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

ADHD (Attention deficit hyperactivity disorder): Diagnosis/Risk

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.
S17443
R76865		 Lee (Controls unexposed, general pop), 2024 Attention-deficit/hyperactivity disorder - ICD-9 code 314, ICD-10 code F92 - Follow up 1-13 years 1st and 2nd trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified 1.44 [1.28;1.61] 322/6,146   89,422/2,245,689 89,744 6,146
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S17444
R76866		 Lee (Controls unexposed, sibling), 2024 Attention-deficit/hyperactivity disorder - ICD-9 code 314, ICD-10 code F92 - Follow up 1-13 years 1st and 2nd trimester population based cohort retrospective sibling excluded Adjustment: Yes Monotherapy: no or not specified 1.01 [0.74;1.37]
excluded (control group) 		-/2,458   -/2,948 - 2,458
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S18372
R77494		 Heuvelman, 2023 Attention deficit hyperactivity disorder -Medical codes or therapy records that indicated that the child had been prescribed ADHD medication - Mean age at end of follow-up 10.04 years, range 4–22 years during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: no or not specified Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 1.09 [0.86;1.39] -/12,093   -/16,330 - 12,093
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S14996
R61413		 Olstad - (Es)citalopram (Controls unexposed, disease free), 2023 Attention deficit hyperactivity disorder (ADHD) diagnosis - ICD-10: F90 - Until 5 years old during pregnancy (anytime or not specified) population based cohort propective unexposed, disease free excluded Adjustment: No Matched Monotherapy: no or not specified 2.71 [1.27;5.80] C
excluded (control group) 		23/306   10/344 33 306
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S14997
R61414		 Olstad - (Es)citalopram (Controls unexposed, sick), 2023 Attention deficit hyperactivity disorder (ADHD) diagnosis - ICD-10: F90 - Until 5 years old during pregnancy (anytime or not specified) population based cohort propective unexposed, sick Adjustment: No Monotherapy: no or not specified Unexposed sick: recent illness/treatment (during or juste before pregnancy or treatment stopped in view of pregnancy) 1.31 [0.69;2.48] C 23/306   18/308 41 306
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S18135
R76864		 Hartwig, 2022 Attention-deficit/hyperactivity disorder (ADHD) - Children receiving medication for ADHD before the age of 16 years - Follow up from at least 4 years old during pregnancy (anytime or not specified) case control sibling Adjustment: Yes Monotherapy: no or not specified 0.95 [0.50;1.74] -/-   0/- - -
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S17049
R76873		 Suarez (Controls unexposed, discontinuers), 2022 Attention Deficit Hyperactivity Disorder - ≥ 2 dates with ICD-9 Dx 314.xx or ≥ 2 dispensings or 1 diagnosis and 1 dispensing - 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) 1.07 [0.99;1.16] 3,883/115,060   1,141/38,038 5,024 115,060
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S17050
R76874		 Suarez (Controls unexposed, general pop), 2022 Attention Deficit Hyperactivity Disorder - ≥ 2 dates with ICD-9 Dx 314.xx or ≥ 2 dispensings or 1 diagnosis and 1 dispensing - 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 1.19 [1.14;1.25]
excluded (control group) 		3,885/115,110   52,434/3,000,907 56,319 115,110
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S12484
R47103		 Yeh, 2021 Attention-deficit/hyperactivity disorder (ADHD - at least twice outpatient visits within each year for ICD-9 code: 314) - At 0-10 years old during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: no or not specified Unexposed sick: old history of illness/treatment (> 12 months before pregnancy) or not specified 2.30 [1.47;3.62] -/163   -/5,243 - 163
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S7671
R46758		 Boukhris (Controls exposed to TCA), 2017 Infants with attention deficit hyperactivity disorder (ADHD-ICD9: 314.0; 314.01; 314.9; ICD10:F90;F90.0;F90.1;F90.2; F90.8;F90.9 or ADHD medications) - Mean 6-7 years old (0-11 years) 2nd and/or 3rd trimester retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: SSRI only 0.77 [0.44;1.34] C
excluded (control group) 		86/1,561   16/227 102 1,561
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S7561
R46759		 Boukhris (Controls unexposed, NOS), 2017 Infants with attention deficit hyperactivity disorder (ADHD-ICD9: 314.0; 314.01; 314.9; ICD10:F90;F90.0;F90.1;F90.2; F90.8;F90.9 or ADHD medications) - Mean 6-7 years old (0-11 years) 2nd and/or 3rd trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes Monotherapy: SSRI only 1.20 [0.90;1.60] 86/1,561   4,430/141,905 4,516 1,561
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S6629
R46765		 Man (Controls exposed to antipsychotics), 2017 Attention-deficit/hyperactivity disorder (ADHD) ( ICD-9-CM diagnosis code 314, or a prescription for an ADHD drug) - Mean 9.3 years (6-14 years) during pregnancy (anytime or not specified) retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: Yes Monotherapy: no or not specified 0.70 [0.38;1.29]
excluded (control group) 		18/-   31/- 49 -
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S6609
R46766		 Man (Controls unexposed, NOS), 2017 Attention-deficit/hyperactivity disorder (ADHD) (ICD-9-CM diagnosis code 314, or a prescription for an ADHD drug) - Mean 9.3 years (6-14 years) during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified 1.11 [0.77;1.60] 18/-   5,564/189,002 5,582 -
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S7549
R46767		 Sujan (Controls unexposed, NOS), 2017 Attention-deficit/hyperactivity disorder (ICD9-10) - Cumulative risk by age 15 years (1-17years) 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified Negative controls: confusion biais +++ 1.60 [1.47;1.75] 476/18,470   32,448/1,562,159 32,924 18,470
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S7840
R46768		 Sujan (Controls unexposed, sibling), 2017 Attention-deficit/hyperactivity disorder (ICD9-10) - Cumulative risk by age 15 years (1-17years) 1st trimester population based cohort retrospective sibling excluded Adjustment: Yes Monotherapy: no or not specified Unexposed sick: old history of illness/treatment (> 12 months before pregnancy) or not specified 0.94 [0.73;1.22]
excluded (control group) 		229/9,063   585/15,906 814 9,063
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S6463
R46763		 Malm (Controls unexposed, disease free), 2016 Attention-Deficit/Hyperactivity Disorder (ADHD) (Hospital Discharge Register - F90) - At 0-14 years old during pregnancy (anytime or not specified) population based cohort retrospective unexposed, disease free excluded Adjustment: Yes Monotherapy: no or not specified 1.66 [1.27;2.16]
excluded (control group) 		-/15,729   -/31,394 - 15,729
ref
S5401
R46764		 Malm (Controls unexposed, sick), 2016 Attention-Deficit/Hyperactivity Disorder (ADHD) (Hospital Discharge Register - F90) - At 0-14 years old 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) 0.98 [0.77;1.24] -/15,729   -/9,651 - 15,729
ref
S473
R46760		 Clements, 2015 Attention-deficit hyperactivity disorder (ADHD) (ICD-9 code of 314.x) - At 2–19 years (mean diagnosis: 8.3 years) during pregnancy (anytime or not specified) case control unexposed (general population or NOS) Adjustment: Yes Matched Monotherapy: no or not specified 1.67 [1.08;2.57] 52/114   2,191/7,760 2,243 114
ref
S7559
R46762		 Laugesen, 2013 Attention deficit hyperactivity disorder ADHD (diagnosis of ADHD or a redemption of a prescription for ADHD medication) - Median 8 years old (1-14 years) during pregnancy (anytime or not specified) population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: SSRI only 1.20 [1.00;1.50] -/11,721   -/816,792 - 11,721
ref
S7560
R46761		 Figueroa, 2010 Attention-deficit/hyperactivity disorder (ADHD - primary or secondary diagnosis of ADHD and prescription claims for stimulants) - At 4-5 years old during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed, sick Adjustment: Yes Monotherapy: no or not specified Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy) 0.91 [0.51;1.60] 23/916   88/3,532 111 916
ref
S8080
R46769		 Oberlander, 2007 Attention deficit/hyperactivity problems (CBCL, Child Behavior Checklist by parents) at 4-years old during pregnancy (anytime or not specified) prospective cohort unexposed, disease free Adjustment: No extrapolated (cont. endpoint) Monotherapy: no or not specified 0.71 [0.21;2.39] -/22   -/14 - 22
ref
Total 14 studies 1.25 [1.09;1.43] 140,185 182,301
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 Lee (Controls unexposed, general pop), 2024Lee, 2024 1 1.44[1.28; 1.61]89,7446,14611%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: moderate Heuvelman, 2023Heuvelman, 2023 1.09[0.86; 1.39]-12,0939%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: criticalROB mesure: moderateROB reporting: low Olstad - (Es)citalopram (Controls unexposed, sick), 2023Olstad -, 2023 2 1.31[0.69; 2.48]413063%ROB confusion: seriousROB selection: unclearROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Hartwig, 2022Hartwig, 2022 0.95[0.50; 1.74]--3%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: unclearROB mesure: criticalROB reporting: moderate Suarez (Controls unexposed, discontinuers), 2022Suarez, 2022 3 1.07[0.99; 1.16]5,024115,06012%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Yeh, 2021Yeh, 2021 2.30[1.47; 3.62]-1635%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: unclearROB mesure: moderateROB reporting: critical Boukhris (Controls unexposed, NOS), 2017Boukhris, 2017 4 1.20[0.90; 1.60]4,5161,5618%ROB confusion: moderateROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Man (Controls unexposed, NOS), 2017Man, 2017 5 1.11[0.77; 1.60]5,582-7%ROB confusion: moderateROB selection: lowROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Sujan (Controls unexposed, NOS), 2017Sujan, 2017 6 1.60[1.47; 1.75]32,92418,47012%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Malm (Controls unexposed, sick), 2016Malm, 2016 7 0.98[0.77; 1.24]-15,7299%ROB confusion: moderateROB selection: lowROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Clements, 2015Clements, 2015 1.67[1.08; 2.57]2,2431146%ROB confusion: seriousROB selection: criticalROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Laugesen, 2013Laugesen, 2013 1.20[1.00; 1.50]-11,72110%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Figueroa, 2010Figueroa, 2010 0.91[0.51; 1.60]1119164%ROB confusion: seriousROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Oberlander, 2007Oberlander, 2007 0.71[0.21; 2.39]-221%ROB confusion: criticalROB selection: lowROB classification: unclearROB missing: criticalROB mesure: criticalROB reporting: moderate Total (14 studies) I2 = 81% 1.25[1.09; 1.43]140,185182,3010.25.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, general pop; 2: Es)citalopram (Controls unexposed, sick; 3: Controls unexposed, discontinuers; 4: Controls unexposed, NOS; 5: Controls unexposed, NOS; 6: Controls unexposed, NOS; 7: Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.24[1.07; 1.43]137,942182,18783%NALee (Controls unexposed, general pop), 2024 Heuvelman, 2023 Olstad - (Es)citalopram (Controls unexposed, sick), 2023 Suarez (Controls unexposed, discontinuers), 2022 Yeh, 2021 Boukhris (Controls unexposed, NOS), 2017 Man (Controls unexposed, NOS), 2017 Sujan (Controls unexposed, NOS), 2017 Malm (Controls unexposed, sick), 2016 Laugesen, 2013 Figueroa, 2010 Oberlander, 2007 12 case control studiescase control studies 1.32[0.76; 2.28]2,24311453%NAHartwig, 2022 Clements, 2015 2 RCTRCT 0.95[0.51; 1.77]-- -NAHartwig, 2022 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.38[1.22; 1.56]135,00938,03456%NALee (Controls unexposed, general pop), 2024 Boukhris (Controls unexposed, NOS), 2017 Man (Controls unexposed, NOS), 2017 Sujan (Controls unexposed, NOS), 2017 Clements, 2015 Laugesen, 2013 Oberlander, 2007 7 unexposed, sickunexposed, sick 1.15[0.96; 1.37]5,176144,26759%NAHeuvelman, 2023 Olstad - (Es)citalopram (Controls unexposed, sick), 2023 Suarez (Controls unexposed, discontinuers), 2022 Yeh, 2021 Malm (Controls unexposed, sick), 2016 Figueroa, 2010 6 sibling designsibling design 0.95[0.51; 1.77]-- -NAHartwig, 2022 1 Tags Adjustment   - No  - No 1.15[0.65; 2.02]413280%NAOlstad - (Es)citalopram (Controls unexposed, sick), 2023 Oberlander, 2007 2   - Yes  - Yes 1.25[1.09; 1.45]140,144181,97384%NALee (Controls unexposed, general pop), 2024 Heuvelman, 2023 Hartwig, 2022 Suarez (Controls unexposed, discontinuers), 2022 Yeh, 2021 Boukhris (Controls unexposed, NOS), 2017 Man (Controls unexposed, NOS), 2017 Sujan (Controls unexposed, NOS), 2017 Malm (Controls unexposed, sick), 2016 Clements, 2015 Laugesen, 2013 Figueroa, 2010 12 extrapolated (cont. endpoint)extrapolated (cont. endpoint) 0.71[0.21; 2.40]-22 -NAOberlander, 2007 1 MatchedMatched 1.67[1.08; 2.58]2,243114 -NAClements, 2015 1 Monotherapy   - no or not specified  - no or not specified 1.26[1.07; 1.48]135,669169,01984%NALee (Controls unexposed, general pop), 2024 Heuvelman, 2023 Olstad - (Es)citalopram (Controls unexposed, sick), 2023 Hartwig, 2022 Suarez (Controls unexposed, discontinuers), 2022 Yeh, 2021 Man (Controls unexposed, NOS), 2017 Sujan (Controls unexposed, NOS), 2017 Malm (Controls unexposed, sick), 2016 Clements, 2015 Figueroa, 2010 Oberlander, 2007 12   - SSRI only  - SSRI only 1.20[1.02; 1.42]4,51613,2820%NABoukhris (Controls unexposed, NOS), 2017 Laugesen, 2013 2 Negative controls   - confusion biais +++  - confusion biais +++ 1.60[1.47; 1.75]32,92418,470 -NASujan (Controls unexposed, NOS), 2017 1 Unexposed sick   - intermediate history of illness/tre ...  - intermediate history of illness/treatment (3-12 months before pregnancy) 1.02[0.87; 1.20]11128,7380%NAHeuvelman, 2023 Malm (Controls unexposed, sick), 2016 Figueroa, 2010 3   - old history of illness/treatment (> ...  - old history of illness/treatment (> 12 months before pregnancy) or not specified 2.30[1.47; 3.61]-163 -NAYeh, 2021 1   - recent illness/treatment (during o ...  - recent illness/treatment (during or juste before pregnancy or treatment stopped in view of pregnancy) 1.07[0.99; 1.16]5,065115,3660%NAOlstad - (Es)citalopram (Controls unexposed, sick), 2023 Suarez (Controls unexposed, discontinuers), 2022 2 All studiesAll studies 1.25[1.09; 1.43]140,185182,30181%NALee (Controls unexposed, general pop), 2024 Heuvelman, 2023 Olstad - (Es)citalopram (Controls unexposed, sick), 2023 Hartwig, 2022 Suarez (Controls unexposed, discontinuers), 2022 Yeh, 2021 Boukhris (Controls unexposed, NOS), 2017 Man (Controls unexposed, NOS), 2017 Sujan (Controls unexposed, NOS), 2017 Malm (Controls unexposed, sick), 2016 Clements, 2015 Laugesen, 2013 Figueroa, 2010 Oberlander, 2007 140.25.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-1.51.70.7440.000Lee (Controls unexposed, general pop), 2024Heuvelman, 2023Olstad - (Es)citalopram (Controls unexposed, sick), 2023Hartwig, 2022Suarez (Controls unexposed, discontinuers), 2022Yeh, 2021Boukhris (Controls unexposed, NOS), 2017Man (Controls unexposed, NOS), 2017Sujan (Controls unexposed, NOS), 2017Malm (Controls unexposed, sick), 2016Clements, 2015Laugesen, 2013Figueroa, 2010Oberlander, 2007

Asymetry test p-value = 0.6943 (by Egger's regression)

slope=0.2767 (0.0885); intercept=-0.4024 (0.9993); t=0.4026; p=0.6943

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 6463, 7671, 6629, 7840, 17050, 14996, 17444

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.38[1.21; 1.57]191,361169,17982%NALee (Controls unexposed, general pop), 2024 Olstad - (Es)citalopram (Controls unexposed, disease free), 2023 Suarez (Controls unexposed, general pop), 2022 Boukhris (Controls unexposed, NOS), 2017 Man (Controls unexposed, NOS), 2017 Sujan (Controls unexposed, NOS), 2017 Malm (Controls unexposed, disease free), 2016 Clements, 2015 Laugesen, 2013 Oberlander, 2007 10 unexposed, sick controlsunexposed, sick controls 1.15[0.96; 1.37]5,176144,26759%NAHeuvelman, 2023 Olstad - (Es)citalopram (Controls unexposed, sick), 2023 Suarez (Controls unexposed, discontinuers), 2022 Yeh, 2021 Malm (Controls unexposed, sick), 2016 Figueroa, 2010 6 exposed to other treatment, sick controlsexposed to other treatment, sick controls 0.74[0.49; 1.11]1511,5610%NABoukhris (Controls exposed to TCA), 2017 Man (Controls exposed to antipsychotics), 2017 2 siblingssiblings 0.97[0.80; 1.17]81411,5210%NALee (Controls unexposed, sibling), 2024 Hartwig, 2022 Sujan (Controls unexposed, sibling), 2017 30.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Halvorsen - SSRI (Attention-deficit/hyperacti ...Halvorsen - SSRI (Attention-deficit/hyperactivity disorder _ Case control studies) 1.27[0.70; 2.29]64%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT2 Halvorsen - SSRI (Attention-deficit/hyperacti ...Halvorsen - SSRI (Attention-deficit/hyperactivity disorder _ Cohort studies) 1.33[1.06; 1.66]52%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT3 metaPregmetaPreg 1.25[1.09; 1.43]81%182,301----Lee (Controls unexposed, general pop), 2024 Heuvelman, 2023 Olstad - (Es)citalopram (Controls unexposed, sick), 2023 Hartwig, 2022 Suarez (Controls unexposed, discontinuers), 2022 Yeh, 2021 Boukhris (Controls unexposed, NOS), 2017 Man (Controls unexposed, NOS), 2017 Sujan (Controls unexposed, NOS), 2017 Malm (Controls unexposed, sick), 2016 Clements, 2015 Laugesen, 2013 Figueroa, 2010 Oberlander, 2007 140.510.01.0