static.cambridge.org€¦  · Web viewPsychotropic drugs with at least one dispensation overlapping the pregnancy* Abbreviations: ATC, Anatomical Therapeutic Chemical Classification

SUPPLEMENTARY APPENDIX

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: Viktorin A, Uher R, Reichenberg A, Levine SZ, Sandin S. Antidepressant medication during pregnancy and autism spectrum disorder.

TABLE OF CONTENTS

Supplementary Table 1. Complete list of ATC codes and names of drugs considered in the study......................page 2

Supplementary Table 2. Psychotropic drugs with at least one dispensation overlapping the pregnancy.............. page 3

Supplementary Figure 1. Antidepressant dispensations around pregnancy..........................................................page 4

Supplementary Figure 2. Medication exposure definition...................................................................................... page 5

Supplementary Table 3. Mental illness sub-groups and corresponding diagnosis codes......................................page 6

Supplementary Figure 3. Relative risks of ASD in offspring of mothers with one, or at least two

medication dispensations overlapping pregnancy....................................................................................................page 7

Supplementary Figure 4. Plotted Schoenfeldt residuals for each covariate with 4 degrees of freedom................page 8

Supplementary Figure 5. Relative risks of ASD in offspring of mothers treated with any antidepressant,

or specifically SSRI antidepressants, non-SSRI antidepressants, or non-antidepressant psychotropic

drugs......................................................................................................................................................................... page 13

Supplementary Figure 6. Relative risks of ASD from bootstrapped analyses....................................................... page 14

Supplementary Figure 7. Relative risks of autistic disorder .................................................................................. page 15

Supplementary Figure 8. Sex-combined and sex-specific relative risks of ASD................................................... page 16

Supplementary Figure 9. Analysis additionally adjusted for socioeconomic status as parental education level... page 17

Supplementary Figure 10. Percentage of mothers with at least one lifetime diagnosis in different

psychiatric disorder categories................................................................................................................................. page 18

Supplementary Figure 11. Relative risks of ASD in offspring of mothers treated with any antidepressant,

compared to control children of mothers not using any psychotropic medication but with increasing mean

number of psychiatric disorders diagnosed during lifetime...................................................................................... page 19

Supplementary Figure 12. Relative risks of ASD in offspring of mothers treated with specific antidepressants,

compared to control children of mothers not using any psychotropic medication but with increasing mean

number of psychiatric disorders diagnosed during lifetime...................................................................................... page 20

Supplementary Figure 13. Percentage of medicated mothers with a lifetime psychiatric diagnosis......................page 21

1

Supplementary Table 1. Complete list of ATC codes and names of drugs considered in the study

Abbreviations: ATC, Anatomical Therapeutic Chemical Classification System.

2

Supplementary Table 2. Psychotropic drugs with at least one dispensation overlapping the pregnancy*

Abbreviations: ATC, Anatomical Therapeutic Chemical Classification System.

* The sample consists of the mothers with at least two dispensations overlapping pregnancy with either antidepressants (N=3 982) or other psychotropic drugs (N=1 626). The table presents the number of mothers with at least one dispensation overlapping pregnancy with the specific psychotropic drugs considered in the study (see Supplementary Table 1). Any drug listed in Supplementary Table 1 not in this table list was not observed in the sample.

3

Supplementary Figure 1. Antidepressant dispensations around pregnancy

4

Supplementary Figure 2. Medication exposure definitions*

* Exposure to medication during pregnancy was established in both parents using dispensation dates, number of pills dispensed, and the DDD - the assumed average maintenance dose per day for a drug used for its main indication in adults, provided by the World Health Organization (WHO). For antidepressants, medication was assumed to cover the time from the dispensation date until an end date based on number of pills dispensed, assuming one pill was consumed per day. For any other psychotropic drug, the medication period was calculated based on the dispensation dates and the number of pills dispensed divided by the medication-specific DDD. Exposed children were those that born to a mother with either 1) only a single dispensation with a medication period overlapping pregnancy, beginning either during pregnancy (example A1), or prior pregnancy (example A2), or 2) at least two dispensations with medication periods overlapping pregnancy (example B1 and example B2).

5

Supplementary Table 3. Mental illness sub-groups and corresponding diagnosis codes*

Abbreviations: ICD, International Classification of Diseases. ADHD, attention deficit hyperactivity disorder. ASD, autism spectrum disorder. NA, not available.

*Note: * at the end of a diagnosis code indicates all sub-categories.

6

Supplementary Figure 3. Relative risks of ASD in offspring of mothers with one, or at least two medication dispensations overlapping pregnancy*

Abbreviations: ASD, autism spectrum disorder. N, number of births to treated mothers. SSRI, selective serotonin re-uptake inhibitor. CI, confidence interval.

* The sample consists of 179 007 children born during 2006 and 2007, of which 1 641 had been diagnosed with ASD. The figure presents relative risks of ASD and two-sided 95% confidence intervals in children of mothers with either a single drug dispensation with a medication period overlapping pregnancy (Supplementary Figure 1 example A1 and example A2), or at least two drug dispensations with medication periods overlapping the pregnancy, compared with unexposed children (Supplementary Figure 1 example B1 and example B2).

1 Mothers not using antidepressant, but other psychotropic medication during pregnancy.

2 Analyses not adjusted for covariates.

3 Analyses adjusted for birthdate, maternal and paternal age, the father's psychotropic medication overlapping the pregnancy, and the mother's one-time dispensations of antidepressant and/or other psychotropic medication that overlapped the pregnancy.

4 Analyses adjusted for the factors listed in 3, and for any diagnosis of depression in the mother's lifetime (yes/no) (see Supplement Table S3 for specific diagnosis codes).

5 Analyses adjusted for the factors listed in 3, and for any diagnosis of specific psychiatric disorder subgroups in either the mother and/or father's life time (yes/no), including depression, anxiety disorders, substance use disorder, bipolar disorder, compulsive disorder, attention deficit hyperactive disorder (ADHD), autism spectrum disorder, intellectual disability, schizophrenia, and 'other psychiatric diagnosis' (see Supplement Table 3 for specific diagnosis codes).

7

Supplementary Figure 4. Plotted Schoenfeldt residuals for each covariate with 4 degrees of freedom

8

9

10

11

12

Supplementary Figure 5. Relative risks of ASD in offspring of mother treated with any antidepressant, or specifically SSRI antidepressants, non-SSRI antidepressants, or non-antidepressant psychotropic drugs*

Abbreviations: ASD, autism spectrum disorder. N, number of births to treated mothers. SSRI, selective serotonin re-uptake inhibitor. CI, confidence interval.

* The sample consists of 179 007 children born during 2006 and 2007, of which 1 641 had been diagnosed with ASD. The figure presents relative risks of ASD and two-sided 95% confidence intervals in children of mothers with at least two dispensations of antidepressants or other psychotropic medications overlapping the pregnancy, compared with unexposed children.

1 Analyses not adjusted for covariates.

2 Analyses adjusted for birthdate, maternal and paternal age, the father's psychotropic medication overlapping the pregnancy, and the mother's one-time dispensations of antidepressant and/or other psychotropic medication that overlapped the pregnancy.

3 Analyses adjusted for the factors listed in 3, and for any diagnosis of depression in the mother's lifetime (yes/no) (see Supplement Table S3 for specific diagnosis codes).

4 Analyses adjusted for the factors listed in 3, and for any diagnosis of specific psychiatric disorder subgroups in either the mother and/or father's life time (yes/no), including depression, anxiety disorders, substance use disorder, bipolar disorder, compulsive disorder, attention deficit hyperactive disorder (ADHD), autism spectrum disorder, intellectual disability, schizophrenia, and 'other psychiatric diagnosis' (see Supplement Table 3 for specific diagnosis codes).

13

Supplementary Figure 6. Relative risks of ASD from bootstrapped analyses*

Abbreviations: ASD, autism spectrum disorder. N, number of births to treated mothers. SSRI, selective serotonin re-uptake inhibitor. CI, confidence interval.

* The sample consists of 179 007 children born during 2006 and 2007, of which 1 641 had been diagnosed with ASD. Bootstrapping was performed with 100 repetitions. The figure presents relative risks of ASD and two-sided 95% confidence intervals in children of mothers with at least two dispensations of antidepressants or other psychotropic medications overlapping the pregnancy, compared with unexposed children.

1 Analyses not adjusted for covariates.

2 Analyses adjusted for birthdate, maternal and paternal age, the father's psychotropic medication overlapping the pregnancy, and the mother's one-time dispensations of antidepressant and/or other psychotropic medication that overlapped the pregnancy.

3 Analyses adjusted for the factors listed in 3, and for any diagnosis of depression in the mother's lifetime (yes/no) (see Supplement Table S3 for specific diagnosis codes).

4 Analyses adjusted for the factors listed in 3, and for any diagnosis of specific psychiatric disorder subgroups in either the mother and/or father's life time (yes/no), including depression, anxiety disorders, substance use disorder, bipolar disorder, compulsive disorder, attention deficit hyperactive disorder (ADHD), autism spectrum disorder, intellectual disability, schizophrenia, and 'other psychiatric diagnosis' (see Supplement Table 3 for specific diagnosis codes).

14

Supplementary Figure 7. Relative risks of autistic disorder*

Abbreviations: N, number of births to treated mothers. SSRI, selective serotonin re-uptake inhibitor. CI, confidence interval.

* The sample consists of 179 007 children born during 2006 and 2007, of which 1 004 had been diagnosed with autistic disorder (ICD-10: F84.0). The figure presents relative risks of ASD and two-sided 95% confidence intervals in children of mothers with at least two dispensations of antidepressants or other psychotropic medications overlapping the pregnancy, compared with unexposed children.

1 Analyses not adjusted for covariates.

2 Analyses adjusted for birthdate, maternal and paternal age, the father's psychotropic medication overlapping the pregnancy, and the mother's one-time dispensations of antidepressant and/or other psychotropic medication that overlapped the pregnancy.

3 Analyses adjusted for the factors listed in 3, and for any diagnosis of depression in the mother's lifetime (yes/no) (see Supplement Table S3 for specific diagnosis codes).

4 Analyses adjusted for the factors listed in 3, and for any diagnosis of specific psychiatric disorder subgroups in either the mother and/or father's life time (yes/no), including depression, anxiety disorders, substance use disorder, bipolar disorder, compulsive disorder, attention deficit hyperactive disorder (ADHD), autism spectrum disorder, intellectual disability, schizophrenia, and 'other psychiatric diagnosis' (see Supplement Table 3 for specific diagnosis codes).

15

Supplementary Figure 8. Sex-combined and sex-specific relative risks of ASD*

Abbreviations: ASD, autism spectrum disorder. N, number of births to treated mothers. CI, confidence interval.

* The sample consists of 179 007 children born during 2006 and 2007, of which 90 090 (51.5%) were males and 84 935 (48.5%) females. There were 1 641 children diagnosed with ASD, of which 1 233 (75.1%) where male and 408 (24.9%) female. The figure presents relative risks of ASD and two-sided 95% confidence intervals in children of mothers with at least two dispensations of antidepressants or other psychotropic medications overlapping the pregnancy, compared with unexposed children.

1 Analyses not adjusted for covariates.

2 Analyses adjusted for birthdate, maternal and paternal age, the father's psychotropic medication overlapping the pregnancy, and the mother's one-time dispensations of antidepressant and/or other psychotropic medication that overlapped the pregnancy.

3 Analyses adjusted for the factors listed in 3, and for any diagnosis of depression in the mother's lifetime (yes/no) (see Supplement Table S3 for specific diagnosis codes).

4 Analyses adjusted for the factors listed in 3, and for any diagnosis of specific psychiatric disorder subgroups in either the mother and/or father's life time (yes/no), including depression, anxiety disorders, substance use disorder, bipolar disorder, compulsive disorder, attention deficit hyperactive disorder (ADHD), autism spectrum disorder, intellectual disability, schizophrenia, and 'other psychiatric diagnosis' (see Supplement Table 3 for specific diagnosis codes).

16

Supplementary Figure 9. Analysis additionally adjusted for socioeconomic status as parental education level*

Abbreviations: N, number of children. CI, confidence interval.

* The sample consists of 179,007 children born during 2006 and 2007, of which 1,641 had been diagnosed with ASD. The figure presents relative risks of ASD and two-sided 95% confidence intervals in children of mothers with at least two dispensations of antidepressant drugs overlapping the pregnancy, compared with unexposed children.

1 A clinically relevant sub-sample consisting of 18,551 children, of which 361 had been diagnosed with ASD. All mothers, both medicated and non-medicated, had at least one diagnosis of depression or an anxiety disorder in their lifetime (Table S3). Thereby, the offspring of mothers with medication during pregnancy is contrasted with offspring of mothers that may share similar underlying factors.

2 Analyses not adjusted for covariates.

3 Analyses adjusted for birthdate, maternal and paternal age, the father's psychotropic medication that overlapped the pregnancy, and the mother's one-time dispensations of psychotropic medication that overlapped the pregnancy.

4 Analyses adjusted for the factors listed in 3, and for any diagnosis of depression in the mother's lifetime (yes/no) (see Supplement Table S3 for specific diagnosis codes).

5 Analyses adjusted for the factors listed in 3, and for any diagnosis of specific psychiatric disorder subgroups in either the mother and/or father's life time (yes/no), including depression, anxiety disorders, substance use disorder, bipolar disorder, compulsive disorder, attention deficit hyperactive disorder (ADHD), autism spectrum disorder, intellectual disability, schizophrenia, and 'other psychiatric diagnosis' (see Supplement Table 3 for specific diagnosis codes).

5 Analyses adjusted for the factors listed in 5, and for socioeconomic status in form of the mothers’ and fathers’ educational length at childbirth according to: 1) Compulsory school shorter than 9 years, 2) Compulsory school 9 years, 3) Upper secondary school up to 2 years, 4) Upper secondary school 3 years, 5) Post-secondary education less than 3 years, 6) University 3 years, and 7) Doctoral education.

17

Supplementary Figure 10. Percentage of mothers with at least one lifetime diagnosis in different psychiatric disorder categories*

Abbreviations: ADHD, attention deficit hyperactivity disorder, ASD, autism spectrum disorder.

* The sample consists of mothers having at least one lifetime depression or anxiety diagnosis, and at least two dispensations of antidepressants (corresponding to the medicated mothers in Figure 2). The exact diagnosis codes for each category are given in Supplementary Table 3.

18

Supplementary Figure 11. Relative risks of ASD in offspring of mothers treated with any antidepressant, compared to control children

of mothers not using any psychotropic medication but with increasing mean number of psychiatric disorders diagnosed during lifetime

* Children of mothers with at least two dispensations of antidepressants overlapping pregnancy (N=3,982), compared to control children

of mothers without any psychotropic medication dispensed with a medication period overlapping pregnancy, but with at least one

lifetime diagnosed psychiatric disorder (N=24,285), at least two lifetime diagnosed psychiatric disorders (N=5839), or at least three

lifetime diagnosed psychiatric disorders (N=1,894). The psychiatric disorders included 11 categories described in Supplementary Table

3, and included: Depression, anxiety disorder, substance use disorder, bipolar disorder, compulsive disorder, ADHD, autism spectrum

disorder, intellectual disability, schizophrenia, and 'other psychiatric diagnosis', each coded as 1 or 0.

19

Supplementary Figure 12. Relative risks of ASD in offspring of mothers treated with specific antidepressants, compared to control

children of mothers not using any psychotropic medication but with increasing mean number of psychiatric disorders diagnosed during

lifetime*

* Children of mothers with at least two dispensations of specific antidepressants overlapping pregnancy, compared to control children of

mothers without any psychotropic medication dispensed with a medication period overlapping pregnancy, but with at least one lifetime

diagnosed psychiatric disorder (N=24,285; black box in plot), at least two lifetime diagnosed psychiatric disorders (N=5839; red circle in

plot), or at least three lifetime diagnosed psychiatric disorders (N=1,894; green diamond in plot). The psychiatric disorders included 11

categories described in Supplementary Table 3, and included: Depression, anxiety disorder, substance use disorder, bipolar disorder,

compulsive disorder, ADHD, autism spectrum disorder, intellectual disability, schizophrenia, and 'other psychiatric diagnosis', each

coded as 1 or 0.

20

Supplementary Figure 13. Percentage of medicated mothers with a lifetime psychiatric diagnosis*

Abbreviations: SSRI, selective serotonin re-uptake inhibitor. ADHD, attention-deficit hyperactive disorder. ASD, autism spectrum disorder.

*The sample consists of the mothers with at least two antidepressant dispensations overlapping the pregnancy (N=3 982) or at least two dispensations of other psychotropic medications overlapping the pregnancy (N=1 626).

21