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

Major congenital malformations

id	Study   Auto Chan (Controls exposed to TCA), 2024Chan (Controls unexposed, general pop), 2024Chan (Controls unexposed, sick), 2024Benevent, 2023Anderson, 2020Jaeger, 2019Richardson, 2019Bérard b (Controls exposed to TCA), 2017Bérard b (Controls unexposed, sick), 2017Jordan, 2016Ozturk - Escitalopram, 2016Furu (Controls unexposed, NOS), 2015Furu (Controls unexposed, sibling), 2015Ban (Controls exposed to TCA), 2014Ban (Controls unexposed, disease free), 2014Ban (Controls unexposed, sick), 2014Vasilakis-Scaramozza (Controls exposed to TCA), 2013Vasilakis-Scaramozza (Controls unexposed, NOS), 2013Klieger-Grossmann - Escitalopram, 2012Nordeng (Controls unexposed, NOS), 2012Nordeng (Controls unexposed, sick), 2012Colvin, 2011Manakova, 2011Reis (Controls exposed to TCA), 2010Reis (Controls unexposed, NOS), 2010Einarson, 2009Diav-Citrin - Fluoxetine or Paroxetine, 2008Maschi - Paroxetine, 2008Oberlander a, 2008Vial - Paroxetine, 2006Wen, 2006Sivojelezova - Citalopram, 2005Casper, 2003Costei - Paroxetine (Controls unexposed, NOS), 2002Costei - Paroxetine (Controls unexposed, sick), 2002Simon (Controls exposed to TCA), 2002Simon (Controls unexposed, NOS), 2002Kulin, 1998Nulman - Fluoxetine (Controls exposed to TCA), 1997Nulman - Fluoxetine (Controls unexposed, NOS), 1997Chambers - Fluoxetine, 1996Pastuszak - Fluoxetine (Controls exposed to TCA), 1993Pastuszak - Fluoxetine (Controls unexposed, NOS), 1993	Lib. in paper	Exposition period  Auto during pregnancy (anytime or not specified)1st trimester2nd trimester3rd trimester2nd and/or 3rd trimesterthroughout pregnancyearly pregnancydays before deliverylate pregnancypreconception-onlypericonceptionalpreconceptional for kinetic reasonat least 1st trimester3 months (or more) before pregnancy or during pregnancy1st and 2nd trimester3 months or more before pregnancy or1st trimesterPaternal exp. genotoxic window only (0–3 months preconception)Paternal exposure: epigenetic window only (3–xxx months preconception)Paternal exposure: genotoxic/epigenetic window (0–xxx months preconception)Paternal exposure: other window	Study type  All studies Case control excluded Only case control	Control type    Auto unexposed (general population or NOS)unexposed, sickunexposed, disease freeexposed to other treatment, sicknot specifiedsiblingwhatever (meta-analysis)	Tags	OR 95%CI	x1/n1 x0/n0	no cases	no exposed	ROB	Ref.
S18158 R76355	Chan (Controls exposed to TCA), 2024	Any major malformations	1st trimester	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No Monotherapy: SSRI only	0.94 [0.58;1.51] C excluded (control group)	70/956   25/322	95	956		ref
S18138 R76241	Chan (Controls unexposed, general pop), 2024	Any major malformations	1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS) excluded	Adjustment: Yes Monotherapy: SSRI only	1.39 [0.94;2.06] excluded (control group)	70/956   22,628/462,377	22,698	956		ref
S18139 R76247	Chan (Controls unexposed, sick), 2024	Any major malformations	1st trimester	retrospective cohort (claims database)	unexposed, sick	Adjustment: Yes Monotherapy: SSRI only Unexposed sick: old history of illness/treatment (> 12 months before pregnancy) or not specified	1.18 [0.65;2.12]	50/714   269/4,413	319	714		ref
S12482 R47055	Benevent, 2023	Major congenital malformations	1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: No Monotherapy: SSRI only	1.00 [0.73;1.39] C	38/1,653   3,365/146,855	3,403	1,653		ref
S7467 R41451	Anderson, 2020	Major birth defects	1st trimester	case control	unexposed (general population or NOS)	Adjustment: No Monotherapy: SSRI only	1.23 [1.08;1.39] C	1,108/1,449   29,522/40,659	30,630	1,449		ref
S15002 R61418	Jaeger, 2019	Major congenital anomalies	2nd trimester excluded	retrospective cohort	unexposed (general population or NOS)	Adjustment: Yes Monotherapy: no or not specified	1.15 [1.04;1.28] excluded (exposition period)	-/-   -/-	-	-		ref
S7479 R22393	Richardson, 2019	Major congenital malformations	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	1.24 [0.60;2.57] C	12/716   19/1,400	31	716		ref
S13265 R51076	Bérard b (Controls exposed to TCA), 2017	Major congenital malformations overall	1st trimester	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No Monotherapy: SSRI only Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy)	0.88 [0.64;1.22] C excluded (control group)	279/2,327   51/382	330	2,327		ref
S7433 R21875	Bérard b (Controls unexposed, sick), 2017	Major congenital malformations overall	1st trimester	retrospective cohort (claims database)	unexposed, sick	Adjustment: Yes Monotherapy: SSRI only Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy)	1.07 [0.93;1.22]	279/2,327   1,650/14,847	1,929	2,327		ref
S5372 R18212	Jordan, 2016	All major congenital anomalies	3 months or more before pregnancy or1st trimester excluded	retrospective cohort (registry)	unexposed (general population or NOS)	Adjustment: Yes Monotherapy: no or not specified	1.09 [0.98;1.21] excluded (exposition period)	400/12,962   13,536/506,155	13,936	12,962		ref
S7518 R22532	Ozturk - Escitalopram, 2016	Major congenital defects	at least 1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	1.17 [0.06;23.30] C	0/30   3/246	3	30		ref
S516 R15346	Furu (Controls unexposed, NOS), 2015	Major birth defects	1st trimester	population based cohort retrospective	unexposed (general population or NOS)	Adjustment: Yes Monotherapy: SSRI only	1.13 [1.06;1.20]	1,357/36,772   71,374/2,266,875	72,731	36,772		ref
S6691 R18753	Furu (Controls unexposed, sibling), 2015	Major birth defects	1st trimester	population based cohort retrospective	sibling excluded	Adjustment: Yes Monotherapy: SSRI only	1.06 [0.91;1.24] excluded (control group)	-/980   -/1,308	-	980		ref
S5881 R14668	Ban (Controls exposed to TCA), 2014	Major congenital anomalies	1st trimester	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No Monotherapy: SSRI only	0.87 [0.66;1.14] C excluded (control group)	204/7,683   74/2,428	278	7,683		ref
S517 R14643	Ban (Controls unexposed, disease free), 2014	Major congenital anomalies	1st trimester	retrospective cohort (claims database)	unexposed, disease free excluded	Adjustment: Yes Monotherapy: SSRI only	1.01 [0.88;1.17] excluded (control group)	204/7,683   8,731/325,294	8,935	7,683		ref
S6700 R18873	Ban (Controls unexposed, sick), 2014	Major congenital anomalies	1st trimester	retrospective cohort (claims database)	unexposed, sick	Adjustment: Yes Monotherapy: SSRI only Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy)	0.93 [0.78;1.11]	204/7,683   380/13,432	584	7,683		ref
S6989 R19774	Vasilakis-Scaramozza (Controls exposed to TCA), 2013	Congenital Anomalies (chromosomal and minor anomalies excluded)	1st trimester	retrospective cohort	exposed to other treatment, sick excluded	Adjustment: No Monotherapy: SSRI only	1.07 [0.71;1.62] C excluded (control group)	51/1,825   42/1,608	93	1,825		ref
S5362 R16692	Vasilakis-Scaramozza (Controls unexposed, NOS), 2013	Congenital Anomalies (chromosomal and minor anomalies excluded)	1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: Yes Matched Monotherapy: SSRI only	0.90 [0.70;1.20]	51/1,825   205/6,617	256	1,825		ref
S5395 R16282	Klieger-Grossmann - Escitalopram, 2012	Major malformation (among live births)	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Matched Monotherapy: SSRI only	1.68 [0.28;10.16] C	3/172   2/191	5	172		ref
S496 R61458	Nordeng (Controls unexposed, NOS), 2012	Major malformations	1st trimester	cohort	unexposed (general population or NOS) excluded	Adjustment: Yes Monotherapy: no or not specified Partial overlapping	1.07 [0.60;1.91] excluded (control group)	12/462   1,550/61,648	1,562	462		ref
S7830 R61472	Nordeng (Controls unexposed, sick), 2012	Major malformations	1st trimester	cohort	unexposed, sick	Adjustment: No Monotherapy: no or not specified Partial overlapping Unexposed sick: intermediate history of illness/treatment (3-12 months before pregnancy)	0.90 [0.46;1.78] C	12/462   30/1,048	42	462		ref
S493 R15233	Colvin, 2011	Any major birth defects	1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	1.05 [0.87;1.27]	115/2,701   3,834/94,561	3,949	2,701		ref
S7579 R23159	Manakova, 2011	Major malformations	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	1.72 [0.10;28.12] C	1/47   1/80	2	47		ref
S6999 R76904	Reis (Controls exposed to TCA), 2010	Relatively severe malformation	early pregnancy	population based cohort retrospective	exposed to other treatment, sick excluded	Adjustment: No Monotherapy: SSRI only	0.72 [0.56;0.93] C excluded (control group)	345/10,170   77/1,662	422	10,170		ref
S5410 R76899	Reis (Controls unexposed, NOS), 2010	Relatively severe malformation	early pregnancy	population based cohort retrospective	unexposed (general population or NOS)	Adjustment: Yes Monotherapy: SSRI only	1.08 [0.97;1.21]	345/10,170   -/1,062,190	-	10,170		ref
S519 R15337	Einarson, 2009	Major malformations	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	1.35 [0.74;2.48] C	19/527   25/928	44	527		ref
S5958 R15305	Diav-Citrin - Fluoxetine or Paroxetine, 2008	Major anomalies	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	1.98 [1.24;3.16] C	34/601   40/1,359	74	601		ref
S7288 R21078	Maschi - Paroxetine, 2008	Major malformations	during pregnancy (anytime or not specified) excluded	prospective cohort	unexposed (general population or NOS)	Adjustment: No Matched Monotherapy: no or not specified	1.00 [0.12;8.46] C excluded (exposition period)	1/58   6/348	7	58		ref
S520 R17636	Oberlander a, 2008	Major congenital anomalies	1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: No Monotherapy: SSRI only	0.91 [0.72;1.14] C	75/2,625   3,369/107,320	3,444	2,625		ref
S507 R16622	Vial - Paroxetine, 2006	Major malformations (excluding chromosomal defects)	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Matched Monotherapy: no or not specified	1.40 [0.60;3.30]	12/535   10/631	22	535		ref
S5405 R16047	Wen, 2006	Major structural anomalies	3 months (or more) before pregnancy or during pregnancy excluded	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: Yes Matched Monotherapy: no or not specified	0.98 [0.59;1.64] excluded (exposition period)	20/972   76/3,878	96	972		ref
S508 R17592	Sivojelezova - Citalopram, 2005	Major malformations	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Matched Monotherapy: no or not specified	1.09 [0.07;17.70] C	1/108   1/118	2	108		ref
S510 R365	Casper, 2003	Major structural anomalies	during pregnancy (anytime or not specified) excluded	prospective cohort	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)	0.40 [0.02;6.93] C excluded (exposition period)	1/31   1/13	2	31		ref
S5954 R15277	Costei - Paroxetine (Controls unexposed, NOS), 2002	Major malformations	3rd trimester	prospective cohort	unexposed (general population or NOS) excluded	Adjustment: No Matched Monotherapy: no or not specified	0.49 [0.01;25.19] C excluded (control group)	0/55   0/27	0	55		ref
S5953 R15274	Costei - Paroxetine (Controls unexposed, sick), 2002	Major malformations	3rd trimester excluded	prospective cohort	unexposed, sick	Adjustment: No Matched Monotherapy: no or not specified Unexposed sick: recent illness/treatment (during or juste before pregnancy or treatment stopped in view of pregnancy)	0.49 [0.01;25.19] C excluded (exposition period)	0/55   0/27	0	55		ref
S6994 R19833	Simon (Controls exposed to TCA), 2002	Major malformations	during pregnancy (anytime or not specified)	retrospective cohort (claims database)	exposed to other treatment, sick excluded	Adjustment: No Monotherapy: SSRI only	1.38 [0.58;3.27] C excluded (control group)	12/185   10/209	22	185		ref
S492 R17421	Simon (Controls unexposed, NOS), 2002	Major malformations	during pregnancy (anytime or not specified) excluded	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: No Matched Monotherapy: SSRI only	1.36 [0.56;3.30] excluded (exposition period)	12/185   9/185	21	185		ref
S513 R360	Kulin, 1998	Major malformations (among neonates)	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	1.06 [0.43;2.62]	9/222   9/235	18	222		ref
S7052 R19929	Nulman - Fluoxetine (Controls exposed to TCA), 1997	Major malformations	at least 1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No Monotherapy: SSRI only	0.97 [0.16;6.00] C excluded (control group)	2/55   3/80	5	55		ref
S514 R359	Nulman - Fluoxetine (Controls unexposed, NOS), 1997	Major malformations	at least 1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Monotherapy: SSRI only	1.55 [0.21;11.32] C	2/55   2/84	4	55		ref
S490 R15180	Chambers - Fluoxetine, 1996	All major structural anomalies	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	1.40 [0.54;3.61] C	9/164   9/226	18	164		ref
S6197 R16351	Pastuszak - Fluoxetine (Controls exposed to TCA), 1993	Major malformations	1st trimester	prospective cohort	exposed to other treatment, sick excluded	Adjustment: No Matched Monotherapy: SSRI only	5.36 [0.25;114.14] C excluded (control group)	2/58   0/60	2	58		ref
S515 R345	Pastuszak - Fluoxetine (Controls unexposed, NOS), 1993	Major malformations	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Matched Monotherapy: SSRI only	1.13 [0.16;8.14] C	2/98   2/110	4	98		ref
					Total	23 studies	1.10 [1.06;1.15]		117,514	71,656
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

Sensitivity analysis

Publication bias and p-hacking diagnosis

Sub-groups analysis using all included studies

excluded 6197, 7052, 5954, 6994, 6999, 496, 6989, 5881, 517, 6691, 13265, 18158, 18138

Umbrella review (other published meta-analyses)