Supplementary Online Content

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1 Supplementary Online Content Brown HK, Ray JG, Wilton AS, Lunsky Y, Gomes T, Vigod SN. Association between serotonergic antidepressant use during pregnancy and autism spectrum disorder in children. JAMA. doi: /jama etable 1. Databases used to derive study variables etable 2. List of data sources and codes used to define key variables etable 3. High-dimensional propensity score algorithm dimensions and covariates in the full cohort etable 4. Baseline characteristics of women in Ontario with a singleton live birth in who were not eligible for the publicly funded drug plan etable 5. Baseline characteristics of serotonergic antidepressant users and non-users in the mood and anxiety disorder-restricted cohort etable 6. Baseline characteristics of serotonergic antidepressant users and non-users in siblings discordant for serotonergic antidepressant exposure in pregnancy etable 7. Association between serotonergic antidepressant exposure and child autism spectrum disorder in the mood and anxiety-restricted cohort etable 8. Baseline characteristics of serotonergic antidepressant users and non-users with recent use in the days before conception efigure 1. Association between serotonergic antidepressant exposure and child autism spectrum disorder, by trimester of exposure, among women with mood and anxiety disorders efigure 2. Association between serotonergic antidepressant exposure and child autism spectrum disorder, by type of serotonergic antidepressant, among women with mood and anxiety disorders This supplementary material has been provided by the authors to give readers additional information about their work.

2 etable 1. Databases used to derive study variables* Database Abbreviation Data held DAD Canadian Institutes of Health Information Discharge Abstract Database National Ambulatory Care Reporting System Ontario Health Insurance Plan database Ontario Drug Benefit database Ontario Mental Health Reporting System Registered Persons Database NACRS OHIP ODB OMHRS RPDB Demographic and clinical information about all hospital admissions and discharges, including transfers and deaths. Emergency department visits, day surgery and mandated outpatient clinics Physicians claims for services provided Prescription drug information for persons under 65 years who are unemployed, have disabilities, or have high prescription costs relative to net household income Mental health clinical and administrative data on adult patients, collected in all facilities in the province of Ontario with designated inpatient mental health beds Individual health card number, date of birth, sex, postal code and death date (where applicable) *Diagnoses in these datasets are recorded using the Canadian Coding Standards for the International Statistical Classification of Diseases and Related Health Problems (hospital) and physician billing claim codes (OHIP).

3 etable 2. List of data sources and codes used to define key variables Variable type Data source(s) Code(s) Exposure Selective Serotonin Reuptake Inhibitors Serotonin-Norepinephrine Reuptake Inhibitors ODB ODB Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline Duloxetine, venlafaxine Exposure timing Trimester 1 ODB 0 to 90 days after conception date Trimester 2/3 ODB 91 days after conception date to delivery date Outcome Autism spectrum disorders DAD/OHIP ICD-9/OHIP: 299; ICD-10: F84 (autism, atypical autism, Asperger s syndrome, other pervasive developmental disorders, pervasive developmental disorders unspecified) Confounders Maternal mood and anxiety disorders recorded in hospital or outpatient databases in the 2 years prior to conception DAD/OMHRS/OHIP ICD-9/OHIP/OMHRS: 296, 300, 308, 309, 311; ICD-10 F30-34, F38-39, F40-42, F43.0, F43.1, F43.8, F43.9, F44, F45.

4 etable 3. High-dimensional propensity score algorithm dimensions and covariates in the full cohort Rank Dimension Code Description Bias Type 1 OHIP 300 Anxiety neurosis, hysteria, neurasthenia, obsessive compulsive neurosis, reactive depression frequent 2 OHIP 300 Anxiety neurosis, hysteria, neurasthenia, obsessive compulsive neurosis, reactive depression 3 OHIP 300 Anxiety neurosis, hysteria, neurasthenia, obsessive compulsive neurosis, reactive depression sporadic once 4 OHIP 311 Depressive or other non-psychotic disorders, not elsewhere once classified 5 ODB Clonazepam sporadic 6 ODB Trazodone Hcl frequent 7 OHIP 296 Manic depressive psychosis, involutional melancholia once 8 OHIP 311 Depressive or other non-psychotic disorders, not elsewhere sporadic classified 9 ODB Clonazepam once 10 ODB Trazodone Hcl sporadic 11 OHIP 311 Depressive or other non-psychotic disorders, not elsewhere frequent classified 12 ODB Trazodone Hcl once 13 NACRS F32 Depressive episode once 14 OHIP 296 Manic depressive psychosis, involutional melancholia sporadic 15 ODB Quetiapine Fumarate sporadic

5 16 OHIP 301 Personality disorders (e.g., paranoid personality, schizoid personality, obsessive compulsive personality) once 17 NACRS F43 Reaction to severe stress, and adjustment disorders once 18 ODB Risperidone sporadic 19 ODB Risperidone once 20 NACRS 2AZ02 Assessment, mental health once 21 ODB Acetaminophen & once Oxycodone Hcl 22 OHIP 304 Drug addiction, dependence sporadic 23 ODB Alprazolam frequent 24 ODB Lorazepam frequent 25 ODB Divalproex Sodium frequent 26 ODB Acetaminophen & frequent Oxycodone Hcl 27 ODB Divalproex Sodium sporadic 28 ODB Quetiapine Fumarate frequent 29 NACRS R45 Symptoms and signs involving emotional state once 30 ODB Alprazolam sporadic 31 ODB Oxycodone Hcl once 32 ODB Risperidone frequent 33 ODB Quetiapine Fumarate once 34 ODB Divalproex Sodium once

6 35 ODB Acetaminophen & frequent Caffeine & Codeine Phosphate 36 NACRS 6AA10 Counseling, mental health once 37 OHIP 304 Drug addiction, dependence once 38 OHIP 296 Manic depressive psychosis, involutional melancholia frequent 39 ODB Clonazepam frequent 40 ODB Lorazepam once 41 DAD F32 Depressive episode once 42 ODB Fluticasone Propionate once 43 ODB Methadone frequent 44 OHIP 999 WITHOUT DIAGNOSIS frequent 45 ODB Diazepam sporadic 46 ODB Alprazolam once 47 NACRS F60 Specific personality disorders once 48 ODB Methadone once 49 ODB Diazepam once 50 OHIP 301 Personality disorders (e.g., paranoid personality, schizoid personality, obsessive compulsive personality) frequent 51 ODB Celecoxib once 52 ODB Diazepam frequent 53 DAD U98 Place of occurrence once 54 ODB Pantoprazole Sodium sporadic 55 ODB Methadone sporadic 56 OHIP 999 WITHOUT DIAGNOSIS < sporadic

7 57 ODB Temazepam once 58 ODB Fluticasone Propionate frequent 59 NACRS Z76 Persons encountering health services in other circumstances once 60 ODB Senna frequent 61 OHIP 919 Abrasions, bruises, contusions and other superficial injury once including non-venomous bites 62 NACRS U98 Place of occurrence once 63 ODB Rabeprazole Sodium frequent 64 OHIP 635 Therapeutic abortion frequent 65 ODB Topiramate sporadic 66 ODB Topiramate once 67 NACRS K52 Other noninfective gastroenteritis and colitis once 68 ODB Albuterol Sulfate once 69 OHIP 298 Other psychoses once 70 NACRS L03 Cellulitis once 71 OHIP 977 Of drugs and medications - including allergy, overdose, once reactions 72 ODB Topiramate frequent 73 OHIP 298 Other psychoses sporadic 74 ODB Oxazepam frequent 75 NACRS M54 Dorsalgia once 76 NACRS X61 Intentional self-poisoning by and exposure to antiepileptic, sedative-hypnotic, antiparkinsonism and psychotropic drugs, not elsewhere classified once 77 ODB Rabeprazole Sodium once

8 78 OHIP 309 Adjustment reaction frequent 79 NACRS R52 Pain, not elsewhere classified once 80 DAD F43 Reaction to severe stress, and adjustment disorders once 81 ODB Ranitidine Hcl frequent 82 ODB Hydrochlorothiazide frequent 83 ODB Meloxicam frequent 84 OHIP 884 Lacerations, open wounds, traumatic amputations - upper once limb(s) 85 NACRS 3ER20 CT, head once 86 ODB Prednisone once 87 ODB Mirtazapine once Convulsions, ataxia, vertigo, headache, except tension headache and migraine < once 88 OHIP ODB Senna once 90 OHIP 466 Acute bronchitis frequent 91 ODB Omeprazole once 92 OHIP 799 Other ill-defined conditions < once 93 ODB Levothyroxine Sodium sporadic 94 ODB Docusate once 95 OHIP 845 Ankle, foot, toes once 96 OHIP 635 Incomplete abortion, complete abortion < once 97 OHIP 930 Foreign body in eye, or other tissues once 98 NACRS J45 Asthma once 99 ODB Dextromethorphan Hbr once 100 ODB Morphine Sulfate once 101 NACRS S99 Other and unspecified injuries of ankle and foot once

9 102 ODB Temazepam frequent 103 OHIP 977 Of drugs and medications - including allergy, overdose, reactions frequent 104 NACRS S93 Dislocation, sprain and strain of joints and ligaments at ankle and foot level once 105 ODB Hydrochlorothiazide sporadic 106 ODB Methylphenidate Hcl sporadic 107 ODB Acetaminophen frequent 108 ODB Albuterol Sulfate frequent 109 NACRS 2HZ24 Electrophysiological measurement, heart once 110 ODB Norethindrone sporadic 111 OHIP 9 Diarrhea, gastro-enteritis, viral gastro-enteritis once 112 OHIP 307 Habit spasms, tics, stuttering, tension headaches, anorexia nervosa, sleep disorders, enuresis once 113 OHIP 848 Other sprains and strains once 114 ODB Oxybutynin Chloride once 115 OHIP 427 Paroxysmal tachycardia, atrial or ventricular flutter or fibrillation, cardiac arrest, other arrythmias sporadic 116 NACRS S89 Other and unspecified injuries of lower leg once 117 ODB Morphine Sulfate frequent 118 DAD F60 Specific personality disorders once 119 OHIP 493 Asthma, allergic bronchitis < once 120 OHIP 781 Leg cramps, leg pain, muscle pain, joint pain, arthralgia, < once joint swelling, masses 121 ODB Budesonide frequent 122 OHIP 346 Migraine frequent 123 OHIP 635 Therapeutic abortion sporadic

10 124 ODB Fluticasone Propionate & sporadic Salmeterol Xinafoate 125 ODB Meperidine Hcl once 126 NACRS Z51 Other medical care frequent 127 OHIP 9 Diarrhea, gastro-enteritis, viral gastro-enteritis frequent 128 ODB Fluticasone Propionate & once Salmeterol Xinafoate 129 ODB Hydrochlorothiazide once 130 ODB Pantoprazole Sodium once 131 ODB Diclofenac Sodium & frequent Misoprostol 132 OHIP 530 Esophagitis, cardiospasm, ulcer of esophagus; stricture, once stenosis, or obstruction of esophagus 133 OHIP 295 Schizophrenia once 134 ODB Meperidine Hcl frequent 135 ODB Doxepin Hcl frequent 136 OHIP 729 Fibrositis, myositis, muscular rheumatism once 137 NACRS 1LZ35 Pharmacotherapy (local), circulatory system NEC once 138 ODB Oxazepam once 139 ODB Lansoprazole sporadic 140 OHIP 895 Family planning, contraceptive advice, advice on < sporadic sterilization or abortion 141 NACRS N83 Noninflammatory disorders of ovary, fallopian tube and once broad ligament 142 ODB Oxycodone Hcl sporadic

11 143 NACRS Y83 Surgical operation and other surgical procedure as the cause once of abnormal reaction of the patient, or of later complication, without mention of misadventure at the time of the procedure 144 OHIP 884 Lacerations, open wounds, traumatic amputations - upper sporadic limb(s) 145 ODB Ramipril once 146 NACRS R21 Rash and other nonspecific skin eruption once 147 OHIP 277 Other metabolic disorders once 148 OHIP 895 Family planning, contraceptive advice, advice on < frequent sterilization or abortion 149 OHIP 724 Lumbar strain, lumbago, coccydynia, sciatica < once 150 ODB Albuterol once 151 ODB Levothyroxine Sodium frequent 152 OHIP 949 Burns - thermal or chemical once 153 NACRS M79 Other soft tissue disorders, not elsewhere classified once 154 OHIP 280 Iron deficiency anaemia once 155 ODB Clotrimazole once 156 OHIP 466 Acute bronchitis < once 157 NACRS T43 Poisoning by psychotic drugs, not elsewhere classified once 158 OHIP 722 Intervertebral disc disorders once 159 ODB Ramipril sporadic 160 OHIP 799 Other ill-defined conditions < frequent 161 OHIP 785 Chest pain, tachycardia, syncope, shock, edema, masses < once 162 ODB Lactulose once

12 163 NACRS S09 Other and unspecified injuries of head once 164 ODB Ranitidine Hcl < once 165 NACRS Z51 Other medical care once 166 ODB Baclofen frequent 167 NACRS R42 Dizziness and giddiness once 168 DAD O70 Perineal laceration during delivery < once 169 ODB Clindamycin Hcl < once 170 ODB Budesonide once 171 ODB Cloxacillin Sodium once 172 NACRS S13 Dislocation, sprain and strain of joints and ligaments at neck level once 173 OHIP 628 Infertility once Budesonide & 174 ODB Formoterol Fumarate once 175 OHIP 280 Iron deficiency anaemia frequent 176 OHIP 295 Schizophrenia sporadic 177 OHIP 575 Cholecystitis, without gall stones sporadic 178 ODB Fluocinonide once 179 OHIP 959 Other injuries or trauma frequent 180 NACRS 3WA10 Xray, ankle joint once 181 NACRS 1KX53 Implantation of internal device, vein NEC once 182 OHIP 309 Adjustment reaction once 183 NACRS T81 Complications of procedures, not elsewhere classified once Convulsions, ataxia, vertigo, headache, except tension headache and migraine frequent 184 OHIP NACRS G43 Migraine once 186 NACRS J18 Pneumonia, organism unspecified once

13 187 OHIP 304 Drug addiction, dependence frequent 188 ODB Moxifloxacin Hcl once 189 NACRS Z71 Persons encountering heatlh services for other counselling and medical advice, not elsewhere classified once 190 OHIP 244 Hypothyroidism - acquired (i.e., myxedema) frequent 191 ODB Metformin Hcl once 192 NACRS R50 Fever of unknown origin once 193 OHIP 592 Cystitis once Leg cramps, leg pain, muscle pain, joint pain, arthralgia, 194 OHIP 781 joint swelling, masses < frequent 195 ODB Cyanocobalamin once 196 OHIP 628 Infertility sporadic 197 NACRS Z33 Pregnant state, incidental once 198 NACRS T78 Adverse effects, not elsewhere classified once 199 ODB Penicillin V Potassium < once 200 ODB Iron Ferrous Gluconate frequent 201 ODB Metformin Hcl sporadic 202 ODB Albuterol frequent 203 NACRS 3SC10 Xray, kidney with ureter and bladder once 204 OHIP 289 Other diseases of blood, marrow, spleen frequent 205 NACRS R20 Disturbances of skin sensation once 206 OHIP 303 Alcoholism frequent 207 NACRS R11 Nausea and vomiting once 208 ODB Hydromorphone Hcl frequent 209 NACRS Z63 Other problems related to primary support group, including family circumstances once

14 210 ODB Morphine Sulfate sporadic 211 NACRS R10 Abdominal and pelvic pain < once 212 ODB Acetaminophen & < once Caffeine & Codeine Phosphate 213 ODB Insulin Lispro once Recombinant 214 NACRS R22 Localized swelling, mass and lump of skin and once subcutaneous tissue 215 NACRS X59 Exposure to unspecified factor once 216 ODB Ethinylestradiol & < frequent Levonorgestrel 217 OHIP 708 Allergic urticaria once 218 OHIP 847 Neck, low back, coccyx frequent 219 ODB Clarithromycin < once 220 OHIP 240 Simple thyroid goitre once 221 OHIP 999 WITHOUT DIAGNOSIS < once 222 OHIP 340 Multiple sclerosis once 223 DAD 5MD60 Cesarean section delivery once 224 NACRS L02 Cutaneous abscess, furuncle and carbuncle once 225 ODB Phenytoin Sodium sporadic 226 OHIP 244 Hypothyroidism - acquired (i.e., myxedema) < once 227 OHIP 455 Haemorrhoids once 228 ODB Levothyroxine Sodium < once 229 OHIP 345 Epilepsy sporadic 230 ODB Dexamethasone frequent

15 231 NACRS T00 Superficial injuries involving multiple body regions once 232 OHIP 575 Cholecystitis, without gall stones frequent 233 OHIP 250 Diabetes mellitus, including complications < once 234 OHIP 634 Incomplete abortion, complete abortion frequent 235 OHIP 380 Otitis externa frequent 236 OHIP 715 Osteoarthritis frequent 237 ODB Prednisone frequent 238 ODB Azithromycin < once 239 ODB Levofloxacin once 240 NACRS R51 Headache once 241 NACRS N39 Other disorders of urinary system < once 242 DAD 5LD07 Fetal heart monitoring during active labour once 243 OHIP 715 Osteoarthritis once 244 OHIP 313 Behaviour disorder once 245 ODB Triamcinolone Acetonide < once 246 OHIP 345 Epilepsy frequent 247 ODB Domperidone Maleate once 248 ODB Baclofen once 249 ODB Drospirenone & sporadic Ethinylestradiol 250 ODB Iron Ferrous Fumarate < once 251 ODB Diclofenac Sodium & once Misoprostol 252 DAD O68 Labour and delivery complicated by fetal stress [distress] once 253 ODB Terbinafine Hcl once 254 NACRS S30 Superficial injury of abdomen, lower back and pelvis once 255 ODB Terbutaline Sulfate frequent

16 256 ODB Norethindrone < once 257 OHIP 901 Divorce once 258 ODB Ethinylestradiol & once Norethindrone 259 OHIP 461 Acute sinusitis < once 260 OHIP 661 Uterine inertia frequent 261 ODB Mesalamine once 262 OHIP 626 Disorders of menstruation < frequent 263 ODB Cefprozil < once 264 OHIP 345 Epilepsy once 265 OHIP 278 Obesity frequent 266 OHIP 303 Alcoholism once 267 NACRS J40 Acute bronchitis once 268 OHIP 427 Paroxysmal tachycardia, atrial or ventricular flutter or fibrillation, cardiac arrest, other arrythmias frequent 269 NACRS 3GY10 Xray, thoracic cavity NEC < once 270 DAD 5PC80 Surgical repair, postpartum < once 271 OHIP 790 Non-specific findings on examination of blood frequent 272 OHIP 285 Other anaemias frequent 273 ODB Tetracycline Hcl < once 274 ODB Ramipril frequent 275 DAD O34 Maternal care for known or suspected abnormality of pelvic once organs 276 NACRS 3VG10 Xray, knee joint once 277 NACRS W00 Fall on same level involving ice and snow once 278 NACRS 1ZZ35 Pharmacotherapy, total body frequent

17 279 NACRS 1GZ35 Pharmacotherapy (local), respiratory system NEC once 280 ODB Cefuroxime Axetil once 281 NACRS S61 Open wound of wrist and hand once 282 NACRS F10 Mental and behavioural disorders due to use of alcohol once 283 NACRS T42 Poisoning by antiepileptic, sedative-hypnotic and once antiparkinsonism drugs 284 DAD O41 Other disorders of amniotic fluid and membranes once 285 ODB Doxepin Hcl sporadic 286 DAD 8550 Infectious and parasitic diseases once 287 ODB Metformin Hcl frequent 288 ODB Omeprazole sporadic 289 ODB Permethrin < once 290 NACRS 1ZZ35 Pharmacotherapy, total body < once 291 NACRS K29 Gastritis and duodenitis once 292 DAD V27 Motorcycle rider injured in noncollision transport accident once 293 NACRS S62 Fracture at wrist and hand level once 294 ODB Medroxyprogesterone < once Acetate 295 ODB Propranolol Hcl once 296 ODB Docusate Sodium < once 297 OHIP 682 Cellulitis, abscess < once 298 OHIP 379 Other disorders of the eye frequent 299 OHIP 829 Other fractures frequent

18 300 ODB Mupirocin once 301 ODB Amoxicillin & once Clavulanic Acid Potassium 302 OHIP 691 Eczema, atopic dermatitis, neurodermatitis < once 303 OHIP 729 Fibrositis, myositis, muscular rheumatism frequent 304 ODB Ethinylestradiol & < once Norgestimate 305 ODB Clioquinol & once Flumetasone Pivalate 306 NACRS R00 Abnormalities of heart beat once 307 OHIP 634 Incomplete abortion, complete abortion < sporadic 308 NACRS H10 Conjunctivitis once 309 OHIP 714 Rheumatoid arthritis, Still's disease frequent 310 OHIP 575 Cholecystitis, without gall stones once 311 NACRS W44 Foreign body entering into or through eye or natural orifice once 312 ODB Benzoyl Peroxide & < once Clindamycin 313 NACRS Y04 Assault by bodily force once 314 OHIP 718 Meniscal tear once 315 ODB Lansoprazole once 316 NACRS 2ZZ13 Specimen collection (for diagnostic testing), total body < once 317 OHIP 285 Other anaemias once 318 OHIP 277 Other metabolic disorders frequent 319 NACRS N89 Other noninflammatory disorders of vagina once 320 OHIP 627 Bleeding (post-menopause) < once

19 321 ODB Doxepin Hcl once 322 OHIP 632 Missed abortion < frequent 323 NACRS R07 Pain in throat and chest < once 324 DAD O36 Maternal care for other known or suspected fetal problems once 325 NACRS N92 Excessive, frequent and irregular menstruation once 326 OHIP 460 Acute nasopharyngitis, common cold < frequent 327 OHIP 10 Primary tuberculous infection, including recent positive TB frequent skin test conversion 328 NACRS S20 Superficial injury of thorax once 329 OHIP 306 Sexual dysfunction once 330 ODB Propranolol Hcl frequent 331 DAD 5MD54 Vacuum traction delivery once 332 NACRS S39 Other and unspecified injuries of abdomen, lower back and once pelvis 333 ODB Naproxen < once 334 OHIP 307 Habit spasms, tics, stuttering, tension headaches, anorexia nervosa, sleep disorders, enuresis frequent 335 OHIP 626 Disorders of menstruation < once 336 OHIP 521 Dental caries, other diseases of hard tissues of teeth (system frequent inserted for dentists' claims) 337 OHIP 491 Chronic bronchitis once 338 NACRS Z09 Follow-up examination after treatment for conditions other once than malignant neoplasms 339 NACRS 3AN20 CAT scan, brain stem once 340 NACRS K80 Cholelithiasis frequent 341 OHIP 650 Normal delivery, uncomplicated pregnancy < sporadic

20 342 ODB Cromolyn Sodium frequent 343 OHIP 314 Hyperkinetic syndrome of childhood once 344 ODB Tretinoin once 345 OHIP 427 Paroxysmal tachycardia, atrial or ventricular flutter or fibrillation, cardiac arrest, other arrythmias once 346 NACRS K08 Other disorders of teeth and supporting structures once 347 ODB Domperidone frequent 348 NACRS W10 Fall on and from stairs and steps once 349 NACRS 3UZ10 Xray, spinal vertebrae once 350 ODB Domperidone once 351 ODB Tretinoin frequent 352 NACRS J01 Acute sinusitis once 353 OHIP 714 Rheumatoid arthritis, Still's disease sporadic 354 ODB Nystatin < once 355 ODB Fusidic Acid < once 356 DAD O75 Other complications of labour and delivery, not elsewhere once classified 357 NACRS B37 Candidiadis once 358 OHIP 998 Of surgical and medical care (e.g., wound infection, wound disruption, other iatrogenic disease) < once 359 NACRS M62 Other disorders of muscle once 360 ODB Diclofenac Sodium < once 361 ODB Metoclopramide Hcl once 362 OHIP 650 Normal delivery, uncomplicated pregnancy < frequent

21 363 NACRS K59 Other functional intestinal disorders once 364 ODB Metronidazole & < once Nystatin 365 OHIP 256 Ovarian dysfunction (e.g., ovarian failure, polycystic frequent ovaries, Stein-Leventhal syndrome) 366 OHIP 898 Marital difficulties frequent 367 NACRS R56 Convulsions, not elsewhere classified frequent 368 NACRS Z30 Contraceptive management once 369 ODB Indomethacin once 370 OHIP 305 Tobacco abuse once 371 ODB Psyllium < once 372 OHIP 401 Essential, benign hypertension < once 373 ODB Hydromorphone Hcl once 374 ODB Labetalol Hcl frequent 375 ODB Ethinylestradiol & sporadic Norethindrone 376 OHIP 959 Other injuries or trauma < once 377 ODB Iron Ferrous Fumarate frequent 378 OHIP 289 Other diseases of blood, marrow, spleen once 379 ODB Lansoprazole frequent 380 OHIP 592 Cystitis frequent 381 NACRS Z72 Problems related to lifestyle once 382 OHIP 998 Of surgical and medical care (e.g., wound infection, wound frequent disruption, other iatrogenic disease) 383 OHIP 78 Warts sporadic 384 NACRS S60 Superficial injury of wrist and hand once 385 OHIP 854 Head injury once

22 386 OHIP 879 Lacerations, open wounds - except limbs < once 387 NACRS M25 Other joint disorders, not elsewhere classified once 388 ODB Sulfamethoxazole & < once Trimethoprim 389 OHIP 898 Marital difficulties once 390 OHIP 298 Other psychoses frequent 391 OHIP 250 Diabetes mellitus, including complications < sporadic 392 OHIP 460 Acute nasopharyngitis, common cold < once 393 OHIP 634 Incomplete abortion, complete abortion < once 394 ODB Fluticasone Propionate & frequent Salmeterol Xinafoate 395 NACRS R25 Abnormal involuntary movements once 396 ODB Cephalexin < once 397 NACRS 3OT20 Xray, abdominal cavity once 398 NACRS W19 Unspecified fall once 399 OHIP 525 Other conditions of teeth and supporting structure < once 400 DAD 8569 Post-operative or post-traumatic infections once 401 DAD 661 Uterine inertia once 402 OHIP 349 Other diseases of central nervous system (e.g., brain abscess, narcolepsy, motor neuron disease, syringomyelia) once 403 NACRS R53 Malaise and fatigue once 404 OHIP 463 Tonsilitis < once 405 OHIP 314 Hyperkinetic syndrome of childhood frequent 406 OHIP 779 Other conditions of fetus or newborn once 407 OHIP 909 Other problems of social adjustment once 408 OHIP 626 Disorders of menstruation < sporadic

23 409 ODB Beclomethasone < once Dipropionate 410 OHIP 380 Otitis externa < once 411 OHIP 899 Parent-child problems (e.g., child-abuse, battered child, once child neglect) 412 OHIP 629 Other disorders of female genital organs < frequent 413 OHIP 894 Laceration, lower once 414 OHIP 99 Other venereal diseases (e.g., herpes genitalis) < once 415 NACRS K80 Cholelithiasis once 416 ODB Ibuprofen < once 417 ODB Propranolol Hcl sporadic 418 NACRS Z04 Examination and observation for other reasons once 419 DAD 650 Normal delivery, uncomplicated pregnancy once 420 OHIP 532 Duodenal ulcer, with or without haemorrhage or perforation once 421 ODB Fusidic Acid Sodium < once 422 DAD 664 Perineal lacerations once 423 ODB Pivampicillin once 424 ODB Hydrocortisone Acetate frequent & Urea 425 OHIP 644 False labour, threatened labour < once 426 ODB Betamethasone Valerate < once 427 NACRS X50 Overexertion and strenuous or repetitive movements < once 428 ODB Permethrin frequent

24 429 NACRS 3OT30 Computerized tomography [CT], abdominal cavity < once 430 NACRS Z53 Persons encountering health services for specific once procedures, not carried out 431 OHIP 669 Delivery with other complications < once 432 OHIP 640 Threatened abortion, haemorrhage in early pregnancy < frequent 433 ODB Erythromycin & once Tretinoin 434 OHIP 555 Regional enteritis, Crohn's disease once 435 NACRS H66 Suppurative and unspecified otitis media once 436 ODB Fluconazole < once 437 ODB Medroxyprogesterone < frequent Acetate 438 NACRS 3PS10 Ultrasound, abdominal cavity once 439 ODB Benzoyl Peroxide & frequent Clindamycin 440 OHIP 78 Warts < once 441 DAD 656 Foetal distress once 442 OHIP 640 Threatened abortion, haemorrhage in early pregnancy < once 443 OHIP 381 Serous otitis media, eustachian tube disorders < once 444 ODB Domperidone Maleate frequent 445 ODB Dexamethasone & Framycetin Sulfate & Gramicidin < once

25 446 ODB Non Pharmaceutical frequent Ingredient 447 OHIP 616 Vulvitis < frequent 448 ODB Atenolol once 449 NACRS 5AB06 Contraction stress test once 450 ODB Clobetasol Propionate < once 451 ODB Albuterol Sulfate & frequent Ipratropium Bromide 452 ODB Rofecoxib once 453 NACRS W18 Other fall on same level once 454 NACRS R05 Cough < once 455 NACRS B34 Viral infection of unspecified site < once 456 ODB Ethinylestradiol & < once Norethindrone Acetate 457 OHIP 662 Prolonged labour once 458 ODB Amcinonide < once 459 ODB Norfloxacin < once 460 DAD K80 Cholelithiasis once 461 OHIP 564 Spastic colon, irritable colon, mucous colitis, constipation frequent 462 ODB Human Insulin Isophane sporadic Recombinant 463 NACRS B96 Other bacterial agents as the cause of diseases classified to once other chapters 464 DAD 8610 Traumatic pneumothorax, with open wound in thorax once

26 465 ODB Terbutaline Sulfate once 466 OHIP 909 Other problems of social adjustment frequent 467 NACRS W22 Striking against or struck by other objects < once 468 OHIP 787 Anorexia, nausea and vomiting, heartburn, dysphagia, < frequent hiccough, hematemesis, jaundice, ascites, abdominal pain, melena, masses 469 ODB Zinc Sulfate < once 470 OHIP 842 Wrist, hand, fingers < once 471 ODB Budesonide & frequent Formoterol Fumarate 472 ODB Phenytoin Sodium once 473 OHIP 786 Epistaxis, hemoptysis, cough, dyspnea, masses, shortness of breath, hyperventilation, sleep apnea < frequent 474 ODB Hydrocortisone Acetate < once 475 NACRS J20 Acute bronchitis once 476 DAD Z29 Need for other prophylactic measures < once 477 ODB Sulfadiazine Silver Salt once 478 NACRS 2ZZ02 Assessment (examination), total body frequent 479 OHIP 340 Multiple sclerosis frequent 480 OHIP 373 Blepharitis once 481 OHIP 565 Anal fissure, anal fistula frequent 482 ODB Injectable Mixture once

27 483 OHIP 349 Other diseases of central nervous system (e.g., brain abscess, narcolepsy, motor neuron disease, syringomyelia) frequent 484 ODB Acetaminophen < once 485 OHIP 646 Other complications of pregnancy (e.g., vulvitis, vaginitis, < once cervicitis, pyelitis, cystitis) 486 OHIP 474 Hypertrophy or chronic infection of tonsils and/or adenoids frequent 487 ODB Drospirenone & < once Ethinylestradiol 488 NACRS R55 Syncope and collapse once 489 ODB Levonorgestrel < once 490 ODB Amoxicillin Trihydrate < frequent 491 OHIP 847 Neck, low back, coccyx < once 492 OHIP 70 Viral hepatitis frequent 493 OHIP 616 Vulvitis < once 494 OHIP 622 Cervical erosion/dysplasia < sporadic 495 OHIP 844 Knee, leg frequent 496 DAD O42 Premature rupture of membranes < once 497 NACRS W25 Contact with sharp glass once 498 DAD O64 Obstructed labour due to malposition and malpresentation once of fetus 499 NACRS R10 Abdominal and pelvic pain < frequent 500 NACRS N94 Pain and other conditions associated with female genital organs and menstrual cycle < once

28 etable 4. Baseline characteristics of women in Ontario with a singleton live birth in who were not eligible for the publicly funded drug plan Non-eligible (n = ) Eligible (n = 38077) Standardized Difference Socio-demographics Maternal age in years: mean (standard deviation) 30.2 (5.5) 26.7 (6.2) 0.63 Maternal age <20 years (3.3) 4190 (11.0) 0.30 Maternal age >35 years (17.1) 4139 (10.9) 0.18 Primiparous (49.9) 9798 (25.7) 0.52 Lowest income quintile a (21.3) (52.3) 0.68 Rural residence (9.7) 3540 (9.3) 0.01 Pre-pregnancy morbidity Diabetes mellitus (1.4) 1129 (3.0) 0.11 Hypertension (2.4) 1132 (3.0) 0.04 Very high resource utilization b 3828 (0.5) 1010 (2.7) 0.17 Psychiatric diagnosis, past 2 years Psychotic disorder 1596 (0.2) 830 (2.2) 0.18 Bipolar or major depressive disorder (3.8) 5110 (13.4) 0.35 Other depressive or anxiety disorder (23.9) (46.8) 0.49 Alcohol or substance abuse (1.8) 3165 (8.3) 0.30 Other psychiatric morbidity (4.9) 4867 (12.8) 0.28 Inpatient psychiatry admissions, past 2 years: median (range) 0 (0-34) 0 (0-26) 0.39 Psychiatric emergency department visits, past 2 years: median (range) 0 (0-48) 0 (0-57) 0.46 Pregnancy-related variables No prenatal ultrasound at <20 weeks (14.4) 6694 (17.6) 0.09 Prenatal care: Obstetrician (34.6) (28.5) 0.13 Inpatient psychiatry admissions: median (range) 0 (0-10) 0 (0-7) 0.18

29 Non-eligible (n = ) Eligible (n = 38077) Standardized Difference Psychiatric emergency department visits: median (range) 0 (0-6) 0 (0-6) 0.15 Gestational diabetes (5.2) 2195 (5.8) 0.03 Gestational hypertension (1.6) 575 (1.5) 0.01 Preeclampsia or eclampsia 8576 (1.2) 425 (1.1) 0.00 Child characteristics Male infant sex (51.4) (50.9) 0.01 Gestational age at birth in weeks: mean (standard deviation) 39.0 (1.7) 38.7 (2.0) 0.17 a Neighbourhood income quintile was measured by linking postal codes with 2006 Census dissemination area information on average household income, which takes into account average household size and community of residence; b Resource utilization is measured using the Johns Hopkins Adjusted Clinical Groups Case-Mix System, which categorizes patients based on their expected consumption of health services from 0 (low) to 5 (very high).

30 etable 5. Baseline characteristics of serotonergic antidepressant users and non-users in the mood and anxiety disorder-restricted cohort Data are presented as a number (%) unless otherwise indicated. Socio-demographic characteristics Maternal age in years: mean (standard deviation) Users (N =2518) Unweighted Non-users (N = 14478) Standardized difference Inverse probability of treatment-weighted using a high-dimensional propensity score Users Non-users Standardized (N = ) (N = ) difference 28.4 (5.9) 26.6 (6.1) (10.3) 26.9 (4.9) 0.02 Maternal age <20 years 120 (4.8) 1310 (11.0) (9.0) (10.3) 0.04 Maternal age 35 years 340 (13.5) 1266 (10.6) (9.1) (11.5) 0.08 Primiparous 669 (26.6) 3869 (26.7) (28.1) (26.8) 0.03 Lowest Neighbourhood 1177 (46.9) 7365 (51.0) (48.0) (50.1) 0.04 income quintile a Rural residence 293 (11.6) 1335 (9.2) (11.0) (9.6) 0.05 Pre-pregnancy morbidity Diabetes mellitus 96 (3.8) 399 (2.8) (2.8) (3.0) 0.01 Hypertension 105 (4.2) 470 (3.3) (3.0) (3.4) 0.02 Very high resource 170 (6.8) 499 (3.5) (4.6) (4.0) 0.03 utilization b Psychiatric diagnosis, past 2 years Psychotic disorder 195 (7.7) 494 (3.4) (5.6) (4.7) 0.04 Bipolar or major depressive disorder 1176 (46.7) 3175 (21.9) (34.4) (25.8) 0.19

31 Inverse probability of treatment-weighted using Unweighted a high-dimensional propensity score Users (N =2518) Non-users (N = 14478) Standardized difference Users (N = ) Non-users (N = ) Standardized difference Other depressive or anxiety 2364 (93.9) (93.9) (93.7) (94.0) 0.01 disorder Alcohol or substance abuse 479 (19.0) 1546 (10.7) (13.3) (12.2) 0.03 Other psychiatric morbidity 684 (27.2) 2628 (18.2) (23.3) (19.8) 0.08 Inpatient psychiatry 0 (0-26) 0 (0-14) (0-26) 0 (0-14) 0.02 admissions, past 2 years: median (range) Psychiatric emergency department visits, past 2 years: median (range) 0 (0-63) 0 (0-41) (0-63) 0 (0-41) 0.06 Pregnancy-related variables No prenatal ultrasound at 359 (14.3) 2408 (16.6) (84.3) (83.6) 0.02 <20 weeks Prenatal care: Obstetrician 495 (19.7) 3725 (25.7) (22.5) (25.6) 0.07 Inpatient psychiatry 0 (0-5) 0 (0-7) (0-5) 0 (0-7) 0.09 admissions: median (range) Psychiatric emergency 0 (0-5) 0 (0-4) (0-5) 0 (0-4) 0.13 department visits: median (range) Gestational diabetes 161 (6.4) 798 (5.5) (5.5) (5.9) 0.01 Gestational hypertension 53 (2.1) 254 (1.8) (2.1) (1.8) 0.02 Preeclampsia or eclampsia 45 (1.8) 165 (1.1) (1.4) (1.2) 0.01 Medications for pain (serotonergic) c 231 (9.2) 443 (3.1) (5.2) (3.7) 0.07

32 Users (N =2518) Unweighted Non-users (N = 14478) Standardized difference Inverse probability of treatment-weighted using a high-dimensional propensity score Users Non-users Standardized (N = ) (N = ) difference Medications for nausea 437 (17.4) 1091 (7.5) (15.5) (8.3) 0.22 (serotonergic) d Child characteristics Male infant sex 1265 (50.2) 7300 (50.4) (49.2) (50.6) 0.03 Gestational age at birth in weeks: mean (standard deviation) 38.3 (2.1) 38.6 (2.0) (3.4) 38.6 (1.6) 0.00 a Neighbourhood income quintile was measured by linking postal codes with 2006 Census dissemination area information on average household income, which takes into account average household size and community of residence; b Resource utilization is measured using the Johns Hopkins Adjusted Clinical Groups Case-Mix System, which categorizes; patients based on their expected consumption of health services from 0 (low) to 5 (very high); c Fentanyl, meperidine, pentazocine, tramadol d Granisetron, metoclopramide, ondansetron.

33 etable 6. Baseline characteristics of serotonergic antidepressant users and non-users in siblings discordant for serotonergic antidepressant exposure in pregnancy Data are presented as a number (%) unless otherwise indicated. Socio-demographic characteristics Maternal age in years: mean (standard deviation) Users (n = 620) Non-users (n = 620) Standardized difference 27.6 (5.3) 25.5 (5.5) 0.38 Maternal age <20 years 27 (4.4) 77 (12.4) 0.29 Maternal age 35 years 53 (8.6) 34 (5.5) 0.12 Primiparous 38 (6.1) 97 (15.7) 0.61 Lowest Neighbourhood income quintile a Rural residence 55 (8.9) 67 (10.8) 0.07 Pre-pregnancy morbidity Diabetes mellitus 25 (4.0) 19 (3.1) 0.05 Hypertension 27 (4.4) 14 (2.3) 0.12 Very high resource utilization b 20 (3.2) 18 (2.9) 0.02 Psychiatric diagnosis, past 2 years Psychotic disorder 35 (5.7) 15 (2.4) 0.16 Bipolar or major depressive disorder 218 (35.2) 133 (21.5) 0.31 Other depressive or anxiety disorder 501 (80.8) 390 (62.9) 0.41 Alcohol or substance abuse 101 (16.3) 80 (12.9) 0.10 Other psychiatric morbidity 131 (21.1) 120 (19.4) 0.04 Inpatient psychiatry admissions, past 2 0 (0-10) years: median (range) Psychiatric emergency department visits, past 2 years: median (range) 0 (0-9) Pregnancy-related variables No prenatal ultrasound at <20 weeks 75 (12.1) 81 (13.1) 0.03 Prenatal care: Obstetrician 122 (19.7) 146 (23.6) 0.09 Inpatient psychiatry admissions: median 0 (0-4) 0 (0-6) 0.10 (range) Psychiatric emergency department visits: 0 (0-4) 0 (0-4) 0.08 median (range) Gestational diabetes 30 (4.8) 33 (5.3) 0.02 Gestational hypertension 20 (3.2) 11 (1.8) 0.09 Preeclampsia or eclampsia < 6 < Medications for pain (serotonergic) c 66 (10.7) 25 (4.0) 0.26 Medications for nausea (serotonergic) d 131 (21.1) 43 (6.9) 0.42

34 Users (n = 620) Non-users (n = 620) Standardized difference Child characteristics Male infant sex 334 (53.9) 325 (52.4) 0.03 Gestational age at birth in weeks: mean (standard deviation) 37.0 (0.5) 36.9 (0.5) 0.05 < 6: Event rate too small to be reported. a Neighbourhood income quintile was measured by linking postal codes with 2006 Census dissemination area information on average household income, which takes into account average household size and community of residence; b Resource utilization is measured using the Johns Hopkins Adjusted Clinical Groups Case-Mix System, which categorizes; patients based on their expected consumption of health services from 0 (low) to 5 (very high); c Fentanyl, meperidine, pentazocine, tramadol d Granisetron, metoclopramide, ondansetron.

35 etable 7. Association between serotonergic antidepressant exposure and child autism spectrum disorder in the mood and anxiety disorder-restricted cohort Group N Personyears N (%) with autism spectrum disorder Incidence per 1,000 personyears (95% confidence interval) Hazard ratio (95% confidence interval) Multivariable-adjusted hazard ratio (95% confidence interval) Crude and multivariable-adjusted analyses Non-users (1.2) 2.43 ( ) 1.00 (Referent) 1.00 (Referent) Users (2.1) 4.75 ( ) 1.91 ( ) 1.60 ( ) Inverse probability of treatment weighted analyses based on a high-dimensional propensity score Non-users (1.2) 2.55 ( ) 1.00 (Referent) - Users ( ( ) 1.62 ( ) - *Adjusted for: maternal age, calendar year of delivery, resource utilization band, psychotic disorder, major mood disorder, alcohol or substance use disorder, other serotonergic medications, psychiatric hospitalization in pregnancy, psychiatric emergency department visit in pregnancy.

36 etable 8. Baseline characteristics of serotonergic antidepressant users and non-users with recent use in the days before conception Socio-demographic characteristics Maternal age in years: mean (standard deviation) Users (n = 2837) Recent users (n = 3092) Standardized difference 28.4 (6.0) 26.2 (5.8) 0.37 Maternal age <20 years 133 (4.7) 330 (10.7) 0.23 Maternal age 35 years 393 (13.9) 262 (8.5) 0.17 Primiparous 745 (26.3) 927 (30.0) 0.08 Lowest Neighbourhood income quintile a (47.3) 0.01 (46.9) Rural residence 325 (11.5) 362 (11.7) 0.01 Pre-pregnancy morbidity Diabetes mellitus 109 (3.8) 85 (2.8) 0.06 Hypertension 120 (4.2) 89 (2.9) 0.07 Very high resource utilization b 175 (6.2) 123 (4.0) 0.10 Psychiatric diagnosis, past 2 years Psychotic disorder 206 (7.3) 143 (4.6) 0.11 Bipolar or major depressive disorder (35.6) 0.12 (41.5) Other depressive or anxiety disorder (81.9) 0.04 (83.3) Alcohol or substance abuse 525 (18.5) 436 (14.1) 0.12 Other psychiatric morbidity 707 (24.9) 646 (20.9) 0.10 Inpatient psychiatry admissions, past 2 years: 0 (0-26) 0 (0-14) 0.09 median (range) Psychiatric emergency department visits, past 2 years: median (range) 0 (0-63) 0 (0-15) 0.10 Pregnancy-related variables 410 (14.5) 514 (16.6) 0.06 No prenatal ultrasound at <20 weeks 604 (21.3) 786 (25.4) 0.10 Prenatal care: Obstetrician 0 (0-5) 0 (0-4) 0.12 Inpatient psychiatry admissions: median 0 (0-5) 0 (0-4) 0.16 (range) Psychiatric emergency department visits: 179 (6.3) 160 (5.2) 0.05 median (range) Gestational diabetes 59 (2.1) 37 (1.2) 0.07 Gestational hypertension 49 (1.7) 41 (1.3) 0.03 Preeclampsia or eclampsia 255 (9.0) 94 (3.0) 0.25 Medications for pain (serotonergic) c 492 (17.3) 229 (7.4) 0.31 Medications for nausea (serotonergic) d 174 (6.1) 29 (0.9) 0.28

37 Users (n = 2837) Child characteristics Male infant sex 1430 (50.4) Gestational age at birth in weeks: mean Recent users (n = 3092) Standardized difference 1553 (50.2) (2.1) 38.7 (2.0) 0.16 (standard deviation) a Neighbourhood income quintile was measured by linking postal codes with 2006 Census dissemination area information on average household income, which takes into account average household size and community of residence; b Resource utilization is measured using the Johns Hopkins Adjusted Clinical Groups Case-Mix System, which categorizes; patients based on their expected consumption of health services from 0 (low) to 5 (very high); c Fentanyl, meperidine, pentazocine, tramadol d Granisetron, metoclopramide, ondansetron.

38 efigure 1. Association between serotonergic antidepressant exposure and child autism spectrum disorder, by trimester of exposure, among women with mood and anxiety disorders Hazard ratios are shown for unweighted and also inverse probability of treatment-weighted by high-dimensional propensity score analyses. The high-dimensional propensity score was re-estimated and inverse probability of treatment weights re-generated for each sub-analysis.

39 efigure 2. Association between serotonergic antidepressant exposure and child autism spectrum disorder, by type of serotonergic antidepressant, among women with mood and anxiety disorders Hazard ratios are shown for unweighted and also inverse probability of treatmentweighted by high-dimensional propensity score analyses. The high-dimensional propensity score was re-estimated and inverse probability of treatment weights regenerated for each sub-analysis. SSRI = Selective Serotonin Reuptake Inhibitor; SNRI = Serotonin-Norepinephrine Reuptake Inhibitor (98% of exposures were with venlafaxine). * Event rates and/or hazard ratios too low to report.