Supplementary Online Content - JAMA...medication during pregnancy, a continuous pattern of dispensations was required according to either a) at least two dispensations during pregnancy

© 2017 American Medical Association. All rights reserved.

Supplementary Online Content

Viktorin A, Uher R, Kolevzon A, Reichenberg A, Levine SZ, Sandin S. Association of

antidepressant medication use during pregnancy with intellectual disability in offspring. JAMA

Psychiatry. Published online July 12, 2017. doi:10.1001/jamapsychiatry.2017.1727

eTable 1. List of Medications Considered in the Study

eTable 2. Psychotropic Drugs During Pregnancy

eTable 3. Detailed Information About Parental Education Levels

eTable 4. Psychiatric Diagnosis Codes Included in the Study

eTable 5. Clinical Subsample Subject Characteristics

eFigure 1. Medication Exposure Definition

eFigure 2. Kaplan-Meier Failure Estimate of Intellectual Disability

eFigure 3. Relative Risks of Intellectual Disability in Children of Mothers With a Single

Dispensation of Any Antidepressant During Pregnancy

eFigure 4. Relative Risks of Intellectual Disability in Children of Mothers With Any Number of

Dispensations of Any Type Antidepressant During Pregnancy

eFigure 5. Plotted Schoenfeldt Residuals for Each Covariate With 4 Degrees of Freedom

eFigure 6. Relative Risks of Mild to Moderate Intellectual Disability

eFigure 7. Relative Risks of Severe Intellectual Disability

eFigure 8. Relative Risks of Intellectual Disability Without Comorbid Autism Spectrum Disorder

eFigure 9. Results From Bootstrapped Analyses

eFigure 10. Sex-Specific and Sex-Combined Relative Risks of Intellectual Disability

eFigure 11. Relative Risks of Intellectual Disability in Children of Mothers Treated With

Antidepressants During Pregnancy, Including Gestational Age and Birth Weight

eFigure 12. Trimester-Specific Relative Risks of Intellectual Disability

eFigure 13. Duration-Dose-Response Effect on the Relative Risk of Intellectual Disability

eFigure 14. Effects of Potential Misclassification in Unexposed Children

eFigure 15. Relative Risks of Intellectual Disability Stratified on Maternal Polypharmacy

eFigure 16. Percentage of Mothers With Medication During Pregnancy and a Psychiatric Diagnosis

Before Child Birth

eFigure 17. Relative risks of Intellectual Disability Due to Exposure to Any Antidepressant During

Pregnancy, Where All Antidepressant Treated Mothers Were Assumed to Have Depression

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eTable 1. List of Medications Considered in the Study*

Abbreviations: ATC, Anatomical Therapeutic Chemical Classification System.

* List of medications with drug names and ATC codes considered in the study.



eTable 2. Psychotropic Drugs During 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 eTable 1). Any drug listed in eTable 1 not in this

table list was not observed in the sample.



eTable 3. Detailed Information About Parental Education Levels

Full Population sample

Antidepressant medication during

pregnancy

Characteristics, N (%) Unexposeda Exposed

b Uncertain

c

Maternal education level

Compulsory school shorter than 9 years 8,179 (4.7) 107 (2.7) 73 (3.1)

Compulsory school 9 years 13,587 (7.9) 620 (15.6) 382 (16.1)

Upper secondary school up to 2 years 19,079 (11.1) 673 (16.9) 387 (16.3)

Upper secondary school 3 years 49,860 (28.9) 1,119

(28.1)

671 (28.2)

Post-secondary education less than 3 years 21,037 (12.2) 486 (12.2) 301 (12.7)

University 3 years 59,315 (34.4) 952 (23.9) 552 (23.2)

Doctoral education 1,589 (0.9) 25 (0.6) 13 (0.6)

Paternal education level

Compulsory school shorter than 9 years 7,732 (4.5) 123 (3.1) 103 (4.3)

Compulsory school 9 years 16,333 (9.5) 506 (12.7) 282 (11.9)

Upper secondary school up to 2 years 35,168 (20.4) 1,013

(25.4)

582 (24.5)

Upper secondary school 3 years 46,771 (27.1) 1,101

(27.7)

680 (28.6)

Post-secondary education less than 3 years 24,063 (13.9) 500 (12.6) 280 (11.8)

University 3 years 40,007 (23.2) 706 (17.7) 431 (18.1)

Doctoral education 2,572 (1.5) 33 (0.8) 21 (0.9)

Abbreviations: N, Number. SD, standard deviation. NA, Not applicable. a Children of mothers with no antidepressant dispensation with a medication period overlapping

pregnancy. b Children of mothers with at least two antidepressant dispensations with medication periods

overlapping pregnancy (eFigure 1 example A1 and example A2). c Children of mothers with a single antidepressant dispensation with a medication period

overlapping pregnancy.



eTable 4. Psychiatric Diagnosis Codes included in the Study*

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.



eTable 5. Clinical Subsample Subject Characteristics

Clinical sub-samplea

Antidepressant medication during pregnancy

Characteristics, No (%) Unexposedb Exposed

c Uncertain

d

Number of offspring 4,976 (62.0) 2,372 (29.6) 673 (8.4)

Offspring with intellectual disability 36 (0.7) 27 (1.1) 6 (0.9)

Offspring with severe intellectual disability 5 (0.1) 3 (0.1) 0 (0.0)

Offspring with intellectual disability without

autism spectrum disorder

28 (0.6) 18 (0.8) 6 (0.9)

Maternal use of psychotropic medication other

than antidepressants during pregnancy

229 (4.6) 448 (18.9) 71 (10.6)

Paternal psychotropic medication during

pregnancy

348 (7.0) 286 (12.1) 64 (9.5)

Birth year

2006 1,912 (38.4) 937 (39.5) 254 (37.7)

2007 3,064 (61.6) 1,435 (60.5) 419 (62.3)

Maternal psychiatric diagnosis 4,976 (100) 2,372 (100) 673 (100)

Paternal psychiatric diagnosis 1,192 (24.0) 590 (24.9) 167 (24.8)

Maternal age (years) at delivery


c Children of mothers with at least two antidepressant dispensations with medication periods

overlapping pregnancy (eFigure 1 example A1 and example A2). d Children of mothers with a single antidepressant dispensation with a medication period

overlapping pregnancy. e Details of mothers’ and fathers’ education within 7 levels is provided in Supplement eTable 3.



eFigure 1. Medication Exposure Definition*

Abbreviations: Disp., dispensation.

* 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. To be classified as using a

medication during pregnancy, a continuous pattern of dispensations was required according to

either a) at least two dispensations during pregnancy (example A in Figure), or b) a single

dispensation (one-time dispensation) during pregnancy, and a second previous dispensation

covering the pregnancy (example B in Figure). However, offspring to mothers with a one-time

dispensation was not included in the main results but analyzed and presented separately (N=2,370;

eFigure 3), and in combination with mothers having at least two dispensations with medication

periods in pregnancy (N=6,361; eFigure 4).



eFigure 2. Kaplan-Meier Failure Estimate of Intellectual Disability*

* Plotted Kaplan-Meier failure estimate of intellectual disability in the children of the cohort,

showing a gradual increase in number of children receiving their first diagnosis of intellectual

disability over follow-up. The children are followed from birth in 2006 and 2007 and throughout

2014 when aged 7 to 8.

0.0

%0

.5%

Pre

va

lence

0 1 2 3 4 5 6 7 8

Analysis time (years)

Kaplan-Meier failure estimate



eFigure 3. Relative Risks of Intellectual Disability in Children of Mothers With a Single

Dispensation of Any Antidepressant During Pregnancy*

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

* The full sample consists of 179,007 children born during 2006 and 2007, of which 873 had been

diagnosed with intellectual disability, and 3,982 had were born to a mother with antidepressant

treatment during pregnancy. The figure presents relative risks of intellectual disability and two-

sided 95% confidence intervals in children of mothers with a single dispensation of an

antidepressant drug overlapping the pregnancy (N=2,379), compared with unexposed children. a A clinically relevant sub-sample consisting of 8,021 children, of which 69 had been diagnosed

with intellectual disability, and 2,372 had were born to a mother with antidepressant treatment

during pregnancy. All mothers, both medicated and non-medicated, had at least one diagnosis of

depression or an anxiety disorder prior child birth (eTable 4). Thereby, the offspring of mothers

with medication during pregnancy is contrasted with offspring of mothers that may share similar

underlying factors. b Analyses not adjusted for covariates.

c Analyses adjusted for birthdate, maternal and paternal age, the father's psychotropic medication

overlapping the pregnancy, and maternal and paternal education level at child birth. d

Analyses adjusted for the factors listed in c, and for any maternal diagnoses of depression prior

child birth (yes/no) (see eTable 4 for specific diagnosis codes). e Analyses adjusted for the factors listed in

c, and for maternal and paternal diagnoses prior child

birth 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 eTable 4 for specific

diagnosis codes).



eFigure 4. Relative Risks of Intellectual Disability in Children of Mothers With Any Number of

Dispensations of Any Type Antidepressant During Pregnancy*

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




sided 95% confidence intervals in children of mothers with any number of dispensations of an

antidepressant drug overlapping the pregnancy (N=6,361), compared with unexposed children. a A clinically relevant sub-sample consisting of 8,021 children, of which 69 had been diagnosed

with intellectual disability, and 3,045 had were born to a mother with any number of antidepressant

dispensations during pregnancy. All mothers, both medicated and non-medicated, had at least one

diagnosis of depression or an anxiety disorder prior child birth (eTable 4). Thereby, the offspring of

mothers with medication during pregnancy is contrasted with offspring of mothers that may share

similar underlying factors. b Analyses not adjusted for covariates.



Analyses adjusted for the factors listed in c, and for any maternal diagnoses of depression prior



birth 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 eTable 4 for specific

diagnosis codes).



eFigure 5. Plotted Schoenfeldt Residuals for Each Covariate With 4 Degrees of Freedom



eFigure 6. Relative Risks of Mild to Moderate Intellectual Disability*

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

CI, confidence interval.

* Relative risks of mild to moderate intellectual disability and two-sided 95% confidence intervals

in children to mothers with antidepressant or other psychotropic medication during pregnancy

compared with children to mothers without any psychotropic medication during pregnancy. The

sample consists of 179,007 children born during 2006 and 2007, of which 767 had been diagnosed

with mild to moderate intellectual disability. a Analyses not adjusted for covariates.

b Analyses adjusted for birthdate, maternal and paternal age, the father's psychotropic medication

overlapping the pregnancy, and maternal and paternal education level at child birth. c Analyses adjusted for the factors listed in

d, and for any maternal diagnosis of depression prior

child birth (yes/no) (see eTable 4 for specific diagnosis codes). d Analyses adjusted for the factors listed in

d, and maternal and paternal diagnoses prior child birth

of specific mental illness subgroups (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 eTable 4 for specific diagnosis codes).



eFigure 7. Relative Risks of Severe Intellectual Disability*



* Relative risks of severe intellectual disability and two-sided 95% confidence intervals in children

to mothers with antidepressant or other psychotropic medication during pregnancy compared with

children to mothers without any psychotropic medication during pregnancy. The sample consists of

179,007 children born during 2006 and 2007, of which 106 had been diagnosed with severe

intellectual disability. a Analyses not adjusted for covariates.












eFigure 8. Relative Risks of Intellectual Disability Without Comorbid Autism Spectrum Disorder*



* Relative risks of intellectual disability without comorbid autism spectrum disorder and two-sided

95% confidence intervals in children to mothers with antidepressant or other psychotropic

medication during pregnancy compared with children to mothers without any psychotropic

medication during pregnancy. The sample consists of 179,007 children born during 2006 and 2007,

of which 513 had been diagnosed with intellectual disability without comorbid autism spectrum

disorder. a Analyses not adjusted for covariates.












eFigure 9. Results From Bootstrapped Analyses*



* Relative risks of intellectual disability and two-sided 95% confidence intervals in children to

mothers with antidepressant or other psychotropic medication during pregnancy compared with

children to mothers without any psychotropic medication during pregnancy. The sample consists of

179,007 children born during 2006 and 2007, of which 873 had been diagnosed with intellectual

disability without comorbid autism spectrum disorder. Bootstrapping was performed with 100

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

b Relative risk and 95% CI for 1) any antidepressant (top in black), 2) SSRI antidepressants (2

nd in

red), 3) other antidepressants (3rd

in green), and 4) other psychotropic drugs (bottom in yellow),

repeated for each level of adjustment. c Analyses not adjusted for covariates.

d Analyses adjusted for birthdate, maternal and paternal age, the father's psychotropic medication

overlapping the pregnancy, and maternal and paternal education level at child birth. e Analyses adjusted for the factors listed in

d, and any maternal diagnosis of depression prior child

birth (yes/no) (see eTable 4 for specific diagnosis codes). f Analyses adjusted for the factors listed in








eFigure 10. Sex-Specific an Sex-Combined Relative Risks of Intellectual Disability*

Abbreviations: N, number of births to treated mothers. RR, relative risk. CI, confidence interval.

* Sex-combined and sex-specific relative risks of intellectual disability and two-sided 95%

confidence intervals in children to mothers with antidepressant medication during pregnancy

compared with children to mothers without any psychotropic medication during pregnancy. 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 873 children diagnosed with intellectual disability,

of which 545 (62.4% of cases; 0.3% of all children) where male, and 328 (37.6% of cases; 0.2% of

all children) female. a Analyses not adjusted for covariates.



c, and for any maternal diagnosis of depression prior

childbirth (yes/no) (see eTable 4 for specific diagnosis codes). d Analyses adjusted for the factors listed in

c, and for maternal or paternal diagnoses prior child birth

of specific psychiatric disorder subgroups (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 eTable 4 for specific diagnosis codes).



eFigure 11. Relative Risks of Intellectual Disability in Children of Mothers Treated With

Antidepressants During Pregnancy, Including Gestational Age and Birth Weight *

Abbreviations: RR, relative risk. CI, confidence interval.

* Relative risks of intellectual disability and two-sided 95% confidence intervals in children to

mothers with antidepressant medication during pregnancy compared with children to mothers

without antidepressant medication during pregnancy. The analyses examine the role of gestational

age and birth weight in the causal pathway.

a Results from Model 4 in Figure 1.

b Model 4 in Figure 1, with additional adjustment for gestational age in days (RR: 0.98; 95% CI

0.98-0.98; p-value < 0.001). All children had gestational age information.

c Model 4 in Figure 1, with additional adjustment for birth weight in grams (RR: 1.00; 95% CI 1.00-

1.00; p-value < 0.001). There were 271 children without birth weight information. In these children,

we used the cohort mean birth weight stratified on offspring sex.

d Model 4 in Figure 1, with additional adjustment for gestational age in days and birth weight in

grams. Gestational age and birth weight were closely correlated in the cohort (Pearson’s correlation

coefficient 0.66; p-value


eFigure 12. Trimester-Specific Relative Risks of Intellectual Disability*

Abbreviations: N, number of children. CI, confidence interval. RR, relative risk.

* Analyses of the association between antidepressant exposure at specific trimesters and intellectual

disability in the offspring. The analyses allowed exposure in several trimesters, and correspond to

Model 4 in the main analysis (Figure 1), adjusting for all included covariates.



eFigure 13. Duration-Dose-Response Effect on the Relative Risk of Intellectual Disability*





sided 95% confidence intervals in children of mothers with at least two dispensations of

antidepressant drugs overlapping the pregnancy, compared with unexposed children. a A clinically relevant sub-sample consisting of 8,021 children, of which 69 had been diagnosed





underlying factors. b Analyses adjusted for the mean difference of antidepressant exposure duration from the mean,

separately in the exposed and unexposed children. This was done by creating an additional

covariate that reflect the deviation from the mean number of days with antidepressant treatment

during pregnancy. Thus, in exposed children, the mean number of days exposed to antidepressants

was estimated at 156 (Table 1), which was set to 0. Children with fewer days of antidepressant

exposure during pregnancy than 156 would get a negative number reflecting the difference in

duration from the mean, and vice versa for children with longer duration. All children unexposed to

maternal antidepressant treatment during pregnancy would have the value 0. For each additional 30

days (approximately a month) of exposure longer than the mean duration of exposure (156 days),

the RR was estimated at 1.01 (95% CI: 0.89-1.15; P-value: 0.88). c Analyses adjusted for duration of medication exposure (explained in

b), birthdate, maternal and

paternal age, the father's psychotropic medication overlapping the pregnancy, and maternal and

paternal education level at child birth. d

Analyses adjusted for the factors listed in c, and for any maternal diagnosis of depression prior

childbirth (yes/no) (see eTable 4 for specific diagnosis codes). e Analyses adjusted for the factors listed in








eFigure 14. Effects of Potential Misclassification in Unexposed Children*

Abbreviations: N, number of children. RR, relative risk. CI, confidence interval.

* To estimate the potential effect of misclassification in children born to mothers without

antidepressant medication in pregnancy, but that may have medication prior conception, the sample

was restricted to children conceived after January 1 2006, to allow six months follow-up prior

conception (the Swedish Prescribed Drug Register began follow-up at July 1 2005). The full sample

consists of 125,257 children, of which 598 had been diagnosed with intellectual disability, and

2,949 were born to a mother with antidepressant treatment during pregnancy. Antidepressant

unexposed children had to be born to a mother without any antidepressant medication in pregnancy,

however, medication in the six months prior conception was not considered. In a second sample of

123,964 children, antidepressant medication in the six months prior conception was considered and

any children defined as unexposed had to be born to a mother with neither antidepressant

medication during pregnancy, nor in the six months preceding pregnancy. This excluded 1,293

children. a Analyses not adjusted for covariates.












eFigure 15. Relative Risks of Intellectual Disability Stratified on Maternal Polypharmacy*

Abbreviations: N, number of children. RR, relative risk. CI, confidence interval.




sided 95% confidence intervals in analyses stratified on maternal polypharmacy, defined as having

any dispensation with a non-antidepressant psychotropic medication with a medication period

overlapping pregnancy. There were 3,059 children of mothers without any dispensation of a non-

antidepressant psychotropic medication in pregnancy, and 923 children of mothers with at least one

dispensation with a non-antidepressant psychotropic medication with a medication period

overlapping pregnancy. a Analyses not adjusted for covariates.












eFigure 16. Percentage of Mothers With Medication During Pregnancy and a Psychiatric Diagnosis

Before Child Birth*

Abbreviations: SSRI, selective serotonin re-uptake inhibitor. ADHD, attention-deficit hyperactive

disorder. ASD, autism spectrum disorder.

* Mothers with medication during pregnancy (at least two dispensations with medication periods

overlapping pregnancy, see eFigure 1; N=5,608) with either SSRI antidepressants (N=3,178), non-

SSRI antidepressants (N=804), or non-antidepressant psychotropic medications (N=1,626), and the

percentage of these mothers having a diagnosis in the Swedish Patient Register.



eFigure 17. Relative Risks of Intellectual Disability Due to Exposure to Any Antidepressant

During Pregnancy, Where All Antidepressant Treated Mothers Were Assumed to Have

Depression*





sided 95% confidence intervals in children of mothers with at least two dispensations of

antidepressant drugs overlapping the pregnancy, compared with unexposed children. Among

mothers with antidepressant medication during pregnancy, 25% lack any psychiatric diagnosis in

the Swedish Patient Register. The Swedish Patient Register lack primary care information, and

antidepressant medication is accompanied with a diagnosis in the Swedish healthcare system.

Therefore, it is possible that the lack of a psychiatric diagnosis in 25% of the mothers with

antidepressant medication cause residual confounding. In an attempt to estimate the size of the

potential residual confounding by lack of psychiatric diagnosis from the primary care, in this

analysis, all mothers with antidepressant medication was also assumed having suffered depression.

Model 3 and Model 4 in the full sample shows the estimated relative risks if all antidepressant

treated mothers were also assumed having suffered depression. a A clinically relevant sub-sample consisting of 8,021 children, of which 69 had been diagnosed





underlying factors. b Analyses not adjusted for covariates.



Analyses adjusted for the factors listed in c, and for any maternal diagnosis of depression prior



birth of specific psychiatric disorder subgroups (yes/no), including depression, anxiety disorders,





Supplementary Online Content - JAMA...medication during pregnancy, a continuous pattern of dispensations was required according to either a) at least two dispensations during pregnancy

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