can be as high as 4-6%, therefore the test is better utilized in pregnancies at high risk for cystic fibrosis, rather than as a screening tool. After birth, traditional methods such as the sweat test can be performed if necessary in order to make a definitive diagnosis.

Conclusions

Our case posed an interesting diagnostic dilemma for a variety of reasons–the early presentation of GI complications of cystic fibrosis, coupled with the negative family history and the additional pathology of a twin-twin transfusion syndrome. The changing dynamics in the amniotic fluid volumes can be explained by the interaction between the two pathologies, the cystic fibrosis and the twin-twin transfusion syndrome. This case also indicates that meconium peritonitis can occur as early as 13 weeks gestation, can be detected by ultrasound and can represent early manifestations of cystic fibrosis.

References

1. McKusick V: Mendelian inheritance in man. 9th edition. John Hopkins Univ Press 1990. p1120.

2. Shepherd RW, Cleghorn GJ: Cystic Fibrosis: Nutritional and Intestinal Disorders, Boca Raton, Fla, CRC Press, 1989, p 76.

3. Papp Z, Toth Z, Szabo M, et al.: Early prenatal diagnosis of cystic fibrosis by ultrasound. Clin Genet 28: 356-358, 1985.

4. Leonidas JC, Berdon WE, Baker DH, et al.: Meconium ileus and its complications: A reappraisal of plain film diagnostic criteria. AJR 108:598-609, 1970.

5. Fakhry J, Reiser M, Shapiro LR, et al.: Increased echogenicity in the lower fetal abdomen: a common normal variant in the second trimester. J Ultrasound Med 5:489-492, 1986.

6. Muller F, Aubry MC, Gasser B, et al.: Prenatal diagnosis of cystic fibrosis II. Meconium ileus in affected fetuses. Prenat Diagn 5:109-117, 1985.

7. Park RW, Grand RJ: Gastrointestinal manifestations of cystic fibrosis: A review. Gastroenterology 81:1143-61, 1981.

8. Foster MA, Nyberg DA, Mahony BS, et al: Meconium peritonitis: prenatal sonographic findings and their clinical significance. Radiology 165:661-5, 1987.