Cholestasis after very preterm birth was associated with adverse neonatal outcomes but no significant long-term liver disease: A population-based study.

AIM: To describe outcome linked to neonatal cholestasis in a defined cohort of very preterm infants. METHODS: Population-based retrospective case-control study of preterm infants, gestational age <30 weeks, surviving for 28 days, in Stockholm County. Cholestasis was defined as conjugated bilirubin ≥30 µmol/L exceeding 20% of total level at least twice and graded as high if exceeding 100 µmol/L. Cholestatic cases were matched on gestational week with two non-cholestatic controls. RESULTS: The incidence rate of cholestasis was 37/250 (14.8%), with increasing rates in lower gestational weeks. Perinatal factors associated with cholestasis were pre-eclampsia and being born small for gestational age. Cholestatic infants had three times more bronchopulmonary dysplasia and eight times more retinopathy of prematurity. The mortality was 13.5% in cholestatic infants versus 2.7% in controls (P = .040). All deceased cholestatic infants had high-grade cholestasis. No surviving infants developed chronic liver disease by 10 years of age. CONCLUSION: Cholestasis was common in very preterm infants and linked to disease severity and adverse outcome. Cholestasis may be an independent risk factor for bronchopulmonary dysplasia and retinopathy of prematurity and more severe cholestasis associated with increased mortality. Cholestasis was not associated with chronic liver disease later in childhood.

CD13 Autoantibodies Are Elevated in Sera From Mothers of Infants With Neonatal Cholestasis of Different Causes.

OBJECTIVES: Human cytomegalovirus (HCMV) infection induces production of CD13-specific autoantibodies, which may promote inflammation and tissue damage. HCMV infection has been suggested as a cause of biliary atresia (BA), but little is known of its role in other forms of neonatal cholestasis. We studied serum levels of CD13-specific autoantibodies in mothers of infants with neonatal cholestasis of different causes, including BA, and in mothers of healthy, term infants without cholestasis, as well as in healthy blood donors. METHODS: Using fluorescence-activated cell sorting, we measured CD13-specific autoantibody levels in serum from the above-mentioned groups. In addition, the effect of serum from mothers of infants with neonatal cholestasis was tested on the differentiation of monocytes into macrophages. RESULTS: CD13-specific autoantibodies were found in mothers of infants with neonatal cholestasis, but not in mothers of infants without cholestasis and healthy blood donors, and were associated with HCMV seropositivity. Sera from mothers of infants with all forms of neonatal cholestasis inhibited differentiation of monocytes into macrophages, but this was not dependent on CD13-specific autoantibodies. CONCLUSIONS: The significantly higher frequency of CD13-specific autoantibodies in mothers of infants with neonatal cholestasis of all forms compared with mothers of healthy infants without cholestasis suggests an association, but does not prove that they are pathogenic. The presence of CD13-specific autoantibodies does not correlate with HCMV IgG serostatus, suggesting a more complicated mechanism that possibly reflects active HCMV infection in these individuals. Further studies are needed to elucidate whether these autoantibodies contribute to the development of cholestasis or represent an epiphenomenon.

Impact of parenteral fat composition on cholestasis in preterm infants.

OBJECTIVES: Parenteral nutrition-associated liver disease (PNALD) is frequently detected in neonatal intensive care units. Parenteral lipid emulsion (PLE) content has been implicated in its pathogenesis. We aimed to study the effect on incidence and outcome of PNALD by replacing soy-based PLE with olive oil-based PLE in a population-based group of preterm infants. METHODS: All infants in Stockholm County with gestational age (GA) <30 weeks were included (n = 615). Infants who died before 28 days of age or were referred to or from other regions were excluded (n = 97). PNALD was defined as conjugated serum bilirubin ≥ 30 µmol/L and exceeding 20% of the total fraction on at least 2 occasions. Two different 2-year time periods were compared: before (SOY period) and after (OLIVE period) switching PLE. For each PNALD case, 2 GA-matched controls were randomly identified. RESULTS: PNALD incidence was 14.8% (37/250) in the SOY period and 12.7% (34/268) in the OLIVE period (P = 0.52). The OLIVE infants with PNALD had more risk factors, such as lower GA and longer periods of parenteral nutrition, for developing PNALD than the SOY infants. Nevertheless, treatment during the SOY period was an independent risk factor for PNALD in logistic regression analysis. CONCLUSIONS: Population-based incidence of PNALD is 1 of 7 in preterm infants with GA < 30 weeks. Changing from soy oil to olive oil-based PLE did not decrease the incidence of PNALD significantly. Olive oil-based PLE carries an equal or slightly decreased risk to develop PNALD compared with soy oil-based PLE.

Population-based incidence and risk factors for cholestasis in hemolytic disease of the fetus and newborn.

OBJECTIVE: To estimate the incidence of cholestasis in neonates with hemolytic disease of the fetus and newborn (HDFN) and investigate risk factors and long-term liver disease. STUDY DESIGN: A population-based cohort study of all infants born with HDFN within the Stockholm region between 2006 and 2015. The study period was the first 90 days of life, and presence of any chronic liver disease was evaluated at two years of age. RESULTS: Cholestasis occurred in 7% (11/149). Median age at detection was 1.1 days. Intrauterine blood transfusions and maternal alloimmunization with multiple red blood cell antibodies including D-, c- or K-antibodies were independent risk factors for cholestasis. No infant had chronic liver disease at two years of age. CONCLUSIONS: Infants with severe HDFN have increased risk for cholestasis, particularly those requiring multiple intrauterine transfusions. Early and repeated screening for conjugated hyperbilirubinemia in the first week of life is needed to ensure adequate management.

High Rate of Cytomegalovirus Detection in Cholestatic Preterm Infants.

Objectives: To evaluate the prevalence of cytomegalovirus (CMV) infection in preterm infants with cholestasis. Study design: Preterm infants (<37 weeks gestational age) with cholestasis were tested for CMV DNA using Taqman PCR in blood cells from sedimented whole blood, plasma, and urine. Infants were regarded as positive for CMV if any sample was tested positive. Their mothers were tested for CMV serostatus simultaneously. A control group of non-cholestatic preterm infants, and their mothers, were tested at a similar age. Results: A total of 69 preterm infants with a median gestational age of 26 weeks and 5 days were included, 45 cholestatic and 24 non-cholestatic. Of the cholestatic infants, 31/45 (69%) were CMV positive vs. 3/24 (13%) of the non-cholestatic infants (p < 0.001). Cholestatic infants were equally preterm as the non-cholestatic ones, but were more severely ill. After adjusting for the risk factors necrotizing enterocolitis, prolonged parenteral nutrition, and gestational age, being CMV positive remained significantly associated with cholestasis in a multivariable logistic regression model. Characteristics of CMV-positive and -negative cholestatic infants showed differences only for necrotizing enterocolitis, occurring in 55% (17/31) of CMV positive vs. 21% (3/14) of CMV negative (p = 0.054), and mortality. Eight cholestatic CMV-positive infants died (26%) vs. none of the CMV-negative infants (p = 0.044). Conclusions: CMV DNA was detected in two out of three cholestatic preterm infants, by far more often than in the non-cholestatic control group. Cholestasis with simultaneous detection of CMV DNA may be associated with increased mortality.