Selective Serotonin Reuptake Inhibitor (SSRI) updated on 07-01-2025

Cognitive developmental disorders/delay (3-6 years old)

R analysis
id Study   Lib. in paper Exposition period    Study type  Control type 
 
Tags OR 95%CI x1/n1 x0/n0 no cases no exposed ROB Ref.
S17049
R76881
Suarez (Controls unexposed, discontinuers), 2022 Intellectual disability - ≥ 2 dates with ICD-9 Dx 317, 318.x, 319 - At ≥ 2 years of age 2nd and/or 3rd trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: no or not specified Unexposed sick: recent illness/treatment (during or juste before pregnancy or treatment stopped in view of pregnancy) 0.95 [0.64;1.40] 170/115,060   56/38,038 226 115,060
ref
S17050
R76882
Suarez (Controls unexposed, general pop), 2022 Intellectual disability - ≥ 2 dates with ICD-9 Dx 317, 318.x, 319 - At ≥ 2 years of age 2nd and/or 3rd trimester retrospective cohort (claims database) unexposed (general population or NOS) excluded Adjustment: Yes Monotherapy: no or not specified 0.97 [0.79;1.20]
excluded (control group)
170/115,110   2,950/3,000,907 3,120 115,110
ref
S10002
R53813
Ames (Controls unexposed, disease free), 2021 Developmental delays or disorders (identified from clinical or educational settings) and with score <11 on the SCQ or score >=11 but did not meet study criteria for ASD after the in-person assessment (presence or absence of co-occurring ID defined by MSEL composite standard scores <=70) (Age NOS). during pregnancy (anytime or not specified) case control unexposed, disease free excluded Adjustment: Yes Monotherapy: no or not specified 1.92 [1.43;2.57]
excluded (control group)
145/226   1,605/3,195 1,750 226
ref
S10003
R53814
Ames (Controls unexposed, sick), 2021 Developmental delays or disorders (identified from clinical or educational settings) and with score <11 on the SCQ or score >=11 but did not meet study criteria for ASD after the in-person assessment (presence or absence of co-occurring ID defined by MSEL composite standard scores <=70) (Age NOS). during pregnancy (anytime or not specified) case control unexposed, sick Adjustment: Yes Monotherapy: no or not specified Unexposed sick: recent illness/treatment (during or juste before pregnancy or treatment stopped in view of pregnancy) 1.38 [0.98;1.95] 145/226   -/- - 226
ref
S482
R53820
Harrington, 2014 Developmental delay (Vineland Adaptive Behavior Scales and Mullen Scales of Early Learning (composite score <=70 on either scale)) - Mean 3.7 years (2-5 years) during pregnancy (anytime or not specified) case control unexposed (general population or NOS) Adjustment: Yes Matched Monotherapy: no or not specified 1.62 [0.59;4.42] 8/19   146/455 154 19
ref
S8046
R53815
Batton, 2013 Mental Developmental Index/ Cognitive Composite score on the Bayley Scales of Infant Development (BSID) at 36 months during pregnancy (anytime or not specified) retrospective cohort unexposed, disease free Adjustment: No extrapolated (cont. endpoint) Monotherapy: SSRI only 0.66 [0.18;2.43] -/15   -/15 - 15
ref
S7051
R53816
Nulman (Controls unexposed, disease free), 2012 Full-scale IQ (The Wechsler Preschool and Primary Scale of Intelligence– Third Edition) at 3-6 years during pregnancy (anytime or not specified) prospective cohort unexposed, disease free excluded Adjustment: No extrapolated (cont. endpoint) Monotherapy: SSRI only 2.85 [1.49;5.47]
excluded (control group)
-/62   -/62 - 62
ref
S5377
R53817
Nulman (Controls unexposed, sick), 2012 Full-scale IQ (The Wechsler Preschool and Primary Scale of Intelligence– Third Edition) at 3-6 years during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No extrapolated (cont. endpoint) Monotherapy: SSRI only Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 1.49 [0.77;2.90] -/62   -/54 - 62
ref
S8013
R53818
Nulman - Fluoxetine (Controls exposed to TCA), 2002 Global IQ with the McCarthy Scales of Children’s Abilities at 30 and 71 months of age throughout pregnancy prospective cohort exposed to other treatment, sick excluded Adjustment: No extrapolated (cont. endpoint) Monotherapy: SSRI only 3.35 [0.60;18.67]
excluded (control group)
-/6   -/18 - 6
ref
S8014
R53819
Nulman - Fluoxetine (Controls unexposed, disease free), 2002 Global IQ with the McCarthy Scales of Children’s Abilities at 30 and 71 months of age throughout pregnancy prospective cohort unexposed, disease free Adjustment: No extrapolated (cont. endpoint) Monotherapy: SSRI only 3.79 [0.66;21.98] -/6   -/16 - 6
ref
Total 6 studies 1.23 [0.97;1.56] 380 115,388
x1: number of endpoints among exposed, n1: number of exposed; x0: number of endpoints among non exposed, n0: number of non exposed; C: calculated odds ratio from numbers of events and effectives

Forest plot

StudyTE95% CIn casesn exposedweightROBABCDEF Suarez (Controls unexposed, discontinuers), 2022Suarez, 2022 1 0.95[0.64; 1.40]226115,06034%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Ames (Controls unexposed, sick), 2021Ames, 2021 2 1.38[0.98; 1.95]-22643%ROB confusion: seriousROB selection: criticalROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Harrington, 2014Harrington, 2014 1.62[0.59; 4.42]154196%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Batton, 2013Batton, 2013 0.66[0.18; 2.43]-153%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Nulman (Controls unexposed, sick), 2012Nulman, 2012 3 1.49[0.77; 2.90]-6212%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: lowROB reporting: moderate Nulman - Fluoxetine (Controls unexposed, disease free), 2002Nulman - Fluoxetine, 2002 4 3.79[0.66; 21.98]-62%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: lowROB reporting: moderate Total (6 studies) I2 = 3% 1.23[0.97; 1.56]380115,3880.210.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, discontinuers; 2: Controls unexposed, sick; 3: Controls unexposed, sick; 4: Controls unexposed, disease free;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.13[0.74; 1.73]226115,14322%NASuarez (Controls unexposed, discontinuers), 2022 Batton, 2013 Nulman (Controls unexposed, sick), 2012 Nulman - Fluoxetine (Controls unexposed, disease free), 2002 4 case control studiescase control studies 1.40[1.01; 1.94]1542450%NAAmes (Controls unexposed, sick), 2021 Harrington, 2014 2 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.43[0.61; 3.36]1544023%NAHarrington, 2014 Batton, 2013 Nulman - Fluoxetine (Controls unexposed, disease free), 2002 3 unexposed, sickunexposed, sick 1.21[0.92; 1.59]226115,34817%NASuarez (Controls unexposed, discontinuers), 2022 Ames (Controls unexposed, sick), 2021 Nulman (Controls unexposed, sick), 2012 3 Tags Adjustment   - No  - No 1.40[0.69; 2.86]-8322%NABatton, 2013 Nulman (Controls unexposed, sick), 2012 Nulman - Fluoxetine (Controls unexposed, disease free), 2002 3   - Yes  - Yes 1.20[0.90; 1.59]380115,30515%NASuarez (Controls unexposed, discontinuers), 2022 Ames (Controls unexposed, sick), 2021 Harrington, 2014 3 extrapolated (cont. endpoint)extrapolated (cont. endpoint) 1.40[0.69; 2.86]-8322%NABatton, 2013 Nulman (Controls unexposed, sick), 2012 Nulman - Fluoxetine (Controls unexposed, disease free), 2002 3 MatchedMatched 1.62[0.59; 4.43]15419 -NAHarrington, 2014 1 Monotherapy   - no or not specified  - no or not specified 1.20[0.90; 1.59]380115,30515%NASuarez (Controls unexposed, discontinuers), 2022 Ames (Controls unexposed, sick), 2021 Harrington, 2014 3   - SSRI only  - SSRI only 1.40[0.69; 2.86]-8322%NABatton, 2013 Nulman (Controls unexposed, sick), 2012 Nulman - Fluoxetine (Controls unexposed, disease free), 2002 3 Unexposed sick   - intermediate history of illness/tre ...  - intermediate history of illness/treatment (3-12 months before pregnancy) 1.49[0.77; 2.89]-62 -NANulman (Controls unexposed, sick), 2012 1   - recent illness/treatment (during o ...  - recent illness/treatment (during or juste before pregnancy or treatment stopped in view of pregnancy) 1.16[0.80; 1.67]226115,28649%NASuarez (Controls unexposed, discontinuers), 2022 Ames (Controls unexposed, sick), 2021 2 All studiesAll studies 1.23[0.97; 1.56]380115,3883%NASuarez (Controls unexposed, discontinuers), 2022 Ames (Controls unexposed, sick), 2021 Harrington, 2014 Batton, 2013 Nulman (Controls unexposed, sick), 2012 Nulman - Fluoxetine (Controls unexposed, disease free), 2002 60.210.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.12.31.0730.000Suarez (Controls unexposed, discontinuers), 2022Ames (Controls unexposed, sick), 2021Harrington, 2014Batton, 2013Nulman (Controls unexposed, sick), 2012Nulman - Fluoxetine (Controls unexposed, disease free), 2002

Asymetry test p-value = 0.5823 (by Egger's regression)

slope=0.0741 (0.2556); intercept=0.5348 (0.8950); t=0.5975; p=0.5823

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 8013, 7051, 10002, 17050

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.59[0.98; 2.57]5,024115,43878%NASuarez (Controls unexposed, general pop), 2022 Ames (Controls unexposed, disease free), 2021 Harrington, 2014 Batton, 2013 Nulman (Controls unexposed, disease free), 2012 Nulman - Fluoxetine (Controls unexposed, disease free), 2002 6 unexposed, sick controlsunexposed, sick controls 1.21[0.92; 1.59]226115,34817%NASuarez (Controls unexposed, discontinuers), 2022 Ames (Controls unexposed, sick), 2021 Nulman (Controls unexposed, sick), 2012 3 exposed to other treatment, sick controlsexposed to other treatment, sick controls 3.35[0.60; 18.69]-6 -NANulman - Fluoxetine (Controls exposed to TCA), 2002 10.510.01.0