If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Corresponding author: Tianyang Zhang, Karolinska Institutet, Department of Clinical Neuroscience, Child and Adolescent Psychiatry Research Center, Gävlegatan 22 (Entré B), Floor 8, SE-11330 Stockholm, Sweden,
Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, SwedenStockholm Health Care Services, Region Stockholm, Stockholm, Sweden
Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, SwedenStockholm Health Care Services, Region Stockholm, Stockholm, SwedenScience for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, SwedenStockholm Health Care Services, Region Stockholm, Stockholm, Sweden
Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, SwedenStockholm Health Care Services, Region Stockholm, Stockholm, Sweden
Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, SwedenStockholm Health Care Services, Region Stockholm, Stockholm, Sweden
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SwedenSchool of Medical Sciences, Örebro University, Örebro, Sweden
Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, SwedenStockholm Health Care Services, Region Stockholm, Stockholm, Sweden
Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, SwedenStockholm Health Care Services, Region Stockholm, Stockholm, Sweden
Post-infectious autoimmune processes are hypothesized to be causally related to both obsessive-compulsive disorder (OCD) and tic disorders, but current evidence is conflicting. This study examined whether prenatal maternal (and paternal, as an internal control) infections and early childhood infections in the offspring (i.e., during the first three years of life) were associated with a subsequent risk of OCD and Tourette syndrome or chronic tic disorder (TS/CTD).
Methods
Individuals exposed to any prenatal maternal infection (n=16,743) and early childhood infection (n=264,346) were identified from a population-based birth cohort, consisting of 2,949,080 singletons born in Sweden between 1973-2003, and were followed up through 2013. Cox proportional hazard regression models were used to estimate hazard ratios (HRs). Sibling analyses were performed to control for familial confounding.
Results
At the population level, and after adjusting for parental psychiatric history and autoimmune diseases, a significantly increased risk of OCD and TS/CTD was found in individuals exposed to prenatal maternal (but not paternal) infections (OCD: HR, 1.33; 95% CI, 1.12-1.57; TS/CTD: HR, 1.60; 95% CI, 1.23-2.09) and early childhood infections (OCD: HR, 1.19; 95% CI, 1.14-1.25; TS/CTD: HR, 1.34; 95% CI, 1.24-1.44). However, these associations were no longer significant in the sibling analyses.
Conclusions
The results do not support the hypothesis that prenatal maternal or early-life infections play a direct causal role in the etiology of either OCD or TS/CTD. Instead, familial factors (e.g., genetic pleiotropy) may explain both the propensity to infections and the liability to OCD and TS/CTD.
Post-infectious autoimmune responses are hypothesized to contribute to the development of neuropsychiatric disorders, such as obsessive-compulsive disorder (OCD) or tic disorders, although current evidence is conflicting (
What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders?.
). For example, group A streptococcus (GAS) infections have been linked to the acute-onset and exacerbation of OCD and/or tic disorder symptoms in prepuberal individuals, leading to the proposal of the Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) syndrome (
Tourette Syndrome Study Group Serial immune markers do not correlate with clinical exacerbations in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.
Tourette Syndrome Study Group Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: a prospective blinded cohort study.
Prospective longitudinal study of children with tic disorders and/or obsessive-compulsive disorder: relationship of symptom exacerbations to newly acquired streptococcal infections.
A Nationwide Study in Denmark of the Association Between Treated Infections and the Subsequent Risk of Treated Mental Disorders in Children and Adolescents.
Group A Streptococcal Infections Are Associated With Increased Risk of Pediatric Neuropsychiatric Disorders: A Taiwanese Population-Based Cohort Study.
), but none of these studies was able to establish causality or to demonstrate a clear temporal association between infections and the onset or exacerbation of OCD and tics.
One powerful strategy to test the post-infectious autoimmune hypothesis could be to focus on infections that occur very early in life (i.e., in utero and early childhood), a period considered critical for neurodevelopment (
What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders?.
). By definition, this approach would ensure that the infection precedes the onset of OCD or tics. A maternal immune activation model has been hypothesized to explain the possible link between a dysregulated immune system in utero and impaired child development (
What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders?.
). Previous research has linked prenatal infections to increased risk of several neurodevelopmental and psychiatric disorders, including autism spectrum disorder (ASD) (
), but similar studies have yet to be conducted in OCD and Tourette syndrome (TS) or chronic tic disorder (CTD). Similarly, we are not aware of previous population-based studies exploring the role of early childhood infections (i.e., during the first three years of life) and the subsequent risk of either OCD or TS/CTD.
In this nationwide birth cohort study, we investigated whether exposure to prenatal maternal infections and early childhood (i.e., during the first three years of life) infections in the offspring were associated with a subsequent risk of OCD and TS/CTD. As an internal control, we also examined the associations between prenatal paternal infections and the outcomes of interest. We systematically adjusted for potential confounders, such as parental psychopathology and autoimmune diseases. The latter are strongly associated with both OCD and TS/CTD (
A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette's/chronic tic disorders.
Maternal autoimmunity and inflammation are associated with childhood tics and obsessive-compulsive disorder: Transcriptomic data show common enriched innate immune pathways.
). We also used a discordant sibling design to test whether the potential association between infections, OCD, and TS/CTD is independent from unmeasured familial factors (e.g., genetic factors).
METHODS AND MATERIALS
Ethical approval was obtained from the Regional Ethical Committee in Stockholm (2013/862-31/5). The requirement for informed consent was waived because the study was register-based and data on the included individuals were pseudonymized.
Data sources
Using the unique personal identification number assigned to each Swedish resident (
What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders?.
), which holds data on more than 99% of all pregnancies and deliveries in Sweden since 1973, including information on antenatal care of the mother and the pediatric examination of the newborns; (
), which covers inpatient hospital admissions since 1969 and outpatient specialist care since 2001, with diagnoses based on the International Classification of Diseases (ICD), eighth (ICD-8; 1969–1986), ninth (ICD-9; 1987–1996), and tenth (ICD-10; 1997–2013) revisions; (
Tourette Syndrome Study Group Serial immune markers do not correlate with clinical exacerbations in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.
), which provides information on each resident’s family pedigree among those born in Sweden after 1933 and those ever registered as residents in Sweden after 1960.
Study population
In this birth cohort study, all 3 041 379 singletons born in Sweden between January 1, 1973 and December 31, 2003 were identified. Individuals who emigrated (n=32 741), died before age 3 (n=17 679) or had missing data on their gestational age (n=7 604) or the mother’s (n=4 506) or father’s (n=29 769) identification number were excluded. The final cohort consisted of 2,949,080 individuals who were followed from the age of three until the date of diagnosis of OCD or TS/CTD, emigration, death or end of the follow-up (December 31, 2013), whichever came first. For the sibling analyses, sets of full siblings were identified within the final cohort.
Variables
Exposures
Prenatal maternal infections were defined as any viral or bacterial infection requiring hospitalization occurring during the pregnancy period, which was calculated by subtracting the offspring’s birth date and the gestational age in days. As an internal comparison, we also extracted data on paternal infections during the index pregnancy period because they are unlikely to be associated with the outcomes.
Early childhood infections were defined as any viral or bacterial infection requiring hospitalization occurred during the first three years of life. Data on infections were obtained from the NPR and were later divided into: any infection (i.e., viral or bacterial), viral infection, and bacterial infection (see ICD codes in Supplementary Table 1).
Outcomes
Diagnoses of OCD and TS/CTD were obtained from the NPR.(
) OCD outcomes were identified as the first instance of a recorded OCD diagnosis made after the age of 6 (to avoid diagnostic misclassification) using ICD codes 300.3 in ICD-8, 300D in ICD-9 or F42 in ICD-10. The ICD codes for OCD in the NPR have excellent inter-rater reliability (κ=0.98) and good validity (positive predictive value=0.72) (
). TS/CTD outcomes were identified using an algorithm including ICD-8 code 306.2, ICD-9 code 307C or ICD-10 codes F95.0, F95.1, F95.2, F95.8, and F95.9, if the diagnosis was made after the age of 3, which excluded those with only transient tics (i.e., tic symptoms lasting less than one year). This algorithm has shown excellent inter-rater reliability (κ=1) and high validity (positive predictive value=0.92) (
Offspring’s birth year, sex, and maternal age at delivery were collected from the Medical Birth Register. From the Multi-Generation Register, we identified the offspring’s registered father and his age at the birth of the index person. From the NPR, we identified maternal and paternal psychiatric history prior to the birth of the index person to control for parental psychopathology, using ICD-8 and ICD-9 codes 290-315 and ICD-10 codes F00-F99. Additionally, to control for parental autoimmunity, we identified lifetime maternal records of autoimmune diseases using a list of ICD codes for 40 autoimmune diseases (see ICD codes in Supplementary Table 2) previously used in population-based studies (
A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette's/chronic tic disorders.
Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of the risk of OCD and TS/CTD separately in the offspring exposed to prenatal or early childhood infections, with attained age as the underlying time scale. We fitted three different Cox regression models for all exposure variables: Model 1 adjusted for offspring’s birth year, sex, and maternal and paternal ages at birth of the index offspring; Model 2 further adjusted for maternal and paternal psychiatric history; and Model 3 further adjusted for lifetime maternal and paternal autoimmune diseases. Robust standard errors were used to account for the familial clustering in the analyses.
To explore the role of familial confounding, sibling analyses using stratified Cox proportional hazards regression models were performed. These analyses, by design, account for about 50% of the genetic background and all the shared environment within each set of full siblings. Siblings who were differently exposed to prenatal maternal or early childhood infections contributed to the risk estimates in the analysis. The sibling analyses adjusted for offspring’s birth year and sex. The unadjusted cumulative incidence for each exposure and outcome was plotted using Kaplan-Meier survival estimates for the main cohort and the sibling cohort.
Data were analyzed from October 7, 2021, to March 4, 2022. P<.05 was considered statistically significant. Statistical analyses were conducted using SAS software, version 9.4 (SAS Institute, Cary, NC) and R version 4.0.5 (R Foundation).
RESULTS
Cohort characteristics
Table 1 summarizes the characteristics of the full cohort. Among 2 949 080 individuals, we identified 16 743 (0.6%) exposed to any prenatal maternal infection and 264 346 (9.0%) exposed to any early childhood infection. At the end of follow up, a total of 18 888 offspring received at least one diagnosis of OCD (median age at first diagnosis, 21.8 years; IQR, 10.4) and 5 479 received at least one diagnosis of TS/CTD (median age at first diagnosis, 12.7 years; IQR, 7.2) (Table 1).
Table 1Descriptive Characteristics of the Birth Cohort.
Characteristic, n (%)
Study Cohort (N=2 949 080)
Prenatal Maternal Infections
Early Childhood Infections
Unexposed (n= 2 932 337)
Exposed (n= 16 743)
Unexposed (n= 2 684 734)
Exposed (n= 264 346)
Male offspring
1 506 849 (51.4)
8 564 (51.1)
1 365 396 (50.9)
150 017 (56.8)
Distribution of years of birth
1973-1983
1 014 282 (34.6)
5 218 (31.2)
968 397 (36.1)
51 103 (19.3)
1984-1993
1 042 900 (35.6)
5 162 (30.8)
918 494 (34.2)
129 568 (49.0)
1994-2003
875 155 (29.8)
6 363 (38.0)
797 843 (29.7)
83 675 (31.7)
Mean age of mothers at birth of index offspring, years ± s.d.
28.02 ± 5.12
27.00 ± 5.57
28.02 ± 5.12
27.99 ± 5.19
Mean age of fathers at birth of index offspring, years ± s.d.
We identified 135 (0.79%) offspring exposed to any prenatal maternal infection and 18 893 (0.64%) unexposed offspring who later received a diagnosis of OCD during the follow-up period. The corresponding figures for offspring who later developed TS/CTD were: 56 (0.33%) exposed and 5 423 (0.18%) unexposed offspring. The Kaplan-Meier estimated cumulative incidence of OCD at the end of the study period was 1.98% (95% CI, 1.57%-2.39%) in offspring exposed to any prenatal maternal infection, compared to 1.42% (95% CI, 1.39%-1.45%) in unexposed offspring (Figure 1A). The cumulative incidence of TS/CTD at the end of the study period was 0.75% (95% CI, 0.17%-1.32%) in offspring exposed to any prenatal maternal infection, compared to 0.26% (95% CI, 0.25%-0.27%) in unexposed individuals (Figure 1C).
Figure 1Cumulative incidence for obsessive-compulsive disorder (OCD) and Tourette syndrome or chronic tic disorder (TS/CTD) in. individuals exposed vs unexposed to prenatal (A, C) or childhood infections (B, D).
Results for the associations between prenatal maternal infections and the risk of OCD and TS/CTD are presented in Table 2. In the minimally-adjusted models (Model 1), offspring exposed to any prenatal maternal infection had an increased risk of OCD (HR, 1.34; 95% CI, 1.13-1.59) and TS/CTD (HR, 1.64; 95% CI, 1.26-2.13), compared with unexposed offspring. Model 2 additionally adjusted for parental psychiatric history and produced similar results to Model 1, although the magnitude of the associations was slightly attenuated. In Model 3, where parental autoimmune diseases were additionally adjusted for, all associations remained robust: offspring exposed to any prenatal maternal infection had an increased risk of OCD (HR, 1.33; 95% CI, 1.12-1.57) and TS/CTD (HR, 1.60; 95% CI, 1.23-2.09), compared with unexposed offspring. When looking at different infection agents, and after adjusting for all measured confounders (Model 3), only bacterial, but not viral, infections were associated with increased risk of OCD (HR, 1.32; 95% CI, 1.06-1.64) and TS/CTD (HR, 1.71; 95% CI, 1.25-2.33).
Table 2Risk of OCD and TS/CTD in Offspring Exposed to Prenatal Maternal Infections, Prenatal Paternal Infections, and Early Childhood Infections.
1 Model 1 adjusted for offspring birth year, sex, maternal and paternal age at birth of offspring.
2 Model 2 adjusted for, in addition to variables in Model 2, maternal and paternal psychiatric disorders.
3 Model 3 adjusted for, in addition to variables in Model 3, maternal and paternal autoimmune diseases.
4 Frequency numbers of any infection may be larger than the sum of viral and bacterial infections because they additionally included infections with unknown agents (viral or bacterial).
Prenatal paternal infections during the index pregnancy period were not significantly associated with risk of either OCD or TS/CTD in any of the three models (Table 2).
Exposure to early childhood infections
We identified 1 983 (0.75%) offspring exposed to any early childhood infection and 16 905 (0.63%) unexposed offspring who later received a diagnosis of OCD; 748 (0.28%) exposed and 4 730 (0.18%) unexposed individuals who received a diagnosis of TS/CTD. The Kaplan-Meier estimated cumulative incidence of OCD at the end of the study period was 1.95% (95% CI, 1.76%-2.14%) in offspring exposed to any early childhood infection, compared to 1.38% (95% CI, 1.36%-1.41%) in unexposed offspring (Figure 1B). The cumulative incidence of TS/CTD at the end of the study period was 0.41% (95% CI, 0.37%-0.46%) in offspring exposed to any early childhood infection, compared to 0.25% (95% CI, 0.24%-0.26%) in unexposed individuals (Figure 1D).
Results for the association between early childhood infections and the risk of OCD and TS/CTD are presented in Table 2. In the minimally-adjusted models (Model 1), offspring exposed to any early childhood infection had an increased risk of OCD (HR, 1.19; 95% CI, 1.14-1.25) and TS/CTD (HR, 1.35; 95% CI, 1.25-1.45), compared with unexposed offspring. Adjusting for parental psychiatric history (Model 2) did not change the results (i.e., overlapping CIs). In the fully adjusted models (Model 3), individuals exposed to any early childhood infection had an increased risk of OCD (HR, 1.19; 95% CI, 1.14-1.25) and TS/CTD (HR, 1.34; 95% CI, 1.24-1.44), compared with unexposed individuals. Both bacterial and viral infections were associated with increased risk of OCD (for viral infections: HR, 1.24; 95% 1.17-1.31; for bacterial infections: HR, 1.22; 95% CI, 1.13-1.32) and TS/CTD (for viral infections: HR, 1.36; 95% CI, 1.24-1.51; for bacterial infections: HR, 1.34; 95% CI, 1.17-1.53).
Sibling Analyses
Clusters of full siblings discordant for the exposures were identified, consisting of 10 720 offspring exposed to prenatal maternal infections and their 16 234 unexposed siblings, and 178 715 offspring exposed to early childhood infections and their 242 119 unexposed siblings. The Kaplan-Meier estimated cumulative incidence of OCD and TS/CTD in exposed vs unexposed clusters of siblings are shown in Figure 2. In the sibling analyses, which also adjusted for offspring’s birth year and sex, neither exposure to prenatal maternal infections nor exposure to early childhood infections remained significantly associated with an increased risk of OCD or TS/CTD (Table 3).
Figure 2Cumulative incidence for obsessive-compulsive disorders (OCD) and Tourette syndrome or chronic tic disorder (TS/CTD) in siblings who were discordant for exposure to prenatal (A, C) or childhood infections (B, D).
This population-based birth cohort study followed nearly three million individuals from birth to up to four decades to investigate the associations between prenatal maternal infections and early childhood (before age 3) infections with the subsequent risk of OCD and TS/CTD in the offspring. Four main findings emerged from this study.
First, after adjusting for all measured confounders, we found that prenatal maternal infections in general were associated with increased risk of OCD (33%) and TS/CTD (60%). However, further analyses revealed that associations were limited to bacterial, but not viral, infections. Prenatal bacterial infections have previously been associated with several other psychiatric disorders, such as ASD (18%) (
). Because, in our cohort, severe viral infections during pregnancy were relatively rare, these specific analyses may have been underpowered.
Second, prenatal paternal infections were not associated with increased risk of OCD or TS/CTD. Consistent results were found in a Danish register-based cohort study, where it was shown that paternal infections during pregnancy were not associated with any mental disorder, regardless of the timing of the infections during the pregnancy, in- or out-patient treatments for the infections or total number of infections (
). Because paternal infections during the index pregnancy are unlikely to directly interfere with fetal development, the increased risk of OCD and TS/CTD when exposed to maternal, but not paternal, infections during pregnancy are potentially in line with a maternal immune activation hypothesis, whereby immune dysregulation in utero is thought to have a deleterious impact on neurodevelopment (
Third, after adjusting for all measured confounders, we found that individuals exposed to early childhood infections before the age of 3 had an 19% increased risk of OCD and 34% of TS/CTD. For both disorders, the risks were similar for bacterial and viral infections. Of note, we were able to detect these associations despite the fact that most streptococcal infections tend to occur later in childhood (
). Additionally, adjusting for parental psychiatric history and autoimmune diseases did not change the results, suggesting a minor contribution of these factors to the association between early life infections and risk of OCD and TS/CTD. Although we have no information on the type of symptom onset (e.g., abrupt vs. insidious), these findings support the idea that post-infectious autoimmune responses (not limited to streptococcal infections) may play a role in the etiology of OCD and TS/CTD. Nevertheless, these associations do not necessarily indicate a direct causal link between infections and OCD or TS/CTD, among other reasons because these analyses do not adjust for unmeasured familial confounding.
Fourth, in our sibling analyses comparing exposed with unexposed siblings within the same nuclear family, all associations attenuated to the null and were no longer significant, suggesting that unmeasured familial confounding largely explains the associations described in the population analyses. In line with our findings, a contributing role of shared maternal genetic effects in the OCD risk architecture has been suggested (
). Moreover, a familial link between OCD, TS/CTD, pediatric acute-onset neuropsychiatric syndrome (PANS), and autoimmune diseases has been well documented (
A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette's/chronic tic disorders.
Establishing a Pediatric Acute-Onset Neuropsychiatric Syndrome Clinic: Baseline Clinical Features of the Pediatric Acute-Onset Neuropsychiatric Syndrome Cohort at Karolinska Institutet.
), although they remain poorly understood, primarily due to the modest size of the current genome-wide association studies of these disorders. Overall, our results do not support the hypothesis that maternal or early-life infections play a direct causal role in the etiology of either OCD or TS/CTD. Instead, the results suggest that familial factors (e.g., genetic pleiotropy) may explain both the propensity to infections and the liability to OCD or TS/CTD. Defects in immunity (innate and adaptive) may lead to increased susceptibility to infections and autoimmune diseases, which may in turn provide compromised protection to the host from pathogens and result in physiological conditions (
What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders?.
). Thus, a “double-hit” scenario seems most plausible, whereby infections may act as a second hit in people with genetic susceptibility to both immune-related conditions and OCD and TS/CTD (
). As the sample sizes of genomic studies continue to grow, it may be possible to identify the specific coding variants of genes that interact with one another and contribute both to the negative impact of prenatal maternal and/or early life infections, as well as the individual's vulnerability to develop OCD and/or TS/CTD. One potential challenge will be the recent discovery that mosaic mutations in genes occur very early in development. (
The strengths of this study are the use of nationwide population-based data, including nearly three million individuals prospectively followed up from birth for several decades, which minimizes the risk of selection and recall bias; the long follow-up time, which can capture OCD and TS/CTD cases that had an onset during adolescence and adulthood; the established validity and reliability of the diagnostic codes (
); the use of inpatient data to identify infection status, which minimizes the risk of misclassification of exposure; and the use of sibling comparisons extracted from the full cohort, which allowed us, for the first time, to account for unmeasured familial confounding.
However, the results should be interpreted in light of some limitations. First, although we made an effort to capture all bacterial and viral infections, we did not have data on a few groups of infections (e.g., ear and eye infections). Additionally, we could not include fungal or parasitic infections, thus their associations with OCD and TS/CTD will require study. Second, we only had data on diagnoses of infections, but no data on what treatments the individuals with these infections received. This may have affected the results because antibiotics and antiviral drugs may affect intestinal microbiota composition and one’s health. Third, not all OCD and TS/CTD cases were captured because many affected individuals do not seek help, particularly those with mild symptoms. Moreover, OCD and TS/CTD cases diagnosed prior to 2001 may be more severe because before 2001 the NPR only registered inpatient diagnoses. Lastly, although sibling analyses control for unmeasured shared confounders, they are sensitive to biases introduced by random measurement error of exposure and unmeasured non-shared confounders within the sibling clusters (
). Carryover effects may also introduce biases to sibling analyses by affecting the status of exposure from previous pregnancies to later pregnancies or from older siblings to younger siblings (
). This limitation was partially addressed by adjusting for parental autoimmunity in the fully adjusted models.
To sum up, in this large birth cohort study, prenatal maternal and early childhood infections were associated with an increased risk of subsequent OCD and TS/CTD. However, these associations were no longer significant in sibling analyses, suggesting that unmeasured familial confounding could largely explain the significant associations observed at the population level. Overall, the results do not support the hypothesis that maternal or early-life infections play a direct causal role in the etiology of either OCD or TS/CTD. Instead, familial factors (e.g., genetic pleiotropy) may explain both the propensity to infections and the liability to OCD and TS/CTD.
ACKNOWLEDGEMENTS
TZ was supported by a doctoral grant from the China Scholarship Council.
CONFLICT OF INTEREST
HL has served as a speaker for Medice, Evolan Pharma, and Shire/Takeda and has received research grants from Shire/Takeda, all outside the submitted work. DM-C receives royalties for contributing articles to UpToDate, Wolters Kluwer Health, outside the submitted work. LFC receives royalties for contributing articles to UpToDate, Wolters Kluwer Health and for editorial work for Elsevier, all outside the submitted work. The rest of authors report no biomedical financial interests or potential conflicts of interest.
What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders?.
Serial immune markers do not correlate with clinical exacerbations in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.
Prospective longitudinal study of children with tic disorders and/or obsessive-compulsive disorder: relationship of symptom exacerbations to newly acquired streptococcal infections.
A Nationwide Study in Denmark of the Association Between Treated Infections and the Subsequent Risk of Treated Mental Disorders in Children and Adolescents.
Group A Streptococcal Infections Are Associated With Increased Risk of Pediatric Neuropsychiatric Disorders: A Taiwanese Population-Based Cohort Study.
A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette's/chronic tic disorders.
Maternal autoimmunity and inflammation are associated with childhood tics and obsessive-compulsive disorder: Transcriptomic data show common enriched innate immune pathways.
Establishing a Pediatric Acute-Onset Neuropsychiatric Syndrome Clinic: Baseline Clinical Features of the Pediatric Acute-Onset Neuropsychiatric Syndrome Cohort at Karolinska Institutet.
01433-0&id=gr1.jpg){kind=link}
01433-0&id=gr2.jpg){kind=link}