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

Language disorders/delay

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
R71331		 Suarez (Controls unexposed, discontinuers), 2022 Developmental Speech or Language Disorder - ≥ 2 dates with ICD-9 Dx 315.3x (except 315.34) - At 1.5 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) 1.16 [1.07;1.26] 4,115/115,060   1,094/38,038 5,209 115,060
ref
S17050
R71339		 Suarez (Controls unexposed, general pop), 2022 Developmental Speech or Language Disorder - ≥ 2 dates with ICD-9 Dx 315.3x (except 315.34) - At 1.5 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 1.12 [1.07;1.17]
excluded (control group) 		4,113/115,110   66,748/3,000,907 70,861 115,110
ref
S7441
R21975		 Brown (Controls unexposed, disease free), 2016 Specific developmental disorders of speech and language (Finnish Hospital Discharge Register - F80) (mean: 4.43 years) during pregnancy (anytime or not specified) population based cohort retrospective unexposed, disease free excluded Adjustment: Yes Monotherapy: no or not specified 1.53 [1.26;1.86]
excluded (control group) 		253/15,596   325/31,207 578 15,596
ref
S7442
R21979		 Brown (Controls unexposed, sick), 2016 Specific developmental disorders of speech and language (Finnish Hospital Discharge Register - F80) (mean: 4.43 years) during pregnancy (anytime or not specified) population based cohort retrospective unexposed, sick Adjustment: Yes Monotherapy: no or not specified Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 1.20 [0.97;1.49] 253/15,596   176/9,537 429 15,596
ref
S8098
R25361		 Skurtveit, 2014 Language delay vs long, complicated sentences (language questionnaire completed by mother) at 3 years - (Use in at least 2 time periods) during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified 2.30 [1.21;4.37] -/-   -/- - -
ref
S7051
R19921		 Nulman (Controls unexposed, disease free), 2012 Verbal 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 2.29 [1.20;4.38]
excluded (control group) 		-/62   -/62 - 62
ref
S5377
R19918		 Nulman (Controls unexposed, sick), 2012 Verbal 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) 1.30 [0.67;2.53] -/62   -/54 - 62
ref
S8013
R24390		 Nulman - Fluoxetine (Controls exposed to TCA), 2002 Language, Verbal comprehension with the Reynell Developmental Language Scale at 15-71 months throughout pregnancy prospective cohort exposed to other treatment, sick excluded Adjustment: No extrapolated (cont. endpoint) Monotherapy: SSRI only 4.35 [1.92;9.83]
excluded (control group) 		-/38   -/45 - 38
ref
S8014
R24396		 Nulman - Fluoxetine (Controls unexposed, disease free), 2002 Language, Expression with the Reynell Developmental Language Scale at 15-71 months throughout pregnancy prospective cohort unexposed, disease free Adjustment: No extrapolated (cont. endpoint) Monotherapy: SSRI only 1.37 [0.59;3.19] -/37   -/34 - 37
ref
S6994
R19842		 Simon (Controls exposed to TCA), 2002 Speech delay (infants’ medical records) - unspecified age during pregnancy (anytime or not specified) retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: SSRI only 1.13 [0.16;8.11] C
excluded (control group) 		2/185   2/209 4 185
ref
S492
R17430		 Simon (Controls unexposed, NOS), 2002 Speech delay (infants’ medical records) - unspecified age during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No Matched Monotherapy: SSRI only 1.00 [0.14;7.18] 2/185   2/185 4 185
ref
Total 6 studies 1.18 [1.09;1.27] 5,642 130,940
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 1.16[1.07; 1.26]5,209115,06084%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Brown (Controls unexposed, sick), 2016Brown, 2016 2 1.20[0.97; 1.49]42915,59612%ROB confusion: moderateROB selection: lowROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Skurtveit, 2014Skurtveit, 2014 2.30[1.21; 4.37]--1%ROB confusion: seriousROB selection: lowROB classification: lowROB missing: criticalROB mesure: criticalROB reporting: moderate Nulman (Controls unexposed, sick), 2012Nulman, 2012 3 1.30[0.67; 2.53]-621%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: moderateROB mesure: lowROB reporting: moderate Nulman - Fluoxetine (Controls unexposed, disease free), 2002Nulman - Fluoxetine, 2002 4 1.37[0.59; 3.19]-371%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: lowROB reporting: moderate Simon (Controls unexposed, NOS), 2002Simon, 2002 5 1.00[0.14; 7.18]41850%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Total (6 studies) I2 = 0% 1.18[1.09; 1.27]5,642130,9400.55.01.0ROB: 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; 5: Controls unexposed, NOS;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.18[1.09; 1.27]5,642130,9400%NASuarez (Controls unexposed, discontinuers), 2022 Brown (Controls unexposed, sick), 2016 Skurtveit, 2014 Nulman (Controls unexposed, sick), 2012 Nulman - Fluoxetine (Controls unexposed, disease free), 2002 Simon (Controls unexposed, NOS), 2002 6 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.83[1.11; 2.99]42220%NASkurtveit, 2014 Nulman - Fluoxetine (Controls unexposed, disease free), 2002 Simon (Controls unexposed, NOS), 2002 3 unexposed, sickunexposed, sick 1.17[1.08; 1.26]5,638130,7180%NASuarez (Controls unexposed, discontinuers), 2022 Brown (Controls unexposed, sick), 2016 Nulman (Controls unexposed, sick), 2012 3 Tags Adjustment   - No  - No 1.30[0.79; 2.16]42840%NANulman (Controls unexposed, sick), 2012 Nulman - Fluoxetine (Controls unexposed, disease free), 2002 Simon (Controls unexposed, NOS), 2002 3   - Yes  - Yes 1.24[1.02; 1.49]5,638130,65654%NASuarez (Controls unexposed, discontinuers), 2022 Brown (Controls unexposed, sick), 2016 Skurtveit, 2014 3 extrapolated (cont. endpoint)extrapolated (cont. endpoint) 1.33[0.79; 2.24]-990%NANulman (Controls unexposed, sick), 2012 Nulman - Fluoxetine (Controls unexposed, disease free), 2002 2 MatchedMatched 1.00[0.14; 7.16]4185 -NASimon (Controls unexposed, NOS), 2002 1 Monotherapy   - no or not specified  - no or not specified 1.24[1.02; 1.49]5,638130,65654%NASuarez (Controls unexposed, discontinuers), 2022 Brown (Controls unexposed, sick), 2016 Skurtveit, 2014 3   - SSRI only  - SSRI only 1.30[0.79; 2.16]42840%NANulman (Controls unexposed, sick), 2012 Nulman - Fluoxetine (Controls unexposed, disease free), 2002 Simon (Controls unexposed, NOS), 2002 3 Unexposed sick   - intermediate history of illness/tre ...  - intermediate history of illness/treatment (3-12 months before pregnancy) 1.21[0.99; 1.48]42915,6580%NABrown (Controls unexposed, sick), 2016 Nulman (Controls unexposed, sick), 2012 2   - recent illness/treatment (during o ...  - recent illness/treatment (during or juste before pregnancy or treatment stopped in view of pregnancy) 1.16[1.07; 1.26]5,209115,060 -NASuarez (Controls unexposed, discontinuers), 2022 1 All studiesAll studies 1.18[1.09; 1.27]5,642130,9400%NASuarez (Controls unexposed, discontinuers), 2022 Brown (Controls unexposed, sick), 2016 Skurtveit, 2014 Nulman (Controls unexposed, sick), 2012 Nulman - Fluoxetine (Controls unexposed, disease free), 2002 Simon (Controls unexposed, NOS), 2002 60.55.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.42.51.2050.000Suarez (Controls unexposed, discontinuers), 2022Brown (Controls unexposed, sick), 2016Skurtveit, 2014Nulman (Controls unexposed, sick), 2012Nulman - Fluoxetine (Controls unexposed, disease free), 2002Simon (Controls unexposed, NOS), 2002

Asymetry test p-value = 0.2226 (by Egger's regression)

slope=0.1221 (0.0443); intercept=0.6820 (0.4727); t=1.4427; p=0.2226

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 8013, 6994, 7051, 7441, 17050

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.49[1.13; 1.96]71,443130,99073%NASuarez (Controls unexposed, general pop), 2022 Brown (Controls unexposed, disease free), 2016 Skurtveit, 2014 Nulman (Controls unexposed, disease free), 2012 Nulman - Fluoxetine (Controls unexposed, disease free), 2002 Simon (Controls unexposed, NOS), 2002 6 unexposed, sick controlsunexposed, sick controls 1.17[1.08; 1.26]5,638130,7180%NASuarez (Controls unexposed, discontinuers), 2022 Brown (Controls unexposed, sick), 2016 Nulman (Controls unexposed, sick), 2012 3 exposed to other treatment, sick controlsexposed to other treatment, sick controls 3.03[0.94; 9.76]422335%NANulman - Fluoxetine (Controls exposed to TCA), 2002 Simon (Controls exposed to TCA), 2002 20.510.01.0