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 data on patients with IMIDs undergoing pregnancy is scarce and often overlooks the impact of comorbidities.

Methods: We investigated 12 selected IMIDs: psoriasis, inflammatory bowel disease, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, systemic lupus erythematosus, psoriatic arthritis, antiphospholipid syndrome, Sjögren's syndrome, vasculitis, sarcoidosis, 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 cesarean section.

Findings: The prevalence rate of pregnancy occurring with people with a previous IMID diagnosis has doubled in the past ten years. We identified 5,784 patients with IMIDs. 17% of the IMIDs group had at least one prenatal IMM prescription. Depending on the type of IMM, from 48% to 70% of the patients taking IMMs before pregnancy continued them throughout pregnancy. Patients with IMIDs had similar but slightly increased risks of PTB (Relative risk (RR)=1·1[1·0, 1·3]), LBW (RR=1·2 [1·0,1·4]), SGA (RR=1·1 [1·0,1·2]), and cesarean section (RR=1·1 [1·1,1·2]) compared to a matched cohort of people without IMIDs. Out of the 12 selected IMIDs, three for PTB, one for LBW, two for SGA, and six for cesarean section had results supporting increased risk.

Interpretation: The association between IMIDs and the increased risk of adverse pregnancy outcomes depend on both the nature of the IMID and the presence of comorbidities.

Keywords: Autoimmune disease; immune mediated inflammatory disease; immunomodulatory medications; multiple chronic conditions; pregnancy.

Figure 1.. Cohort selection flow chart

GA Gestational Age; IMIDs Immune-mediated Inflammatory Disease 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.

Figure 2.. Characteristics of the IMIDs group

APS Antiphospholipid Syndrome; IBD Inflammatory Bowel Disease; IMIDs Immune-mediated Inflammatory Disease 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 IMIDs patients 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. Subsets size below 15 were not displayed. The most common and least common diagnosis was psoriasis(n=1871) and systemic sclerosis(n=54), respectively.

Figure 3.. IMMs prescription pattern of the IMIDs group

APS Antiphospholipid Syndrome; IBD Inflammatory Bowel Disease; IMID Immune-mediated Inflammatory Disease; IMMs Immunomodulatory Medications; LMP Last Menstrual Period; MS Multiple Sclerosis; PsO Psoriasis; PsA Psoriatic Arthritis; Sc Sarcoidosis; SLE Systemic Lupus Erythematosus; SpA Spondyloarthritis; SjS Sjörgen’s Syndrome; SSc Systemic Sclerosis; Va Vasculitis; 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 Figure S1. D. IMMs continuation rate. Majority of patients, who were exposed to IMMs during 180 days 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.

Figure 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 cesarean 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; PsO Psoriasis; PsA Psoriatic Arthritis; RR Relative Risk; Sc Sarcoidosis; SGA Small for Gestational Age; SLE Systemic Lupus Erythematosus; SpA Spondyloarthritis; SjS Sjörgen’s Syndrome; SSc Systemic Sclerosis; Va Vasculitis; 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 cesarean 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