A comprehensive management guide for cholestasis of pregnancy entitled “SMFM Consult Series #53: Intrahepatic Cholestasis of Pregnancy” was published in AJOG on November 13, 2020.1 One positive aspect of this publication is that many of the recommendations are in line with advice we at ICP Care often give. This includes treatment with ursodiol as a first line medication, diagnosis with a level of 10 on a bile acid test, no need to fast for bile acid testing, and recommendations for fetal monitoring during pregnancy. Hopefully the new guide from SMFM makes diagnosis clearer, despite many labs having different reference ranges listed for their bile acid tests.
One major change in the article is the new recommendations for delivery timing. This recommendation may come across as concerning for our community and our moms. I would like to use this blog post to discuss these recommendations and the research behind them and to hopefully reassure you that women with cholestasis of pregnancy will continue to receive appropriate care.
Currently ACOG recommends a delivery window at 36 0/7-37 0/7 weeks for all cholestasis pregnancies.2 These recommendations do not stress what bile acids levels deliver at what point in this timeframe. As of this blog post, ACOG has not changed these recommendations.
The new article from SMFM discusses 3 different bile acid groups with the respective recommendations for delivery:
-A higher risk group: Bile acids above 100; delivery at 36 0/7 weeks
-A moderate risk group: Bile acids 40-99; delivery in the earlier portion of the 36 0/7-39 0/7 window
-A lower risk group: Bile acids below 40; delivery window of 36 0/7-39 0/7 weeks1
I want to reassure you that this article is not saying that all cholestasis pregnancies need to continue until 39 weeks. In fact, the article still includes 36 weeks in all delivery timing windows regardless of bile acids levels. Recently published studies have shown that the risk of stillbirth is not as high as previously thought in a subset of women with cholestasis of pregnancy with low bile acids. The prior delivery windows were derived from studies that did not separate women based on bile acid levels.4 The more recent articles were able to determine more accurate risks for specific groups of cholestasis of pregnancy patients.
This article still stresses the importance of early delivery in any cases of cholestasis of pregnancy with more severe (approaching 40) bile acids. In these cases, delivery timing will not be altered significantly by this article.
Publications from SMFM are very evidence based in their recommendations. A lot of the recommendations for management come from a recent meta-analysis by Ovadia et al in the Lancet in 2019. 3 This study was a large collection of cholestasis pregnancies and was used to determine the stillbirth rate was based on bile acid levels. The study in the Lancet showed that for bile acids under 40, the stillbirth rate was 0.13%. For bile acids 40-99, the stillbirth rate was 0.28% and for bile acids above 100, this rate jumped up to 3.4%. It does need to be noted that many of the women in this study were delivered by 38 weeks of pregnancy. SMFM acknowledges that it is unknown if some of those early deliveries might have mitigated a small proportion of the risk.1
In pregnancies with low bile acids that continued to 39 weeks of gestation in the meta-analysis, there was not a significant increase in stillbirth rates between 36 and 39 weeks.3 The recommendations from SMFM are based largely upon these findings. 1
The authors of the SMFM article stress that the treatment and management of a cholestasis pregnancy should still be individualized between a provider and a patient. The positive note is that the window does still include the option of a delivery at 36-37 weeks as per ACOG. The authors also recommend that with bile acids over 40, that delivery should still occur in the early portion of the 36 0/7-39 0/7 window similar to ACOG recommendations. Later delivery should be only considered with mild cases of cholestasis.
The article discusses bile acid evaluation after diagnosis and discusses that weekly testing may not be necessary. This was clarified with the authors and bile acids should still be followed in pregnancy but a specific recommendation for how often they should be measured was not made. They probably do need to be followed more closely towards the end of pregnancy to determine delivery timing as higher bile acids would lead to an earlier delivery. For diagnosis in early pregnancy, they can be followed at a longer interval and then followed more closely near the end when planning delivery. Timing of delivery should always be based on your highest bile acid regardless of if they are lowered with treatment. It is important to continue to measure bile acids so that if they are increasing, you know that you are not a candidate for delivery in the later part of the window.
I know that the delivery window is a big change for everybody who has been using the 36 0/7-37 0/7 weeks for the past few years. However, the window is just being slightly expanded for some cases. ICP Care advocates for delivery in the early part of that window with elevations of bile acids nearing 40 or higher. We can never say with cholestasis that there is a “no risk” group as there are stillbirths that will still occur unfortunately. Exact delivery timing needs to be determined by a collaboration between a patient and their provider. Intrahepatic Cholestasis of Pregnancy moms know that anxiety can play a role in determining delivery timing and we will each have our place where we feel comfortable in this window. Hopefully by reviewing the evidence, you can be empowered to have this conversation with your physician and decide on an appropriate management plan. It is our hope that this remains an individualized decision and that early delivery is still an option for women, even with mild bile acids. The recent evidence suggests that in some cholestatic pregnancies we should be more aggressive and in some cases we might not need to be as aggressive as there is less risk. This decision still needs to take into account maternal concerns.
Laura Bonebrake, MD, FACOG
ICP Care Medical Advisory Board Member
1 Society for Maternal-Fetal Medicine (SMFM), Lee RH, Pettker CM. Society for Maternal-Fetal Medicine (SMFM) Consult Series #53: Intrahepatic Cholestasis of Pregnancy. Am J Obstet Gynecol. 2020 Nov 13:S0002-9378(20)31284-9. doi: 10.1016/j.ajog.2020.11.002. Epub ahead of print. PMID: 33197417.
2 ACOG Committee Opinion No. 764: Medically Indicated Late-Preterm and Early-Term Deliveries. Obstet Gynecol. 2019 Feb;133(2):e151-e155. doi: 10.1097/AOG.0000000000003083. PMID: 30681545.
3 Ovadia C, Seed PT, Sklavounos A, Geenes V, Di Ilio C, Chambers J, Kohari K, Bacq Y, Bozkurt N, Brun-Furrer R, Bull L, Estiú MC, Grymowicz M, Gunaydin B, Hague WM, Haslinger C, Hu Y, Kawakita T, Kebapcilar AG, Kebapcilar L, Kondrackienė J, Koster MPH, Kowalska-Kańka A, Kupčinskas L, Lee RH, Locatelli A, Macias RIR, Marschall HU, Oudijk MA, Raz Y, Rimon E, Shan D, Shao Y, Tribe R, Tripodi V, Yayla Abide C, Yenidede I, Thornton JG, Chappell LC, Williamson C. Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses. Lancet. 2019 Mar 2;393(10174):899-909. doi: 10.1016/S0140-6736(18)31877-4. Epub 2019 Feb 14. Erratum in: Lancet. 2019 Mar 16;393(10176):1100. PMID: 30773280; PMCID: PMC6396441.
4 Puljic A, Kim E, Page J, esakoff T, Shaffer B, LaCoursiere DY, Caughey AB. The risk of infant and fetal death by each additional week of expectant management in intrahepatic cholestasis of pregnancy by gestational age. Am J Obstet Gynecol. 2015 May;212(5):667.e1-5. Doi: 10.1016/j.ajog.2015.02.012. Epub 2015 Feb 14. PMID: 25687562.