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

Low Apgar score (< 7) (at 5 min)

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.
S18442
R78279		 Lee (Controls exposed to TCAs), 2025 5-minute Apgar score<7 during pregnancy (anytime or not specified) retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: SSRI only 0.42 [0.12;1.44] C
excluded (control group) 		5/1,465   5/613 10 1,465
ref
S18408
R77701		 Lee (Controls unexposed, general pop), 2025 5-minute Apgar score<7 during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes Monotherapy: SSRI only 0.65 [0.26;1.62] 5/1,465   1,721/463,440 1,726 1,465
ref
S18216
R76434		 Martin - Sertraline, 2024 Low Apgar score at 5 min (<7) during pregnancy (anytime or not specified) population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: substance alone among all Antidep (SSRI, SNRI, ...) 1.96 [1.82;2.10] 979/31,719   30,996/2,078,011 31,975 31,719
ref
S14995
R61359		 Lyn, 2023 Apgar score less than seven at 5 minute during pregnancy (anytime or not specified) retrospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 10.26 [1.13;489.94] -/130   -/259 - 130
ref
S12951
R49152		 Heinonen - Sertraline, 2021 Low Apgar score (at 5 min) 3rd trimester randomized controlled trial unexposed, sick Adjustment: Randomisation Monotherapy: SSRI only 0.33 [0.01;21.64] C 0/8   0/3 0 8
ref
S13112
R49967		 Marks - Sertraline (Controls exposed to Bupropion), 2021 5 Min APGAR <7 during pregnancy (anytime or not specified) retrospective cohort exposed to other treatment, sick Adjustment: No Monotherapy: substance alone among all Antidep (SSRI, SNRI, ...) 1.05 [0.76;1.46] C 213/1,653   50/406 263 1,653
ref
S5461
R24126		 Levy, 2020 Apgar 5min <7 throughout pregnancy retrospective cohort unexposed (general population or NOS) Adjustment: No Matched Monotherapy: no or not specified 3.08 [0.31;30.20] C 3/82   1/82 4 82
ref
S7921
R23969		 Giardinelli (Controls unexposed, disease free), 2018 Apgar score <7 at 5 min during pregnancy (anytime or not specified) prospective cohort unexposed, disease free excluded Adjustment: No Monotherapy: no or not specified 5.00 [0.52;48.34] C
excluded (control group) 		4/24   1/26 5 24
ref
S7916
R23960		 Giardinelli (Controls unexposed, sick), 2018 Apgar score <7 at 5 min during pregnancy (anytime or not specified) 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) 2.10 [0.35;12.76] C 4/24   2/23 6 24
ref
S7569
R22726		 Hogue, 2017 5-minute Apgar score less than 7 (in full-term neonates) during pregnancy (anytime or not specified) retrospective cohort unexposed (general population or NOS) Adjustment: Yes Monotherapy: SSRI only 2.70 [0.11;62.20] 2/117   1/116 3 117
ref
S13007
R49380		 Bakaysa, 2016 Low APGAR scores at 5 minutes (< 7) late pregnancy retrospective cohort unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 8.80 [2.40;32.00] 12/112   2/224 14 112
ref
S7570
R22765		 Kivistö, 2016 Low (<7) Apgar score at 5 min during pregnancy (anytime or not specified) retrospective cohort unexposed (general population or NOS) Adjustment: Yes Monotherapy: SSRI only 2.30 [1.50;3.52] 27/358   780/24,402 807 358
ref
S6107
R15969		 Malm (Controls unexposed, disease free), 2015 5-minute Apgar score <7 during pregnancy (anytime or not specified) population based cohort retrospective unexposed, disease free excluded Adjustment: Yes Monotherapy: no or not specified 1.72 [1.46;2.02]
excluded (control group) 		376/15,729   383/31,394 759 15,729
ref
S5374
R15953		 Malm (Controls unexposed, sick), 2015 5-minute Apgar score <7 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) 1.68 [1.34;2.12] 376/15,729   113/9,652 489 15,729
ref
S6156
R16088		 Jensen b, 2013 Apgar score < 7 at 5 min during pregnancy (anytime or not specified) population based cohort retrospective unexposed, disease free Adjustment: Yes Monotherapy: no or not specified 1.96 [1.52;2.54] -/7,208   -/628,898 - 7,208
ref
S5428
R20504		 Colvin, 2012 APGAR at 5 mins <6 2nd and/or 3rd trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No Monotherapy: no or not specified 1.25 [0.76;2.05] 16/1,063   1,144/94,561 1,160 1,063
ref
S5379
R17679		 Roca, 2011 Apgar score minute 5≤7 during pregnancy (anytime or not specified) prospective cohort unexposed, disease free Adjustment: No Matched Monotherapy: no or not specified 0.66 [0.03;16.49] C 0/84   1/168 1 84
ref
S5406
R15091		 Calderon-Margalit, 2009 APGAR Score at 5 minute <7 during pregnancy (anytime or not specified) prospective cohort unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified 2.02 [0.68;6.00] -/132   -/2,493 - 132
ref
S491
R16209		 Lund (Controls unexposed, disease free), 2009 Apgar score 5 min (< 8) during pregnancy (anytime or not specified) prospective cohort unexposed, disease free excluded Adjustment: Yes Monotherapy: no or not specified 4.44 [2.58;7.63]
excluded (control group) 		16/329   635/51,770 651 329
ref
S6162
R16213		 Lund (Controls unexposed, sick), 2009 Apgar score 5 min (< 8) during pregnancy (anytime or not specified) prospective cohort unexposed, sick Adjustment: No Monotherapy: no or not specified Unexposed sick: old history of illness/treatment (> 12 months before pregnancy) or not specified 4.86 [2.74;8.62] C 16/329   51/4,902 67 329
ref
S5408
R16602		 Wisner (Controls unexposed, disease free), 2009 Apgar Score ≤7 at 5 minutes throughout pregnancy prospective cohort unexposed, disease free excluded Adjustment: No Monotherapy: no or not specified 8.60 [0.87;84.80] C
excluded (control group) 		3/48   1/130 4 48
ref
S6249
R16610		 Wisner (Controls unexposed, sick), 2009 Apgar Score ≤7 at 5 minutes throughout pregnancy 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) 0.87 [0.08;9.05] C 3/48   1/14 4 48
ref
S15011
R61496		 Lennestal, 2007 Low Apgar score (<7 at 5 min) late pregnancy population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Monotherapy: no or not specified 2.22 [1.58;3.12] 33/-   -/- - -
ref
S6994
R19832		 Simon (Controls exposed to TCA), 2002 Apgar score at 5 minutes ≤7 during pregnancy (anytime or not specified) retrospective cohort (claims database) exposed to other treatment, sick excluded Adjustment: No Monotherapy: SSRI only 2.41 [1.10;5.30] C
excluded (control group) 		20/185   10/209 30 185
ref
S492
R17420		 Simon (Controls unexposed, NOS), 2002 Apgar score at 5 minutes ≤7 during pregnancy (anytime or not specified) retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes Matched Monotherapy: SSRI only 2.78 [1.17;6.26] 20/185   8/185 28 185
ref
Total 19 studies 1.90 [1.58;2.29] 36,547 60,446
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), 2025Lee, 2025 1 0.65[0.26; 1.62]1,7261,4653%ROB confusion: moderateROB selection: lowROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Martin - Sertraline, 2024Martin - Sertraline, 2024 1.96[1.82; 2.10]31,97531,71916%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Lyn, 2023Lyn, 2023 10.26[1.13; 489.94]-1300%ROB confusion: criticalROB selection: criticalROB classification: unclearROB missing: unclearROB mesure: unclearROB reporting: moderate Heinonen - Sertraline, 2021Heinonen - Sertraline, 2021 0.33[0.01; 21.64]080%ROB confusion: unclearROB selection: lowROB classification: lowROB missing: criticalROB mesure: lowROB reporting: low Marks - Sertraline (Controls exposed to Bupropion), 2021Marks - Sertraline, 2021 2 1.05[0.76; 1.46]2631,65311%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Levy, 2020Levy, 2020 3.08[0.31; 30.20]4821%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Giardinelli (Controls unexposed, sick), 2018Giardinelli, 2018 3 2.10[0.35; 12.76]6241%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Hogue, 2017Hogue, 2017 2.70[0.11; 62.20]31170%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Bakaysa, 2016Bakaysa, 2016 8.80[2.40; 32.00]141122%ROB confusion: criticalROB selection: unclearROB classification: unclearROB missing: unclearROB mesure: unclearROB reporting: moderate Kivistö, 2016Kivistö, 2016 2.30[1.50; 3.52]8073589%ROB confusion: seriousROB selection: criticalROB classification: moderateROB missing: criticalROB mesure: moderateROB reporting: moderate Malm (Controls unexposed, sick), 2015Malm, 2015 4 1.68[1.34; 2.12]48915,72913%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: moderateROB mesure: moderateROB reporting: moderate Jensen b, 2013Jensen b, 2013 1.96[1.52; 2.54]-7,20812%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Colvin, 2012Colvin, 2012 1.25[0.76; 2.05]1,1601,0638%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Roca, 2011Roca, 2011 0.66[0.03; 16.49]1840%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Calderon-Margalit, 2009Calderon-Margalit, 2009 2.02[0.68; 6.00]-1322%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Lund (Controls unexposed, sick), 2009Lund, 2009 5 4.86[2.74; 8.62]673296%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Wisner (Controls unexposed, sick), 2009Wisner, 2009 6 0.87[0.08; 9.05]4481%ROB confusion: criticalROB selection: lowROB classification: lowROB missing: lowROB mesure: moderateROB reporting: moderate Lennestal, 2007Lennestal, 2007 2.22[1.58; 3.12]--11%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Simon (Controls unexposed, NOS), 2002Simon, 2002 7 2.78[1.17; 6.26]281854%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: moderate Total (19 studies) I2 = 58% 1.90[1.58; 2.29]36,54760,4460.250.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, general pop; 2: Controls exposed to Bupropion; 3: Controls unexposed, sick; 4: Controls unexposed, sick; 5: Controls unexposed, sick; 6: Controls unexposed, sick; 7: Controls unexposed, NOS;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.91[1.58; 2.30]36,54760,43860%NALee (Controls unexposed, general pop), 2025 Martin - Sertraline, 2024 Lyn, 2023 Marks - Sertraline (Controls exposed to Bupropion), 2021 Levy, 2020 Giardinelli (Controls unexposed, sick), 2018 Hogue, 2017 Bakaysa, 2016 Kivistö, 2016 Malm (Controls unexposed, sick), 2015 Jensen b, 2013 Colvin, 2012 Roca, 2011 Calderon-Margalit, 2009 Lund (Controls unexposed, sick), 2009 Wisner (Controls unexposed, sick), 2009 Lennestal, 2007 Simon (Controls unexposed, NOS), 2002 18 case control studiescase control studies 0 RCTRCT 0.33[0.01; 21.64]-8 -NAHeinonen - Sertraline, 2021 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.97[1.66; 2.33]35,71842,65531%NALee (Controls unexposed, general pop), 2025 Martin - Sertraline, 2024 Lyn, 2023 Levy, 2020 Hogue, 2017 Bakaysa, 2016 Kivistö, 2016 Jensen b, 2013 Colvin, 2012 Roca, 2011 Calderon-Margalit, 2009 Lennestal, 2007 Simon (Controls unexposed, NOS), 2002 13 unexposed, sickunexposed, sick 2.24[1.04; 4.82]56616,13868%NAHeinonen - Sertraline, 2021 Giardinelli (Controls unexposed, sick), 2018 Malm (Controls unexposed, sick), 2015 Lund (Controls unexposed, sick), 2009 Wisner (Controls unexposed, sick), 2009 5 exposed to other treatment, sickexposed to other treatment, sick 1.05[0.76; 1.46]2631,653 -NAMarks - Sertraline (Controls exposed to Bupropion), 2021 1 Tags Adjustment   - No  - No 2.27[1.17; 4.39]1,5193,52574%NALyn, 2023 Marks - Sertraline (Controls exposed to Bupropion), 2021 Levy, 2020 Giardinelli (Controls unexposed, sick), 2018 Bakaysa, 2016 Colvin, 2012 Roca, 2011 Lund (Controls unexposed, sick), 2009 Wisner (Controls unexposed, sick), 2009 9   - Randomisation  - Randomisation 0.33[0.01; 21.64]-8 -NAHeinonen - Sertraline, 2021 1   - Yes  - Yes 1.93[1.75; 2.13]35,02856,91312%NALee (Controls unexposed, general pop), 2025 Martin - Sertraline, 2024 Hogue, 2017 Kivistö, 2016 Malm (Controls unexposed, sick), 2015 Jensen b, 2013 Calderon-Margalit, 2009 Lennestal, 2007 Simon (Controls unexposed, NOS), 2002 9 MatchedMatched 2.59[1.21; 5.57]333510%NALevy, 2020 Roca, 2011 Simon (Controls unexposed, NOS), 2002 3 Monotherapy   - no or not specified  - no or not specified 2.16[1.64; 2.83]1,74524,94151%NALyn, 2023 Levy, 2020 Giardinelli (Controls unexposed, sick), 2018 Bakaysa, 2016 Malm (Controls unexposed, sick), 2015 Jensen b, 2013 Colvin, 2012 Roca, 2011 Calderon-Margalit, 2009 Lund (Controls unexposed, sick), 2009 Wisner (Controls unexposed, sick), 2009 Lennestal, 2007 12   - SSRI only  - SSRI only 1.70[0.89; 3.25]2,5642,13347%NALee (Controls unexposed, general pop), 2025 Heinonen - Sertraline, 2021 Hogue, 2017 Kivistö, 2016 Simon (Controls unexposed, NOS), 2002 5   - substance alone among all Antidep ( ...  - substance alone among all Antidep (SSRI, SNRI, ...) 1.47[0.80; 2.69]32,23833,37292%NAMartin - Sertraline, 2024 Marks - Sertraline (Controls exposed to Bupropion), 2021 2 Unexposed sick   - intermediate history of illness/tre ...  - intermediate history of illness/treatment (3-12 months before pregnancy) 1.68[1.34; 2.11]48915,729 -NAMalm (Controls unexposed, sick), 2015 1   - old history of illness/treatment (> ...  - old history of illness/treatment (> 12 months before pregnancy) or not specified 4.86[2.74; 8.62]67329 -NALund (Controls unexposed, sick), 2009 1   - recent illness/treatment (during o ...  - recent illness/treatment (during or juste before pregnancy or treatment stopped in view of pregnancy) 1.51[0.36; 6.32]10720%NAGiardinelli (Controls unexposed, sick), 2018 Wisner (Controls unexposed, sick), 2009 2 All studiesAll studies 1.90[1.58; 2.29]36,54760,44658%NALee (Controls unexposed, general pop), 2025 Martin - Sertraline, 2024 Lyn, 2023 Heinonen - Sertraline, 2021 Marks - Sertraline (Controls exposed to Bupropion), 2021 Levy, 2020 Giardinelli (Controls unexposed, sick), 2018 Hogue, 2017 Bakaysa, 2016 Kivistö, 2016 Malm (Controls unexposed, sick), 2015 Jensen b, 2013 Colvin, 2012 Roca, 2011 Calderon-Margalit, 2009 Lund (Controls unexposed, sick), 2009 Wisner (Controls unexposed, sick), 2009 Lennestal, 2007 Simon (Controls unexposed, NOS), 2002 190.150.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-5.05.62.5550.000Lee (Controls unexposed, general pop), 2025Martin - Sertraline, 2024Lyn, 2023Heinonen - Sertraline, 2021Marks - Sertraline (Controls exposed to Bupropion), 2021Levy, 2020Giardinelli (Controls unexposed, sick), 2018Hogue, 2017Bakaysa, 2016Kivistö, 2016Malm (Controls unexposed, sick), 2015Jensen b, 2013Colvin, 2012Roca, 2011Calderon-Margalit, 2009Lund (Controls unexposed, sick), 2009Wisner (Controls unexposed, sick), 2009Lennestal, 2007Simon (Controls unexposed, NOS), 2002

Asymetry test p-value = 0.9759 (by Egger's regression)

slope=0.6525 (0.0611); intercept=-0.0137 (0.4474); t=0.0306; p=0.9759

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 6994, 491, 5408, 6107, 7921, 18442

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 2.05[1.74; 2.41]37,16158,78548%NALee (Controls unexposed, general pop), 2025 Martin - Sertraline, 2024 Lyn, 2023 Levy, 2020 Giardinelli (Controls unexposed, disease free), 2018 Hogue, 2017 Bakaysa, 2016 Kivistö, 2016 Malm (Controls unexposed, disease free), 2015 Jensen b, 2013 Colvin, 2012 Roca, 2011 Calderon-Margalit, 2009 Lund (Controls unexposed, disease free), 2009 Wisner (Controls unexposed, disease free), 2009 Lennestal, 2007 Simon (Controls unexposed, NOS), 2002 17 unexposed, sick controlsunexposed, sick controls 2.24[1.04; 4.82]56616,13868%NAHeinonen - Sertraline, 2021 Giardinelli (Controls unexposed, sick), 2018 Malm (Controls unexposed, sick), 2015 Lund (Controls unexposed, sick), 2009 Wisner (Controls unexposed, sick), 2009 5 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.13[0.54; 2.40]3033,30368%NALee (Controls exposed to TCAs), 2025 Marks - Sertraline (Controls exposed to Bupropion), 2021 Simon (Controls exposed to TCA), 2002 30.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Vlenterie - SSRI (Low 5-min Apgar score)Vlenterie - SSRI (Low 5-min Apgar score) 1.40[0.80; 2.40]-U,Sunexposed, sickAnyduring pregnancy (anytime or not specified)studies TTT3 Vlenterie - SSRI (Low 5-min Apgar score)Vlenterie - SSRI (Low 5-min Apgar score) 1.70[1.10; 2.80]-U,GPunexposed (general population or NOS)Anyduring pregnancy (anytime or not specified)studies TTT3 metaPregmetaPreg 1.90[1.58; 2.29]58%60,446----Lee (Controls unexposed, general pop), 2025 Martin - Sertraline, 2024 Lyn, 2023 Heinonen - Sertraline, 2021 Marks - Sertraline (Controls exposed to Bupropion), 2021 Levy, 2020 Giardinelli (Controls unexposed, sick), 2018 Hogue, 2017 Bakaysa, 2016 Kivistö, 2016 Malm (Controls unexposed, sick), 2015 Jensen b, 2013 Colvin, 2012 Roca, 2011 Calderon-Margalit, 2009 Lund (Controls unexposed, sick), 2009 Wisner (Controls unexposed, sick), 2009 Lennestal, 2007 Simon (Controls unexposed, NOS), 2002 190.510.01.0