Croen et al. 4444. Croen LA, Grether JK, Yoshida CK, Odouli R, Hendrick V. Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry 2011; 68:1104-12. (2011, USA) |
ADs (before pregnant 1st, 2nd & 3rd trimesters) |
Population-based case-control study. Kaiser Permanent Medical Care Program in Northern California (KPNC) between January 1995 and June 1999. Cases (n = 298 and their mothers): children with ASD. Controls (n = 1,507 and their mothers): children without ASD randomly selected KPNC in January 1995-November 2002. Exposure: ADs dispensed at a KPNC pharmacy |
ASD and maternal use of ADs during the year prior to delivery: 2.2 (1.2-4.3%). ASD and 1st trimester AD: 3.8 (1.8-7.8). No association with history of mental illnesses in the absence of antenatal exposure to ADs |
Data on pharmacy dispensing may not reflect actual use. No control of confounders (maternal data/lifestyle) |
6 |
A 2-fold increase in risk of ASD associated with antenatal exposure to ADs. Risk of ASD was even higher for exposures to ADs in the 1st trimester of pregnancy |
Hviid et al. 3636. Hviid A, Melbye M, Pasternak B. Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism. N Engl J Med 2013; 369:2406-15. (2013, Denmark) |
SSRI (before and during pregnancy) |
Population-based cohort (all 626,875 singleton live births in Denmark) January 1996-December 2005, with follow-up until January 1st, 2010, or until the child reached 10 years of age, died or was lost to follow-up, or received a diagnosis of ASD (Danish Psychiatric Central Register) |
3,892 ASD cases. No use of SSRIs (before and pregnancy) vs. prenatal SSRI: fully adjusted RR = 1.20 (0.90-1.61). No SSRI vs. use of SSRI before but not during pregnancy: fully adjusted RR = 1.46 (1.17-1.81) |
Large cohort. Reduced potential for selection and recall biases. Low prevalence of pregnancy-related use of SSRI. No control of potential confounders (mother data/lifestyle) |
8 |
No significant association between antenatal exposure to SSRIs and increased risk of ASD in children |
Sørensen et al. 4040. Sørensen MJ, Grønborg TK, Christensen J, Parner ET, Vestergaard M, Schendel D, et al. Antidepressant exposure in pregnancy and risk of autism spectrum disorders. Clin Epidemiol 2013; 5:449-59. (2013, Denmark) |
ADs (during pregnancy) |
Population-based cohort of all children born alive in Denmark (n = 668,468) January 1996-December 2006. ASD diagnosis by December 2010, from Danish Psychiatric Central Register; ICD-10 code F84.0, F84.1, F84.5, F84.8, F84.9). Exposure: women filling a prescription for ADs 30 days before conception to day of birth. From Danish National Prescription Registry (January 1996-December 2006) |
Prevalence of ASD = 1.5% (5,437 children), average age of diagnosis 6.7 years. ASD: prenatally AD vs. unexposed: adjusted HR: 1.5 (1.2-1.9). Children born to mothers with affective disorders: AD vs. unexposed; adjusted HR: 1.2 (0.7-2.1). AD vs. unexposed siblings in families with at least one child with ASD: adjusted HR: 0.9 (0.4-2.0) |
Large cohort. Low potential for selection, recall and misclassification biases. Prescription filling data may not reflect actual use. No control of confounding (mother data/lifestyle) |
8 |
Association of antenatal AD with ASD was not significant when confounding (maternal illness, and family-related factors) was controlled |
Rai et al. 4848. Rai D, Lee BK, Dalman C, Golding J, Lewis G, Magnusson C. Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study. BMJ 2013; 346:f2059. (2013, Sweden) |
SSRI & non-SSRI (pregnancy) |
Population-based nested case-control study (Stockholm cohort, 589,114 people 0-17 years, 2001-2007). 4,429 ASD cases (2,601 without intellectual disability); 43,277 controls (age and sex-matched). ASD cases: ICD-9 (299.0), ICD-10 (F84.0) and DSM-IV (299). AD use: drug use data from first antenatal interview - Swedish Medical Birth Register |
Mother’s (but not father’s) depression associated with ASD: OR: 1.49 (1.08-2.08). Depression plus prenatal AD (SSRI or non-SSRI) and ASD (adjusted disorders other than depression): 3.34 (1.5-7.47). AD and ASD: 1.90 (1.15-3.14), AD and ASD without intellectual disability: 2.54 (1.37-4.68) |
Mother’s depression possibly under ascertained. Confounding: AD use may reflect severe depression and thus severe depression (not AD) would be in fact associated with ASD |
8 |
Prenatal AD (SSRI & non-SSRI) associated with ASD without intellectual disability. Association may be non-causal: additional. Further research needed to clarify whether AD use would reflect severe maternal depression |
Rai et al. 4949. Rai D, Lee BK, Dalman C, Newschaffer C, Lewis G, Magnusson C. Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ 2017; 358:j2811. (2017, Sweden) |
SSRI & non-SSRI (pregnancy) |
Prospective cohort study (Stockholm county, 2001-2011, 254,610 individuals aged 4-17 years, including 5,378 with ASD). ASD: ICD-9 (299.0), ICD-10 (F84.0) and DSM-IV (299). AD use: drug use data from first antenatal interview - Swedish Medical Birth Register. AD use: drug use data from first antenatal interview - Swedish Medical Birth Register |
3,342 children prenatally exposed to AD. 4.1% had ASD compared to a prevalence of 2.9% among those not exposed to AD whose mothers had mental illnesses. Adjusted OR: 1.45 (1.13-1.85). Risk increase concerned children with ASD with no intellectual disability |
Large sample size (total population of Stockholm county) and multisource ascertainment of cases. Absence of detailed measurements of severity of depression in pregnancy. No trimester assessment |
8 |
Weak (OR = 1.45) association of ASD in pregnancy (particularly ASD without intellectual disability) with AD (SSRI & non-SSRI) |
El Marroun et al. 5050. El Marroun H, White TJ, van der Knaap NJ, Homberg JR, Fernández G, Schoemaker NK, et al. Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children. Br J Psychiatry 2014; 205:95-102. (2014, Netherlands) |
SSRI (pregnancy) |
5,976 children (study embedded in the ongoing population-based cohort: Generation R Study). Births from April 2002 to January 2006. SSRI exposure: maternal self-report assessed by questionnaires, prescription records from pharmacies. Parent reported autistic symptoms (traits) using Child Behavior Checklists and Social Responsiveness Scale. |
Adjuested (including adjustment for postnatal maternal depression) OR, pervasive develop. problems, prenatal SSRI vs. unexposed: 1.91 (1.13-3.47). Autistic traits (social responsiveness scale) β = 0.15, 95%CI: 0.08-0.22 |
Prospective study using 2 measures of autistic symptoms. SSRI-treated women may have overestimated problems with their child. No clinical assessments of ASD. Small number of SSRI-exposed children. Residual confounding remained |
6 |
Results suggested association between prenatal SSRI and autistic traits in children |
Harrington et al. 4747. Harrington RA, Lee LC, Crum RM, Zimmerman AW, Hertz-Picciotto I. Prenatal SSRI use and offspring with autism spectrum disorder or developmental delay. Pediatrics 2014; 133:e1241-8. (2014, USA) |
SSRI (1st, 2nd & 3rd trimester) |
Population-based case-control study. CHARGE (Childhood Autism Risks from Genetics and Environment). Mother-child pairs. Children 2-5 years old from California with ASD (n = 492) or DD other than ASD (n = 154) and typical development, TD (n = 320). Interview (SSRI use, mental health history, sociodemographic information) |
OR: among boys (♂) prenatally exposed to SSRI: ASD vs. TD: 2.91 (1.07-7.93). 1st trimester: 3.22 (1.17-8.84) |
Relatively large sample of cases. Potential recall bias. Residual confounding by indication of SSRI, no assessment of depression severity. No data on SSRI dosage |
8 |
In boys, prenatal exposure to SSRI increases risk of ASD |
Gidaya et al. 4545. Gidaya NB, Lee BK, Burstyn I, Yudell M, Mortensen EL, Newschaffer CJ. In utero exposure to selective serotonin reuptake inhibitors and risk for autism spectrum disorder. J Autism Dev Disord 2014; 44:2558-67. (2014, Denmark) |
SSRI (pre-conception, 1st, 2nd & 3rd trimesters) |
Population-based (Danish Civil Registration System) case-control study. All children (singleton or one selected at random from multiple births) born alive in Denmark (n = 628,408) Januarty 1997-December 2006. Cases: ASD diagnosis (Danish National Hospital Register, January 1999-March 2011). Controls without ASD. 10 per case. Exposure: dispensed. From: Danish Drug Prescription Registry |
1.5% of cases and 0.7% of controls exposed to SSRI during pregnancy. Adjusted OR, ASD vs. maternal SSRI use (> 45 days); preconception; 2.1 (1.6-2.8); 1st trimester; 2.4 (1.7-3.3); 2nd trimester; 2.4 (1.6-3.5); 3rd trimester; 2.9 (1.9-4.4). Adjusted for: age, child sex, mother depression; other SSRI indications |
Large population-based case-control study. Residual confounding by indication of SSRI and severity of maternal depression |
8 |
Study results suggest that antenatal exposure to SSRI increases child’s risk associated with ASD |
Clements et al. 4141. Clements CC, Castro VM, Blumenthal SR, Rosenfield HR, Murphy SN, Fava M, et al. Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system. Mol Psychiatry 2015; 20:727-34. (2015, USA) |
SSRI/non-SSRI (pre-conception, 1st, 2nd & 3rd trimesters) |
Case-control study. Cases: children from The Partners HealthCare EHR (New England, Boston, Massachusetts) with 2-19 years, if they had at least one ICD-9 code of 299, 1997-2000. Cases: 1,377 children with ASD; Controls: no prior history of ASD, ADHD or intellectual disability; matched (1:3) for birth year, birth hospital, sex, insurance type (proxy for socioeconomic status), ethnicity, preterm vs. full term. AD prescription (outpatient EHR) and dispensing (inpatient pharmacy) |
Adjusted OR; pre-pregnancy (adjusted mother’s depression) 1.62 (1.17-2.23). Pregnancy (pre-pregnancy-delivery), non-adjusted 1.49 (1.01-2.18), adjuested 1.10 (0.70-1.70), 1st trimester 1.47 (0.81-2.61), 2nd trimester (1.34 (0.77-2.27), 3rd trimester 1.08 (0.61-1.88) |
Relatively large sample of cases. Confounding by indication, misclassification bias |
7 |
ASD risk associated with prenatal ADs was no longer significant after controlling for maternal depression |
Boukhris et al. 4646. Boukhris T, Sheehy O, Mottron L, Bérard A. Antidepressant use during pregnancy and the risk of autism spectrum disorder in children. JAMA Pediatr 2016; 170:117-24. (2016, Canada) |
ADs (1st, 2nd & 3rd trimesters) |
Population-based cohort, January 1998-December 2009. 145,456 full-term singleton infants born alive. ASD: children with at least 1 ASD diagnosis between date of birth and last follow-up |
1,054 (0.7%, 4♂:1♀) with ASD. Age of children at the end of follow-up was 6.24 (3.19) years. 2nd/3rd trimester adjuested HR; ADs = 1.87 (1.15-3.04), SSRIs = 2.17 (1.20-3.93). Adjuested for maternal depression: ADs = 1.75 (1.03-2.97) |
Large cohort, 11-year follow-up. Prescription filling data (may not reflect actual use), lack of control of potential confounders (mother data/lifestyle) |
8 |
Antenatal ADs, (predominantly SSRIs), in the 2nd/3rd trimester increases ASD risk |
Castro et al. 3737. Castro VM, Kong SW, Clements CC, Brady R, Kaimal AJ, Doyle AE, et al. Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study. Transl Psychiatry 2016; 6:e708. (2016, USA) |
SSRI/non-SSRI (pre-pregnancy, 1st, 2nd & 3rd trimester) |
Case-control study. Cases: children from The Partners HealthCare EHR with 2-19 years, at least one ICD-9 code of 299. 1997-2010. Cases: 1,245. ASD; Controls: no prior history of ASD, ADHD or intellectual disability; matched (1:3) for birth year, birth hospital, sex, insurance type (proxy for socioeconomic status), ethnicity, preterm vs full term. Mother-child pairs included in the previous report by Clements et al. 41 were excluded. AD prescription (outpatient EHR) and dispensing (inpatient pharmacy) |
Adjusted OR; pre-pregnancy (adjusted for maternal depression) 1.54 (1.02-2.30). Pregnancy (pre-pregnancy-delivery), non-adjusted 0.99 (0.63-1.51), adjusted 0.90 (0.50-1.54), 1st trimester 0.89 (0.40-1.78), 2nd trimester (1.11 (0.50-2.26), 3rd trimester 0.85 (0.38-1.74) |
Relatively large sample of cases. Some risk of confounding by indication, misclassification bias |
7 |
Pre-pregnancy only use of ADs associated with ASD. No association between mother use of AD in pregnancy and ASD |
Sujan et al. 4242. Sujan AC, Rickert ME, Öberg AS, Quinn PD, Hernández-Díaz S, Almqvist C, et al. Associations of maternal antidepressant use during the first trimester of pregnancy with preterm birth, small for gestational age, autism spectrum disorder, and attention-deficit/hyperactivity disorder in offspring. JAMA 2017; 317:1553-62. (2017, Sweden) |
ADs (1st trimmester) |
Retrospective cohort study: Swedish offspring born 1996-2012 followed through 2013, death or emigration. Maternal self-reported 1st trimester use and dispensation of ADs; data from Medical Birth Register, and Prescribed Drug Register. ASD inpatient and outpatient diagnoses made by a specialist according to ICD-9 and ICD-10 criteria (Swedish registers) |
Analytical cohort (1,580,629 children, 48.6% females), 1.4% were exposed (mother self-report) to ADs during 1st trimester and of these, 82% were exposed to SSRIs. ASD exposed vs. unexposed; HR: 2.0 (1.8-2.3). Siblings analysis adjusted pregnancy, maternal, paternal traits; ASD; 0.8 (0.6-1.1) |
Large population based sample (cohort study), Sibling analysis. Exposure conferred both to self-report and dispensation. Recall bias. No assessment of maternal depression severity. 1st trimester exposure only. Mostly SSRIs |
8 |
After taking into account confounding; no association of 1st trimester exposure to ADs with ASD |
Malm et al. 3535. Malm H, Brown AS, Gissler M, Gyllenberg D, Hinkka-Yli-Salomäki S, McKeague IW, et al. Gestational exposure to selective serotonin reuptake inhibitors and offspring psychiatric disorders: a national register-based study. J Am Acad Child Adolesc Psychiatry 2016; 55:359-66. (2016, Finland) |
SSRI (pregnancy) |
Population-based cohort study. Data from Finnish National Registers. 845,345 singleton live births in Finland between January 1996-December 2010. Age range from birth to age 14, mother child pairs - National Medical Birth Register. Drug Reimbursement Register (prescription drug purchases). Outcome: ASD |
ASD, adjusted HR; SSRI gestation vs. Mother psychiatric disease and no medication, 0.88 (0.65-1.20), SSRI pregnancy vs. SSRI pre-pregnancy only, 1.30 (0.88-1.92), SSRI pregnancy vs. no maternal disease, no medication, 1.40 (1.02-1.92) |
Large population based prospective cohort. No pregnancy trimester. analysis. No confirmation of adherence to purchased drugs. No information on postnatal environment |
7 |
Taking into account maternal illness, prenatal SSRI was not associated with increased risk of ASD. |
Brown et al. 3838. 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 2017; 317:1544-52. (2017, Canada) |
SSRI/SNRI (during pregnancy) |
Retrospective cohort study using health administrative data from Ontario, Canada, children (35,906 singleton births) born to mothers receiving public prescription drug (4.2% births) from 2002-2010. Outcome followed through 2014. ASD diagnosed after the age of 2 years |
ASD adjusted HR; SSRI vs. unexposed 1.59 (1.17-2.17), sibling analysis, 1.60 (0.69-3.74) |
No remarkable strength limited to women in Ontario’s publicly funded drug plan (lower social class). Potential misclassification bias (filled-out prescriptions not used) |
8 |
Prenatal exposure to SSRI or SNRI was not associated to ASD in children |
Viktorin et al. 3939. Viktorin A, Uher R, Reichenberg A, Levine SZ, Sandin S. Autism risk following antidepressant medication during pregnancy. Psychol Med 2017; 47:2787-96. (2017, Sweden) |
ADs (pregnancy) |
Population based cohort of 179,007 Swedish children born in 2006-2007 followed through 2014 when they were aged 7 and 8. Mother and children identified in the Swedish Medical Birth Register. Exposure: data on prescription drug dispensed - Swedish Drug Register, ASD; ICD-10 codes F84.0, F84.1, F84.2, F84.3, F84.4, F84.5, F84.8, F84.9 - Swedish Patient Register |
ASD adjusted RR (95%CI), full sample, ADs vs. unexposed: 1.23 (0.96-1.57). Subsample of mothers with at least one diagnosis of depression or anxiety in their lifetime; ADs (2 dispensations overlapping pregnancy) vs. unexposed: 1.07 (0.80-1.43). citalopram/escitalopram: 1.47 (0.92-2.35), clomipramine: 2.86 (1.04-7.82) |
Nationwide population-based cohort. Severity of maternal mental illness not known |
8 |
Prenatal exposure to ADs was not causally associated with ASD in children |
Hagberg et al. 4343. Hagberg KW, Robijn AL, Jick S. Maternal depression and antidepressant use during pregnancy and the risk of autism spectrum disorder in offspring. Clin Epidemiol 2018; 10:1599-612. (2018, UK) |
ADs (pre-pregnancy, 1st, 2nd & 3rd trimester) |
Cohort study (with nested sibling case-control analysis) using a population-based electronic medical database (UK Medical Practice Research Datalink, CPRD). Mothers (aged 13 to 44 years) and their live born singleton infants, born between 1989 and 2011. Cohort entry was baby delivery date minus 365 days. Children: at least 3 years of follow-up after birth. 3 cohorts of exposed women (depressed treated with AD); depressed untreated with AD in pregnancy; non-depressed treated with AD in pregnancy). 194,494 mother-baby pairs; 2,154 with ASD |
RR; unexposed vs. treated depression: 1.72 (1.54-1.93); unexposed vs. untreated depression: 1.50 (1.28-1.75); unexposed vs. AD for disorders other than depression: 0.73 (0.41-1.29). Sibling analysis yield results similar to those of main study. Additional analysis indicated that risk of ASD increased with increasing severity of depression (duration of last episode of untreated depression; < 12 months vs. 12-35.9 months) |
Large population-based cohorts. Assessment of effects of untreated depression and severity of untreated depression. No remarkable weakness |
9 |
Pregnant women with depression have increased risk of having a child with ASD, whether or not she used ADs during pregnancy |