Parental Rheumatoid Arthritis and Autism Spectrum Disorders in Offspring: A Danish Nationwide Cohort Study

NEW RESEARCH Parental Rheumatoid Arthritis and Autism Spectrum Disorders in Offspring: A Danish Nationwide Cohort Study Ane Lilleøre Rom, PhD, Chun Sen Wu, PhD, Jørn Olsen, PhD, Damini Jawaheer, PhD, Merete Lund Hetland, DMSc, Lina Steinrud Mørch, PhD Objective: Maternal rheumatoid arthritis (RA) has been associated with an increased risk of autism spectrum disorder (ASD) in the offspring. We assessed the potential influence of both maternal and paternal RA on the risk of ASD in offspring to disentangle the influence of genetic inheritance from other conditions potentially leading to fetal programming. Method: The nationwide cohort study included all children born alive from 1977 to 2008 in Denmark (N ¼ 1,917,723). Cox regression models were used to calculate hazard rate ratios (HR) of ASD in offspring exposed to maternal or paternal RA, compared to unexposed children. Results: Maternal RA was associated with an approximately 30% increased risk of ASD in the offspring (HR ¼ 1.31 and 95% CI ¼ 1.06 1.63). Also, paternal RA seemed to increase the risk of ASD by approximately 30% (HR ¼ 1.33, 95% CI ¼ 0.97 1.82). Conclusion: Our findings suggest maternal as well as paternal RA to be associated with an increased risk of ASD in the offspring, indicating that genetic factors associated with RA may also play a role in the etiology of ASD in children of parents with RA. Key words: rheumatoid arthritis, autism spectrum disorders, offspring, parental history, maternal history J Am Acad Child Adolesc Psychiatry 2018;57(1):28 32. A utism spectrum disorder (ASD) is a broad spectrum of earlyonset neuropsychiatric disorders characterized by a combination of deficits in communication and social interaction, and the presence of repetitive and stereotyped behaviors and interests. 1 The worldwide prevalence of ASD is approximately 1%, and environmental as well as genetic factors are believed to play a role in the etiology of ASD. 1 Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease affecting approximately 1% of the population, and women are affected 2 to 3 times more often than men. 2 A family history of autoimmune diseases, including maternal RA, has previously been associated with an increased risk of ASD in offspring, 3-7 and an increased prevalence of RA has been found among women with an elevated level of anti-brain antibodies, who were also mothers of children with ASD. 8,9 Furthermore, altered autoimmune responses including higher levels of autoantibodies have been reported in children with ASD. 10 Finally, other neuropsychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) 11 and Tourette disorder 12 have also been associated with autoimmune diseases in the mother, suggesting a potential role of autoimmunity in the pathophysiology of these disorders. 11,12 Maternal autoimmunity may have an adverse impact on fetal brain development through immune mediators including cytokines, T cells, and autoantibodies that may reach the fetal circulation. 8,13,14 Thus, it has been argued that the association between maternal RA and ASD in offspring may be caused by maternal immune components acting in utero. 3,6 On the other hand, studies analyzing genetic associations across these diseases have suggested that common genetic paths may exist between ASD and autoimmune diseases, 15 including RA. 16,17 More specifically, a number of studies have focused on the association between human leukocyte antigen (HLA)-DRB1*04, a major susceptibility allele for RA, 16 which has also been found in offspring with ASD and their mothers. 17 In this study, we assessed the potential influence of both maternal and paternal RA on the risk of ASD in the offspring to try to disentangle a potential genetic inheritance from other types of fetal programming. If genetic factors play a role, an increased risk of ASD may be expected in children of mothers with RA and/or in children of fathers with RA. If only intrauterine factors are important, we should see an association in children only of mothers with RA. METHOD We used data from various Danish national registries, which were linked by the unique identification number assigned to all citizens in Denmark. Through the Danish Medical Birth Registry, we established a nationwide cohort of all children (singletons) born alive in Denmark from 1977 to 2008, a total of 1,917,723 children. The study population and data sources are further described in a previous article. 18 The study was approved by the Danish Data Protection Agency (Jr. no. 2016-41-4737). Parental Rheumatoid Arthritis Maternal and paternal RA was identified in The Danish National Hospital Registry from 1977 to 2008 by the use of diagnoses from the International Classification of Diseases (ICD). The 8 th Revision (ICD-8) was used from 1977 through 1993 (ICD-8: 712.19, 712.39, 712.59), and the 10 th Revision (ICD-10) was used from 1994 onward (ICD-10: M05 and M06 [except M06.1 Stills Disease]). 28 www.jaacap.org Journal of the American Academy of Child & Adolescent Psychiatry

PARENTAL RHEUMATOID ARTHRITIS AND AUTISM SPECTRUM DISORDER IN OFFSPRING Exposure to maternal or paternal RA was recorded if the mother or father was registered with a main or a secondary discharge diagnosis of RA in the Danish National Hospital Registry. The date of first hospitalization (from 1977) or first visit at an outpatient clinic (from 1995) with a diagnosis of RA was used as the time point of clinically recognized disease. This date was also used to disentangle fetal exposure to clinical RA (i.e., RA diagnosed before birth) and fetal exposure to preclinical RA (i.e., RA first diagnosed after birth). Autism Spectrum Disorder Children who were diagnosed with ASD were identified in (1) the Danish National Hospital Registry, which holds nationwide records on all somatic admissions in Denmark (data available from 1977 to end of 2010), and (2) in the Danish Psychiatric Central Registry, which contains admissions to all psychiatric hospitals in Denmark (data available from 1977 to end of 2007). All diagnoses were based on ICD-8 codes given from 1977 to 1993 (299.00, 299.01, 299.02, 299.03) and ICD-10 codes from 1994 onward (F84.0, F84.1, F84.5, F84.8, F84.9). The term ASD is used throughout the article to encompass this group of pervasive developmental disorders. Statistical Analyses We used Cox proportional hazards models to estimate hazard rate ratios (HR) for ASD in offspring of parents with RA (maternal or paternal RA). Age of the child (in days) was used as underlying time scale. Children were followed from the time of birth until age at diagnosis of ASD, age at death, age at emigration, age 30 years, or end of follow-up (December 31, 2010), whichever came first. The reference group included children who were not exposed to maternal or paternal RA, respectively. The adjusted models included the exposure variables (paternal or maternal RA, respectively), age of the child (as underlying time scale), and year of birth. The additionally adjusted models furthermore included a priori selected potential confounders: maternal and paternal age at time of childbirth (in years), maternal educational level (low/middle/high), and parity (1/>1). The models assessing the influence of maternal RA also included paternal RA (yes/no), whereas the models assessing the influence of paternal RA included maternal RA (yes/no). Separate analyses were made for children exposed to clinical RA and children exposed to preclinical RA. In sensitivity analyses, we restricted the cohort to firstborn children to take into account dependency between siblings. We stratified the analyses according to sex of the child to examine potential sex differences. Additional adjustment was made for maternal smoking during pregnancy (smoker/nonsmoker) (data available from 1997), and the influence of potential mediating variables was explored. Thus, the changes in effect estimates were evaluated after adjustment for gestational age at birth (in weeks), birth weight (in grams), Apgar score at 5 minutes (<7/7) (data available from 1997), cerebral palsy, and epilepsy in the child. Because the transition from ICD-8 to ICD-10 (in 1994) has improved the definition of the diagnostic entities of ASD, we conducted a sensitivity analysis restricted to the period from 1994 onward. Since follow-up on ASD diagnoses after the year 2007 was conducted using data from the Danish National Hospital Registry, an additional analysis was made of children who were followed up no longer than the end of 2007, to assess the potential influence on our results of the use of different sources for ASD diagnoses. Because the validity of RA diagnoses is believed to be more specific, when diagnosed as inpatients or when registered more than once in the Danish National Hospital Registry, the following sensitivity analyses were performed: (1) exposed children were restricted to those of parents with RA diagnosed as inpatients or (2) to children diagnosed with RA more than once during the study period. We performed complete case analyses including children with complete information in the fully adjusted models (i.e., 94% of the children). Statistical analyses were performed using SAS statistical software (version 9.2; SAS Institute, Cary, NC). RESULTS A total of 1,917,723 children born in Denmark from 1977 to 2008 were identified. Of these, 13,556 were born to mothers with clinical or preclinical RA, and 6,330 children had fathers with clinical or preclinical RA. During a mean follow-up of 16 years, a total of 8,985 children were diagnosed with ASD. Characteristics of the study population are shown in Table 1 and further described in a previous article. 18 Maternal RA was associated with an approximately 30% increased risk of ASD in the offspring (HR ¼ 1.31, 95% CI ¼ 1.06 1.63) and paternal RA with an HR of 1.33 (95% CI ¼ 0.97 1.82) (Table 2). Both maternal and paternal preclinical RA were associated with ASD in the offspring (HR ¼ 1.39, 95% CI ¼ 1.11 1.75 and HR ¼ 1.45, 95% CI ¼ 1.04 2.03, respectively). The number of exposed cases was too low to conduct robust risk estimates for exposure to parental clinical RA. When restricting the analyses to firstborn children of mothers with RA, the estimates were slightly strengthened (HR ¼ 1.43, 95% CI ¼ 1.06 0.93). Additional adjustment for the sex of the child did not change the estimates, and no interaction with the sex of the child was found on the multiplicative scale (p ¼.53). Adjustment for maternal smoking or Apgar score (available from the year 1997) did not change the risk estimates of the associations between parental RA and ASD in offspring, compared to risk estimates not adjusted for these factors (based on data from 1997 and onward) (Table S1, available online). Likewise, the risk estimate did not change after adjustment for birth weight, gestational age at birth, cerebral palsy, or epilepsy in the child (Table S1, available online). A restriction to the time period from 1994 onward revealed similar findings (Table S1, available online). Also, when children were followed up until the end of 2007, the results did not change (Table S1, available online). When restricting exposed children to children of parents diagnosed with RA while inpatients, estimates were slightly strengthened, whereas for children of parents recorded with a diagnosis of RA more than once, the risk estimates slightly attenuated, probably due to low power (Table S1, available online). DISCUSSION Findings from this large nationwide cohort of children suggest that maternal RA may be associated with an increased risk of ASD in the offspring. Furthermore, paternal RA tends to be associated with ASD in the offspring, indicating that genetic factors associated with RA may play a role in the pathophysiology of ASD. Previous studies have indicated that maternal immune activation, and more specifically exposure to maternal cytokines in utero, affect neurological, immunological, and behavioral abnormalities in offspring. 4,6,10 These studies are in line with recent studies describing elevated levels of anti-brain antibodies in mothers of children with ASD in midgestational serum profiles, 9 as well as in blood samples taken years after the birth. 8 Our findings support that exposure to maternal immune components in utero may influence the risk of ASD in offspring later in life. However, we also found an increased risk of ASD among children exposed to paternal RA, suggesting that genetic factors may also play a role in the etiology of ASD. Although paternal autoimmune disease has been associated with ASD in the offspring, 7,19 until now, paternal RA specifically has not. 3 Furthermore, we found maternal as well as paternal preclinical RA (i.e., RA diagnosed after pregnancy) associated with an increased risk of ASD in the offspring, which supports the hypothesis that genetic factors play a role. It has been shown that individuals with RA and ASD share a common genetic predisposition to HLA-DRB1*04 alleles, indicating that common genetic paths do exist between RA and ASD. 16,17 In casecontrol studies, an increased frequency of HLA-DRB1*04 alleles has been found, but only in offspring with ASD and their mothers, not their fathers. 20-22 Moreover, significant transmission disequilibrium for HLA- DRB1*04 has been found for transmissions from maternal grandparents to mothers of offspring with ASD, but not for transmissions from mothers Journal of the American Academy of Child & Adolescent Psychiatry www.jaacap.org 29

ROM et al. TABLE 1 Characteristics of the Cohort at Time of Birth Unexposed to Maternal RA (n ¼ 1,904,167) Maternal RA (n ¼ 13,556) Unexposed to Paternal RA (n ¼1,911,393) Paternal RA (n ¼ 6,330) Maternal age, y, mean ± SD 28.35 (4.9) 28.46 (5.1) 28.35 (4.9) 28.41 (5.1) Maternal education, n (%) a Low 691,042 (36.3) 5,852 (43.2) 694,132 (36.3) 2,762 (43.6) Middle 587,882 (30.9) 3,970 (29.3) 589,998 (30.9) 1,854 (29.3) High 578,780 (30.4) 3,388 (25.0) 580,601 (30.4) 1,567 (24.8) Parity, mean ± SD 1.75 (0.9) 1.77 (0.9) 1.75 (0.9) 1.78 (0.87) Maternal smoking, n (%) a,b Smoker 128,600 (17.2) 597 (20.5) 128,933 (17.2) 264 (21.0) Nonsmoker 591,922 (79.1) 2,172 (74.5) 593,154 (79.1) 940 (74.7) Paternal age, y, mean ± SD 31.14 (5.8) 31.10 (6.0) 31.14 (5.8) 32.08 (6.4) Other parent RA, n (%) Yes 6,273 (0.3) 57 (0.4) 13,499 (0.7) 57 (0.9) No 1,897,894 (99.7) 13,499 (99.6) 1,897,894 (99.3) 6,273 (99.1) Birth year, n (%) 1977L1980 230,120 (12.1) 3,066 (22.6) 231,704 (12.1) 1,482 (23.4) 1981L1984 199,873 (10.5) 2,198 (16.2) 201,056 (10.5) 1,015 (16.0) 1985L1988 215,627 (11.3) 1,952 (14.4) 216,657 (11.3) 922 (14.6) 1989L1992 247,294 (13.0) 1,884 (13.9) 248,249 (13.0) 929 (14.7) 1993L1996 262,817 (13.8) 1,542 (11.4) 263,635 (13.8) 724 (11.4) 1997L2000 255,132 (13.4) 1,195 (8.8) 255,789 (13.4) 538 (8.5) 2001L2004 246,348 (12.9) 930 (6.9) 246,878 (12.9) 400 (6.3) 2005L2008 249,956 (13.0) 789 (5.8) 247,425 (12.9) 320 (5.1) Sex, n (%) Male 978,038 (51.4) 6,920 (51.1) 981,668 (51.4) 3,290 (52.0) Female 926,129 (48.6) 6,636 (48.9) 929,725 (48.6) 3,040 (48.0) Apgar score, n (%) a,b <7 5,438 (0.7) 27 (0.9) 5,460 (0.7) 5 (0.4) 7 734,715 (98.2) 2,865 (98.3) 736,343 (98.2) 1,234 (98.6) Gestational age, mean ± SD weeks 39.5 (1.8) 39.4 (1.9) 39.5 (1.8) 39.4 (1.9) Birth weight, g, mean ± SD 3,479 (567) 3,404 (584) 3,478 (567) 3,449 (561) Cerebral palsy, n (%) a Yes 6,845 (0.4) 56 (0.4) 6,878 (0.4) 23 (0.4) No 1,897,322 (99.6) 13,500 (99.6) 1,904,515 (99.6) 6,307 (99.6) Note: RA ¼ rheumatoid arthritis. a Columns do not sum to 100% because of missing values. b 1997 2008. or fathers to offspring with ASD, indicating that the HLA-DRB1*04 allele may act in mothers of offspring with ASD during pregnancy to contribute to ASD in their offspring. Even though a more specific test in the form of a transmission disequilibrium test was used in the latter study, all studies were small, 17,20-22 and the authors encourage larger studies to address a potential effect of HLA-DRB1*04 allele in ASD. 17 Therefore, we cannot rule out that larger studies would be able to identify transmissions from mothers or fathers to offspring with ASD. Risk factors such as preterm birth, low birth weight, 23 and epilepsy in the child 24 have been associated with maternal RA and risk of ASD. 25,26 Also, low Apgar score and cerebral palsy serving as proxies for asphyxia during birth could affect the risk of ASD. 25 In this study, these factors did not change the associations between parental RA and ASD in the offspring. An important strength of this study is the population-based design, which enabled us to include approximately 2 million children, hereof more than 19,000 children exposed to parental RA. We followed these children for an average of 16 years (range 0 30 years), and almost 9,000 children had a diagnosis of ASD during this period. In contrast to others, we were able to estimate the influence of maternal as well as paternal RA, and we included children of parents diagnosed with RA before as well as after the birth of the child. Furthermore, we were able to take into consideration some important confounders. ASD in the offspring was based on a diagnosis of ASD in either the Danish National Hospital Register or in the Danish Psychiatric Central Registry. Clinical diagnoses of ASD reported to the Danish Psychiatric Central Registry are applied by teams consisting of specialists in child and adolescent psychiatry by the use of clinical assessments in accordance with internationally standardized procedures. 27 The full spectrum of ASD diagnoses in the Danish Psychiatric Central Registry has not been evaluated. However, in a previous study, the diagnosis of childhood autism in the Danish Psychiatric Central Registry has been thoroughly validated. 27 Of 499 children diagnosed with childhood autism in the Danish Psychiatric Central Registry, the diagnosis was confirmed in 94% of cases, according to a coding guide based on DSM-IV criteria, 28 and 97% of cases fell within the ASD diagnosis. 27 In our cohort, approximately 25% of children with ASD were diagnosed with childhood 30 www.jaacap.org Journal of the American Academy of Child & Adolescent Psychiatry

PARENTAL RHEUMATOID ARTHRITIS AND AUTISM SPECTRUM DISORDER IN OFFSPRING TABLE 2 Hazard Rate Ratios (HR) With 95% Confidence Intervals for Autism Spectrum Disorder (ASD) in Children of Mothers or Fathers With Rheumatoid Arthritis (RA) Adjusted c Additionally Adjusted n ASD HR (95% CI) ASD HR (95% CI) Maternal RA a 13,556 83 1.33 (1.07-1.65) 81 1.31 (1.06-1.63) d Paternal RA b 6,330 42 1.40 (1.03-1.90) 39 1.33 (0.97-1.82) e Note: a Reference group included children not exposed to maternal RA. b Reference group included children not exposed to paternal RA. c Adjusted for birth year. d Additionally adjusted for maternal age, paternal age, parity, maternal education and paternal RA. e Additionally adjusted for maternal age, paternal age, parity, maternal education and maternal RA. autism. In the present study, diagnoses of ASD from the Danish Psychiatric Central Registry were available until end of 2007. Analyses restricted to this period showed similar findings. Furthermore, the transition from ICD-8 to ICD-10 from 1994 has improved the definition of the diagnostic entities of ASD considerably, 27 and when restricting the analyses in the present study to the period from 1994 onward (ICD-10 codes available), the risk estimates did not change. Furthermore, a potential misclassification due to changes in the diagnostic criteria for ASD is expected to be nondifferential. The registries used in this study identified children diagnosed with ASD while inpatients at a psychiatric department or at a somatic hospital during the study period. From the year 1995, children who did not require an inpatient admission but were diagnosed with ASD in an outpatient setting were also included. Thus, it is possible that some children with less severe ASD were not captured in the current study, especially before the year 1995, which may lower the actual number of ASD cases in our study. This potential misclassification is expected to be nondifferential, thereby, if anything, causing an underestimation of the association assessed. Furthermore, most children in Denmark are in daycare from the age of 1 until they start school, 29 thus providing the opportunity for authorities (in daycare or school) to detect potential symptoms and characteristics of neurodevelopmental disorders in the child. In Denmark, children suspected to have ASD are most often referred to a child psychiatric clinic, where they are diagnosed by a child psychiatrist. Also, a specialized diagnostic assessment of children suspected to have ASD is generally necessary to be enrolled in special services, and the diagnostic evaluation and treatment are free of charge. Therefore, we consider the number of missed children with ASD in the current study to be very low. Parental RA was based on the first registered diagnosis of RA in the Danish National Hospital Registry during the period under study. Since it has been shown that RA diagnoses in the Danish National Hospital Registry were more often confirmed in patients diagnosed as inpatients (up to 80%), in patients diagnosed more than once with RA (up to 91%), 30 we restricted the exposed children to children of mothers diagnosed as inpatients and to children of mothers diagnosed more than once with RA. After doing this, the estimates remained approximately similar, indicating no major impact of misclassification of the RA diagnoses. Some children in our cohort may have been wrongly classified as unexposed to parental RA, namely children of parents with RA who did not seek medical treatment, and children of parents who were diagnosed with RA after the surveillance period ended. Such a misclassification would tend to weaken the risk estimates, but not much. However, as almost all hospitals in Denmark are public hospitals with services free of charge (i.e., tax paid), the number of parents suffering from symptoms of RA who did not seek treatment is expected to be low. Also, after restricting the analyses to children born from 1977 to 1995, the results remained the same. In this period, the parents had longer follow-up (until 2010) for identification of potential RA. Thus, this analysis indicated no major impact of some children potentially being classified falsely as unexposed, which is not surprising, as the unexposed group comprises almost 2 million unexposed children, leaving limited room for false-negative results to influence our findings. We are aware that, for example, prenatal exposure to infection, febrile episodes and use of antibiotics during pregnancy could influence the risk of ASD in offspring. 31-34 Recently, acetaminophen (or paracetamol) use during pregnancy was found to be associated with an increased risk of ASD in offspring. 35 We were not able to include information on maternal self-medication with either acetaminophen or nonsteroidal antiinflammatory drugs during pregnancy. Likewise we had no access to information on use of specific RA treatment during pregnancy. However, we found a similar increased risk of ASD among children exposed to paternal RA but born to non-ra mothers, indicating limited confounding by use of paracetamol or other factors related to RA pregnancies. Children of non-ra mothers were not exposed to specific RA treatment during pregnancy, indicating that these factors seem to have a minor (if any) confounding influence in our population. In conclusion, in this study, maternal as well as paternal RA was associated with an increased risk of ASD in the offspring, suggesting that genetic factors with pleiotropic effects may play a role in the etiology of ASD in children of parents with RA. Accepted October 3, 2017. Dr. Rom is with the Research Unit Women s and Children s Health, The Juliane Marie Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. Dr. Wu is with the Research Unit of Gynecology and Obstetrics, Institute of Clinical Research, University of Southern Denmark, Odense, and Odense University Hospital. Dr. Olsen is with the Section for Epidemiology, University of Aarhus, Aarhus, Denmark, and Fielding School of Public Health, University of California, Los Angeles. Dr. Jawaheer is with the Children s HospitalOakland Research Institute, Oakland, CA. Dr. Hetland is with Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Dr. Mørch is with the Gynaecological Clinic, The Juliane Marie Centre, Copenhagen University Hospital, and Danish Cancer Society Research Centre, Virus, Lifestyle and Genes Unit, Copenhagen. The study was supported by the Research Committee of Copenhagen University Hospital, Rigshospitalet and the Danish Rheumatism Association. The funding source had no involvement in study design; the collection, analysis, and interpretation of data; writing of the report; or the decision to submit the article for publication. Dr. Mørch served as the statistical expert for this research. Disclosure: Dr. Mørch has accepted a position as Senior Epidemiologist at Novo Nordisk, since the initial submission of this manuscript. Drs. Rom, Wu, Olsen, Jawaheer, and Hetland report no biomedical financial interests or potential conflicts of interest. Correspondence to Ane Lilleøre Rom, PhD, Research Unit Women s and Children s Health, The Juliane Marie Centre, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, section 7821, DK-2100 Copenhagen, Denmark; e-mail: ane.lilleoere.rom@regionh.dk 0890-8567/$36.00/ª2017 American Academy of Child and Adolescent Psychiatry https://doi.org/10.1016/j.jaac.2017.10.002 Journal of the American Academy of Child & Adolescent Psychiatry www.jaacap.org 31

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PARENTAL RHEUMATOID ARTHRITIS AND AUTISM SPECTRUM DISORDER IN OFFSPRING TABLE S1 Results of Sensitivity Analyses of the Association Between Parental Rheumatoid Arthritis (RA) and Autism Spectrum Disorders (ASD) in Offspring Maternal RA Ever Paternal RA Ever HR (95% CI) HR (95% CI) Main analyses Adjusted a 1.33 (1.07e1.65) 1.40 (1.03e1.90) Additionally adjusted 1.31 (1.06e1.63) b 1.33 (0.97e1.82) c Sensitivity analyses, adjusted for b/c and: Sex of child 1.32 (1.06e1.64) 1.32 (0.96e1.81) Birthweight 1.31 (1.05e1.63) 1.30 (0.94e1.78) Gestational age 1.33 (1.07e1.65) 1.36 (1.00e1.86) Epilepsy in child 1.28 (1.03e1.60) 1.32 (0.97e1.81) Apgar score at 5 min d 1.24 (0.74e2.05) NA Maternal smoking d 1.32 (0.80e2.20) NA Exclusion of: Children diagnosed with epilepsy e 1.37 (1.09e1.72) 1.31 (0.94e1.84) Children diagnosed with cerebral palsy f 1.31 (1.05e1.63) 1.30 (0.94e1.79) Restriction to: Firstborn children g 1.43 (1.06e1.93) NA Children of parents diagnosed as inpatients h 1.39 (1.08e1.80) 1.48 (1.03e2.11) Children of parents diagnosed with RA more than once i 1.27 (0.96e1.68) 1.41 (0.95e2.00) 1994e2010 (ICD-10 codes of ASD) j 1.33 (1.07e1.67) 1.31 (0.94e1.81) 1977e2007 (ASD diagnoses from DPCR) k 1.34 (1.08e1.66) 1.34 (0.99e1.85) Note: DPCR ¼ Danish Psychiatric Central Registry; HR ¼ hazard ratio; ICD-10 ¼ International Classification of Diseases, 10 th Revision; NA¼ not applicable (due to low number of events). a Adjusted only for birth year (N ¼ 1,917,723). b Adjusted for maternal age, paternal age, parity, maternal education, birth year, and paternal RA (n ¼ 1,870,912). c Adjusted for maternal age, paternal age, parity, maternal education, birth year, and maternal RA (n ¼ 1,870,912). d Data available from 1997 (n ¼ 737,858). After restricting to this period, the R adjusted for b/c was 1.23 (0.74e2.04) for exposure to maternal RA; for exposure to paternal RA: NA. e n ¼ 1,839,532. f n ¼ 1,864,213. g n ¼ 864,603. h n ¼ 1,003,183. i n ¼ 1,870,912. j n ¼ 1,842,062. k n ¼ 1,811,800. Journal of the American Academy of Child & Adolescent Psychiatry www.jaacap.org 32.e1