Maternal-fetal outcomes in patients with immune-mediated inflammatory diseases, with consideration of comorbidities: a retrospective cohort study in a large U.S. healthcare system

Abstract

Background: Immune-mediated inflammatory diseases (IMIDs) are likely to complicate maternal health. However, literature on patients with IMIDs undergoing pregnancy is scarce and often overlooks the presence of comorbidities. We aimed to evaluate the impact of IMIDs on adverse pregnancy outcomes after assessing and addressing any discrepancies in the distribution of covariates associated with adverse pregnancy outcomes between patients with and without IMIDs.

Methods: We conducted a retrospective cohort study using data from an integrated U.S. community healthcare system that provides care across Alaska, California, Montana, Oregon, New Mexico, Texas, and Washington. We used a database containing all structured data from electronic health record (EHRs) and analyzed the cohort of pregnant people who had live births from January 1, 2013, through December 31, 2022. We investigated 12 selected IMIDs: psoriasis, inflammatory bowel disease, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, systemic lupus erythematosus, psoriatic arthritis, antiphospholipid syndrome, Sjögren's syndrome, vasculitides, sarcoidosis, and systemic sclerosis. We characterized patients with IMIDs prior to pregnancy (IMIDs group) based on pregnancy/maternal characteristics, comorbidities, and pre-pregnancy/prenatal immunomodulatory medications (IMMs) prescription patterns. We 1:1 propensity score matched the IMIDs cohort with people who had no IMID diagnoses prior to pregnancy (non-IMIDs cohort). Outcome measures were preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA), and caesarean section.

Findings: Our analytic cohort had 365,075 people, of which 5784 were in the IMIDs group and 359,291 were in the non-IMIDs group. The prevalence rate of pregnancy of at least 20 weeks duration in people with a previous IMID diagnosis has doubled in the past ten years. 17% of the IMIDs group had at least one prenatal IMM prescription. Depending on the type of IMM, 48%-70% of the patients taking IMMs before pregnancy continued them throughout pregnancy. Overall, patients with one or more of these 12 IMIDs had increased risk of PTB (Relative risk (RR) = 1.1 [1.0, 1.3]; p = 0.08), LBW (RR = 1.2 [1.0, 1.4]; p = 0.02), SGA (RR = 1.1 [1.0, 1.2]; p = 0.03), and caesarean section (RR = 1.1 [1.1, 1.2], p < 0.0001) compared to a matched cohort of people without IMIDs. When adjusted for comorbidities, patients with rheumatoid arthritis (PTB RR = 1.2, p = 0.5; LBW RR = 1.1, p = 0.6) and/or inflammatory bowel disease (PTB RR = 1.2, p = 0.3; LBW RR = 1.0, p = 0.8) did not have significantly increased risk for PTB and LBW.

Interpretation: For patients who have been pregnant for 20 weeks or greater, the association between IMIDs and adverse pregnancy outcomes depends on both the nature of the IMID and the presence of comorbidities. Because this study was limited to pregnancies resulting in live births, results must be interpreted together with other studies on early pregnancy loss and stillbirth in patient with IMIDs.

Funding: National Institutes of Health.

Keywords: Autoimmune disease; Immune mediated inflammatory disease; Immunomodulatory medications; Multiple chronic conditions; Pregnancy.

Fig. 1

Cohort selection flow chart. IMIDs group was propensity score matched 1:1 on confounding variables to generate the matched non-IMIDs group. Individual IMID groups were propensity score matched 1:1 on pregnancy/maternal characteristics and comorbidities variables to generate corresponding matched control groups. GA, gestational age; IMIDs, immune-mediated inflammatory disease.

Fig. 2

Characteristics of the IMIDs group. APS, antiphospholipid syndrome; IBD, inflammatory bowel disease; IMIDs, immune-mediated inflammatory disease; SLE, systemic lupus erythematosus. (A) Number of IMIDs diagnosis per patient. 93% of the IMIDs group had one IMID diagnosis. 7% of the IMIDs group had more than one IMID diagnosis. (B) IMIDs prevalence rate over time from 2013 to 2022. Prevalence rate was the proportion of patients with prior IMIDs delivered among patients delivered in the corresponding year. IMIDs prevalence rate gradually increased from 1% to 2% from 2013 to 2022, except in the year 2021. (C) IMIDs diagnosis distribution across the IMIDs group. The horizontal bars on the left indicates the sample size of the individual IMID group. The vertical bars on the tops are the number of patients who had the single IMID or combination of IMIDs shown in the corresponding column. Subsets size below 15 were not displayed. The most common and least common diagnosis was psoriasis (n = 1871) and systemic sclerosis (n = 54), respectively.

Fig. 3

IMMs prescription pattern of the IMIDs group. 5-ASA, 5-aminosalicyclic-acid derivative; CD, cluster of differentiation; IL, interleukins; IMID, immune-mediated inflammatory disease; IMMs, immunomodulatory medications; JAK, Janus Kinase; LMP, last menstrual period; MS, multiple sclerosis; PsA, psoriatic arthritis; PsO, psoriasis; S1P, sphingosine-1-phosphate; Sc, sarcoidosis; SLE, systemic lupus erythematosus; SpA, spondyloarthritis; SjS, Sjögren’s syndrome; SSc, systemic sclerosis; TNF, tumor necrosis factor; Va, Vasculitides. (A) Number of IMMs prescribed per patient during pregnancy. 83% of the IMIDs group did not have any IMMs prescription. 17% had at least one IMMs prescription during pregnancy. (B) Prenatal IMMs prescription rate of individual IMID groups. The descending order of prenatal IMMs prescription rate of individual IMID groups were SLE (39.4%), RA (32.1%), SjS (31.3%), IBD (27.8%), Va (21.4%), PsA (20.8%), Sc (19.3%), APS (15.6%), SSc (14.8%), MS (12.6%), SpA (10.8%), and PsO (6.7%). (C) Prenatal IMMs prescription rate of the IMIDs group based on the type of IMMs. Glucocorticoids (steroids), hydroxychloroquine, 5-ASA, and TNF-α inhibitors were most commonly prescribed prenatally among the IMIDs group. Prenatal prescription rates were 8%, 5%, 4%, and 3%. Prenatal IMMs prescription rates of individual IMID groups based on the type of IMMs are displayed in Supplementary Figure S1. (D) IMMs continuation rate. Majority of patients, who were exposed to IMMs during the 180-day prepregnancy period, continued their prescription throughout the delivery. Continuation rates ranged from 48 to 70%. (E) IMMs prescription patterns among patients who prescribed corresponding IMMs at least once from LMP-180 days to delivery date. Pre, first, second, and third columns indicate 180 days prepregnancy period, first second and third trimester. Colored and gray portions, respectively indicate exposed and unexposed patients for corresponding time periods.

Fig. 4

Adverse pregnancy outcomes of the IMIDs group, propensity score matched non-IMIDs group, and sensitivity analysis propensity score matched non-IMIDs group. APS, antiphospholipid syndrome; Csec, caesarean section; LBW, low birth weight; PTB, preterm birth; IBD, inflammatory bowel disease; IMID, immune-mediated inflammatory disease; IMMs, immunomodulatory medications; LMP, last menstrual period; MS, multiple sclerosis; PS, propensity score; PsO, psoriasis; PsA, psoriatic arthritis; RR, relative risk; Sc, sarcoidosis; SGA, small for gestational age; SLE, systemic lupus erythematosus; SpA, spondyloarthritis; SjS, Sjögren’s syndrome; SSc, systemic sclerosis; Va, vasculitides; Sensitivity analysis was performed to assess the influence of comorbidities on the association between IMIDs and risk of adverse pregnancy outcomes. The IMIDs group had slightly elevated risk of PTB (RR = 1.1 [1.0, 1.3]), LBW (RR = 1.2 [1.0, 1.4]), SGA (RR = 1.1 [1.0, 1.2]), and c-section (RR = 1.1 [1.1, 1.2]). Of 12 individual IMID, SpA, SLE, APS was associated with increased risk of PTB (SpA RR = 1.5 [1.0, 2.2]; SLE RR = 2.4 [1.6, 3.6]; APS RR = 2.1 [1.2, 3.8]). SLE was the only IMID correlated with enhanced risk of LBW (RR = 3.5 [2.1, 5.8]). RA and SLE patients were 1.3 ([1.0, 1.6]) and 1.9 ([1.4, 2.6]) times more likely to deliver SGA babies. IBD, RA, PsA, SpA, SLE, APS, and SjS patients had elevated likelihood of caesarean section delivery (IBD RR = 1.3 [1.1, 1.4], RA RR = 1.2 [1.0, 1.4], PsA RR = 1.3 [1.0, 1.8], SpA RR = 1.3 [1.1, 1.5], SLE RR = 1.3 [1.1, 1.5], APS RR = 1.7 [1.3, 2.2], SjS RR = 1.5 [1.1, 2.1]). When the comorbidities were not controlled, the IMIDs group’s risk of PTB and LBW increased by 0.2. In addition, the risk of PTB and LBW of IBD and RA patients increased and gained statistical significance (IBD: PTB RR = 1.3 [1.0, 1.7], LBW RR = 1.4 [1.0, 1.9]; RA: PTB RR = 1.4 [1.0, 2.0], LBW RR = 1.5 [1.0, 2.3]). The association between APS and the risk of LBW also elevated and became statistically significant (APS LBW RR = 3.0 [1.3, 6.9]). Statistical significance was reported as follows. p < 0.0001:∗∗∗∗, 0.0001 ≤ p < 0.001:∗∗∗, 0.001 ≤ p < 0.01:∗∗, 0.01 ≤ p < 0.05:∗, 0.05 ≤ p < 0.1:+, 0.1 < p:ns. RR, 95% confidence intervals, and p-value for results shown in Supplementary Figure S4 are in Supplementary Materials in Supplementary Table S9.