Maternal biologic factors can affect fetal fraction in cell-free DNA-based prenatal screening assays, thereby limiting effectiveness. Higher rates of indeterminate results from low fetal fraction have been described in cases of autoimmune disease in pregnancy. Existing studies are confounded by the concomitant maternal use of anticoagulants, which may independently influence test characteristics.
To evaluate differences in fetal fraction, indeterminate results, and total cell-free DNA concentration for women with autoimmune disease compared to controls using our in-house developed non-invasive prenatal screening platform in the absence of maternal anticoagulation use.
A retrospective, single institution cohort study of a previously validated cell-free DNA-based non-invasive prenatal screening assay using a low-pass whole genome sequencing platform between 2017 and 2019. A diagnosis of autoimmune disease included systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and others. Immunomodulator therapies included biologics, corticosteroids, hydroxychloroquine, azathioprine, and intravenous immunoglobulin. Women on anticoagulation were excluded. We evaluated the association between autoimmune disease and fetal fraction, indeterminate results, and total cell-free DNA concentration using univariate and multivariate analyses, stratifying for immunomodulator therapy and adjusting for body mass index, fetal sex, and gestational age at sample collection.
1,445 patients met inclusion criteria. Forty-three women had a confirmed autoimmune disease, with 25 not on immunomodulator therapy and 18 on immunomodulator therapy. The mean fetal fraction for women with autoimmune disease was significantly lower compared to controls (9.7% vs. 11.9%, p=0.004). The rate of indeterminate results was significantly higher for women with autoimmune disease compared to controls (16.3% vs. 3.5%; p<0.001). The total cell-free DNA concentration was not statistically different between groups (94.8 pg/uL for autoimmune disease vs. 83.9 pg/uL for controls, p=0.06). In logistic regression, women with autoimmune disease had a significantly higher odds of an indeterminate result compared to controls, (aOR 5.3, 95%CI 2.0, 14.2). Linear regression showed a significant negative association between autoimmune disease and fetal fraction (aβ -2.1, 95%CI -3.4, -0.6). Stratifying by treatment status, mean fetal fraction was 9.8%, 9.6%, and 11.9% for women with autoimmune disease not on immunomodulator therapy, autoimmune disease on immunomodulator therapy, and controls, respectively (p=0.02). The rate of indeterminate results increased in a stepwise fashion from 3.5% to 11.1% to 20.0% for controls, autoimmune disease on immunomodulator therapy, and autoimmune disease not on immunomodulator therapy, respectively (p<0.001). Logistic regression demonstrated higher odds of an indeterminate result for women with autoimmune disease not on immunomodulator therapy compared to controls, (aOR 7.3, 95%CI 2.3, 22.5). Autoimmune disease not on immunomodulator therapy was negatively associated with fetal fraction compared to controls (aβ -2.2, 95%CI -4.2, -0.3).
Women with autoimmune disease have lower fetal fraction and higher rates of indeterminate results compared to women without autoimmune disease. There was no difference in total cell-free DNA concentration. Treatment of maternal autoimmune disease with immunomodulator therapy may decrease the indeterminate result rate.

Copyright © 2021. Published by Elsevier Inc.

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