Management of pregnancy in Crigler Najjar syndrome type 2

Crigler Najjar syndrome is associated with indirect hyperbilirubinemia due to a deficiency of enzyme Uridine Di Phospho Glucoronosyl Transferase (UDPGT). Presented here is a case of a female in the first trimester of pregnancy, who was diagnosed to have type 2 Crigler Najjar syndrome. We also discuss the management of this rare disease especially in pregnancy. Unconjugated bilirubin can cross the placental barrier causing neurological damage in the newborn. Patient was carefully monitored during pregnancy and treatment with phenobarbitone in low doses was adjusted such that the serum bilirubin levels were below 10 mg/dL. Crigler Najjar syndrome being rare needs to be diagnosed early in pregnancy to avoid adverse fetal outcomes. Phenobarbitone being an inducer of enzyme UDPGT is used as the first line of treatment and is not teratogenic in the low doses used. Treatment protocol followed was on the basis of previous reported cases and successful perinatal outcome was achieved.     

Neurological dysfunction induced by bilirrubin

Introduction

“Kernicterus” is a term currently used to describe bilirrubin induced brain injury in the neuro-pathological studies. This is a confusing term and nowadays we prefer bilirrubin encephalopathy or bilirrubin induced neurological dysfunction. The clinical signs vary and it is clearly decreasing in prevalence in developed countries.

Material and methods

We review a series of 7 patients with bilirrubin encephalopathy and variable neurological manifestations, who were seen in the Neuropaediatric Department in the last 10 years. Only one patient died in the neonatal period with hyperbilirubinaemia, sepsis and multi-organ failure.

Results

Diverse aetiological factors were related to hyperbilirubinaemia. All patients had clinical symptoms due to hyperbilirubinaemia. Neuroimaging during the neonatal period showed involvement of the nucleus pallidus, with hyperintensity in T1 in the brain MR scan as the most consistent finding. All the patients who survived developed neurological signs and we try to correlate them with biochemical, clinical, neuroimaging and neurophysiological parameters.

Conclusions

An increase in the number of patients with bilirrubin encephalopathy has been observed over the last few years, and we attempt to find out the causes. The increased survival of the low birth weight newborns, the increase in the immigration population and the use of diagnostic neuroimaging contribute to this increase. It is a great challenge for the neonatologist and for neuropaediatricians to prevent its occurrence and to minimise the effects of bilirrubin encephalopathy.     

Clinical implication of the difference between transcutaneous bilirubinometry and total serum bilirubin for the classification of newborns at risk of hyperbilirubinemia

Objectives

1) To determine the relationship between transcutaneous bilirubin measurements (TcB), performed using BiliCheck™ or Minolta Air-Shields JM-103®, and total serum bilirubin levels (TSB) and 2) to evaluate the predictive accuracy of TcB measurements for risk using the nomogram recommended by the Canadian Pediatric Society (CPS).

Methods

A total of 154 healthy term neonates from the newborn nursery at McMaster Children's Hospital meeting the inclusion criteria were enrolled. TcB measurements were performed within 30 min of obtaining the TSB measurement.

Results

Both devices showed a good correlation with the laboratory method (BiliCheck™-Vitros, R² = 0.86; Minolta Air-Shields JM-103®-Vitros, R² = 0.85), but underestimated the serum bilirubin. Applying the risk classification using the 40th, 75th, and 95th percentile of the Bhutani nomogram a 6%, 0%, and 1% false negative rate was found for BiliCheck™ and 62%, 74% and 81% for the Minolta Air-Shields JM-103® device. After correcting for the differences using either the bias or the 95% CI the false negative rate was reduced to zero in all cases.

Conclusion

TcB measurements cannot be directly applied to a TSB nomogram but must be adjusted for any observed biases in order to avoid misclassifying newborns at risk for hyperbilirubinemia.     

MRI在新生儿核黄疸诊断中的应用

目的 探讨新生儿核黄疸的MRI表现,为临床诊断与随访提供客观的影像学依据. 方法 21例具有典型临床表现的核黄疸患儿在生后接受了头部高场MRI检查,场强为1.5 Tesla,扫描序列包括T1WI,T2WI和DWI,2名不知被检者病史的放射科医师分析MRI 结果.结果 21例新生儿生后2～11天首次MRI检查有19例(约占90.5%)TIWI上双侧苍白球信号对称性增高(其中3例3个月后复查MRI显示T2WI上双侧苍白球对称性高信号),另外2例(约占9.5 %)信号未见改变.上述病例DWI上信号均未见特殊改变. 结论 新生儿期核黄疸主要表现为T1WI上双侧苍白球对称性高信号;后遗症期核黄疸主要表现为T2WI上双侧苍白球对称性高信号;DWI对诊断核黄疸无帮助.     

MRI成像在新生儿核黄疸诊断中的应用价值

目的 探讨MRI常规序列在新生儿核黄疸的诊断价值.方法 回顾性分析我院2014年5月至2016年8月经临床确诊的35例病理性核黄疸新生儿头颅MRI图像.年龄3~25 d,平均14 d.观察患儿双侧苍白球在T1WI、T2WI、T2FLAIR、DWI及ACD图上的信号变化规律.结果 35例病理性核黄疸新生儿中,26例T1WI上双侧苍白球区表现为对称性高信号;5例T1WI表现为双侧苍白球后部对称性高信号,T2WI、T2FLAIR、DWI及ADC图上未见异常改变;另外4例各序列均未见异常信号;5例病理性核黄疸患儿在随后2~3个月随访、复查中出现脑后遗症改变,均表现为双侧苍白球区T2WI对称性高信号,ADC图上呈稍高信号,T1WI、T2FLAIR及DWI上未见异常信号.结论 MRI常规扫描序列T1WI、T2WI及ADC图分别对新生儿病理性核黄疸急性期及后遗症期的诊断及预后判定具有重要价值.     

Cost-effectiveness analysis of a system-based approach for managing neonatal jaundice and preventing kernicterus in Ontario

OBJECTIVE:

To evaluate the incremental cost-effectiveness of a system-based approach for the management of neonatal jaundice and the prevention of kernicterus in term and late-preterm (≥35 weeks) infants, compared with the traditional practice based on visual inspection and selected bilirubin testing.

STUDY DESIGN:

Two hypothetical cohorts of 150,000 term and late-preterm neonates were used to compare the costs and outcomes associated with the use of a system-based or traditional practice approach. Data for the evaluation were obtained from the case costing centre at a large teaching hospital in Ontario, supplemented by data from the literature.

RESULTS:

The per child cost for the system-based approach cohort was $176, compared with $173 in the traditional practice cohort. The higher cost associated with the system-based cohort reflects increased costs for predischarge screening and treatment and increased postdischarge follow-up visits. These costs are partially offset by reduced costs from fewer emergency room visits, hospital readmissions and kernicterus cases. Compared with the traditional approach, the cost to prevent one kernicterus case using the system-based approach was $570,496, the cost per life year gained was $26,279, and the cost per quality-adjusted life year gained was $65,698.

CONCLUSION:

The cost to prevent one kernicterus case using the system-based approach is much lower than previously reported in the literature.     

UGT1A1基因G71R突变与新生儿不明原因严重高胆红素血症相关

目的探讨尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)基因G71R突变与新生儿严重高胆红素血症的相关性。方法采用病例对照研究的方法,病例组为复旦大学附属儿科医院(我院)收治的不明原因严重高胆红素血症(血清总胆红素水平≥342μmol·L-1)新生儿,采用PCR对外周血UGT1A1基因进行检测。对照组为我院新生儿出生缺陷生物样本数据库中血清总胆红素水平221μmol·L-1病例。病例组及对照组新生儿均要求胎龄≥35周,出生体重≥2 500 g。结果病例组和对照组各65例。UGT1A1 G71R是病例组中最常见的突变类型(73.8%,48/65)。对照组UGT1A1 G71R突变位点与既往Meta分析中提取的中国健康新生儿对比,在基因型分布及等位基因频率上差异均无统计学意义(P0.05)。病例组和对照组UGT1A1基因G71R突变中A等位基因频率分别为0.5和0.15,差异有统计学意义(P0.001),把握度为0.993。与携带G/G基因型新生儿相比,UGT1A1 G71R突变(A/A+G/A基因)可增加新生儿严重高胆红素血症的发病风险(OR=7.373,95%CI:3.395~16.008),把握度为1.0。结论 UGT1A1基因G71R突变与新生儿不明原因严重高胆红素血症相关。     

晚期早产儿高胆红素血症的分析

目的探讨晚期早产儿高胆红素血症的发病情况及围生期管理。 方法选取2013年10月至2015年3月,于四川大学华西第二医院新生儿科住院治疗的276例晚期早产儿中,被诊断为高胆红素血症的35例晚期早产儿为研究对象,纳入研究组;再采取等距抽样方法,从其余241例非高胆红素血症的晚期早产儿中,选取35例纳入对照组。采用回顾性分析方法,收集2组患儿的一般临床资料,并逐一对以下项目进行分析：①采用χ²检验或Fisher确切概率法,对2组患儿的性别、出生胎龄、入院日龄、入院途径、适于胎龄(AGA)儿、小于胎龄(SGA)儿、大于胎龄(LGA)儿、分娩方式构成比,以及胎膜早破、宫内或生后窒息、头颅血肿及母亲孕期疾病发生率进行比较。②了解纳入研究的276例晚期早产儿中,高胆红素血症发生率,以及高胆红素血症患儿中男、女患儿所占比例。③研究组35例晚期早产儿患儿的性别、入院日龄、入院途径、出生胎龄、AGA儿与LGA儿、分娩方式、出生医疗机构构成比,以及重度与极重度高胆红素血症发生率及伴发疾病或病因、胆红素脑病发生率、再入院率。 结果①研究组与对照组患儿的出生胎龄、入院日龄及途径、早产儿类型、分娩方式构成比,以及胎膜早破发生率、宫内或生后窒息发生率比较,差异均有统计学意义(χ²＝12.011,P＝0.002;χ²＝16.931,P<0.001;χ²＝31.895,P<0.001;χ²＝13.473,P＝0.001;χ²＝18.913,P<0.001;χ²＝5.927,P＝0.019;χ²＝8.454,P＝0.004)。2组患儿的性别构成比、头颅血肿发生率、母亲孕期疾病发生率比较,差异均无统计学意义(P>0.05)。②纳入研究的276例晚期早产儿中,高胆红素血症发生率为12.7%(35/276)。35例高胆红素血症晚期早产儿中,男、女性别比为1.9∶1。③研究组35例高胆红素血症晚期早产儿中,出生胎龄为34^＋0～36^＋6周,重度与极重度高胆红素血症患儿均为15例,重度和极重度高胆红素血症患儿所占比例为85.7%(30/35),无危险性高胆红素血症发生;入院日龄≤7 d者居多,占60.0%(21/35),此类患儿系产科母婴同室出院后由门、急诊收入新生儿科者,再入院率高达94.3%(33/35)。研究组晚期早产儿的出生医疗机构中,二级医院和三级医院所占比例相当,分别占45.7%(16/35)和48.6%(17/35)。35例高胆红素血症晚期早产儿的伴发疾病或病因中,合并严重感染患儿的占比为17.1%(6/35)、ABO血型不合溶血病为11.4%(4/35)、头颅血肿为5.7%(2/35)、葡萄糖-6-磷酸脱氢酶(G6PD)缺乏症为2.9%(1/35),同时合并上述多种病因为5.7%(2/35),但是仍然有57.1%(20/35)患儿未找到导致高胆红素血症发生的明确病因。研究组35例高胆红素血症晚期早产儿中,胆红素脑病发生率高,为40.0%(14/35),换血率亦较高,为62.9%(22/35)。 结论高胆红素血症晚期早产儿中,重度、极重度高胆红素血症所占比例高,胆红素脑病发生率高,其中患儿为男性、入院日龄≤7 d、出生胎龄为35^＋0～35^＋6周、AGA儿、自然分娩、有伴发疾病者所占比例高。临床重视对医护人员进行新生儿高胆红素血症规范管理的培训、强化对出院新生儿黄疸监测的力度等围生期管理措施,这对降低高胆红素血症晚期早产儿的伤残,提高其生存质量具有重要意义。