AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

Meconium ileus (MI) is among the most common causes of intestinal obstruction in the newborn, accounting for 9-33% of neonatal intestinal obstructions. MI is the earliest clinical manifestation of cystic fibrosis (CF) and occurs as either simple or complicated in approximately 16-20% of patients who have CF, although MI also occurs in patients who do not have CF. Clinically, CF is characterized by the triad of (1) chronic obstruction and infection of the respiratory tract, (2) exocrine pancreatic insufficiency, and (3) elevated sweat chloride levels.

In 1905, Landsteiner described the association between inspissated meconium in a newborn and pathologic changes in the pancreas. He speculated that an enzyme deficiency causing pancreatic fibrosis also led to abnormally thick meconium. In 1936, Fanconi was first to use the term cystic fibrosis to describe the combination of pancreatic insufficiency and chronic pulmonary disease in childhood. Anderson associated MI with CF 2 years later, noting that the histologic lesions in the pancreas were identical in both conditions.

In 1946, Glanzman was first to suggest that abnormal intestinal mucus causes inspissation of meconium. In 1952, Buchanan chemically analyzed inspissated meconium from infants with MI. A year later, Bodian attributed the abnormally viscid nature of meconium in MI to abnormal mucus secreted by the intestines of patients with CF.

A possible MI diagnosis should raise the suspicion of CF in the fetus. Antenatal diagnosis of MI can be confirmed in 2 groups. In the low-risk group, the diagnosis is suspected when routine prenatal ultrasonography reveals the sonographic appearances of MI. The high-risk group consists of all pregnancies subsequent to the birth of a child with CF. Parents of a child with CF are obligate carriers of a CF mutation.

History of the Procedure

Before 1948, the prognosis for infants with MI was uniformly poor despite surgical treatment. In that year Hiatt and Wilson of Babies & Children's Hospital of New York reported the first successful surgical management of 5 infants with MI, using intraoperative disimpaction of meconium with saline instilled into the bowel via a tube enterostomy. In 1989, Fitzgerald proposed a similar technique in which an appendectomy is performed and a cecostomy catheter is placed through the appendiceal stump to insert irrigant and to evacuate impacted meconium.

Problem

In the simple form, thickened meconium begins to form in utero. It obstructs the mid ileum, causing proximal dilatation, bowel wall thickening, and congestion.

Frequency

• MI is among of the most common causes of intestinal obstruction in newborns, accounting for 9-33% of neonatal intestinal obstructions.
• MI is the earliest clinical manifestation of CF, occurring in approximately 16-20% of patients with the condition.
• Of all operative cases of CF, 38% are due to MI.
• CF is an autosomal recessive disease; its estimated heterozygote frequency in white people is up to 1 in 20. Each offspring of 2 heterozygote parents has a 25% chance of developing CF. A family history of CF has been noted in 10-40% of new patients with MI. Allan, in a 1981 review of 488 families with at least one child with CF, reported an MI recurrence rate of 39% in families with a previously affected sibling.

Etiology

Genetic causes of cystic fibrosis

• In 1989, the CF locus was localized through linkage analysis to the long arm of human chromosome 7, band q31. The disease is caused by mutations in the gene that codes for the cell membrane protein CF transmembrane (conductance) regulator (CFTR). This protein is an adenosine 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 causes abnormal electrolyte content in the environment external to the apical surface of epithelial membranes. This leads to desiccation and reduced secretion clearance from tubular structures lined by affected epithelia.
• The most common mutation of the CFTR gene is a 3 base pair deletion that removes a phenylalanine residue at amino acid position 508 of CFTR. This is called the DF508 mutation. More than 1437 CFTR mutations have been reported to the CF Genetic Consortium, as of November 2005. About 41% (595) of these mutations are missense, and approximately 50% of individuals with CF are homozygous for DF508; another 25-30% have one copy of DF508 plus another mutation.
• Certain alleles cluster with increased frequency in specific populations. For example, W1282X is common in Ashkenazi Jewish people, and A455E is common both in Dutch people and in individuals from northern Quebec. D1152H is the third most prevalent in Ashkenazi and other ethnic Jewish groups. Past tests were only for F508del, G542X, N1303K, and 3849+10KbC>T. The prevalence of D1152 mutation in Jewish population comprises 5.2% of all CFTR mutations.
• Genotype-phenotype correlation demonstrates that DF508 homozygosity nearly always confers a pancreatic exocrine insufficiency. Individuals with 1 or 2 copies of missense mutations (eg, R117H) tend to be pancreatic sufficient and have milder disease. The incidence of MI is higher in patients who are homozygous for DF508 or who have DF508 plus G542X. Conversely, not all patients with these genotypes have MI, so other non-CFTR factors, either genetic and/or environmental, must be involved in MI pathogenesis.
• Regarding MI, no specific haplotype variant is available to determine its presence; however, 79% of the patients who have DF508 mutations presented initially with abdominal pain instead of lung problems.
• Due to the significant variability in disease presentation, evidence supports the role of modifier genes. Studies in CF model mice have shown an increase in mast cells and neutrophils as part of the immune response.
• For example, the Kitl gene plays a vital role in the differentiation of mast cells, as demonstrated by a decreased expression of Mcpt2. Another focus would be the proteins selectin and ICAM-1, which facilitate neutrophil extravasation. Neutrophils and mast cells release proteases, prostaglandins, and histamine that influence mucus production.
• The 129/Sv allelic contribution in mice yields a milder inflammatory response and was potentially linked to chromosomes 1, 9, and 10.
• The regulation of these genes and processes may help explain the range of variability in similar genetic mutations.

Pathophysiology

• Meconium in patients with MI has higher protein and lower carbohydrate concentration than that in control populations. In 1958, Green, Clarke, and Schwachman found that albumin was the major protein present in the meconium of infants with MI. The concentration of albumin is 5-10 times higher, along with a significant increase in the liver's production of intraluminal glutamyltranspeptidase (GGTP) and 5'-nucleotidase in the meconium that causes MI. Addition of albumin to normal meconium makes it viscid; addition of pancreatic protease liquefies the viscid mass. This led to the belief that pancreatic insufficiency played a central role in MI pathogenesis, although pancreatic insufficiency is not the sole cause of abnormal meconium in MI. In 1988, Lands et al reported 2 infants with CF and MI, aged 9 and 11 months, who displayed no clinical evidence of pancreatic insufficiency.
• Abnormal intestinal motility may also contribute to MI development. Some patients with CF have prolonged small intestinal transit times. Non-CF diseases associated with abnormal gut motility (eg, Hirschsprung disease, chronic intestinal pseudo-obstruction) have been associated with MI-like disease, suggesting that decreased peristalsis may allow increased resorption of water, thus favoring MI development.
• In the murine model of CF, developed in 1992, newborn mice had severe intestinal obstruction at birth with minimal pulmonary or pancreatic involvement. These animal studies support the concept that MI may occur in patients with sufficient pancreatic activity. The lack of concordance between MI and severity of pancreatic disease suggests that intraluminal intestinal factors contribute to MI development.
• Postnatally, intestinal disease is characterized by a glandular abnormality that produces hyperviscous mucus. How mutations of the CF gene generate abnormal mucins is not fully described, nor is the developmental sequence of mucin secretion in the fetal intestine, although the CFTR ion channel defect possibly leads to dehydration of intraluminal contents. The meconium of fetuses with CF and MI has increased viscosity and decreased water content compared to healthy controls.

Clinical

• Patients with simple MI usually present with abdominal distension at birth, eventually progressing to failure to pass meconium, bilious vomiting, and progressive abdominal distension. Often, examination reveals dilated loops of bowel with a doughy character that indent on palpation. The rectum and anus usually are narrow, a finding possibly misinterpreted as anal stenosis.
• Patients with complicated MI present more dramatically at birth with severe abdominal distension, sometimes accompanied by abdominal wall erythema and edema. Abdominal distension may be severe enough to cause respiratory distress. Signs of peritonitis include tenderness, abdominal wall edema, distension, and clinical evidence of sepsis. A palpable mass may indicate pseudocyst formation. Often, the neonate is in extremis and needs urgent resuscitation and surgical exploration.
• CF is characterized clinically by the following triad:
  • Chronic obstruction and infection of the respiratory tract
  • Exocrine pancreatic insufficiency
  • Elevated sweat chloride levels
• Approximately 10% of patients with CF remain pancreatic sufficient and tend to have a milder course.
• Other clinical variants have been described recently, such as adult males with bilateral absence of the vas deferens who have little other clinical involvement. Absence of the vas deferens is considered an atypical presentation of CF, and 80% of men with this presentation have at least one CFTR gene mutation. In 1995, Zielenski reported the most common of these mutations is the IVS8/5T mutation.

INDICATIONS

Section 3 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

Surgical exploration is indicated for patients with progressive distension, signs of peritonitis, or clinical deterioration.

Surgery is always indicated for complicated MI. Complicated MI requires resection more often than simple MI and always requires temporary stomas.

The following complications require surgical management:

• Persistent or worsening abdominal distension
• Persistent bowel obstruction
• Enlarging abdominal mass
• Intestinal atresia
• Volvulus
• Perforation
• Meconium cyst formation with peritonitis
• Bowel necrosis

RELEVANT ANATOMY

Section 4 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

Fetuses with CF have abnormal development of the pancreas and intestinal tract. CFTR expression can be detected in the pancreatic ductules at 18 weeks' gestation. In patients with CF, abnormal pancreatic secretions obstruct the duct system, leading to autodigestion of the acinar cells, fatty replacement, and ultimately, fibrosis. Beginning in utero, this progressive process occurs variably over time. Approximately two thirds of infants later diagnosed with CF by neonatal screening have pancreatic insufficiency at birth. Approximately 10% of patients with CF remain pancreatic sufficient and tend to have a milder course.

CONTRAINDICATIONS

Section 5 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

See Treatment.

WORKUP

Section 6 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

Lab Studies

• Immunoreactive trypsinogen (IRT) is a pancreatic enzyme that can help with diagnosing CF in neonates with MI, when IRT relative ratios are elevated greater than the 99th percentile. IRT plus sweat test increased sensitivity and specificity in screening. Only 2 had MI with a normal IRT relative ratio, supporting a false negative rate of 7%; however, when checked at days 9 and 12, the IRT relative ratio was elevated greater than the 99th percentile. IRT levels do not differentiate between simple and complicated MI (p <0.001).

Imaging Studies

• Ultrasonographic evaluation
• • Prenatal sonographic characteristics associated with MI include hyperechoic masses (ie, inspissated meconium in the terminal ileum), dilated bowel, and inability to visualize the gallbladder. Normal fetal meconium, when visualized in the second and third trimesters, usually is hypoechoic or isoechoic to adjacent abdominal structures. (Hyperechoic mass is defined as a mass with greater sonographic density than liver or bone.) The sensitivity of intra-abdominal echogenic masses for CF detection reportedly ranges from 30-70%. This finding as a sonographic marker of MI is plagued by difficulties, including subjective assessment of echogenicity and an extensive differential diagnosis.
  • In addition to MI, hyperechoic bowel may occur with Down syndrome, intrauterine growth retardation, prematurity, in utero cytomegalovirus (CMV) infection, intestinal atresias, abruptio placenta, and fetal demise. The importance of hyperechoic fetal bowel relates to gestational age at detection, ascites, calcification, volume of amniotic fluid, and presence of other fetal anomalies. Furthermore, a prenatal diagnosis of MI using the sonographic feature of hyperechoic bowel must consider the parents' a priori risk. The positive predictive value of hyperechoic masses in a high-risk fetus is estimated at 52%, while the predictive value for a low-risk fetus is just 6.4%.
  • While reviews of pregnancies with 1-in-4 risk of CF show a 25-60% association between hyperechoic bowel and CF, this association is less prevalent in the general population. In 1992, Dicke and associates reviewed 12,776 fetal ultrasounds performed after 14 weeks' gestation and noted hyperechoic bowel in 30 (0.2%) of these patients. Of these, 13.3% had CF. This team also reported a 16.7% associated risk of perinatal death, a 23.3% risk of growth retardation, and a 3.3% risk of genetic abnormality.
  • Note that hyperechoic bowel is a normal variant in both the second and third trimesters. Hyperechoic bowel, when it occurs as an isolated event early during the second trimester, may represent a normal variant and indicates the need for follow-up prenatal examinations. Although increased risk of MI and CF is associated with hyperechoic bowel, the prevalence, degree of risk, and decisions involving prenatal management remain uncertain.
  • Prenatal ultrasonographic findings of dilated bowel in association with CF have been reported less frequently than findings of hyperechoic bowel.
  • In MI, bowel dilation is caused by a meconium obstruction but mimics similar findings in the following conditions:
    • Midgut volvulus
    • Congenital bands
    • Bowel atresia
    • Intestinal duplication
    • Internal hernia
    • Meconium plug syndrome
    • Hirschsprung disease
  • However, studies that show correlation between dilated fetal bowel and MI suggest that dilated fetal bowel warrants parental testing for CF and continued sonographic surveillance of the fetus.
  • In addition to the findings of increased abdominal echogenicity and bowel dilation, the inability to visualize the gallbladder on fetal ultrasonography is associated with CF. Combined with other sonographic features, nonvisualization of the gallbladder can help detect the disease prenatally. However, exercise caution in interpreting an absent gallbladder because the differential diagnosis includes biliary atresia, omphalocele, and diaphragmatic hernia.
  • Sonographic characteristics of fetal bowel obstruction are neither sensitive nor specific for MI. In general, a rate of sonographic detection for MI or meconium peritonitis can be up to 19%. Interpretation of these sonographic findings must consider the fetus' risk of CF. While ultrasonographic findings that suggest MI in a high-risk fetus indicate a high probability of CF, similar suspicious findings in a low-risk fetus warrant consideration of DNA testing or, at the very least, serial follow-up examinations.
• Referral: Consider referral to specialized facility. When MI is diagnosed prenatally, the authors recommend immediate referral to a tertiary care facility equipped to manage the needs of the mother, fetus, neonate, and family. A multidisciplinary team of perinatologists, neonatologists, obstetricians, pediatric surgeons, and CF specialists is prepared for the delivery of these high-risk neonates. The team performs serial sonographic examinations on a monthly basis prior to delivery, a procedure that allows early detection of potential complications to prepare clinicians for special or urgent medical or surgical needs upon delivery.
• Abdominal radiography
• • In about 71% of uncomplicated MI cases, abdominal radiography reveals a characteristic pattern of unevenly dilated loops of bowel with variable air-fluid levels. Air-fluid levels may be absent because of the viscid nonliquid nature of the inspissated meconium. Bubbles of gas may become evident as air mixes with the tenacious meconium. While this soap bubble appearance (or Neuhauser sign) depends on the viscosity of the meconium and is not a constant feature, this radiographic feature is is highly suggestive of MI. Although none of these features alone is diagnostic for MI, they strongly suggest the diagnosis when combined with a family history of CF.
  • Radiologic findings in complicated MI vary, based upon the associated complication. Speckled calcification visible on abdominal plain radiography strongly suggests intrauterine intestinal perforation and meconium peritonitis. Visible obstruction and a large dense mass with a rim of calcification suggest a pseudocyst. In 1970, however, Leonidas reported no radiologic findings that suggest a complication in a third of patients with complicated MI.
  • In utero perforation can lead to meconium peritonitis or meconium pseudocyst formation; only postoperative evaluation may differentiate between CF-related and non–CF-related meconium peritonitis or meconium pseudocyst formation.

Other Tests

• When MI is suspected based on clinical and radiographic evidence, a contrast barium enema may be performed for diagnosis. One study showed a barium enema to be diagnostic in 45 (52%) patients. If MI is likely, follow the contrast enema with a therapeutic Gastrografin enema.
• • Some physicians advocate water-soluble contrast initially for both diagnosis and treatment. Controlled dilutions of Gastrografin remain the agent of choice for diagnosis and evacuation of inspissated meconium.
  • Fluoroscopically monitor contrast instillation in patients with MI to visualize a small-caliber colon (described as the microcolon of disuse), which often contains small "rabbit pellets" (ie, scybala) of meconium.
  • Progression of the contrast proximally may also outline pellets of inspissated meconium. Contrast that is successfully refluxed proximal to the obstruction allows observation of the dilated loops of small bowel.

Diagnostic Procedures

• Prenatal testing for cystic fibrosis
• • Prenatal diagnosis allows the clinician to prepare for the medical and psychological needs of the parents, fetus, and newborn before, during, and after delivery.
  • Noninvasive CFTR analysis involves a technique for recovering DNA from cells obtained by buccal brushing. This technique can determine the carrier status of the parents of a fetus with suspected CF, based on sonographic findings of MI. Although these tests are highly specific, commercial tests screen for no more than 70 of the more than 1437 CF mutations, so be cautious in interpreting a negative test result.
  • Amniocentesis can provide subsequent fetal evaluation when both parents have identified CF mutations.
  • When only one or neither parent has an identified CF mutation, but the couple has a previous child with CF, the status of the fetus can be predicted by restriction fragment length polymorphism (RFLP) analysis. Genetic material from both parents, the affected sibling, and the fetus must be available for RFLP testing. If the results predict CF in the fetus, referral to a tertiary care facility facilitates genetic counseling and consultation with specialists in maternal-fetal medicine.
  • If DNA analysis or amniocentesis tests are refused or if results are nondiagnostic, the authors recommend close sonographic follow-up at 6-week intervals.
• Postnatal diagnosis of cystic fibrosis
• • Suspect CF in patients with fetal or neonatal bowel obstruction and perform diagnostic tests as soon as possible.
  • Males with congenital bilateral absence of vas deferens (CBAVD) have been shown to possess a CFTR mutation for CF 75-80% of the time. With this condition, one may palpate the epididymis head; however, the structures derived from the Wolffian ducts under the control of the gonads, caudal epididymis, and vas deferens are absent. This anomaly may prove useful when looking for immediate support regarding a diagnosis of CF.
  • A diagnosis of CF should be confirmed or refuted by a sweat test that meets all National Committee for Clinical Laboratory Standards (NCCLS) criteria. A sweat test may be performed any time after the first 48 hours of life if the neonate is not edematous. The minimum amount of sweat needed is either 75 mg or 15 µL, a quantity that may be difficult to obtain from young infants. Never pool sweat from multiple sites to obtain the required quantity because the rate of sweating determines electrolyte content.
  • Mutation analysis, performed on buccal or on blood cells using a Guthrie card, helps confirm the diagnosis if it yields at least one known CF mutation. Refer patients with confirmed CF to a regional or satellite CF center for counseling and education about this complex chronic disease. CF center physicians can also assist postoperative management of nutritional or respiratory problems.
• To obtain a list of accredited centers, call 1-800-FIGHT CF or see the Cystic Fibrosis Foundation Web site.
  

TREATMENT

Section 7 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

Medical therapy

Manage both simple and complicated MI in newborns as an intestinal obstruction. Perform resuscitative measures, including mechanical respiratory support, if necessary. Initiate intravenous hydration with gastric decompression, evaluate and correct any coagulation disorders, and begin empiric antibiotic coverage. Immediately obtain a surgical evaluation when MI is suspected or diagnosed.

Gastrografin enemas

In 1969, Noblett introduced the use of Gastrografin enemas to treat 4 infants with MI. Variations on this approach are now the preferred initial method to treat uncomplicated MI.

Gastrografin, marketed by Bristol-Myers Squibb of Princeton, NJ, is meglumine diatrizoate, a hyperosmolar, water-soluble, radiopaque solution containing 0.1% polysorbate 80 (Tween 80) and 37% organically bound iodine. The solution's osmolarity is 1900 µOsm/L.

• The reported success rate of Gastrografin enemas for patients with uncomplicated MI is 63-83%. In a 2005 analysis, the success rate was only 35% (15 out of 42 patients) for simple MI relief, while 64.2% (27) of patients needed surgery to relieve the obstruction.
• Noblett's criteria for proceeding with this therapy require the following:
• • The initial diagnostic contrast enema must exclude other causes of neonatal distal intestinal obstruction.
  • The infant must show signs of uncomplicated MI and no clinical or radiologic evidence of complicating factors (eg, volvulus, gangrene, perforation, peritonitis, atresia of the small bowel).
  • The infant should be well prepared for the enema, with adequate fluid and electrolyte replacement and correction of hypothermia.
  • The enema must be performed under fluoroscopic control.
  • Intravenous antibiotics should be administered.
  • Close surgical supervision is imperative from the initial evaluation through the hospital course.
• The procedure is as follows:
• • Upon instillation, fluid is drawn into the intestinal lumen to hydrate and soften the meconium mass. Both transient osmotic diarrhea and diuresis follow. Adequate resuscitation and hydration in anticipation of these fluid losses is paramount.
  • Under fluoroscopic control, infuse a 25-50% solution of Gastrografin slowly at low hydrostatic pressure through a catheter inserted into the rectum. Avoid balloon inflation to minimize the risk of rectal perforation.
  • To help deconcentrate the inspissated meconium, 1% N-acetylcysteine may be added to the enema solution. The procedure requires a slow infusion, carefully monitored under fluoroscopy.
  • Upon completion, withdraw the catheter and obtain an abdominal radiograph to exclude perforation.
  • Return the infant to the neonatal care unit for intensive monitoring and fluid resuscitation.
  • To help complete the evacuation, warm saline enemas containing 1% N-acetylcysteine may be used. This procedure usually prompts rapid passage of semiliquid meconium, which continues for 24-48 hours.
  • Obtain radiographs in 8-12 hours, or as clinically indicated, to confirm evacuation of the obstruction and to exclude late perforation.
  • A second enema may be necessary for nonoperative management of MI if evacuation is incomplete or if the first attempt at Gastrografin evacuation does not reflux contrast into dilated bowel.
  • If necessary, serial Gastrografin enemas can be performed at 6- to 24-hour intervals.
  • Surgical exploration is indicated for patients with progressive distension, signs of peritonitis, or clinical deterioration.
  • Following successful evacuation and resuscitation, Noblett suggests administering a 10% N-acetylcysteine solution (5 mL q6h) through a nasogastric (NG) tube to liquefy upper GI secretions.
  • Feedings, including supplemental pancreatic enzymes for infants with confirmed CF, may be initiated when signs of obstruction have subsided, usually within 48 hours.
• Potential complications include the following:
• • Perforation
  • • Rectal perforation can be avoided by carefully placing the catheter under fluoroscopic guidance and avoiding inflating balloon-tipped catheters. In 1987, Ein and Shandling reported a 23% perforation rate in patients treated with inflated balloon catheters.
    • Early perforation that occurs during enema administration is usually apparent under fluoroscopy. Perforation risk increases with repeated enemas.
    • Late perforation can occur 12-48 hours after the enema. Potential causes include severe bowel distension by fluid osmotically drawn into the intestine (the apparent etiology in experimental models) or by direct injury to the bowel mucosa by the contrast medium.
    • Delayed perforation associated with extensive bowel necrosis has been reported. The pathogenesis of intestinal perforation associated with necrotizing enterocolitis is believed to be the ischemia produced by intestinal distension.
  • Hypovolemic shock: Hypovolemic shock is a profound risk when delivering hypertonic enemas.
  • Ischemia: Ischemia caused by overdistension is worsened by hypoperfusion; this hypoperfusion is caused by the hypovolemia that results from poor fluid resuscitation. Adequate fluid resuscitation (ie, 150 mL/kg/d minimum), including anticipated fluid losses from osmotic diarrhea and diuresis, is mandatory.

Surgical therapy

A number of surgical approaches to treat uncomplicated MI have been proposed over the years; variable success rates have been achieved. Individualize the approach for each infant.

The goal of operative management in simple uncomplicated MI is to evacuate meconium from the intestine while preserving maximal intestinal length.

Surgery is always indicated for complicated MI. Complicated MI requires resection more often than simple MI and may require temporary stomas.

The following complications require surgical management:

• Persistent or worsening abdominal distension
• Persistent bowel obstruction
• Enlarging abdominal mass
• Intestinal atresia
• Volvulus
• Perforation
• Meconium cyst formation with peritonitis
• Bowel necrosis

Intraoperative details

Several variations of the technique used by Hiatt and Wilson have involved placing indwelling ostomy tubes for postoperative bowel irrigation decompression and/or feeding. In 1970, O'Neill described success with tube enterostomy, with and without resection. In 1981, Harberg described a similar procedure using a T-tube enterostomy. In either situation, begin irrigations on the first postoperative day; after successfully clearing the obstruction (ie, 7-14 d), the physician may remove the tube and allow the enterocutaneous fistula to close spontaneously.

Subsequent surgical techniques have revolved around resection, anastomosis, and enterostomy, through which postoperative irrigations can be delivered. The Mikulicz double-barreled enterostomy first reported by Gross in 1953, has the following distinct advantages:

• The procedures reduce operating and anesthetic times because complete evacuation of inspissated meconium is unnecessary.
• The procedures avoid intra-abdominal anastomosis, which eliminates the risk of anastomotic leakage.
• The bowel can be opened following complete closure of the abdominal wound, which reduces intraperitoneal contamination risk.

Following surgery, solubilizing agents can be administered through the proximal or distal limbs of the stoma, per rectum, or by NG tube. In the classic description, a crushing clamp may be applied to the 2 limbs to create continuity for distal flow of intestinal fluids.

Disadvantages of this and other procedures employing resection and stoma(s) are potential postoperative fluid losses through high-volume stomas, bowel shortening by resection, and the need for a second procedure to reestablish intestinal continuity.

A distal chimney enterostomy, described by Bishop and Koop in 1957, involves resection with anastomosis between the end of the proximal segment and the side of the distal segment of bowel, approximately 4 cm from the opening of the distal segment. The open end is brought out as the ileostomy. This technique allows normal GI transit while providing a means for managing distal obstruction through the ileostomy, should it occur.

The reverse of the Bishop-Koop enterostomy is the proximal enterostomy described by Santulli in 1961.

• In this technique, following resection, the end of the distal limb is anastomosed to the side of the proximal limb. The end of the proximal limb is brought out as the enterostomy. This arrangement enhances proximal irrigation and decompression, and evacuation of the proximal small bowel at the time of surgery is unnecessary.
• As with distal chimney enterostomy, a catheter is placed for access to the distal limb. The catheter exits through the stoma to provide a means to irrigate the distal bowel.
• This technique's apparent disadvantage is the presence of a high-output stoma and the inherent risk of dehydration.
• Take care to replenish fluids, electrolytes, and nutrients in accordance with the stomal output.
• Reinstallation of stomal output from the proximal to the distal limb often is performed via the indwelling catheter.

Resection with primary anastomosis was suggested first by Swenson in 1962. Initially, this technique had difficulties and complications with leakage from the anastomosis. More recently, Chappell in 1977 and Mabogunje in 1982 have reported improved results. These authors emphasize the necessity of adequately resecting the compromised bowel, completely evacuating proximal and distal meconium, and preserving an adequate blood supply to the anastomosis.

The author prefers a modification of the technique originally described by Gross in 1953 to manage infants with uncomplicated MI.

• This modified technique begins by performing a celiotomy with a muscle-sparing horizontal incision just above the umbilicus.
• Upon exploration, a decision is made, based upon the viability and length of the bowel, either to create an enterotomy for irrigation and evacuation of the meconium or to resect the segment of impacted intestine.
• The author then creates side-by-side separate enterostomies without creating a common wall.
• Stomas are placed within the abdominal incision to the right; these may be covered with a single ostomy collecting device.
• Postoperatively, each stoma may be irrigated to remove residual meconium.
• Instillation of dilute enteral feedings high in glutamine, via the distal stoma, may also be performed to stimulate growth of the unused distal bowel.
• Intestinal continuity is usually restored within 6 weeks if bowel function resumes and the infant tolerates oral feedings.

Due to associated hepatic pathology, a liver transplant may be indicated. A study of 10 patients with CF who received orthotopic liver transplants (OLTX) found a mortality rate of 40%; all 4 patients who died had a history of MI. This is contrasted with the 6 patients who survived; 4 of these 6 (67%) had a history of MI. OLTX mortality was also associated with worse nutrition and development, a need for preoperative pancreatic enzymes, a higher incidence of pancreatic insufficiency, being transplanted at an older age, and, probably most important, a longer waiting time until transplantation.

A case study of a 7-month-old boy with CF who needed a new liver and small intestine supports that early multivisceral transplantation can be safely performed. The boy weighed 6 kg ( <5th percentile at age of transplantation) and gained weight to 12 kg (75th percentile at age 3.6 y). Overall, intestinal transplant survival rate is 77% and 64% for the first year and 5 years, respectively, while the 1-year graft survival rate is 67%, and the 5-year graft survival rate is 37%. Additionally, 87% of patients who receive intestinal transplant no longer require total parenteral nutrition (TPN).

Postoperative details

Initial postoperative management involves ongoing resuscitation. Carefully replace the fluid losses caused by surgery and by preoperative diuresis and diarrhea (if a Gastrografin enema was attempted). Adjust ongoing maintenance fluids and replace insensible fluids lost, as well as GI losses (ie, losses from NG suction and ileostomy).

Instillation of N-acetylcysteine via an NG tube or via ileostomy helps solubilize residual meconium.

As soon as possible (ie, 6 wk) close the stomas placed in the course of surgical management to help avoid prolonged problems with fluid, electrolyte, and nutritional losses.

Follow-up

Nutritional management

Infants with uncomplicated MI and CF may receive breast milk or routine infant formula, enzymes, and vitamins. Use caution when prescribing enteric enzyme medication to patients with MI and CF. Reported complications include fibrosing colonopathy from excessive enzyme doses and distal intestinal obstruction syndrome (DIOS). Generic substitutions for proprietary medications have also been associated with treatment failures.

Patients who have a complicated surgical course require either continuous enteral feedings or TPN. The author recommends predigested infant formulas (eg, Alimentum, Pregestimil), for enteral feeding.

Prestenotic dilation of the small bowel caused by a meconium obstruction theoretically could cause mucosal damage that, in turn, could contribute to poor peristalsis or malabsorption. Patients who have had complicated MI and/or sizable bowel resection and who are fed enterally may tolerate continuous feedings better than bolus feedings.

Because bowel mucosa may or may not be damaged by stasis, begin feedings with predigested diluted formula, usually half strength, at low volume. Once this diluted formula is well tolerated, the physician may increase formula strength and then volume. During this process, look for signs of feeding intolerance (eg, abdominal distention, heme-positive stools, increasing emesis).

Once oral feedings begin, administer oral pancreatic enzymes, even with predigested formulas, starting at 2000-4000 lipase units per 120 mL of full-strength formula. For example, an infant who weighs 2.5 kg and who is receiving formula at 4 mL/kg/h should be administered half of a 4000-lipase Pancrease capsule PO q12h. Capsules containing enteric-coated microspheres can be opened. Capsule contents can be mixed with applesauce and administered orally.

Do not crush the microcapsules because crushing exposes the enzymes to stomach acid during oral administration, which destroys the enzymes.

Uncrushed pancreatic enzymes should be administered even with formulas that contain medium-chain triglyceride (MCT) oil.

If pancreatic enzymes cause skin breakdown, a zinc oxide ointment (Desitin) can be applied to perianal skin.

COMPLICATIONS

Section 8 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

• Complicated MI may cause volvulus, atresia, necrosis, perforation, meconium peritonitis, and pseudocyst formation.
• Infants with MI are at risk for cholestasis, particularly if they have received or are receiving TPN. Monitor alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin levels weekly.
• Infants who have had significant bowel resection (ie, >33%) may be difficult to manage, especially if the ileocecal valve has been resected. In addition, an ileostomy may lead to excessive fluid and sodium losses. Take down ostomies as soon as possible. In the interim, if access to the distal defunctionalized bowel is feasible, administer ostomy-drip feeds of glutamine-enriched formula at low volumes to enhance bowel growth and to help prevent bacterial translocation.
• Gastric acid hypersecretion occurs in patients with short-bowel syndrome.
• • The acidic intestinal environment inactivates pancreatic enzymes and prevents dissolution of enteric-coated microcapsules. Histamine 2 receptor blockers may be used as an adjunct to pancreatic enzyme therapy in patients who have had significant bowel resections.
  • Patients with the double burden of excessive sweat and intestinal sodium losses may require compensation for total body sodium deficit. Measure urine sodium levels in infants with ileostomies, especially those who do not grow, even if serum sodium levels are within the reference range. Infants with urine sodium levels less than 10 mEq/L need sodium (and possibly bicarbonate) supplementation.
• Pulmonary complications include the following:
• • Although clinical lung disease usually does not develop early, mucus plugging and atelectasis can occur. Immediately postoperatively, initiate vigorous prophylactic pulmonary care with chest physiotherapy. Do not use the head-down position because this increases the risk of gastroesophageal reflux (GER) and aspiration.
  • Infants should receive nebulized albuterol (2.5 mg bid), followed by chest physiotherapy.
  • Prophylactic antibiotics are unnecessary. Antibiotic therapy, if needed, should be based on respiratory tract cultures.

Other potential complications of cystic fibrosis

Gastroesophageal reflux

GER occurs with increased prevalence in patients with CF, and reflux may also exacerbate the respiratory status of the patient with CF. Pathological reflux, ie, endoscopic and histologic esophagitis, is present in over 50% of patients with CF. Most patients with CF have an abnormal quantity of reflux as defined by pH probe, and it has been reported with prominent respiratory symptoms. Clearly, early diagnosis and treatment of this condition is of prime importance if the complications of pathological reflux are to be curtailed and respiratory function maximized.

The particular mechanism of GER in CF is unclear, but a number of factors may contribute to the increased susceptibility of this patient group to the development of pathological GER. First, most reflux episodes in CF occur during transient lower esophageal sphincter (LES) relaxations. These transient relaxations are increased during distension of the gastric fundus, a feature that can predispose these patients to reflux especially when receiving large supplemental bolus feeds. This cycle of events may be further exacerbated in the event of poor gastric emptying. Gastric emptying of liquids was initially thought to be delayed in patients with CF.

Second, the head-down posture adopted during chest physiotherapy places gastric liquid content in an optimum position at the LES for reflux in the event of a transient period of relaxation. Associated coughing and forced expiration, which both increase the abdominothoracic pressure gradient, also facilitates reflux action.

Last, medications such as theophylline and beta-adrenergic drugs, used in the treatment of respiratory disease in patients with CF, are known to decrease the resting tone in the LES and could conceivably facilitate reflux activity.

Biliary tract disease

Gallbladder disease is prevalent in the CF population, with abnormal oral cholecystograms in 46% and cholelithiasis in 12%. Abnormalities described in patients with CF include, a microgallbladder containing thick colorless "white bile" with occlusion of the cystic duct, gallstones, biliary dyskinesia, and sclerosing cholangitis. Bile acid metabolism is disturbed in patients with pancreatic insufficiency who are not receiving adequate pancreatic enzyme supplementation. Bile acids are likely bound to malabsorbed fat and, as a result, are lost in feces, which in turn depletes the bile acid pool and supersaturates cholesterol in the gallbladder. This condition promotes stone formation.

Many patients with CF and gallbladder sludge or stones are asymptomatic, but approximately 4% have the classic symptomatology of cholecystitis. A laparoscopic cholecystectomy is the treatment of choice in such cases because postoperative pain is less and therefore pulmonary compromise is less when compared to the classic open technique. The role of cholecystectomy in patients with asymptomatic gallstones remains unclear.

Distal intestinal obstruction

DIOS (formally called meconium ileus equivalent) is a recurrent postneonatal partial or complete intestinal obstruction unique to patients with CF. Most cases occur in adolescents and adults, but all age groups can be affected with an overall incidence of approximately 15%.

The exact etiology is unknown, but these patients are more likely to have a history of steatorrhea from pancreatic exocrine insufficiency despite adequate enzyme therapy. One study also showed that, of 27 patients with DIOS, 17 (63%) had a history of MI as an infant. A number of aspects peculiar to gastrointestinal function of patients with CF may help, in part, to explain this syndrome. These include abnormal intestinal mucins, abnormal intraluminal water and electrolyte content, and inherently slow intestinal motility. The latter may be because neurotensin, a gastrointestinal hormone that delays motility, is secreted from the distal ileum when unabsorbed fat reaches that location. Some additional precipitating factors may be relative dehydration, especially in a postoperative period, inadequate enzyme supplementation, and changes in diet.

The cardinal features of the syndrome are cramping abdominal pain, often localized to the right lower quadrant (RLQ), a palpable mass in the RLQ, and decreased frequency of defecation. Different degrees of obstruction are present, from partial, which is most common, to complete with vomiting, distension, and absolute constipation. Colicky pain may be provoked by meals, which may then result in anorexia as a method to avoid further pain. Physical examination in uncomplicated DIOS usually reveals a tender mass in the RLQ with no evidence of peritonitis. No fecal impaction or dehydrated stool is noted on rectal examination, and the stool is heme negative.

The nonspecific nature of DIOS, with no pathognomonic radiologic features, means that an accurate diagnosis of abdominal pain in the patient with CF is not easy. Plain supine and erect abdominal radiography is still, however, the most helpful initial investigation when the diagnosis is suspected. This shows bubbly granular material in the right iliac fossa and variable degrees of small-bowel obstruction, ie, air-fluid levels with proximal small-bowel dilatation. Plain radiography supports, but does not prove, the diagnosis. Inspissated material in the right iliac fossa can also be demonstrated with a water-soluble contrast enema. In doing so, intussusception can be excluded and the investigation itself may prove therapeutic in some cases of DIOS.

Particular difficulty is faced in the event of partial small-bowel obstruction caused by adhesions from previous abdominal surgery or appendiceal disease, which occurs in 1.5-2% of patients with CF, less than the general population occurrence of 8.6%. Abdominal pain is a common symptom of patients with CF and, because they are often already being treated with antibiotics and steroids, the classic clinical signs and symptoms of appendicitis are often masked and the critical diagnosis missed. This results in a high incidence of perforation and substantial morbidity in this patient group. Despite the blunting of clinical signs, evidence of pyrexia and a leukocytosis may still be present.

Depending on the appendix location, a contrast enema may show deformity of the cecum with an associated mass effect and not the typical inspissated material features of DIOS. Abdominal ultrasonography or, if necessary, CT scanning shows free fluid or an abscess collection in the region of the cecum. In such cases, treatment should then proceed with appendectomy. If the diagnosis is still in doubt, the surgeon could opt to start with a laparoscopic investigation and then proceed appropriately in light of the findings.

In the absence of partial small-bowel obstruction due to adhesions, appendiceal disease, or complete obstruction, DIOS is suitable for a trial of medical management. After adequate rehydration, a balanced polyethylene glycol–electrolyte solution, such as GoLYTELY or Colyte, can be administered orally or by NG tube. The dose is 20-40 mL/kg/h with a maximum of 1200 mL/h. Prokinetic agents, such as metoclopramide, can be used to limit the amount of nausea and bloating. Successful treatment is judged by the passage of stool, resolution of symptoms, and the disappearance of a previously palpable right iliac fossa mass. Sequential plain abdominal radiography helps to document the resolution of DIOS, but if symptoms persist, then the differential diagnosis already outlined must be reconsidered.

The use of enemas at the diagnostic stage is outlined. Contrast enemas should also be used for patients with emesis due to DIOS after placement of a NG tube for gastric suction. As long as the patient remains clinically stable, the contrast enemas may be repeated at intervals of several hours over several days. However, careful monitoring of the patient must be initiated before, during, and after the procedure because large fluid and electrolyte shifts can be induced by the contrast material.

When complete obstruction or evidence of peritonitis is present, surgical intervention is necessary and all oral or rectal therapies are contraindicated. A NG tube should be passed to help with decompression and adequate resuscitative measures initiated. At laparotomy, the bowel wall feels thickened and filled with tenacious material. It can be decompressed and irrigated with Gastrografin, usually via a small catheter placed through the appendix stump, as previously described for meconium ileus. Leaving an irrigating tube in situ is also possible to irrigate the bowel postoperatively.

Gastrointestinal neoplasms

The overall risk of cancer in patients with CF is similar to that of the general population; however, risk of digestive tract cancers is increased. These include tumors of the esophagus, stomach, small intestine, large intestine, liver or biliary tract, and pancreas.

The differential localization and expression of the cystic fibrosis transmembrane conductance regulator gene may have a role to play in the neoplastic disease process. Furthermore, increased cellular turnover in response to the persistent irritation of GER, gallstones, or steatorrhea in digestive tract organs may also offer an explanation to these findings.

Fibrosing colonopathy

Fibrosing colonopathy is a newly described entity in children with CF. A longitudinal study showed that, of the children with CF who developed fibrosing colonopathy, 89% (8) of patients went to surgery, and 63% (5) of them received a subtotal colectomy. Findings at laparotomy (in children with CF who presented with presumed DIOS that did not respond to medical therapy) include colonic strictures with histopathological changes of postischemic ulceration repair, with mucosal and submucosal fibrosis, destruction of the muscularis mucosa, and eosinophilia. In some patients, a change from conventional enteric-coated pancreatic enzymes to high-strength products 12-15 months before presentation has been described. In the largest case-control study reported, the absolute dose of pancreatic enzymes, rather than the type of enzyme, was the strongest predictor of fibrosing colonopathy.

The diagnosis of fibrosing colonopathy should be considered in patients with CF who have been exposed to high doses of pancreatic enzymes and present with symptoms of abdominal pain, distension, chylous ascites, change in bowel habit, or failure to thrive. Continued diarrhea may also be a prominent feature, which unfortunately may prompt the family to increase supplemental enzymes further. On occasion, the diarrhea may be bloody. A barium enema may reveal mucosal irregularity, loss of haustral markings with a foreshortened colon with varying degrees of stricture formation. In some cases, the whole colon has been involved. Colonoscopy may show an erythematous mucosa and areas of narrowing, from which taking multiple forcep-pinch biopsies is advisable.

Initial management should reduce enzyme dosage to the recommended levels of 500-2500 lipase units/kg per meal. This should be accompanied with adequate nutritional supplementation, which may be enteral elemental feeding or even total parenteral nutrition for a time. Those patients who show signs of unrelenting failure to thrive, obstruction, uncontrollable diarrhea, or chylous ascites then need surgical intervention.

When surgery is planned electively for patients with intractable symptoms, gentle bowel preparation can be administered preoperatively. The aim of surgical intervention is to resect the affected bowel and make a primary anastomosis. Unfortunately, this is not possible in the event of pancolonic or rectal involvement, and as a result, the patient requires an ostomy. This is often the safest option; patients and parents must be fully aware and prepared for it preoperatively. Whether this condition completely resolves with a reduction in enzyme dosage and surgical resection is unclear, so the operated group also requires regular follow-up for any signs of deterioration.

Rectal prolapse

Rectal prolapse occurs in approximately 20%-23% of patients with CF. The initial prolapse occurs most commonly in patients aged 1-3 years and can be recurrent in nature. It may also be the sole presenting feature of a new patient with CF in about 4-8% of all cases.

Factors that directly predispose this group to prolapse include constipation, diarrhea with increased frequency and volume of movement, malabsorption, and colonic distension. Indirect contributors relate to increased intra-abdominal pressure caused by coughing or pulmonary hyperinflation.

Initial management involves manually reducing the prolapse. Medical management to maximize fat absorption then aids the overall control. Reassure parents that the number of prolapse episodes is likely to reduce with age. However, further intervention is warranted in a small group when they have persistent pain or incontinence with each episode of prolapse.

The acute prolapse is easily reduced if action is taken promptly before edema formation. Parents can be taught to grasp the herniated bowel with the fingertips of a gloved hand and apply circumferential pressure with an inward push. Sustained pressure may be required to achieve full reduction. If prolapse immediately recurs, then the buttocks can be strapped together with adhesive tape for 7-14 days.

Recurrent prolapse can be treated by a rectal submucosal injection. The procedure is performed under general anesthetic after the rectum has been emptied with a suppository. With the patient in the lithotomy position, the needle is inserted through the skin just outside the mucocutaneous junction and guided into position by a finger placed in the rectum. As the needle is slowly withdrawn, 2-3 mL of 5% phenol in almond oil or hypertonic sodium chloride solution (30%) are injected in a linear track into 4 different quadrants. A single treatment controls approximately 90% of cases. Linear electrocauterization in the 4 quadrants has also been described to produce a perirectal inflammation. This technique requires a longer hospital stay and may be complicated with rectal bleeding and or rectal stenosis.

When all conservative options are exhausted, a surgical approach may then be considered. However, many different operations have been described to control rectal prolapse. Through a transabdominal approach, the rectum can be fixed to the hollow of the sacrum by a prosthetic or fascia lata graft sutured to the bowel and the presacral fascia, thus creating a new pelvic floor. Other operations include rectal suspension and levator ani muscle repair through a posterior sagittal approach. The diversity of options highlights the unsatisfactory results often achieved in these difficult cases.

OUTCOME AND PROGNOSIS

Section 9 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

Hiatt and Wilson reported the first survivors with MI in 1948, and early series reported 50-67% mortality rates. The advent of improved nonoperative and operative treatments, nutritional support, and treatment of bacterial infection have combined to improve reported survival rates for infants with both complicated and simple MI to 85-100%. Of the MI mortalities, Escobar et al showed 8 (9%) deaths over 32 years, with 5 of these patients having complicated MI and 3 having simple MI.

However, patients with CF who have a history of MI have significantly worse pulmonary outcomes after age 8-10 years, as measured by forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), forced expiratory flow at 25-75% (FEF25-75), and total lung capacity (TLC). Whether the MI was treated surgically or medically did not change future pulmonary status. Overall, patients with CF and MI have worse lung function and a higher rate of obstructive disease than patients with CF who do not have a history of MI. These data support MI as being a different phenotype in CF.

An epidemiological study of 27,703 patients formalized a baseline risk, using age of CF diagnosis and the initial disease presentation in order to build survival models and demonstrate disease severity in isolated patients with CF. This study revealed that patients diagnosed by MI had statistically significant higher risks of a shorter lifespan (1.80; 95% CI: 1.27-2.56, p = 0.001), acquiring Pseudomonas aeruginosa (1.23; 95% CI: 1.08-1.39, p = 0.001), and a trend toward FEV1 below 70% (OR = 1.39, p = 0.07) in comparison to the SCREEN group diagnosed by a newborn screening program. Additionally, each year increase in age at diagnosis resulted in a 3% decrease in risk of shortened lifespan (95% CI: 0.96-0.98, p < 0.001), a 5% decrease in acquiring P aeruginosa (95% CI: 0.93-0.97, p < 0.001), and 3% decreased risk in FEV1 less than 70% (95% CI: 0.95-0.99, p < 0.001).

Prenatal diagnosis of MI with obstetrical ultrasonography, coupled with improved biochemical and molecular techniques for diagnosis of CF, now enable a perinatal team to counsel a family about the likelihood of CF in the fetus. Prenatal diagnosis also allows physicians to monitor and manage an affected fetus to ensure an optimal outcome. Advances in neonatal care and surgical procedures for infants with CF complicated by MI have greatly improved survival rates.

FUTURE AND CONTROVERSIES

Section 10 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

Advances in perinatal diagnosis and management of MI and CF, combined with greater understanding of the CFTR protein, have vastly improved the outlook for affected infants. Continued successful care for these patients depends upon prenatal diagnosis, multidisciplinary care, and innovative antenatal therapy strategies.

Future goals should include discoveries of new ways to reduce the perinatal complications that increase morbidity, mortality, and medical care costs.

The ability to detect both MI and CF prenatally means physicians should begin to consider strategies that would prevent simple MI from progressing to complex MI. The creation of mouse models for CF provides a unique opportunity to study the basic pathophysiology of MI. This knowledge should enable the development and prospective evaluation of new treatments for this disorder. Future prenatal interventions such as gene therapy may even prevent MI.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• References

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