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Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses
背景与目的
妊娠期肝内胆汁淤积症与围产期不良预后有关，但与特定生化指标浓度的相关性尚不清楚。本研究旨在量化妊娠期肝内胆汁淤积症患者血清胆汁酸浓度升高对围产期不良影响，并明确胆汁酸浓度升高是否与死胎和早产风险有关。
方 法
我们通过检索PubMed、Web of Science和Embase 数据库进行系统回顾，收集从数据库建立之初到2018年6月1日为止发表的有关妊娠期肝内胆汁淤积症孕妇血清胆汁酸浓度升高时的围产期结局的研究报告。将基于瘙痒和血清胆汁酸浓度升高的妊娠期肝内胆汁淤积症，伴或不伴肝转氨酶浓度升高的研究作为纳入标准。符合条件的研究包括病例对照、队列研究、群体性研究、至少有30名参与者的随机对照试验，以及报道了胆汁酸浓度和围产期结局的研究。排除了报告偏差潜在风险较高的研究，包括病例报告、不包含队列研究的试验，或在同一个单位中连续观察到的病例，也排除了试验人群中有高偏差风险的研究（明确排除预后差的婴儿亚组）、会议摘要和没有明确同行评审的致编辑信函。我们还收集了两所英国医院未公布的数据，进行随机效应meta分析以明确围产期不良预后的风险。从病例对照研究中收集产妇和围产期预后的汇总数据，并从所有研究的作者处获取个体患者数据（IPD）（IPD分析不需要对照组），使用逻辑回归和逐步逻辑回归评估生化指标和不良预后之间的关系。
结 果
我们评估了109篇全文文章，其中23篇研究符合汇总数据meta分析（5557例妊娠肝内胆汁淤积症病例和165136例对照组），27篇提供了IPD（5269例妊娠肝内胆汁淤积症病例）。4936例妊娠期肝内胆汁淤积症患者中有45例（0.83%）发生死胎，163947例对照妊娠中有519例（0.32%）发生死胎（OR：1.46；95%CI：0.73–2.89; I²=59.8%）。在单胎妊娠中，死胎与最大总胆汁酸浓度（ROC AUC：0·83；95% CI：0.74–0.92]）相关，而与谷丙转氨酶无关（ROC AUC：0·46；95% CI：0.35–0.57）。对于单胎妊娠合并肝内胆汁淤积症的孕妇，血清总胆汁酸浓度小于40µmol/L的2310例患者中发生死胎3例，血清总胆汁酸浓度为40-99μmol/L的1412例患者中发生4例，血清总胆汁酸浓度为100μmol/L及以上的524例患者中发生18例。
结 论
当血清胆汁酸浓度为100µmol/L及以上时，单胎妊娠合并肝内胆汁淤积症的孕妇死胎风险增加。由于大多数妊娠期肝内胆汁淤积症孕妇的胆汁酸浓度低于此浓度，如果重复检测胆汁酸浓度直至分娩，死胎的风险可能与一般人群中的孕妇相似。
原始文献摘要
McCann ME, de Graaff JC, Dorris L, et al. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial[J].The Lancet. 2019,393(10172):664-677.DOI:10.1016/s0140-6736(18)32485-1.
Background：Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth.
Methods：We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and populationbased studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134.
Findings：We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73–2·89]; I²=59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74–0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35–0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02–0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 µmol/L versus four (0·28%; 0·08–0·72) of 1412 cases with total bile acids of 40–99 µmol/L (hazard ratio [HR] 2·35 [95% CI 0·52–10·50]; p=0·26), and versus 18 (3·44%; 2·05–5·37) of 524 cases for bile acids of 100 µmol/L or more (HR 30·50 [8·83–105·30]; p<0·0001).
Interpretation：The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 µmol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery.
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翻译：王贵龙 编辑：何幼芹 审校：王贵龙
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