Increased Risk for Neurodevelopmental Disorders in Children With Orofacial Clefts

Accepted Manuscript Increased Risk for Neurodevelopmental Disorders in Children With Orofacial Clefts Karin K. Tillman, MD, Malin Hakelius, MD, PhD, Jonas Höijer, MSc, Mia Ramklint, MD, PhD, Lisa Ekselius, MD, PhD, Daniel Nowinski, MD, PhD, Fotios C. Papadopoulos, MD, PhD PII:

S0890-8567(18)31334-0

DOI:

10.1016/j.jaac.2018.06.024

Reference:

JAAC 2323

To appear in:

Journal of the American Academy of Child & Adolescent Psychiatry

Received Date: 15 March 2018 Revised Date:

31 May 2018

Accepted Date: 7 June 2018

Please cite this article as: Tillman KK, Hakelius M, Höijer J, Ramklint M, Ekselius L, Nowinski D, Papadopoulos FC, Increased Risk for Neurodevelopmental Disorders in Children With Orofacial Clefts, Journal of the American Academy of Child & Adolescent Psychiatry (2018), doi: https://doi.org/10.1016/ j.jaac.2018.06.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Increased Risk for Neurodevelopmental Disorders in Children With Orofacial Clefts RH = Orofacial Clefts and Mental Disorders Karin K. Tillman, MD, Malin Hakelius, MD, PhD, Jonas Höijer, MSc, Mia Ramklint, MD, PhD, Lisa Ekselius, MD, PhD, Daniel Nowinski, MD, PhD, Fotios C. Papadopoulos, MD, PhD

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Editorial Clinical Guidance Supplemental Material CME

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Accepted June 22, 2018

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Drs. Tillman, Hakelius, Ramklint, Ekselius, Nowinski, and Papadopoulos are with Uppsala University, Sweden. Mr. Höijer is with the Institute of Environmental Medicine, Karolinska Institutet, Solna, Sweden. This study was financially supported by Medical Training and Research Agreement Funds (ALF) from Uppsala University Hospital. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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This study was presented as a poster at the American Academy of Child and Adolescent Psychiatry’s 65th Annual Meeting; Seattle, WA; October 22-27, 2018, and as an abstract at the European Psychiatric Association’s Annual Meeting, Nice, France, March 3-6, 2018. Jonas Höijer served as the statistical expert for this research.

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The authors wish to thank Clinical Genetician Eva-Lena Stattin, MD, PhD, of the Uppsala University Hospital, for assistance and genetic advice for this study.

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Disclosure: Drs. Tillman, Hakelius, Ramklint, Ekselius, Nowinski, Papadopoulos and Mr. Höijer report no biomedical financial interests or potential conflicts of interest. Correspondence to Karin Tillman, MD, Uppsala University, Child and Adolescent Psychiatry, Department of Neuroscience, Uppsala University Hospital, entrance 10, Uppsala, 75185, Sweden; e-mail: [email protected]

ACCEPTED MANUSCRIPT Abstract Objectives: Children with orofacial clefts (OFC) may have an increased risk of poor mental health. This study aimed to investigate the risk of psychiatric diagnoses in individuals with OFC, stratified by cleft type.

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Method: A nationwide register-based cohort of all individuals born with non-

syndromic OFC in Sweden between 1973 and 2012 (n=7842) was compared to a matched cohort (n=78409) as well as to their unaffected siblings. The risk of

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psychiatric diagnoses, suicide attempts and suicides was examined by crude and

interaction terms in the models.

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adjusted Cox regression models. Effect modification by sex was investigated with

Results: Children with cleft lip (CL) had a significant higher risk for any psychiatric disorder, intellectual disability and language disorders, children with cleft lip and palate (CLP) had additionally an increased risk for Autism Spectrum Disorder (ASD).

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Children with cleft palate only (CPO) presented risk increases for the same diagnoses as children with CL and CLP, but with higher hazard ratios, and additionally for psychotic disorders, attention-deficit/hyperactivity disorder (ADHD) and other

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behavioral or emotional disorders in childhood. Sex stratification indicated higher risk

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increases among females in CL and CLP but not in CPO. Siblings without OFC were less likely to be diagnosed with any psychiatric disorder, intellectual disability, language disorder, ASD and ADHD compared to their siblings with OFC. Conclusion: Children with non-syndromic clefts had a significantly higher risk of neurodevelopmental disorders and this risk is unlikely to be explained by familial influences such as inherited genetic or shared environmental factors.

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ACCEPTED MANUSCRIPT Introduction

Orofacial clefts (OFC) are one of the most common congenital malformations.1 OFC arise in about 1 per 500 live born babies in Sweden2. The OFC are on an anatomically

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basis grossly divided into three different subtypes of clefts; cleft lip (CL), cleft lip and palate (CLP) and cleft palate only (CPO) where CPO is pathophysiologically regarded as a separate condition in relation to CLP and CL. Approximately 30% of OFC are

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associated with a known genetic syndrome (syndromic OFC), but the remaining 70% of clefts occur without a known syndrome identified (non-syndromic OFC)3,4. More

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than 300 cleft related syndromes have been described and CPO is more likely to be syndromic than CL and CLP. OFC occur at gestational week 5 to 8 when the neural crest cells differentiate from the neural tube and migrate to the facial region. Inheritance may be chromosomal, sporadic or related to environmental teratogens 5,6.

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Known maternal risk factors include smoking7,8, alcohol consumption8, diabetes, nutritional factors (e.g. vitamin A, folic acid insufficiency) and anticonvulsant

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medication9.

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Depending on the cleft type different concerns for the child may arise. Children with OFC need multidisciplinary care from birth to adulthood, including staged surgical treatment as well as monitoring of the various cleft associated symptoms and features such as difficulties with feeding, hearing, dento-facial growth, speech and appearance. Multidisciplinary care for OFC with long-term follow-up until the age of 19 was established in Sweden during in the 1960s and is today conducted through 6 regional cleft lip and palate centers. Surgical protocols have gradually evolved over time and with some variations in surgical techniques between centers. The longitudinal

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ACCEPTED MANUSCRIPT assessments of facial growth and speech are today to large extent harmonized nationally through the network Swedecleft. All Swedish children are monitored at the primary care level for general growth, hearing, vision, and development according to

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national guidelines.

Another area of concern is cognitive development and language skills. Cognitive dysfunction in children with OFC has been documented over time10. Also non-

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syndromic clefts have been found to be associated with poor academic achievement, a lower verbal IQ and deficits in rapid verbal labeling, verbal fluency and short term

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memory11. Among children with non-syndromic OFC the prevalence of learning disabilities, particularly specific reading disorders, has been estimated to be between 30% and 46%12,13. Less attention has been placed on executive functioning skills (attention, organization, monitoring, planning and initiation) or psychiatric disorders

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and most previous studies have been based on small samples in a clinical setting, with only few of them distinguishing between the cleft subtypes. Earlier research has found different patterns of deficits for patients with CL, CLP and CPO with more severe

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disabilities reported in the CPO group. Children with CLP have shown more deficits in verbal expressive skills while children with CPO have demonstrated poorer

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associative and expressive language skills14. Recent work suggests that frontal and prefrontal function may be impaired in many children with clefts, recommending further examination of executive functions during follow-up15.

Danish adults born with OFC have been reported to have an increased risk for inpatient treatment for psychiatric disorders16, as well as increased all-cause mortality and suicide17. A recent extension of this Danish study where outpatient visits and

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ACCEPTED MANUSCRIPT emergency room visits were also included and a differentiation between the different types of clefts were made, pointed out a significantly increased risk for psychiatric disorders among individuals with non-syndromic OFC compared to controls18. Recently a large Swedish population-based study showed that CL and CPO increase

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the risk for psychotropic drug use in adolescence, however, there was no distinction

made between the different groups of psychotropic drugs or psychiatric indications19. The majority of previous studies are small, underpowered, clinically based and

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focusing on psychological symptoms rather than psychiatric disorders as a medical

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diagnosis.

The aim of this study was to test the hypothesis that patients with non-syndromic OFC have an increased risk for a psychiatric diagnosis later in life. As a secondary aim, we wanted to explore if such an increased risk can be explained by familial

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influences such as inherited genetic or shared environmental factors by studying

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psychiatric outcomes among the unaffected full siblings of the children with OFC.

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ACCEPTED MANUSCRIPT Methods Data sources Data were obtained from the National Board of Health and Welfare in Sweden and Statistics Sweden. All registers use the ten-digit National Registration Number

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(NRN), a unique personal identifier assigned to all Swedish residents, which allows linkage studies. In the data we received, identification numbers were replaced with

arbitrary numbers, thereby securing anonymity. The following registers were used:

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the Swedish Medical Birth Register (MBR), the National Patient Register (NPR), the Swedish Cause-of death register, the Register of Total Population (RTP), the Multi-

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Generation Register (MGR), the Migration Register, the Census of the population and housing, and the longitudinal integration database for health insurance and labor market studies (LISA).

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The MBR has information on more than 99% of all births in Sweden since 1973, concerning pregnancy, delivery, and the neonatal period. Information is collected from medical records from the prenatal, delivery and neonatal care and includes data

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such as mother diagnoses before and during pregnancy, tobacco use, alcohol use,

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medical drug use, mode of delivery, analgesia and anaesthesia, birth weight, body length, head circumference, duration of pregnancy, Apgar score and infant diagnoses.20

The NPR has nearly complete nationwide coverage for discharge diagnoses in both somatic and psychiatric settings in Sweden based on the International Classification of Diseases (ICD). It has full coverage of all inpatient care in Sweden since 1987. Each record includes admission and discharge dates, the main discharge diagnosis and

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ACCEPTED MANUSCRIPT secondary diagnoses. Outpatient specialist visits including day surgery and psychiatric care from both private and public caregivers are included since 2001 and the coverage has increased from approximately 75% initially to 87% in 201121.

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The Swedish Cause-of Death Register includes all individuals who died either in Sweden or abroad since 1952 and who were registered in Sweden by the time of

death. The data are based on death certificates that provide information on date as

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well as underlying main and secondary causes of death using the International

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Classification of Diseases (ICD)22.

The Register of Total Population includes information about the country of birth.

Data available from the Swedish Multi-Generation Register allow for linkage of

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individuals born in 1932 and later to parents, siblings, and offspring. Only pregnancies leading to live births can be identified in the Swedish Multi-Generation

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Register. 23

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The Uppsala Ethics Committee approved the study (Reg. No. 2012/363).

Participants

We identified through MBR and NPR 7900 children born in Sweden between January 1, 1973 and December 31, 2012, who received the diagnosis of OFC at birth or prior to 5 years of age.

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ACCEPTED MANUSCRIPT Two comparison groups were used: (i) 10 individuals without diagnosis for OFC malformation from the general population, matched according to the month and year of birth, sex and county of birth, and (ii) all unaffected siblings of the OFC patients with less than 20 years age difference, identified in the Multi Generation Register,

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enabling us to control for familial influences such as inherited genetic or shared environmental factors.

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We excluded 58 individuals without any identified matched individuals to compare

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with.

Comorbid diagnoses of any congenital malformations, deformations and chromosomal abnormalities (ICD 8 and 9 codes 740-759 and ICD-10 codes Q00-Q99, except for the facial cleft codes (749 in ICD-8 and 9 and Q35-Q37 in ICD-10)) were

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identified as syndromic indicators in both cases and comparison groups in order to adjust the analyses for possible non-identified syndromic OFC.

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All subjects were observed from their date of birth until outcome, emigration, death or

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end of the study on December 31, 2012 whichever occurred first.

Exposure

The exposure was a diagnosis of CL, CLP or CPO as indicated in the MBR or NPR by their International Classification of Diseases ICD-8, ICD-9 or ICD-10 diagnoses. The ICD-codes for CL were 749.10-749.13(ICD-8), 749B(ICD-9) and Q36 (ICD-10) and for CLP the codes were 749.20-749.24(ICD-8), 749C(ICD-9) and Q37 (ICD-10) and for CPO the codes were 749.00(ICD-8), 749A(ICD-9) and Q35 (ICD-10).

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ACCEPTED MANUSCRIPT Outcome measures Information on psychiatric diagnoses and suicide attempts was extracted from the NPR and suicides were extracted from the Swedish Cause of Death Register. We studied the following psychiatric diagnoses (see Table S1, available online, for the

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respective ICD-codes): any psychiatric disorder, intellectual disability (including

mental retardation in ICD-8), speech and language disorders, psychotic disorders, bipolar disorder, depression, autism spectrum disorder (ASD), attention-deficit

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hyperactivity disorder (ADHD), other behavioral/emotional disorders with onset in

childhood, neurotic, stress related or somatoform disorder, eating disorders, alcohol

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and substance use disorder, personality disorder, suicide attempt, suicide.

When analyzing the mean age at first diagnosis for each of the above psychiatric disorders, we noticed a clear discrepancy for the age at first diagnosis with an eating

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disorder, namely a mean age of 7.8 years among children with OFC and 14.5 years among the children without OFC. As the ICD-8 and ICD-9 codes for eating disorders were not specific, we considered those events as probable feeding difficulties early in

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life misclassified as eating disorders. Thereafter we restricted the diagnosis of eating

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disorder to those who received such a diagnosis at the age of 10 or older.

Covariates

We controlled the multivariate analyses for confounders and mediators such as perinatal complications and somatic indicators, year and season of birth, sex, congenital malformations or known genetic syndromes, parental psychiatric morbidity and sociodemographic factors among parents.

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ACCEPTED MANUSCRIPT Perinatal variables were collected from the MBR; Gestational age at birth was dichotomized into term birth (≥ 37 gestational weeks) or preterm birth (<37 gestational weeks). Small for gestational age was defined as less than -2 Standard Deviations (SD). Birth weight was defined as low if <2500g. Low Apgar score was

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defined as < 7 at 5 minutes after birth. A binary variable was created for gestational complications (preterm, small for gestational age [SGA], low Apgar and low birth weight) and was used in the models. Season of birth was categorized as winter

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(December to February), spring (March to May), summer (June to August) and

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autumn (September to November).

Sociodemographic variables and parental mental health variables were accessed through linkage via the MGR to the biological parents. Age of parents at the time of birth was identified and we used the mean age of the parents or the age of one parent

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if the other’s was missing for the multivariate analyses.

Data on maternal country of birth from the MBR were aggregated across regions:

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Sweden, other Nordic countries and Other Countries. Information on the educational

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level of parents was retrieved from the Education Register, the LISA database and the Census of the population and housing from the years 1985. Parental education was entered into the model as a categorical variable using five categories according to the Swedish Education Terminology: 0-9 years, 10-11 years, 12-14 years and >14 years (university). The highest level of education obtained by either of the parents was used in the analysis.

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ACCEPTED MANUSCRIPT Parental psychiatric morbidity was defined as having at least one psychiatric diagnosis (codes 290-315 in ICD-8, 290-319 in ICD-9 and F00-F98 in ICD-10) in the NPR, or a suicide attempt (codes E950-E959 in ICD-8 and ICD-9 and X60-X84 in ICD-10) in the NPR, or a death by suicide in the Cause of Death Register. This

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ordinal variable would take the value of 0 if none of the parents had psychiatric

morbidity, 1 if only one parent had psychiatric morbidity and 2 of both parents had

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psychiatric morbidity. The variable was treated as time varying in the analyses.

Statistical analysis

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The data were analyzed using the statistical software Stata v.13.24 Crude and adjusted Cox proportional hazard regression models were used with age as the underlying time scale to investigate hazard ratios and 95% confidence intervals (CI) for the outcomes. Since the controls and siblings cannot be considered as independent from the

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corresponding case, cluster robust variance-covariance estimation was used25. We compared the individuals with OFC with the matched comparison cohort with nonaffected individuals and with the sibling cohort. Additional analyses were stratified by

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cleft type. For the continuous covariates concerning parental age and year of birth, we

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used restricted cubic spline to avoid forcing the relationship to the outcomes to be linear.

In order to examine a possible moderating effect of sex, we estimated separate Cox models where an interaction term of sex and the exposure (OFC, CL, CLP, CPO) was included. From these models the p-value of the interaction term was calculated. However, some of these models were not possible to estimate because of too rare outcomes in one of the two sexes.

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ACCEPTED MANUSCRIPT Results Descriptive characteristics of the study population for the studied cohorts are demonstrated in Table S2, available online. A total of 7842 children with OFC and 78409 matched children without OFC were observed for 1654328 person-years.

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Among the children with OFC, 2526 (32%) were diagnosed with CL, 3048 (39%) with CLP and 3436 (43%) with CPO. Almost 20% of the children with OFC (CL

15.4%, CLP 19.1% and CPO 23.2%) received at least one diagnosis of a psychiatric

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disorder, compared to 11% of the children without OFC.

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More specifically, children with OFC were more likely to receive a diagnosis of any psychiatric disorder (aHR 1.63, 95% CI 1.53-1.73), intellectual disability (aHR 4.19, 95% CI 3.63-4.84), language disorder (aHR 4.89, 95% CI 4.08-5.87), ASD (aHR 1.96, 95% CI 1.65-2.33), psychotic disorder (aHR 1.62, 95% CI 1.15-2.29), ADHD

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(aHR 1.25, 95% CI 1.08-1.46), other behavioral and emotional disorders with onset in childhood (aHR 1.43, 95% CI 1.23-1.65) and personality disorders (aHR 1.35, 95%

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CI 1.00-1.82) (Figure 1,Tables S3-6, available online).

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Children with cleft lip (CL) had a significant higher risk for any psychiatric disorder, intellectual disability and language disorders. Children with cleft lip and palate (CLP) had additionally an increased risk for ASD. Children with cleft palate only (CPO) presented with higher hazard ratios, and additionally for psychotic disorders, ADHD and other behavioral or emotional disorders in childhood (Figure 1A-D, Tables S3-6). Interestingly, children born with CL presented with a risk decrease for depression (aHR 0.73, 95% CI 0.54-0.98).

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ACCEPTED MANUSCRIPT No significant risk increase was found among any of the stratified cleft types for suicide-attempts, death by suicide, affective disorders, neurotic or anxiety disorders, eating disorders, alcohol or psychoactive substance abuse and a modest but significant

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risk increase for personality disorders was only seen in the OFC analysis.

In the sex-specific analyses, we found within the OFC cohort, risk increases that were significantly higher among females than among males for any psychiatric disorder

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(interaction p-value=0.007), intellectual disability (interaction p-value=0.017),

language disorders (interaction p-value=0.023), ASD (interaction p-value=0.015), and

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other behavioral and emotional disorders with onset in childhood (interaction pvalue=0.005), whereas the sex difference was borderline significant for psychotic disorders (interaction p-value=0.089) and ADHD (interaction p-value=0.089) and not significant for personality disorder (interaction p-value=0.5) Our analyses also

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detected a borderline significant sex difference among individuals born with CL and the risk for depression, where mostly the males presented with a risk decrease for depression (aHR 0.54 95% CI 0.33-0.87, interaction p-value 0.081) (Figure 1, Table

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S3-6, available online). These sex differences with generally higher risk increases for

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females persisted in some of the analyses after stratification into the different cleft types, and most evidently among children born with CLP.

A total of 9637 full siblings to our individuals with OFC were studied in the sibling cohort. The unaffected full siblings without OFC were less likely to be diagnosed with any psychiatric disorder, intellectual disability, language disorders, ASD and ADHD, whereas no significant different risk pattern was observed for psychotic

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ACCEPTED MANUSCRIPT disorders, other behavioral disorders in childhood and personality disorders (Figure 1,

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Tables S7-10, available online).

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ACCEPTED MANUSCRIPT Discussion In this large Swedish nationwide register cohort study, we found a significant risk increase of being diagnosed with a psychiatric disorder, and specifically with intellectual disability, language disorders, ASD, ADHD, psychotic disorder, other

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behavioral and emotional disorders with onset in childhood and personality disorders, among children born with an OFC compared with children without an OFC. Our

sibling analyses confirmed decreased risks for any psychiatric disorder, intellectual

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disability, language disorders, ASD and ADHD among siblings without OFC,

suggesting that the associations with these diagnoses are unlikely to be explained by

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familial influences. There was no significant increase of suicide attempts or suicides and no increased risk of anxiety disorders, depression, bipolar disorder, eating disorders, alcohol or substance use disorders.

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When investigating the different subtypes of OFC the risk increases differed. The overall risk increase for psychiatric morbidity was highest among individuals with CPO and lowest among those with CL. Those findings remained significant when

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adjusted for sociodemographic, perinatal and somatic covariates. Our findings are in

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line with the results from a previous large population-based cohort study from Denmark where a higher risk of psychiatric disorders emerged among individuals with non-syndromic OFC and especially for CPO when stratifying for different cleft types. The Danish study also revealed a higher mortality in suicide, a finding that was not seen in our study18. Interestingly, our study revealed substantially higher risk increases for all neuropsychiatric diagnoses compared with the Danish study. A plausible explanation could be a higher detection rate of neurodevelopmental disorders in the OFC population in Sweden and possibly more support services

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ACCEPTED MANUSCRIPT following the diagnosis. This would also be relevant when interpreting the higher risk for suicide and suicidal attempts seen in Denmark, but not in Sweden among individuals with OFC.

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The highest risk increases among children with non-syndromic OFC are seen for the

diagnoses intellectual disability and language disorders, followed by autism spectrum disorder (ASD) and psychosis. An increased risk for an ADHD diagnosis was seen

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among children with OFC and CPO, whereas an increased risk for an ASD diagnosis was evident in all cleft types except for CL, in which the increased risk was

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statistically significant only among females. There is an interesting notable discrepancy in the sizes of the risk increases for the different psychiatric diagnoses. The risk increase for other psychiatric diagnoses than intellectual disability and language disorders among OFC, and within each subtype (CL, CLP or CPO) are

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approximately half that risk, suggesting a stronger neurodevelopmental association for intellectual disability and language disorders.

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There is emerging evidence that bipolar disorder and schizophrenia have a common genetic pathway and we expected a risk increase not only for psychotic disorders, but

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also for bipolar disorder26,27. Our results with an increased risk only for psychotic disorders may support the notion of different trajectories for schizophrenia and bipolar disorder leading to different phenotypes. Another plausible explanation could be the fact that bipolar disorder was diagnosed less frequently in previous years, other diagnoses were used instead, and this could have obscured a risk increase in our study. Moreover, the mean age at a diagnosis of bipolar disorder in our study was approximately 25 years among individuals with OFC and their matched non-affected

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ACCEPTED MANUSCRIPT individuals, where the respective age for a diagnosis of psychotic disorder was 23 years. Thus, it can be assumed that the age of our cohort could have been a restricting factor in capturing more diagnoses of bipolar disorder. A larger study population or a longer follow up period could possibly detect and reveal an association between OFC

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and bipolar disorder.

The cognitive deficits and poorer mental health among children born with OFC have

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earlier been attributed to secondary factors, including low self-esteem, depressed mood and hearing and speech deficits28-30 Psychological factors in the child’s

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environment are crucial for the child’s mental development. However, it is possible that these deficits are instead the result of an abnormal brain development. Our finding of no increased risk for mood disorders or anxiety-related disorders, which are consistent with the recent results from Denmark, support the hypothesis of

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neurodevelopmental differences as a major common pathophysiologic mechanism for the association between OFC and psychiatric disorders18.

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It has been suggested that facial malformations may be associated with aberrant brain development31. Interestingly, associations between non-syndromic OFC and structural

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brain anomalies have been reported in children and adolescents with clefts32,33. These midline brain anomalies have been associated with intellectual disability, developmental delay and schizophrenia in previous studies34,35. The relatively high incidence of central nervous system abnormalities among individuals with nonsyndromic OFC, being approximately 13 times higher compared to the general population36, provides additional support for the hypothesis that cognitive and language deficits as well as other psychiatric disorders may be the result of underlying

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ACCEPTED MANUSCRIPT neurodevelopmental abnormalities. The craniofacial skeleton and the brain are derived from the same ectodermal tissues and their development is closely linked during early morphogenesis37,38.

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To further elucidate the possible mechanisms behind the association between OFC

and neurodevelopmental disorders we studied all unaffected full siblings. Children

without OFC were less likely, compared to their siblings with any OFC or CPO, to be

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diagnosed with any psychiatric disorder, intellectual disability, language disorders, ASD and ADHD, whereas no significant different risk pattern was observed for

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psychotic disorders, other behavioral disorders in childhood and personality disorders. Siblings without OFC had, compared to their siblings with CL or CLP, decreased risk only for any psychiatric disorder, intellectual disability and language disorders. The results from the siblings’ analyses suggest that the strong associations with

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intellectual disability and language disorders and the modest associations with ASD and ADHD are unlikely to be explained by familial influences such as inherited genetic or shared environmental factors, supporting the theory that these

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neuropsychiatric diagnoses and OFC might be the result of the same abnormal

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neurodevelopment.

Interestingly, we also found a risk decrease for depression among children with CL and the risk decrease was mostly seen among males with CL. This finding which may be a chance finding is difficult to interpret in terms of a biological or psychological resilience for the development of major depression in children with CL, especially as males with CPO showed an increased risk for depression. A rather more plausible explanation could be that males with CL are less prone to seek by own

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ACCEPTED MANUSCRIPT initiative the healthcare system for depressive symptoms. Such symptoms often have their onset later than symptoms of neurodevelopmental disorders which debut in childhood and which might be brought to the attention of the healthcare system by family members. If this finding is replicated, more focus on detecting depressive

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symptoms in males with CL would be indicated. The increased risk of depression

among males with CPO could be explained by secondary factors due to an underlying neuropsychiatric disorder. There is evidence that depression is the most common

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comorbidity among individuals with neuropsychiatric disorders, especially when

transitioning from adolescence to adulthood39. A combination of being less prone to

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seek care for treatment and a non-detected neuropsychiatric disorder leading to high levels of distress could possibly be an explanation to the higher rates of suicide among OFC in Denmark and if so, that indicates the importance of consistent follow

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up and screening of children with OFC for neurodevelopmental disorders.

Finally, our sex-specific analyses revealed significant interactions with higher risks among females with OFC for any psychiatric disorder, intellectual disability,

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language disorders, ASD and other behavioral disorders. A similar pattern was seen

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among children with CL and CLP, although not reaching statistical significance. A possible explanation of a higher vulnerability of the female brain to the underlying neurodevelopmental mechanisms in OFC cannot be totally dismissed, but is not supported by the fact that no such patterns could be seen among children with CPO, who had the highest risk increases for neurodevelopmental disorders. An alternative explanation might be a sex-specific diagnostic bias, with females being less often diagnosed due to different presentation of symptoms or symptoms severity. Recent

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ACCEPTED MANUSCRIPT studies have shown that females are more likely to be diagnosed with a neurodevelopmental disorder when they have additional comorbid features40,41.

The major strength of this study is the study design of a nationwide, register-based

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cohort with long follow-up time. This has provided us a unique opportunity to study a large sample of patients with clefts, which is crucial when investigating relatively rare conditions. We were also able to explore possible different patterns among patients

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with different types of OFC malformations. Information collected from registers

eliminates the risk of recall bias and selection bias. Another important strength is the

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availability of data used for our multivariate analyses to adjust for confounders. Moreover, the sibling cohort enabled us to match on many unmeasured factors, including cultural background, parental characteristics and child-rearing practices, and genetics42.

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The diagnoses for identifying our study population and the psychiatric diagnoses were obtained from the National Patient Register. The validity of the psychiatric diagnoses

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in the NPR is considered high as measured by moderate to high positive predictive values for psychiatric diagnoses 43-45. It should be kept in mind though that psychiatric

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symptoms, such as mild depressive and anxiety symptoms, that are not severe enough to require psychiatric care are treated within the primary health care system, and those diagnoses registered in primary care are not included in the Swedish Patient Register.

The study also has some limitations. A number of individuals with OFC received several different ICD-codes for their cleft-type. This clinical misclassification may have resulted in results being diluted or exaggerated when stratified by cleft- type.

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ACCEPTED MANUSCRIPT There is a possibility that some individuals with OFC are classified as non-syndromic although they might have unidentified associated malformations or anomalies that can be associated with intellectual disability or other psychiatric disorders. Clinicians sometimes have difficulties identifying the correct code for genetic conditions and

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associated anomalies. This is expected to have occurred more often in the earlier born individuals of the cohort and we have adjusted for calendar year in our multivariate analyses to eliminate this risk. In order to decrease the risk even more for non-

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detected syndromic OFC, we also decided to rather be over-inclusive in our definition of what diagnoses could indicate syndromic OFC and therefore adjusted for all

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congenital malformations and chromosomal abnormalities in our multivariate analysis.

Lastly, there have been changes over time in the diagnostic criteria in ICD-8,9 and 10

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for specific neuropsychiatric diagnoses that could possible result in some uncertainty in the validity of our outcome measures. We have decided to analyze the diagnosis mental retardation according to the ICD-8 together with the diagnosis intellectual

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disability according to ICD-9 and 10. Due to the lack of specific ICD-8 codes for

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ADHD and ASD, the individuals that died before the 9th version of ICD were therefore not included in the analyses for ADHD and ASD.

This large nationwide register study showed that children with non-syndromic OFC in Sweden have an increased risk of being diagnosed with a neurodevelopmental disorder compared to children without clefts. The highest risk was for CPO, followed by CLP while children with CL had the lowest, but still significant, risk increase. There was no overall risk increase for mood disorders or anxiety-related disorders,

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ACCEPTED MANUSCRIPT indicating that neurodevelopmental and neurological structural differences may play a major role for the observed associations. The full siblings’ analyses suggest that the higher risk of psychiatric disorders among individuals with orofacial clefts is unlikely to be explained by familial influences such as inherited genetic or shared

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environmental factors.

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ACCEPTED MANUSCRIPT References 1.

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palate: association with other congenital malformations. J Clin Pediatr Dent.

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Goodacre TS, Marc C. Cleft lip and palate: current management.

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http://dx.doi.org/10.1016/j.paed.2008.03.008. 2008;18(6):283-292. Burdi AR. Cleft Lip and Palate. New York: Springer; 2006.

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Little J, Cardy A, Arslan MT, Gilmour M, Mossey PA, United Kingdom-based casecontrol s. Smoking and orofacial clefts: a United Kingdom-based case-control study. Cleft Palate Craniofac J. 2004;41(4):381-386.

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MJ E. Neuropsychological perspectives of cleft lip and palate. Multidisciplinary management of cleft lip and palate. . Philadelphia: W. B. Saunders Company; 1990.

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Broder HL, Richman LC, Matheson PB. Learning disability, school achievement,

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Nilsson S, Merlo J, Lyberg-Ahlander V, Psouni E. Psychotropic drug use in adolescents born with an orofacial cleft: a population-based study. BMJ Open. 2015;5(4):e005306.

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with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381(9875):1371-1379. Forero DA, Herteleer L, De Zutter S, et al. A network of synaptic genes associated

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with schizophrenia and bipolar disorder. Schizophr Res. 2016;172(1-3):68-74. 28.

Kapp-Simon KA, Simon DJ, Kristovich S. Self-perception, social skills, adjustment, and inhibition in young adolescents with craniofacial anomalies. Cleft Palate Craniofac J. 1992;29(4):352-356.

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Millard T, Richman LC. Different cleft conditions, facial appearance, and speech: relationship to psychological variables. Cleft Palate Craniofac J. 2001;38(1):68-75.

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Richman LC. Self-reported social, speech, and facial concerns and personality adjustment of adolescents with cleft lip and palate. Cleft Palate J. 1983;20(2):108112.

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Nopoulos P, Langbehn DR, Canady J, Magnotta V, Richman L. Abnormal brain

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structure in children with isolated clefts of the lip or palate. Arch Pediatr Adolesc Med. 2007;161(8):753-758. 32.

Adamson CL, Anderson VA, Nopoulos P, Seal ML, Da Costa AC. Regional brain

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morphometric characteristics of nonsyndromic cleft lip and palate. Dev Neurosci. 2014;36(6):490-498.

Chollet MB, DeLeon VB, Conrad AL, Nopoulos P. Morphometric analysis of brain

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shape in children with nonsyndromic cleft lip and/or palate. J Child Neurol. 2014;29(12):1616-1625. 34.

Nopoulos P, Swayze V, Flaum M, Ehrhardt JC, Yuh WT, Andreasen NC. Cavum septi

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pellucidi in normals and patients with schizophrenia as detected by magnetic resonance imaging. Biol Psychiatry. 1997;41(11):1102-1108. Bodensteiner JB, Schaefer GB, Craft JM. Cavum septi pellucidi and cavum vergae in

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Mueller AA, Sader R, Honigmann K, Zeilhofer HF, Schwenzer-Zimmerer K. Central nervous malformations in presence of clefts reflect developmental interplay. Int J Oral Maxillofac Surg. 2007;36(4):289-295.

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Kjaer I. Human prenatal craniofacial development related to brain development under normal and pathologic conditions. Acta Odontol Scand. 1995;53(3):135143.

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Marcucio RS, Cordero DR, Hu D, Helms JA. Molecular interactions coordinating the development of the forebrain and face. Dev Biol. 2005;284(1):48-61.

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Lugnegard T, Hallerback MU, Gillberg C. Psychiatric comorbidity in young adults with a clinical diagnosis of Asperger syndrome. Res Dev Disabil. 2011;32(5):1910-

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differences and autism: setting the scene for future research. J Am Acad Child

Polyak A, Rosenfeld JA, Girirajan S. An assessment of sex bias in

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neurodevelopmental disorders. Genome Med. 2015;7:94.

Frisell T, Oberg S, Kuja-Halkola R, Sjolander A. Sibling comparison designs: bias from non-shared confounders and measurement error. Epidemiology. 2012;23(5):713-720.

Ludvigsson JF, Andersson E, Ekbom A, et al. External review and validation of the

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Swedish national inpatient register. BMC Public Health. 2011;11:450. Sellgren C, Landen M, Lichtenstein P, Hultman CM, Langstrom N. Validity of

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bipolar disorder hospital discharge diagnoses: file review and multiple register

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linkage in Sweden. Acta Psychiatr Scand. 2011;124(6):447-453. Ruck C, Larsson KJ, Lind K, et al. Validity and reliability of chronic tic disorder and obsessive-compulsive disorder diagnoses in the Swedish National Patient Register. BMJ Open. 2015;5(6):e007520.

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ACCEPTED MANUSCRIPT Figure 1. Adjusted Cox-Derived Hazard Ratios (aHRs) With 95% CIs for Psychiatric Diagnoses, Suicide Attempts and Suicide Among Children With Orofacial Clefts Compared to Children Without Clefts.

A. Children with orofacial cleft (OFC) B. Children with cleft lip (CL) C. Children with cleft lip and palate (CLP)

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D. Children with cleft palate only (CPO)

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clefts compared to their full siblings with clefts.

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Note: aHRs are presented separately for males and females as well as for siblings without

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A. Orofacial clefts (OFC)

12

*

8

*

OFC males

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OFC total

aHR

2

*

non−OFC siblings

* p−value for sex*OFC interaction < 0.05 + p−value for sex*OFC interaction < 0.10

+

4

OFC females

* +

*

+

1

.5

.25

.1 Any Intellectual Language Psychotic psychiatric disability disorders disorders

Bipolar Depression Eating disorders

ASD

ADHD

Other Neurotic, Alcohol Personality Suicide behavioral stress and drug disorders attempts disorders related use

Suicide

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B. Cleft lip (CL)

12

CL males

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CL total

CL females

non−CL siblings

+ p−value for sex*CL interaction < 0.10

8

4

2

+

aHR

+ 1

.5

.25

.1 Any Intellectual Language Psychotic psychiatric disability disorders disorders

Bipolar Depression Eating disorders

ASD

ADHD

Other Neurotic, Alcohol Personality Suicide behavioral stress and drug disorders attempts disorders related use

Suicide

EP

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C. Cleft lip and palate (CLP)

12

*

8

4

* aHR

2

CLP males

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CLP total

*

CLP females

non−CLP siblings

* p−value for sex*CLP interaction < 0.05 + p−value for sex*CLP interaction < 0.10

+

*

1

.5

.25

.1 Any Intellectual Language Psychotic psychiatric disability disorders disorders

Bipolar Depression Eating disorders

ASD

ADHD

Other Neurotic, Alcohol Personality Suicide behavioral stress and drug disorders attempts disorders related use

Suicide

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D. Cleft palate only (CPO)

12

CPO males

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CPO total

CPO females

non−CPO siblings

+ p−value for sex*CPO interaction < 0.10

8

4

aHR

2

+

1

.5

.25

.1 Any Intellectual Language Psychotic psychiatric disability disorders disorders

Bipolar Depression Eating disorders

ASD

ADHD

Other Neurotic, Alcohol Personality Suicide behavioral stress and drug disorders attempts disorders related use

Suicide

ACCEPTED MANUSCRIPT Table S1 International Classification of Diseases (ICD)-8, 9 and 10 Codes for Specific Psychiatric Disorders ICD-9

ICD-10

290-315

290-319

F00-F99

310-315

317-319

F70- F79

Speech and language disorders

306,00 781,59

315D

F80 R47

Psychotic disorders

295 297-299 (except 298,00)

295 297 298 (except 298A)

Bipolar disorder

296 (except 296,00)

Depression

298,00 300,40 790,20

296 (except 296B, 296X) 298A 300E 311

Eating Disorders

306,50

307B 307F

F50

ASD

-

299

F84

ADHD

-

Other behavioral/emotional disorders with onset in childhood

308,99

Neurotic, stress related or somatoform disorder

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Alcohol and substance use disorder Personality disorder Suicide attempt Suicide

F20-F29 F30-F31

F32-F33

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300 (except 300,40); 305 306,80 306,98 307,99 291 303 294,30 304 971 301 E950-E959 E950-E959

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Any psychiatric disorder Intellectual disability/ Mental retardation

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ICD-8

314

F90

312-313

F91-F98

300 (except 300E) 306 307W 308 309

F40-F48

291 303 305A 292 304 305X 301 E950-E959 E950-E959

F10-F16 F18 F19 F60 X60-X84 X60-X84

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Note: ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder

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Table S2 Descriptive Characteristics of Individuals with Orofacial Clefts (OFC) and the Matched comparison cohorts CLP Comparison cohort, n(%)

7842 4531 (57.8%) 3311 (42.2%)

78409 45336(57.8%) 33073(42.2%)

2526 1596 (63.2%) 930(36.8%)

25253 15955(63.2%) 9298 (36.8%)

1810 (23.1%) 4750 (60.6%) 1202 (15.3%) 80 (1.0%)

18112(23.1%) 48959(62.4%) 11026(14.1%) 312 (0.4%)

605 (24.0%) 1528 (60.5%) 375 (14.8%) 18 (0.7%)

877 (11.2%) 4609 (58.8%) 2226 (28.4%) 130 (1.7%)

8796 (11.2%) 47120(60.1%) 21584(27.5%) 909 (1.2%)

1292 (16.5%) 6470 (82.5%) 80 (1.0%)

11917(15.2%) 66180(84.4%) 312 (0.4%)

1111 (14.2%) 6601 (84.2%) 130 (1.7%)

6384 (81.4%) 287 (3.7%)

CPO

Affected individuals, n(%)

Comparison cohort, n(%)

Affected individuals, n(%)

Comparison cohort, n(%)

3048 2009 (65.9%) 1039 (34.1%)

30476 20107(66.0%) 10369(34.0%)

3436 1625 (47.3%) 1811 (52.7%)

34356 16271(47.4%) 18085(52.6%)

5727 (22.7%) 15886(62.9%) 3546 (14.0%) 94 (0.4%)

733 (24.0%) 1817 (59.6%) 443 (14.5%) 55 (1.8%)

7169 (23.5%) 19045(62.5%) 4146 (13.6%) 116 (0.4%)

716 (20.8%) 2117 (61.6%) 590 (17.2%) 13 (0.4%)

7491 (21.8%) 21597(62.9%) 5141 (15.0%) 127 (0.4%)

274 (0.8%) 1548 (61.3%) 673 (26.6%) 31 (1.2%)

2760 (10.9%) 15178(60.1%) 7012 (27.8%) 303 (1.2%)

364 (11.9%) 1771 (58.1%) 834 (27.4%) 79 (2.6%)

3518 (11.5%) 18383(60.3%) 8226 (27.0%) 349 (1.1%)

355 (10.3%) 1966 (57.2%) 1085 (31.6%) 30 (0.9%)

3608 (10.5%) 20465(59.6%) 9899 (28.8%) 384 (1.1%)

400 (15.8%) 2108 (83.5%) 18 (0.7%)

3894 (15.4%) 21265(84.2%) 94 (0.4%)

492 (16.1%) 2501 (82.1%) 55 (1.8%)

4501 (14.8%) 25859(84.9%) 116 (0.4%)

604 (17.6%) 2819 (82.0%) 13 (0.4%)

5250 (15.3%) 28979(84.3%) 127 (0.4%)

10049(12.8%) 67451(86.0%) 909 (1.2%)

352 (13.9%) 2143 (84.8%) 31 (1.2%)

3263 (12.9%) 21687(85.9%) 303 (1.2%)

421 (13.8%) 2548 (83.6%) 79 (2.6%)

3989 (13.1%) 26138(85.8%) 349 (1.1%)

508 (14.8%) 2898 (84.3%) 30 (0.9%)

4299 (12.5%) 29673(86.4%) 384 (1.1%)

62624(79.9%) 2798 (3.6%)

2109 (83.5%) 84 (3.3%)

20274(80.3%) 918 (3.6%)

2482 (81.4%) 97 (3.2%)

24210(79.4%) 1049 (3.4%)

2777 (80.8%) 138 (4.0%)

27563(80.2%) 1199 (3.5%)

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Affected individuals, n(%)

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Comparison cohort, n(%)

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Total sample Male Female Sociodemographic indicators Maternal age, year ≤24 25-34 ≥35 Unknown Paternal age ≤24 25-34 ≥35 Unknown Maternal Psychiatric history Yes No Unknown Paternal Psychiatric History Yes No Unknown Maternal Region of Birth Sweden Other Nordic country

CL

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OFC Affected individuals, n(%)

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8971 (11.4%) 4016 (5.1%)

217 (8.6%) 116 (4.6%)

2966 (11.7%) 1095 (4.3%)

224 (7.3%) 245 (8.0%)

3438 (11.3%) 1779 (5.8%)

356 (10.4%) 165 (4.8%)

4123 (12.0%) 1471 (4.3%)

450 (5.7%) 1964 (25.0%) 2932 (37.4%) 2379 (30.3%) 117 (1.5%)

4338 (5.5%) 17950(22.9%) 29300(37.4%) 25953(33.1%) 868 (1.1%)

144 (5.7%) 599 (23.7%) 949 (37.6%) 804 (31.8%) 30 (1.2%)

1413 (5.6%) 5716 (22.6%) 9513 (37.7%) 8341 (33.0%) 270 (1.1%)

168 (5.5%) 761 (25.0%) 1137 (37.3%) 918 (30.1%) 64 (2.1%)

1739 (5.7%) 7104 (23.3%) 11310 37.1%) 10014(32.9%) 309 (1.0%)

197 (5.7%) 840 (24.4%) 1317 (38.3%) 1049 (30.5%) 33 (1.0%)

1718 (5.0%) 7337 (21.4%) 13058(38.0%) 11895(34.6%) 348 (1.0%)

661 (8.4%) 6673 (85.1%) 508 (6.5%)

4326 (5.5%) 69977(89.2%) 4106 (5.2%)

177 (7.0%) 2231 (88.3%) 118 (4.7%)

1421 (5.6%) 22699(89.9%) 1133 (4.5%)

260 (8.5%) 2539 (83.3%) 249 (8.2%)

1670 (5.5%) 26998(88.6%) 1808 (5.9%)

324 (9.4%) 2941 (85.6%) 171 (5.0%)

1900 (5.5%) 30954(90.1%) 1502 (4.4%)

476 (6.1%) 6823 (87.0%) 543 (6.9%)

2197 (2.8%) 71918(91.7%) 4294 (5.5%)

123 (4.9%) 2277 (90.1%) 126 (5.0%)

685 (2.7%) 23369(92.5%) 1199 (4.7%)

177 (5.8%) 2614 (85.8%) 257 (8.4%)

858 (2.8%) 27749(91.1%) 1869 (6.1%)

251 (7.3%) 2993 (87.1%) 192 (5.6%)

948 (2.8%) 31814(92.6%) 1594 (4.6%)

100 (1.3%) 496 (6.3%) 3371 (43.0%) 3344 (42.6%) 531 (6.8%)

394 (0.5%) 2574 (3.3%) 31481(40.1%) 39776(50.7%) 4184 (5.3%)

33 (1.3%) 116 (4.6%) 1077 (42.6%) 1177 (46.6%) 123 (4.9%)

121 (0.5%) 806 (3.2%) 10126(40.1%) 13040(51.6%) 1160 (4.6%)

35 (1.1%) 203 (6.7%) 1261 (41.4%) 1296 (42.5%) 253 (8.3%)

148 (0.5%) 995 (3.3%) 11862(38.9%) 15641(51.3%) 1830 (6.0%)

51 (1.5%) 266 (7.7%) 1526 (44.4%) 1407 (40.9%) 186 (5.4%)

187 (0.5%) 1157 (3.4%) 14080(41.0%) 17380(50.6%) 1552 (4.5%)

193 (2.5%) 6783 (86.5%) 866 (11.0%)

773 (1.0%) 70094(89.4%) 7542 (9.6%)

39 (1.5%) 2249 (89.0%) 238 (9.4%)

255 (1.0%) 22754(90.1%) 2244 (8.9%)

58 (1.9%) 2594 (85.1%) 396 (13.0%)

297 (1.0%) 26998(88.6%) 3181 (10.4%)

126 (3.7%) 3008 (87.5%) 302 (8.8%)

359 (1.0%) 31242(90.9%) 2755 (8.0%)

1154 (14.7%) 5881 (75.0%) 807 (10.3%)

6805 (8.7%) 64229(81.9%) 7375 (9.4%)

307 (12.2%) 1994 (78.9%) 225 (8.9%)

2215 (8.8%) 20850(82.6%) 2188 (8.7%)

450 (14.8%) 2221 (72.9%) 377 (12.4%)

2626 (8.6%) 24740(81.2%) 3110 (10.2%)

582 (16.9%) 2586 (75.3%) 268 (7.8%)

2971 (8.6%) 28677(83.5%) 2708 (7.9%)

5843 (7.5%)

444 (17.6%)

1901 (7.5%)

791 (26.0%)

2325 (7.6%)

1261 (36.7%)

2575 (7.5%)

2150 (27.4%)

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673 (8.6%) 498 (6.4%)

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Outside Nordic countries Unknown Parental education 0-9 years 10-11 12-14 >14 Unknown Perinatal and somatic indicators Preterm birth Term birth Unknown Child Small for Gestational Age SGA No SGA Unknown Birthweight Birthweight <1500g 1500-2499g 2500-3499g ≥3500g Unknown Apgar Apgar <7 at 5 min Apgar ≥7 at 5 min Unknown Gestational Complications Yes No Unknown Any congenital malformations, deformations and chromosomal abnormalities Yes

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72566(92.5%)

2082 (82.4%)

23352(92.5%)

2257 (74.0%)

28151(92.4%)

2175 (63.3%)

31781(92.5%)

469 (6.0%) 1547 (19.7%) 2297 (29.3%) 1849 (23.6%) 1680 (21.4%)

4690 (6.0%) 15465(19.7%) 22965(29.3%) 18489(23.6%) 16800(21.4%)

130 (5.1%) 510 (20.2%) 680 (26.9%) 644 (25.5%) 562 (22.2%)

1300 (5.1%) 5096 (20.2%) 6797 (26.9%) 6440 (25.5%) 5620 (22.3%)

206 (6.8%) 606 (19.9%) 925 (30.3%) 697 (22.9%) 614 (20.1%)

2060 (6.8%) 6057 (19.9%) 9249 (30.3%) 6970 (22.9%) 6140 (20.1%)

151 (4.4%) 532 (15.5%) 1004 (29.2%) 903 (26.3%) 846 (24.6%)

1510 (4.4%) 5319 (15.5%) 10038 29.2%) 9029 (26.3%) 8460 (24.6%)

1950 (24.9%) 2084 (26.6%) 1989 (25.4%) 1819 (23.2%)

19494(24.9%) 20848(26.6%) 19880(25.4%) 18187(23.2%)

641 (25.4%) 682 (27.0%) 629 (24.9%) 574 (22.7%)

6407 (25.4%) 6818 (27.0%) 6290 (24.9%) 5738 (22.7%)

805 (26.4%) 827 (27.1%) 745 (24.4%) 671 (22.0%)

8047 (26.4%) 8279 (27.2%) 7441 (24.4%) 6709 (22.0%)

805 (23.4%) 896 (26.1%) 916 (26.7%) 819 (23.8%)

8048 (23.4%) 8960 (26.1%) 9159 (26.7%) 8189 (23.8%)

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5692 (72.6%)

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No Year of Birth 1965-1974 1975-1984 1985-1994 1995-2004 2005-2012 Birth month Winter Dec-Feb Spring Mar-May Summer June-Aug Autumn Sep-Nov

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Note: CL = cleft lip; CLP = cleft lip and palate; CPO = cleft palate only; SGA = smal for gestitional age

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Table S3 Adjusted Cox-Derived Hazard Ratios (aHRs) With 95% CIs for Psychiatric Diagnoses Among Children With Non–Syndromic Orofacial Cleft (OFC) Compared to Children Without OFC MALES OFC, N=4531a No OFC N=45336a

Adjusted HR (95% CI)b

Events among males with OFC/ without OFC (N,%)

FEMALES OFC, N=3311a No OFC N =33073a

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TOTAL OFC, N=7842a No OFC N=78409a

Adjusted HR (95% CI)b

p value for sexaOFC interaction

Mean age at event for OFC (No OFC)

705 (21.3%)/ 3677 (11.1%)

1.73 (1.57, 1.89)

0.007

12.6(17.1)

3.82 (3.15, 4.63)

198 (6.0%)/ 198 (0.6%)

4.71 (3.77, 5.87)

0.017

9.4(11.5)

148 (3.3%)/ 262 (0.6%)

4.41 (3.54, 5.51)

90 (2.7%)/ 88 (0.3%)

6.14 (4.39, 8.58)

0.023

7.4(7.4)

1.62 (1.15, 2.29)

26 (0.6%)/ 192 (0.4%)

1.28 (0.82, 2.01)

22 (0.7%)/ 87 (0.3%)

2.46 (1.41, 4.30)

0.089

23.2(23.4)

35 (0.4%)/ 313 (0.4%)

1.05 (0.70, 1.56)

16 (0.4%)/ 143 (0.3%)

1.14 (0.65, 2.03)

19 (0.6%)/ 170 (0.5%)

0.97 (0.55, 1.71)

0.703

25.8(25.3)

239 (3.0%)/ 2133 (2.7%)

0.99 (0.84, 1.15)

108 (2.4%)/ 967 (2.1%)

0.99 (0.80, 1.25)

131 (4.0%)/ 1166 (3.5%)

0.97 (0.78, 1.20)

0.902

23(23.4)

Eating disorders

96 (1.2%)/ 550 (0.7%)

0.89 (0.61, 1.29)

2 (0.0%)/ 39 (0.1%)

0.61 (0.15, 2.40)

34 (1.0%)/ 370 (1.1%)

0.91 (0.62, 1.35)

0.561

19.6(19.3)

ASD

191 (2.4%)/ 765 (1.0%)

1.96 (1.65, 2.33)

119 (2.6%)/ 551 (1.2%)

1.72 (1.39, 2.13)

72 (2.2%)/ 214 (0.7%)

2.54 (1.91, 3.37)

0.015

15.1(15.3)

ADHD

227 (2.9%)/ 1597 (2.0%)

1.25 (1.08, 1.46)

154 (3.4%)/ 1169 (2.6%)

1.18 (0.98, 1.42)

73 (2.2%)/ 428 (1.3%)

1.42 (1.09, 1.84)

0.089

14.8(16.6)

Other behavioral

238 (3.0%)/ 1488 (1.9%)

1.43 (1.23, 1.65)

146 (3.2%)/ 1055 (2.3%)

1.28 (1.06, 1.54)

92 (2.8%)/ 433 (1.3%)

1.69 (1.34, 2.12)

0.005

9.3(10.2)

Neurotic, stressrelated

382 (4.9%)/ 3239 (4.1%)

1.04 (0.93, 1.18)

165 (3.6%)/ 1516 (3.3%)

0.99 (0.82, 1.18)

217 (6.6%)/ 1723 (5.2%)

1.09 (0.93, 1.29)

0.398

20.1(22.4)

Events among children with OFC/ without OFC (N,%)

Any psychiatric

1529 (19.5%)/ 8777 (11.2%)

1.63 (1.53, 1.73)

824 (18.2%)/ 5100 (11.2%)

1.54(1.42, 1.67)

Intellectual disability

419 (5.3%)/ 539 (0.7%)

4.19 (3.63, 4.84)

221 (4.9%)/ 341 (0.8%)

Language disorders

238 (3.0%)/ 350 (0.4%)

4.89 (4.08, 5.87)

Psychotic

48 (0.6%)/ 279 (0.4%)

Bipolar

M AN U

TE D

EP

AC C

Depression

Adjusted HR (95% CI)b

Events among females with OFC/ without OFC (N,%)

SC

Diagnosis

ACCEPTED MANUSCRIPT

203 (2.6%)/ 1976 (2.5%)

1.03 (0.88, 1.21)

134 (3.0%)/ 1251 (2.8%)

1.08 (0.89, 1.32)

69 (2.1%)/ 725 (2.2%)

0.94 (0.72, 1.22)

0.577

21.3(21.1)

Personality disorders

70 (0.9%)/ 455 (0.6%)

1.35 (1.00, 1.82)

31 (0.7%)/ 195 (0.4%)

1.58 (1.03, 2.41)

39 (1.2%)/ 260 (0.8%)

1.19 (0.79, 1.79)

0.536

23.6(24.7)

Suicide attempt

86 (1.1%)/ 816 (1.0%)

0.91 (0.71, 1.17)

37 (0.8%)/ 357 (0.8%)

1.02 (0.71, 1.47)

49 (1.5%)/ 459 (1.4%)

0.81 (0.57, 1.14)

0.541

21.8(21.4)

8 (0.1%)/ 53 (0.1%)

1.15 (0.46, 2.88)

5 (0.1%)/ 47 (0.1%)

0.74 (0.24, 2.24)

3 (0.1%)/ 6 (0.0%)

-

0.085

26.2(24.9)

Suicide

RI PT

Alcohol and drug Use

Note: ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder When performing analyses for the outcome of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), individuals that died before the introduction of International Classification of Diseases (ICD)-9 were excluded, because those diagnoses were not included in ICD-8. Thus, those hazard ratios (HR) were calculated on the basis of 3288 females/4508 males with OFC and 32910 females/45085 males without OFC.

M AN U

SC

a

b

AC C

EP

TE D

Adjusted for perinatal complications (born preterm, low Apgar score (defined as < 7 at 5 minutes after birth), Small for Gestational Age and low birth weight <2500g, all congenital malformations, deformations and chromosomal abnormalities, sex (in the non-stratified per sex analyses), season and year of birth, and different sociodemographic factors among parents (mean age of the parents, maternal country of birth, parental level of education) and parental psychiatric morbidity.

ACCEPTED MANUSCRIPT

Table S4 Adjusted Cox-Derived Hazard Ratios (aHRs) with 95% CIs for Psychiatric Diagnoses Among Children With Non–Syndromic Cleft lip (CL) Compared to Children Without Orofacial Cleft (OFC) MALES CL, N=1596a No OFC N=15955a

Adjusted HR (95% CI)b

Events among males with CL/ without OFC (N,%)

FEMALES CL, N=930* No OFC N =9298*

RI PT

TOTAL CL, N=2526a No OFC N=25253a

Adjusted HR (95% CI)b

p value for sexaCL interaction

Mean age at event for CL (No OFC)

163 (17.5%)/ 1055 (11.3%)

1.38 (1.14, 1.66)

0.100

14.1(16.6)

2.78 (1.88, 4.11)

37 (4.0%)/ 57 (0.6%)

3.64 (2.35, 5.64)

0.318

9.3(11.1)

28 (1.8%)/ 103 (0.6%)

2.34 (1.49, 3.67)

13 (1.4%)/ 26 (0.3%)

3.33 (1.64, 6.79)

0.238

6.3(6.7)

1.50 (0.83, 2.74)

11 (0.7%)/ 63 (0.4%)

1.54 (0.77, 3.09)

4 (0.4%)/ 24 (0.3%)

1.45 (0.44, 4.86)

0.775

27.8(22.9)

14 (0.6%)/ 101 (0.4%)

1.17 (0.63, 2.18)

9 (0.6%)/ 48 (0.3%)

1.57 (0.71, 3.46)

5 (0.5%)/ 53 (0.6%)

0.81 (0.29, 2.26)

0.253

27.3(25.3)

Depression

63 (2.5%)/ 684 (2.7%)

0.73 (0.54, 0.98)

26 (1.6%)/ 347 (2.2%)

0.54 (0.33, 0.87)

37 (4.0%)/ 337 (3.6%)

0.90 (0.61, 1.34)

0.081

23.9(23.2)

Eating disorders

21 (0.8%)/ 171 (0.7%)

0.75 (0.36, 1.56)

0 (0.0%)/ 12 (0.1%)

-

9 (1.0%)/ 109 (1.2%)

0.81 (0.39, 1.71)

0.733

17.2(19.2)

ASD

37 (1.5%)/ 246 (1.0%)

1.30 (0.91, 1.85)

22 (1.4%)/ 184 (1.2%)

1.04 (0.67, 1.63)

15 (1.6%)/ 62 (0.7%)

2.08 (1.14, 3.80)

0.085

14.9(14.9)

ADHD

59 (2.3%)/ 530 (2.1%)

1.10 (0.83, 1.45)

41 (2.6%)/ 405 (2.6%)

1.02 (0.74, 1.42)

18 (1.9%)/ 125 (1.4%)

1.29 (0.76, 2.19)

0.284

16.4(16.4)

Other behavioral

64 (2.5%)/ 534 (2.1%)

1.12 (0.85, 1.47)

43 (2.7%)/ 403 (2.5%)

1.01 (0.72, 1.41)

21 (2.3%)/ 131 (1.4%)

1.42 (0.88, 2.30)

0.156

8.6(10.0)

Neurotic, stressrelated

106 (4.2%)/ 1014 (4.0%)

0.85 (0.68, 1.07)

48 (3.0%)/ 514 (3.2%)

0.80 (0.57, 1.12)

58 (6.2%)/ 500 (5.4%)

0.91 (0.66, 1.25)

0.548

22.0(21.8)

Events among children with CL/ without OFC (N,%)

Adjusted HR (95% CI)b

Any psychiatric

388 (15.4%)/ 2838 (11.2%)

1.25 (1.12, 1.41)

225 (14.1%)/ 1783 (11.2%)

1.17 (1.01, 1.36)

Intellectual disability

80 (3.2%)/ 171 (0.7%)

3.08 (2.30, 4.12)

43 (2.7%)/ 114 (0.7%)

Language disorders

41 (1.6%)/ 129 (0.5%)

2.62 (1.80, 3.82)

Psychotic

15 (0.6%)/ 87 (0.3%)

Bipolar

M AN U

TE D

EP

AC C

Events among females with CL/ without OFC (N,%)

SC

Diagnosis

ACCEPTED MANUSCRIPT

67 (2.7%)/ 645 (2.6%)

1.03 (0.79, 1.34)

47 (2.9%)/ 440 (2.8%)

1.08 (0.79, 1.48)

20 (2.2%)/ 205 (2.2%)

0.92 (0.56, 1.51)

0.779

21.7(21.4)

Personality disorders

26 (1.0%)/ 137 (0.5%)

1.40 (0.83, 2.36)

10 (0.6%)/ 57 (0.4%)

1.26 (0.56, 2.82)

16 (1.7%)/ 80 (0.9%)

-

-

25.8(24.0)

Suicide attempt

29 (1.1%)/ 255 (1.0%)

0.99 (0.65, 1.50)

11 (0.7%)/ 117 (0.7%)

0.99 (0.53, 1.82)

18 (1.9%)/ 138 (1.5%)

0.97 (0.55, 1.72)

0.857

23.7(21.3)

2 (0.1%)/ 16 (0.1%)

0.77 (0.10, 6.07)

2 (0.1%)/ 15 (0.1%)

0.83 (0.10, 6.62)

0 (0.0%)/ 1 (0.0%)

-

-

27.2(24.1)

Suicide

RI PT

Alcohol and drug Use

SC

Note: ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CL = cleft lip. a

M AN U

When performing analyses for the outcome of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), individuals that died before the introduction of International Classification of Diseases (ICD)-9 were excluded, because those diagnoses were not included in ICD-8. Thus, those HR were calculated on the basis of 926 females/1592 males with CL and 9253 females/15868 males without orofacial cleft. b

AC C

EP

TE D

Adjusted for perinatal complications (born preterm, low Apgar score (defined as < 7 at 5 minutes after birth), Small for Gestational Age and low birth weight <2500g, all congenital malformations, deformations and chromosomal abnormalities, sex (in the non-stratified per sex analyses), season and year of birth, and different sociodemographic factors among parents (mean age of the parents, maternal country of birth, parental level of education) and parental psychiatric morbidity.

ACCEPTED MANUSCRIPT Table S5 Adjusted Cox-Derived Hazard Ratios (aHRs) With 95% CIs for Psychiatric Diagnoses Among Children With Non–Syndromic Cleft Lip (CL) and Palate (CLP) Compared to Children Without Orofacial Cleft (OFC)

MALES CLP, N=2009a No OFC N=20107a

Events among children with CLP/ without OFC (N,%)

Events among males with CLP/ without OFC (N,%)

Adjusted HR (95% CI)b

Any psychiatric

582 (19.1%)/ 3371 (11.1%)

1.62 (1.47, 1.79)

338 (16.8%)/ 2238 (11.1%)

1.44 (1.27, 1.64)

Intellectual disability

149 (4.9%)/ 221 (0.7%)

4.16 (3.31, 5.22)

78 (3.9%)/ 159 (0.8%)

Language disorders

85 (2.8%)/ 144 (0.5%)

4.73 (3.57, 6.26)

Psychotic

18 (0.6%)/ 135 (0.4%)

Bipolar

Adjusted HR (95% CI)b

p value for sexaCLP interaction

Mean age at event for CLP (No OFC)

244 (23.5%)/ 1133 (10.9%)

1.94 (1.64, 2.28)

<0.001

13.1(17.2)

3.25 (2.38, 4.42)

71 (6.8%)/ 62 (0.6%)

6.14 (4.31, 8.76)

0.002

9.6(11.6)

59 (2.9%)/ 116 (0.6%)

4.24 (3.07, 5.85)

26 (2.5%)/ 28 (0.3%)

6.73 (3.61, 12.54)

0.113

8.6(7.5)

1.03 (0.55, 1.93)

7 (0.3%)/ 99 (0.5%)

0.46 (0.17, 1.27)

11 (1.1%)/ 36 (0.3%)

2.86 (1.18, 6.96)

0.009

24.1(22.7)

9 (0.3%)/ 115 (0.4%)

0.76 (0.35, 1.64)

2 (0.1%)/ 68 (0.3%)

0.39 (0.10, 1.55)

7 (0.7%)/ 47 (0.5%)

1.14 (0.41, 3.18)

0.153

24.9(24.8)

Depression

96 (3.1%)/ 799 (2.6%)

1.06 (0.83, 1.36)

54 (2.7%)/ 438 (2.2%)

1.19 (0.87, 1.63)

42 (4.0%)/ 361 (3.5%)

0.90 (0.60, 1.35)

0.255

22.9(23.5)

Eating disorders

30 (1.0%)/ 187 (0.6%)

0.95 (0.51, 1.77)

1 (0.0%)/ 18 (0.1%)

0.56 (0.09, 3.54)

13 (1.3%)/ 112 (1.1%)

1.01 (0.52, 1.98)

0.654

19.7(19.5)

ASD

58 (1.9%)/ 309 (1.0%)

1.51 (1.11, 2.06)

42 (2.1%)/ 246 (1.2%)

1.37 (0.95, 1.96)

16 (1.6%)/ 63 (0.6%)

2.12 (1.16, 3.85)

0.232

14.9(14.9)

ADHD

81 (2.7%)/ 656 (2.2%)

1.06 (0.83, 1.37)

60 (3.0%)/ 514 (2.6%)

1.05 (0.79, 1.40)

21 (2.0%)/ 142 (1.4%)

1.13 (0.67, 1.91)

0.716

14.5(16.3)

Other behavioral

80 (2.6%)/ 601 (2.0%)

1.15 (0.90, 1.47)

53 (2.6%)/ 459 (2.3%)

1.04 (0.77, 1.41)

27 (2.6%)/ 142 (1.4%)

1.32 (0.85, 2.06)

0.076

9.4(10.9)

Neurotic, stressrelated

157 (5.2%)/ 1221 (4.0%)

1.11 (0.91, 1.35)

71 (3.5%)/ 688 (3.4%)

0.89 (0.67, 1.20)

86 (8.3%)/ 533 (5.1%)

1.34 (1.03, 1.76)

0.017

20.4(22.7)

TE D

EP

AC C

Events among females with CLP/ without OFC (N,%)

SC

Diagnosis

M AN U

Adjusted HR (95% CI)b

FEMALES CLP, N=1039a No OFC N =10369a

RI PT

TOTAL CLP, N=3048a No OFC N=30476a

ACCEPTED MANUSCRIPT

77 (2.5%)/ 753 (2.5%)

1.02 (0.79, 1.33)

55 (2.7%)/ 527 (2.6%)

1.05 (0.77, 1.42)

22 (2.1%)/ 226 (2.2%)

0.98 (0.61, 1.57)

0.911

21.5(21.4)

Personality disorders

21 (0.7%)/ 176 (0.6%)

1.24 (0.74, 2.08)

9 (0.4%)/ 96 (0.5%)

1.14 (0.55, 2.35)

12 (1.2%)/ 80 (0.8%)

1.37 (0.63, 2.96)

0.764

22.1(25.1)

Suicide attempt

35 (1.1%)/ 303 (1.0%)

0.83 (0.54, 1.26)

14 (0.7%)/ 163 (0.8%)

0.83 (0.45, 1.52)

21 (2.0%)/ 140 (1.4%)

0.81 (0.44, 1.48)

0.793

23.1(21.3)

4 (0.1%)/ 21 (0.1%)

1.59 (0.35, 7.22)

1 (0.0%)/ 18 (0.1%)

-

3 (0.3%)/ 3 (0.0%)

-

-

24.8(25.8)

Suicide

RI PT

Alcohol and drug Use

Note: ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder When performing analyses for the outcome of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), individuals that died before the introduction of International Classification of Diseases (ICD)-9 were excluded, because those diagnoses were not included in ICD-8. Thus, those hazard ratios (HR) were calculated on the basis of 1031 females/1996 males with CLP and 10322 females/20006 males without orofacial cleft.

SC

a

M AN U

b

AC C

EP

TE D

Adjusted for perinatal complications (born preterm, low Apgar score (defined as < 7 at 5 minutes after birth), Small for Gestational Age and low birth weight <2500g, all congenital malformations, deformations and chromosomal abnormalities, sex (in the non-stratified per sex analyses), season and year of birth, and different sociodemographic factors among parents (mean age of the parents, maternal country of birth, parental level of education) and parental psychiatric morbidity.

ACCEPTED MANUSCRIPT Table S6 Adjusted Cox-Derived Hazard Ratios (aHRs) With 95% CIs for Psychiatric Diagnoses Among Children With Non–Syndromic Cleft Palate Only (CPO) Compared to Children Without Orofacial Cleft (OFC) TOTAL CPO, N=3436a No OFC N=34356a

MALES CPO, N=1625a No OFC N=16271a

Events among children with CPO/ without OFC (N,%)

Adjusted HR (95% CI)b

p value for sexaCPO interactio n

Mean age at event for CPO (No OFC)

Any psychiatric

796 (23.2%)/ 3666 (10.7%)

2.01 (1.85, 2.19)

388 (23.9%)/ 1764 (10.8%)

2.13 (1.88,2.41)

408(22.5%)/ 1902 (10.5%)

1.90(1.69, 2.14)

0.901

10.7(16.5)

Intellectual disability

266 (7.7%)/ 229 (0.7%)

5.23 (4.26, 6.42)

137 (8.4%)/ 120 (0.7%)

5.30 (3.99, 7.04)

129 (7.1%)/ 109 (0.6%)

5.13 (3.81, 6.92)

0.379

8.6(11.2)

Language disorders

151 (4.4%)/ 149 (0.4%)

7.09 (5.42, 9.29)

87 (5.4%)/ 100 (0.6%)

6.77 (4.77, 9.62)

64 (3.5%)/ 49 (0.3%)

7.76 (5.10, 11.82)

0.181

6.6(7.4)

Psychotic

20 (0.6%)/ 90 (0.3%)

2.16 (1.22, 3.83)

11 (0.7%)/ 54 (0.3%)

1.97 (0.87, 4.44)

9 (0.5%)/ 36 (0.2%)

2.66 (1.20, 5.89)

0.597

20.2(23.8)

Bipolar

19 (0.6%)/ 134 (0.4%)

1.44 (0.83, 2.49)

8 (0.5%)/ 40 (0.2%)

2.67 (1.13, 6.35)

11 (0.6%)/ 94 (0.5%)

1.07 (0.52, 2.19)

0.191

25.0(25.0)

Depression

105 (3.1%)/ 888 (2.6%)

1.11 (0.88, 1.40)

41 (2.5%)/ 295 (1.8%)

1.47 (1.02, 2.12)

64 (3.5%)/ 593 (3.3%)

0.95 (0.71, 1.27)

0.266

22.3(22.5)

Eating disorders

55 (1.6%)/ 261 (0.8%)

1.00 (0.61, 1.64)

1 (0.1%)/ 16 (0.1%)

0.94 (0.12, 7.50)

18 (1.0%)/ 192 (1.1%)

1.00 (0.60, 1.67)

0.733

20.1(19.1)

ASD

117 (3.4%)/ 330 (1.0%)

2.74 (2.19, 3.43)

68 (4.2%)/ 205 (1.3%)

2.71 (2.02, 3.64)

49 (2.7%)/ 125 (0.7%)

2.72 (1.92, 3.84)

0.535

15.0(14.8)

ADHD

126 (3.7%)/ 653 (1.9%)

1.59 (1.29, 1.96)

81 (5.0%)/ 429 (2.6%)

1.56 (1.20, 2.05)

45 (2.5%)/ 224 (1.2%)

1.56 (1.13, 2.16)

0.388

13.8(15.9)

Other behavioral

136 (4.0%)/ 609 (1.8%)

1.93 (1.57, 2.36)

75 (4.6%)/ 382 (2.3%)

1.79 (1.36, 2.38)

61 (3.4%)/ 227 (1.3%)

2.03 (1.53, 2.70)

0.086

8.6(9.4)

Neurotic, stressrelated

160 (4.7%)/ 1322 (3.8%)

1.15 (0.96, 1.38)

61 (3.8%)/ 473 (2.9%)

1.30 (0.98, 1.74)

99 (5.5%)/ 849 (4.7%)

1.08 (0.86, 1.36)

0.255

18.4(21.9)

Adjusted HR (95% CI)b

AC C

EP

TE D

M AN U

Adjusted HR (95% CI)b

Events among females with CPO/ without OFC (N,%)

RI PT

Diagnosis

SC

Events among males with CPO/ without OFC (N,%)

FEMALES CPO, N=1811a No OFC N =18085a

ACCEPTED MANUSCRIPT

79 (2.3%)/ 799 (2.3%)

1.04 (0.82, 1.34)

44 (2.7%)/ 423 (2.6%)

1.11 (0.79, 1.56)

35 (1.9%)/ 376 (2.1%)

0.97 (0.67, 1.39)

0.823

20.9(20.4)

Personality disorders

24 (0.7%)/ 171 (0.5%)

1.24 (0.76, 2.03)

12 (0.7%)/ 57 (0.4%)

2.42 (1.19, 4.92)

12 (0.7%)/ 114 (0.6%)

0.78 (0.40, 1.52)

0.123

22.7(24.5)

Suicide attempt

31 (0.9%)/ 334 (1.0%)

0.88 (0.59, 1.31)

15 (0.9%)/ 108 (0.7%)

1.49 (0.84, 2.65)

16 (0.9%)/ 226 (1.2%)

0.62 (0.36, 1.07)

0.11

20.7(21.1)

2 (0.1%)/ 18 (0.1%)

1.24 (0.26, 5.89)

2 (0.1%)/ 16 (0.1%)

1.23 (0.26, 5.89)

0 (0.0%)/ 2 (0.0%)

-

-

28.5(25.2)

Suicide

RI PT

Alcohol and drug Use

SC

Note: ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder a When performing analyses for the outcome of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), individuals that died before the introduction of International Classification of Diseases (ICD)-9 were excluded, because those diagnoses were not included in ICD-8. Thus, those HR were calculated on the basis of 1800 females/1616 males with CPO and 18008 females/16200 males without OFC.

M AN U

b

AC C

EP

TE D

Adjusted for such as perinatal complications (born preterm, low Apgar score (defined as < 7 at 5 minutes after birth), Small for Gestational Age and low birth weight <2500g, all congenital malformations, deformations and chromosomal abnormalities, sex (in the non-stratified per sex analyses), season and year of birth, and different sociodemographic factors among parents (mean age of the parents, maternal country of birth, parental level of education) and parental psychiatric morbidity.

ACCEPTED MANUSCRIPT Table S7 Adjusted Cox-Derived Hazard Ratios (Ahrs) With 95% CIs for Psychiatric Diagnoses Among Full Siblings Without Orofacial Cleft (OFC) Compared to Their Siblings With Orofacial Cleft (OFC). MALE SIBLINGS No OFC, N=4891a OFC, N=3984a

FEMALE SIBLINGS No OFC, N =4500a OFC, N=2900a

RI PT

TOTAL SIBLINGS No OFC, N=9637a OFC, N=6884a Events among siblings without OFC/ with OFC (N,%)

Adjusted HR (95% CI)b

Events among male siblings without OFC/ males OFC (N,%)

Adjusted HR (95% CI)b

Events among female siblings without OFC/ females OFC (N,%)

Adjusted HR (95% CI)b

Any psychiatric

1176 (12.2%)/ 1357 (19.7%)

0.697 (0.639, 0.760)

598 (12.2%)/ 728 (18.3%)

0.716 (0.635, 0.807)

578 (12.8%)/ 629 (21.7%)

0.679 (0.597, 0.773)

Intellectual disability

97 (1.0%)/ 381 (5.5%)

0.367 (0.289, 0.466)

62 (1.3%)/ 200 (5.0%)

0.421 (0.310, 0.572)

35 (0.8%)/ 181 (6.2%)

0.314 (0.212, 0.464)

Language disorders

53 (0.5%)/ 204 (3.0%)

0.277 (0.197, 0.388)

37 (0.8%)/ 131 (3.3%)

0.303 (0.205, 0.449)

16 (0.4%)/ 73 (2.5%)

0.233 (0.125, 0.437)

0.259

Psychotic

42 (0.4%)/ 42 (0.6%)

0.732 (0.439, 1.220)

23 (0.5%)/ 21 (0.5%)

1.031 (0.525, 2.027)

19 (0.4%)/ 21 (0.7%)

0.472 (0.218, 1.023)

-

Bipolar

43 (0.4%)/ 28 (0.4%)

1.228 (0.656, 2.298)

17 (0.3%)/ 11 (0.3%)

1.591 (0.626, 4.039)

26 (0.6%)/ 17 (0.6%)

1.068 (0.445, 2.561)

-

303 (3.1%)/ 209 (3.0%)

1.119 (0.914, 1.370)

121 (2.5%)/ 93 (2.3%)

1.174 (0.858, 1.606)

182 (4.0%)/ 116 (4.0%)

1.069 (0.816, 1.402)

-

56 (0.6%)/ 33 (0.5%)

1.038 (0.624, 1.728)

3 (0.1%)/ 1 (0.0%)

-

53 (1.2%)/ 32 (1.1%)

0.978 (0.575, 1.662)

-

ASD

122 (1.3%)/ 172 (2.5%)

0.736 (0.577, 0.940)

85 (1.7%)/ 104 (2.6%)

0.871 (0.648, 1.170)

37 (0.8%)/ 68 (2.4%)

0.539 (0.341, 0.852)

-

ADHD

192 (2.0%)/ 203 (3.0%)

0.785 (0.638, 0.966)

128 (2.6%)/ 137 (3.5%)

0.846 (0.654, 1.095)

64 (1.4%)/ 66 (2.3%)

0.698 (0.483, 1.007)

-

Other behavioral

187 (1.9%)/ 214 (3.1%)

0.798 (0.646, 0.985)

112 (2.3%)/ 133 (3.3%)

0.766 (0.589, 0.997)

75 (1.7%)/ 81 (2.8%)

0.899 (0.632, 1.280)

0.661

Neurotic, stressrelated

471 (4.9%)/ 337 (4.9%)

0.995 (0.850, 1.166)

187 (3.8%)/ 140 (3.5%)

1.093 (0.853, 1.400)

284 (6.3%)/ 197 (6.8%)

0.937 (0.761, 1.153)

0.267

M AN U

TE D

EP

Eating disorders

AC C

Depression

SC

Diagnosis

p value for sexaOFC interaction

0.014

ACCEPTED MANUSCRIPT

Personality disorders Suicide attempt Suicide

241 (2.5%)/ 182 (2.6%)

0.862 (0.699, 1.063)

143 (2.9%)/ 118 (3.0%)

0.858 (0.655, 1.124)

98 (2.2%)/ 64 (2.2%)

0.857 (0.604, 1.214)

0.459

68 (0.7%)/ 59 (0.9%)

0.805 (0.544, 1.192)

22 (0.4%)/ 26 (0.7%)

0.698 (0.359, 1.355)

46 (1.0%)/ 33 (1.1%)

0.868 (0.523, 1.442)

-

107 (1.1%)/ 73 (1.1%)

1.056 (0.769, 1.451)

36 (0.7%)/ 31 (0.8%)

0.887 (0.542, 1.451)

71 (1.6%)/ 42 (1.4%)

1.233 (0.796, 1.908)

-

13 (0.1%)/ 8 (0.1%)

2.129 (0.637, 7.122)

9 (0.2%)/ 5 (0.1%)

3.143 (0.862, 11.458)

3 (0.1%)/ 3 (0.1%)

-

-

RI PT

Alcohol and drug Use

Note: ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder When performing analyses for the outcome of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), individuals that died before the introduction of International Classification of Diseases (ICD)-9 were excluded, because those diagnoses were not included in ICD-8. Thus, those hazard ratios (HR) were calculated on the basis of 4485 females/4870 males without OFC and 2882 female/3962 male siblings with OFC.

SC

a

M AN U

b

AC C

EP

TE D

Adjusted for perinatal complications (born preterm, low Apgar score (defined as < 7 at 5 minutes after birth), Small for Gestational Age and low birth weight <2500g, all congenital malformations, deformations and chromosomal abnormalities, sex (in the non-stratified per sex analyses), season and year of birth, and different sociodemographic factors among parents (mean age of the parents, maternal country of birth, parental level of education) and parental psychiatric morbidity.

ACCEPTED MANUSCRIPT Table S8 Adjusted Cox-Derived Hazard Ratios (aHRs) With 95% CIs for Psychiatric Diagnoses Among Full Siblings Without Orofacial Cleft (OFC) Compared to Their Siblings With Non–Syndromic Cleft Lip (CL). TOTAL SIBLINGS No OFC, N=3191a CL, N=2253a

MALE SIBLINGS No OFC, N=1608a CL, N=1437a

FEMALE SIBLINGS No OFC, N =1505a CL, N=816a

Events among siblings without OFC/ with CL (N,%)

Adjusted HR (95% CI)**

Events among male siblings without OFC/ with CL (N,%)

Adjusted HR (95% CI)b

Events among female siblings without OFC/ with CL (N,%)

Adjusted HR (95% CI)b

Any psychiatric

379 (11.9%)/ 347 (15.4%)

0.824 (0.705, 0.964)

181 (11.3%)/ 203 (14.1%)

0.875 (0.707, 1.084)

198 (13.2%)/ 144 (17.6%)

0.795 (0.625, 1.010)

0.567

Intellectual disability

38 (1.2%)/ 73 (3.2%)

0.660 (0.441, 0.987)

22 (1.4%)/ 39 (2.7%)

0.840 (0.495, 1.425)

16 (1.1%)/ 34 (4.2%)

0.520 (0.279, 0.970)

-

Language disorders

15 (0.5%)/ 32 (1.4%)

0.467 (0.235, 0.930)

12 (0.7%)/ 23 (1.6%)

0.590 (0.280, 1.244)

3 (0.2%)/ 9 (1.1%)

0.172 (0.026, 1.115)

0.085

Psychotic

11 (0.3%)/ 13 (0.6%)

0.828 (0.338, 2.027)

5 (0.3%)/ 10 (0.7%)

0.833 (0.186, 3.729)

6 (0.4%)/ 3 (0.4%)

1.032 (0.208, 5.129)

0.617

Bipolar

10 (0.3%)/ 12 (0.5%)

0.440 (0.139, 1.397)

5 (0.3%)/ 7 (0.5%)

0.659 (0.176, 2.460)

5 (0.3%)/ 5 (0.6%)

0.249 (0.044, 1.391)

-

104 (3.3%)/ 55 (2.4%)

1.404 (0.969, 2.034)

39 (2.4%)/ 22 (1.5%)

2.227 (1.282, 3.869)

65 (4.3%)/ 33 (4.0%)

1.053 (0.660, 1.682)

-

Eating disorders

21 (0.7%)/ 9 (0.4%)

1.136 (0.454, 2.844)

2 (0.1%)/ 0 (0.0%)

-

19 (1.3%)/ 9 (1.1%)

0.978 (0.385, 2.488)

-

ASD

47 (1.5%)/ 33 (1.5%)

1.225 (0.780, 1.925)

26 (1.6%)/ 20 (1.4%)

1.407 (0.811, 2.440)

21 (1.4%)/ 13 (1.6%)

0.957 (0.457, 2.005)

-

ADHD

51 (1.6%)/ 55 (2.4%)

0.686 (0.474, 0.993)

30 (1.9%)/ 38 (2.7%)

0.704 (0.440, 1.126)

21 (1.4%)/ 17 (2.1%)

0.672 (0.355, 1.274)

-

Other behavioral

50 (1.6%)/ 60 (2.7%)

0.664 (0.455, 0.970)

30 (1.9%)/ 41 (2.9%)

0.639 (0.401, 1.017)

20 (1.3%)/ 19 (2.3%)

0.714 (0.375, 1.357)

-

Neurotic, stressrelated

150 (4.7%)/ 92 (4.1%)

1.122 (0.835, 1.509)

54 (3.4%)/ 41 (2.9%)

1.350 (0.853, 2.138)

96 (6.4%)/ 51 (6.3%)

0.999 (0.683, 1.461)

-

SC

M AN U

TE D

EP

AC C

Depression

RI PT

Diagnosis

p value for sexaOFC interaction

ACCEPTED MANUSCRIPT

80 (2.5%)/ 63 (2.8%)

0.845 (0.592, 1.207)

48 (3.0%)/ 45 (3.1%)

0.839 (0.534, 1.319)

32 (2.1%)/ 18 (2.2%)

0.884 (0.473, 1.652)

-

Personality disorders

21 (0.7%)/ 23 (1.0%)

0.676 (0.353, 1.297)

6 (0.4%)/ 10 (0.7%)

0.963 (0.312, 2.973)

15 (1.0%)/ 13 (1.6%)

0.631 (0.286, 1.390)

0.491

Suicide attempt

35 (1.1%)/ 25 (1.1%)

0.903 (0.533, 1.530)

12 (0.7%)/ 10 (0.7%)

1.010 (0.425, 2.402)

23 (1.5%)/ 15 (1.8%)

0.841 (0.412, 1.720)

0.583

6 (0.2%)/ 2 (0.1%)

3.755 (0.539, 26.172)

5 (0.3%)/ 2 (0.1%)

3.301 (0.540, 20.182)

1 (0.1%)/ 0 (0.0%)

-

-

Suicide

SC

Note: ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder

RI PT

Alcohol and drug Use

a

M AN U

When performing analyses for the outcome of ADHD and ASD, individuals that died before the introduction of International Classification of Diseases (ICD)-9 were excluded, because those diagnoses were not included in ICD-8. Thus, those hazard ratios (HR) were calculated on the basis of 1503 female/1601 male siblings without OFC and 812 female/1433 male siblings with CL.

b

AC C

EP

TE D

Adjusted for perinatal complications (born preterm, low Apgar score (defined as < 7 at 5 minutes after birth), Small for Gestational Age and low birth weight <2500g, all congenital malformations, deformations and chromosomal abnormalities, sex (in the non-stratified per sex analyses), season and year of birth, and different sociodemographic factors among parents (mean age of the parents, maternal country of birth, parental level of education) and parental psychiatric morbidity.

ACCEPTED MANUSCRIPT Table S9 Adjusted Cox-Derived Hazard Ratios (aHRs) with 95% CIs for Psychiatric Diagnoses Among Full Siblings Without Orofacial Cleft (OFC) Compared to Their Siblings With Non–Syndromic Cleft Lip and Palate (CLP) TOTAL SIBLINGS No OFC, N=3651a CLP, N=2632a

FEMALE SIBLINGS No OFC, N =1693a CLP, N=898a

MALE SIBLINGS No OFC, N=1870a CLP, N=1734a

Events among siblings without OFC/ with CLP (N,%)

Adjusted HR (95% CI)b

Events among male siblings without OFC/ with CLP (N,%)

Adjusted HR (95% CI)b

Events among female siblings without OFC/ with CLP (N,%)

Adjusted HR (95% CI)**

Any psychiatric

449(12.3%)/ 509 (19.3%)

0.708 (0.614, 0.817)

224 (12.0%)/ 287 (16.6%)

0.801 (0.659, 0.974)

225 (13.3%)/ 222 (24.7%)

0.606 (0.486, 0.754)

0.003

Intellectual disability

36 (1.0%)/ 134 (5.1%)

0.392 (0.263, 0.586)

23 (1.2%)/ 67 (3.9%)

0.568 (0.342, 0.942)

13 (0.8%)/ 67 (7.5%)

0.257 (0.132, 0.501)

0.006

Language disorders

14 (0.4%)/ 69 (2.6%)

0.211 (0.112, 0.395)

9 (0.5%)/ 50 (2.9%)

0.205 (0.098, 0.432)

19 (2.1%)/ 5 (0.3%)

0.220 (0.071, 0.681)

0.994

Psychotic

18 (0.5%)/ 16 (0.6%)

0.730 (0.300, 1.778)

9 (0.5%)/ 5 (0.3%)

1.856 (0.458, 7.521)

9 (0.5%)/ 11 (1.2%)

0.355 (0.109, 1.158)

-

Bipolar

20 (0.5%)/ 8 (0.3%)

2.536 (0.857, 7.504)

7 (0.4%)/ 2 (0.1%)

3.527 (0.000, 0.000)

13 (0.8%)/ 6 (0.7%)

1.959 (0.381, 10.067)

0.605

123 (3.4%)/ 83 (3.2%)

1.151 (0.825, 1.606)

51 (2.7%)/ 46 (2.7%)

1.055 (0.663, 1.677)

72 (4.3%)/ 37 (4.1%)

1.243 (0.764, 2.023)

-

Eating disorders

27 (0.7%)/ 13 (0.5%)

0.948 (0.398, 2.260)

1 (0.1%)/ 1 (0.1%)

-

26 (1.5%)/ 12 (1.3%)

0.871 (0.347, 2.192)

-

ASD

44 (1.2%)/ 52 (2.0%)

0.977 (0.612, 1.562)

33 (1.8%)/ 36 (2.1%)

1.196 (0.714, 2.001)

11 (0.7%)/ 16 (1.8%)

0.587 (0.201, 1.718)

-

ADHD

81 (2.2%)/ 70 (2.7%)

1.051 (0.734, 1.505)

55 (3.0%)/ 52 (3.0%)

1.170 (0.763, 1.794)

26 (1.5%)/ 18 (2.0%)

0.802 (0.414, 1.553)

-

Other behavioral

69 (1.9%)/ 74 (2.8%)

0.927 (0.640, 1.344)

41 (2.2%)/ 49 (2.8%)

0.920 (0.584, 1.450)

28 (1.7%)/ 25 (2.8%)

0.946 (0.514, 1.741)

-

Neurotic, stressrelated

178 (4.9%)/ 136 (5.2%)

0.848 (0.656, 1.095)

73 (3.9%)/ 58 (3.3%)

1.109 (0.741, 1.661)

105 (6.2%)/ 78 (8.7%)

0.687 (0.490, 0.964)

-

SC

M AN U

TE D

EP

AC C

Depression

RI PT

Diagnosis

p value for sexaCLP interaction

ACCEPTED MANUSCRIPT

104 (2.8%)/ 65 (2.5%)

1.072 (0.769, 1.496)

59 (3.2%)/ 45 (2.6%)

1.069 (0.704, 1.624)

45 (2.7%)/ 20 (2.2%)

1.036 (0.573, 1.872)

0.32

Personality disorders

30 (0.8%)/ 19 (0.7%)

0.854 (0.441, 1.653)

10 (0.5%)/ 8 (0.5%)

1.007 (0.349, 2.905)

20 (1.2%)/ 11 (1.2%)

0.757 (0.304, 1.883)

-

Suicide attempt

47 (1.3%)/ 27 (1.0%)

1.430 (0.815, 2.506)

18 (1.0%)/ 10 (0.6%)

1.364 (0.622, 2.988)

29 (1.7%)/ 17 (1.9%)

1.489 (0.650, 3.411)

-

7 (0.2%)/ 4 (0.2%)

2.182 (0.000, 0.000)

4 (0.2%)/ 1 (0.1%)

-

2 (0.1%)/ 3 (0.3%)

0.000 (0.000, 0.000)

-

Suicide

RI PT

Alcohol and drug Use

SC

Note: ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder a When performing analyses for the outcome of ADHD and ASD, individuals that died before the introduction of International Classification of Diseases (ICD)-9 were excluded, because those diagnoses were not included in ICD-8. Thus, those hazard ratios (HR) were calculated on the basis of 1687 female/1859 male siblings without OFC and 891 female/1721 male siblings with CLP

M AN U

b

AC C

EP

TE D

Adjusted for perinatal complications (born preterm, low Apgar score (defined as < 7 at 5 minutes after birth), Small for Gestational Age and low birth weight <2500g, all congenital malformations, deformations and chromosomal abnormalities, sex (in the non-stratified per sex analyses), season and year of birth, and different sociodemographic factors among parents (mean age of the parents, maternal country of birth, parental level of education) and parental psychiatric morbidity.

ACCEPTED MANUSCRIPT Table S10 Adjusted Cox-Derived Hazard Ratios (aHRs) With 95% CIs for Psychiatric Diagnoses Among Full Siblings Without Orofacial Cleft (OFC) Compared to Their Siblings With Non–Syndromic Cleft Palate Only (CPO). TOTAL SIBLINGS No OFC, N=4242a CPO, N=3039a

FEMALE SIBLINGS No OFC, N =1973a CPO, N=1599a

Adjusted HR (95% CI)b

Events among male siblings without OFC/ with CPO (N,%)

Adjusted HR (95% CI)b

Events among female siblings without OFC/ with CPO (N,%)

Adjusted HR (95% CI)b

519 (12.2%)/ 718 (23.6%)

0.605 (0.531, 0.690)

261 (12.1%)/ 350 (24.3%)

0.532 (0.443, 0.638)

258 (13.1%)/ 368 (23.0%)

0.695 (0.578, 0.836)

0.212

Intellectual disability

42 (1.0%)/ 243 (8.0%)

0.253 (0.176, 0.364)

28 (1.3%)/ 126 (8.8%)

0.255 (0.161, 0.405)

14 (0.7%)/ 117 (7.3%)

0.255 (0.137, 0.474)

-

Language disorders

30 (0.7%)/ 137 (4.5%)

0.217 (0.142, 0.332)

21 (1.0%)/ 82 (5.7%)

0.209 (0.124, 0.351)

9 (0.5%)/ 55 (3.4%)

0.231 (0.101, 0.524)

0.149

Psychotic

14 (0.3%)/ 18 (0.6%)

0.512 (0.227, 1.154)

9 (0.4%)/ 9 (0.6%)

0.850 (0.280, 2.584)

5 (0.3%)/ 9 (0.6%)

0.243 (0.053, 1.115)

0.512

Bipolar

21 (0.5%)/ 14 (0.5%)

1.194 (0.478, 2.985)

7 (0.3%)/ 4 (0.3%)

2.028 (0.356, 11.553)

14 (0.7%)/ 10 (0.6%)

1.025 (0.328, 3.203)

-

130 (3.1%)/ 93 (3.1%)

1.012 (0.748, 1.368)

49 (2.3%)/ 35 (2.4%)

0.856 (0.514, 1.426)

81 (4.1%)/ 58 (3.6%)

1.096 (0.738, 1.627)

-

Eating disorders

23 (0.5%)/ 17 (0.6%)

1.108 (0.523, 2.348)

0 (0.0%)/ 0 (0.0%)

-

23 (1.2%)/ 17 (1.1%)

1.109 (0.525, 2.343)

-

ASD

48 (1.1%)/ 106 (3.5%)

0.469 (0.329, 0.669)

36 (1.7%)/ 59 (4.1%)

0.524 (0.337, 0.814)

12 (0.6%)/ 47 (3.0%)

0.377 (0.178, 0.796)

-

ADHD

86 (2.0%)/ 113 (3.7%)

0.674 (0.497, 0.914)

58 (2.7%)/ 71 (5.0%)

0.671 (0.452, 0.997)

28 (1.4%)/ 42 (2.6%)

0.710 (0.435, 1.160)

-

Other behavioral

99 (2.3%)/ 121 (4.0%)

0.825 (0.612, 1.113)

62 (2.9%)/ 67 (4.7%)

0.768 (0.526, 1.122)

37 (1.9%)/ 54 (3.4%)

1.002 (0.606, 1.657)

-

Neurotic, stressrelated

211 (5.0%)/ 144 (4.7%)

1.103 (0.872, 1.395)

81 (3.8%)/ 51 (3.5%)

1.051 (0.715, 1.545)

130 (6.6%)/ 93 (5.8%)

1.147 (0.854, 1.540)

0.843

SC

M AN U

TE D

Depression

EP

Any psychiatric

RI PT

Events among siblings without OFC/ with CPO (N,%)

AC C

Diagnosis

MALE SIBLINGS No OFC, N=2157a CPO, N=1440a

p value for sexaCPO interaction

ACCEPTED MANUSCRIPT

86 (2.0%)/ 71 (2.3%)

0.747 (0.528, 1.055)

49 (2.3%)/ 38 (2.6%)

0.728 (0.453, 1.170)

37 (1.9%)/ 33 (2.1%)

0.779 (0.467, 1.301)

-

Personality disorders

25 (0.6%)/ 18 (0.6%)

1.155 (0.567, 2.351)

8 (0.4%)/ 8 (0.6%)

0.463 (0.128, 1.675)

17 (0.9%)/ 10 (0.6%)

1.905 (0.808, 4.494)

0.198

Suicide attempt

44 (1.0%)/ 28 (0.9%)

1.173 (0.693, 1.986)

12 (0.6%)/ 12 (0.8%)

0.599 (0.257, 1.397)

32 (1.6%)/ 16 (1.0%)

1.712 (0.877, 3.342)

0.333

6 (0.1%)/ 2 (0.1%)

2.161 (0.395, 11.834)

4 (0.2%)/ 2 (0.1%)

1.342 (0.318, 5.654)

1 (0.1%)/ 0 (0.0%)

-

-

Suicide

RI PT

Alcohol and drug Use

Note: ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder When perforing analyses for the outcome of ADHD and ASD, individuals that died before the introduction of International Classification of Diseases (ICD)-9 were excluded, because those diagnoses were not included in International Classification of Diseases (ICD)-8. Thus, those HR were calculated on the basis of 1966 female/2150 male siblings without OFC and 1592 female/1432 male siblings with CPO.

SC

a

M AN U

b

AC C

EP

TE D

Adjusted for perinatal complications (born preterm, low Apgar score (defined as < 7 at 5 minutes after birth), Small for Gestational Age and low birth weight <2500g, all congenital malformations, deformations and chromosomal abnormalities, sex (in the non-stratified per sex analyses), season and year of birth, and different sociodemographic factors among parents (mean age of the parents, maternal country of birth, parental level of education) and parental psychiatric morbidity.