Management of intrahepatic cholestasis in pregnancy

Intrahepatic cholestasis of pregnancy is a complication in 0·2–2% of pregnancies,1Williamson C Geenes V Intrahepatic cholestasis of pregnancy.Obstet Gynecol. 2014; 124: 120-133Crossref PubMed Scopus (240) Google Scholar causing pruritis and increased serum bile acids, liver transaminases, and, occasionally, bilirubin. It has been associated with severe adverse pregnancy outcomes, including fetal distress, spontaneous and iatrogenic preterm birth, and stillbirth,1Williamson C Geenes V Intrahepatic cholestasis of pregnancy.Obstet Gynecol. 2014; 124: 120-133Crossref PubMed Scopus (240) Google Scholar for which no effective treatment is yet known.2Gurung V Stokes M Middleton P Milan SJ Hague W Thornton JG Interventions for treating cholestasis in pregnancy.Cochrane Database Syst Rev. 2013; 6 (CD000493.)Google Scholar Ursodeoxycholic acid, which is regularly prescribed, improves biochemical parameters and reduces, although on a limited scale (evidence is conflicting), pruritis.3Chappell LC Gurung V Seed PT Chambers J Williamson C Thornton JG Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial.BMJ. 2012; 344: e3799-e3899Crossref PubMed Scopus (123) Google Scholar Antenatal fetal monitoring strategies have not proven effective, resulting in substantial variation in the timing of delivery due to attempts to balance risks of stillbirth against increasingly understood neonatal and childhood complications from late preterm and early term delivery.4Chan E Quigley MA School performance at age 7 years in late preterm and early term birth: a cohort study.Arch Dis Child Fetal Neonatal Ed. 2014; 99: F451-F457Crossref PubMed Scopus (85) Google Scholar, 5Rabie NZ Bird TM Magann EF Hall RW McKelvey SS ADHD and developmental speech/language disorders in late preterm, early term and term infants.J Perinatol. 2015; 35: 660-664Crossref PubMed Scopus (31) Google Scholar This problem is reflected in the scarcity of national guidelines worldwide. The guidelines published in 2011 by the Royal College of Obstetricians and Gynaecologists encourage open discussion with women about the scarce evidence supporting early term delivery to minimise stillbirth risk.6Kenyon AP Girling J Obstetric cholestasis. RCOG Greentop Guideline No. 43, 2011. Royal College of Obstetricians and Gynaecologists, London2011Google Scholar However, subsequent authors have used decision analytic techniques to recommend delivery at 36 weeks of gestation.7Lo JO Shaffer BL Allen AJ Little SE Cheng YW Caughey AB Intrahepatic cholestasis of pregnancy and timing of delivery.J Matern Neonatal Med. 2015; 28: 2254-2258Crossref PubMed Scopus (43) Google Scholar In the context of this uncertainty, in The Lancet, Caroline Ovadia and colleagues8Ovadia C Seed PT Sklavounos A et al.Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses.Lancet. 2019; (published online Feb 14.)http://dx.doi.org/10.1016/S0140-6736(18)31877-4Summary Full Text Full Text PDF PubMed Scopus (203) Google Scholar aim to clarify the association of biochemical markers and adverse perinatal outcomes. They did an aggregate meta-analysis of 23 studies comparing perinatal outcomes of women with intrahepatic cholestasis of pregnancy (n=5557) with healthy controls (n=165 136), as well as the first individual patient data (IPD) meta-analysis from 27 studies exploring the association between perinatal outcomes and biochemical markers in 5269 pregnancies. Their aggregate meta-analysis shows evidence of the associations of intrahepatic cholestasis of pregnancy with increased risks of stillbirth (odds ratio 1·46 [95% CI 0·73–2·89]), spontaneous preterm birth (3·47 [3·06–3·95]), iatrogenic preterm birth (3·65 [1·94–6·85]), meconium stained liquor (2·60 [1·62–4·16]), and neonatal unit admission (2·12 [1·48–3·03]) compared with healthy controls. Importantly, the IPD meta-analysis shows that elevated total bile acid concentrations are highly predictive for stillbirth in singleton pregnancies (area under the receiver operating characteristic curve 0·83 [95% CI 0·74–0·92]). This finding provides some guidance to clinicians, since it shows the increased stillbirth numbers only exceeded those of the general population once total bile acid concentrations were of 100 μmol/L or more; the stillbirth prevalence after 24 weeks of gestation was 3·44% (95% CI 2·05–5·37) for women with intrahepatic cholestasis of pregnancy compared with 0·3–0·4% from pooled national average data among included countries. Usefully, the authors associated a cutoff concentration with clinically relevant outcomes, rather than basing it on the 95th percentile of the normal distribution. Clinicians and women can be reassured that stillbirth rates seem similar to the general population while total bile acid concentrations remain less than 100 μmol/L; however, weekly testing is advised because the increase in total bile acids with advancing gestation9Tribe RM Dann AT Kenyon AP Seed P Shennan AH Mallet A Longitudinal profiles of 15 serum bile acids in patients with intrahepatic cholestasis of pregnancy.Am J Gastroenterol. 2010; 105: 585-595Crossref PubMed Scopus (63) Google Scholar might increase the stillbirth risk. The issues clinicians faced in balancing the risks of stillbirth against those of late preterm or early term delivery might thus be resolved without the use of an intervention study. In comparison, in women with total bile acid concentrations of 100 μmol/L or more, delivery should probably occur by 35–36 weeks of gestation. Since this is the minority of women with intrahepatic cholestasis of pregnancy, overall, a reduction in iatrogenic preterm birth due to intrahepatic cholestasis of pregnancy is to be expected. IPD studies have limitations. Bias remains a possibility depending on the quality of data collected by the initial trialists, specifically in unblinded studies, in which high bile acid concentrations might have been a reason for induction. Also, excluding stillbirth, adverse pregnancy outcomes have been defined differently between individually included studies. The development of core outcome sets should assist with ongoing improvement in data for IPD analysis in the future. However, IPD provide some evidence on predictors of clinically meaningful outcomes, such as stillbirth, for which it is difficult for individual studies to reach adequate power. Furthermore, the use of existing data improves efficiency, timely provision of information, and cost-effectiveness in research, none of which could be achieved by a new, adequately powered cohort study. Development of international networks facilitates optimal data use in future studies. Such collaborations could assist in addressing the concerns of bias relating to stillbirth risk beyond 37 weeks among those women with bile acids of less than 100 μmol/L because of the high numbers of iatrogenic deliveries. For example, the IPD analysis included trials from China done during a period when delivery for intrahepatic cholestasis of pregnancy with bile acid of 40 μmol/L or more at 37 completed weeks was recommended. Liu and colleagues10Liu X Landon MB Chen Y Cheng W Perinatal outcomes with intrahepatic cholestasis of pregnancy in twin pregnancies.J Matern Neonatal Med. 2016; 29: 2176-2181Crossref PubMed Scopus (22) Google Scholar did a large cohort study of 1319 cases of intrahepatic cholestasis of pregnancy that was not included in this IPD analysis. On excluding 11 cases of intrahepatic cholestasis of pregnancy with bile acids of 100 μmol/L or more, the 163 cases with bile acids of 40–99 μmol/L were not associated with increased stillbirth risk.10Liu X Landon MB Chen Y Cheng W Perinatal outcomes with intrahepatic cholestasis of pregnancy in twin pregnancies.J Matern Neonatal Med. 2016; 29: 2176-2181Crossref PubMed Scopus (22) Google Scholar This supports Ovadia and colleagues' findings and indicates that a threshold of 100 μmol/L or more is also applicable in a Chinese population, where the incidence of intrahepatic cholestasis of pregnancy is high.8Ovadia C Seed PT Sklavounos A et al.Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses.Lancet. 2019; (published online Feb 14.)http://dx.doi.org/10.1016/S0140-6736(18)31877-4Summary Full Text Full Text PDF PubMed Scopus (203) Google Scholar Although important questions such as the benefit of ursodeoxycholic acid for reducing stillbirth remain, the approach of Ovadia and colleagues8Ovadia C Seed PT Sklavounos A et al.Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses.Lancet. 2019; (published online Feb 14.)http://dx.doi.org/10.1016/S0140-6736(18)31877-4Summary Full Text Full Text PDF PubMed Scopus (203) Google Scholar paves the way for improving the clinical management of conditions with rare, but devastating, outcomes. BWM is a consultant for ObsEva, Merck, Merck KGaA, and Guerbet, and is supported by a NHMRC Practitioner Fellowship (GNT1082548), outside the area of work commented on here. KRP and LX declare no competing interests. Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analysesThe 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. Full-Text PDF Open Access