Abstract
Introduction:
Previous research identified AIH as linked to unfavorable obstetrical outcomes in a US nationwide retrospective study from 2012-2016. Our aim is to update the literature and strengthen the AIH-pregnancy outcomes relationship.
Methods:
Using the National Inpatient Sample database in the US, from 2016 to 2020, we compared pregnant females with a diagnosis of AIH to those with and without other chronic liver diseases (CLD), using ICD-10-CM codes. Baseline characteristics were analyzed using T-test and Chi-Square, and multivariate regression was used to estimate the differences in maternal outcomes adjusted for age, race, insurance status, geographical location, hospital characteristics, and comorbid conditions.
Results:
Out of 19,392,328 hospitalizations for pregnant females ≥ 18 years old from 2016 to 2020, 1,095 had AIH, 179,655 had CLD, and 19,206,696 had no CLD. No mortality was observed among individuals with AIH. When compared to individuals without CLD, AIH was associated with 82% increase in the odds of preterm delivery (AIH: 8% vs. Without CLD: 5%, adjusted Odds Ratio = 1.82, 95%CI: 1.06 – 3.14), with no significant differences in gestational diabetes mellitus, hypertensive complications, and postpartum hemorrhage, and a 0.6 day longer hospital stay. Furthermore, there were no significant differences in outcomes between AIH and CLD.
Conclusions:
Our study reinforces the association of AIH with adverse obstetrical outcomes (e.g., preterm delivery), however, we found that there is no difference in GDM and hypertensive complications, as suggested in prior studies. Therefore, further investigations are needed to clarify the association between AIH and these obstetrical complications.
Keywords: Autoimmune hepatitis, Chronic Liver Disease, Pregnancy, Obstetrical complications
INTRODUCTION
Autoimmune hepatitis (AIH) is characterized by chronic liver inflammation arising from an autoimmune response [1]. AIH has been found to exhibit higher prevalence in females of child-bearing age and in individuals of Caucasian ethnicity [2]. Multiple risk factors, including environmental, genetic, and history of autoimmune diseases (such as Celiac disease, rheumatoid arthritis, Hashimoto thyroiditis, autoimmune gastritis), as well as infections (measles, Herpes simplex or Epstein-Barr viruses, hepatitis A, B or C infections), have been associated with AIH [3-5]. The clinical presentation of AIH can range from asymptomatic elevation of transaminase levels to acute symptomatic hepatitis, chronic cirrhosis, and fulminant liver failure [1].
The presence of AIH defines a high-risk pregnancy due to the autoimmune state and potential adverse effects of curative medications [6]. Prior studies have demonstrated that AIH is linked to an increased risk of obstetrical complications, encompassing adverse maternal outcomes such as gestational diabetes mellitus (GDM), hypertensive complications, and intrahepatic cholestasis of pregnancy, as well as fetal complications including premature birth, fetal loss, and small-for-gestational-age infants [7-9]. Fisher et al. reported that incomplete response to AIH treatment during pregnancy was associated with worse outcomes for both mothers and fetuses [10]. Wang et al. previously identified a correlation between AIH and adverse obstetrical outcomes in a nationwide retrospective study conducted in the United States (US) from 2012 to 2016 [8].
The objective of our study was to update the literature and further elucidate the relationship between AIH and pregnancy outcomes in the US from 2016 to 2020.
MATERIALS AND METHODS
Data source:
In our study, we utilized the National (Nationwide) Inpatient Sample (NIS) database to conduct a retrospective longitudinal analysis spanning from 2016 to 2020, focusing on hospitalizations of pregnant females with secondary diagnoses of autoimmune hepatitis (AIH) or other chronic liver diseases (CLD). The NIS database, developed as part of the Healthcare Cost and Utilization Project (HCUP), is a representative sample of 20% of discharges from non- federal acute care hospitals in the United States, designed to provide robust estimates of healthcare utilization, cost, quality, and outcomes at regional and national levels [11, 12]. The database employs the International Classification of Diseases, Tenth Revision, Clinical Modification/Procedure Coding System (ICD-10-CM/PCS) codes from October 2015 onwards [13]. The principal diagnosis in the NIS database refers to the condition that prompted the patient's admission, while secondary diagnoses include other coexisting diagnoses identified during the same admission, as indicated by the ICD codes. As per the Data User Agreement for HCUP, cell sizes <11 were not reported and suppressed.
Study population and variables:
Our study focused on analyzing inpatient hospital admissions of pregnant women ≥ 18 years old who had secondary diagnoses of autoimmune hepatitis (AIH), other CLD, or no CLD, spanning from the years 2016 to 2020. The variables examined included age, race, primary insurance, median household income based on patients’ zip codes, hospital characteristics such as region, teaching status, and size, as well as primary and secondary outcomes (detailed below). We utilized the Charlson comorbidity index (CCI) to assess comorbidities and mortality risk in our patient population [14]. ICD-10 codes were employed to identify adult pregnant female patients who were admitted with secondary diagnoses of AIH and other CLD, with the exclusion of patients below 18 years of age. The ICD-10 codes used in this study are listed in supplemental table 1, and were captured from Wang et al. in a previous NIS study on the outcomes of pregnancy in autoimmune hepatitis in pregnant females [8]. However, the ICD-10 code for AIH (K75.4) has been later shown to have a low positive predictive value (PPV: 77%) when used alone [15]. The exclusion of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) from the hospitalization records with ICD-10 codes of AIH increased its PPV for the identification of AIH to 90% [15]. This validated algorithm further required the exclusion of records with recent immune checkpoint inhibitors to increase the PPV of the ICD-10 code for AIH to 93% [15]. However, the NIS does not allow the identification of prior medication use; therefore, we have selected our patient population with AIH based on the exclusion of patients with PBC and PSC only (Figure 1). ICD-10 codes for other CLDs included chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), disorders of copper or iron metabolism, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and any unspecified cirrhosis [8]. Further, to better explore the differences between AIH and other CLD, records with combined codes for AIH and CLD were excluded from this study, as previously done by Wang et al (Figure 1) [8].
Fig. 1.
Flowchart of our study population
*AIH: Autoimmune hepatitis; CLD: Chronic liver disease (s); PBC: Primary biliary cirrhosis; PSC: Primary sclerosing cholangitis.
Patient and hospital characteristics:
We retrieved data on age (18-24.9, 25-29.9, 30-34.9, ≥ 35 years), race (non-Hispanic White, non-Hispanic Black, Hispanic, Other), primary insurance (Medicare, Medicaid, Private Insurance, Self-pay), income quartile (lowest quartile, second quartile, third quartile, highest quartile), hospital characteristics (hospital region, teaching status, bed size) [11] and the Charlson comorbidity index (0, 1, 2, ≥ 3) [16].
Outcome measures:
The primary objective of this study was to investigate the mortality among adult pregnant females with secondary diagnoses of autoimmune hepatitis (AIH) and other chronic liver diseases (CLD), in comparison to those without underlying CLD. Secondary outcomes included length of stay (LOS), total hospital charges (THC), and obstetrical complications, such as GDM, hypertensive complications (including preeclampsia, eclampsia, hemolysis, and elevated liver enzymes, and low platelet syndrome (HELLP)), preterm delivery, and postpartum hemorrhage (PPH). We did not evaluate for spontaneous abortion, mainly because these are primarily managed in the outpatient setting [8]. Adjustments for confounders were made to account for potential influencing factors on the outcomes (age, race, insurance status, geographical location, hospital characteristics, and comorbid conditions). The reporting of this study adheres to the "Strengthening the Reporting of Observational Studies in Epidemiology" (STROBE) reporting guidelines, provided in the Supplementary table 2.
Statistical analysis:
Statistical analysis was conducted using Stata/SE® Version 17.0 software (StataCorp, Texas, USA) on weighted samples obtained from the NIS database. Comparative analyses were performed to assess patients with autoimmune hepatitis (AIH), other chronic liver diseases (CLD), and those without CLD. Multivariate logistic regression analysis was employed to estimate the Odds ratio of mortality and other outcomes, with a 95% confidence interval (95%CI), while adjusting for potential confounders at both hospital and patient levels. T-Test and Chi-Square tests were utilized to compare the characteristics of adult patients with and without underlying CLD. A significance threshold of p<0.05 was set to determine statistical significance in all analyses throughout the study.
RESULTS
Prevalence of AIH in pregnant females:
Within the study period of 2016 to 2020, a total of 19,392,328 adult pregnant patients were admitted. Among these, 1,095 (6/100,000 people) were diagnosed with AIH (including 0.5% with liver cirrhosis), and 179,655 were diagnosed with CLD (926/100,000 people) (1% with liver cirrhosis). The majority of patients did not have any CLD (98%, N=19,206,696). The prevalence of AIH in pregnant females exhibited relative stability over the study period (Figure 2).
Fig. 2.
Trends of autoimmune hepatitis (AIH) in pregnant females from 2016 to 2020
Baseline characteristics:
Individuals hospitalized with diagnosis of AIH significantly older than those without CLD (Age≥35 years: AIH: 27% vs. Without CLD: 18%, p<0.01) (Table 1). A non-Hispanic White predominance was seen in patients with AIH; however, this was more pronounced in patients with CLD (AIH: 56% vs. CLD: 61%, p<0.01). When compared to patients with CLD, those with AIH had more non-Hispanic Blacks (AIH: 16%, CLD: 11%, p<0.01), while there were no significant differences with patients without CLD (p=0.12) (Table 1).
Table 1.
Baseline characteristics of individuals with autoimmune hepatitis (AIH), other chronic liver diseases (CLD), and those with chronic liver diseases.
| AIH Percentage (No.) |
CLD Percentage (No.) |
Without CLD Percentage (No) |
P AIH vs. CLD |
P AIH vs. Without CLD |
|
|---|---|---|---|---|---|
| All hospitalizations | 100% (1,095) | 100% (179,655) | 100% (19,206,696) | ||
| Age | 0.12 | < 0.01 | |||
| 18 – 24.9 years | 15.5% (170) | 15.3% (27,545) | 23.7% (4,551,253) | ||
| 25 – 29.9 years | 2653% (290) | 32.0% (57,540) | 29.1% (5,592,397) | ||
| 30 – 34.9 years | 30.6% (335) | 31.3% (56,210) | 28.8% (5,529,647) | ||
| ≥35 years | 27.4% (300) | 21.4% (38,360) | 18.4% (3,533,298) | ||
| Race | < 0.01 | 0.26 | |||
| Non-Hispanic White | 55.7% (590) | 60.5% (104,975) | 52.0% (9,585,444) | ||
| Non-Hispanic Black | 16.0% (170) | 11.3% (19,640) | 15.8% (2,919,325) | ||
| Hispanic | 17.5% (185) | 11.3% (19,510) | 20.8% (3,840,323) | ||
| Others | 10.8% (115) | 16.9% (29,423) | 11.4% (2,095,249) | ||
| Insurance status | < 0.01 | < 0.01 | |||
| Medicare | 2.5% (20) | 2.2% (3,055) | 0.8% (124,920) | ||
| Medicaid | 32.1% (260) | 69.5% (98,075) | 43.8% (6,620,076) | ||
| Private insurance | 63.6% (515) | 25.2% (35,555) | 52.6% (7,938,984) | ||
| Self-Pay | 1.8% (15) | 3.1% (4,395) | 2.8% (417,680) | ||
| Median household income | < 0.01 | 0.22 | |||
| Lowest Quartile | 24.0% (260) | 35.9% (63,425) | 28.2% (5,363,548) | ||
| Second Quartile | 22.6% (245) | 27.8% (49,150) | 25.4% (4,835,722) | ||
| Third Quartile | 29.0% (315) | 21.4% (37,895) | 24.6% (4,684,517) | ||
| Highest Quartile | 24.4% (265) | 14.9% (26,380) | 21.8% (4,148,468) | ||
| Hospital region | 0.16 | 0.06 | |||
| Northeast | 19.6% (215) | 20.0% (35,935) | 16.0% (3,069,884) | ||
| Midwest | 26.0% (285) | 20.2% (36,325) | 21.0% (4,014,703) | ||
| South | 34.3% (375) | 39.7% (71,260) | 39.3% (7,553,030) | ||
| West | 20.1% (220) | 20.1% (36,135) | 23.8% (4,569,078) | ||
| Hospital teaching status | 0.09 | < 0.01 | |||
| Teaching | 81.4% (680) | 75.8% (109,570) | 70.5% (11,107,102) | ||
| Non-teaching | 18.6% (155) | 24.2% (34,920) | 29.6% (4,592,143) | ||
| Hospital size | 0.69 | 0.08 | |||
| Small | 16.9% (185) | 15.9% (28,480) | 19.0% (3,646,218) | ||
| Medium | 24.7% (270) | 27.1% (48,775) | 30.0% (5,769,504) | ||
| Large | 58.6% (640) | 57.0% (102,400) | 51.0% (9,790,973) | ||
| Comorbidities | < 0.01 | < 0.01 | |||
| 0 | 71.2% (780) | 48.4% (86,970) | 92.6% (17,782,291) | ||
| 1 | 25.1% (275) | 43.9% (77,790) | 6.9% (1,314,714) | ||
| 2 | 2.7% (30) | 6.1% (11,030) | 0.4% (83,510) | ||
| ≥3 | 0.9% (<11) | 1.6% (2,865) | 0.1% (25,550) | ||
| Comorbid conditions | |||||
| Smoking | 4.6% (50) | 31.8% (57,100) | 4.5% (878,155) | < 0.01 | 1.00 |
| Dyslipidemia | 1.8% (20) | 1.1% (1,945) | 0.3% (65,450) | < 0.01 | < 0.01 |
| Obesity | 16.0% (175) | 13.4% (24,120) | 11.4% (2,184,609) | 0.27 | 0.03 |
| Hypertension | 4.6% (50) | 4.3% (7,750) | 2.2% (421,680) | 0.85 | 0.02 |
| Diabetes mellitus | 12.3% (135) | 8.3% (16,050) | 6.2% (1,182,345) | 0.08 | < 0.01 |
| Alcohol use disorder | 0.0% (<11) | 1.4% (2,485) | 0.1% (23,605) | 0.09 | 0.61 |
| Liver cirrhosis | 0.5% (<11) | 1.0% (1,945) | N/A | 0.37 | N/A |
Pregnant females with AIH were more likely to have higher incomes than those with CLD (Highest quartile: AIH: 24% vs. CLD: 15%, p<0.01), while there was no significant difference between AIH and those without CLD (p=0.22). The presence of AIH in pregnant females was associated with a significantly higher proportion of Private insurance payers than those with and without CLD, more so when compared to patients with CLD (AIH: 64%, CLD: 25%, Without CLD: 53%, p<0.01). Compared to pregnant females without CLD, pregnant females with AIH were also more likely to be treated in teaching hospitals (AIH: 82% vs. Without CLD: 71%, p<0.01), however, there were no significant differences in hospital size (Table 1).
Comorbid conditions:
Pregnant females with CLD were more likely to have 3 or more comorbidities as compared to those with AIH and without CLD (AIH: 0.9%, CLD: 1.6%, and Without CLD: 0.1%, p<0.01). Compared to pregnant females with AIH, those with CLD were more likely to be smokers (AIH: 5% vs. CLD: 32%, p<0.01) (Table 1). Furthermore, when compared to individuals without CLD, patients with AIH had a significantly increased prevalence of dyslipidemia (AIH: 2% vs. Without CLD: 0%, p<0.01), diabetes mellitus (AIH: 12% vs. Without CLD: 6%, p<0.01), and hypertension (AIH: 5% vs. Without CLD: 2%, p=0.02) (Table 1).
Obstetrical outcomes:
There was no case of maternal mortality observed among pregnant females with AIH (AIH: 0% (N<11); CLD: 0% (N= 110); Without CLD=0% (N=1,615)), as well as no case of cesarean delivery; therefore, no comparison analysis was possible with hospitalizations with and without CLD.
When comparing hospitalized individuals with AIH to those with CLD, we found no significant difference in the odds of GDM (AIH: 13% vs. CLD: 9%, adjusted Odds ratio (aOR) = 0.89, 95%CI: 0.37 – 2.17), hypertensive complications (AIH: 8% vs. CLD: 7%, aOR = 0.88, 95%CI: 0.48 – 1.60), preterm delivery (AIH: 8% vs. CLD: 8%, aOR = 1.27, 95%CI: 0.74 – 2.17), and PPH (AIH: 5% vs. CLD: 5%, aOR = 0.79, 95%CI: 0.35 – 1.78) (Figure 3A).
Fig. 3.
Obstetrical complications among hospitalized pregnant females with autoimmune hepatitis (AIH), other chronic liver diseases (CLD), and without CLD. Hospitalizations with AIH were associated with higher odds of preterm delivery (PD) when compared to those without CLD, and no significant changes in the odds of gestational diabetes mellitus, hypertensive complications, and postpartum hemorrhage when compared to patients with and without CLD
*Adjusted for age, sex, race, income, insurance status, hospital characteristics, Charlson comorbidity index, and comorbid conditions
Hospitalized pregnant females with AIH compared to those without CLD, were at increased odds of preterm delivery (AIH: 8% vs. Without CLD: 5%, aOR = 1.82, 95%CI: 1.06 – 3.14); however, there was no significant difference in GDM (AIH: 13% vs. Without CLD: 8%, aOR = 1.83, 95%CI: 0.98 – 3.43), PPH (AIH: 5% vs. Without CLD: 4%, aOR = 0.97, 95%CI: 0.43 – 2.19), and hypertensive complications (AIH: 8% vs. Without CLD: 6%, aOR = 1.07, 95%CI: 0.58 – 1.97) (Figure 3B).
Hospital utilization and healthcare costs:
Patients with AIH stayed on average 0.6 day longer as compared to those without CLD (AIH: 3.3 days vs. Without CLD: 2.6 days, adjusted Mean Difference (aMD) = 0.6 day, 95%CI: 0.08 – 1.04), without significant differences in total charges (AIH: 30, 615 US Dollars (USD) vs. Without CLD: 21,408 USD, aMD = 8,810 USD, 95%CI: −2,573 – 20,194). Further, hospitalizations with AIH and CLD did not exhibit any differences in LOS (AIH: 3.3 days vs. CLD: 3.4 days, aMD = 0.0 day, 95%CI: −0.45 – 0.54), or THC (AIH: 30, 615 USD vs. Without CLD: 27,312 USD, aMD = 5,057 USD, 95%CI: −6,574 – 16,688).
DISCUSSION
Maternal complications:
Our study failed to demonstrate a significant difference in GDM among pregnant female hospitalizations associated with a diagnosis of AIH, as compared to those with and without CLD. However, a previous study by Wang et al. reported a 2.2-fold increase in the risk of GDM in pregnant females with AIH compared to those with other types of CLD, and a 2.4-fold increase compared to those without CLD, during the period of 2008 to 2016 [8]. However, the ICD-10 codes used to include hospitalizations with AIH was later shown to have a weak PPV (77%), and later re-adjusted by excluding patients with PBC and PSC, increasing its PPV to 90% [15]. Furthermore, a systematic review and meta-analysis also found an increased risk of GDM in pregnant females with AIH compared to those without AIH [17]. Therefore, larger scale studies will be required to identify the relationship between AIH and GDM.
In addition, Wang et al. also reported an increased risk of hypertensive complications in hospitalized pregnant females with AIH compared to those with CLD (aOR 1.77) and those without CLD (aOR 2.4) [8]. However, our study did not find any statistically significant difference in hypertensive complications among pregnant women with AIH compared to those with CLD or without CLD. This result is consistent with the findings of Tengfei et al., who also did not find any statistically significant difference in the risk of gestational hypertension and preeclampsia [17]. This may be attributed to improvements in preconception counseling and monitoring of patients with AIH. Moreover, Tengfei et al showed that AIH disease activity tends to decrease during pregnancy, with cases of remission during pregnancy [17]. No cases of maternal death were reported in our study population. However, previous literature has shown that women with liver cirrhosis may be at increased risk [9].
Perinatal complications:
Despite the advancements in practice guidelines and treatment options, evidence suggests that pregnant females with autoimmune hepatitis (AIH) still face increased risks of certain obstetrical complications, such as preterm delivery and GDM, compared to the general population [17]. In regards to perinatal complications, our study revealed that pregnant females with AIH had an 82% increase in the odds of PD compared to those without CLD, with no difference between AIH and CLD. The 2008-2016 Nationwide study performed by Wang et al. concluded that AIH in pregnant females was associated with a higher risk of PD when compared to hospitalizations without CLD (aOR 2.0) [8]. These results were further corroborated by international studies. In fact, Sharma et al., in a Nationwide study in Sweden from 1992-2016 including 309 live births in females with AIH, found a 5-fold increase in the odds of preterm birth in females with AIH as compared to the general population (OR = 5.1) [18]. Moreover, Stokkeland et al found similar results in Denmark from 2006-2011, in a Nationwide study including 171 in females with AIH, showing a 3-fold increase in the risk of preterm delivery in pregnant females with AIH as compared to the general population (RR =3.2) [19]. Last, Si et al., in a systematic review and meta-analysis described a 3-fold (RR = 3.2) increases in PD among pregnant females with AIH when compared to those without AIH [17]. However, Wang et al [8] did not find a statistically significant difference in PD risks between pregnant females with AIH and CLD, suggesting that the risk of PD may not be specific to AIH but rather associated with liver disease in general.
Hospital utilization and healthcare costs:
Our study also revealed a longer LOS among pregnant patients with AIH compared to those without CLD, likely attributable to the increased morbidity observed in AIH patients. Recent clinical practice guidelines emphasize the importance of incorporating pre-conception counseling in females of reproductive age with AIH [20].
Strengths and limitations:
Our study has several strengths. The NIS database allowed us to review a total of 19 million adult pregnant hospitalizations of pregnant females, and more than 1,120 pregnant females with AIH which confers this study generalizability, as well as power and statistical significance. We exclusively used ICD-10 CM codes, which were available from a previous study conducted by Wang et al. [8], which helped maintain uniformity during the coding process of the STATA analysis, and reduce the likelihood of coding error.
We acknowledge several limitations in our study. First, the NIS does not include federal hospitals, reducing the scope of coverage of the database [13]. Second, the NIS includes individual hospitalizations, rather than individual cases, which might overestimate the study population. This could explain our finding that hospitalizations are associated with the increased proportion of hospitalizations with a higher income, likely due to increased healthcare access and utilization by patients with higher incomes. Further, our study included a high number of comparisons, increasing the risk of type 1 error due to the multiple comparison problems. Moreover, ICD-10 codes for liver cirrhosis remain suboptimal for identifying patients with liver cirrhosis [21]. In addition, the NIS does not allow reliably assessing data on medication use (e.g. corticosteroids, immunosuppressant) and disease activity. Further, we were unable to establish a causal relationship between autoimmune hepatitis (AIH) and pregnancy outcomes in our current study. Additionally, we did not evaluate the impact of AIH on fetal outcomes associated with AIH in our study. Moreover, data on liver transplantation has not been included in this study. These limitations highlight the need for further research to address these gaps and provide a more comprehensive understanding of the relationship between AIH and pregnancy outcomes. Finally, potential coding errors during the identification of our variables may have occurred.
CONCLUSIONS
Our findings suggest that individuals with autoimmune hepatitis (AIH) face an increased odds of experiencing adverse outcomes during pregnancy (e.g., preterm delivery), and is associated with prolonged hospital stays. As a result, pre-conceptual counseling, careful assessment of disease activity before conception, and close monitoring during pregnancy are recommended to mitigate these risks and optimize maternal and fetal health outcomes.
Supplementary Material
Footnotes
Disclosures and declarations:
The authors declare no competing interests.
There was no explicit support or funding for this research.
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