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1 Supplementary Online Content Huybrechts KF, Hernández-Díaz S, Patorno E, et al. Antipsychotic use in pregnancy and the risk for congenital malformations. JAMA Psychiatry. Published online August 17, doi: /jamapsychiatry etable 1. List of Antipsychotic Medications Included etable 2. Diagnostic Codes for Congenital Malformations etable 3. Women With Exposure to an Atypical AP During the First Trimester etable 4. Women With Exposure to a Typical AP During the First Trimester etable 5. Women With Exposure to Aripiprazole During the First Trimester etable 6. Women with Exposure to Olanzapine During the First Trimester etable 7. Women With Exposure to Quetiapine During the First Trimester etable 8. Women With Exposure to Risperidone During the First Trimester etable 9. Women With Exposure to Ziprasidone During the First Trimester etable 10. Relative Risks Comparing the Risk for Malformations Between AP-Exposed and Unexposed Women etable 11. Relative Risk for Malformations Between AP-Exposed and Unexposed Women: Sensitivity Analyses Using High-Dimensional PS and Restriction etable 12. Fully Adjusted Relative Risk for Malformations Between AP-Exposed and Unexposed Women: Sensitivity Analyses Varying Exposure and Outcome Definition etable 13. Fully Adjusted Relative Risk for Malformations Between AP-Exposed and Unexposed Women Stratified by Low, Medium, and High Dose etable 14. Relative Risk for Malformations Between Risperidone-Exposed and Unexposed Women Varying the Exposure Definition to Filling at Least 2 Prescriptions During The First Trimester etable 15. Relative Risk for Malformations Between Risperidone Continuers and Discontinuers Using Different Definitions for Discontinuers efigure 1. Study Diagram efigure 2. Study Flowchart eresults. Quantification of the Potential Impact of Missing Terminations This supplementary material has been provided by the authors to give readers additional information about their work.

2 etable 1. List of Antipsychotic Medications Included Atypical antipsychotics Typical antipsychotics Aripiprazole, Asenapine, Clozapine, Iloperidone, Lurasidone, Olanzapine, Olanzapine/fluoxetine, Paliperidone, Quetiapine, Risperidone, Ziprasidone Chlorpromazine, chlorprothixene, fluphenazine, haloperidol, loxapine, mesoridazine, molindone, perphenazine, perphenazine/amitriptyline, pimozide, promazine, thioridazine, thiothixene, trifluoperazine, triflupromazine

3 etable 2. Diagnostic Codes for Congenital Malformations Malformation Group ICD-9 Code 1. Central Nervous System 740.xx-742.xx 2. Eye Anomalies 743.xx (exclude if only 743.6x and 743.8x) 3. Ear Anomalies 744.xx (exclude if only 744.1x, , , and 744.4x-744.9x) 4. Cardiovascular Anomalies 745.xx-747.xx (exclude if only AND preterm, AND preterm, 746.4x, 746.6x, , 747.0x and preterm, and preterm, 747.5x) 5. Other vascular (non-cardiac) 747.6x-747.9x (exclude if only ) 6. Respiratory malformations 748.xx (do not count if only 748.1x) 7. Oral cleft 749.xx 8. Gastrointestinal 750.xx-751.xx (do not count if only 750.0x, 750.1x, , 751.0x) 9. Genital (male and female) 752.xx-753.xx (do not count if only , ) (in addition, do not count 752.5x if preterm) 10. Urinary 753.xx (do not include if only 753.7x) 11. Musculoskeletal (no limbs, includes omphalocele ad gastroschisis) 754.xx and 756.xx (do not count if only 754.3x, , , 756.2x) 12. Limb defects 755.xx (exclude if only ) 13. Other 757.xx; 759.xx (excl if only , )

4 etable 3. Women With Exposure to an Atypical AP During the First Trimester Characteristic Unadjusted Adjusted (1) Atypical APM (N=9,258) (3) Atypical APM (N=9,237) (N=1,289,826) Age, mean () Year of delivery, N (%) , , , , , , , , , , , , , , Race, N (%) White 5, , , , Black 2, , , , Hispanic , , Other or unknown , , Multiple gestation, N (%) , , Antipsychotic indications, N (%) Bipolar disorder 3, , , , Psychosis , , Depression 2, , , , Schizophrenia , Anxiety 2, , , , ADHD , , Other psychiatric disorders , , Other mental and neurological conditions, N (%)

5 Characteristic Unadjusted Adjusted (1) Atypical APM (N=9,258) (3) Atypical APM (N=9,237) (N=1,289,826) Adjustment disorder , , Delirium , Sleep disorders , , Personality disorder , , Alcohol abuse or dependence , , Chronic fatigue syndrome , , Drug abuse or dependence , , Epilepsy or convulsions , , Migraine/headache 1, , , , Chronic maternal illness, N (%) Diabetes , , Hypertension , , Obesity , , Renal disease , , Smoking , , Other psychotropic medications, N (%) Anticonvulsants 2, , , , Antidepressants 6, , , ,070, Anxiolytics , , Barbituates , , Benzodiazepines 2, , , , Other hypnotics 1, , , , Stimulants for ADHD , ,

6 Characteristic Unadjusted Adjusted (1) Atypical APM (N=9,258) (3) Atypical APM (N=9,237) (N=1,289,826) Other medications, N (%) Antidiabetics , , Antihypertensives , , Buphrenophine , , Insulin , , Methadone , Naloxone , , Naltrexone , Opioids 3, , , , Suspected teratogens, N (%) (2) 1, , , , N of distinct prescriptions, excluding APMs, mean () Patients hospitalized, N (%) , , Proxies for severity Comorbidity Index, mean () N of diagnoses, mean () N of outpatient physician visits, mean () N of hospitalizations, mean () N of days hospitalized, mean () N of ER visits, mean () (1) All characteristics included in PS. To account for PS, the untreated observations were weighted using the distribution of the treated among 50 PS strata. Observations from the non-overlapping regions of the PS distributions were trimmed.

7 (2) Suspected teratogens included fluconazole, methimazole, danazol, propylthiouracil, progestins, and corticosteroids. Women exposed to known teratogens (warfarin, angiotensin converting enzyme inhibitors, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide) were excluded from the cohort. (3) All antipsychotics were administered orally, except for 22 risperidone users who received injections. : ard deviation; Diff: ardized Difference Medicaid Analytic extract,

8 etable 4. Women With Exposure to a Typical AP During the First Trimester Characteristic Unadjusted Adjusted (1) Typical APM (N=733) Typical APM (N=727) (N=1,297,638) Age, mean () Year of delivery, N (%) , , , , , , , , Race, N (%) White , , Black , , Hispanic , , Other or unknown , , Multiple gestation, N (%) , , Antipsychotic indications, N (%) Bipolar disorder , , Psychosis , , Depression , , Schizophrenia , Anxiety , , ADHD , , Other psychiatric disorders , ,

9 Characteristic Unadjusted Adjusted (1) Typical APM (N=733) Typical APM (N=727) (N=1,297,638) Other mental and neurological conditions, N (%) Adjustment disorder , , Delirium * * * * 11, Sleep disorders , , Personality disorder , , Alcohol abuse or , , dependence Chronic fatigue , , syndrome Drug abuse or , , dependence Epilepsy or convulsions , , Migraine/headache , , Chronic maternal illness, N (%) Diabetes , , Hypertension , , Obesity , , Renal disease * * 3, * * 10, Smoking , , Other psychotropic medications, N (%) Anticonvulsants , ,

10 Characteristic Unadjusted Adjusted (1) Typical APM (N=733) Typical APM (N=727) (N=1,297,638) Antidepressants , ,070, Anxiolytics , , Barbituates , , Benzodiazepines , , Other hypnotics , , Stimulants for ADHD , , Other medications, N (%) Antidiabetics , , Antihypertensives , , Buphrenophine * * 1, * * 17, Insulin , , Methadone * * * * 4, Naloxone * * 1, * * 17, Naltrexone * * * * 2, Opioids , , Suspected teratogens, N , , (%) (2) N of distinct prescriptions, excluding APMs, mean () Patients hospitalized, N , , (%) Proxies for severity Comorbidity Index, mean

11 Characteristic Unadjusted Adjusted (1) () N of diagnoses, mean () N of outpatient physician visits, mean () N of hospitalizations, mean () N of days hospitalized, mean () N of ER visits, mean Typical APM (N=733) Typical APM (N=727) (N=1,297,638) () *: Cell sizes 10 (and their corresponding %) have been suppressed in accordance with CMS' cell size suppression policy (1) All characteristics included in PS. To account for PS, the untreated observations were weighted using the distribution of the treated among 50 PS strata. Observations from the non-overlapping regions of the PS distributions were trimmed. (2) Suspected teratogens included fluconazole, methimazole, danazol, propylthiouracil, progestins, and corticosteroids. Women exposed to known teratogens (warfarin, angiotensin converting enzyme inhibitors, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide) were excluded from the cohort. : ard deviation; Diff: ardized Difference Medicaid Analytic extract,

12 etable 5. Women With Exposure to Aripiprazole During the First Trimester Characteristic Unadjusted Adjusted (1) Aripiprazole (N=1,756) Aripiprazole (N=1,752) (N=957,012) Age, mean () Year of delivery, N (%) , , , , , , , , , Race, N (%) White 1, , , , Black , , Hispanic , , Other or unknown , , Multiple gestation, N (%) , , Antipsychotic indications, N (%) Bipolar disorder , , Psychosis , , Depression , , Schizophrenia , Anxiety , , ADHD , , Other psychiatric disorders , ,

13 Characteristic Unadjusted Adjusted (1) Aripiprazole (N=1,756) Aripiprazole (N=1,752) (N=957,012) Other mental and neurological conditions, N (%) Adjustment disorder , , Delirium , Sleep disorders , , Personality disorder , , Alcohol abuse or , , dependence Chronic fatigue syndrome , , Drug abuse or dependence , , Epilepsy or convulsions , , Migraine/headache , , Chronic maternal illness, N (%) Diabetes , , Hypertension , , Obesity , , Renal disease , , Smoking , , Other psychotropic medications, N (%) Anticonvulsants , , Antidepressants 1, , , ,

14 Characteristic Unadjusted Adjusted (1) Aripiprazole (N=1,756) Aripiprazole (N=1,752) (N=957,012) Anxiolytics , , Barbituates , , Benzodiazepines , , Other hypnotics , , Stimulants for ADHD , , Other medications, N (%) Antidiabetics , , Antihypertensives , , Buphrenophine , , Insulin , , Methadone * * * * 4, Naloxone , , Naltrexone * * * * 1, Opioids , , Suspected teratogens, N , , (%) (2) N of distinct prescriptions, excluding APMs, mean () Patients hospitalized, N (%) , , Proxies for severity Comorbidity Index, mean () N of diagnoses, mean

15 Characteristic Unadjusted Adjusted (1) () N of outpatient physician visits, mean () N of hospitalizations, mean () N of days hospitalized, Aripiprazole (N=1,756) Aripiprazole (N=1,752) (N=957,012) mean () N of ER visits, mean () *: Cell sizes 10 (and their corresponding %) have been suppressed in accordance with CMS' cell size suppression policy (1) All characteristics included in PS. To account for PS, the untreated observations were weighted using the distribution of the treated among 50 PS strata. Observations from the non-overlapping regions of the PS distributions were trimmed. (2) Suspected teratogens included fluconazole, methimazole, danazol, propylthiouracil, progestins, and corticosteroids. Women exposed to known teratogens (warfarin, angiotensin converting enzyme inhibitors, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide) were excluded from the cohort. : ard deviation; Diff: ardized Difference Medicaid Analytic extract,

16 etable 6. Women With Exposure to Olanzapine During the First Trimester Characteristic Unadjusted Adjusted (1) Olanzapine (N=1,394) Olanzapine (N=1,392) (N=1,231,441) Age, mean () Year of delivery, N (%) , , , , , , , , Race, N (%) White , , Black , , Hispanic , , Other or unknown , , Multiple gestation, N (%) , , Antipsychotic indications, N (%) Bipolar disorder , , Psychosis , , Depression , , Schizophrenia , Anxiety , , ADHD , , Other psychiatric disorders , ,

17 Characteristic Unadjusted Adjusted (1) Olanzapine (N=1,394) Olanzapine (N=1,392) (N=1,231,441) Other mental and neurological conditions, N (%) Adjustment disorder , , Delirium , Sleep disorders , , Personality disorder , , Alcohol abuse or , , dependence Chronic fatigue , , syndrome Drug abuse or , , dependence Epilepsy or convulsions , , Migraine/headache , , Chronic maternal illness, N (%) Diabetes , , Hypertension , , Obesity , , Renal disease * * 3, * * 6, Smoking , , Other psychotropic medications, N (%) Anticonvulsants , ,

18 Characteristic Unadjusted Adjusted (1) Olanzapine (N=1,394) Olanzapine (N=1,392) (N=1,231,441) Antidepressants , ,040, Anxiolytics , , Barbituates , , Benzodiazepines , , Other hypnotics , , Stimulants for ADHD , , Other medications, N (%) Antidiabetics , , Antihypertensives , , Buphrenophine * * 1, * * 6, Insulin , , Methadone * * * * 3, Naloxone * * 1, * * 7, Naltrexone * * * * 2, Opioids , , Suspected teratogens, N , , (%) (2) N of distinct prescriptions, excluding APMs, mean () Patients hospitalized, N , , (%) Proxies for severity Comorbidity Index, mean

19 Characteristic Unadjusted Adjusted (1) () N of diagnoses, mean () N of outpatient physician visits, mean () N of hospitalizations, mean () N of days hospitalized, mean () N of ER visits, mean Olanzapine (N=1,394) Olanzapine (N=1,392) (N=1,231,441) () *: Cell sizes 10 (and their corresponding %) have been suppressed in accordance with CMS' cell size suppression policy (1) All characteristics included in PS. To account for PS, the untreated observations were weighted using the distribution of the treated among 50 PS strata. Observations from the non-overlapping regions of the PS distributions were trimmed. (2) Suspected teratogens included fluconazole, methimazole, danazol, propylthiouracil, progestins, and corticosteroids. Women exposed to known teratogens (warfarin, angiotensin converting enzyme inhibitors, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide) were excluded from the cohort. : ard deviation; Diff: ardized Difference Medicaid Analytic extract,

20 etable 7. Women With Exposure to Quetiapine During the First Trimester Characteristic Unadjusted Adjusted (1) Quetiapine (N=4,221) Quetiapine (N=4,213) (N=1,161,955) Age, mean () Year of delivery, N (%) , , , , , , , , , , , , , , Race, N (%) White 2, , , , Black , , Hispanic , , Other or unknown , , Multiple gestation, N (%) , , Antipsychotic indications, N (%) Bipolar disorder 1, , , , Psychosis , , Depression 1, , , , Schizophrenia , Anxiety 1, , , , ADHD , , Other psychiatric disorders , ,

21 Characteristic Unadjusted Adjusted (1) Quetiapine (N=4,221) Quetiapine (N=4,213) (N=1,161,955) Other mental and neurological conditions, N (%) Adjustment disorder , , Delirium , Sleep disorders , , Personality disorder , , Alcohol abuse or , , dependence Chronic fatigue , , syndrome Drug abuse or , , dependence Epilepsy or convulsions , , Migraine/headache , , Chronic maternal illness, N (%) Diabetes , , Hypertension , , Obesity , , Renal disease , , Smoking , , Other psychotropic medications, N (%) Anticonvulsants 1, , , ,

22 Characteristic Unadjusted Adjusted (1) Quetiapine (N=4,221) Quetiapine (N=4,213) (N=1,161,955) Antidepressants 3, , , ,094, Anxiolytics , , Barbituates , , Benzodiazepines 1, , , , Other hypnotics , , Stimulants for ADHD , , Other medications, N (%) Antidiabetics , , Antihypertensives , , Buphrenophine , , Insulin , , Methadone , , Naloxone , , Naltrexone * * * * 2, Opioids 1, , , , Suspected teratogens, N , , (%) (2) N of distinct prescriptions, excluding APMs, mean () Patients hospitalized, N , , (%) Proxies for severity Comorbidity Index, mean

23 Characteristic Unadjusted Adjusted (1) () N of diagnoses, mean () N of outpatient physician visits, mean () N of hospitalizations, mean () N of days hospitalized, mean () N of ER visits, mean Quetiapine (N=4,221) Quetiapine (N=4,213) (N=1,161,955) () *: Cell sizes 10 (and their corresponding %) have been suppressed in accordance with CMS' cell size suppression policy (1) All characteristics included in PS. To account for PS, the untreated observations were weighted using the distribution of the treated among 50 PS strata. Observations from the non-overlapping regions of the PS distributions were trimmed. (2) Suspected teratogens included fluconazole, methimazole, danazol, propylthiouracil, progestins, and corticosteroids. Women exposed to known teratogens (warfarin, angiotensin converting enzyme inhibitors, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide) were excluded from the cohort. : ard deviation; Diff: ardized Difference Medicaid Analytic extract,

24 etable 8. Women With Exposure to Risperidone During the First Trimester Characteristic Unadjusted Adjusted (1) Risperidone (N=1,566) Risperidone (N=1,565) (N=1,290,485) Age, mean () Year of delivery, N (%) , , , , , , , , Race, N (%) White , , Black , , Hispanic , , Other or unknown , , Multiple gestation, N (%) , , Antipsychotic indications, N (%) Bipolar disorder , , Psychosis , , Depression , , Schizophrenia , Anxiety , , ADHD , , Other psychiatric disorders , ,

25 Characteristic Unadjusted Adjusted (1) Risperidone (N=1,566) Risperidone (N=1,565) (N=1,290,485) Other mental and neurological conditions, N (%) Adjustment disorder , , Delirium , Sleep disorders , , Personality disorder , , Alcohol abuse or , , dependence Chronic fatigue , , syndrome Drug abuse or , , dependence Epilepsy or convulsions , , Migraine/headache , , Chronic maternal illness, N (%) Diabetes , , Hypertension , , Obesity , , Renal disease * * 1, * * 8, Smoking , , Other psychotropic medications, N (%) Anticonvulsants , ,

26 Characteristic Unadjusted Adjusted (1) Risperidone (N=1,566) Risperidone (N=1,565) (N=1,290,485) Antidepressants 1, , , ,124, Anxiolytics , , Barbituates , , Benzodiazepines , * * 4, Other hypnotics , , Stimulants for ADHD , , Other medications, N (%) Antidiabetics , , Antihypertensives , , Buphrenophine * * 9, * * 4, Insulin , , Methadone * * * * 2, Naloxone * * 1, * * 5, Naltrexone * * * * 2, Opioids , , Suspected teratogens, N , , (%) (2) N of distinct prescriptions, excluding APMs, mean () Patients hospitalized, N , , (%) Proxies for severity Comorbidity Index, mean

27 Characteristic Unadjusted Adjusted (1) () N of diagnoses, mean () N of outpatient physician visits, mean () N of hospitalizations, mean () N of days hospitalized, mean () N of ER visits, mean Risperidone (N=1,566) Risperidone (N=1,565) (N=1,290,485) () *: Cell sizes 10 (and their corresponding %) have been suppressed in accordance with CMS' cell size suppression policy (1) All characteristics included in PS. To account for PS, the untreated observations were weighted using the distribution of the treated among 50 PS strata. Observations from the non-overlapping regions of the PS distributions were trimmed. (2) Suspected teratogens included fluconazole, methimazole, danazol, propylthiouracil, progestins, and corticosteroids. Women exposed to known teratogens (warfarin, angiotensin converting enzyme inhibitors, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide) were excluded from the cohort. : ard deviation; Diff: ardized Difference Medicaid Analytic extract,

28 etable 9. Women With Exposure to Ziprasidone During the First Trimester Characteristic Unadjusted Adjusted (1) Ziprasidone (N=697) Ziprasidone (N=696) (N=979,614) Age, mean () Year of delivery, N (%) , , , , , , , , Race, N (%) White , , Black , , Hispanic , , Other or unknown , , Multiple gestation, N (%) , , Antipsychotic indications, N (%) Bipolar disorder , , Psychosis , , Depression , , Schizophrenia , Anxiety , , ADHD , , Other psychiatric disorders , ,

29 Characteristic Unadjusted Adjusted (1) Ziprasidone (N=697) Ziprasidone (N=696) (N=979,614) Other mental and neurological conditions, N (%) Adjustment disorder , , Delirium , Sleep disorders , , Personality disorder , , Alcohol abuse or , , dependence Chronic fatigue , , syndrome Drug abuse or , , dependence Epilepsy or convulsions , , Migraine/headache , , Chronic maternal illness, N (%) Diabetes , , Hypertension , , Obesity , , Renal disease * * * * 5, Smoking , , Other psychotropic medications, N (%) Anticonvulsants , ,

30 Characteristic Unadjusted Adjusted (1) Ziprasidone (N=697) Ziprasidone (N=696) (N=979,614) Antidepressants , ,078, Anxiolytics , , Barbituates , , Benzodiazepines , , Other hypnotics , , Stimulants for ADHD , , Other medications, N (%) Antidiabetics , , Antihypertensives , , Buphrenophine * * 12, * * 16, Insulin * * * * 20, Methadone * * 1, * * Naloxone * * 1, * * 18, Naltrexone * * 14, * * 3, Opioids , , Suspected teratogens, N , , (%) (2) N of distinct prescriptions, excluding APMs, mean () Patients hospitalized, N , , (%) Proxies for severity Comorbidity Index, mean

31 Characteristic Unadjusted Adjusted (1) () N of diagnoses, mean () N of outpatient physician visits, mean () N of hospitalizations, mean () N of days hospitalized, mean () N of ER visits, mean Ziprasidone (N=697) Ziprasidone (N=696) (N=979,614) () *: Cell sizes 10 (and their corresponding %) have been suppressed in accordance with CMS' cell size suppression policy (1) All characteristics included in PS. To account for PS, the untreated observations were weighted using the distribution of the treated among 50 PS strata. Observations from the non-overlapping regions of the PS distributions were trimmed. (2) Suspected teratogens included fluconazole, methimazole, danazol, propylthiouracil, progestins, and corticosteroids. Women exposed to known teratogens (warfarin, angiotensin converting enzyme inhibitors, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide) were excluded from the cohort. : ard deviation; Diff: ardized Difference Medicaid Analytic extract,

32 etable 10. Relative Risks Comparing the Risk for Malformations Between AP-Exposed and Unexposed Women Exposure Group Exposed Unexposed RR 95% CI Outcomes Total N Outcomes Total N UNADJUSTED Congenital malformation overall Typical antipsychotics ,494 1,331, (0.81, 1.68) Atypical antipsychotics 412 9,258 43,494 1,331, (1.24, 1.50) Aripiprazole 75 1,756 43,494 1,331, (1.05, 1.63) Olanzapine 59 1,394 43,494 1,331, (1.01, 1.66) Quetiapine 182 4,221 43,494 1,331, (1.15, 1.52) Risperidone 80 1,566 43,494 1,331, (1.26, 1.94) Ziprasidone ,494 1,331, (0.78, 1.67) Cardiac Malformation Typical antipsychotics * ,405 1,331, (0.64, 2.18) Atypical antipsychotics 150 9,258 15,405 1,331, (1.19, 1.64) Aripiprazole 27 1,756 15,405 1,331, (0.91, 1.93) Olanzapine 20 1,394 15,405 1,331, (0.80, 1.92) Quetiapine 70 4,221 15,405 1,331, (1.14, 1.81) Risperidone 29 1,566 15,405 1,331, (1.12, 2.30) Ziprasidone * ,405 1,331, (0.58, 2.14) ADJUSTED FOR PSYCHIATRIC INDICATIONS Congenital malformation overall Typical antipsychotics ,478 1,331, (0.69, 1.45) Atypical antipsychotics 409 9,240 43,493 1,331, (1.02, 1.23) Aripiprazole 73 1,750 43,247 1,325, (0.83, 1.30) Olanzapine 56 1,335 43,413 1,329, (0.82, 1.36) Quetiapine 182 4,213 43,478 1,331, (0.95, 1.26)

33 Exposure Group Exposed Unexposed RR 95% CI Outcomes Total N Outcomes Total N Risperidone 76 1,472 43,487 1,331, (1.05, 1.63) Ziprasidone ,418 1,270, (0.61, 1.31) Cardiac Malformation Typical antipsychotics * ,400 1,331, (0.49, 1.80) Atypical antipsychotics 148 9,240 15,405 1,331, (0.98, 1.35) Aripiprazole 26 1,750 15,307 1,325, (0.72, 1.55) Olanzapine 18 1,335 15,380 1,329, (0.61, 1.52) Quetiapine 70 4,213 15,398 1,331, (0.94, 1.49) Risperidone 28 1,472 15,402 1,331, (0.96, 2.01) Ziprasidone * ,677 1,270, (0.46, 1.69) FULLY ADJUSTED Congenital malformation overall Typical antipsychotics ,464 1,297, (0.62, 1.31) Atypical antipsychotics 410 9,237 42,529 1,289, (0.96, 1.16) Aripiprazole 74 1,752 33, , (0.76, 1.19) Olanzapine 59 1,392 40,171 1,231, (0.85, 1.41) Quetiapine 181 4,213 39,291 1,161, (0.88, 1.17) Risperidone 80 1,565 42,443 1,290, (1.02, 1.56) Ziprasidone , , (0.60, 1.28) Cardiac Malformation Typical antipsychotics * ,015 1,297, (0.39, 1.43) Atypical antipsychotics 148 9,237 15,040 1,289, (0.90, 1.24) Aripiprazole 26 1,752 11, , (0.64, 1.37) Olanzapine 20 1,392 14,316 1,231, (0.64, 1.53) Quetiapine 70 4,213 13,984 1,161, (0.85, 1.35)

34 Exposure Group Exposed Unexposed RR 95% CI Outcomes Total N Outcomes Total N Risperidone 29 1,565 15,062 1,290, (0.88, 1.81) Ziprasidone * , , (0.44, 1.63) *: Cell sizes 10 (and their corresponding %) have been suppressed in accordance with CMS' cell size suppression policy Medicaid Analytic extract

35 etable 11. Relative Risk for Malformations Between AP-Exposed and Unexposed Women: Sensitivity Analyses Using High-Dimensional PS and Restriction Exposure Group Exposed Unexposed RR 95% CI Outcomes Total N Outcomes Total N ADJUSTED FOR HIGH-DIMENSIONAL PROPENSITY SCORE (hdps) Congenital malformation overall Typical antipsychotics ,396 1,137, (0.64, 1.35) Atypical antipsychotics 410 9,236 43,318 1,324, (0.98, 1.19) Aripiprazole 75 1,754 34, , (0.81, 1.26) Olanzapine 59 1,391 41,614 1,278, (0.87, 1.43) Quetiapine 181 4,211 40,154 1,199, (0.89, 1.19) Risperidone 80 1,563 41,669 1,266, (1.10, 1.69) Ziprasidone ,599 1,052, (0.65, 1.38) Cardiac Malformation Typical antipsychotics * ,228 1,137, (0.45, 1.65) Atypical antipsychotics 148 9,236 15,341 1,324, (0.94, 1.30) Aripiprazole 27 1,754 12, , (0.74, 1.56) Olanzapine 20 1,391 14,769 1,278, (0.67, 1.59) Quetiapine 69 4,211 14,283 1,199, (0.87, 1.39) Risperidone 29 1,563 14,778 1,266, (0.96, 1.98) Ziprasidone * ,520 1,052, (0.49, 1.81) RESTRICTED TO SCHIZOPHRENIA, BIPOLAR DISORDER, PSYCHOSIS Congenital malformation overall Typical antipsychotics , (0.63, 1.68) Atypical antipsychotics 209 3, , (1.10, 1.51) Aripiprazole , (0.98, 1.72) Olanzapine , (0.89, 1.77) Quetiapine 92 1, , (1.05, 1.61) Risperidone , (0.92, 1.75)

36 Ziprasidone , (0.52, 1.44) Cardiac Malformation Typical antipsychotics * , (0.59, 2.64) Atypical antipsychotics 79 3, , (1.04, 1.76) Aripiprazole , (0.85, 2.18) Olanzapine , (0.71, 2.26) Quetiapine 34 1, , (0.92, 1.92) Risperidone , (1.10, 2.8) Ziprasidone * , (0.33, 1.94) RESTRICTED + ADJUSTED FOR OTHER INDICATIONS Congenital malformation overall Typical antipsychotics , (0.56, 1.60) Atypical antipsychotics 191 3, , (0.97, 1.35) Aripiprazole , (0.87, 1.58) Olanzapine , (0.87, 1.78) Quetiapine 89 1, , (0.98, 1.53) Risperidone , (0.79, 1.55) Ziprasidone , (0.48, 1.36) Cardiac Malformation Typical antipsychotics * , (0.62, 2.76) Atypical antipsychotics 75 3, , (0.98, 1.67) Aripiprazole , (0.89, 2.29) Olanzapine , (0.68, 2.27) Quetiapine 34 1, , (0.92, 1.92) Risperidone , (1.06, 2.78) Ziprasidone * , (0.34, 2.02) RESTRICTED + FULLY ADJUSTED Congenital malformation overall Typical antipsychotics , (0.57, 1.51) Atypical antipsychotics 209 3, , (0.99, 1.35)

37 Aripiprazole , (0.86, 1.50) Olanzapine , (0.84, 1.67) Quetiapine 92 1, , (0.92, 1.41) Risperidone , (0.86, 1.64) Ziprasidone , (0.51, 1.39) Cardiac Malformation Typical antipsychotics * , (0.43, 1.91) Atypical antipsychotics 79 3, , (0.93, 1.57) Aripiprazole , (0.71, 1.80) Olanzapine , (0.69, 2.19) Quetiapine 34 1, , (0.81, 1.67) Risperidone , (1.03, 2.62) Ziprasidone * , (0.31, 1.81) *: Cell sizes 10 (and their corresponding %) have been suppressed in accordance with CMS' cell size suppression policy Medicaid Analytic extract

38 etable 12. Fully Adjusted Relative Risk for Malformations Between AP-Exposed and Unexposed Women: Sensitivity Analyses Varying Exposure and Outcome Definition Exposure Group Exposed Unexposed RR 95% CI Outcomes Total N Outcomes Total N EXPOSURE DEFINED AS FILLING AT LEAST TWO PRESCRIPTIONS DURING THE FIRST TRIMESTER Congenital malformation overall Typical antipsychotics * , , (0.39, 1.66) Atypical antipsychotics 177 3,798 40,866 1,226, (0.94, 1.25) Aripiprazole , , (0.75, 1.56) Olanzapine ,250 1,143, (0.62, 1.51) Quetiapine 84 1,851 39,792 1,182, (0.87, 1.33) Risperidone , , (1.01, 2.10) Ziprasidone , , (0.66, 1.98) Cardiac Malformation Typical antipsychotics * , , (0.24, 2.29) Atypical antipsychotics 70 3,798 14,502 1,226, (0.93, 1.47) Aripiprazole * 555 9, , (0.53, 1.94) Olanzapine * ,312 1,143, (0.59, 2.17) Quetiapine 33 1,851 14,171 1,182, (0.81, 1.59) Risperidone , , (1.09, 3.19) Ziprasidone * , , (0.39, 2.75) EXPOSURE DEFINED AS DAYS SUPPLY OVERLAP WITH THE FIRST TRIMESTER Congenital malformation overall Typical antipsychotics ,688 1,304, (0.62, 1.29) Atypical antipsychotics 414 9,290 42,530 1,289, (0.97, 1.17) Aripiprazole 78 1,858 33, , (0.77, 1.18) Olanzapine 64 1,459 40,392 1,238, (0.9, 1.45) Quetiapine 188 4,379 39,567 1,173, (0.88, 1.16) Risperidone 91 1,719 42,643 1,298, (1.07, 1.6) Ziprasidone , , (0.59, 1.23)

39 Cardiac Malformation Typical antipsychotics * ,081 1,304, (0.41, 1.5) Atypical antipsychotics 149 9,290 15,042 1,289, (0.91, 1.25) Aripiprazole 28 1,858 11, , (0.66, 1.38) Olanzapine 21 1,459 14,389 1,238, (0.65, 1.53) Quetiapine 73 4,379 14,072 1,173, (0.86, 1.36) Risperidone 35 1,719 15,128 1,298, (0.99, 1.92) Ziprasidone * , , (0.45, 1.54) OUTCOME DEFINED BASED ON CODES IN INFANT CLAIMS ONLY Congenital malformation overall Typical antipsychotics ,660 1,297, (0.52, 1.19) Atypical antipsychotics 377 9,237 37,724 1,289, (0.95, 1.15) Aripiprazole 69 1,752 29, , (0.75, 1.19) Olanzapine 53 1,392 35,570 1,231, (0.82, 1.40) Quetiapine 164 4,213 34,911 1,161, (0.85, 1.15) Risperidone 74 1,565 37,638 1,290, (1.01, 1.57) Ziprasidone , , (0.61, 1.32) Cardiac Malformation Typical antipsychotics * ,849 1,297, (0.37, 1.45) Atypical antipsychotics 141 9,237 12,879 1,289, (0.94, 1.31) Aripiprazole 25 1,752 10, , (0.65, 1.42) Olanzapine 18 1,392 12,204 1,231, (0.64, 1.60) Quetiapine 67 4,213 11,960 1,161, (0.89, 1.43) Risperidone 27 1,565 12,890 1,290, (0.89, 1.88) Ziprasidone * , , (0.48, 1.75) *: Cell sizes 10 (and their corresponding %) have been suppressed in accordance with CMS' cell size suppression policy Medicaid Analytic extract

40 etable 13. Fully Adjusted Relative Risk for Malformations Between AP-Exposed and Unexposed Women Stratified by Low, Medium, and High Dose Exposure Group Exposed Unexposed RR (95% CI) Outcomes Total N Outcomes Total N PS-adjusted Congenital malformation overall Aripiprazole Low dose , , (0.88, 1.71) Medium dose ,127 1,025, (0.43, 1.12) High dose , , (0.64, 1.38) Olanzapine Low dose ,127 1,200, (0.85, 1.68) Medium dose ,407 1,061, (0.61, 1.63) High dose ,750 1,196, (0.59, 1.72) Quetiapine Low dose 47 1,279 35,523 1,026, (0.68, 1.19) Medium dose 57 1,093 37,424 1,092, (0.97, 1.61) High dose 78 1,846 34, , (0.78, 1.21) Risperidone Low dose , , (0.96, 2.09) Medium dose ,483 1,126, (0.76, 1.67) High dose ,823 1,094, (0.97, 1.90) Ziprasidone Low dose , , (0.74, 2.24) Medium dose * , , (0.44, 1.71) High dose * , , (0.27, 1.29) Cardiac Malformation

41 Exposure Group Exposed Unexposed RR (95% CI) Outcomes Total N Outcomes Total N PS-adjusted Aripiprazole Low dose * , , (0.50, 1.85) Medium dose * ,854 1,025, (0.49, 1.96) High dose * , , (0.48, 1.77) Olanzapine Low dose * ,854 1,200, (0.42, 1.66) Medium dose * ,267 1,061, (0.74, 2.90) High dose * ,806 1,196, (0.31, 2.15) Quetiapine Low dose 19 1,279 12,658 1,026, (0.64, 1.57) Medium dose 18 1,093 13,291 1,092, (0.69, 1.74) High dose 33 1,846 12, , (0.78, 1.53) Risperidone Low dose * , , (0.43, 2.10) Medium dose * ,253 1,126, (0.28, 1.60) High dose ,676 1,094, (1.32, 3.28) Ziprasidone Low dose * , , (0.64, 3.64) Medium dose * 225 8, , (0.14, 2.22) High dose * , , (0.15, 2.32) *: Cell sizes 10 (and their corresponding %) have been suppressed in accordance with CMS' cell size suppression policy Dose (mg) tertiles: Aripiprazole: <=5; 5 < Dose <= 10; >10 Olanzapine: <=5, 5 < dose <=10, >10

42 Quetiapine: <=50; 50 < Dose <= 100; >100 Risperidone: <1; 1<= to <2; >=2 Ziprasidone: <=40; 40 < Dose <= 80; >80 Medicaid Analytic extract

43 etable 14. Relative Risk for Malformations Between Risperidone-Exposed and Unexposed Women Varying the Exposure Definition to Filling at Least 2 Prescriptions During The First Trimester Exposure Group Risperidone Exposed Unexposed RR (95% CI) Outcomes Total N Outcomes Total N Congenital malformation overall PS-adjusted , , (1.01, 2.1) hdps-adjusted ,341 1,244, (1.04, 2.16) Cardiac Malformation PS-adjusted , , (1.09, 3.19) hdps-adjusted ,215 1,244, (1.11, 3.25) Medicaid Analytic extract

44 etable 15. Relative Risk for Malformations Between Risperidone Continuers and Discontinuers Using Different Definitions for Discontinuers Unexposed Group Exposed Unexposed RR (95% CI) Outcomes Total N Outcomes Total N UNADJUSTED Congenital malformation overall no Rx from start of pregnancy , (0.82, 1.70) no Rx from 4 weeks before pregnancy , (0.72, 1.60) no Rx from 6 weeks before pregnancy (0.73, 1.74) no Rx from 8 weeks before pregnancy (0.77, 2.21) Cardiac Malformation no Rx from start of pregnancy , (0.75, 2.46) no Rx from 4 weeks before pregnancy , (0.64, 2.34) no Rx from 6 weeks before pregnancy (0.70, 3.09) no Rx from 8 weeks before pregnancy * (0.86, 7.44) PS-ADJUSTED Congenital malformation overall no Rx from start of pregnancy , (0.70, 1.43) no Rx from 4 weeks before pregnancy , (0.75, 1.71) no Rx from 6 weeks before pregnancy (0.71, 1.75) no Rx from 8 weeks before pregnancy (0.90, 2.98) Cardiac Malformation no Rx from start of pregnancy , (0.49, 1.46) no Rx from 4 weeks before pregnancy , (0.64, 2.68) no Rx from 6 weeks before pregnancy (0.72, 4.01) no Rx from 8 weeks before pregnancy * (0.77, 7.87)

45 *: Cell sizes 10 (and their corresponding %) have been suppressed in accordance with CMS' cell size suppression policy Medicaid Analytic extract

46 efigure 1. Study Diagram