By Ahizechukwu C. Eke, MD, PhD, MPH
Assistant Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: Ursodeoxycholic acid might be beneficial in reducing the risk of spontaneous preterm birth and meconium-stained amniotic fluid, but not stillbirths, in women with pregnancies complicated by obstetric cholestasis.
SOURCE: Ovadia C, Sajous J, Seed PT, et al. Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: A systematic review and individual participant data meta-analysis. Lancet Gastroenterol Hepatol 2021;6:547-558.
Obstetric cholestasis is the most common pregnancy-specific hepatic disorder.1 In the United States, the prevalence varies between 0.32% and 5.6% of all pregnancies. It is seen most commonly in Hispanic women of South American descent (Chilean and Bolivian).2-4 It is characterized by generalized itching involving the palms and soles of the feet (typically in the absence of a rash), caused by elevated serum bile acids.1 The etiology of obstetric cholestasis is not completely understood. However, genetic, hormonal, and environmental factors may contribute to the pathogenesis.1 Although obstetric cholestasis commonly develops in the third trimester of pregnancy, there have been several reports of cases of obstetric cholestasis in the first and second trimesters of pregnancy.
In pregnancies complicated by obstetric cholestasis, ursodeoxycholic acid therapy often is used for pruritus. It functions by decreasing hepatic cholesterol secretion, an important rate-limiting step in the formation of bile acids.5 Although there are data to suggest that ursodeoxycholic acid improves itching from obstetric cholestasis, controversy exists as to whether ursodeoxycholic acid improves maternal and fetal outcomes.6-9 Therefore, Ovadia and colleagues designed this study to determine if ursodeoxycholic acid therapy is beneficial in improving perinatal outcomes.10 This study is an individual patient data meta-analysis of all observational studies and randomized clinical trials that reported the use of ursodeoxycholic acid during pregnancy in women with intrahepatic cholestasis of pregnancy. Studies met inclusion criteria if they reported at least one of the following outcomes: stillbirth, preterm birth, neonatal intensive care admission, meconium-stained amniotic fluid, or neonatal death.1 Studies were excluded if they did not report on any maternal or fetal outcomes in women diagnosed with intrahepatic cholestasis of pregnancy.10 The primary outcome was the prevalence of stillbirth in women using ursodeoxycholic acid therapy for obstetric cholestasis.10 Secondary maternal outcomes included onset of labor (spontaneous or induced), mode of delivery (spontaneous vaginal, assisted vaginal, elective cesarean, or emergency cesarean), preeclampsia, gestational diabetes, and postpartum hemorrhage, while secondary fetal outcomes included a composite of spontaneous birth, iatrogenic birth, and total preterm birth; early preterm birth (< 34 gestational weeks); neonatal intensive care unit admission; meconium-stained amniotic fluid; umbilical cord arterial pH < 7.0; Apgar score of < 7 at five minutes of life; perinatal death; small for gestational age; large for gestational age; and spontaneous preterm birth.10
To compare women who used ursodeoxycholic acid therapy with women who did not, the investigators performed an individual participant data meta-analysis using multilevel mixed-effects logistic regression, or logistic regression with a Huber-White correction. Individual patient data analyses were done for all studies and in different subgroups (observational studies vs. randomized clinical trials). Adjustments were made for bile acid concentrations at baseline, number of fetuses, and maternal parity because of the associations between these confounders and adverse perinatal outcomes. Eighty-five studies met inclusion criteria. However, individual participant data were available for only 32 published studies (6,670 pregnancies), including four randomized controlled trials and two unpublished cohort studies (339 pregnancies), totaling 7,009 participants. Of the 7,009 participants for whom data were provided, 35 were excluded from the analysis (unknown therapy), and 6,974 had sufficient data for inclusion (822 from the four randomized controlled trials), of whom 4,726 (67.8%) took ursodeoxycholic acid therapy and 2,248 (32.2%) did not.
The prevalence of the primary outcome (stillbirth) was not statistically significant between women who received ursodeoxycholic acid therapy compared to those who did not (0.7; [35/5,097 fetuses] vs. 0.6% [12/2,038 fetuses]; adjusted odds ratio [aOR], 1.04; 95% confidence interval [CI], 0.35-3.07; P = 0.95). Ursodeoxycholic acid therapy reduced the prevalence of spontaneous preterm birth in women with obstetric cholestasis compared to those not on therapy (aOR, 0.55; 95% CI, 0.35-0.88; P = 0.012). Ursodeoxycholic acid also significantly reduced the prevalence of the composite outcome of spontaneous birth, iatrogenic birth, and total preterm birth in the subgroup analysis involving randomized controlled trials, although this was driven largely by the reduction in total preterm birth (aOR, 0.60; 95% CI, 0.39-0.91; P = 0.016). The odds of meconium-stained amniotic fluid was reduced with ursodeoxycholic acid therapy compared to no therapy (aOR, 0.69; 95% CI, 0.50-0.95; P = 0.02). There were no statistically significant differences in all other secondary out-comes in pregnant women with obstetric cholestasis treated with ursodeoxycholic acid compared to those not treated.
COMMENTARY
Ursodeoxycholic acid therapy was associated with a lower odds of spontaneous preterm birth in all study types (randomized clinical trials and observational studies). The anti-inflammatory actions of ursodeoxycholic acid and reduction of serum bile acid concentrations within the uterine myometrium might explain ursodeoxycholic acid’s ability to reduce the prevalence of preterm birth.11 Although ursodeoxycholic acid is used off-label during pregnancy in cases of obstetric cholestasis, it is thought to be safe, with minimal gastrointestinal adverse effects.10 Although stillbirth was not shown to be statistically significant in this individual-level data meta-analysis, it is important to understand that stillbirth is a relatively rare pregnancy outcome, and this individual participant meta-analysis was not sufficiently powered to demonstrate differences in stillbirths between women whose pregnancies were complicated by obstetric cholestasis on ursodeoxycholic acid therapy compared to those not on therapy.8
In this individual participant meta-analysis, Ovadia and colleagues also demonstrated a reduction in the composite outcome of spontaneous birth, iatrogenic birth, and total preterm birth in the randomized controlled trial-only subgroup analyses.10 This demonstrates the value of well-designed randomized controlled trials of intervention studies.10 When considering individual participant data from all study designs, adjustment of comparisons by the main confounders (baseline bile acid concentrations, parity, and number of fetuses) showed a significant effect of ursodeoxycholic acid on the composite outcomes (which was non-significant when all other study types were included), reflecting how poorly matched the treatment groups were in terms of the main influencers of perinatal outcomes obstetric cholestasis.10 This meta-analysis also demonstrates the advantage of individual patient data meta-analyses compared to aggregate meta-analyses.12 Prior aggregate meta-analyses overestimated the effect sizes of ursodeoxycholic acid on pregnancy outcomes in women with obstetric cholestasis.8,13 Individual patient meta-analysis is regarded as the gold standard for aggregation of studies because it allows for more powerful and consistent analyses, as well as better characterization of subgroups and outcomes, compared to those that are based on aggregate meta-analyses.12
In summary, although ursodeoxycholic acid reduced the risk of preterm birth and meconium staining of the amniotic fluid, clinicians should not reassure women with obstetric cholestasis that therapy with ursodeoxycholic acid reduces the risk of stillbirth. The Society for Maternal Fetal Medicine continues to support the use of ursodeoxycholic acid in the management of pruritus in women presenting with obstetric cholestasis.14
REFERENCES
- Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol 2009;15:2049-2066.
- Laifer SA, Stiller RJ, Siddiqui DS, et al. Ursodeoxycholic acid for the treatment of intrahepatic cholestasis of pregnancy. J Matern Fetal Med 2001;10:131-135.
- Lee RH, Goodwin TM, Greenspoon J, Incerpi M. The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol 2006;26:527-532.
- Bull LN, Hu D, Shah S, et al. Intrahepatic cholestasis of pregnancy (ICP) in U.S. Latinas and Chileans: Clinical features, ancestry analysis, and admixture mapping. PLoS One 2015;10:e0131211.
- Parquet M, Metman EH, Raizman A, et al. Bioavailability, gastrointestinal transit, solubilization and faecal excretion of ursodeoxycholic acid in man. Eur J Clin Invest 1985;15:171-178.
- Bacq Y, Sentilhes L, Reyes HB, et al. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: A meta-analysis. Gastroenterology 2012;143:1492-1501.
- Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology 2004;40:467-474.
- Chappell LC, Bell JL, Smith A, et al. Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): A randomised controlled trial. Lancet 2019;394:849-860.
- Kenyon AP, Piercy CN, Girling J, et al. Obstetric cholestasis, outcome with active management: A series of 70 cases. BJOG 2002;109:282-288.
- Ovadia C, Sajous J, Seed PT, et al. Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: A systematic review and individual participant data meta-analysis. Lancet Gastroenterol Hepatol 2021;6:547-558.
- Wan JF, Chu SF, Zhou X, et al. Ursodeoxycholic acid protects interstitial Cajal-like cells in the gallbladder from undergoing apoptosis by inhibiting TNF-α expression. Acta Pharmacol Sin 2018;39:1493-1500.
- Tudur Smith C, Marcucci M, Nolan SJ, et al. Individual participant data meta-analyses compared with meta-analyses based on aggregate data. Cochrane Database Syst Rev 2016;9:MR000007.
- Palma J, Reyes H, Ribalta J, et al. Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: A randomized, double-blind study controlled with placebo. J Heptatol 1997;27:1022-1028.
- Society for Maternal-Fetal Medicine (SMFM); Lee RH, Greenberg M, Metz TD, Pettker CM. Society for Maternal-Fetal Medicine Consult Series #53: Intrahepatic cholestasis of pregnancy: Replaces Consult #13, April 2011. Am J Obstet Gynecol 2021;224:B2-B9.
