Neonatal jaundice is commonly observed among newborn infants, caused by hyperbilirubinemia. Severe hyperbilirubinemia should be recognized and treated to prevent kernicterus, a condition characterized by irreversible neurological damage. In most cases, hyperbilirubinemia results from a physiological increase in the unconjugated bilirubin concentration, combined with immature mechanisms for conjugation and enhanced enterohepatic circulation. However, certain conditions (e.g. prolonged jaundice, onset in the first 24 hours after birth, rapid rise in serum bilirubin, etc.) should raise the suspicion of an underlying pathologic mechanism. In general, unconjugated hyperbilirubinemia can be caused by (1) an increased, pathologic production of bilirubin, (2) a deficiency of hepatic uptake, (3) an impaired conjugation of bilirubin, (4) an increased enterohepatic circulation of bilirubin, or (5) a combination of the above . In case of pathologic unconjugated hyperbilirubinemia, an increased production of bilirubin due to hemolysis is the most likely cause. Therefore, a common approach in the diagnostic work-up of neonatal unconjugated hyperbilirubinemia is to differentiate between hemolytic and non-hemolytic diseases as a first step .
We present a newborn with severe prolonged neonatal hyperbilirubinemia without signs of hemolysis, which proved to be caused by a disorder generally classified in the hemolytic group of unconjugated hyperbilirubinemia.
A full term baby boy was born as the first child of a mother of Surinamese, Sephardic Jewish and Chinese descent. The mother was using an antidepressant (Efexor®, venlafaxine) during pregnancy, which was otherwise uncomplicated. Delivery was spontaneous and without instrumentation. Physical examination of the newborn was unremarkable. Birth weight was 2960 gram. After birth mother and child were discharged from the hospital. The boy was exclusively breastfed and showed adequate growth. Jaundice was noticed by the parents on the second day, but no further action was taken. On the ninth day after birth poor feeding and lethargy were noticed, and the patient was referred for bilirubin measurement. This revealed a total serum bilirubin (TSB) of 25.0 mg/dL (427 µmol/L). On the same day he was admitted to our hospital. Physical examination on admission showed marked jaundice but was otherwise normal. Specifically, there were no signs of infection, lethargy or encephalopathy.
Initial laboratory results revealed: TSB 26.5 mg/dL (454 µmol/L); indirect bilirubin 26.1 mg/dL (446 µmol/L); hemoglobin concentration 10.9 mmol/L; hematocrit 47%; Reticulocytes 22 o/oo; lactate dehydrogenase (LDH) 401 units/L; antiglobulin test negative; blood group B; Rhesus positive. The mother’s blood group was AB, Rhesus negative. Markers for infection were not increased. Thyroid function was normal.
Pyruvate kinase and glutathione reductase activity were also normal. Glucose 6 phosphate dehydrogenase (G6PD) activity was decreased: 1.6 U/g Hb (normal values for age < 3 months: 5.0 to 7.8 U/g Hb). DNA-analysis for Gilbert’s syndrome, commonly associated with glucose 6 phosphate dehydrogenase (G6PD) deficiency, tested negative.
Blood group antagonism was deemed unlikely because of a negative antiglobulin test. The normal and stable hemoglobin concentration, the absence of reticulocytosis and LDH concentration within the reference range suggested a non-hemolytic disease process responsible for the hyperbilirubinemia. Since the newborn was exclusively breastfed, breast milk jaundice was initially thought to be the most plausible explanation, although this usually does not require therapy. The use of venlafaxine was also considered a possible explanation. When the hyperbilirubinemia persisted despite several days of phototherapy, we decided to reconsider our differential diagnosis. Although a non-hemolytic cause for the persisting jaundice was still considered most likely because of the lack of signs of hemolysis, we decided to test for erythrocyte enzyme deficiencies, while awaiting the course of the hemoglobin concentration.
Phototherapy was started immediately after admission. Eleven days of intermittent phototherapy were needed to achieve the stable and acceptable bilirubin concentration of 21.5 mg/dL (368 µmol/L).
Outcome and follow-up
During follow-up until the age of six months the patient showed adequate growth and development. Jaundice and bilirubin levels showed a steady decline. At three months of age TSB was 2.7 mg/dL (47 µmol/L). No complications were noted. He was discharged from the outpatient clinic at the age of six months.
This case report describes a newborn with G6PD deficiency developing hyperbilirubinemia without hemolysis. Since the newborn lacked any signs of infection and the initial diagnostic work-up showed no indications of iso-immunization, hemolysis or hypothyroidism, breast milk jaundice was initially believed to be the most likely cause of the neonatal hyperbilirubinemia. Venlafaxine related jaundice was also considered. However, a relationship between neonatal hyperbilirubinemia and the use of venlafaxine during pregnancy has not been convincingly shown in the literature. One retrospective study of pregnant women using antidepressants reported higher rates of jaundice among the exposed newborns (n = 76) compared to unexposed newborns . However, of these 76 exposed newborns, only 9 (11.8%) had mothers that had used venlafaxine, and therefore its exact contribution to the development of neonatal jaundice remains unclear.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect, being present in more than 400 million people worldwide . The most well known clinical presentation is drug-induced or infection-induced acute hemolytic anemia with jaundice. The role of hemolysis in the development of jaundice in G6PD deficient newborns has been given much attention in the last decade. However, the mechanism by which G6PD deficiency causes neonatal hyperbilirubinemia is not yet fully understood. Several studies have demonstrated that hemolysis is not directly related to the TSB (as measured by COHb levels) in jaundiced newborns with G6PD deficiency    . Kaplan et al. suggested that multiple causes are implicated in the development of neonatal jaundice in G6PD deficient newborns, including decreased bilirubin conjugation. This impairment in conjugation has been associated with Gilbert’s syndrome , but our patient tested negative for Gilbert syndrome. The etiology of impaired conjugation in the majority of patients with neonatal jaundice and G6PD deficiency without Gilbert’s syndrome is unknown   .
While the exact mechanism for developing neonatal jaundice in G6PD deficient infants has yet to be elucidated, it is important to recognize that G6PD deficiency can cause hyperbilirubinemia by both hemolytic and non-hemolytic pathways.
- G6PD deficiency should be considered in a newborn with prolonged hyperbilirubinemia, despite the absence of hemolytic markers.
- While G6PD deficiency is often classified as a hemolytic cause of neonatal hyperbilirubinemia, evidence suggests that both hemolytic as well as non-hemolytic pathways exist which can lead to hyperbilirubinemia in a newborn.
- The mechanism by which G6PD deficiency causes neonatal jaundice is not clear.
A.A. Anas 1, M.W. Bijlsma 2, R. Knol 3 & A.A. Kempen 4
1 Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
A.A. Anas was working as a pediatric intern in the Onze Lieve Vrouwe Gasthuis at the time of writing.
2 Department of Paediatrics, VU University Medical Center, Amsterdam, The Netherlands.
3 Department of Paediatrics, Kennemer Gasthuis, Haarlem, The Netherlands.
4 Department of Paediatrics, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.
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