Fetal Growth Associated with Maternal Rheumatoid Arthritis and Juvenile Idiopathic Arthritis

Background Prior studies indicated that women with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) are at twice higher risk of developing adverse pregnancy outcomes, this include preterm births and infants with low birth weight. A wide knowledge gap exists in our current understanding of how RA and JIA affect fetal growth during pregnancy. Objective We aimed to evaluate fetal growth among patients with RA/JIA by comparing fetal growth indicators of offspring born to this population, compared to individuals without RA/JIA. We hypothesized that fetal growth among patients with RA/JIA is reduced, compared to individuals without RA/JIA. Study Design We conducted a population-based cohort study in Denmark from 2008-2018 which included 503,491 individuals with singleton pregnancies. Among them, 2,206 were patients with RA and JIA. We linked several nationwide databases and clinical registries in Denmark to achieve our aim. Through the Danish Fetal Medicine Database (DFMD), we obtained fetal biometric measurements gathered from second trimester fetal ultrasound scans. We used International Classification of Diseases (ICD)-10 codes to identify pregnant patients with RA/JIA from the Danish National Patient Registry and linked them to the DFMD, other variables of interest were obtained from different Danish clinical registries. Next, we computed fetal growth gradient between second trimester and birth, using the mean difference in Z-score distances for each fetal growth indicator. We also estimated the risk of small for gestational age (SGA), all outcomes were compared between pregnant individuals with and without RA/JIA and adjusted for confounders. Results Maternal RA and JIA was not associated with a reduction of estimated fetal weight (EFW) at mid-pregnancy [adjusted mean EFW Z-score difference of 0.05 (95% CI 0.01, 0.10; p =0.022)], but lower birth weights were observed among offspring [adjusted mean Z-score difference of -0.08 (95% CI -0.13, -0.04; p <0.001)]. We observed reduced mean Z-score differences in weight gradient from second trimester to birth among offspring of patients with RA/JIA who used corticosteroids [-0.26 (95% CI -0.11, -0.41; p <0.001)], and sulfasalazine [-0.61 (95% CI -0.45, -0.77; p <0.001)] during pregnancy. Maternal RA/JIA was also associated with SGA [aOR of 1.47 (95% CI 1.16, 1.83; p <0.001)]. Similarly, the risk estimates were higher among corticosteroid [aOR 3.44 (95% CI 2.14, 5.25; p <0.001)] and sulfasalazine [(aOR 2.28 (95% CI 1.22, 3.88; p =0.005)) users. Conclusion Among pregnant patients with RA/JIA, fetal growth restriction may be most apparent after 18 to 22 weeks of gestational age. Closer antenatal monitoring around this period should be considered for this population. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Dr. Chock is supported by KL2 Yale Center of Clinical Investigation Physician Scientist Development Award. Dr. Thunbo is supported by the Graduate School of Health at Aarhus University, Helga and Peter Kornings Foundation, Danish Diabetes Association, Danish Medical Association under Danica Pension, and Dagmar Marshall's Foundation. Dr. Pedersen is supported by a Borregaard Clinical Ascending Investigator Grant from the Novo Nordisk Foundation (NNF18OC0054457). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Yale University IRB, exemption determination granted. Yale IRB Protocol ID: 2000034411 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Individual-level data cannot be shared publicly due to the requirements of the registry holders and the general data protection regulation in order to protect the privacy of individuals.