Pregnancy and liver-related outcomes after alcohol-associated hepatitis: A global multicenter study

Abstract

Background:

The incidence of alcohol-associated hepatitis (AH) is rising in women of reproductive age. While the adverse effects of alcohol on pregnancy are well documented, there is limited data on pregnancy in women with a history of AH.

Methods:

This study was completed by using the TriNetX Research Network. The primary objectives were to evaluate the incidence of pregnancy and related complications in pregnancies following an episode of AH (AH pregnancies) compared to pregnancies in healthy patients (control pregnancies). The secondary objective was to assess long-term liver-related complications and mortality in women with AH who experienced a pregnancy compared to no pregnancy. Propensity score matching was used for comparative analyses to balance cohorts by age, race, ethnicity, prior delivery, and obesity status.

Results:

The incidence of pregnancy was significantly lower in women with AH compared to controls (26 vs. 54 cases per 1000 person-years, p<0.001). AH pregnancies were associated with higher odds of spontaneous abortion (OR 2.0, 95% CI: 1.2 to 3.3, p =0.011), pre-eclampsia (OR 1.9, 95% CI: 1.1 to 3.0, p =0.002), peri-partum hemorrhage (OR 2.7, 95% CI: 1.3 to 5.6, p =0.007) and perinatal psychiatric disorders (OR 3.2, 95% CI: 1.6 to 6.2, p =0.001). The incidence of cirrhosis and hepatic decompensation were similar between women with AH who experienced a pregnancy compared to no pregnancy, but Kaplan Meier analysis revealed a significantly faster time to event in the no-pregnancy group.

Conclusions:

Pregnancies following AH diagnosis were associated with adverse pregnancy outcomes. Pregnancy after AH does not reduce the overall risk of developing advanced liver disease but may delay disease progression. These findings highlight the importance of tailored reproductive counseling and support for this population.

INTRODUCTION

The prevalence of alcohol use disorder (AUD) and alcohol-associated liver disease (ALD) is rising globally, especially among young women, and in recent years there has been a surge in alcohol-associated hepatitis (AH).¹ AH is a systemic inflammatory syndrome caused by heavy alcohol use (≥ 5 standard drinks per day for ≥ 6 mo) in patients with or without underlying chronic liver disease.² Alcohol consumption to this degree can affect reproductive health, including potential dysregulation of the hypothalamic-pituitary-gonadal axis and/or direct toxicity to reproductive organs.³ As a result, women with AUD may experience irregular menstruation, amenorrhea, and/or difficulty with fertility.³

In the context of pregnancy, prenatal and antenatal alcohol consumption has been associated with a higher risk of pregnancy loss and preterm birth.⁴,⁵ While there is abundant literature related to alcohol use in pregnancy, there are limited data on pregnancy outcomes in women with ALD. Studies have shown that cirrhosis increases the risk of certain adverse maternal and fetal outcomes in pregnancy, but women with ALD comprise a small minority of patients in these studies.⁶ In a study that focused on ALD specifically, women diagnosed with ALD prior to pregnancy were more likely to experience preterm birth and deliver small-for-gestational-age infants compared to age-matched controls.⁷ However, this study was not matched for demographic factors that may affect pregnancy outcomes (eg, race, ethnicity, and the presence of obesity⁸,⁹), and the severity of liver disease was unclear.

AH is unique in the context of pregnancy for several reasons. First, AH is a systemic inflammatory condition that extends beyond heavy alcohol use alone. Second, even though portal hypertension may be present in AH,¹⁰ only a fraction of women with AH have underlying cirrhosis.¹¹ For these reasons, existing data on pregnancy outcomes in AUD and alcohol-associated cirrhosis may not apply to women with recent AH. Looking beyond the perinatal period, whether pregnancy influences the trajectory of liver disease is also poorly understood. Studying liver-related outcomes in women with AH who experience pregnancy may provide valuable insight into the intersection of reproductive health and liver disease.

With the rising rates of AH in young women, it is likely that pregnancies following AH will become more common in clinical practice, and having the knowledge to counsel these patients will be increasingly important. This study sought to address some of the aforementioned gaps with the following aims: (1) to evaluate pregnancy-related outcomes in women with recent AH compared to healthy controls and (2) to evaluate liver-related outcomes in women with AH who experience a subsequent pregnancy.

METHODS

This analysis was completed using the TriNetX Research Network—a network of over 100 health care organizations across 5 countries. TriNetX is a global, federated research network that provides real-time access to anonymized data sets derived from the electronic health records of participating health care organizations. Our primary objective was to evaluate whether an episode of AH during reproductive years (age 18–45) affects the incidence of pregnancy and pregnancy-related outcomes. The secondary objective was to evaluate whether pregnancy after an episode of AH affects long-term liver-related outcomes and all-cause mortality.

Incidence of pregnancy

The incidence of pregnancy was calculated for 3 groups: (1) women aged 18–45 years with ≥ 1 episode of AH, (2) women aged 18–45 years with AUD, and (3) women aged 18–45 with no history of AUD, AH, liver or biliary disease. Incidence rates were reported as cases per 1000 person-years (1000-py) and compared using incidence rate ratios. In addition to comparing AH and controls, we compared the incidence of pregnancy in women with AH to women with AUD to assess whether AH affects fertility beyond heavy alcohol consumption. The probability of pregnancy was assessed after stratification by serum bilirubin levels (< 3 mg/dL, 3–6 mg/dL, and > 6 mg/dL) and visualized using time-to-event curves.

Pregnancy-related outcomes

Pregnancy-related outcomes were assessed in pregnancy events occurring in women aged 18–45 years between January 1, 2014 and December 31, 2023. The AH group included pregnancies that occurred within 3 years of an AH diagnosis, and the control group consisted of pregnancies with no prior history of liver or biliary disease. Pregnancy-related outcomes were defined using the International Classification of Diseases, Tenth Revision and organized as individual codes and diagnostic blocks. Related diagnoses within a block were combined into a composite outcome when appropriate (eg, O11, O14, and O15 were reported as “pre-eclampsia or eclampsia”). The follow-up period for pregnancy-related outcomes was extended to 12 months after the index pregnancy event to account for any delayed coding of postpartum events. The International Classification of Diseases, Tenth Revision codes used to define cohorts and outcomes were detailed in Supplemental Table 1, http://links.lww.com/HC9/B930.

Outcomes were reported as percentages when sample sizes were sufficient (≥ 10 events per group). Propensity score matching was used to balance cohorts by age, race, ethnicity, obesity diagnosis, and prior live birth. Associations between AH and pregnancy-related outcomes were assessed using OR with 95% CI. Sensitivity analyses were performed in 2 cohorts: (1) a “pure ALD” cohort excluding other etiologies of chronic liver disease and (2) a “pure AH” cohort excluding patients with other chronic liver disease or co-existing alcohol-associated cirrhosis.

Secondary analyses were conducted to better elucidate how AH may influence pregnancy outcomes. First, pregnancy outcomes were analyzed based on the time interval between AH diagnosis and the index pregnancy (in years). Second, we compared pregnancies following a single AH diagnosis and those following recurrent AH episodes. Lastly, we completed a subgroup analysis of nulliparous women, comparing outcomes in women who experienced their first pregnancy following AH diagnosis compared to first-time pregnancies in the control cohort. Nulliparous women with AH were further stratified by the time interval between AH diagnosis and the first pregnancy (less than 1 y, 1–3 y).

Focused analyses

Hypertensive disorders

A separate analysis was performed to evaluate the relationship between AH and the hypertensive disorders of pregnancy. For this analysis, we matched cohorts by aspirin use in addition to age, race, ethnicity, prior live birth, and obesity since aspirin therapy has been shown to lower the risk of pre-eclampsia.¹² We completed subgroup analyses in (1) patients with Body mass index < 35 kg/m², given the increased risk of pre-eclampsia in obesity,¹³ and (2) in those without a prior history of hypertensive disease in pregnancy. Lastly, we compared the incidence of pre-eclampsia or eclampsia in AH pregnancies with and without baseline aspirin therapy.

Perinatal mental health conditions

Severe AUD is often comorbid with psychiatric conditions. Because pre-pregnancy psychiatric history is one of the main risk factors for perinatal mental health disorders,¹⁴ we performed additional analyses in cohorts matched for baseline psychiatric comorbidities, including schizophrenia, non-mood psychotic disorders, generalized anxiety disorder, manic disorder, and major depressive disorder. Pregnancies in women with a history of perinatal mental health disorders were also excluded. A composite outcome was used to assess the incidence of new perinatal mental health illnesses to capture conditions diagnosed during (O99.34) and after pregnancy (F53). As a surrogate marker, we also evaluated new prescriptions for commonly used anti-depressant medications in the year following index pregnancy.

Liver-related outcomes

Liver-related outcomes were compared in women with AH who experienced a subsequent pregnancy and those with AH who did not experience a subsequent pregnancy. Propensity score matching was used to create cohorts balanced by age, race, ethnicity, and bilirubin level (bilirubin ≥ 3 mg/dL and < 3 mg/dL). Baseline liver profiles were compared at the time of the index AH event. The receipt of medication-assisted therapy (MAT) for AUD with either naltrexone, acamprosate, disulfiram, baclofen, topiramate, or gabapentin was assessed over 3 years. Three years was selected as the follow-up time to overlap with the pregnancy period used in the study.

Clinical outcomes, including the incidence of cirrhosis, ascites, HE, bleeding varices, spontaneous bacterial peritonitis, hepatorenal syndrome, and death, were assessed over 10 years. A composite outcome for decompensated liver disease was defined as having any of the queried decompensations. The cumulative incidence of each outcome was reported as a percentage and compared using absolute risk differences with 95% CI. Next, Kaplan-Meier analyses with log-rank tests were used to compare time-to-event and HR with 95% CI to summarize this risk over time.

Analysis

Statistical analyses were completed using the TriNetX Research Software. Time-to-event curves were plotted outside TriNetX using line-level survival data. Significance was evaluated at p<0.05, while outcomes with 0.05<p<0.10 were considered a trend. This study was reviewed and approved by the institutional review board at UMass Chan Medical School.

RESULTS

A total of 10,186 women aged 18–45 years were diagnosed with AH between January 1, 2014 and December 31, 2023. The incidence of pregnancy was significantly lower in the AH cohort compared to both healthy controls (26.6 vs. 54.4 pregnancies per 1000 person-years; incidence rate ratios 0.51, 95% CI: 0.46 to 0.52, p<0.001) and AUD alone (26.6 vs. 43.8 cases per 1000 person-years, incidence rate ratios 0.61, 95% CI: 0.57 to 0.65, p<0.001. In the AH cohort, the incidence of pregnancy was inversely associated with serum bilirubin strata (Figure 1).

FIGURE 1.

Days from AH. Abbreviation: AH, alcohol-associated hepatitis.

Pregnancy-related outcomes

Five hundred and thirty-one pregnancies occurring within 3 years of an AH diagnosis were identified. After matching, 1062 pregnancies were included in the analyses (531 with AH, 531 controls) (Table 1). The mean age was 32.7±5 y at the index pregnancy event (p =1.000). Most pregnancies were in Caucasian (69.3% AH vs. 69.3% controls, p=NS) and non-Hispanic (74.5% AH vs. 75.7% controls, p=NS) women. Baseline liver profiles were significantly different in AH pregnancies, including higher AST (107 vs. 23 IU/L, p<0.001), ALT (86 vs. 21 IU/L, p<0.001), ALP (116 vs. 73 IU/L, p<0.001), total bilirubin (1.7 vs. 0.5 mg/dL, p<0.001) and lower mean platelet count (227 cells 10⁹/L vs. 266 cells 10⁹/L, p=0.007). Baseline serum creatinine (p=0.158) and albumin (p=0.312) were similar between the groups. Inflammatory markers were notably higher in the AH cohort, but these differences were not significant with the available sample size. Alcohol use was reported in 18.0% of AH pregnancies, and the incidence of ascites and jaundice were 6.2% and 4.3%, respectively.

TABLE 1.

Demographic data of women with AH compared to propensity-matched controls

Baseline	AH group (n=531)	Control group (n=531)	P
Demographics
Age, mean±SD	32.7±4.7	32.6±4.7	0.917
White, %	69.3	69.3	1.000
Black or African American, %	12.8	12.6	0.927
Hispanic or Latino, %	11.7	11.7	1.000
Asian, %	1.9	1.9	1.000
Covariates
Overweight or obesity, %	15.4	15.8	0.866
Prior pregnancy, %	9.4	7.2	0.182
Delivery event, %	5.6	5.6	1.000
Baseline Labs, mean±SD
ALT (U/L)	85.5±266	20.8±18.6	0.009
AST (U/L)	107±151	23.1±19	<0.001
ALP (U/L)	116.0±73	73.1±33	<0.001
Bilirubin, Total (mg/dL)	1.7±2.8	0.5±0.2	<0.001
Creatinine (mg/dL)	0.7±0.3	0.7±0.2	0.158
Albumin (g/dL)	3.9±0.7	4.1±0.6	0.009
Platelets (10³/uL)	227±98	266±74	<0.001
Hemoglobin (g/dL)	12.3±2.0	12.6±1.7	0.076
Ferritin (ng/mL)	486.1±1252	50.9±39	0.105
C reactive protein (mg/L)	16.6±28	5.3±7	0.100

Abbreviation: AH, alcohol-associated hepatitis.

Complications of pregnancy

Abortive outcomes were more common in AH pregnancies compared to control pregnancies (14.6% vs. 8.0%, p<0.001), and AH was associated with nearly 2-fold higher odds of spontaneous abortion specifically (OR 1.95, 95% CI: 1.16 to 3.28, p=0.011) (Table 2). Maternal disorders related to pregnancy were also more common in AH pregnancies (39.0% vs. 30.7%, p=0.005). Specifically, AH was associated with 1.8 times higher odds of early pregnancy bleeding (OR 1.78, 95% CI: 1.07 to 2.97, p=0.024), 2.5-times higher odds of excessive vomiting (OR 2.46, 95% CI: 1.38 to 4.40, p=0.002), 2.2-times higher odds of genitourinary infections (OR 2.22, 9% CI: 1.14 to 4.33, p=0.017), and 2.9-times higher odds of pre-eclampsia or eclampsia (OR 2.89, 95% CI: 1.54 to 5.42, p=0.001). In contrast, a similar proportion of pregnancies in each cohort required maternal care related to the fetus and amniotic cavity (35.4% vs. 39.9%, p=0.163). Within this cohort, there was no association between AH and care for malpresentation (OR 1.09, 95% CI: 0.68 to 1.73, p=0.732), abnormality of maternal pelvic organs (OR 0.80, 95% CI: 0.55 to 1.17, p=0.252), premature rupture of membranes (OR 0.86, 95% CI: 0.46 to 1.60, p=0.633), or placental disorders (OR 1.10, 95% CI: 0.60 to 2.02, p=0.757). As a composite outcome, pregnancies after AH were associated with 1.8-fold higher odds of experiencing a placental disorder, placenta previa, or placental abruption (OR 1.80, 95% CI: 1.06 to 3.05, p=0.027). Sensitivity analyses in the pure ALD and pure AH cohorts are reported in Supplemental Table 2, http://links.lww.com/HC9/B930.

TABLE 2.

Pregnancy outcomes of AH compared to controls

Outcome variable	AH (n=531)	Control (n=531)	OR (95% CI)	P
Pregnancy with abortive outcome	14.1	7.7	1.97 (1.32–2.94)	0.001
Spontaneous abortion	8.1	4.3	1.95 (1.16–3.28)	0.011
Edema spectrum	19.8	12.6	1.71 (1.22–2.38)	0.002
Gestational hypertension only	4.7	6.2	0.75 (0.44–1.27)	0.280
Pre-eclampsia	9.0	5.1	1.86 (1.14–3.02)	0.012
Composite pre-eclampsiaa	10.0	5.6	1.85 (1.16–2.95)	0.009
Maternal disorders predominantly related to pregnancy	39.0	30.7	1.44 (1.12–1.86)	0.005
Early pregnancy hemorrhage	8.1	4.7	1.78 (1.07–2.97)	0.024
Excessive vomiting	7.5	3.2	2.46 (1.38–4.40)	0.002
Genitourinary infections	5.3	2.4	2.22 (1.14–4.33)	0.017
Diabetes in pregnancy	7.3	8.7	0.84 (0.64–1.30)	0.429
Other conditions related to pregnancyb	28.4	19.0	1.69 (1.27–2.26)	<0.001
Abnormality in antenatal screening	4.9	3.4	1.47 (0.80–2.71)	0.218
Maternal care related to the fetus and amniotic cavity	35.4	39.5	0.84 (0.65–1.07)	0.163
MC for malpresentation of fetus	7.5	7.0	1.09 (0.68–1.73)	0.723
MC for abnormality of pelvic organs	10.5	12.8	0.80 (0.55–1.17)	0.252
MC for known or suspected fetal abnormality and damage	9.4	8.3	1.15 (0.75–1.76)	0.517
MC for other fetal problems	19.6	16.8	1.21 (0.89–1.65)	0.233
Premature rupture of membranes	3.6	4.1	0.86 (0.46–1.60)	0.633
Placental disorders	5.1	2.8	1.83 (0.97–3.50)	0.059
False labor	3.8	4.1	0.91 (0.49–1.68)	0.753
Complications of labor & delivery	25.2	27.5	0.89 (0.68–1.17)	0.403
Preterm delivery	4.3	3.4	1.29 (0.69–2.42)	0.426
Abnormal forces of laborc	5.1	4.3	1.18 (0.67–2.08)	0.562
Umbilical complications	6.4	6.0	1.07 (0.64–1.75)	0.799
Postpartum hemorrhage	4.7	3.0	1.59 (0.84–3.01)	0.152
Abnormal fetal heart rate	9.8	7.5	1.33 (0.87–2.05)	0.191
Any fetal stress in L&D	11.1	9.0	1.26 (0.84–1.88)	0.262

^a Includes pre-existing hypertension with pre-eclampsia (O11), pre-eclampsia (O14), and eclampsia (O15).

^b Other conditions related to pregnancy include but are not limited to excessive weight gain, low weight gain, and liver and biliary tract diseases.

^c Abnormal forces of labor include but are not limited to inadequate contractions, hypertonic contractions, and precipitous labor.

Abbreviations: AH, alcohol-associated hepatitis; L&D, labor and delivery; MC, maternal care.

Overall, the incidence of adverse pregnancy-related outcomes was similar for pregnancies occurring within 1, 2, and 3 years of AH (Table 3). However, in nulliparous women (n=387), adverse events were numerically more common in pregnancies occurring 1–3 years after AH (n=173) compared to pregnancies within 1 year of AH (n=214), though these differences were not statistically significant (Supplemental Table 3, http://links.lww.com/HC9/B930). With respect to the number of AH episodes, all maternal adverse outcomes, except early pregnancy bleeding, were more common in pregnancies following recurrent AH (n=318) when compared to pregnancies following a single episode of AH (n=230) (Table 4, Supplemental Table 4, http://links.lww.com/HC9/B930).

TABLE 3.

Pregnancy outcomes, by time since AH diagnosis

	AH within 1 y of pregnancy (n=376), (%)	AH within 2 y of pregnancy (n=479), (%)	AH within 3 y of pregnancy (n=531), (%)
Spontaneous abortion	32 (8.5)	37 (7.7)	43 (8.1)
Pre-eclampsia-eclampsiaa	35 (9.3)	48 (10.0)	53 (10.0)
Early bleeding	32 (8.5)	40 (8.4)	43 (8.1)
Genitourinary infections	19 (5.1)	25 (5.2)	28 (5.3)
Placental conditionsa	26 (6.9)	38 (7.9)	40 (7.5)
Preterm labor	16 (4.3)	22 (4.6)	23 (4.3)

^a Composite outcomes.

Abbreviation: AH, alcohol-associated hepatitis.

TABLE 4.

Pregnancy outcomes, by number of AH diagnosis

	No AH episodes (n=>3mil)a	1 AH episode (n=230)	≥ 2 AH episodes (n=318)
Spontaneous abortion, %	3.5	6.1	10.4
Pre-eclampsia, %	3.8	7.0	10.4
Early pregnancy bleeding, %	4.8	10.9	6.6
Gestational diabetes, %	5.6	5.7	8.5
Placental disorders, %	5.1	5.2	9.4
Alcohol use during pregnancy, %	0.1	12.6	21.1
Maternal care for other fetal problems, %	15.1	19.6	20.1
Perinatal mental health conditions, %	2.6	7.8	10.4

Pregnancy-related outcomes in unmatched cohorts of patients with no history of AH, only 1 episode of AH prior to pregnancy, and 2 or more episodes of AH prior to pregnancy.

^a Numbers may differ slightly from Table 2 due to using the full sample of patients without propensity matching.

Abbreviation: AH, alcohol-associated hepatitis.

Complications of labor and delivery

One in 4 pregnancies had a documented complication of labor and delivery (25.2% vs. 25.7%, p=0.403) (Table 2). There was no association between AH and preterm delivery (OR 1.29, 95% CI: 0.69 to 2.42, p=0.426), umbilical cord complications (OR 1.07, 95% CI: 0.64 to 1.75, p=0.799), fetal heart rate abnormalities (OR 1.33, 95% CI: 0.87 to 2.05, p=0.191), fetal stress during delivery (OR 1.26, 95% CI: 0.84 to 1.88, p=0.262), or delivery by means of Cesarean section (OR 1.10, 95% CI: 0.75 to 1.60, p=0.632). While bleeding events were rare overall (n=36 of 1062), AH was associated with 2.7 times higher odds of experiencing intrapartum or postpartum hemorrhage (OR 2.68, 95% CI: 1.28 to 5.62, p=0.007).

Hypertensive disorders of pregnancy

Hypertensive disorders of pregnancy were significantly more common in pregnancies following AH (19.8% vs. 12.6%, p<0.001). In the cohorts balanced for aspirin use, the baseline systolic blood pressure was similar between groups (119±16 vs. 117±14 mm Hg, p=0.238), but newly elevated systolic blood pressure > 140 mm Hg was more common in AH pregnancies (16.8% vs. 7.0%, p<0.001). Though attenuated from the base analysis, pregnancy after AH was associated with 2.5 times higher odds of pre-eclampsia or eclampsia (OR 2.50, 95% CI: 1.48 to 4.33, p<0.001). This persisted in the subgroup of women with body mass index < 35 kg/m² (n=346) (OR 2.27, 95% CI: 1.12 to 4.58, p=0.019) and when excluding those with a history of hypertensive diseases in pregnancy (OR 1.91, 95% CI: 1.07 to 3.39, p=0.026). In the subset of AH pregnancies without a history of hypertensive diseases in pregnancy, aspirin use (n=1105) was not associated with less frequent pre-eclampsia or eclampsia compared to no aspirin use (n=330) (10.5% vs 7.6%, p=0.347).

Perinatal mental health disorders

In the base analysis, AH was associated with a 3.2-fold higher odds of having a perinatal mental health condition (OR 3.19, 95% CI: 1.64 to 6.23, p<0.001). After further matching for the history of major depressive disorder (17%), generalized anxiety disorder (21%), manic disorders (2%), and non-mood psychotic disorders (6%), this relationship was attenuated but remained significant (OR 1.87, 95% CI: 1.35 to 2.57, p<0.001). Excluding the subset of women with a history of perinatal mental health conditions, these remained significantly more common in the AH cohort (15.9% vs. 10.1%, p=0.008). In addition, the incidence of new anti-depressant prescriptions was notably higher in AH pregnancies compared to controls (14.1% vs. 4.8%, p<0.001).

Liver-related outcomes

Alcohol and liver-related outcomes were compared in 896 women with AH, including 499 women with pregnancy following AH and 499 women without a subsequent pregnancy. Cohorts were matched for age, race, ethnicity, obesity, and bilirubin (< 3 and > 3 mg/dL) (Table 5). In the 3 years following AH, 1 in 4 women received MAT for AUD. There was a trend between receiving MAT and having a subsequent pregnancy as compared to no pregnancy (29.7% vs. 25.0%, p=0.102). Prescribed medications including the use of acamprosate (9.2% vs. 10.2%, p=0.833), disulfiram (4.0% vs. 3.4%, p=0.615), topiramate (3.8% vs. 2.6%, p=0.218), baclofen (3.6% vs. 3.2%, p=0.727), and naltrexone (16.6% vs. 12.6%, p=0.072) were similar in those with and without a pregnancy.

TABLE 5.

Liver-related outcomes in women with AH and pregnancy compared to no pregnancy (30–3600)

Variable	AH + subsequent pregnancy (n=499)	AH - no subsequent pregnancy (n=499)	P
Demographics
Age*, mean±SD	31.6±4.6	31.6±4.6	0.983
Body mass index, mean±SD	26.3±6.6	26.4±7.3	0.935
White*, %	71.1	71.1	1.000
Black or African American*, %	11.8	11.6	0.922
Hispanic or Latino*, %	10.2	9.8	0.833
Asian*, %	2.0	2.0	1.000
Baseline AH labs, mean±SD
ALT (U/L)	78.6±143.6	81.6±108.7	0.787
AST (U/L)	130.7±139.9	143.4±139.2	0.288
ALP (U/L)	121.4±73.3	138.5±104.3	0.025
Bilirubin, total (mg/dL)	1.9±3.4	3.0±5.1	0.003
Creatinine (mg/dL)	0.7±0.3	0.6±0.3	0.553
MAT prescriptions (3-year)
Acamprosate, %	9.2	10.2	0.833
Naltrexone, %	16.6	12.6	0.073
Disulfiram, %	4.0	3.4	0.615
Topiramate, %	3.8	2.6	0.218
Baclofen, %	3.6	3.2	0.727
Gabapentin, %	37.3	31.7	0.062
Any medication, %	29.7	25.0	0.102
Any medication + gabapentin, %	49.8	41.8	0.010
Liver-related outcomes (10-year)
Cirrhosis—all, %	31.1	32.5	0.634
Cirrhosis—new, %	18.1	19.4	0.639
Ascites—all, %	23.4	27.5	0.146
Ascites—new, %	9.1	9.6	0.796
Bleeding varices, %	5.8	4.4	0.314
HE, %	9.6	11.4	0.353
Spontaneous bacterial peritonitis, %	4.0	6.0	0.147
Hepatorenal syndrome, %	3.6	6.2	0.047
Composite decompensationa, %	21.2	24.4	0.227
Mortality
Deceased, 3 y, %	2.8	10.8	<0.001
Deceased, 10 y, %	4.8	19.0	<0.001
Deceased, 30–10 y	4.8	12.3	<0.001

^a Includes any of the following: ascites, varices with bleeding, HE.

^*indicates demographic variables included in propensity score matching; additional matched variables included obesity diagnosis and prior live birth

Abbreviation: AH, alcohol-associated hepatitis.

The cumulative incidence of cirrhosis was similar in women who experienced a subsequent pregnancy (18.1%) and in those who did not experience a pregnancy (19.4%), with no statistically significant difference observed in crude risk measures (absolute risk differences: -0.01, 95% CI: -0.07 to 0.04, p=0.639). However, Kaplan-Meier survival analysis revealed a significantly lower hazard of cirrhosis among the pregnancy group compared to the no-pregnancy group (HR 0.58, 95% CI: 0.41 to 0.81, log-rank χ²=10.4, p=0.001) (Figure 2). There were similar trends observed in the queried hepatic decompensations between the 2 groups. Despite similar cumulative incidence, pregnancy following AH was associated with a reduced hazard of ascites (HR 0.59, 95% CI: 0.46 to 0.75, log-rank p < 0.001), HE (HR 0.54, 95% CI: 0.37 to 0.80, log-rank p=0.002), spontaneous bacterial peritonitis (HR 0.38, 95% CI: 0.31 to 0.69, log-rank p=0.001), and hepatorenal syndrome (HR 0.48, 95% CI: 0.26 to 0.90, log-rank p =0.019) (Table 6). Both the overall mortality (2.8% vs. 19.0%, p<0.001) and survival probability were significantly lower in the women who experienced a subsequent pregnancy (HR 0.23, 95% CI: 0.14 to 0.36; log-rank, p<0.001) compared to those who did not experience a pregnancy.

FIGURE 2.

Cirrhosis diagnosis following AH in women with a subsequent pregnancy (purple) compared to no subsequent pregnancy (green). Kaplan- Meier analysis of new cirrhosis diagnosis following AH in women with a subsequent pregnancy (purple, n=499) compared to no subsequent pregnancy (green, n=499). Abbreviation: AH, alcohol-associated hepatitis.

TABLE 6.

Univariable analysis comparing time to liver-related events and event probability in women with AH with a subsequent pregnancy versus no pregnancy

Outcome	HR (95% CI)	Log-rank χ2	P
Cirrhosisa	0.578 (0.41–0.81)	10.35	0.001
Ascites	0.589 (0.46–0.75)	18.52	<0.001
Esophageal varices	0.842 (0.48–1.47)	0.37	0.546
Hepatic encephalopathy	0.542 (0.37–0.80)	9.97	0.002
Spontaneous bacterial peritonitis	0.383 (0.31–0.69)	11.14	0.001
Hepatorenal syndrome	0.482 (0.26–0.90)	5.53	0.019
Further decompensation	0.575 (0.44–0.75)	17.50	<0.001
Deceased	0.226 (0.14–0.36)	45.57	<0.001

^a Patients with cirrhosis prior to index AH were excluded from the incident cirrhosis outcome (n=117 AH+pregnancy; n=154 AH-no pregnancy).

Abbreviation: AH, alcohol-associated hepatitis​​​​​​.

DISCUSSION

In this large, multi-center research network, we explored how AH during reproductive years influences fertility and pregnancy and whether pregnancy after an episode of AH affects long-term outcomes in liver disease. Incident pregnancy was nearly 2 times lower in women with AH compared to reproductive-aged women without liver or biliary disease, and the probability of pregnancy declined with increasing serum bilirubin. In those who had a pregnancy, pregnancies following an episode of AH led to higher risks of pregnancy loss and several life-threatening pregnancy-related complications, including hypertensive disorders, early and late pregnancy bleeding, and perinatal mental health disorders. With respect to liver disease, women who experienced at least 1 pregnancy after AH had a similar overall risk of cirrhosis and hepatic decompensation at the end of 10 years but a slower disease progression.

It is well established that alcohol use has the potential to lower fertility by affecting the hypothalamic-pituitary and gonadal axis.³ There is strong data supporting reduced fertility in women with heavy alcohol use, whereas studies evaluating mild to moderate alcohol use have been inconsistent.¹⁵ In this study, not only was the incidence of pregnancy in women with AH lower than in healthy controls, but it was also lower than in women with AUD alone. This is important as it supports the notion that AH affects reproductive health beyond the influence of alcohol alone. In addition, the declining incidence of pregnancy with higher serum bilirubin demonstrates that fertility is lower with more severe liver disease.

Of the pregnancy outcomes, hypertensive disorders, such as pre-eclampsia and eclampsia, were notably more common in AH pregnancies. Pre-eclampsia and eclampsia are life-threatening conditions that affect up to 2%–10% of pregnancies worldwide.¹⁶,¹⁷ The incidence of pre-eclampsia in our control cohort (5.6%) was consistent with population estimates. However, pre-eclampsia was nearly twice as common in AH pregnancies, highlighting a serious potential risk associated with AH. Risk factors for pre-eclampsia include age, black race, obesity, and hypertension, all of which were balanced between the cohorts with propensity matching in our study.¹⁸ Cirrhosis has been shown to increase the risk of pre-eclampsia, but the relationship between prenatal alcohol use and pre-eclampsia is not fully elucidated.⁴,¹⁹,²⁰ A recent study from the Danish nationwide registry suggested that heavy alcohol exposure was associated with lower odds of pre-eclampsia.⁴ However, this study may not reflect alcohol use to the extent seen in women with AH, as the definition of healthy alcohol exposure was either the receipt of MAT for AUD or a diagnosis of an alcohol-associated condition within 1 year of giving birth. Likewise, a recent study including >500,000 births over a five-year period in the Swedish National Registry found that pre-eclampsia was more common in women with moderate or severe alcohol use as defined by the Alcohol Use Disorders Identification Test—Consumption, but this relationship failed to meet the significance on adjusted analyses.¹⁹ It is possible that differences in our results are related to the poor correlation between Alcohol Use Disorders Identification Test—Consumption scores and the severity of AH or the systemic syndrome of AH beyond alcohol use.²¹ The systemic syndrome of AH serves as a potential biological link to pre-eclampsia. In fact, systemic inflammation in the setting of increased pro-inflammatory cytokines (eg, interleukin-6) is central to the pathophysiology of both conditions.²²,²³ While interleukin levels were not available in the TriNetX database to test this hypothesis, inflammatory markers, including c-reactive protein and serum ferritin levels, were notably higher in the AH cohort, which supports this hypothesis. It is possible that the association between AH and pre-eclampsia in our study was related to the additive effects of alcohol use and systemic inflammation and/or underlying liver disease, though this is beyond the scope of this study.

Our findings also demonstrate a critical difference in the risk of perinatal mental health conditions in women who become pregnant after AH. In the United States, an estimated 5%–15% of pregnancies are complicated by a mental health condition, such as perinatal depression.²⁴ Perinatal mental health conditions are associated with long-term adverse effects on both the birthing person and the offspring and have been identified as a high-priority issue by the American College of Obstetricians and Gynecologists.²⁵ The risk of perinatal mood or anxiety disorder among healthy controls in our study was less than 5%, which is lower than expected compared to the general population and may be related to the higher age and White racial predominance in this cohort.²⁶,²⁷ The incidence of perinatal mental health disorders was over 3 times higher in women with recent AH, a relationship that remained significant when matching for baseline psychiatric comorbidities and excluding women with a history of perinatal mental health conditions. It is crucial to highlight this association as the detrimental effects on both mother and child can be mitigated with early diagnosis and intervention.²⁵ In addition, there has been an alarming rise in AH among younger women of lower socioeconomic status, a group already at an elevated baseline risk for perinatal mood or anxiety disorders and may benefit from increased levels of support.²⁸

Beyond the perinatal period, we were also interested in whether pregnancy influenced the course of liver disease in women with AH. Pregnancy is a state of high estrogen.²⁹ Despite estrogen being generally protective against hepatic fibrosis, it can also increase the susceptibility of the liver to alcohol-induced liver damage in women.³⁰,³¹ In this study, the overall incidence of cirrhosis 10 years after AH was the same in women with and without a pregnancy, but disease progression was delayed in the pregnancy group. This delayed progression may have clinical relevance, as slower disease progression often correlates with better overall prognosis and quality of life. Although the incidence of cirrhosis was similar, mortality was significantly lower in the pregnancy group which may suggest that extrahepatic events drive the differences in mortality between these groups.

This study has several strengths. To our knowledge, this is the first study looking at pregnancy outcomes after an episode of AH and provides valuable insight into the reproductive and liver-related outcomes in this growing cohort of patients. Using the TriNetX database, we were able to include multiple health care organizations both in the United States and across the globe. In addition, the use of TriNetX allows for staging or linking of the index event ensuring that only pregnancies after AH were included in these analyses. The ability to follow outcomes for several years after an index event allows for greater insight into the potential influence of AH on pregnancy outcomes within the limitations of a retrospective study.

Our study has several limitations, including potential confounding bias and misclassification bias. The potential for confounding bias is inherent to observational studies. To limit this risk, we utilized propensity cohort matching for age, race, and ethnicity when comparing outcomes between groups. Similarly, misclassification bias is inherent to International Classification of Diseases, Tenth Revision code-based studies, though the TriNetX database minimizes misclassification through its use of natural language processing. Further, we believe the risk of misclassification bias to be limited in our study as several of the results align with expected findings, including (1) elevated liver profile in women with AH and (2) the risk of pregnancy outcomes (pre-eclampsia, postpartum hemorrhage) in healthy controls. Lastly, we did not have access to patient-level or organizational-level data due to privacy limitations in TriNetx that would have allowed further investigation with respect to insurance and socioeconomic factors or further statistical analyses.

CONCLUSIONS

Ultimately, our results suggest that women with AH are less likely to become pregnant and are more likely to experience adverse pregnancy-related outcomes. Patients who experience pregnancy after AH may have delayed progression of liver disease and more favorable long-term outcomes compared to nonpregnant counterparts. To our knowledge, there are no studies to date that have explored pregnancy outcomes in this group. The results of this study are important for reproductive counseling for women who experience AH and to inform future studies in this growing population of women. They also highlight the importance of multidisciplinary care, including hepatology, obstetrics, and mental health services, to address the complex needs of this high-risk population.

Supplementary Material

hc9-9-e0663-s001.docx ^{(24.5KB, docx)}