Advertisement

Prenatal and early childhood infections and subsequent risk of obsessive-compulsive disorder and tic disorders: A nationwide, sibling-controlled study

  • Tianyang Zhang
    Correspondence
    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,
    Affiliations
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
    Search for articles by this author
  • Gustaf Brander
    Affiliations
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden

    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
    Search for articles by this author
  • Josef Isung
    Affiliations
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
    Search for articles by this author
  • Kayoko Isomura
    Affiliations
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
    Search for articles by this author
  • Anna Sidorchuk
    Affiliations
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
    Search for articles by this author
  • Henrik Larsson
    Affiliations
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    School of Medical Sciences, Örebro University, Örebro, Sweden
    Search for articles by this author
  • Zheng Chang
    Affiliations
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    Search for articles by this author
  • David Mataix-Cols
    Affiliations
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
    Search for articles by this author
  • Lorena Fernández de la Cruz
    Affiliations
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
    Search for articles by this author
Open AccessPublished:July 18, 2022DOI:https://doi.org/10.1016/j.biopsych.2022.07.004

      Abstract

      Background

      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.

      Key words

      BACKGROUND

      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 (
      • Martino D.
      • Johnson I.
      • Leckman J.F.
      What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders?.
      ,
      • Pérez-Vigil A.
      • Fernández de la Cruz L.
      • Brander G.
      • Isomura K.
      • Gromark C.
      • Mataix-Cols D.
      The link between autoimmune diseases and obsessive-compulsive and tic disorders: A systematic review.
      ). 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 (
      • Swedo S.E.
      • Leonard H.L.
      • Garvey M.
      • Mittleman B.
      • Allen A.J.
      • Perlmutter S.
      • et al.
      Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases.
      ). However, conclusive evidence supporting the association between GAS infections, OCD, and tics has remained elusive (
      • Martino D.
      • Schrag A.
      • Anastasiou Z.
      • Apter A.
      • Benaroya-Milstein N.
      • Buttiglione M.
      • et al.
      Association of Group A Streptococcus Exposure and Exacerbations of Chronic Tic Disorders.
      ,
      • Singer H.S.
      • Gause C.
      • Morris C.
      • Lopez P.
      Tourette Syndrome Study Group
      Serial immune markers do not correlate with clinical exacerbations in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.
      ,
      • Kurlan R.
      • Johnson D.
      • Kaplan E.L.
      Tourette Syndrome Study Group
      Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: a prospective blinded cohort study.
      ,
      • Leckman J.F.
      • King R.A.
      • Gilbert D.L.
      • Coffey B.J.
      • Singer H.S.
      • Dure L.S.
      • et al.
      Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study.
      ,
      • Luo F.
      • Leckman J.F.
      • Katsovich L.
      • Findley D.
      • Grantz H.
      • Tucker D.M.
      • et al.
      Prospective longitudinal study of children with tic disorders and/or obsessive-compulsive disorder: relationship of symptom exacerbations to newly acquired streptococcal infections.
      ,
      • Martino D.
      • Chiarotti F.
      • Buttiglione M.
      • Cardona F.
      • Creti R.
      • Nardocci N.
      • et al.
      The relationship between group A streptococcal infections and Tourette syndrome: a study on a large service-based cohort.
      ,
      • Schrag A.E.
      • Martino D.
      • Wang H.
      • Ambler G.
      • Benaroya-Milshtein N.
      • Buttiglione M.
      • et al.
      Lack of Association of Group A Streptococcal Infections and Onset of Tics: European Multicenter Tics in Children Study.
      ). Some evidence emerging from population-based studies partially supports the PANDAS hypothesis (
      • Köhler-Forsberg O.
      • Petersen L.
      • Gasse C.
      • Mortensen P.B.
      • Dalsgaard S.
      • Yolken R.H.
      • et al.
      A Nationwide Study in Denmark of the Association Between Treated Infections and the Subsequent Risk of Treated Mental Disorders in Children and Adolescents.
      ,
      • Orlovska S.
      • Vestergaard C.H.
      • Bech B.H.
      • Nordentoft M.
      • Vestergaard M.
      • Benros M.E.
      Association of Streptococcal Throat Infection With Mental Disorders: Testing Key Aspects of the PANDAS Hypothesis in a Nationwide Study.
      ,
      • Wang H.C.
      • Lau C.I.
      • Lin C.C.
      • Chang A.
      • Kao C.H.
      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 (
      • Martino D.
      • Johnson I.
      • Leckman J.F.
      What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders?.
      ,
      • Nusslock R.
      • Miller G.E.
      Early-Life Adversity and Physical and Emotional Health Across the Lifespan: A Neuroimmune Network Hypothesis.
      ). 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 (
      • Martino D.
      • Johnson I.
      • Leckman J.F.
      What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders?.
      ,
      • Miller A.H.
      • Raison C.L.
      The role of inflammation in depression: from evolutionary imperative to modern treatment target.
      ,
      • Bilbo S.D.
      • Schwarz J.M.
      Early-life programming of later-life brain and behavior: a critical role for the immune system.
      ,
      • Estes M.L.
      • McAllister A.K.
      Maternal immune activation: Implications for neuropsychiatric disorders.
      ,
      • Han V.X.
      • Patel S.
      • Jones H.F.
      • Nielsen T.C.
      • Mohammad S.S.
      • Hofer M.J.
      • et al.
      Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review.
      ,
      • Han V.X.
      • Patel S.
      • Jones H.F.
      • Dale R.C.
      Maternal immune activation and neuroinflammation in human neurodevelopmental disorders.
      ,
      • Jain S.
      • Baer R.J.
      • McCulloch C.E.
      • Rogers E.
      • Rand L.
      • Jelliffe-Pawlowski L.
      • et al.
      Association of Maternal Immune Activation during Pregnancy and Neurologic Outcomes in Offspring.
      ). Previous research has linked prenatal infections to increased risk of several neurodevelopmental and psychiatric disorders, including autism spectrum disorder (ASD) (
      • Tioleco N.
      • Silberman A.E.
      • Stratigos K.
      • Banerjee-Basu S.
      • Spann M.N.
      • Whitaker A.H.
      • et al.
      Prenatal maternal infection and risk for autism in offspring: A meta-analysis.
      ), attention-deficit/hyperactivity disorder (ADHD) (
      • Mann J.R.
      • McDermott S.
      Are maternal genitourinary infection and pre-eclampsia associated with ADHD in school-aged children?.
      ,
      • Silva D.
      • Colvin L.
      • Hagemann E.
      • Bower C.
      Environmental risk factors by gender associated with attention-deficit/hyperactivity disorder.
      ), depression (
      • Al-Haddad B.J.S.
      • Jacobsson B.
      • Chabra S.
      • Modzelewska D.
      • Olson E.M.
      • Bernier R.
      • et al.
      Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero.
      ), and psychosis (
      • Lee Y.H.
      • Cherkerzian S.
      • Seidman L.J.
      • Papandonatos G.D.
      • Savitz D.A.
      • Tsuang M.T.
      • et al.
      Maternal Bacterial Infection During Pregnancy and Offspring Risk of Psychotic Disorders: Variation by Severity of Infection and Offspring Sex.
      ,
      • Benros M.E.
      • Nielsen P.R.
      • Nordentoft M.
      • Eaton W.W.
      • Dalton S.O.
      • Mortensen P.B.
      Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study.
      ,
      • Buka S.L.
      • Tsuang M.T.
      • Torrey E.F.
      • Klebanoff M.A.
      • Bernstein D.
      • Yolken R.H.
      Maternal infections and subsequent psychosis among offspring.
      ), 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 (
      • Pérez-Vigil A.
      • Fernández de la Cruz L.
      • Brander G.
      • Isomura K.
      • Gromark C.
      • Mataix-Cols D.
      The link between autoimmune diseases and obsessive-compulsive and tic disorders: A systematic review.
      ,
      • Mataix-Cols D.
      • Frans E.
      • Pérez-Vigil A.
      • Kuja-Halkola R.
      • Gromark C.
      • Isomura K.
      • et al.
      A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette's/chronic tic disorders.
      ,
      • Jones H.F.
      • Ho A.C.C.
      • Sharma S.
      • Mohammad S.S.
      • Kothur K.
      • Patel S.
      • et al.
      Maternal thyroid autoimmunity associated with acute-onset neuropsychiatric disorders and global regression in offspring.
      ,
      • Jones H.F.
      • Han V.X.
      • Patel S.
      • Gloss B.S.
      • Soler N.
      • Ho A.
      • et al.
      Maternal autoimmunity and inflammation are associated with childhood tics and obsessive-compulsive disorder: Transcriptomic data show common enriched innate immune pathways.
      ,
      • Dalsgaard S.
      • Waltoft B.L.
      • Leckman J.F.
      • Mortensen P.B.
      Maternal history of autoimmune disease and later development of tourette syndrome in offspring.
      ). 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 (
      • Ludvigsson J.F.
      • Otterblad-Olausson P.
      • Pettersson B.U.
      • Ekbom A.
      The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research.
      ), we linked several national registers: (
      • Martino D.
      • Johnson I.
      • Leckman J.F.
      What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders?.
      ) the Medical Birth Register (
      • Axelsson O.
      The Swedish medical birth register.
      ), 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; (
      • Pérez-Vigil A.
      • Fernández de la Cruz L.
      • Brander G.
      • Isomura K.
      • Gromark C.
      • Mataix-Cols D.
      The link between autoimmune diseases and obsessive-compulsive and tic disorders: A systematic review.
      ) the National Patient Register (NPR) (
      • Ludvigsson J.F.
      • Andersson E.
      • Ekbom A.
      • Feychting M.
      • Kim J.L.
      • Reuterwall C.
      • et al.
      External review and validation of the Swedish national inpatient register.
      ), 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; (
      • Swedo S.E.
      • Leonard H.L.
      • Garvey M.
      • Mittleman B.
      • Allen A.J.
      • Perlmutter S.
      • et al.
      Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases.
      ) the Total Population Register (
      • Ludvigsson J.F.
      • Almqvist C.
      • Bonamy A.K.
      • Ljung R.
      • Michaelsson K.
      • Neovius M.
      • et al.
      Registers of the Swedish total population and their use in medical research.
      ), which contains information about emigration since 1961 and immigration since 1969 from and to Sweden; (
      • Martino D.
      • Schrag A.
      • Anastasiou Z.
      • Apter A.
      • Benaroya-Milstein N.
      • Buttiglione M.
      • et al.
      Association of Group A Streptococcus Exposure and Exacerbations of Chronic Tic Disorders.
      ) the Cause of Death Register (
      • Brooke H.L.
      • Talback M.
      • Hornblad J.
      • Johansson L.A.
      • Ludvigsson J.F.
      • Druid H.
      • et al.
      The Swedish cause of death register.
      ), which includes dates and causes of more than 99% of all deaths of Swedish residents since 1961; and (
      • Singer H.S.
      • Gause C.
      • Morris C.
      • Lopez P.
      Tourette Syndrome Study Group
      Serial immune markers do not correlate with clinical exacerbations in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.
      ) the Multi-Generation Register (
      • Ekbom A.
      The Swedish Multi-generation Register.
      ), 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.(
      • Rück C.
      • Larsson K.J.
      • Lind K.
      • Perez-Vigil A.
      • Isomura K.
      • Sariaslan A.
      • et al.
      Validity and reliability of chronic tic disorder and obsessive-compulsive disorder diagnoses in the Swedish National Patient Register.
      ) 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) (
      • Rück C.
      • Larsson K.J.
      • Lind K.
      • Perez-Vigil A.
      • Isomura K.
      • Sariaslan A.
      • et al.
      Validity and reliability of chronic tic disorder and obsessive-compulsive disorder diagnoses in the Swedish National Patient Register.
      ). 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) (
      • Rück C.
      • Larsson K.J.
      • Lind K.
      • Perez-Vigil A.
      • Isomura K.
      • Sariaslan A.
      • et al.
      Validity and reliability of chronic tic disorder and obsessive-compulsive disorder diagnoses in the Swedish National Patient Register.
      ).

      Covariates

      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 (
      • Mataix-Cols D.
      • Frans E.
      • Pérez-Vigil A.
      • Kuja-Halkola R.
      • Gromark C.
      • Isomura K.
      • et al.
      A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette's/chronic tic disorders.
      ,
      • Isung J.
      • Williams K.
      • Isomura K.
      • Gromark C.
      • Hesselmark E.
      • Lichtenstein P.
      • et al.
      Association of Primary Humoral Immunodeficiencies With Psychiatric Disorders and Suicidal Behavior and the Role of Autoimmune Diseases.
      ).

      Statistical analysis

      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 InfectionsEarly Childhood Infections
      Unexposed (n= 2 932 337)Exposed (n= 16 743)Unexposed (n= 2 684 734)Exposed (n= 264 346)
      Male offspring1 506 849 (51.4)8 564 (51.1)1 365 396 (50.9)150 017 (56.8)
      Distribution of years of birth
      1973-19831 014 282 (34.6)5 218 (31.2)968 397 (36.1)51 103 (19.3)
      1984-19931 042 900 (35.6)5 162 (30.8)918 494 (34.2)129 568 (49.0)
      1994-2003875 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 ± 5.1227.00 ± 5.5728.02 ± 5.1227.99 ± 5.19
      Mean age of fathers at birth of index offspring, years ± s.d.30.87 ± 5.9830.17 ± 6.5430.87 ± 5.9830.85 ± 6.07
      Lifetime maternal autoimmune diseases270 348 (9.2)2 353 (14.1)245 011 (8.8)27 690 (10.5)
      Lifetime paternal autoimmune diseases214 265 (7.3)1 355 (8.1)196 049 (7.3)15 571 (5.9)
      Maternal psychiatric history73 740 (2.5)1 237 (7.4)64 270 (2.4)10 707 (4.1)
      Paternal psychiatric history71 506 (2.4)779 (4.7)63 318 (2.4)8 967 (3.4)
      Abbreviation: s.d., standard deviation.

      Exposure to prenatal maternal infections

      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 thumbnail gr1
      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.
      Exposed Cohort n (%)Unexposed Cohort n (%)Model 11 HR (95% CI)Model 22 HR (95% CI)Model 33 HR (95% CI)
      Risk of OCD
      Prenatal maternal infections
      Any infection4135 (0.79)18 893 (0.64)1.34 (1.13-1.59)1.26 (1.06-1.50)1.33 (1.12-1.57)
      Viral infections49 (0.87)18 839 (0.64)1.33 (1.00-1.76)1.24 (0.93-1.64)1.31 (0.99-1.74)
      Bacterial infections83 (0.74)18 805 (0.64)1.33 (1.07-1.65)1.26 (1.02-1.57)1.32 (1.06-1.64)
      Prenatal paternal infections
      Any infection444 (0.61)18 844 (0.64)0.97 (0.72-1.31)0.92 (0.68-1.23)0.97 (0.72-1.30)
      Viral infections13 (0.50)18 875 (0.64)0.80 (0.46-1.38)0.73 (0.43-1.26)0.80 (0.46-1.37)
      Bacterial infections27 (0.66)18 861 (0.64)1.04 (0.72-1.52)1.01 (0.69-1.47)1.04 (0.71-1.52)
      Early childhood infections
      Any infection41 983 (0.75)16 905 (0.63)1.19 (1.14-1.25)1.17 (1.12-1.23)1.19 (1.14-1.25)
      Viral infections1 184 (0.79)17 704 (0.63)1.24 (1.17-1.32)1.21 (1.14-1.28)1.24 (1.17-1.31)
      Bacterial infections614 (0.77)18 274 (0.63)1.22 (1.13-1.33)1.20 (1.11-1.31)1.22 (1.13-1.32)
      Risk of TS/CTD
      Prenatal maternal infections
      Any infection456 (0.33)5 423 (0.18)1.64 (1.26-2.13)1.49 (1.15-1.94)1.60 (1.23-2.09)
      Viral infections12 (0.21)5 467 (0.19)1.13 (0.64-2.00)1.00 (0.57-1.77)1.10 (0.62-1.94)
      Bacterial infections40 (0.36)5 439 (0.18)1.74 (1.27-2.37)1.59 (1.17-2.18)1.71 (1.25-2.33)
      Prenatal paternal infections
      Any infection416 (0.22)5 463 (0.19)1.07 (0.66-1.75)0.96 (0.59-1.57)1.05 (0.64-1.72)
      Viral infections6 (0.23)5 473 (0.19)1.12 (0.50-2.50)0.94 (0.42-2.09)1.10 (0.49-2.45)
      Bacterial infections9 (0.22)5 470 (0.19)1.10 (0.57-2.11)1.03 (0.53-1.97)1.08 (0.56-2.08)
      Early childhood infections
      Any infection4748 (0.28)4 730 (0.18)1.35 (1.25-1.45)1.31 (1.21-1.42)1.34 (1.24-1.44)
      Viral infections433 (0.29)5 046 (0.18)1.38 (1.25-1.52)1.33 (1.20-1.47)1.36 (1.24-1.51)
      Bacterial infections223 (0.28)5 256 (0.18)1.35 (1.18-1.54)1.32 (1.16-1.51)1.34 (1.17-1.53)
      Abbreviations: CI, confidence interval; HR, hazard ratio; OCD, obsessive-compulsive disorder; TS/CTD, Tourette syndrome or chronic tic disorder.
      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).

      Exposure to prenatal paternal infections

      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 thumbnail gr2
      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).
      Table 3Risk of OCD and TS/CTD in Offspring Exposed vs Unexposed to Prenatal Maternal or Early Childhood Infections in the Sibling Cohort.
      Prenatal Maternal InfectionsEarly Childhood Infections
      No. (%)HR (95% CI),

      Adjusted for offspring’s year of birth and sex
      No. (%)HR (95% CI),

      Adjusted for offspring’s year of birth and sex
      Exposed (n= 10 720)Unexposed (n=16 234)Exposed (n=178 715)Unexposed (n=242 119)
      OCD84 (0.78)117 (0.72)0.92 (0.65-1.30)1,241 (0.69)1,772 (0.73)0.93 (0.85-1.01)
      TS/CTD32 (0.30)36 (0.22)1.35 (0.77-2.37)432 (0.24)507 (0.21)0.97 (0.83-1.13)
      CI, confidence interval; HR, hazard ratio; OCD, obsessive-compulsive disorder; TS/CTD, Tourette syndrome or chronic tic disorder.

      DISCUSSION

      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%) (
      • Jiang H.Y.
      • Xu L.L.
      • Shao L.
      • Xia R.M.
      • Yu Z.H.
      • Ling Z.X.
      • et al.
      Maternal infection during pregnancy and risk of autism spectrum disorders: A systematic review and meta-analysis.
      ), ADHD (29%-51%) (
      • Mann J.R.
      • McDermott S.
      Are maternal genitourinary infection and pre-eclampsia associated with ADHD in school-aged children?.
      ,
      • Silva D.
      • Colvin L.
      • Hagemann E.
      • Bower C.
      Environmental risk factors by gender associated with attention-deficit/hyperactivity disorder.
      ), and psychotic disorders (80%) (
      • Lee Y.H.
      • Cherkerzian S.
      • Seidman L.J.
      • Papandonatos G.D.
      • Savitz D.A.
      • Tsuang M.T.
      • et al.
      Maternal Bacterial Infection During Pregnancy and Offspring Risk of Psychotic Disorders: Variation by Severity of Infection and Offspring Sex.
      ). 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 (
      • Lydholm C.N.
      • Köhler-Forsberg O.
      • Nordentoft M.
      • Yolken R.H.
      • Mortensen P.B.
      • Petersen L.
      • et al.
      Parental Infections Before, During, and After Pregnancy as Risk Factors for Mental Disorders in Childhood and Adolescence: A Nationwide Danish Study.
      ). 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 (
      • Knuesel I.
      • Chicha L.
      • Britschgi M.
      • Schobel S.A.
      • Bodmer M.
      • Hellings J.A.
      • et al.
      Maternal immune activation and abnormal brain development across CNS disorders.
      ). However, alternative explanations are possible, such as genetic maternal effects (
      • Mahjani B.
      • Klei L.
      • Hultman C.M.
      • Larsson H.
      • Devlin B.
      • Buxbaum J.D.
      • et al.
      Maternal Effects as Causes of Risk for Obsessive-Compulsive Disorder.
      ).
      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 (
      • Shaikh N.
      • Leonard E.
      • Martin J.M.
      Prevalence of streptococcal pharyngitis and streptococcal carriage in children: a meta-analysis.
      ). 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 (
      • Mahjani B.
      • Klei L.
      • Hultman C.M.
      • Larsson H.
      • Devlin B.
      • Buxbaum J.D.
      • et al.
      Maternal Effects as Causes of Risk for Obsessive-Compulsive Disorder.
      ). Moreover, a familial link between OCD, TS/CTD, pediatric acute-onset neuropsychiatric syndrome (PANS), and autoimmune diseases has been well documented (
      • Mataix-Cols D.
      • Frans E.
      • Pérez-Vigil A.
      • Kuja-Halkola R.
      • Gromark C.
      • Isomura K.
      • et al.
      A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette's/chronic tic disorders.
      ,
      • Gromark C.
      • Harris R.A.
      • Wickström R.
      • Horne A.
      • Silverberg-Mörse M.
      • Serlachius E.
      • et al.
      Establishing a Pediatric Acute-Onset Neuropsychiatric Syndrome Clinic: Baseline Clinical Features of the Pediatric Acute-Onset Neuropsychiatric Syndrome Cohort at Karolinska Institutet.
      ). Genetic correlations with immune-related phenotypes have been suggested for both OCD (
      • Teixeira A.L.
      • Rodrigues D.H.
      • Marques A.H.
      • Miguel E.C.
      • Fontenelle L.F.
      Searching for the immune basis of obsessive-compulsive disorder.
      ,
      • Rodriguez N.
      • Morer A.
      • González-Navarro E.A.
      • Gassó P.
      • Boloc D.
      • Serra-Pagès C.
      • et al.
      Human-leukocyte antigen class II genes in early-onset obsessive-compulsive disorder.
      ) and TS/CTD (
      • Tsetsos F.
      • Yu D.
      • Sul J.H.
      • Huang A.Y.
      • Illmann C.
      • Osiecki L.
      • et al.
      Synaptic processes and immune-related pathways implicated in Tourette syndrome.
      ,
      • Tylee D.S.
      • Sun J.
      • Hess J.L.
      • Tahir M.A.
      • Sharma E.
      • Malik R.
      • et al.
      Genetic correlations among psychiatric and immune-related phenotypes based on genome-wide association data.
      ,
      • Keszler G.
      • Kruk E.
      • Kenezloi E.
      • Tarnok Z.
      • Sasvari-Szekely M.
      • Nemoda Z.
      Association of the tumor necrosis factor -308 A/G promoter polymorphism with Tourette syndrome.
      ), 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 (
      • Martino D.
      • Johnson I.
      • Leckman J.F.
      What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders?.
      ,
      • Isung J.
      • Williams K.
      • Isomura K.
      • Gromark C.
      • Hesselmark E.
      • Lichtenstein P.
      • et al.
      Association of Primary Humoral Immunodeficiencies With Psychiatric Disorders and Suicidal Behavior and the Role of Autoimmune Diseases.
      ,
      • Isung J.
      • Isomura K.
      • Almqvist C.
      • Lichtenstein P.
      • Larsson H.
      • Wester T.
      • et al.
      Association of chronic and acute inflammation of the mucosa-associated lymphoid tissue with psychiatric disorders and suicidal behavior.
      ). 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 (
      • Estes M.L.
      • McAllister A.K.
      Maternal immune activation: Implications for neuropsychiatric disorders.
      ,
      • Meyer U.
      Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems.
      ). 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. (
      • Fasching L.
      • Jang Y.
      • Tomasi S.
      • Schreiner J.
      • Tomasini L.
      • Brady M.V.
      • et al.
      Early developmental asymmetries in cell lineage trees in living individuals.
      )

      Strengths and limitations

      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 (
      • Rück C.
      • Larsson K.J.
      • Lind K.
      • Perez-Vigil A.
      • Isomura K.
      • Sariaslan A.
      • et al.
      Validity and reliability of chronic tic disorder and obsessive-compulsive disorder diagnoses in the Swedish National Patient Register.
      ); 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 (
      • Sjölander A.
      • Frisell T.
      • Kuja-Halkola R.
      • Öberg S.
      • Zetterqvist J.
      Carryover Effects in Sibling Comparison Designs.
      ). 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 (
      • Sjölander A.
      • Frisell T.
      • Kuja-Halkola R.
      • Öberg S.
      • Zetterqvist J.
      Carryover Effects in Sibling Comparison Designs.
      ). 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.

      Supplementary Material

      References

        • Martino D.
        • Johnson I.
        • Leckman J.F.
        What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders?.
        Front Neurol. 2020; 11567407
        • Pérez-Vigil A.
        • Fernández de la Cruz L.
        • Brander G.
        • Isomura K.
        • Gromark C.
        • Mataix-Cols D.
        The link between autoimmune diseases and obsessive-compulsive and tic disorders: A systematic review.
        Neurosci Biobehav Rev. 2016; 71: 542-562
        • Swedo S.E.
        • Leonard H.L.
        • Garvey M.
        • Mittleman B.
        • Allen A.J.
        • Perlmutter S.
        • et al.
        Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases.
        Am J Psychiatry. 1998; 155: 264-271
        • Martino D.
        • Schrag A.
        • Anastasiou Z.
        • Apter A.
        • Benaroya-Milstein N.
        • Buttiglione M.
        • et al.
        Association of Group A Streptococcus Exposure and Exacerbations of Chronic Tic Disorders.
        Neurology. 2021; 96: e1680-e1693
        • Singer H.S.
        • Gause C.
        • Morris C.
        • Lopez P.
        • Tourette Syndrome Study Group
        Serial immune markers do not correlate with clinical exacerbations in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.
        Pediatrics. 2008; 121: 1198-1205
        • Kurlan R.
        • Johnson D.
        • Kaplan E.L.
        • Tourette Syndrome Study Group
        Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: a prospective blinded cohort study.
        Pediatrics. 2008; 121: 1188-1197
        • Leckman J.F.
        • King R.A.
        • Gilbert D.L.
        • Coffey B.J.
        • Singer H.S.
        • Dure L.S.
        • et al.
        Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study.
        J Am Acad Child Adolesc Psychiatry. 2011; 50 (e3): 108-118
        • Luo F.
        • Leckman J.F.
        • Katsovich L.
        • Findley D.
        • Grantz H.
        • Tucker D.M.
        • et al.
        Prospective longitudinal study of children with tic disorders and/or obsessive-compulsive disorder: relationship of symptom exacerbations to newly acquired streptococcal infections.
        Pediatrics. 2004; 113: e578-e585
        • Martino D.
        • Chiarotti F.
        • Buttiglione M.
        • Cardona F.
        • Creti R.
        • Nardocci N.
        • et al.
        The relationship between group A streptococcal infections and Tourette syndrome: a study on a large service-based cohort.
        Dev Med Child Neurol. 2011; 53: 951-957
        • Schrag A.E.
        • Martino D.
        • Wang H.
        • Ambler G.
        • Benaroya-Milshtein N.
        • Buttiglione M.
        • et al.
        Lack of Association of Group A Streptococcal Infections and Onset of Tics: European Multicenter Tics in Children Study.
        Neurology. 2022; 98: e1175-e1183
        • Köhler-Forsberg O.
        • Petersen L.
        • Gasse C.
        • Mortensen P.B.
        • Dalsgaard S.
        • Yolken R.H.
        • et al.
        A Nationwide Study in Denmark of the Association Between Treated Infections and the Subsequent Risk of Treated Mental Disorders in Children and Adolescents.
        JAMA Psychiatry. 2019; 76: 271-279
        • Orlovska S.
        • Vestergaard C.H.
        • Bech B.H.
        • Nordentoft M.
        • Vestergaard M.
        • Benros M.E.
        Association of Streptococcal Throat Infection With Mental Disorders: Testing Key Aspects of the PANDAS Hypothesis in a Nationwide Study.
        JAMA Psychiatry. 2017; 74: 740-746
        • Wang H.C.
        • Lau C.I.
        • Lin C.C.
        • Chang A.
        • Kao C.H.
        Group A Streptococcal Infections Are Associated With Increased Risk of Pediatric Neuropsychiatric Disorders: A Taiwanese Population-Based Cohort Study.
        J Clin Psychiatry. 2016; 77: e848-e854
        • Nusslock R.
        • Miller G.E.
        Early-Life Adversity and Physical and Emotional Health Across the Lifespan: A Neuroimmune Network Hypothesis.
        Biol Psychiatry. 2016; 80: 23-32
        • Miller A.H.
        • Raison C.L.
        The role of inflammation in depression: from evolutionary imperative to modern treatment target.
        Nat Rev Immunol. 2016; 16: 22-34
        • Bilbo S.D.
        • Schwarz J.M.
        Early-life programming of later-life brain and behavior: a critical role for the immune system.
        Front Behav Neurosci. 2009; 3: 14
        • Estes M.L.
        • McAllister A.K.
        Maternal immune activation: Implications for neuropsychiatric disorders.
        Science. 2016; 353: 772-777
        • Han V.X.
        • Patel S.
        • Jones H.F.
        • Nielsen T.C.
        • Mohammad S.S.
        • Hofer M.J.
        • et al.
        Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review.
        Transl Psychiatry. 2021; 11: 71
        • Han V.X.
        • Patel S.
        • Jones H.F.
        • Dale R.C.
        Maternal immune activation and neuroinflammation in human neurodevelopmental disorders.
        Nat Rev Neurol. 2021; 17: 564-579
        • Jain S.
        • Baer R.J.
        • McCulloch C.E.
        • Rogers E.
        • Rand L.
        • Jelliffe-Pawlowski L.
        • et al.
        Association of Maternal Immune Activation during Pregnancy and Neurologic Outcomes in Offspring.
        J Pediatr. 2021; 238: 87-93.e3
        • Tioleco N.
        • Silberman A.E.
        • Stratigos K.
        • Banerjee-Basu S.
        • Spann M.N.
        • Whitaker A.H.
        • et al.
        Prenatal maternal infection and risk for autism in offspring: A meta-analysis.
        Autism Res. 2021; 14: 1296-1316
        • Mann J.R.
        • McDermott S.
        Are maternal genitourinary infection and pre-eclampsia associated with ADHD in school-aged children?.
        J Atten Disord. 2011; 15: 667-673
        • Silva D.
        • Colvin L.
        • Hagemann E.
        • Bower C.
        Environmental risk factors by gender associated with attention-deficit/hyperactivity disorder.
        Pediatrics. 2014; 133: e14-22
        • Al-Haddad B.J.S.
        • Jacobsson B.
        • Chabra S.
        • Modzelewska D.
        • Olson E.M.
        • Bernier R.
        • et al.
        Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero.
        JAMA Psychiatry. 2019; 76: 594-602
        • Lee Y.H.
        • Cherkerzian S.
        • Seidman L.J.
        • Papandonatos G.D.
        • Savitz D.A.
        • Tsuang M.T.
        • et al.
        Maternal Bacterial Infection During Pregnancy and Offspring Risk of Psychotic Disorders: Variation by Severity of Infection and Offspring Sex.
        Am J Psychiatry. 2020; 177: 66-75
        • Benros M.E.
        • Nielsen P.R.
        • Nordentoft M.
        • Eaton W.W.
        • Dalton S.O.
        • Mortensen P.B.
        Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study.
        Am J Psychiatry. 2011; 168: 1303-1310
        • Buka S.L.
        • Tsuang M.T.
        • Torrey E.F.
        • Klebanoff M.A.
        • Bernstein D.
        • Yolken R.H.
        Maternal infections and subsequent psychosis among offspring.
        Arch Gen Psychiatry. 2001; 58: 1032-1037
        • Mataix-Cols D.
        • Frans E.
        • Pérez-Vigil A.
        • Kuja-Halkola R.
        • Gromark C.
        • Isomura K.
        • et al.
        A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette's/chronic tic disorders.
        Mol Psychiatry. 2018; 23: 1652-1658
        • Jones H.F.
        • Ho A.C.C.
        • Sharma S.
        • Mohammad S.S.
        • Kothur K.
        • Patel S.
        • et al.
        Maternal thyroid autoimmunity associated with acute-onset neuropsychiatric disorders and global regression in offspring.
        Dev Med Child Neurol. 2019; 61: 984-988
        • Jones H.F.
        • Han V.X.
        • Patel S.
        • Gloss B.S.
        • Soler N.
        • Ho A.
        • et al.
        Maternal autoimmunity and inflammation are associated with childhood tics and obsessive-compulsive disorder: Transcriptomic data show common enriched innate immune pathways.
        Brain Behav Immun. 2021; 94: 308-317
        • Dalsgaard S.
        • Waltoft B.L.
        • Leckman J.F.
        • Mortensen P.B.
        Maternal history of autoimmune disease and later development of tourette syndrome in offspring.
        J Am Acad Child Adolesc Psychiatry. 2015; 54 (e1): 495-501
        • Ludvigsson J.F.
        • Otterblad-Olausson P.
        • Pettersson B.U.
        • Ekbom A.
        The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research.
        Eur J Epidemiol. 2009; 24: 659-667
        • Axelsson O.
        The Swedish medical birth register.
        Acta Obstet Gynecol Scand. 2003; 82: 491-492
        • Ludvigsson J.F.
        • Andersson E.
        • Ekbom A.
        • Feychting M.
        • Kim J.L.
        • Reuterwall C.
        • et al.
        External review and validation of the Swedish national inpatient register.
        BMC Public Health. 2011; 11: 450
        • Ludvigsson J.F.
        • Almqvist C.
        • Bonamy A.K.
        • Ljung R.
        • Michaelsson K.
        • Neovius M.
        • et al.
        Registers of the Swedish total population and their use in medical research.
        Eur J Epidemiol. 2016; 31: 125-136
        • Brooke H.L.
        • Talback M.
        • Hornblad J.
        • Johansson L.A.
        • Ludvigsson J.F.
        • Druid H.
        • et al.
        The Swedish cause of death register.
        Eur J Epidemiol. 2017; 32: 765-773
        • Ekbom A.
        The Swedish Multi-generation Register.
        Methods Mol Biol. 2011; 675: 215-220
        • Rück C.
        • Larsson K.J.
        • Lind K.
        • Perez-Vigil A.
        • Isomura K.
        • Sariaslan A.
        • et al.
        Validity and reliability of chronic tic disorder and obsessive-compulsive disorder diagnoses in the Swedish National Patient Register.
        BMJ Open. 2015; 5e007520
        • Isung J.
        • Williams K.
        • Isomura K.
        • Gromark C.
        • Hesselmark E.
        • Lichtenstein P.
        • et al.
        Association of Primary Humoral Immunodeficiencies With Psychiatric Disorders and Suicidal Behavior and the Role of Autoimmune Diseases.
        JAMA Psychiatry. 2020; 77: 1147-1154
        • Jiang H.Y.
        • Xu L.L.
        • Shao L.
        • Xia R.M.
        • Yu Z.H.
        • Ling Z.X.
        • et al.
        Maternal infection during pregnancy and risk of autism spectrum disorders: A systematic review and meta-analysis.
        Brain Behav Immun. 2016; 58: 165-172
        • Lydholm C.N.
        • Köhler-Forsberg O.
        • Nordentoft M.
        • Yolken R.H.
        • Mortensen P.B.
        • Petersen L.
        • et al.
        Parental Infections Before, During, and After Pregnancy as Risk Factors for Mental Disorders in Childhood and Adolescence: A Nationwide Danish Study.
        Biol Psychiatry. 2019; 85: 317-325
        • Knuesel I.
        • Chicha L.
        • Britschgi M.
        • Schobel S.A.
        • Bodmer M.
        • Hellings J.A.
        • et al.
        Maternal immune activation and abnormal brain development across CNS disorders.
        Nat Rev Neurol. 2014; 10: 643-660
        • Mahjani B.
        • Klei L.
        • Hultman C.M.
        • Larsson H.
        • Devlin B.
        • Buxbaum J.D.
        • et al.
        Maternal Effects as Causes of Risk for Obsessive-Compulsive Disorder.
        Biol Psychiatry. 2020; 87: 1045-1051
        • Shaikh N.
        • Leonard E.
        • Martin J.M.
        Prevalence of streptococcal pharyngitis and streptococcal carriage in children: a meta-analysis.
        Pediatric. 2010; 126: e557-e564
        • Gromark C.
        • Harris R.A.
        • Wickström R.
        • Horne A.
        • Silverberg-Mörse M.
        • Serlachius E.
        • et al.
        Establishing a Pediatric Acute-Onset Neuropsychiatric Syndrome Clinic: Baseline Clinical Features of the Pediatric Acute-Onset Neuropsychiatric Syndrome Cohort at Karolinska Institutet.
        J Child Adolesc Psychopharmacol. 2019; 29: 625-633
        • Teixeira A.L.
        • Rodrigues D.H.
        • Marques A.H.
        • Miguel E.C.
        • Fontenelle L.F.
        Searching for the immune basis of obsessive-compulsive disorder.
        Neuroimmunomodulation. 2014; 21: 152-158
        • Rodriguez N.
        • Morer A.
        • González-Navarro E.A.
        • Gassó P.
        • Boloc D.
        • Serra-Pagès C.
        • et al.
        Human-leukocyte antigen class II genes in early-onset obsessive-compulsive disorder.
        World J Biol Psychiatry. 2019; 20: 352-358
        • Tsetsos F.
        • Yu D.
        • Sul J.H.
        • Huang A.Y.
        • Illmann C.
        • Osiecki L.
        • et al.
        Synaptic processes and immune-related pathways implicated in Tourette syndrome.
        Transl Psychiatry. 2021; 11: 56
        • Tylee D.S.
        • Sun J.
        • Hess J.L.
        • Tahir M.A.
        • Sharma E.
        • Malik R.
        • et al.
        Genetic correlations among psychiatric and immune-related phenotypes based on genome-wide association data.
        Am J Med Genet B Neuropsychiatr Genet. 2018; 177: 641-657
        • Keszler G.
        • Kruk E.
        • Kenezloi E.
        • Tarnok Z.
        • Sasvari-Szekely M.
        • Nemoda Z.
        Association of the tumor necrosis factor -308 A/G promoter polymorphism with Tourette syndrome.
        Int J Immunogenet. 2014; 41: 493-498
        • Isung J.
        • Isomura K.
        • Almqvist C.
        • Lichtenstein P.
        • Larsson H.
        • Wester T.
        • et al.
        Association of chronic and acute inflammation of the mucosa-associated lymphoid tissue with psychiatric disorders and suicidal behavior.
        Transl Psychiatry. 2019; 9: 227
        • Meyer U.
        Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems.
        Biol Psychiatry. 2014; 75: 307-315
        • Fasching L.
        • Jang Y.
        • Tomasi S.
        • Schreiner J.
        • Tomasini L.
        • Brady M.V.
        • et al.
        Early developmental asymmetries in cell lineage trees in living individuals.
        Science. 2021; 371: 1245-1248
        • Sjölander A.
        • Frisell T.
        • Kuja-Halkola R.
        • Öberg S.
        • Zetterqvist J.
        Carryover Effects in Sibling Comparison Designs.
        Epidemiology. 2016; 27: 852-858