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Paediatr Child Health. 2009 Jul-Aug; 14(6): 389–392.
PMCID: PMC2735383

Language: English | French

Jaundice in a neonate with congenital diaphragmatic hernia

Abstract

A six-week-old boy presented to the emergency department with worsening jaundice. His medical history included congenital diaphragmatic hernia repaired shortly after birth. Significant jaundice, unresponsive to phototherapy, was noted on the eighth day of life. His total bilirubin level decreased when he was advanced to full oral feeds. However, on the 23rd day of life, the patient’s conjugated bilirubin level had tripled. This was attributed to total parenteral nutrition, and the patient was discharged home. Over the next month, his jaundice worsened. The patient was readmitted and ultimately diagnosed with cytomegalovirus (CMV) hepatitis. After treatment with ganciclovir, his hepatitis completely resolved. CMV infection is a common cause of neonatal hepatitis and congenital malformation. Prolonged neonatal jaundice that does not improve with transitioning from total parenteral nutrition to oral feeds warrants further evaluation. Simple laboratory investigation can avoid unnecessary and potentially harmful medical and surgical interventions. Early treatment of neonatal CMV infection reduces the risk of long-term neurological and hepatic complications.

Keywords: Cholestasis, Congenital diaphragmatic hernia, Cytomegalovirus, Neonatal hepatitis, Neonatal jaundice

Résumé

Un garçon de six semaines est arrivé au département d’urgence en raison de l’aggravation d’une jaunisse. Ses antécédents médicaux incluaient une hernie diaphragmatique congénitale réparée peu après la naissance. On a remarqué une jaunisse importante, réfractaire à la photothérapie, au huitième jour de vie. Le taux de bilirubine totale du nourrisson a diminué lorsqu’il a commencé à recevoir des boires complets par voie orale. Cependant, au 23e jour de vie, son taux de bilirubine conjuguée avait triplé, ce qu’on attribuait à l’alimentation parentérale totale. On lui a donné son congé à domicile. Au cours du mois subséquent, sa jaunisse s’est aggravée. Le patient a été réhospitalisé et a fini par obtenir un diagnostic d’hépatite à cytomégalovirus (CMV). Après un traitement au ganciclovir, son hépatite s’est complètement résorbée. L’infection à CMV est une cause fréquente d’hépatite néonatale et de malformation congénitale. Une jaunisse néonatale prolongée qui ne s’améliore pas après la transition de l’alimentation parentérale totale aux boires par voie orale justifie une évaluation plus approfondie. Une simple exploration de laboratoire permet d’éviter des interventions médicales et chirurgicales inutiles au potentiel néfaste. Le traitement rapide de l’infection à CMV néonatale réduit le risque de complications neurologiques et hépatiques à long terme.

CASE PRESENTATION

A six-week-old boy presented to the emergency department with a three-week history of worsening jaundice. He was born via spontaneous vaginal delivery at 38 3/7 weeks, weighing 3.1 kg, to a 34-year-old gravida 2, para 1 to 2 mother. The pregnancy was uncomplicated. The mother had a fever of 38.3°C, 3 h before delivery. The baby developed respiratory distress at 5 min of life. A chest radiograph revealed a herniated bowel in the left hemithorax. The congenital diaphragmatic hernia was repaired on the 12th day of life (DOL). The baby required mechanical ventilation for the first 17 DOLs and received multiple leukocyte-reduced blood product transfusions pre- and postsurgery. Significant jaundice was noted on the eighth DOL, with total and conjugated bilirubin levels of 13.8 mg/dL and 1.2 mg/dL, respectively, rising to a peak of 15.9 mg/dL on the 13th DOL. Phototherapy was given from the eighth to 11th DOL. Before discharge on the 23rd DOL, the total serum bilirubin level had decreased to 8.2 mg/dL, while the conjugated bilirubin level had increased to 3.7 mg/dL. This was attributed to receiving total parenteral nutrition (TPN) from birth to the 13th DOL. The patient’s aspartate aminotransferase and alanine aminotransferase levels were normal, and no further evaluation was performed. Since his discharge home, he was feeding well with breastmilk and formula. His stools were yellow.

On physical examination, the patient’s vital signs were normal; his weight was 3.9 kg, height was 54 cm and head circumference was 37.5 cm, which were in the seventh, 13th and 15th percentiles, respectively. The examination was notable for scleral icterus, jaundiced skin, a healing abdominal scar and soft liver palpable 2 cm below the right costal margin. His stool and urine were yellow.

Laboratory investigation revealed a white blood cell count of 16.8×109/L (26% neutrophils and 63% lymphocytes), hemoglobin level of 13.9 g/L, platelet count of 574×109/L, total bilirubin level of 15.4 mg/dL, conjugated bilirubin level of 8.2 mg/dL, aspartate aminotransferase level of 383 U/L (normal 7 U/L to 36 U/L), alanine aminotransferase level of 349 U/L (normal 4 U/L to 45 U/L), alkaline phosphatase level of 815 U/L (normal for infants 150 U/L to 420 U/L) and gamma-glutamyl transferase level of 311 U/L (normal 8 U/L to 67 U/L). The patient’s electrolytes, glucose, renal function tests, albumin and international normalized ratio were normal.

Hospital course (Figure 1)

Figure 1
Schematic presentation of clinical and biological events. ALT Alanine aminotransferase; AST Aspartate aminotransferase; CDH Congenital diaphragmatic hernia; CMV Cytomegalovirus; GGT Gamma-glutamyl transferase; HIDA Hydroxy iminodiacetic acid; TPN Total ...

An abdominal ultrasound showed a homogenous, normal-sized liver lacking biliary tract dilation and a contracted gallbladder. But, a radionucleotide hydroxy iminodiacetic acid (HIDA) scan following five days of phenobarbital pre-treatment demonstrated no appreciable radiotracer excretion into the biliary system or bowel up to 24 h after radioisotope administration. His liver biopsy demonstrated portal inflammatory infiltrate, extensive cholestasis, giant cell transformation and focal bridging fibrosis. These findings were consistent with acute hepatitis with focal duct injury and loss. The patient’s intraoperative cholangiogram was normal.

The patient’s liver viral culture and cytomegalovirus (CMV) antibody probe were negative. Further evaluation of his thyroid-stimulating hormone, urine, blood bacterial culture, alpha-1-antitrypsin, plasma amino acids and urine organic acids showed normal results. Serology for toxoplasma, herpes simplex virus, rubella, syphilis and hepatitis A and C was negative. Hepatitis B surface antigen antibody screen was positive and hepatitis B e antibody and hepatitis B surface antigen were negative. Epstein-Barr virus (EBV) immunoglobulin (Ig) G was positive, with a negative IgM and polymerase chain reaction (PCR). CMV IgM and IgG were positive. Cystic fibrosis mutations were negative. Maternal CMV status was unknown.

On the 10th day of hospitalization (53rd DOL), the previously sent serum CMV PCR revealed 298,400 copies/mL; urine CMV culture became positive. Computed tomography of the brain and retinal and hearing examinations were normal. He was treated with intravenous ganciclovir 5 mg/kg/dose twice per day for six weeks. He tolerated treatment well without developing neutropenia. Due to the severity of his cholestasis, treatment was supplemented with oral ursodiol and vitamins A, D, E and K. His CMV PCR gradually decreased to undetectable levels after one month of treatment, and bilirubin levels decreased slowly to normal levels after six weeks of treatment. The child’s hearing and developmental progress were followed.

DISCUSSION

Final diagnosis: CMV hepatitis

Prolonged hyperbilirubinemia lasting beyond the first two weeks of life warrants evaluation. Obstructive jaundice is defined as a conjugated serum bilirubin concentration of greater than 2 mg/dL or 20% of total bilirubin levels. Due to the risk of cirrhosis, anatomical lesions must first be excluded. Ultrasonography can identify choledochal cysts and most cases of biliary atresia. Approximately 10% of patients with biliary atresia have a gallbladder and require a HIDA scan for further diagnosis. However, the specificity of the HIDA scan decreases when the conjugated bilirubin level is greater than 3 mg/dL to 4 mg/dL; a cholangiogram may be necessary to exclude biliary atresia.

After extrahepatic biliary atresia, 40% of neonatal (four to six weeks) cholestasis is due to hepatitis (1). Neonatal hepatitis may cause latent or acute cholestasis and may progress to cirrhosis (1). Noninfectious causes include TPN, idiopathic neonatal or giant cell hepatitis, and congenital hepatic fibrosis. TPN-associated cholestasis occurs most commonly with prolonged (greater than two weeks) use and improves after initiation of oral feeds. A thorough investigation should be performed before diagnosing TPN-associated cholestasis. Infectious causes of neonatal hepatitis include congenital infections (toxoplasma, rubella, CMV, herpes simplex virus, EBV and syphilis), varicella zoster virus, parvovirus B19, EBV, hepatitis B and enteroviruses (1,2). CMV is the most common viral cause (3).

Other causes of neonatal cholestasis include biliary duct hypoplasia (isolated or in Alagille syndrome), cystic fibrosis, bacterial sepsis and metabolic diseases (ie, tyrosinemia, galactosemia, storage diseases, progressive familial intrahepatic cholestasis and alpha-1-antitrypsin deficiency) (2).

Epidemiology

CMV is the most common and severe cause of congenital viral infection in developed countries (4). It affects approximately 2% of all live births – 40,000 infants born annually in the United States (2,5).

The likelihood and severity of congenital infection depends on the maternal infection status (2). Women from higher-income groups are more likely to be CMV-seronegative than women from lower-income groups (6). CMV-seronegative women have a higher risk of acquiring a CMV infection and transmitting the infection transplacentally to the baby (2,6). CMV-seropositive women may develop recurrent CMV infection (ie, reinfection with a different strain or reactivation). Intrauterine transmission of the virus occurs more frequently with maternal infection later in pregnancy; however, fetal damage is more severe when infection occurs in the first trimester (2,57).

Neonates also acquire CMV infection from exposure to maternal genital tract secretions at delivery, breastfeeding, blood transfusion and daycare centre attendance (2,5,7). Postnatal CMV infection can present one to three months after exposure and is usually milder than congenital and perinatal infections (2). The risk of CMV infection from blood transfusion is reduced by using seronegative blood donors and leukocyte-depleted blood for neonates.

Clinical presentation

Clinical severity varies from asymptomatic infection (90% of cases) to systemic life-threatening disease (1,2,4,6). CMV is the leading nongenetic cause of sensorineural hearing loss, and the leading infectious cause of mental retardation and congenital malformation (2,4). Neurodevelopmental consequences, including mental retardation, cerebral palsy, seizures, and visual and auditory defects, may take months to years to manifest (2,4).

Clinical signs of CMV infection include pneumonitis, hepatitis, thrombocytopenia, chorioretinitis, pancreatitis and lymphadenopathy (2,4). Ten per cent of symptomatic newborns have severe classic cytomegalic inclusion disease (CID). Children with CID may have intrauterine growth retardation, microcephaly, periventricular calcifications, ventriculomegaly, cerebral atrophy, chorioretinitis, sensorineural hearing loss, hepatosplenomegaly, jaundice, thrombocytopenia, hemolytic anemia and purpuric ‘blueberry muffin’ rash (2). CID has a 25% mortality rate. Intracerebral calcifications are often seen with cognitive and audiological sequelae.

Some believe that CMV may trigger bile duct injury in the pathogenesis of biliary atresia; however, this has not been proven (8).

CMV has also been associated with hydrops fetalis and malformations of the gastrointestinal tract, heart, kidneys and teeth (2) There have been previous reports of inguinal hernia and bilateral congenital eventration of the diaphragm associated with congenital CMV infection (2,9). The congenital diaphragmatic hernia in our case may have been related to the CMV infection, but the pathogenesis is unclear.

Diagnosis

Most infants with cholestasis are evaluated at one to two months of age; thus, it may be impossible to distinguish among prenatal, perinatal and postnatal infections (2,3). Severe and early presentation suggests congenital infection, as in the present child, whose conjugated bilirubin level rose to abnormal levels before one month of age. The diagnosis of neonatal CMV infection requires a positive viral culture (from urine or tissue) (1,4). CMV serology is unreliable due to frequent false-positive results (2). Diagnosis can also be made by detection of CMV early antigen (from tissue or blood) (1) and PCR. CMV PCR is becoming widely used to monitor disease activity and response to antiviral therapy, and may predict long-term outcomes (4). The classic histological finding in CMV disease, the giant inclusion cell (‘owl’s eye’), may not always be detected on tissue biopsy (1,2). Liver biopsy may demonstrate nonspecific hepatitis and cholestasis (2). The brain computed tomography scan evaluating for intracranial calcifications is an important diagnostic and prognostic study for infants with CMV. In addition, psychomotor development and hearing must be regularly monitored during the early years of life.

Treatment

There is limited information concerning the efficacy and safety of antiviral therapy with ganciclovir in neonates (1,3). Studies (2,10) have shown that intravenous ganciclovir may reduce the risk of sensorineural hearing loss. Although, hepatitis may spontaneously resolve, there is considerable risk of cirrhosis and portal hypertension (1,2). An increasing number of studies (14,6) suggest that intravenous ganciclovir therapy may improve the clinical course of neonatal cholestatic disease. Specific guidelines have not yet been established (13); however, a six-week treatment course is generally recommended (2). The most common side effect of ganciclovir therapy is dose-dependent neutropenia. Many studies also advocate the use of fat-soluble vitamins and ursodiol in the treatment of persistent/severe cholestasis (3). Oral valganciclovir might be another option; clinical trials are underway.

LESSONS FOR THE CLINICIAN

  • Prolonged neonatal jaundice that does not improve with transitioning from TPN to oral feeds cannot be attributed to TPN-associated cholestasis.
  • CMV is the most common infectious cause of neonatal hepatitis.
  • The combination of congenital malformation and prolonged hyperbilirubinemia raises the index of suspicion for congenital CMV infection.
  • Early diagnosis and treatment of severe neonatal CMV infection is recommended to reduce the risk of long-term neurological and hepatic complications.

REFERENCES

1. Ozkan TB, Mistik R, Dikici B, Nazlioglu HO. Antiviral therapy in neonatal cholestatic cytomegalovirus hepatitis. BMC Gastroenterol. 2007;7:9. [PMC free article] [PubMed]
2. Remington JS, Klein JO, Wilson CB, Baker CJ, editors. Infectious Diseases of the Fetus and Newborn Infant. 6th edn. Philadelphia: Elsevier Saunders; 2006. pp. 739–81.
3. Fischler B, Casswall TH, Malmborg P, Nemeth A. Ganciclovir treatment in infants with cytomegalovirus infection and cholestasis. J Pediatr Gastroenterol Nutr. 2002;34:154–7. [PubMed]
4. Lanari M, Lazzarotto T, Venturi V, et al. Neonatal cytomegalovirus blood load and risk of sequelae in symptomatic and asymptomatic congenitally infected newborns. Pediatrics. 2006;117:e76–83. [PubMed]
5. Stagno S, Cloud GA. Working parents: The impact of day care and breast-feeding on cytomegalovirus infections in offspring. Proc Natl Acad Sci USA. 1994;91:2384–9. [PubMed]
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7. Trincado DE, Rawlinson WD. Congenital and perinatal infections with cytomegalovirus. J Paediatr Child Health. 2001;37:187–92. [PubMed]
8. Fischler B, Ehrnst A, Forsgren M, et al. The viral association of neonatal cholestasis in Sweden, a possible link between cytomegalovirus and extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr. 1998;27:57–64. [PubMed]
9. Wayne ER, Burrington JD, Myers DN, Cotton E, Block W. Bilateral eventration of the diaphragm in a neonate with congenital cytomegalic inclusion disease. J Pediatr Gastroenterol Nutr. 1973;83:164–5. [PubMed]
10. Kimberlin DW, Lin CY, Sánchez PJ, et al. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: A randomized, controlled trial. J Pediatr Gastroenterol Nutr. 2003;143:16–25. [PubMed]

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