Meconium Disease

Genetics

In 1989, the CF locus was localized through linkage analysis to human chromosome 7q31, and it was discovered that mutations in the CF transmembrane (conductance) regulator ( CFTR ) gene result in CF. The cell membrane protein coded by CFTR is a 3′-5′-cyclic adenosine monophosphate (cAMP)-induced chloride channel, which also regulates the flow of other ions across the apical surface of epithelial cells. The alteration in CFTR results in an abnormal electrolyte content in the environment external to the apical surface of epithelial membranes. This leads to desiccation and reduced clearance of secretions from tubular structures lined by affected epithelia.

The most common mutation of the CFTR gene, F508del (previously known as ΔF508 ), is a three-base-pair deletion that results in the removal of a phenylalanine residue at amino acid position 508 of the CFTR . Although there are currently 2012 mutations listed in the CFTR database, the F508del mutation is responsible for approximately 70% of abnormal CF genes. In families with MI, there is a significantly higher occurrence rate than the expected 25% for an autosomal recessive genetic disorder according to Mendelian genetics. In one series, 79% of CF patients with the F508del mutation presented with abdominal complaints (including MI) rather than pulmonary complaints. However, there is no evidence of distinct allelic frequencies or haplotypic variants in CF patients with MI compared with those without, or in CF patients with significant liver disease.

Gastrointestinal Pathophysiology

CF is characterized by mucoviscidosis of exocrine secretions throughout the body resulting from abnormal transport of chloride ions across apical membranes of epithelial cells via calcium-activated chloride channels. The role of intracellular Ca ²⁺ concentration on these channels may impact the pathophysiology of CF. Abnormal bicarbonate transport also affects mucin formation in CF. The clinical result is chronic obstruction and infection of the respiratory tract, insufficiency of the exocrine pancreas, and elevated sweat chloride levels. Other clinical variants, such as patients with chronic sinusitis or adult males with congenital bilateral absence of the vas deferens (CBAVD), who typically have little other clinical involvement, have been described ( Fig. 32.2 ). In patients with CBAVD, the CFTR genotype usually includes at least one mild mutation not typical of CF patients. The mild-mutation allele is frequently associated with a severe mutation on the other allele, such as the F508del mutation. CBAVD has been described in a patient with F508del and G551D mutations, both of which were categorized as severe. The allele G551D is the third most common CF-associated mutation, and patients affected by this mutation may have pancreatic insufficiency, pulmonary symptoms, and an episode of MI equivalent, indicating CBAVD may be associated with a more severe CF phenotype.

Development of both the pancreas and intestinal tract in fetuses with CF is abnormal. In patients with CF, abnormal pancreatic secretions obstruct the ductal system leading to autodigestion of the acinar cells, fatty replacement of pancreatic parenchyma, and fibrosis. Although this process begins in utero, it occurs variably over time. Regardless, pancreatic insufficiency is prevalent in young infants with CF and has a significant impact on growth and nutrition.

Pancreatic insufficiency plays a central role in the pathogenesis of MI. Congenital stenosis of the pancreatic ducts is associated with meconium-induced bowel obstruction. This is further supported by the fact that two-thirds of infants found to have CF by neonatal screening are pancreatic insufficient at birth. However, approximately 10% of patients with CF are pancreatic sufficient and tend to have a milder course. Also, pancreatic lesions are variable at birth and become more severe in CF children older than 1 year of age. This finding suggests that pancreatic insufficiency is not the leading cause of abnormal meconium in MI. It appears that a prevalence of intestinal glandular abnormalities contribute more significantly to the production of abnormal meconium ( Fig. 32.3A ). The lack of concordance between MI and the severity of pancreatic disease and the preponderance of intestinal glandular lesions implies that intraluminal intestinal factors contribute more to the development of MI than the absence of pancreatic secretions ( Fig. 32.3B ).

Abnormal intestinal motility may also contribute to the development of MI. Some patients with CF have prolonged small intestinal transit times. Also, the CFTR ion channel defect results in an exocrine secretion that is rich in sodium and chloride that can lead to further dehydration of the intraluminal contents, resulting in impaired clearance. Non-CF diseases associated with abnormal gut motility, such as Hirschsprung disease and chronic intestinal pseudo-obstruction, have been associated with MI-like disease, signifying that decreased peristalsis may allow for increased reabsorption of water thus favoring the development of abnormal meconium. One of the authors recently cared for a patient with MI and no genetic nor clinical diagnosis of CF. Although rare, this has been described.

Prenatal Diagnosis and Screening

The American College of Obstetrics and Gynecology recommends all women of reproductive age should be offered CF carrier screening. Based on the results of CF screening, the antenatal diagnosis of MI can be made in two different groups: a high-risk group and a low-risk group. In the low-risk group, the diagnosis is suspected when the sonographic appearances of MI are found on routine prenatal ultrasound (US) in a mother with a negative CF carrier screen. Sonographic findings consistent with MI in a fetus with parents who are known carriers of CF, and pregnancies subsequent to the birth of a CF-affected child, are considered high-risk. CF was associated with increased relative risk (95% CI) of 3.5 (2.5–4.9), 1.6 (1.1–2.4), 3.0 (2.2–4.0), and 6.8 (1.7–26.5) for low birth weight (LBW) neonates, small-for-gestational-age (SGA) neonates, preterm birth, and infant death, respectively. Parents of a child with CF are considered to be obligate carriers of a CF mutation.

An algorithm has been established that may be useful in decision making and management of the fetus suspected of having MI ( Fig. 32.4 ). The algorithm has been updated to include newer recommendations discussed below. If both parents are carriers, evaluation of the fetus should be made by chorionic villus sampling or amniocentesis. In a pregnancy where CF is suspected, sonographic examinations are performed monthly until delivery. This evaluation allows the early detection of potential complications and prepares the clinicians for special or urgent medical or surgical needs on delivery.

Recently, the Society of Obstetricians and Gynecologists of Canada (SOGC) – Canadian College of Medical Geneticists (CCMG) guidelines were updated to recommend offering women and their partners the ability to obtain appropriate genetic carrier screening information and possible diagnosis of genetic disorders preferably preconception. This would allow for an informed choice regarding genetic carrier screening and reproductive options (e.g., prenatal diagnosis, preimplantation genetic diagnosis, egg or sperm donation, or adoption). The Joint SOGC–CCMG opinion stated that preconception or prenatal education and counseling for reproductive carrier screening requires a discussion about testing within the three perinatal genetic carrier screening/diagnosis time periods including preconception, prenatal, and neonatal for conditions currently being screened for and diagnosed. This new information should be added to the standard reproductive carrier screening protocols that are already being utilized to the maternity provider through the informed consent process with the patient.

Sonographic Evaluation

Sonographic characteristics associated with MI include a hyperechoic, intra-abdominal mass (inspissated meconium) ( Fig. 32.5 ), dilated bowel, and nonvisualization of the gallbladder. Normal fetal meconium, when visualized in the second and third trimesters, is usually hypoechoic or isoechoic to adjacent abdominal structures. The sensitivity of intra-abdominal echogenic masses in the detection of MI/CF is reported to be between 30% and 70%. In addition to MI, hyperechoic bowel has been reported with Down syndrome, intrauterine growth retardation, prematurity, in utero cytomegalovirus infection, intestinal atresia, abruptio placenta, and fetal demise. The importance of hyperechoic fetal bowel is related to gestational age at detection, ascites, calcification, volume of amniotic fluid, and the presence of other fetal anomalies. The positive predictive value of hyperechoic masses in a high-risk fetus is estimated to be 52%, but is only 6.4% in the low-risk fetus. It is important to note that hyperechoic bowel has been found to be a normal variant in both the second and third trimesters.

The finding of dilated bowel on prenatal US, in association with a family history of CF, has been reported less frequently than that of hyperechoic bowel. In MI, bowel dilation is caused by obstruction from meconium, but mimics findings in midgut volvulus, congenital bands, intestinal atresia, intestinal duplication, internal hernia, meconium plug syndrome, and Hirschsprung disease. The correlation of dilated fetal bowel and MI suggests that dilated fetal bowel warrants parental testing for CF and continued sonographic surveillance of the fetus.

The inability to visualize the gallbladder on fetal US has also been associated with CF. Combined with other sonographic features, nonvisualization of the gallbladder can be useful in the prenatal detection of the disease. However, caution should be exercised in the interpretation of an absent gallbladder as the differential diagnosis also includes biliary atresia, omphalocele, diaphragmatic hernia, chromosomal abnormalities, and a normal pregnancy.

Recently magnetic resonance imaging (MRI) was compared with US and found to provide useful additional information regarding meconium distribution in the small bowel helping to clarify the level of obstruction. MRI was additionally useful in the assessment of colon and rectal contents, serving as essentially a “fetal enema.” Abnormally diminished meconium in the rectum suggested CF or combined small-bowel and colonic obstruction, information that was useful in parenteral counseling and preparation for postnatal care.

Clinical Presentation

MI is categorized as either simple or complicated. The thickened meconium begins to form in utero. As it obstructs the mid-ileum, proximal bowel dilatation and thickening along with congestion occur. Approximately one-half of these neonates present with simple uncomplicated obstruction. The remaining patients present with complications of MI, including volvulus, gangrene, atresia, and/or perforation, which may result in meconium peritonitis and giant cystic meconium peritonitis.