Perinatal death by bile acid levels in intrahepatic cholestasis of pregnancy: a systematic review

Intrahepatic cholestasis of pregnancy (ICP) is characterized by the elevation of total bile acids (TBAs). The primary concern in women with ICP is the increased risk of stillbirth. ICP is generally considered as “mild” when TBA levels range from 10 to 39 µmol/L and “severe” with levels greater than 40 µmol/L, although levels of TBA ≥100 µmol/L have been also considered as a further threshold of severity. To quantify the association between different severities of ICP (TBA 10–39, 40–99, and ≥100 µmol/L) and perinatal death. Medline, Embase, Scopus, Web of Sciences, and ClinicalTrial.gov were searched from the inception of each database to February 2019. Randomized, cohort, case-control, or case series studies reporting maternal and perinatal outcomes on women with ICP by the three prespecified TBA levels (10–39, 40–99, and ≥100 µmol/L) were included. We excluded multiple gestations and trials which included an intervention. The analysis was performed with Pearson chi-square and Fisher’s exact test as appropriate. Continuous outcomes were compared using metaregression with inverse variance weighting using reported sample sizes and standard deviations. Pairwise comparisons used a Bonferroni correction to control for multiple testing. Six articles including 1280 singleton pregnancies affected by ICP were included in the systematic review. Out of the 1280 singleton pregnancies affected by ICP included, 118 had ICP with TBA ≥100 µmol/L. Perinatal death was more common in women with TBA ≥100 µmol/L (0.4% for TBA 10-39 μmol/L <i>versus</i> 0.3% for TBA 40-99 μmol/L <i>versus</i> 6.8% for TBA ≥ 100 μmol/L, <i>p</i> versus 8.6% <i>versus</i> 18.2% respectively, <i>p</i> versus 21.6% <i>versus</i> 35.8% respectively, <i>p</i>versus 18.4% <i>versus</i> 31.6% respectively, <i>p</i> Maternal TBA ≥100 µmol/L is associated with a 6.8% incidence of perinatal death, most of which (5.9% overall) are stillbirths, while TBA &lt;100 µmol/L are associated with an incidence of perinatal death of 0.3%. It may be reasonable to consider late preterm delivery (at about 35–36 weeks) in women with TBA ≥100 µmol/L.

妊娠期肝内胆汁淤积症（Intrahepatic cholestasis of pregnancy, ICP）以总胆汁酸（total bile acids, TBAs）水平升高为主要临床特征。ICP患者最主要的临床风险为死胎发生风险显著升高。目前临床通常将总胆汁酸水平处于10~39 µmol/L的ICP患者判定为"轻度"，水平≥40 µmol/L者判定为"重度"；另有研究将总胆汁酸≥100 µmol/L作为进一步的严重程度分层阈值。本研究旨在量化不同严重程度分层（总胆汁酸10~39、40~99及≥100 µmol/L）的ICP患者与围产儿死亡之间的关联。本研究检索了Medline、Embase、Scopus、Web of Sciences及ClinicalTrial.gov数据库，检索时限为各数据库建库起至2019年2月。纳入采用随机对照试验、队列研究、病例对照研究或病例系列研究设计，且依据预设的3种总胆汁酸分层标准（10~39、40~99及≥100 µmol/L）报告ICP孕妇母婴结局的相关研究；排除多胎妊娠及涉及干预措施的临床试验。数据分析采用适配的Pearson卡方检验与Fisher确切概率法；连续型结局指标采用逆方差加权的Meta回归进行比较，权重基于研究报告的样本量与标准差计算；组间两两比较采用Bonferroni校正以控制多重检验偏倚。本系统评价共纳入6篇文献，涉及1280例确诊ICP的单胎妊娠病例。其中118例患者的总胆汁酸水平≥100 µmol/L。围产儿死亡发生率在总胆汁酸≥100 µmol/L的患者中显著升高：总胆汁酸10~39 µmol/L组为0.4%，40~99 µmol/L组为0.3%，≥100 µmol/L组为6.8%。总胆汁酸≥100 µmol/L的妊娠女性围产儿死亡发生率为6.8%，其中绝大多数（总体占比5.9%）为死胎；而总胆汁酸<100 µmol/L的患者围产儿死亡发生率仅为0.3%。对于总胆汁酸≥100 µmol/L的ICP患者，可考虑在妊娠35~36周左右实施晚期早产分娩，以优化围产结局。