Crigler-Najjar type II in pregnancy: A case report

Abstract

Crigler-Najjar is a rare, autosomal recessive disorder that results in mutations causing a complete absence (type I) or deficiency (type II) of the hepatic uridine diphospho-glucuronosyl transferase (UDPGT) enzyme. Both forms, however, result in unconjugated hyperbilirubinaemia which can lead to kernicterus and potentially death. Phenobarbitone can be used as an enzyme inducer in Type II to facilitate a reduction in total serum bilirubin. We report two consecutive pregnancies in a 29-year-old woman with Crigler-Najjar Type II syndrome. Phenobarbitone therapy was commenced in the first pregnancy at 16 weeks’ gestation and was associated with favorable biochemical and clinical outcomes. There were no reports of long-term neonatal neurological sequelae. Tertiary center, multidisciplinary care is recommended for optimal pregnancy outcomes.

Introduction

Crigler-Najjar syndrome (CNS) is a rare, autosomal recessive disorder affecting 1 in 1,000,000 births. ¹ It results in mutations causing a complete absence (type I) or deficiency (type II) of the hepatic uridine diphospho-glucuronosyl transferase (UDPGT) enzyme. Typically, enzyme activity in type II is less than 10% which is sufficient to maintain unconjugated bilirubin levels below that which have been associated with neurological damage. Both forms, however, result in unconjugated hyperbilirubinaemia which can lead to kernicterus and potentially death. ¹

Case

We report two consecutive pregnancies in a 29-year Caucasian woman with Crigler-Najjar Type II syndrome. Her baseline total serum bilirubin level was 368 micromoles/L (normal range 0–21 micromol/L), conjugated bilirubin of 16 micromoles/L (normal range <5 micromol/L) and albumin of 41 g/L (normal range 35−50 g/L). At 16 weeks’ gestation of the first pregnancy, she was seen by the obstetric physicians who commenced phenobarbitone 30 mg in the evening with uptitration to 60 mg at night seven days later with a rapid reduction in her serum total bilirubin (156 micromol/L) and icterus (see Figure 1). Phototherapy was also considered but as the woman lived rurally this option was not logistically feasible.

Figure 1.

Total serum bilirubin by gestation.

The pregnancy was complicated by gestational diabetes with a fasting blood sugar level of 5.1 mmol/L (normal range < 5.1 mmol/L) and she required insulin therapy from 27 weeks’ gestation. Bile acids were normal and there was no evidence of hepatic synthetic dysfunction or intrinsic coagulopathy as evidence by a normal prothrombin time performed at 27 weeks’ gestation. She continued phenobarbitone 60 mg daily throughout the remainder of her pregnancy and underwent an emergency caesarean section at 38 weeks’ gestation for fetal distress during labour. The neonate weighed 3180 g, had a peak serum bilirubin of 181 micromol/L and underwent 23 h of phototherapy with no long-term neurological sequelae. The mother was advised that a copper intrauterine device would be a preferred method of contraception if desired.

While the plan was to reduce the dose of phenobarbitone to 30 mg at night after delivery, the patient preferred to continue on 60 mg due to the clinical improvement in jaundice and good tolerance of the medication without side effects. Two years later, the woman was referred for repeat antenatal monitoring during her second pregnancy; 60 mg phenobarbitone at night was continued throughout with stable serum bilirubin at similar levels to those in her first pregnancy. Gestational diabetes required insulin treatment from 27 weeks’ gestation to control fasting hyperglycaemia but the pregnancy was otherwise uncomplicated. Due to her previous caesarean section, she was delivered at 38 weeks and six days of gestation. The infant weighed 3225 g and had neonatal jaundice with a peak serum bilirubin of 219 micromol/L requiring 24 h of phototherapy. Neither infant underwent genetic testing for a mutation in the genes encoding UDGPGT as there was no history of hyperbilirubinaemia in the father and it was considered highly unlikely that he would be a carrier. She was advised to use barrier contraception while awaiting her husband's vasectomy as they did not desire further pregnancies.

Discussion

Crigler-Najjar syndrome (CNS) is a rare condition caused by mutations causing complete deficiency (type I) or severely reduced (type II) of the hepatic uridine diphospho-glucoronosyl transferase enzyme (UDPGT) that catalyses the conjugation of bilirubin with glucouronic acid within hepatocytes facilitating its excretion in bile. Type I presents at birth and is associated with severe jaundice and kernicterus. Untreated patients are at serious risk of neurological damage. Type II, however, is associated with a better outcome and often presents later in life. ² The residual UDPGT activity of less than 10% is sufficient to maintain serum bilirubin below the level associated with neurological sequelae. Unlike type I, type II responds to phenobarbitone treatment which stimulates UDPGT? Production resulting in a 25% reduction in serum bilirubin. Both type I and type II Crigler-Najjar result in congenital unconjugated hyperbilirubinaemia. Acute illness, prolonged fasting or the stress of pregnancy can, however, lead to an increase in bilirubin levels.^1,3–5

In healthy individuals, unconjugated bilirubin is bound to albumin. When the level of unconjugated bilirubin exceeds the albumin-binding capacity it deposits in tissues such as the basal ganglia, hippocampus and cerebellum. Symptoms include hypotonia, lethargy and anorexia, and in severe cases ataxia, dyspraxia and kernicterus. Without treatment, kernicterus can lead to a poor prognosis and eventually death. ⁵

Evidence suggests that Crigler-Najjar type II is not associated with maternal risk. ⁶ However, as unconjugated bilirubin is transported to the fetus from the mother across the placenta there is a risk of kernicterus and sometimes even death.^1,3 Fetal unconjugated bilirubin levels often parallel those found in the mother. ⁷ While it is currently unknown what level of unconjugated bilirubin is neurotoxic for the developing fetus it is recommended to keep the maternal unconjugated total serum bilirubin concentration less than 200 micromol/L. ⁷ Premature and sick neonates are more sensitive to hyperbilirubinaemia than those born at full term. ⁴

Phenobarbitone acts as an enzyme inducer and facilitates hepatic metabolism and excretion of bilirubin. ⁸ Studies have shown that the administration of phenobarbitone antenatally is linked to reduced levels of serum bilirubin levels in the fetus and newborn.^8,9 While its use in the first trimester has been linked to facial dysmorphism and intellectual disability this is typically only seen when used in dosages exceeding 750–1000 mg per day. ¹⁰ Consequently, dosages less than 50–60 mg per day are recommended during pregnancy. ¹ It is believed that phototherapy decreases the level of indirect bilirubin present in the solution as well as stimulates UDPGT activity. ⁸ Other therapies predominantly aimed at Crigler-Najjar type I include exchange transfusions, albumin infusions or liver transplantation. ⁴

Phenobarbitone has low milk to plasma ratio and binds to neonatal proteins at a low level. With a long plasma half-life, it does however have the theoretical risk of accumulating in infants exposed to maternal phenobarbitone. Despite this, plasma levels of phenobarbitone in infants exposed to maternal phenobarbitone from breast milk are considerably less than the recommended pediatric dose. Based on this, the consensus is that phenobarbitone poses minimal risk to infants via maternal lactation. In cases of excessive neonatal drowsiness or poor weight gain, drug discontinuation could be considered. ¹¹

Guidelines recommend preconception genetic counselling and administration of folic acid 10 mg per day. Antenatal care should be conducted at a tertiary center that is capable of performing rapid bilirubin assays and providing phototherapy for the infant. Maternal unconjugated bilirubin levels are monitored with the aim to keep levels under 200 micromol/L. ⁷ Drugs that increase unbound, unconjugated bilirubin such as sulfonamides, salicylates, frusemide, ampicillin and ceftriaxone should be avoided. ¹ Long-term (at least 18 months) neurological follow-up, with particular attention to hearing assessment, of the child is also encouraged.^1,7

While no specific modifications to regional anesthesia were performed for this patient it is recommended that consideration is made to ¹ avoiding drugs that cause displacement of bilirubin from albumin such as propofol, sulfonamides, ceftriaxone, ampicillin, salicylates and furosemide, or that are considered hepatotoxic, ² minimize situations of stress including dehydration and fasting and ³ ensuring the mean arterial pressure is maintained above 60 mmHg thereby ensuring adequate portal blood flow.^12,13 Similarly, local anesthetics which have a lower degree of protein binding (e.g. lignocaine 55-65%) are preferred over those that have a high protein affinity (e.g. bupivacaine 85–90% and ropivacaine 94%). Theoretically, this minimizes the effect on serum bilirubin: protein ratio. ¹²

As hormonal contraceptives undergo hepatic metabolism and elimination their use has been associated with hepatobiliary damage. Consequently, the risk of hyperbilirubinaemia exacerbations must be considered when counselling patients with Crigler-Najjar type II on postpartum contraceptive options and ideally their use should be avoided. ¹⁴

Pregnancy in Crigler-Najjar syndrome is rare, with only nine previously reported cases. We report the 10th case of this disorder in pregnancy. Similar to the published literature, this case similarly demonstrates the safety and beneficial effect of phenobarbitone therapy to both mothers and neonates.