UDCA tied to reduction in risk of stillbirth, preterm birth in women with ICP

Among women with intrahepatic cholestasis of pregnancy (ICP), ursodeoxycholic acid (UDCA) treatment was associated with a reduction in the risk of composite adverse perinatal outcomes of stillbirth and preterm birth (PTB), a meta-analysis suggests.

ICP entails an increased risk of perinatal complications, including PTB, meconium-stained amniotic fluid, neonatal unit admission, and stillbirth. [J Matern Fetal Neonatal Med 2018;31:1913-1920; Lancet 2019;393:899-909; Am J Obstet Gynecol 2015;213: 570.e1-8]

Though not approved for use in pregnancy, UDCA is deemed safe for ICP. “[However,] there is no consensus as to its benefit for women or their babies,” said the researchers. Evidence on its effects on perinatal outcomes are conflicting; some reveal unclear findings or no improvement, while other data support the use of UDCA for the management of ICP. [Cochrane Database Syst Rev 2020;7:CD000493; Lancet 2019;394:849-860; Am J Obstet Gynecol 2021;224:B2-B9]

“[Moreover,] studies … were not of sufficient quality to provide clear evidence for [the use of UDCA] in ICP. To our knowledge, no study has reported the effect of UDCA using individual participant data, or had sufficient statistical power to show any effect of UDCA on stillbirth,” they added.

The researchers conducted a meta-analysis using data from 34 studies (n=6,974; four randomized controlled trials [RCTs]). More than a third (68 percent) of participants had a history of UDCA treatment. The primary outcome was prevalence of stillbirth. A composite of stillbirth and PTB was included as a key secondary outcome due to the likelihood of having insufficient data to achieve statistical power for the primary outcome. [Lancet Gastroenterol Hepatol 2021;6:547-558]

Similar incidences of stillbirth were seen between women who did and did not receive UDCA in all studies (0.7 percent vs 0.6 percent; adjusted odds ratio [adjOR], 1.04; p=0.95) and in the analyses confined to RCTs only (0.2 percent vs 0.7 percent; adjOR, 0.29; p=0.25). A similar trend was observed in the cohort on singleton pregnancies (0.6 percent for both; adjOR, 0.71; p=0.73 [all studies] and 0.3 percent vs 0.5 percent; adjOR, 0.40; p=0.46 [RCTs only]).

Looking at the key secondary endpoint, a significant reduction was observed among UDCA vs non-UDCA recipients when restricting the analysis to RCTs (17 percent vs 25 percent; adjOR, 0.60; p=0.016). According to the researchers, this effect may be attributed to the reduced risk of total PTB (<37 weeks’ gestation; 17 percent vs 25 percent; adjOR, 0.61; p=0.019), which could have been driven by the reduced risk of spontaneous PTB (7 percent vs 12 percent; adjOR, 0.56; p=0.052).

The secondary outcomes were further corroborated by data confined to singleton pregnancies in RCTs only, be it in terms of the composite outcome (11 percent vs 18 percent; adjOR, 0.51; p=0.002), total PTB (11 percent vs 18 percent; adjOR, 0.51; p=0.002), or spontaneous PTB (5 percent vs 9 percent; adjOR, 0.46; p=0.015).

“[P]revention of late PTB (before 37 gestational weeks) is of considerable benefit, [as] these babies are at a higher risk of post-partum respiratory impairment, delayed feeding, early childhood mortality, neurodevelopmental disability, and longer-term cognitive defects than are children born at term,” said the researchers.

Moreover, when stratifying by bile acid category on post hoc analysis, a significant reduction in spontaneous PTB was observed in UDCA-treated women with singleton pregnancies with bile acid concentrations ranging from 40 to 100 μmol/L; hazard ratio, 0.35; p=0.048). “[As] adverse outcomes in ICP are associated with higher bile acid concentrations, [this finding implies that] women with more severe disease are likely to glean the greatest benefit from UDCA,” said the researchers.

“[Taken together, the findings provide] evidence for the clinical benefit of antenatal UDCA treatment,” the researchers concluded. “This study suggests that UDCA should be offered as part of antenatal treatment for ICP … particularly to women with a disease onset before 37 gestational weeks and serum bile acid concentrations of ≥40 μmol/L.”