Successful Pregnancy Outcome In Maternal Crigler Najjar Syndrome Type II

Shakuntala PN

ISSN 0972-5997

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Mangalore, India

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OJHAS Vol. 11, Issue 3: (Jul-Sep 2012)

Case Report
Successful Pregnancy Outcome In Maternal Crigler Najjar Syndrome Type II.

Authors
Shakuntala PN, Poornima M, Padmalatha VV, Shubha R Rao,
Department of Obstetrics and Gynaecology, St. Martha’s Hospital, Bengaluru, India.

Address for Correspondence
Dr. Shakuntala PN,
Department of Obstetrics and Gynaecology,
St. Martha’s Hospital,
Bengaluru, India.
E-mail: shakuntala_pn@yahoo.com

Citation
Shakuntala PN, Poornima M, Padmalatha VV, Rao SR. Successful Pregnancy Outcome In Maternal Crigler Najjar Syndrome Type II. Online J Health Allied Scs. 2012;11(3):12. Available at URL: http://www.ojhas.org/issue43/2012-3-12.htm

Open Access Archives
http://cogprints.org/view/subjects/OJHAS.html
http://openmed.nic.in/view/subjects/ojhas.html

Submitted: Jul 29, 2012; Accepted: Oct 3, 2012; Published: Oct 25, 2012

This work is licensed under a Creative Commons Attribution-No Derivative Works 2.5 India License

This Article

Abstract: Estimated incidence of Crigler-Najjar syndrome(CNS) is 1 case per 1,000,000 births(1 million). The overall prevalence of CN syndrome is unknown, with only several hundred people reported to have this disease. It is interestingly very rare to encounter a pregnant adult women with congenital jaundice. Pregnancy in CN type II patients is a diagnostic and a therapeutic challenge because of the high risk of bilirubin encephalopathy with serious neurological damage as life-threatening complications for the fetus. To date 8 pregnancy outcome have been reported from 5 women and we report the6 woman with a successful 9 th pregnancy outcome. We have discussed detail history, presentation and management during pregnancy and care of the new born.
Keywords : Crigler Najjer Syndrome type II; Unconjugated hyperbilurubinemia; Phenobarbitone; Phototherapy.

Introduction

Crigler Najjar Syndrome (CNS) is a rare autosomal recessive condition associated with two types in clinical practice. CNS Type I is characterised by complete deficiency and CNS type II by severely reduced activity of hepatic microsomal bilirubin- uridine 5-diphosphate-glucuronosyltransferase (UDPG-T)(1). First case of CNS type I was reported by Crigler and Najjar in 1952 which results in severe unconjugated hyperbilirubinemia and thus neurologic impairment (kernicterus) in the new born, Affected individuals do not respond to Phenobarbital therapy, need prolonged hours of intensive phototherapy, exchange transfusions and, without liver transplantation, usually die in infancy from kernicterus.(1,2) Arias first described CNS Type II, causes milder unconjugated hyperbilirubinemia and responds to phenobarbital treatment and present with episodes of jaundice responding to phenobarbitone.(3-5) The gene coding for UDPG-T, UGT1A1, has been mapped to 2q37 and mutations associated with both type I and type II have been reported.(6-8) Maternal CNS type II is a rare clinical entity with only 8 pregnancies reported from 5 CNS type II pregnant women. We present the 9^th pregnancy from 6th woman with CNS type II. Due to paucity of information, we reviewed the literature and with the experience shared by authors,(9-17) were able to have a successful experience through out pregnancy, delivery and the puerperium and we are very grateful to all the authors.

Case Report:

A 27 year old Gravida 2, para 0, abortion 1, living 0, presented to us at 24 weeks of gestation, with complaints of malaise, low grade fever, yellow discolouration of sclera, high coloured urine. She revealed a past history of first episode of severe jaundice at 5 months of age requiring hospital admission, responded to phototherapy and daily dose of phenobarbitone. Multiple episodes of treatable jaundice were reported. As it is customery in hindu society(tamil origin), women being admitted repeatedly for problems are looked down upon and her mother took the help of ayurvedic practioner, which is indegenious to our country and had noticed alleviation of episodes of jaundice. Husband was also of tamil origin and was unaware of her situation. Following her first abortion 2 years back at 12 weeks of pregnancy associated with sever jaundice, she was investigated at a tertiary centre and produced a stamped referral slip as a case of Crigler Najjar syndrome type II. She responded to phenobarbitone 60 mg/day and 2 years later had a spontaneous conception, with no antenatal care at any medical centre. She looked deeply icteric and dehydrated with 24 weeks of pregnancy. After reviewing the earlier diagnosis and discussing with our gastroenterology collegues we decided to treat her with tablet phenobarbitone 60 mg once a day, maintain hydration and supportive care. Her complete haemogram was normal, anti HIV , anti HbsAg , anti HBC, anti HBE antibodies were negative. She had raised total bilurubin of 13.3 mg/dl, conjugate bilurubin of 0.1 mg/dl, unconjugated bilurubin :13.2 mg/dl. Normal total proteins: 7.4 g/dl, albumin:4.1 mg/dl, normal liver enzymes.blood group was A negative and husband was A positive Ultrasonography of upper abdomen was normal, without any organomegaly. Obstetric scan documented a single live intrauterine pregnancy with fetus in breech, corresponding to dates, normal placenta, liquor volume and no gross congential anomaly. A fetal echo performed was normal. She was kept on follow up every 2 weekly and we plotted her unconjugated bilurubin levels as shown in figure-1 . at 29 completed weeks she had an episode of premature contractions and so we administered steroids to enhance fetal lung maturity. Her unconjugated bilurubin levels were between 8-9 mg/dl.we continued with phenobarbitone, oral haematenics, calcium, multi vitamin and protein supplements. She went into spontaneous labour at 35-36 weeks of pregnancy and delivered a live male baby weighing 2200 grams, length of baby was 43 centimeters with an APGAR score of 5,6,7,8 at1,5,10,and 15 minutes respectively, length of cord was 34 cms and shifted to neonatal intensive care unit. Neonate had the following Haemoglobin was - 16.9 gm% PCV: 57.3%. reticulocyte count-0.3%, total wbc count - 10,000 cells/mm³, Platelet count: 1.95 lakh/ mm³PBS: normocytic and normochromic Blood group and type: A positive. Direct Coombs Test was negative. Total bilurubin- 12.1 mg/dl, direct- 0.6, indirect- 11.5, C-Reactive Protien- 26 mg/litre. Neonatal hyperbilurubinemia table-2 and hypoglycaemia were treated with Intravenous Phenobarbitone. 5 mg/kg body weight 12 hrly and dextrose bolus respectively. By 16 hours of birth baby needed phototherapy as his total bilurubin was stalling. Hence, intensive phototherapy has to be started, total serum bilurubin levels started to decline , by day 5 total Serum bilurubin reached values below 5 mg/dl and declined to reach 3.3 mg/dl and 1.3 mg/dl by day 8 and 14 respectively. Baby was discharged on day 14 .

Discussion

Crigler-Najjar Syndrome (CNS) is a rare autosomal recessive disorder of bilurubin conjugation as substantiated by many authors.(6-8) Incidence of CNS is probably less than 1 case per 1,000,000 births. Only a few hundred cases have been described in literature and the exact prevalence is unknown (Table-1).

Table 1: Review of literature
Author, year	Disease type	Maternal serum bilirubin, mg/dl	Maternal treatment	Delivery	Newborn treatment/outcome
Taylor et al (9), 1991	CNS type I	17–21.8	None	Caesarean section	Phototherapy/quadriplegic
Smith et al(10)., 1994	CNS type II	5.3–9.6	None	Spontaneous, vaginal, at term	No treatment required/normal
Ito et al(11).,2001	CNS type II(2 pregnancies)	NA	Phototherapy, Phenobarbital	NA	Normal
Holstein et al.(12), 2005	CNS type II	4.2–8.9	Phototherapy, Phenobarbital	Primary caesarean section	No treatment required/normal
Pinkee et al.(13), 2005	CNS type II	10.8 (at delivery)	None	Spontaneous, vaginal, at term	Blood transfusion, phototherapy, phenobarbital/normal
Gajdos et al.(14), 2006	CNS type I	13.5–23.5	Phototherapy, Albumin infusions	Caesarean section	Phototherapy/normal
Passuello.(16) V et al 2009	CNS type II	4–6 mg/dl	Phenobarbitone and insulin for GDM	Vaginal	Normal
Hannam.S et al,(17) 2008	CNS type I	200-300 micro mol/L	Phototherapy	Emergency cesarean	Phototherapy and phenobarbitone, double exchange transfusion
Hannam.S,et al(17) 2008	CNS type I	399-510micro mol/L	Phototherapy, Albumin	Vaginal	Phototherapy and phenobarbitone, double exchange transfusion
Holstein et al.(15), 2010	CNS type II, 2 pregnancies	4.2 mg/dl and 5.5 mg/dl until delivery.	Phototherapy, Phenobarbitone	Both pregnancies primary caesarean section	No treatment required/normal
Shakuntala et al 2012, Present case	CNS type II	8-9 mg/dl until delivery	Phenobarbitone	Spontaneous vaginal	Phototherapy and phenobarbitone/ normal.
NA: not available

Type I presents at birth and is more severe form associated with kernicterus and neurologic morbidity, whereas, type II CNS has late neonatal presentation, lower serum unconjugated bilurubin concentration, which responds to phototherapy and phenobarbital therapy.

Due to the rarity of the condition, about 4 pregnancies have been reported in 4 cases of maternal CNS type I and 8 pregnacies from 5 maternal CNS type II (Table-1).

With the knowledge we gained by reviewing the literature we realised it would be prudent to start phenobarbital therapy from her past history, rather than debate her genetic basis and perform a liver biopsy which she anyway declined. Gilbert’s syndrome was the other possibility, usualty it presents with hyperbilurubinemai during puberty possibly because of the inhibition of bilirubin glucuronidation by endogenous steroid hormones. Anti HIV, anti HbsAg, anti HBC, anti HBE antibodies were negative ruling out hepatitis, she was not in sepsis as total count was 10,000 cells/mm³. Her blood group was A Rh typing was negative. We kept her on a close follow up for every two weekly serum total, conjugated and unconjugated bilurubin levels which is depicted in Figure-1. Values have ranged from 4.2-10.8 mg/dl, present case it was maintained between 8-9 mg/dl on Phenobarbital therapy 60 mg daily. Similar observations were shared by other authors.(10-13,15,16) Good maternal and fetal outcomes have been reported when, dual treatment consisting of phototherapy during embryogenesis and phenobarbital during the rest of the pregnancy.(15) Though we did not have an opportunity to use phototherapy during the embryogenesis as the patient registered with us at 24 weeks, our maternal and fetal outcomes concur with Ito et al and Holstein et al, Passuello V et al.(11,12,15,16) Rest of the pregnancy and antenatal care was carried out as usual procedure with the fetal anomaly scan, cardiac scan,growth parameter, liquor volume , placental maturity all were correlating with the period of gestation. She had an episode of preterm pain at 29 weeks of gestation and betamethasone 12 miiligrams was given intramuscularly 24 hours apart to enhance lung maturity, to prevent the further burden on immature liver. However, she continued pregnancy and delivered a male baby weighing 2200 grams, length of 43 centimeters at 35-36 weeks of gestation. Baby had initial cyanosis and on bagging and masking the APGAR score improved. But, due to the high risk associated with preterm birth and maternal CNS type II ,baby was immediately transferred to the neonatal intensive care unit. Figure 2 reflects the serial serum total bilurubin levels measured in the baby. At 4 hours and 16 hours of birth total bilurubin levels were 11.5 mg/dl and 11.2 mg/dl even with commencement of f intravenous phenobarbitone 5 mg/kg body weight.hence intensive phototherapy was started at 16 hours of birth. Baby recovered by 8 days and was discharged on request by the parents. Baby had normal developmental miles stones until 1 year of follow up. Similar treatment modalities and nennatal outcomes have been report by some authors.(10-13,15,16) We continued the use of oral Phenobarbital therapy in the mother who later followed up with gastroenterologists. She did not report any puerperial problems.


Figure:1 Maternal levels of unconjugated bilurubin in mg/dl plotted on the Vertical axis.Horizontal axis depicts pregnancy in weeks, PD-1 week post delivery. Inital values of 13.03 mg/dl has substantially decreased following the start of Phenobarbital therapy- 60 mg/day-red line.	Figure 2: Neonatal total serum bilurubin levels .Vertical axis –mg/dl and neonatal age in hours after birth on horizontal axis, d- days.

We report this case due to its rarity, may be the 6^th case of maternal Crigler-Najjar Syndrome Type II who successfully delivered the 9^th such baby. When suddenly encountered by such pregnant women with congenital jaundice we were faced with a clinical dielemma, as to are we offering the correct standard of care to optimise the maternal and fetal outcome? This clinical scenario also highlights the importance of basic history taking and consider this condition also in the differential diagnosis of hyperbilurubinemia in pregnancy, which typically has elevated uncongugated bilurubin levels, normal liver enzymes and proteins, may be with an affected member in the family.

Data suggest that pregnancy need not be contraindicated in Crigler-Najjar Syndrome Type II. But prompt recognition and interdisciplinary involvement of paediatrician, obstetrician, gastroenterologists, blood bank officer and laboratory technician in these high risk pregnancies we can achieve optimum maternal and fetal outcome( prevent neurologic morbidity and sequale).

Acknowledgement:

We would like to thank the patient and her family for their ever day to day co-operation. We also thank all the members of Department of Obstetrics, Paediatrics, Gastroenterology, Medicine, Bood bank officials, maternity nurses, Lab technicians and pharmacy members for their valuable inputs. We are grateful to sisters of Good Sheperd convent for all the moral, spiritual and financial support rendered to the patient and her family, without their help we clinicians would not be able to report this case.

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