Treatment of nonpsychotic major depression during pregnancy: patient safety and challenges

Figures & data

Table 1 Summary of the current US Food and Drug Administration (FDA) pregnancy safety categories

Category	Definition	Antidepressants by FDA pregnancy-safety category
A	Adequate and well-controlled studies in pregnant women have not demonstrated fetal risk with exposure in the first trimester of pregnancy, and there is no evidence of risk with exposure in the second or third trimesters.	None
B	There are no adequate and well-controlled studies in pregnant women, and animal studies have not shown evidence of fetal risk.	Tetracyclic antidepressants: maprotiline
C	There are no adequate and well-controlled studies in pregnant women, but animal studies have shown evidence of fetal risk. For pregnant women, potential benefits may warrant use of the medication in pregnant women despite possible risks.	SSRIs: citalopram, escitalopram, fluoxetine, fluvoxamine, sertraline SNRIs: desvenlafaxine, duloxetine, venlafaxine TCAs: amitriptyline, amoxapine, clomipramine, doxepin, trimipramine MAOIs: isocarboxazid, phenelzine, selegiline, tranylcypromine Miscellaneous: bupropion, mirtazapine, nefazodone, trazodone, vilazodone, vortioxetine
D	There is positive evidence of human fetal risk based on investigational or postmarketing experience, but potential benefits may warrant use of the medication in pregnant women despite possible risks.	SSRIs: paroxetine TCAs: imipramine, nortriptyline
X	Animal or human studies have shown fetal abnormalities and/or there is positive evidence of human fetal risk based on investigational or postmarketing experience; risks from the medication clearly outweigh potential benefit.	None
N	The FDA has not classified the medication.	TCAs: desipramine, protriptyline

Abbreviations: SSRIs, selective serotonin-reuptake inhibitors; SNRIs, serotonin–norepinephrine reuptake inhibitors; TCAs, tricyclic antidepressants; MAOIs, monoamine oxidase inhibitors.

Table 2 Meta-analyses of observational studies of antenatal AD use and the risk of congenital malformations

Reference	Studies, n	Exposure groups	Main results	Confounding and bias
Myles et al^Citation105	Major malformations: 16 Minor malformations: 4	SSRI, first trimester (n=23,919) No SSRI	Any malformation: all SSRIs, OR 1.10 (95% CI 1.03–1.16); paroxetine, OR 1.29 (95% CI 1.11–1.49); fluoxetine, OR 1.14 (95% CI 1.01–1.30); sertraline, OR 1.01 (95% CI 0.88–1.17); citalopram, OR 1.04 (95% CI 0.92–1.17)	Separate analyses conducted for studies that considered early versus continuous SSRI exposure; controlled for tobacco, alcohol, or illicit drug use; controlled for maternal age; controlled for maternal parity; and exclusion of chromosomal or genetic abnormalities.
Grigoriadis et al^Citation107	12	Any AD (n=17,915) No AD	Any malformation: RR 0.93 (95% CI 0.85–1.02) Major malformations: RR 1.07 (95% CI 0.99–1.17)	Systematic Assessment of Quality in Observational Research (SAQOR) tool used to evaluate individual study quality.
Riggin et al^Citation108	21	Fluoxetine, first trimester (cohort studies, n=11,225; case-control studies, n=9,800)	Any malformation: cohort studies, OR 1.12 (95% CI 0.98–1.28); case-control studies, OR 3.72 (95% CI 0.74–18.79)
Bar-Oz et al^Citation106	6	Paroxetine, first trimester (n=2,621) No paroxetine AD exposure No teratogen exposure	Paroxetine versus other AD or known nonteratogens: Any malformation: OR 1.31 (95% CI 1.03–1.67) Paroxetine versus other AD: Any malformation: OR 1.30 (95% CI 0.92–1.80) Paroxetine versus known nonteratogens: Any malformation: OR 1.54 (95% CI 0.99–2.41)	Diagnostic tests in pregnancy: Significantly greater use in AD users versus nonusers; no significant difference between paroxetine and other AD, using population-based registry data. Diagnostic tests in infancy: Significantly higher rates of echocardiograms with in utero SSRI exposure versus no AD exposure, using population-based registry data. Indication: Significantly higher proportion of use for anxiety disorders with paroxetine versus other SSRIs.
Rahimi et al^Citation109	9	SSRI, any exposure during pregnancy (n=1,102) Unexposed to SSRI	Any major malformation: OR 1.39 (95% CI 0.91–2.15)
Addis et al^Citation110	4	Fluoxetine, first trimester (n=367)	Any major malformation: weighted average 2.6% (95% CI 1%–4.2%)

Abbreviations: SSRI, selective serotonin-reuptake inhibitor; OR, odds ratio; CI, confidence interval; RR, relative risk; AD, antidepressant.

Table 3 Meta-analyses of observational studies of antenatal AD use and the risk of cardiac malformations

Reference	Studies, n	Exposure groups	Main results	Confounding and bias
Myles et al^Citation105	9	SSRI, first trimester (n=22,412) No SSRI	Any cardiac malformation: OR 1.15 (95% CI 0.999–1.32); paroxetine OR 1.44 (95% CI 1.12–1.86); fluoxetine 1.25 (95% CI 0.98–1.60); sertraline OR 0.93 (95% CI 0.70–1.24); Citalopram OR 1.03 (95% CI 0.80–1.32)	Separate analyses conducted for studies that considered early versus continuous SSRI exposure; controlled for tobacco, alcohol, or illicit drug use; controlled for maternal age; controlled for maternal parity; and exclusion of chromosomal or genetic abnormalities.
Grigoriadis et al^Citation107	Any cardiovascular malformation: 13 Septal heart defects: 9 Ventral septal defects: 5	Any AD (n=22,537) No AD	Any cardiovascular malformation: RR 1.36 (95% CI 108–1.71); paroxetine RR 1.43 (95% CI 1.08–1.88); fluoxetine RR 1.17 (95% CI 0.89–1.55) Septal heart defects (any): RR 1.40 (95% CI 1.10–1.77) Ventral septal defects: RR 1.54 (95% CI 0.71–1.33)	Systematic Assessment of Quality in Observational Research (SAQOR) tool used to evaluate individual study quality.
Riggin et al^Citation108	16	Fluoxetine, first trimester (cohort studies, n=7,874; case-control studies, n= 13,346)	Any cardiac malformation: cohort studies, OR 1.6 (95% CI 1.31–1.95); case-control studies OR 0.63 (95% CI 0.39–1.03)
Bar-Oz et al^Citation106	Meta-analysis RC:4 CC:2	Paroxetine, first trimester (n=5,332) Nonparoxetine AD exposure No teratogen exposure	Paroxetine versus other AD or known nonteratogens: Cardiac malformation (any): OR 1.72 (95% CI 1.22–2.42) Paroxetine versus other AD: Cardiac malformation (any): OR 1.70 (95% CI 1.17–2.46) Paroxetine versus known nonteratogens: Cardiac malformation (any): OR 3.47 (95% CI 0.90–12.21)	Diagnostic tests in pregnancy: Significantly greater use in AD users versus nonusers; no significant difference between paroxetine and other AD, using population-based registry data. Diagnostic tests in infancy: Significantly higher rates of echocardiograms with in utero SSRI exposure versus no AD exposure, using population-based registry data. Indication: Significantly higher proportion of use for anxiety disorders with paroxetine versus other SSRIs.
Rahimi et al^Citation109	8	SSRI, any exposure during pregnancy (n=906) Unexposed to SSRI	Cardiovascular malformation: OR 1.19 (95% CI 0.53–2.68)

Abbreviations: SSRI, selective serotonin-reuptake inhibitor; OR, odds ratio; CI, confidence interval; RR, relative risk; AD, antidepressant; RC, retrospective cohort study; CC, case control study.

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