Exploring the effect of maternal autoimmune diseases on behavioral and social difficulties risk in children born preterm: evidence from EPIPAGE-2 study

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This prospective population-based cohort study used data from the French EPIPAGE-2 study, which included liveborn infants delivered at 22 to 34 weeks’ gestation in 2011 and followed them to 5 years of age. Neurodevelopmental outcomes at 2 years’ corrected age and at 5 years were assessed. Among 3609 children (155 [4.3%] exposed), maternal autoimmune diseases were initially associated with more impaired personal-social skills on the Ages & Stages Questionnaire at 2 years and a lower prevalence of high Social Communication Questionnaire scores at 5 years, but these associations were no longer statistically significant after adjustment. No significant associations were found between maternal autoimmune diseases and global developmental delay, ASD risk, or behavioral difficulties at 2 or 5 years in adjusted analyses. Subgroup analyses by gestational age and by exposure to immunosuppressive therapy also showed no increased risk. In this national preterm birth cohort, maternal autoimmune diseases during pregnancy were not associated with increased early behavioral or social communication difficulties in offspring, suggesting that, in the context of contemporary antenatal care, such conditions may not confer additional early neurodevelopmental risk beyond that related to prematurity itself. Health sciences/Diseases/Psychiatric disorders/Autism spectrum disorders Health sciences/Biomarkers/Predictive markers Figures Figure 1 Figure 2 Introduction The aetiology of autism spectrum disorder (ASD) involves a complex interplay of genetic and environmental factors 1 . Among these, maternal immune activation (MIA), which is typically related to infections or autoimmune flare-ups during pregnancy, is associated with an increased risk of ASD in offspring 2 . There is a wealth of epidemiological evidence supporting this link, with children born during the 1918–1919 influenza pandemic showing increased rates of ASD 3 , 4 ; exposure to the rubella pandemic in the 1960s during pregnancy conferring up to a 10% ASD risk. Maternal autoimmune diseases are also associated with a twofold increase in the likelihood of ASD in offspring 5 . While the exact mechanisms behind this association are unclear, it is hypothesised that MIA directly affects the foetal brain 6 . Indeed, in mice model, administration of poly(I:C) (a viral mimicking) during mid-gestation induces a robust MIA leading to core ASD-like phenotypes in the offspring 7 . Fortunately, in the majority of pregnancies, the foetus is resilient to the effects of MIA suggesting that other factors may influence the onset of ASD in offspring. In line with this, recent animal studies suggest that MIA acts as a disease primer, with perinatal or postnatal environmental factors acting as second hits, eventually resulting in the emergence of ASD 2 . Prematurity is defined as any live birth occurring before 37 weeks of gestation 8 . It affects around 10–11% of newborns worldwide, with an estimated 13–15 million preterm births occurring globally each year 9 . It is the leading cause of death in children under five 9 , 10 . Despite improvements in neonatal care, prematurity remains a significant contributor to childhood morbidity and long-term health complications. Among them, prematurity is associated with an increased risk of ASD and large epidemiological studies have shown that the earlier a child is born, the greater the likelihood of developing ASD 11 . This association is not solely genetic, but may also be partly directly linked to the consequences of inflammation on the foetal brain. Experimental and clinical studies suggest that elevated levels of pro-inflammatory cytokines and microglial activation induced by premature birth can impair neuronal migration, synaptogenesis, and myelination, leading to altered brain connectivity and function 12 – 14 . Accordingly, preterm infants often exhibit markers of systemic and central nervous system inflammation, which correlate with long-term ASD outcomes 15 . This study, using data from the EPIPAGE-2 study, a national French prospective cohort of children born preterm, therefore aimed to explore how MIA may be associated with behavioural and socio-communication difficulties in the offspring of children born preterm. Methods Study population EPIPAGE-2 (Etude épidémiologique sur les petits âges gestationnels) is a prospective, national, population-based cohort study that aimed to include all births at 22–34 weeks' gestation in all maternity units in 24 of the 25 French regions in 2011 16 . We included all children born alive between 23 and 34 completed weeks surviving at 5 years of age. We excluded patients with severe congenital cerebral malformation, patients with prenatal infections history (particularly Cytomegalovirus, toxoplasmosis), clinical or histological chorioamnionitis. Patients with missing information on chorioamnionitis or on maternal autoimmune diseases were also excluded. All participants were invited to participate in a standardized follow-up at 2 years’ corrected age and 5 years. The 2-year assessment include specific screening questionnaire. The French version of the 24-month ASQ (second edition), which has been validated in France, was completed by parents 17 . The ASQ comprises 30 items covering five domains of development (gross motor skills, fine motor skills, communication abilities, problem-solving abilities, and personal and social skills), which are rated on a three-point Likert scale: 'Yes', 'Sometimes' or 'Not yet'. The Modified Checklist for Autism in Toddlers (M-CHAT) is a widely used screening tool for ASD in children aged 16 to 30 months 18 . The 20-item questionnaire evaluates key developmental domains, including social interaction, communication, and behavioural patterns indicative of ASD. Parents or caregivers complete the M-CHAT based on their observations of the child’s typical behaviours. The 5-year assessment included an interview with the parents, a self-administered parental questionnaire, a clinical examination by a paediatrician and an evaluation by a psychologist. These assessments were performed in 110 centers that were specifically opened for the study. Paediatricians and psychologists were trained to ensure consistency in their evaluations. However, assessors were not blinded to the child’s gestational age. If a child was too disabled to participate, parental permission was sought to contact rehabilitation centres and provide them with information to enable classification of the child's disabilities. Parents also completed the Strengths and Difficulties Questionnaire (SDQ) 19 to rate emotional, conduct, hyperactivity/inattention, and peer relationship difficulties 20 . A total score is calculated by summing the scores of each domain, with a higher score indicating more difficulties. The questionnaire is not used for diagnosis. Results are reported with cut-offs for a contemporary sample born at term from the population-based ELFE cohort as a reference 21 . Exposure The exposed children were defined by the presence of a maternal autoimmune disease. The diagnosis of maternal autoimmune disease was made according to maternal medical record during pregnancy or at the time of delivery. To limit the heterogeneity, we only focused on maternal autoimmune disease for maternal immune activation. The systemic autoimmune diseases included lupus, polyangiitis, antiphospholipid syndrome and systemic scleroderma (n = 23); the endocrine autoimmune diseases included Graves' disease, Hashimoto's thyroiditis, Addison's disease and type 1 diabetes (n = 79); and the gastrointestinal autoimmune diseases included coeliac disease, haemorrhagic rectocolitis, Crohn's disease, autoimmune hepatitis and Berger's disease (n = 27) ; rheumatological and muscular autoimmune diseases (rheumatoid arthritis and spondyloarthritis; n = 8); neurological autoimmune diseases (multiple sclerosis, Guillain–Barré syndrome and peripheral neuropathy; n = 9); dermatological autoimmune diseases (psoriasis and morphea; n = 6); others (mastocytosis, sarcoidosis and other unspecified autoimmune diseases; n = 6). Outcome At two years of age, according to US norms, ASQ positive screening (defined below as global development delay) was defined as a score of less than two standard deviations (SDs) below the mean for any of the five domains. The M-CHAT results are scored to identify children at low, moderate or high risk of ASD, thereby guiding subsequent diagnostic evaluation 22 . Risk of ASD was defined by the failure of at least 3 on 23 items. At 5 years of age, children were invited to undergo a comprehensive neurodevelopmental evaluation 11 . Children with a total SDQ score greater than or equal to the 90th centile of the reference sample are considered to have a substantially raised probability of being formally diagnosed with mental health problems. Autism spectrum disorders dimensions were assessed using the Social Communication Questionnaire (SCQ) 23 . Children with a total SCQ score greater than or equal to the 90th centile of the reference sample are considered at risk for ASD. Statistical analysis We first described maternal, obstetric, and neonatal characteristics of the study population according to exposure to maternal autoimmune disease. We then assessed the association between autoimmune disease exposure and child behavioral and social development outcomes at ages 2 and 5 years. Descriptive statistics were weighted to account for the differences in survey design between gestational age groups (used to obtain enough cases despite the low incidence of extremely preterm births) 24 . Multivariable logistic regression was used to assess the association between MIA and neurodevelopmental outcomes at 2 and 5 years adjusted for potential confounders, including maternal age, primiparity, maternal country of birth, education level, socio-economic status, and smoking during pregnancy. Gestational age and child’s sex was also included in the models to account for differences between exposure groups among survivors. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using cluster-robust variance estimate to account for unmeasured dependence between twins from the same family. Missing data were treated using multiple imputation by chained equations. The proportion of missing data per covariate ranged from 0% to 7% for perinatal variables, exceeding 5% only for maternal education, gestational diabetes, and hypertension during pregnancy. Missing data rates for ASQ and M-CHAT scores at 2 years were 23% and 25%, respectively, while SDQ and SCQ scores at 5 years had missing rates of 40% and 43%. We generated 50 datasets, imputed with 20 iterations each, and combined the results following Rubin’s rules (29). A large number of predictors were included in the imputation models to strengthen the missing-at-random (MAR) assumption and enhance the reliability of the imputed values. We reported estimates from complete-case analyses and from analyses based on multiple imputation for missing data. A sensitivity analysis was conducted using propensity score matching to compare exposed and unexposed children, controlling for maternal age, primiparity, maternal birth in France, maternal level of education, parents’ socio-economic status, and tobacco use during pregnancy 25 . A 1:1 matching algorithm without replacement was applied using a caliper of 0.2 standard deviations of the logit of the propensity score. Matching balance was assessed using standardized differences, with values below 10% indicating acceptable balance. After matching, gestational age and child’s sex were included as covariates in the outcome model to adjust for residual imbalance and reduce selection bias. Finally, we performed subgroup analyses: one restricted to children born at 27–34 weeks of gestation and one for children whose mothers were not treated with immunosuppressive therapy during pregnancy as autoimmune diseases treatment is a modulating factor of MIA. All tests were two-sided, and p < 0.05 was considered statistically significant. Statistical analyses were performed with R 4.5.1. Ethics approval The study was approved by the National Data Protection Authority (CNIL n°911009), by the consultative Committee on the Treatment of Data on Personal Health for Research Purposes (reference n°10.626) and by the Committee for the Protection of People Participating in Biomedical Research (reference CPP SC-2873). Results Of the 4,060 eligible preterm neonates (born at 22–34 weeks, without major malformations), 3,609 were included, of whom 3,454 (95.7%) were unexposed and 155 (4.3%) were exposed to maternal immune disorders. Of these 3,609 participating children 2,157 (59.8%) underwent a full assessment at five years of age ( Fig. 1 ) . The maternal and neonatal characteristics of participating and non-participating children at five years are presented in Table S1 . Non-participating mothers were younger and less likely to have been born in France. They also had a lower socio-economic status, smoked more and received less infertility treatment. Non-participating children were more often born between 32 and 34 weeks than participating children. Table 1 summarises maternal and neonatal characteristics according to MIA exposure among liveborn children. Specifically, preeclampsia occurred less frequently in mothers with a history of autoimmune disorders (16.5% vs. 8.7%, p-value = 0.038), who were also more likely to use aspirin during pregnancy (4.6% vs. 15.8%, p-value < 0.001). They used also more frequently immunosuppressive treatments (0.5% vs. 13.6%, p-value < 0.001) and antidiabetic treatments (3.4% vs. 33.8%, p-value < 0.001). Exposed children were more frequently born at later gestational ages (p < 0.001). Accordingly, even though exposed children have the same proportion of severe neonatal morbidities, the have a better chance of survival at discharge (98.3 vs. 95.1, p-value = 0.004) and at 5 years (98.4 vs. 94.7, p-value < 0.001). There was also a lower proportion of males in the exposed group (54.2% vs 43.7%, p-value = 0.040). Table 1 Maternal and neonatal characteristics according to maternal autoimmune disease exposure, among liveborn children. Data are No./total (weighted %), unless otherwise indicated. Denominators vary according to the number of missing data for each variable. Percentages are weighted to consider the differences in survey design between gestational age groups. Maternal autoimmune diseases No (n = 3896) Yes (n = 164) n/N (%) n/N (%) p-value Maternal characteristics at birth Maternal age 35 years 852/3896 (22.1) 51/164 (30.1) Primiparous 2109/3860 (55.1) 88/163 (45.5) 0.11 Birth in France 2973/3821 (80.0) 135/163 (85.4) 0.25 Level of education Less than high school 406/3277 (11.8) 12/151 (8.8) 0.32 High school 1327/3277 (40.6) 50/151 (32.6) 1–2 years of graduate studies 706/3277 (21.2) 44/151 (24.1) 3 + years of graduate studies 838/3277 (26.4) 45/151 (34.5) Parents’ socio-economic status a Executive 800/3659 (22.8) 37/160 (24.4) 0.54 Intermediate 761/3659 (21.5) 38/160 (26.6) Administration 1004/3659 (27.3) 41/160 (25.1) Service, trade 502/3659 (13.8) 27/160 (15.5) Worker, unemployed 592/3659 (14.6) 17/160 (8.5) Tobacco use during pregnancy 790/3775 (20.4) 36/159 (22.5) 0.67 Maternal obstetrical characteristics Infertility treatment 628/3778 (17.7) 28/161 (13.7) 0.38 Gestational diabetes 295/3608 (9.6) 14/151 (9.6) 0.99 Hypertension during pregnancy 672/3641 (16.5) 29/153 (13.0) 0.39 Preeclampsia 737/3817 (16.5) 27/160 (8.7) 0.038 Placental abruptio 177/3805 (3.5) 8/163 (4.6) 0.58 Treatment during pregnancy Aspirin 190/3809 (4.6) 29/160 (15.8) < 0.001 Antihypertensive treatment 619/3817 (14.2) 32/162 (12.7) 0.68 Antidiabetic treatment 99/3807 (3.4) 50/163 (33.8) < 0.001 Immunosuppressive treatment b 17/3810 (0.5) 23/162 (13.6) < 0.001 Antenatal Corticosteroid 2991/3825 (76.2) 138/162 (78.6) 0.62 Cause of preterm birth Preterm labour 1588/3896 (43.8) 45/164 (32.4) 0.12 Preterm premature rupture of membranes 699/3896 (18.5) 39/164 (26.5) Hypertensive disorders or Placental abruption 943/3896 (20.8) 43/164 (18.8) Isolated fetal growth restriction 264/3896 (6.6) 12/164 (5.5) Other 402/3896 (10.3) 25/164 (16.8) Multiple pregnancy 1324/3896 (35.7) 56/164 (37.7) 0.75 Neonatal characteristics Gestational age groups (weeks) 24–26 596/3896 (5.5) 16/164 (2.7) < 0.001 27–31 2264/3896 (28.0) 80/164 (18.0) 32–34 1036/3896 (66.6) 68/164 (79.4) Sex male 2098/3896 (54.2) 76/164 (43.7) 0.040 Small for gestational age c 1438/3891 (34.7) 67/164 (36.4) 0.73 Severe neonatal morbidities d 533/3478 (7.5) 18/153 (5.9) 0.46 Severe cerebral abnormalities 250/3681 (3.4) 9/161 (2.8) 0.66 Severe bronchopulmonary dysplasia 193/3533 (2.2) 7/155 (1.4) 0.34 necrotizing enterocolitis stage 2–3 121/3653 (1.9) 2/156 (1.4) 0.73 Severe retinopathy of prematurity stage > 3 21/3698 (0.2) 2/160 (0.3) 0.56 Late onset sepsis 586/3659 (8.0) 29/161 (8.0) > 0.99 Survival status Deaths in maternity 143/3896 (1.6) 3/164 (0.5) 0.004 Deaths in the NICU 283/3896 (3.3) 6/164 (1.2) Discharge alive 3470/3896 (95.1) 155/164 (98.3) Survivors at 5 years 3454/3896 (94.7) 155/164 (98.3) < 0.001 a Defined as the highest occupational status between occupations of the mother and the father, or mother only if living alone b Among mothers unexposed, there was 1 case of liver transplantation, 2 cases of kidney transplantation, 1 lymphangioma, and other treatment indications were unidentified. c Small-for-gestational-age was defined as birth weight less than the 10th percentile for gestational age and sex based on French intrauterine “EPOPé” growth curves (Ego 2006). d Among admitted to a neonatal unit. Severe neonatal morbidity was defined as severe bronchopulmonary dysplasia or necrotizing enterocolitis stage 2–3 or severe retinopathy of prematurity stage > 3 or any of the following severe cerebral abnormalities on cranial ultrasonography: intraventricular haemorrhage grade III or IV or cystic periventricular leukomalacia or late onset sepsis. Neurodevelopmental outcomes of age 2 corrected age and 5 years First, we examined the association between maternal autoimmune disease exposure during pregnancy and behavioural and communication outcomes in offspring. Regarding global developmental delay at two years of corrected age, no association was found. However, across the ASQ domains, we found that children whose mothers had autoimmune diseases had more severe personal-social skills (OR: 1.94, 95% CI: 1.01–3.75, p = 0.043), but not in the other ASQ dimensions (communication, gross motor, fine motor, problem-solving). Regarding autistic traits (as measured by the M-CHAT), no difference was found between the two groups. After adjustment, the association with the personal-social subscore of the ASD age at 2 years corrected was no longer statistically significant, either with or without multiple imputation (respectively, aOR: 1.39 [95% CI: 0.82 to 2.35] and aOR: 1.29 [95% CI: 0.75 to 2.23]). ( Table 2 and supplemental Table 2) . Table 2 Behaviour and communication outcome at 2 and 5 years according to maternal autoimmune disease exposure. Data are No./total (weighted %), unless otherwise indicated. Denominators vary according to the number of missing data for each variable. Percentage are weighted to consider the differences in survey design between gestational age groups. Maternal autoimmune diseases Exposed vs Unexposed, Unexposed (n = 3454) Exposed (n = 155) OR (95% CI) aOR (95% CI) a aOR (95% CI) a , after multiple Imputation aOR (95% CI), matching sample b n/N (%) n/N (%) p-value At 2 years’ corrected age Global developmental delay (ASQ score c ) 1037/2664 (34.5) 48/129 (36.4) 0.78 1.08 (0.63 to 1.87) 0.97 (0.62 to 1.53) 0.90 (0.61 to 1.32) 0.94 (0.57 to 1.54) By domain, Communication 629/2835 (18.3) 29/134 (18.6) 0.96 1.02 (0.53 to 1.96) 1.08 (0.62 to 1.88) 1.08 (0.65 to 1.79) 1.21 (0.62 to 2.38) Gross motor 296/2758 (7.7) 10/131 (6.4) 0.72 0.82 (0.27 to 2.49) 0.71 (0.34 to 1.52) 0.81 (0.45 to 1.47) 0.72 (0.34 to 1.55) Fine motor 312/2748 (10.7) 12/131 (5.9) 0.11 0.52 (0.23 to 1.19) 0.91 (0.48 to 1.73) 0.85 (0.47 to 1.52) 0.96 (0.43 to 2.13) Problem solving 313/2699 (10.6) 11/129 (10.6) 0.99 1.00 (0.46 to 2.17) 0.71 (0.36 to 1.39) 0.80 (0.47 to 1.38) 0.62 (0.29 to 1.36) Personal-social 439/2746 (13.3) 25/131 (23.0) 0.043 1.94 (1.01 to 3.75) 1.39 (0.82 to 2.35) 1.29 (0.75 to 2.23) 1.46 (0.65 to 3.27) Autistic traits (M-CHAT d ) 561/2587 (20.8) 15/123 (13.1) 0.20 0.58 (0.25 to 1.34) 0.56 (0.30 to 1.08) 0.65 (0.38 to 1.10) 0.60 (0.30 to 1.20) At 5 years of age Behavioural difficulties e Total SDQ score > 90th percentile e 189/2057 (8.7) 7/92 (4.4) 0.18 0.48 (0.16 to 1.43) 0.66 (0.26 to 1.69) 0.96 (0.47 to 1.94) 0.97 (0.36 to 2.61) By domain, Emotional symptoms 225/2060 (10.3) 10/92 (7.2) 0.40 0.67 (0.26 to 1.72) 0.99 (0.47 to 2.06) 1.03 (0.63 to 1.69) 0.99 (0.50 to 1.97) Conduct problems 187/2062 (8.6) 7/93 (7.7) 0.81 0.88 (0.32 to 2.40) 0.73 (0.31 to 1.74) 0.81 (0.46 to 1.42) 0.92 (0.43 to 1.96) Hyperactivity 270/2061 (12.5) 15/93 (12.4) 0.97 0.98 (0.45 to 2.13) 1.41 (0.77 to 2.60) 1.29 (0.82 to 2.05) 1.38 (0.68 to 2.81) Peer problems 222/2060 (10.0) 10/93 (7.1) 0.42 0.69 (0.27 to 1.73 0.85 (0.37 to 1.93) 0.98 (0.55 to 1.73) 0.97 (0.40 to 2.33) Social communication difficulties f 247/1983 (11.1) 9/90 (3.6) < 0.001 0.30 (0.14 to 0.64) 0.98 (0.45 to 2.12) 0.98 (0.53 to 1.81) 1.02 (0.42 to 2.48) Abbreviations: ASQ, Ages & Stages Questionnaire; M-CHAT, Modified Checklist for Autism in Toddlers; SCQ, Social Communication Questionnaire; SDQ, Strengths and difficulties questionnaire. a Logistic regression analysis with cluster robust variance estimates to account for non-independence of twins, adjusted on maternal age, primiparity, maternal birth in France, maternal level of education, parents’ socio-economic status, tobacco use during pregnancy, gestational age and child sex. b Propensity score matched sample, 155 children in exposed group are matched to 155 non-exposed, adjusted on gestational age and child sex, after multiple imputation. c Risk of developmental delay is defined by an ASQ score 90th percentile of the reference group of term-born children, corresponds to SDQ score ≥ 19. f Defined by total SCQ score > 90th percentile of the reference group of term-born children, corresponds to SCQ score ≥ 11. At age 5, we did not find any difference in behavioural difficulties based on SDQ. Although, the prevalence of high SCQ (SCQ > 90th percentiles) was lower in children exposed to maternal autoimmune diseases suggesting less frequent social communication difficulties [OR:0.30 (95%CI; 0.14 to 0.64), p-value < 0.001) ( Table 2 and supplemental Table 2) , the association was no longer significant after adjustment (aOR: 0.98 [95% CI: 0.45 to 2.12] and aOR with multiple imputation: 0.98 [95% CI; 0.53 to 1.81] Sensitivity analysis Next, we performed several sensitivity analyses. First, we used a matched sample. The characteristics of the sample before and after matching are shown in Supplementary Fig. 1 . In the matched sample, we still found no difference in communication (aOR: 1.21 [95% CI:0.62 to 2.38]) or personal-social at 2 years corrected age (aOR: 1.46 [95% CI: 0.65 to 3.27]) or in SCQ scores above the 90th percentile at 5 years (aOR: 1.02 [95% CI: 0.42 to 2.48]) ( Table 2 ) . Second, since there were more extremely premature children in the unexposed group, we ran the analysis on children aged 27–34 weeks only and found no difference at either age 2 or 5 (Fig. 2 ) . Finally, we investigated the association of immunosuppressive therapy on the outcome of neurodevelopmental disorders (NDDs) in offspring (Supplementary Table 3) . No difference was found between exposed and unexposed children without a history of immunosuppressive therapy at ages 2 corrected age and 5. Discussion In this study we did not observe association between maternal autoimmune disease during pregnancy and behavioural or communication difficulties in the offspring of children born preterm, confirming previous results 26 . This suggest that in the specific context of preterm birth, maternal autoimmune diseases may not represent a major over-risk factor for early neurodevelopmental disorders. This result may seem counterintuitive, but there are several hypotheses that could explain this observation. Firstly, both maternal autoimmune diseases and preterm birth are strongly associated with inflammation 2 , 12 . Several recent studies have highlighted the negative impact of inflammation on brain development, which is known to influence foetal brain development through mechanisms such as microglial activation and cytokine signalling 27 – 29 . It is possible that when inflammation is already elevated due to maternal autoimmune disease, the additional inflammatory burden associated with preterm birth does not further amplify neurodevelopmental processes. We hypothesised that this might indicate a saturation of neuroimmune pathways. In this context, a ceiling effect could occur, whereby neuroimmune mechanisms are maximally activated and the impact of prematurity on neurodevelopment is limited. Secondly, we observed that preeclampsia was less prevalent among mothers with autoimmune diseases, while the use of aspirin during pregnancy was more common. This finding is interesting because, although the exact pathophysiology of preeclampsia is unknown, it is a major risk factor for prematurity and ASD in offspring 30 , 31 and aspirin has long been recognised as an effective strategy for preventing the onset of preeclampsia 32 . Although there is considerable evidence that mothers with autoimmune diseases are at greater risk of obstetric and birth complications 33 , our results may reflect the more intensive prenatal care provided to women with autoimmune disorders. This is suggested by the fact that children in the exposed group were born at a slightly more advanced gestational age and have better short- and medium-term survival, which could mitigate the cumulative adverse effects of MIA and prematurity. Several limitations should be noted. Firstly, the maternal autoimmune exposure group was heterogeneous and based on clinical diagnosis rather than biomarkers. Consequently, we lacked detailed information on disease severity and activity during pregnancy and the exact treatments used. A second limitation of the study is the loss to follow-up. To address this, we used multiple imputation, and the results were consistent with those from the complete case analysis. Exposure rates were similar in participants and non-participants, minimizing selection bias. Loss to follow-up may have underestimated neurodevelopmental disorders rates but likely did not affect the association directions. Third, the number of children exposed was relatively small, which limited our statistical power to detect small effect sizes, particularly in subgroup analyses. However, sensitivity analysis was conducted using propensity score matching to compare exposed and unexposed children, providing additional support for our findings. More, EPIPAGE 2 is a large prospective population-based cohort, with 93% participation rate at birth, giving good external validity to our results, comprehensive clinical and follow-up data, and validated screening tools at two key stages of early childhood. In addition, to our knowledge, this is the first study to investigate the intersection between immune-mediated risk factors and behavioural and communication disorders in children born preterm. Thirdly, while the ASQ, SDQ and SCQ are validated screening instruments, they are not diagnostic tools and may be subject to classification bias. Our findings are reassuring for clinicians and patients alike. When closely monitored and appropriately cared for, maternal autoimmune diseases do not appear to increase the risk of early neurodevelopmental disorders in preterm children. However, further research using biomarkers of MIA, standardised diagnostic assessments and long-term follow-up is needed to confirm these findings in adolescence and adulthood. Declarations Conflicts of interest: none Acknowledgements This study was funded by Fondation de France (11779), French Institute of Public Health Research/Institute of Public Health, National Research Agency through the French Equipex Programme of Investments in the Future (ANR-11-EQPX0038). References Lord C, Brugha TS, Charman T, Cusack J, Dumas G, Frazier T et al. Autism spectrum disorder. Nat Rev Dis Primers 2020; 6: 5. Han VX, Patel S, Jones HF, Dale RC. Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. Nat Rev Neurol 2021; 17: 564–579. Brown AS. Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. Developmental Neurobiology 2012; 72: 1272–1276. Kępińska AP, Iyegbe CO, Vernon AC, Yolken R, Murray RM, Pollak TA. 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Neuroinflammation in preterm babies and autism spectrum disorders. Pediatr Res 2019; 85: 155–165. Angelidou A, Asadi S, Alysandratos K-D, Karagkouni A, Kourembanas S, Theoharides TC. Perinatal stress, brain inflammation and risk of autism-review and proposal. BMC Pediatr 2012; 12: 89. Van der Zwart S, Knol EF, Gressens P, Koopman C, Benders M, Roze E. Neuroinflammatory markers at school age in preterm born children with neurodevelopmental impairments. Brain Behav Immun Health 2024; 38: 100791. Lorthe E, Benhammou V, Marchand-Martin L, Pierrat V, Lebeaux C, Durox M et al. Cohort Profile: the Etude Epidémiologique sur les Petits Ages Gestationnels-2 (EPIPAGE-2) preterm birth cohort. International Journal of Epidemiology 2021; 50: 1428–1429m. Flamant C, Branger B, Nguyen The Tich S, De La Rochebrochard E, Savagner C, Berlie I et al. Parent-Completed Developmental Screening in Premature Children: A Valid Tool for Follow-Up Programs. PLoS ONE 2011; 6: e20004. Wieckowski AT, Williams LN, Rando J, Lyall K, Robins DL. Sensitivity and Specificity of the Modified Checklist for Autism in Toddlers (Original and Revised): A Systematic Review and Meta-analysis. JAMA Pediatr 2023; 177: 373–383. Goodman R. The Strengths and Difficulties Questionnaire: a research note. J Child Psychol Psychiatry 1997; 38: 581–586. Goodman R. Psychometric Properties of the Strengths and Difficulties Questionnaire. Journal of the American Academy of Child & Adolescent Psychiatry 2001; 40: 1337–1345. Charles MA, Thierry X, Lanoe J-L, Bois C, Dufourg M-N, Popa R et al. Cohort Profile: The French national cohort of children (ELFE): birth to 5 years. International Journal of Epidemiology 2020; 49: 368–369j. Aishworiya R, Ma VK, Stewart S, Hagerman R, Feldman HM. Meta-analysis of the Modified Checklist for Autism in Toddlers, Revised/Follow-up for Screening. Pediatrics 2023; 151: e2022059393. Berument SK, Rutter M, Lord C, Pickles A, Bailey A. Autism screening questionnaire: diagnostic validity. Br J Psychiatry 1999; 175: 444–451. Lorthe E, Benhammou V, Marchand-Martin L, Pierrat V, Lebeaux C, Durox M et al. Cohort Profile: the Etude Epidémiologique sur les Petits Ages Gestationnels-2 (EPIPAGE-2) preterm birth cohort. Int J Epidemiol 2021; 50: 1428–1429m. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika 1983; 70: 41–55. Ellul P, Wallez S, Acquaviva E, Rosenzwajg M, Klatzmann D, Delorme R et al. Children with a history of both maternal immune activation and prematurity are not at increased risk of ADHD symptoms. Eur Child Adolesc Psychiatry 2024; 33: 2001–2004. Becher B, Spath S, Goverman J. Cytokine networks in neuroinflammation. Nat Rev Immunol 2017; 17: 49–59. Faust TE, Gunner G, Schafer DP. Mechanisms governing activity-dependent synaptic pruning in the developing mammalian CNS. Nat Rev Neurosci 2021; 22: 657–673. Estes ML, McAllister AK. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci 2015; 16: 469–486. Carter S, Lin JC, Chow T, Martinez MP, Qiu C, Feldman RK et al. Preeclampsia Onset, Days to Delivery, and Autism Spectrum Disorders in Offspring: Clinical Birth Cohort Study. JMIR Public Health Surveill 2024; 10: e47396. An H, Jin M, Li Z, Zhang L, Li H, Zhang Y et al. Impact of gestational hypertension and pre-eclampsia on preterm birth in China: a large prospective cohort study. BMJ Open 2022; 12: e058068. Rolnik DL, Nicolaides KH, Poon LC. Prevention of preeclampsia with aspirin. Am J Obstet Gynecol 2022; 226: S1108–S1119. Singh M, Wambua S, Lee SI, Okoth K, Wang Z, Fayaz FFA et al. Autoimmune diseases and adverse pregnancy outcomes: an umbrella review. BMC Med 2024; 22: 94. Additional Declarations The authors have declared there is NO conflict of interest to disclose Supplementary Files 251219Supplemental.docx Supplemental Material Cite Share Download PDF Status: Under Review Version 1 posted Reviewer # 2 agreed at journal 26 Apr, 2026 Review # 1 received at journal 06 Apr, 2026 Reviewer # 1 agreed at journal 24 Mar, 2026 Reviewers invited by journal 04 Feb, 2026 Editor assigned by journal 01 Feb, 2026 Submission checks completed at journal 01 Feb, 2026 First submitted to journal 31 Jan, 2026 Unknown event 28 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8698441","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":586050092,"identity":"431b90df-42ca-4a5a-9471-d1ec8a0cebd1","order_by":0,"name":"Pierre Ellul","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIie3PuwrCMBSA4RMOJEuxayd9hUiHWvBhWlxFBJcOBVsC3XTWt9BJ3FoCnfoIDoLgLBTEqajxsghtR4f8Sy7wkRMAne4fw/faYUDSC4AHQI7tCH1sspUiyNu99iTSaEMchnkZBNClaHA5DA8TB5Be6ogr6GhdFGArMs7PMzdCXNURLg2bxAn4iSJU+pvUlLWDcWmWJK5grsigehLEBmIgiSPw1GAkaUEef7FJlFv9BOk0WyzP/l40EMeUJxKFw57JxPZ4ux78HRMNg70W63NOgdeDL/mW/tzodDqd7g5MyUIYwXlu/AAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-1862-6952","institution":"Université Paris Cité","correspondingAuthor":true,"prefix":"","firstName":"Pierre","middleName":"","lastName":"Ellul","suffix":""},{"id":586050093,"identity":"2c125c80-910f-4dda-b2a1-c1abe9abe5e4","order_by":1,"name":"Laeticia Marchand-Martin","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Laeticia","middleName":"","lastName":"Marchand-Martin","suffix":""},{"id":586050094,"identity":"6512fe9e-e6a6-4015-944b-04c7051c55bc","order_by":2,"name":"Fanny Salmon","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Fanny","middleName":"","lastName":"Salmon","suffix":""},{"id":586050095,"identity":"d12f5cc1-e4cc-496c-91d5-d500bb15b025","order_by":3,"name":"Pierre-Yves Ancel","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Pierre-Yves","middleName":"","lastName":"Ancel","suffix":""},{"id":586050096,"identity":"7c9a0d39-c5ec-42d3-813a-4a5fc7a98b54","order_by":4,"name":"Veronique Pierrat","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Veronique","middleName":"","lastName":"Pierrat","suffix":""},{"id":586050097,"identity":"56cee8fe-5d78-48f0-af9a-e5e87ac5f3f9","order_by":5,"name":"Mathilde Letouzey","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Mathilde","middleName":"","lastName":"Letouzey","suffix":""}],"badges":[],"createdAt":"2026-01-26 09:05:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8698441/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8698441/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102297129,"identity":"0b466d7d-7eca-4a7b-80f0-37098f4d917a","added_by":"auto","created_at":"2026-02-10 10:25:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":49905,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea \u003c/sup\u003eNo survivors were born at 22 weeks and only one survivor was born at 23 weeks.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Parental questionnaire completed with Social Communication Questionnaire (SCQ) and/or Strengths and difficulties Questionnaire (SDQ).\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8698441/v1/471b1b38a64a93381b84583f.png"},{"id":102217928,"identity":"cd9d4dec-0a26-48b8-90a7-ef7ba606d14e","added_by":"auto","created_at":"2026-02-09 13:14:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":61177,"visible":true,"origin":"","legend":"\u003cp\u003eBehavior and communication outcome at 2 and 5 years according to maternal autoimmune disease exposure, by gestational age groups. Abbreviations: ASQ, Ages \u0026amp; Stages Questionnaire; M-CHAT, Modified Checklist for Autism in Toddlers; SCQ, Social Communication Questionnaire; SDQ, Strengths and difficulties questionnaire. Logistic regression analysis with cluster robust variance estimates to account for non-independence of twins, adjusted on maternal age, primiparity, maternal birth in France, maternal level of education, parents’ socio-economic status, tobacco use during pregnancy, gestational age weeks and child sex. Result after multiple imputation.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Risk of developmental delay is defined by an ASQ score \u0026lt; 2 SDs from the mean in any of the five ASQ domains.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Positive M-CHAT is defined by at least 3 of the 23 items failed.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u003c/sup\u003e Cut-off \u003cu\u003e\u0026gt;\u003c/u\u003e 90th percentile of the reference group of term-born children, corresponds to SDQ score ≥ 19.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ed\u003c/sup\u003e Defined by total SCQ score \u003cu\u003e\u0026gt;\u003c/u\u003e 90th percentile of the reference group of term-born children, corresponds to SCQ score ≥ 11\u003c/p\u003e","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8698441/v1/f7a434b143445b61dc0b5924.png"},{"id":102302179,"identity":"5bcf6b82-20fe-4dff-ae10-02389ac1f2d8","added_by":"auto","created_at":"2026-02-10 11:24:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1530251,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8698441/v1/804d88b0-33d8-455a-b16f-b47249436b16.pdf"},{"id":102217929,"identity":"71f537a0-55dc-4ca0-a25f-ab290ee9e66f","added_by":"auto","created_at":"2026-02-09 13:14:07","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":55282,"visible":true,"origin":"","legend":"Supplemental Material","description":"","filename":"251219Supplemental.docx","url":"https://assets-eu.researchsquare.com/files/rs-8698441/v1/2e335fef5651519e446a9ca5.docx"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose","formattedTitle":"Exploring the effect of maternal autoimmune diseases on behavioral and social difficulties risk in children born preterm: evidence from EPIPAGE-2 study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe aetiology of autism spectrum disorder (ASD) involves a complex interplay of genetic and environmental factors \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Among these, maternal immune activation (MIA), which is typically related to infections or autoimmune flare-ups during pregnancy, is associated with an increased risk of ASD in offspring \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. There is a wealth of epidemiological evidence supporting this link, with children born during the 1918\u0026ndash;1919 influenza pandemic showing increased rates of ASD \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e; exposure to the rubella pandemic in the 1960s during pregnancy conferring up to a 10% ASD risk. Maternal autoimmune diseases are also associated with a twofold increase in the likelihood of ASD in offspring \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. While the exact mechanisms behind this association are unclear, it is hypothesised that MIA directly affects the foetal brain \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Indeed, in mice model, administration of poly(I:C) (a viral mimicking) during mid-gestation induces a robust MIA leading to core ASD-like phenotypes in the offspring \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Fortunately, in the majority of pregnancies, the foetus is resilient to the effects of MIA suggesting that other factors may influence the onset of ASD in offspring. In line with this, recent animal studies suggest that MIA acts as a disease primer, with perinatal or postnatal environmental factors acting as second hits, eventually resulting in the emergence of ASD \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePrematurity is defined as any live birth occurring before 37 weeks of gestation \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. It affects around 10\u0026ndash;11% of newborns worldwide, with an estimated 13\u0026ndash;15\u0026nbsp;million preterm births occurring globally each year \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. It is the leading cause of death in children under five \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Despite improvements in neonatal care, prematurity remains a significant contributor to childhood morbidity and long-term health complications. Among them, prematurity is associated with an increased risk of ASD and large epidemiological studies have shown that the earlier a child is born, the greater the likelihood of developing ASD \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. This association is not solely genetic, but may also be partly directly linked to the consequences of inflammation on the foetal brain. Experimental and clinical studies suggest that elevated levels of pro-inflammatory cytokines and microglial activation induced by premature birth can impair neuronal migration, synaptogenesis, and myelination, leading to altered brain connectivity and function \u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Accordingly, preterm infants often exhibit markers of systemic and central nervous system inflammation, which correlate with long-term ASD outcomes \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis study, using data from the EPIPAGE-2 study, a national French prospective cohort of children born preterm, therefore aimed to explore how MIA may be associated with behavioural and socio-communication difficulties in the offspring of children born preterm.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy population\u003c/p\u003e \u003cp\u003eEPIPAGE-2 (Etude \u0026eacute;pid\u0026eacute;miologique sur les petits \u0026acirc;ges gestationnels) is a prospective, national, population-based cohort study that aimed to include all births at 22\u0026ndash;34 weeks' gestation in all maternity units in 24 of the 25 French regions in 2011 \u003csup\u003e16\u003c/sup\u003e. We included all children born alive between 23 and 34 completed weeks surviving at 5 years of age. We excluded patients with severe congenital cerebral malformation, patients with prenatal infections history (particularly Cytomegalovirus, toxoplasmosis), clinical or histological chorioamnionitis. Patients with missing information on chorioamnionitis or on maternal autoimmune diseases were also excluded.\u003c/p\u003e \u003cp\u003eAll participants were invited to participate in a standardized follow-up at 2 years\u0026rsquo; corrected age and 5 years.\u003c/p\u003e \u003cp\u003eThe 2-year assessment include specific screening questionnaire. The French version of the 24-month ASQ (second edition), which has been validated in France, was completed by parents \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. The ASQ comprises 30 items covering five domains of development (gross motor skills, fine motor skills, communication abilities, problem-solving abilities, and personal and social skills), which are rated on a three-point Likert scale: 'Yes', 'Sometimes' or 'Not yet'. The Modified Checklist for Autism in Toddlers (M-CHAT) is a widely used screening tool for ASD in children aged 16 to 30 months \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. The 20-item questionnaire evaluates key developmental domains, including social interaction, communication, and behavioural patterns indicative of ASD. Parents or caregivers complete the M-CHAT based on their observations of the child\u0026rsquo;s typical behaviours.\u003c/p\u003e \u003cp\u003eThe 5-year assessment included an interview with the parents, a self-administered parental questionnaire, a clinical examination by a paediatrician and an evaluation by a psychologist. These assessments were performed in 110 centers that were specifically opened for the study. Paediatricians and psychologists were trained to ensure consistency in their evaluations. However, assessors were not blinded to the child\u0026rsquo;s gestational age. If a child was too disabled to participate, parental permission was sought to contact rehabilitation centres and provide them with information to enable classification of the child's disabilities. Parents also completed the Strengths and Difficulties Questionnaire (SDQ) \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e to rate emotional, conduct, hyperactivity/inattention, and peer relationship difficulties \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. A total score is calculated by summing the scores of each domain, with a higher score indicating more difficulties. The questionnaire is not used for diagnosis. Results are reported with cut-offs for a contemporary sample born at term from the population-based ELFE cohort as a reference \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eExposure\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eThe exposed children were defined by the presence of a maternal autoimmune disease. The diagnosis of maternal autoimmune disease was made according to maternal medical record during pregnancy or at the time of delivery. To limit the heterogeneity, we only focused on maternal autoimmune disease for maternal immune activation.\u003c/p\u003e \u003cp\u003eThe systemic autoimmune diseases included lupus, polyangiitis, antiphospholipid syndrome and systemic scleroderma (n\u0026thinsp;=\u0026thinsp;23); the endocrine autoimmune diseases included Graves' disease, Hashimoto's thyroiditis, Addison's disease and type 1 diabetes (n\u0026thinsp;=\u0026thinsp;79); and the gastrointestinal autoimmune diseases included coeliac disease, haemorrhagic rectocolitis, Crohn's disease, autoimmune hepatitis and Berger's disease (n\u0026thinsp;=\u0026thinsp;27) ; rheumatological and muscular autoimmune diseases (rheumatoid arthritis and spondyloarthritis; n\u0026thinsp;=\u0026thinsp;8); neurological autoimmune diseases (multiple sclerosis, Guillain\u0026ndash;Barr\u0026eacute; syndrome and peripheral neuropathy; n\u0026thinsp;=\u0026thinsp;9); dermatological autoimmune diseases (psoriasis and morphea; n\u0026thinsp;=\u0026thinsp;6); others (mastocytosis, sarcoidosis and other unspecified autoimmune diseases; n\u0026thinsp;=\u0026thinsp;6).\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eOutcome\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eAt two years of age, according to US norms, ASQ positive screening (defined below as global development delay) was defined as a score of less than two standard deviations (SDs) below the mean for any of the five domains. The M-CHAT results are scored to identify children at low, moderate or high risk of ASD, thereby guiding subsequent diagnostic evaluation \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Risk of ASD was defined by the failure of at least 3 on 23 items.\u003c/p\u003e \u003cp\u003eAt 5 years of age, children were invited to undergo a comprehensive neurodevelopmental evaluation \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Children with a total SDQ score greater than or equal to the 90th centile of the reference sample are considered to have a substantially raised probability of being formally diagnosed with mental health problems. Autism spectrum disorders dimensions were assessed using the Social Communication Questionnaire (SCQ) \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Children with a total SCQ score greater than or equal to the 90th centile of the reference sample are considered at risk for ASD.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003e We first described maternal, obstetric, and neonatal characteristics of the study population according to exposure to maternal autoimmune disease. We then assessed the association between autoimmune disease exposure and child behavioral and social development outcomes at ages 2 and 5 years. Descriptive statistics were weighted to account for the differences in survey design between gestational age groups (used to obtain enough cases despite the low incidence of extremely preterm births) \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMultivariable logistic regression was used to assess the association between MIA and neurodevelopmental outcomes at 2 and 5 years adjusted for potential confounders, including maternal age, primiparity, maternal country of birth, education level, socio-economic status, and smoking during pregnancy. Gestational age and child\u0026rsquo;s sex was also included in the models to account for differences between exposure groups among survivors. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using cluster-robust variance estimate to account for unmeasured dependence between twins from the same family. Missing data were treated using multiple imputation by chained equations. The proportion of missing data per covariate ranged from 0% to 7% for perinatal variables, exceeding 5% only for maternal education, gestational diabetes, and hypertension during pregnancy. Missing data rates for ASQ and M-CHAT scores at 2 years were 23% and 25%, respectively, while SDQ and SCQ scores at 5 years had missing rates of 40% and 43%. We generated 50 datasets, imputed with 20 iterations each, and combined the results following Rubin\u0026rsquo;s rules (29). A large number of predictors were included in the imputation models to strengthen the missing-at-random (MAR) assumption and enhance the reliability of the imputed values. We reported estimates from complete-case analyses and from analyses based on multiple imputation for missing data.\u003c/p\u003e \u003cp\u003eA sensitivity analysis was conducted using propensity score matching to compare exposed and unexposed children, controlling for maternal age, primiparity, maternal birth in France, maternal level of education, parents\u0026rsquo; socio-economic status, and tobacco use during pregnancy \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. A 1:1 matching algorithm without replacement was applied using a caliper of 0.2 standard deviations of the logit of the propensity score. Matching balance was assessed using standardized differences, with values below 10% indicating acceptable balance. After matching, gestational age and child\u0026rsquo;s sex were included as covariates in the outcome model to adjust for residual imbalance and reduce selection bias.\u003c/p\u003e \u003cp\u003eFinally, we performed subgroup analyses: one restricted to children born at 27\u0026ndash;34 weeks of gestation and one for children whose mothers were not treated with immunosuppressive therapy during pregnancy as autoimmune diseases treatment is a modulating factor of MIA.\u003c/p\u003e \u003cp\u003eAll tests were two-sided, and p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Statistical analyses were performed with R 4.5.1.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthics approval\u003c/strong\u003e \u003cp\u003e The study was approved by the National Data Protection Authority (CNIL n\u0026deg;911009), by the consultative Committee on the Treatment of Data on Personal Health for Research Purposes (reference n\u0026deg;10.626) and by the Committee for the Protection of People Participating in Biomedical Research (reference CPP SC-2873).\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eOf the 4,060 eligible preterm neonates (born at 22\u0026ndash;34 weeks, without major malformations), 3,609 were included, of whom 3,454 (95.7%) were unexposed and 155 (4.3%) were exposed to maternal immune disorders. Of these 3,609 participating children 2,157 (59.8%) underwent a full assessment at five years of age \u003cstrong\u003e(\u003c/strong\u003eFig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eThe maternal and neonatal characteristics of participating and non-participating children at five years are presented in \u003cstrong\u003eTable \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/strong\u003e. Non-participating mothers were younger and less likely to have been born in France. They also had a lower socio-economic status, smoked more and received less infertility treatment. Non-participating children were more often born between 32 and 34 weeks than participating children.\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e summarises maternal and neonatal characteristics according to MIA exposure among liveborn children. Specifically, preeclampsia occurred less frequently in mothers with a history of autoimmune disorders (16.5% vs. 8.7%, p-value\u0026thinsp;=\u0026thinsp;0.038), who were also more likely to use aspirin during pregnancy (4.6% vs. 15.8%, p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.001). They used also more frequently immunosuppressive treatments (0.5% vs. 13.6%, p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and antidiabetic treatments (3.4% vs. 33.8%, p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Exposed children were more frequently born at later gestational ages (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Accordingly, even though exposed children have the same proportion of severe neonatal morbidities, the have a better chance of survival at discharge (98.3 vs. 95.1, p-value\u0026thinsp;=\u0026thinsp;0.004) and at 5 years (98.4 vs. 94.7, p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.001). There was also a lower proportion of males in the exposed group (54.2% vs 43.7%, p-value\u0026thinsp;=\u0026thinsp;0.040).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eMaternal and neonatal characteristics according to maternal autoimmune disease exposure, among liveborn children. Data are No./total (weighted %), unless otherwise indicated. Denominators vary according to the number of missing data for each variable. Percentages are weighted to consider the differences in survey design between gestational age groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMaternal autoimmune diseases\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNo (n\u0026thinsp;=\u0026thinsp;3896)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eYes (n\u0026thinsp;=\u0026thinsp;164)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en/N (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en/N (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMaternal characteristics at birth\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMaternal age\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;25 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e703/3896 (16.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15/164 (9.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.20\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u0026ndash;34 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2341/3896 (61.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e98/164 (60.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;35 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e852/3896 (22.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e51/164 (30.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePrimiparous\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2109/3860 (55.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e88/163 (45.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBirth in France\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2973/3821 (80.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e135/163 (85.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.25\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLevel of education\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLess than high school\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e406/3277 (11.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e12/151 (8.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.32\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh school\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1327/3277 (40.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e50/151 (32.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u0026ndash;2 years of graduate studies\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e706/3277 (21.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e44/151 (24.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u0026thinsp;+\u0026thinsp;years of graduate studies\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e838/3277 (26.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e45/151 (34.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eParents\u0026rsquo; socio-economic status\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003ea\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eExecutive\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e800/3659 (22.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e37/160 (24.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.54\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIntermediate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e761/3659 (21.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e38/160 (26.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAdministration\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1004/3659 (27.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e41/160 (25.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eService, trade\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e502/3659 (13.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e27/160 (15.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWorker, unemployed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e592/3659 (14.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e17/160 (8.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTobacco use during pregnancy\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e790/3775 (20.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e36/159 (22.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.67\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMaternal obstetrical characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eInfertility treatment\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e628/3778 (17.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e28/161 (13.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.38\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eGestational diabetes\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e295/3608 (9.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e14/151 (9.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHypertension during pregnancy\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e672/3641 (16.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e29/153 (13.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.39\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePreeclampsia\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e737/3817 (16.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e27/160 (8.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.038\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePlacental abruptio\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e177/3805 (3.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e8/163 (4.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.58\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment during pregnancy\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAspirin\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e190/3809 (4.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e29/160 (15.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAntihypertensive treatment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e619/3817 (14.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e32/162 (12.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.68\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAntidiabetic treatment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e99/3807 (3.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e50/163 (33.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eImmunosuppressive treatment\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e17/3810 (0.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23/162 (13.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAntenatal Corticosteroid\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2991/3825 (76.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e138/162 (78.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.62\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCause of preterm birth\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePreterm labour\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1588/3896 (43.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e45/164 (32.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.12\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePreterm premature rupture of membranes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e699/3896 (18.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e39/164 (26.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHypertensive disorders or Placental abruption\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e943/3896 (20.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e43/164 (18.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIsolated fetal growth restriction\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e264/3896 (6.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e12/164 (5.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOther\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e402/3896 (10.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e25/164 (16.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMultiple pregnancy\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1324/3896 (35.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e56/164 (37.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.75\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNeonatal characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eGestational age groups (weeks)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24\u0026ndash;26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e596/3896 (5.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e16/164 (2.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27\u0026ndash;31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2264/3896 (28.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e80/164 (18.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32\u0026ndash;34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1036/3896 (66.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e68/164 (79.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSex male\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2098/3896 (54.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e76/164 (43.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.040\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSmall for gestational age\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003ec\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1438/3891 (34.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e67/164 (36.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.73\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSevere neonatal morbidities\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003ed\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e533/3478 (7.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e18/153 (5.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.46\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere cerebral abnormalities\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e250/3681 (3.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e9/161 (2.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.66\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere bronchopulmonary dysplasia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e193/3533 (2.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7/155 (1.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.34\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enecrotizing enterocolitis stage 2\u0026ndash;3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e121/3653 (1.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2/156 (1.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.73\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere retinopathy of prematurity stage\u0026thinsp;\u0026gt;\u0026thinsp;3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e21/3698 (0.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2/160 (0.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.56\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLate onset sepsis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e586/3659 (8.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e29/161 (8.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSurvival status\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDeaths in maternity\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e143/3896 (1.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e3/164 (0.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.004\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDeaths in the NICU\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e283/3896 (3.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e6/164 (1.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDischarge alive\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e3470/3896 (95.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e155/164 (98.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSurvivors at 5 years\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e3454/3896 (94.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e155/164 (98.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003e\u003csup\u003ea\u003c/sup\u003e Defined as the highest occupational status between occupations of the mother and the father, or mother only if living alone\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003e\u003csup\u003eb\u003c/sup\u003e Among mothers unexposed, there was 1 case of liver transplantation, 2 cases of kidney transplantation, 1 lymphangioma, and other treatment indications were unidentified.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003e\u003csup\u003ec\u003c/sup\u003e Small-for-gestational-age was defined as birth weight less than the 10th percentile for gestational age and sex based on French intrauterine \u0026ldquo;EPOP\u0026eacute;\u0026rdquo; growth curves (Ego 2006).\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003e\u003csup\u003ed\u003c/sup\u003e Among admitted to a neonatal unit. Severe neonatal morbidity was defined as severe bronchopulmonary dysplasia or necrotizing enterocolitis stage 2\u0026ndash;3 or severe retinopathy of prematurity stage\u0026thinsp;\u0026gt;\u0026thinsp;3 or any of the following severe cerebral abnormalities on cranial ultrasonography: intraventricular haemorrhage grade III or IV or cystic periventricular leukomalacia or late onset sepsis.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003ch3\u003eNeurodevelopmental outcomes of age 2 corrected age and 5 years\u003c/h3\u003e\n\u003cp\u003eFirst, we examined the association between maternal autoimmune disease exposure during pregnancy and behavioural and communication outcomes in offspring. Regarding global developmental delay at two years of corrected age, no association was found. However, across the ASQ domains, we found that children whose mothers had autoimmune diseases had more severe personal-social skills (OR: 1.94, 95% CI: 1.01\u0026ndash;3.75, p\u0026thinsp;=\u0026thinsp;0.043), but not in the other ASQ dimensions (communication, gross motor, fine motor, problem-solving). Regarding autistic traits (as measured by the M-CHAT), no difference was found between the two groups. After adjustment, the association with the personal-social subscore of the ASD age at 2 years corrected was no longer statistically significant, either with or without multiple imputation (respectively, aOR: 1.39 [95% CI: 0.82 to 2.35] and aOR: 1.29 [95% CI: 0.75 to 2.23]). \u003cstrong\u003e(\u003c/strong\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e \u003cstrong\u003eand supplemental Table\u0026nbsp;2)\u003c/strong\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBehaviour and communication outcome at 2 and 5 years according to maternal autoimmune disease exposure. Data are No./total (weighted %), unless otherwise indicated. Denominators vary according to the number of missing data for each variable. Percentage are weighted to consider the differences in survey design between gestational age groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMaternal autoimmune diseases\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eExposed vs Unexposed,\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eUnexposed (n\u0026thinsp;=\u0026thinsp;3454)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eExposed (n\u0026thinsp;=\u0026thinsp;155)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eOR (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eaOR (95% CI)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eaOR (95% CI)\u003csup\u003ea\u003c/sup\u003e, after multiple Imputation\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eaOR (95% CI), matching sample\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en/N (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en/N (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAt 2 years\u0026rsquo; corrected age\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eGlobal developmental delay (ASQ score\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003ec\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1037/2664 (34.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e48/129 (36.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.78\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.08 (0.63 to 1.87)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97 (0.62 to 1.53)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.90 (0.61 to 1.32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.94 (0.57 to 1.54)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBy domain,\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCommunication\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e629/2835 (18.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e29/134 (18.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.96\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.02 (0.53 to 1.96)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.08 (0.62 to 1.88)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.08 (0.65 to 1.79)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.21 (0.62 to 2.38)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGross motor\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e296/2758 (7.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e10/131 (6.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.82 (0.27 to 2.49)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.71 (0.34 to 1.52)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.81 (0.45 to 1.47)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.72 (0.34 to 1.55)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFine motor\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e312/2748 (10.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e12/131 (5.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.52 (0.23 to 1.19)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.91 (0.48 to 1.73)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.85 (0.47 to 1.52)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.96 (0.43 to 2.13)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eProblem solving\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e313/2699 (10.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e11/129 (10.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00 (0.46 to 2.17)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.71 (0.36 to 1.39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.80 (0.47 to 1.38)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.62 (0.29 to 1.36)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePersonal-social\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e439/2746 (13.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e25/131 (23.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.043\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.94 (1.01 to 3.75)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.39 (0.82 to 2.35)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.29 (0.75 to 2.23)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.46 (0.65 to 3.27)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAutistic traits (M-CHAT\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003ed\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e561/2587 (20.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15/123 (13.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.58 (0.25 to 1.34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.56 (0.30 to 1.08)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.65 (0.38 to 1.10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.60 (0.30 to 1.20)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAt 5\u0026thinsp;years of age\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBehavioural difficulties\u003c/strong\u003e \u003csup\u003e\u003cstrong\u003ee\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTotal SDQ score \u0026gt;\u0026thinsp;90th percentile\u003csup\u003ee\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e189/2057 (8.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7/92 (4.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.48 (0.16 to 1.43)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.66 (0.26 to 1.69)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.96 (0.47 to 1.94)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97 (0.36 to 2.61)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBy domain,\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEmotional symptoms\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e225/2060 (10.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e10/92 (7.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.67 (0.26 to 1.72)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99 (0.47 to 2.06)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.03 (0.63 to 1.69)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99 (0.50 to 1.97)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eConduct problems\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e187/2062 (8.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7/93 (7.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.81\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.88 (0.32 to 2.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.73 (0.31 to 1.74)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.81 (0.46 to 1.42)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.92 (0.43 to 1.96)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHyperactivity\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e270/2061 (12.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15/93 (12.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.97\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.98 (0.45 to 2.13)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.41 (0.77 to 2.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.29 (0.82 to 2.05)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.38 (0.68 to 2.81)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePeer problems\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e222/2060 (10.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e10/93 (7.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.42\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.69 (0.27 to 1.73\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.85 (0.37 to 1.93)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.98 (0.55 to 1.73)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97 (0.40 to 2.33)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSocial communication difficulties\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003ef\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e247/1983 (11.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e9/90 (3.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.30 (0.14 to 0.64)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.98 (0.45 to 2.12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.98 (0.53 to 1.81)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.02 (0.42 to 2.48)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003eAbbreviations:\n\u003cp\u003eASQ, Ages \u0026amp; Stages Questionnaire; M-CHAT, Modified Checklist for Autism in Toddlers; SCQ, Social Communication Questionnaire; SDQ, Strengths and difficulties questionnaire.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Logistic regression analysis with cluster robust variance estimates to account for non-independence of twins, adjusted on maternal age, primiparity, maternal birth in France, maternal level of education, parents\u0026rsquo; socio-economic status, tobacco use during pregnancy, gestational age and child sex.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Propensity score matched sample, 155 children in exposed group are matched to 155 non-exposed, adjusted on gestational age and child sex, after multiple imputation.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u003c/sup\u003e Risk of developmental delay is defined by an ASQ score\u0026thinsp;\u0026lt;\u0026thinsp;2 SDs from the mean in any of the five ASQ domains.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ed\u003c/sup\u003e Positive M-CHAT is defined by at least 3 of the 23 items failed.\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ee\u003c/sup\u003e Cut-off \u0026gt; 90th percentile of the reference group of term-born children, corresponds to SDQ score\u0026thinsp;\u0026ge;\u0026thinsp;19.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ef \u003c/sup\u003eDefined by total SCQ score \u0026gt; 90th percentile of the reference group of term-born children, corresponds to SCQ score\u0026thinsp;\u0026ge;\u0026thinsp;11.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAt age 5, we did not find any difference in behavioural difficulties based on SDQ. Although, the prevalence of high SCQ (SCQ \u0026gt;\u0026thinsp;90th percentiles) was lower in children exposed to maternal autoimmune diseases suggesting less frequent social communication difficulties [OR:0.30 (95%CI; 0.14 to 0.64), p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.001) \u003cstrong\u003e(\u003c/strong\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e \u003cstrong\u003eand supplemental Table\u0026nbsp;2)\u003c/strong\u003e, the association was no longer significant after adjustment (aOR: 0.98 [95% CI: 0.45 to 2.12] and aOR with multiple imputation: 0.98 [95% CI; 0.53 to 1.81]\u003c/p\u003e\n\u003ch3\u003eSensitivity analysis\u003c/h3\u003e\n\u003cp\u003eNext, we performed several sensitivity analyses. First, we used a matched sample. The characteristics of the sample before and after matching are shown in \u003cstrong\u003eSupplementary Fig.\u0026nbsp;1\u003c/strong\u003e. In the matched sample, we still found no difference in communication (aOR: 1.21 [95% CI:0.62 to 2.38]) or personal-social at 2 years corrected age (aOR: 1.46 [95% CI: 0.65 to 3.27]) or in SCQ scores above the 90th percentile at 5 years (aOR: 1.02 [95% CI: 0.42 to 2.48]) \u003cstrong\u003e(\u003c/strong\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e. Second, since there were more extremely premature children in the unexposed group, we ran the analysis on children aged 27\u0026ndash;34 weeks only and found no difference at either age 2 or 5 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFinally, we investigated the association of immunosuppressive therapy on the outcome of neurodevelopmental disorders (NDDs) in offspring \u003cstrong\u003e(Supplementary Table\u0026nbsp;3)\u003c/strong\u003e. No difference was found between exposed and unexposed children without a history of immunosuppressive therapy at ages 2 corrected age and 5.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study we did not observe association between maternal autoimmune disease during pregnancy and behavioural or communication difficulties in the offspring of children born preterm, confirming previous results \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. This suggest that in the specific context of preterm birth, maternal autoimmune diseases may not represent a major over-risk factor for early neurodevelopmental disorders. This result may seem counterintuitive, but there are several hypotheses that could explain this observation.\u003c/p\u003e \u003cp\u003eFirstly, both maternal autoimmune diseases and preterm birth are strongly associated with inflammation \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Several recent studies have highlighted the negative impact of inflammation on brain development, which is known to influence foetal brain development through mechanisms such as microglial activation and cytokine signalling \u003csup\u003e\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. It is possible that when inflammation is already elevated due to maternal autoimmune disease, the additional inflammatory burden associated with preterm birth does not further amplify neurodevelopmental processes. We hypothesised that this might indicate a saturation of neuroimmune pathways. In this context, a ceiling effect could occur, whereby neuroimmune mechanisms are maximally activated and the impact of prematurity on neurodevelopment is limited.\u003c/p\u003e \u003cp\u003eSecondly, we observed that preeclampsia was less prevalent among mothers with autoimmune diseases, while the use of aspirin during pregnancy was more common. This finding is interesting because, although the exact pathophysiology of preeclampsia is unknown, it is a major risk factor for prematurity and ASD in offspring \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e and aspirin has long been recognised as an effective strategy for preventing the onset of preeclampsia \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Although there is considerable evidence that mothers with autoimmune diseases are at greater risk of obstetric and birth complications\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e, our results may reflect the more intensive prenatal care provided to women with autoimmune disorders. This is suggested by the fact that children in the exposed group were born at a slightly more advanced gestational age and have better short- and medium-term survival, which could mitigate the cumulative adverse effects of MIA and prematurity.\u003c/p\u003e \u003cp\u003eSeveral limitations should be noted. Firstly, the maternal autoimmune exposure group was heterogeneous and based on clinical diagnosis rather than biomarkers. Consequently, we lacked detailed information on disease severity and activity during pregnancy and the exact treatments used. A second limitation of the study is the loss to follow-up. To address this, we used multiple imputation, and the results were consistent with those from the complete case analysis. Exposure rates were similar in participants and non-participants, minimizing selection bias. Loss to follow-up may have underestimated neurodevelopmental disorders rates but likely did not affect the association directions. Third, the number of children exposed was relatively small, which limited our statistical power to detect small effect sizes, particularly in subgroup analyses. However, sensitivity analysis was conducted using propensity score matching to compare exposed and unexposed children, providing additional support for our findings. More, EPIPAGE 2 is a large prospective population-based cohort, with 93% participation rate at birth, giving good external validity to our results, comprehensive clinical and follow-up data, and validated screening tools at two key stages of early childhood. In addition, to our knowledge, this is the first study to investigate the intersection between immune-mediated risk factors and behavioural and communication disorders in children born preterm. Thirdly, while the ASQ, SDQ and SCQ are validated screening instruments, they are not diagnostic tools and may be subject to classification bias.\u003c/p\u003e \u003cp\u003eOur findings are reassuring for clinicians and patients alike. When closely monitored and appropriately cared for, maternal autoimmune diseases do not appear to increase the risk of early neurodevelopmental disorders in preterm children. However, further research using biomarkers of MIA, standardised diagnostic assessments and long-term follow-up is needed to confirm these findings in adolescence and adulthood.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflicts of interest:\u003c/h2\u003e \u003cp\u003enone\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThis study was funded by Fondation de France (11779), French Institute of Public Health Research/Institute of Public Health, National Research Agency through the French Equipex Programme of Investments in the Future (ANR-11-EQPX0038).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLord C, Brugha TS, Charman T, Cusack J, Dumas G, Frazier T \u003cem\u003eet al.\u003c/em\u003e Autism spectrum disorder. \u003cem\u003eNat Rev Dis Primers\u003c/em\u003e 2020; 6: 5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHan VX, Patel S, Jones HF, Dale RC. 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Prevention of preeclampsia with aspirin. \u003cem\u003eAm J Obstet Gynecol\u003c/em\u003e 2022; 226: S1108\u0026ndash;S1119.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSingh M, Wambua S, Lee SI, Okoth K, Wang Z, Fayaz FFA \u003cem\u003eet al.\u003c/em\u003e Autoimmune diseases and adverse pregnancy outcomes: an umbrella review. \u003cem\u003eBMC Med\u003c/em\u003e 2024; 22: 94.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"translational-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"tp","sideBox":"Learn more about [Translational Psychiatry](http://www.nature.com/tp/)","snPcode":"41398","submissionUrl":"https://mts-tp.nature.com/cgi-bin/main.plex","title":"Translational Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8698441/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8698441/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMaternal immune activation (MIA) and preterm birth have both been associated with increased risk of autism spectrum disorder but their combined impact in preterm children is unclear. This prospective population-based cohort study used data from the French EPIPAGE-2 study, which included liveborn infants delivered at 22 to 34 weeks\u0026rsquo; gestation in 2011 and followed them to 5 years of age. Neurodevelopmental outcomes at 2 years\u0026rsquo; corrected age and at 5 years were assessed. Among 3609 children (155 [4.3%] exposed), maternal autoimmune diseases were initially associated with more impaired personal-social skills on the Ages \u0026amp; Stages Questionnaire at 2 years and a lower prevalence of high Social Communication Questionnaire scores at 5 years, but these associations were no longer statistically significant after adjustment. No significant associations were found between maternal autoimmune diseases and global developmental delay, ASD risk, or behavioral difficulties at 2 or 5 years in adjusted analyses. Subgroup analyses by gestational age and by exposure to immunosuppressive therapy also showed no increased risk. In this national preterm birth cohort, maternal autoimmune diseases during pregnancy were not associated with increased early behavioral or social communication difficulties in offspring, suggesting that, in the context of contemporary antenatal care, such conditions may not confer additional early neurodevelopmental risk beyond that related to prematurity itself.\u003c/p\u003e","manuscriptTitle":"Exploring the effect of maternal autoimmune diseases on behavioral and social difficulties risk in children born preterm: evidence from EPIPAGE-2 study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-09 13:14:02","doi":"10.21203/rs.3.rs-8698441/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-04-26T09:50:49+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-04-06T15:46:08+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-03-24T14:33:53+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-02-05T03:30:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-01T12:52:52+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-01T12:52:17+00:00","index":"","fulltext":""},{"type":"submitted","content":"Translational Psychiatry","date":"2026-01-31T19:38:10+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2026-01-28T17:30:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"translational-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"tp","sideBox":"Learn more about [Translational Psychiatry](http://www.nature.com/tp/)","snPcode":"41398","submissionUrl":"https://mts-tp.nature.com/cgi-bin/main.plex","title":"Translational Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2422ff34-a567-436f-a5ba-1c7af7456d32","owner":[],"postedDate":"February 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":62350868,"name":"Health sciences/Diseases/Psychiatric disorders/Autism spectrum disorders"},{"id":62350869,"name":"Health sciences/Biomarkers/Predictive markers"}],"tags":[],"updatedAt":"2026-02-09T13:14:02+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-09 13:14:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8698441","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8698441","identity":"rs-8698441","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}