Intrahepatic Cholestasis of Pregnancy Recurrence in a Subsequent Pregnancy

Abstract

Reported recurrence rates of intrahepatic cholestasis of pregnancy (ICP) range from 40% to 90% based on prior literature, but data remain limited. In a retrospective cohort, we aimed to evaluate the rate of ICP recurrence and risk factors associated with recurrence. Among 104 patients with ICP in an index pregnancy, 46 experienced recurrence (44%) of ICP in subsequent pregnancy. A peak total bile acid (TBA) level greater than 40 micromoles/L in the index pregnancy was significantly associated with ICP recurrence; shorter interpregnancy intervals were associated with lower risk. These findings contribute to the literature on the risk of ICP recurrence in a modern, racially diverse cohort and highlight elevated TBA level as a predictor of recurrence.

Intrahepatic cholestasis of pregnancy (ICP) is the most common hepatobiliary disease of pregnancy and is associated with significant perinatal morbidity and mortality.¹ The etiology is considered multifactorial, influenced by hormonal, environmental, and genetic factors.^1,2 Prior studies estimate an ICP recurrence rate after an affected pregnancy of 40–90%. However, these studies were completed in predominantly White European and Asian populations, reducing generalizability.^1–4 Our objective was to estimate the recurrence of ICP in subsequent pregnancy and identify risk factors associated with ICP recurrence in a modern, racially diverse population.

METHODS

This was a retrospective cohort study of individuals with singleton, nonanomalous live births at a single academic center in Queens, New York, between 2015 and 2024. The electronic medical record was queried using International Classification of Diseases, Ninth and Tenth Revision codes (Appendix 1, available online at http://links.lww.com/AOG/E268). Patients with ICP in an index pregnancy who received care in the subsequent pregnancy at our institution were included. Those with documentation of ICP in a pregnancy before the index pregnancy were excluded. The primary outcome was recurrence of ICP in the subsequent pregnancy. Secondarily, we evaluated the association between candidate risk factors and ICP recurrence. Baseline demographic and pregnancy characteristics were compared for patients with and without ICP recurrence using t tests or Wilcoxon rank sum tests for continuous measures and χ² or Fisher exact tests for categorical measures, as appropriate. To assess strength of association, univariable logistic regression was performed and presented as odds ratios (ORs) and 95% CIs. P<.05 indicated statistical significance. All statistical analyses were performed with STATA IC 15.1. The study was approved by the center’s IRB.

RESULTS

Of 104 patients with ICP in an index pregnancy, 46 (44.2%, 95% Cl 34.6–53.8%) experienced ICP recurrence in the subsequent pregnancy. Those with recurrent ICP, compared with those without, were more likely to self-identify as Hispanic (84.8%, 95% CI, 71.1–93.7% vs 65.5%, 95% CI, 51.9–77.5%; P=.03), but there were no differences in age or comorbid health conditions (Table 1). Patients with recurrent ICP had higher peak total bile acid (TBA) levels in the index pregnancy (median 22.1 micromoles/L, interquartile range 14.6–42.1 micromoles/L) compared with those without recurrent ICP (median 15.3 micromoles/L, interquartile range 10.9–23.0 micromoles/L). A higher proportion of patients with peak TBA levels greater than 40 micromoles/L in the index pregnancy experienced recurrent ICP compared with those without recurrence (30.4%, 95% CI, 17.7–45.8% vs 6.9%, 95% CI, 1.9–16.7%, P<.01). A short interpregnancy interval (defined as time from delivery to next conception less than 18 months) was associated with decreased odds of ICP recurrence (OR 0.39, 95% CI, 0.16–0.91; Fig. 1).

Table 1.

Maternal Baseline Characteristics and Laboratory Findings in Patients With Intrahepatic Cholestasis of Pregnancy in Index Pregnancies and Subsequent Pregnancies

	Recurrent ICP (n=546, 44.2%)	Nonrecurrent ICP (n=558, 55.8%)	P
Index pregnancy
Age (y)	27.9±5.7	29.0±5.5	.33
Obesity (prepregnancy BMI 30 or higher)	17 (37.0)	15 (25.9)	.22
Ethnicity			.14
African	1 (2.2)	1 (1.7)	.87
Bengali	2 (4.4)	11 (19.0)	.03
Hispanic	39 (84.8)	38 (65.5)	.03
Southeast Asian	2 (4.4)	2 (3.5)	.81
Additional ethnicities	2 (4.4)	6 (10.3)	.25
Nulliparous	33 (71.7)	43 (74.1)	.78
Prior unexplained intrauterine fetal death	2 (4.4)	0 (0.0)	.11
Comorbidities
Pregestational diabetes mellitus	0 (0.00)	1 (1.7)	.37
Gestational diabetes mellitus	4 (8.7)	10 (17.2)	.21
Hypertensive disorders of pregnancy	2 (4.4)	8 (13.8)	.11
Any prior hepatobiliary disease	6 (13.0)	6 (10.3)	.67
History hyperlipidemia	2 (4.4)	4 (6.9)	.58
ICP characteristics
Gestational age at diagnosis (wk)	34.3±4.7	35.2±3.8	.33
Peak TBA (micromoles/L)	22.1 (14.6–42.1)	15.3 (10.9–23.0)	.01
Gestational age at peak TBA	35.0±3.3	35.8±3.3	.23
TBA cohort’s peak TBA (micromoles/L)			<.01
10–19	20 (43.5)	37 (63.8)
20–39	12 (26.1)	17 (29.3)
Greater than 40	14 (30.4)	4 (6.9)
Max ALT during pregnancy	39.5 (22–72)	25 (15–46)	.07
Max AST during pregnancy	30.5 (24–49)	28 (19–43)	.21
Ursodiol treatment	28 (60.9)	24 (41.4)	.06
Obstetric outcomes
Gestational age at delivery (wk)	36.9±1.9	37.8±1.6	.02
Preterm delivery	13 (28.3)	7 (12.1)	.04
Meconium-stained amniotic fluid	6 (13.0)	3 (5.2)	.16
Subsequent pregnancy
Advanced maternal age	15 (32.6)	19 (32.8)	.99
Interpregnancy interval (mo)	44.3±23.7	32.7±19.3	<.01
Short interpregnancy interval	11 (23.9)	26 (44.8)	.03

ICP, intrahepatic cholestasis of pregnancy; BMI, body mass index; TBA, total bile acid; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Data are mean±SD, n (%), or median (interquartile range) unless otherwise specified.

Fig. 1.

Univariable logistic regression for recurrent intrahepatic cholestasis of pregnancy. TBA, total bile acid.

Rosenberg. ICP Recurrence in Subsequent Pregnancy. Obstet Gynecol 2025.

DISCUSSION

In this single-center cohort study, we found a recurrence rate of 44.2% for ICP in a subsequent pregnancy. Peak TBA levels greater than 40 micromoles/L during the index pregnancy were associated with a higher risk of recurrence; a short interval pregnancy was potentially protective.

Our findings are similar to those in previous studies identifying a 40–90% ICP recurrence risk.^4,5 In a Finnish study investigating the genetic basis of ICP, the recurrence risk was 92% in familial ICP cases and 40% in sporadic cases.⁴ Williamson et al⁵ found a 90% ICP recurrence rate in an all-White U.K. population, but the study relied on patient surveys rather than biochemical confirmation, risking over-estimation of recurrence. Conversely, Wang et al³ found a 55% recurrence risk for severe ICP in a Chinese cohort, with early-onset ICP and chronic hepatitis B identified as risk factors for recurrence.

Most patients in our study self-identified as Hispanic, expanding our understanding of ICP recurrence in a patient population previously underrepresented. The varying recurrence rates across studies to date likely reflect the influence of both genetic and environmental factors on ICP recurrence.

Limitations of this study include the retrospective design and absence of data on family history of ICP or ICP genetic testing. There was underrepresentation of non-Hispanic White, Black, and Asian patients in our study population, limiting generalizability. The small sample size precluded multivariable modeling with adjustment for confounders. Caution should be used in interpretation of findings; the wide CIs suggest that additional studies with larger sample sizes are warranted.

Strengths of our study include the diverse patient population and biochemical validation of ICP recurrence. This study contributes to our understanding of ICP recurrence in heterogeneous populations.