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

All congenital malformations (majors, minors, majors and minors, or unspecified)

id	Study   Auto Chan (Controls exposed to TCA), 2024Chan (Controls unexposed, general pop), 2024Chan (Controls unexposed, sick), 2024Benevent, 2023Anderson, 2020Jaeger, 2019Richardson, 2019Giardinelli (Controls unexposed, disease free), 2018Giardinelli (Controls unexposed, sick), 2018Bérard 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), 2014Engelstad (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, 2011Roca, 2011Reis (Controls exposed to TCA), 2010Reis (Controls unexposed, NOS), 2010Davidson, 2009Einarson, 2009Diav-Citrin - Fluoxetine or Paroxetine, 2008Maschi - Paroxetine, 2008Oberlander a, 2008Davis, 2007Vial - Paroxetine, 2006Wen, 2006Sivojelezova - Citalopram, 2005Casper, 2003Heikkinen - Fluoxetine only, 2003Costei - Paroxetine (Controls unexposed, NOS), 2002Costei - Paroxetine (Controls unexposed, sick), 2002Heikkinen - Citalopram only, 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 R76414	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 R76415	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 R76416	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 R61412	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 R41452	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 R76431	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 R22392	Richardson, 2019	Any congenital malformations	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	1.17 [0.73;1.89] C	28/716   47/1,400	75	716		ref
S7921 R23971	Giardinelli (Controls unexposed, disease free), 2018	Any congenital malformations	during pregnancy (anytime or not specified)	prospective cohort	unexposed, disease free excluded	Adjustment: No Monotherapy: no or not specified	1.09 [0.02;56.91] C excluded (control group)	0/24   0/26	0	24		ref
S7916 R23962	Giardinelli (Controls unexposed, sick), 2018	Any congenital malformations	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)	0.96 [0.02;50.35] C excluded (exposition period)	0/24   0/23	0	24		ref
S13265 R51077	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 R23390	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 R23401	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 R23409	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 R23399	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 R23400	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 R23387	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 R23388	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 R23389	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
S12948 R49137	Engelstad (Controls unexposed, sick), 2014	Congenital Anomalies	during pregnancy (anytime or not specified) excluded	retrospective cohort	unexposed, sick	Adjustment: No Monotherapy: SSRI only	0.43 [0.13;1.45] C excluded (exposition period)	4/126   9/128	13	126		ref
S6989 R23418	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 R23419	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 R23402	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 R61457	Nordeng (Controls unexposed, NOS), 2012	Any Malformation	1st trimester	cohort	unexposed (general population or NOS) excluded	Adjustment: Yes Monotherapy: no or not specified Partial overlapping	1.22 [0.81;1.84] excluded (control group)	25/462   2,829/61,648	2,854	462		ref
S7830 R61471	Nordeng (Controls unexposed, sick), 2012	Any 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)	0.99 [0.61;1.61] C	25/462   57/1,048	82	462		ref
S493 R23393	Colvin, 2011	Any birth defects	1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	1.12 [0.94;1.32]	145/2,701   4,571/94,561	4,716	2,701		ref
S7579 R23161	Manakova, 2011	Major and minor malformations	1st trimester	prospective cohort	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	3.51 [0.31;39.81] C	2/47   1/80	3	47		ref
S5379 R17682	Roca, 2011	Any malformations	during pregnancy (anytime or not specified) excluded	prospective cohort	unexposed, disease free	Adjustment: No Matched Monotherapy: no or not specified	0.65 [0.17;2.48] C excluded (exposition period)	3/84   9/168	12	84		ref
S6999 R76993	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 R76924	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
S10040 R36267	Davidson, 2009	Congenital malformations	throughout pregnancy	retrospective cohort	unexposed, disease free	Adjustment: No Matched Monotherapy: no or not specified	0.95 [0.02;50.34] C	0/21   0/20	0	21		ref
S519 R23398	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 R23396	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 R23404	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 R23407	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
S5394 R20631	Davis, 2007	One or more malformation of interest (NOS)	1st trimester	retrospective cohort (claims database)	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	0.97 [0.81;1.16]	108/805   6,723/49,031	6,831	805		ref
S507 R23420	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 R23421	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 R23417	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 R23391	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
S10192 R37357	Heikkinen - Fluoxetine only, 2003	Malformations (NOS)	during pregnancy (anytime or not specified) excluded	prospective cohort	unexposed (general population or NOS)	Adjustment: No Monotherapy: no or not specified	0.90 [0.02;50.25] C excluded (exposition period)	0/11   0/10	0	11		ref
S5954 R23394	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 R23395	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
S18242 R76542	Heikkinen - Citalopram only, 2002	Malformations	throughout pregnancy	prospective cohort	unexposed (general population or NOS)	Adjustment: No Matched Monotherapy: no or not specified	1.00 [0.02;55.80] C	0/10   0/10	0	10		ref
S6994 R23415	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 R23416	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 R23403	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 R23405	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 R23406	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 R23392	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 R23413	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 R23414	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	26 studies	1.10 [1.06;1.14]		125,197	72,492
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, 7921, 18158, 18138

Umbrella review (other published meta-analyses)