Oral ibuprofen promoted cholestatic liver disease in very low birth weight infants with patent ductus arteriosus

Objectives: Hemodynamically significant patent ductus arteriosus (hsPDA) in very low birth weight (VLBW) infants is routinely treated in many countries with oral ibuprofen. This study retrospectively assessed whether the risk of cholestatic liver disease (CLD) increased due to oral ibuprofen administration in VLBW infants.

Methods: A total of 122 VLBW preterm infants (26∼32 weeks, birth weight<1500g) diagnosed with patent ductus arteriosus (PDA) admitted to our neonatal intensive care unit (NICU) between September 2016 to August 2018 were included. Sixty-four infants were diagnosed with hs-PDA and received ibuprofen treatment. VLBW infants with PDA untreated with ibuprofen served as controls. Soybean oil and fat emulsions were routinely added to parenteral nutrition (PN). Once CLD was diagnosed, the fat emulsions were immediately replaced with multi-oil fat emulsion injections. To assess the independent association of treatment and duration of ibuprofen with CLD and duration of fasting and PN, binary logistic regression or multivariate linear regression analyses were conducted, adjusting for major confounders (birth weight, gestational age, Clinical Risk Index for Babies, and cholestasis-associated risk factors).

Results: The duration of PN increased due to ibuprofen treatment for 6.559 days (95% CI: 1.769, 11.349; P=0.008), and the risk of prolonged fasting (cutoff>5 days) might have increased due to ibuprofen treatment (OR: 3.043, 95% CI: 0.965, 9.594; P=0.057). Furthermore, CLD was influenced by ibuprofen treatment (OR: 6.730; 95% CI: 1.279, 35.41; P=0.024), early thrombocytopenia 7 days postnatal (OR: 6.996; 95% CI: 1.769, 27.658; P=0.004), and late onset sepsis (OR: 6.976; 95% CI: 1.561, 31.169; P=0.011). Further analysis adjusting for cholestasis-associated risk factors revealed that CLD was influenced by the duration of ibuprofen treatment (OR: 2.864; 95% CI: 1.104, 7.422; P=0.030), Platlets counts 7 days postnatal (OR: 0.971; 95% CI: 0.950, 0.994; P=0.013), and duration of antibiotics (OR: 1.134; 95% CI: 1.002, 1.282; P=0.046).

Conclusions: This retrospective study indicated oral ibuprofen duration-dependently increased the risk of CLD in VLBW infants with PDA, and early thrombocytopenia served as the critical risk factor.