What are the maternal and neonatal risks and benefits associated with the use of SSRIs (if any) during pregnancy - regarding fetal development, long-term neurodevelopmental outcomes?

Comment by InpharmD Researcher

Available evidence suggests that SSRIs are effective for maintaining maternal mental health during pregnancy and generally have a more favorable safety profile than serotonin norepinephrine reuptake inhibitors (SNRIs). However, data indicate that SSRI use may be associated with a small absolute risk of birth defects, preterm birth, poor neonatal adaptation, and, if taken during the first trimester, potential cardiac malformations. SSRIs may also modestly increase the risk of persistent pulmonary hypertension of the newborn, although sertraline appears to carry the lowest risk. Ultimately, treatment decisions must balance potential fetal and neonatal risks against the consequences of untreated maternal depression, which can compromise maternal health and increase the likelihood of adverse neonatal outcomes.

Background

According to a statement from the American College of Obstetricians and Gynecologists (ACOG) reaffirmed in 2014, the absolute risks of birth defects associated with the use of selective serotonin reuptake inhibitors (SSRIs) identified in some case-control studies were not significant or small. However, the risk of depression relapse if treatment is discontinued should be considered. Therefore, they recommend that treatment with SSRIs or SNRIs during pregnancy should be individualized (Level C recommendation). Of note, paroxetine (Paxil) should be avoided by pregnant women and women who plan to become pregnant (Level B recommendation). [1]

A 2020 review described the human and animal literature reporting the effects of perinatal SSRIs on anxiety and depression in offspring. A cross-sectional study and another population-based study revealed that maternal depression symptoms (not prenatal SSRI exposure) are related to anxiety and depression symptoms of their children. Several smaller longitudinal cohort studies showed that while prenatal SSRI exposure was related to increased anxiety symptoms at three years, these behaviors did not continue to six years. Moreover, another study suggested that increased risk of prenatal SSRIs exposure affecting childhood anxiety at five years can be due to SSRI exposure during ≥ 28 weeks pregnancy. Another study based on exposure to SSRIs during maternal pregnancy reported that SSRIs exposure was related to increased anxiety behaviors in children aged 3 years compared to siblings without SSRIs exposure, regardless of maternal depression symptoms. The authors concluded that while the majority of human studies show prenatal SSRIs exposure does not increase anxiety behaviors in children, it was noted that the risk for anxious behavior might appear later in life. No specific SSRIs were mentioned in the review. [2]

A 2020 umbrella review of 22 meta-analyses found four “highly suggestive” associations: first, antidepressant exposure is associated with the risk of preterm birth (relative risk, 1.68; 95% confidence interval [CI] 1.52 to 1.86); second, any time exposure to SSRIs and the risk of preterm birth (1.43; CI 1.22 to 1.37); third, respiratory distress (1.33; CI 1.14 to 1.55); and SSRI exposure during the first trimester of pregnancy and the risk of cardiovascular malformations (1.25; CI 1.13 to 1.39). The authors concluded antidepressant exposure during pregnancy on neonatal outcomes have been extensively studied, but few of the associations are graded as high-quality evidence. [3]

Another 2020 systematic review of meta-analyses found almost all meta-analyses that included data on fluoxetine or paroxetine suggested that women who used these SSRIs individually during the first trimester of pregnancy had a significantly higher proportion of infants with major anomalies. The authors speculated sertraline may be slightly safer than citalopram in the context of major anomalies in the infant. Numerically, escitalopram and fluvoxamine appear to be the safest among SSRIs, but both agents are severely limited by the number of patients taking these agents in contrast to other SSRIs. [4]

A 2019 systematic review, meta-analysis, and network meta-analysis examined the association between prenatal exposure to SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) and the risk for persistent pulmonary hypertension of the newborn (PPHN). The analysis included 11 studies involving 156,978 women and their offspring who were exposed to SSRIs or SNRIs during pregnancy. The primary outcome focused on evaluating the risk for PPHN after maternal exposure to these antidepressants, with findings indicating a significant association between exposure during any trimester and an increased risk for PPHN (odds ratio [OR] 1.82; 95% CI 1.31 to 2.54). The 2018 analysis further revealed, through network meta-analysis, that sertraline might present the lowest risk for PPHN among SSRIs, supported by a ranking indicating it was most likely to have the lowest associated risk for this condition (p= 0.83). Sensitivity analyses underscored a more pronounced risk when exposure occurred after the 20th week of gestation. Despite high heterogeneity in some studies, the authors concluded that SSRIs and SNRIs during pregnancy are linked to a doubled risk of PPHN in newborns, with sertraline emerging as a potentially safer option among the evaluated antidepressants. [5]

A 2023 meta-analysis meticulously conducted a systematic review to assess the association between maternal exposure to SSRIs or SNRIs during pregnancy and the risk of congenital abnormalities in offspring. The analysis encompassed 21 cohort studies and 7 case-control studies. The systematic approach provided a comprehensive delineation of risks associated with specific congenital abnormalities, emphasizing cardiovascular anomalies, anomalies of the kidney and urinary tract, and digestive system malformations. The findings of the meta-analysis discerned that maternal exposure to SSRIs was linked with a heightened risk of congenital cardiovascular abnormalities, with a pooled OR of 1.25 (95% CI 1.20 to 1.30), indicating a substantive increase in risk compared with non-exposed populations. Similarly, exposure to SNRIs was associated with higher risks in these categories, with the OR for cardiovascular abnormalities markedly higher at 1.64 (95% CI 1.36 to 1.97) after adjusting for potential publication bias using the trim and fill method. The meta-analysis highlighted that the teratogenic risks varied between SSRIs and SNRIs, with the latter posing a more significant risk across several anomaly categories. Overall, this nuanced understanding underscores the critical need for healthcare providers to weigh the benefits and risks of antidepressant prescriptions during pregnancy, taking into account specific patient histories and the differential teratogenic profiles of SSRIs and SNRIs. Notably, the study did not evaluate safety outcomes related to breastfeeding. [6]

Finally, a 2017 review evaluated the safety of SSRIs and SNRIs during pregnancy and lactation. The review noted that both SSRIs and SNRIs cross the placental and blood-brain barriers and are excreted in breast milk, potentially affecting fetal and neonatal brain development. Clinical findings associated with prenatal exposure to these antidepressants include spontaneous abortions, preterm births, low birth weight, intrauterine growth retardation, and poor neonatal adaptation (PNA), with symptoms such as respiratory difficulties, feeding problems, and irritability. PNA was particularly linked to exposure in the third trimester. Some effects, such as persistent pulmonary hypertension of the newborn and neurobehavioral symptoms, may reflect direct drug toxicity or withdrawal. Although no increased risk of serious malformations was generally observed, treatment with paroxetine has been associated with congenital heart defects. Experimental studies did not confirm morphological abnormalities but suggested possible functional and behavioral changes, particularly involving brain plasticity and sexual development. Overall, the review concluded that both treated and untreated maternal depression carry risks, and the potential for SSRIs and SNRIs to cause long-term neurodevelopmental effects may warrant further research. Notably, the authors did not report any specific safety differences between SSRIs and SNRIs during pregnancy and breastfeeding. [7]

References:

[1] ACOG Practice Bulletin: Clinical management guidelines for obstetrician-gynecologists number 92, April 2008 (replaces practice bulletin number 87, November 2007). Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol. 2008;111(4):1001-20. Reaffirmed in 2014.
[2] Fischer Fumeaux CJ, Morisod Harari M, Weisskopf E, et al. Risk-benefit balance assessment of SSRI antidepressant use during pregnancy and lactation based on best available evidence - an update. Expert Opin Drug Saf. 2019;18(10):949-963. doi:10.1080/14740338.2019.1658740
[3] Biffi A, Cantarutti A, Rea F, Locatelli A, Zanini R, Corrao G. Use of antidepressants during pregnancy and neonatal outcomes: An umbrella review of meta-analyses of observational studies. J Psychiatr Res. 2020;124:99-108. doi:10.1016/j.jpsychires.2020.02.023
[4] Uguz F. Selective serotonin reuptake inhibitors and the risk of congenital anomalies: a systematic review of current meta-analyses. Expert Opin Drug Saf. 2020;19(12):1595-1604. doi:10.1080/14740338.2020.1832080
[5] Masarwa R, Bar-Oz B, Gorelik E, Reif S, Perlman A, Matok I. Prenatal exposure to selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors and risk for persistent pulmonary hypertension of the newborn: a systematic review, meta-analysis, and network meta-analysis. Am J Obstet Gynecol. 2019;220(1):57.e1-57.e13. doi:10.1016/j.ajog.2018.08.030
[6] Huang W, Page RL, Morris T, Ayres S, Ferdinand AO, Sinha S. Maternal exposure to SSRIs or SNRIs and the risk of congenital abnormalities in offspring: A systematic review and meta-analysis. PLoS One. 2023;18(11):e0294996. Published 2023 Nov 29. doi:10.1371/journal.pone.0294996
[7] Dubovicky M, Belovicova K, Csatlosova K, Bogi E. Risks of using SSRI / SNRI antidepressants during pregnancy and lactation. Interdiscip Toxicol. 2017;10(1):30-34. doi:10.1515/intox-2017-0004
Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What are the maternal and neonatal risks and benefits associated with the use of SSRIs (if any) during pregnancy - regarding fetal development, long-term neurodevelopmental outcomes?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-5 for your response.

 

Antidepressant use During Pregnancy Ratings and Recommendations

Drug

Drugs in Pregnancy and Lactation (Briggs)

Pregnancy Recommendation

FDA Package Insert (Statements on Human Data Only; Animal data and risk not included). Read prescribing information in full for relevant clinical details.

 Tricyclic Antidepressants

Amitriptyline

 Human Data Suggest Low Risk Amitriptyline has been shown to cross the placenta. Although a causal relationship has not been established, there have been a few reports of adverse events, including CNS effects, limb deformities, or developmental delay, in infants whose mothers had taken amitriptyline during pregnancy.

There are no adequate and well-controlled studies in pregnant women. Amitriptyline hydrochloride should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. (PI 2021)

Amoxapine

 Limited Human Data—Animal Data Suggest Risk There are no adequate and well-controlled studies in pregnant women. Amoxapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (PI 2015)

ClomiPRAMINE

 Human Data Suggest Risk in 1st and 3rd Trimesters There are no adequate or well-controlled studies in pregnant women. Withdrawal symptoms, including jitteriness, tremor and seizures, have been reported in neonates whose mothers had taken clomipramine hydrochloride until delivery. Clomipramine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (PI 2021)

Desipramine

 Human Data Suggest Risk Safe use of desipramine hydrochloride during pregnancy and lactation has not been established; therefore, if it is to be given to pregnant patients, nursing mothers, or women of childbearing potential, the possible benefits must be weighed against the possible hazards to mother and child. Animal reproductive studies have been inconclusive. (P1 2021)

Doxepin

 Human Data Suggest Low Risk Since there is no experience in pregnant women who have received this drug, safety in pregnancy has not been established. There has been a report of apnea and drowsiness occurring in a nursing infant whose mother was taking doxepin. (PI 2020)

Imipramine

 Human Data Suggest Low Risk There have been no well-controlled studies conducted with pregnant women to determine the effect of Imipramine hydrochloride tablets, USP on the fetus. However, there have been clinical reports of congenital malformations associated with the use of the drug. Although a causal relationship between these effects and the drug could not be established, the possibility of fetal risk from the maternal ingestion of Imipramine hydrochloride tablets, USP cannot be excluded. Therefore, Imipramine hydrochloride tablets, USP should be used in women who are or might become pregnant only if the clinical condition clearly justifies potential risk to the fetus. (PI 2020)

Nortriptyline

 Human Data Suggest Low Risk Safe use of nortriptyline hydrochloride during pregnancy and lactation has not been established; therefore, when the drug is administered to pregnant patients, nursing mothers, or women of childbearing potential, the potential benefits must be weighed against the possible hazards. Animal reproduction studies have yielded inconclusive results. (PI 2020)
Protriptyline No Human Data—Animal Data Suggest Low Risk Safe use in pregnancy and lactation has not been established; therefore, use in pregnant women, nursing mothers or women who may become pregnant requires that possible benefits be weighed against possible hazards to mother and child. (PI 2020)
Selective Serotonin Reuptake Inhibitors*
Citalopram Human Data Suggest Risk in 3rd Trimester

There are no adequate and well-controlled studies in pregnant women; therefore, citalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (PI 2021)
Escitalopram Human Data Suggest Risk in 3rd Trimester

Pregnancy: SSRI use, particularly later in pregnancy, may increase the risk for persistent pulmonary hypertension and symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulties, hypotonia, tremor, irritability) in the neonate. (PI 2021)
FLUoxetine Human Data Suggest Risk in 3rd Trimester It has been shown that SSRIs (including fluoxetine) can cross the placenta. Published epidemiological studies of pregnant women exposed to fluoxetine have not established an increased risk of major birth defects, miscarriage, and other adverse developmental outcomes. Several publications reported an increased incidence of cardiovascular malformations in children with in utero exposure to fluoxetine. However, these studies results do not establish a causal relationship. Methodologic limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders and confirmatory studies. However, these studies cannot definitely establish or exclude any drug-associated risk during pregnancy. (PI 2020)
FluvoxaMINE Human Data Suggest Risk in 3rd Trimester Consider both potential risks and benefits when treating a pregnant woman. (PI 2021)
PARoxetine Human Data Suggest Risk

CONTRAINDICATED IN PREGNANCY

Menopausal VMS does not occur during pregnancy and Paroxetine Capsules may cause fetal harm (PI 2021)
Sertraline Human Data Suggest Risk in 3rd Trimester Overall, available published epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in comparator populations. (PI 2021)
Vilazodone Human Data Suggest Risk in 3rd Trimester There are no adequate and well-controlled studies of VIIBRYD in pregnant women. (PI 2020)
Dopamine-Reuptake Blocking Compounds
BuPROPion Limited Human Data Suggest Low Risk Data from the international bupropion Pregnancy Registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall. The Registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. (PI 2019)
Serotonin/Norepinephrine Reuptake Inhibitors*
Desvenlafaxine Human Data Suggest Risk in 3rd Trimester Published epidemiological studies of pregnant women exposed to the parent compound venlafaxine have not reported a clear association with major birth defects or miscarriage. (PI 2021)
DULoxetine Human Data Suggest Risk in 3rd Trimester Data from a postmarketing retrospective claims-based cohort study found an increased risk for postpartum hemorrhage among 955 pregnant women exposed to duloxetine in the last month of pregnancy compared to 4,128,460 unexposed pregnant women (adjusted relative risk: 1.53; 95% CI: 1.08-2.18). The same study did not find a clinically meaningful increase in the risk for major birth defects in the comparison of 2532 women exposed to duloxetine in the first trimester of pregnancy to 1,284,827 unexposed women after adjusting for several confounders. (PI 2021)
Levomilnacipran  -- The available data on levomilnacipran use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. (PI 2020)
Milnacipran Human Data Suggest Risk in 3rd Trimester There are no adequate or well-controlled studies in pregnant women [...] based on animal data, may cause fetal harm. (PI 2021)
Venlafaxine Human Data Suggest Risk in 3rd Trimester There are no adequate and well-controlled studies in pregnant women. (PI 2021)
5-HT2 Receptor Antagonist Properties
Nefazodone Limited Human Data—Animal Data Suggest Moderate Risk There are no adequate and well-controlled studies in pregnant women. (PI 2021)
TraZODone Limited Human Data—Animal Data Suggest Low Risk While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association with trazodone use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. All available studies have methodological limitations, including small sample size and inconsistent comparator groups. (PI 2021)
5HT3 Receptor Antagonist Properties*
Vortioxetine  -- There are limited human data on TRINTELLIX use during pregnancy to inform any drug-associated risks. However, there are clinical considerations regarding neonates exposed to SSRIs and SNRIs, including TRINTELLIX, during the third trimester of pregnancy. (PI 2021)
Noradrenergic Antagonist
Mirtazapine Limited Human Data—Animal Data Suggest Moderate Risk Prolonged experience with mirtazapine in pregnant women, based on published observational studies and postmarketing reports, has not reliably identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. (PI 2020)
Monoamine Oxidase Inhibitors
Isocarboxazid Limited Human Data—No Relevant Animal Data It is also not known whether isocarboxazid can cause embryo/fetal harm when administered to a pregnant woman or can affect reproductive capacity. (PI 2021)
Phenelzine Limited Human Data—Animal Data Suggest Moderate Risk The safe use of phenelzine sulfate during pregnancy or lactation has not been established. (PI 2020)
Selegiline Limited Human Data—Animal Data Suggest Low Risk There are no adequate and well-controlled studies in pregnant women. Selegiline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (PI 2020)
Tranylcypromine Limited Human Data—No Relevant Animal Data There are limited published reports of placental infarction and congenital anomalies in association with use of tranylcypromine sulfate tablets during pregnancy; however, these reports may not adequately inform the presence or absence of drug-associated risk with the use of tranylcypromine sulfate tablets during pregnancy. (PI 2021)



References:

Briggs GG, Towers CV, Forinash AB. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. 12. Edition. Wolters Kluwer; 2021.
DailyMed [Internet]. Bethesda (MD): U.S. National Library of Medicine. [2021] - Available from: https://dailymed.nlm.nih.gov/dailymed/. Accessed October 14, 2021

* SSRIs, SNRIs, and Vortioxetine carry a similar warning regarding nonteratogenic effects: "Pregnancy: Third trimester use may increase risk for persistent pulmonary hypertension/respiratory distress and withdrawal in the newborn."

Appendix- Briggs' Definitions of Pregnancy Recommendations

Compatible
The human pregnancy experience, either for the drug itself or drugs in the same class or with similar mechanisms of action, is adequate to demonstrate that the embryo–fetal risk is very low or nonexistent. Animal reproduction data are not relevant.

No (Limited) Human Data—Probably Compatible
There may or may not be human pregnancy experience, but the characteristics of the drug suggest that it does not represent a significant risk to the embryo–fetus. For example, other drugs in the same class or with similar mechanisms are compatible or the drug does not obtain significant systemic concentrations. Any animal reproduction data are not relevant.

Compatible—Maternal Benefit >> Embryo–Fetal Risk
There may or may not be human pregnancy experience, but the potential maternal benefit far outweighs the known or unknown embryo–fetal risk. Animal reproduction data are not relevant.

Human Data Suggest Low Risk
There is limited human pregnancy experience, either for the drug itself or drugs in the same class or with similar mechanisms of action, including the 1st trimester, suggesting that the drug does not represent a significant risk of developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) at any time in pregnancy. The limited human pregnancy data outweighs any animal reproduction data.

No (Limited) Human Data—Animal Data Suggest Low Risk
Either there is no human pregnancy experience or the few pregnancy exposures have not been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). The drug does not cause developmental toxicity (at doses that did not cause maternal toxicity) in all animal species studied at doses ≤10 times the human dose based on body surface area (BSA) or AUC.

No (Limited) Human Data—Animal Data Suggest Moderate Risk
Either there is no human pregnancy experience or the few pregnancy exposures have not been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). The drug causes developmental toxicity (at doses that did not cause maternal toxicity) in one animal species at doses ≤10 times the human dose based on body surface area (BSA) or AUC*.

*AUC = area under the plasma concentration vs. time curve; a measure of the systemic exposure of a drug
No (Limited) Human Data—Animal Data Suggest Risk
Either there is no human pregnancy experience or the few pregnancy exposures have not been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). The drug causes developmental toxicity (at doses that did not cause maternal toxicity) in two animal species at doses ≤10 times the human dose based on body surface area (BSA) or AUC*.

No (Limited) Human Data—Animal Data Suggest High Risk
Either there is no human pregnancy experience or the few pregnancy exposures have not been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). The drug causes developmental toxicity (at doses that did not cause maternal toxicity) in three or more animal species at doses ≤10 times the human dose based on body surface area (BSA) or AUC*.

Contraindicated—1st Trimester
Human exposures in the 1st trimester, either to the drug itself or to drugs in the same class or with similar mechanisms of action, have been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). The drug should not be used in the 1st trimester.

Contraindicated—2nd and 3rd Trimesters
Human exposures in the 2nd and 3rd trimesters, either to the drug itself or to drugs in the same class or with similar mechanisms of action, have been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavior deficits, or death). The drug should not be used in the 2nd and 3rd trimesters.

Contraindicated
Human exposures at any time in pregnancy, either to the drug itself or to drugs in the same class or with similar mechanisms of action, have been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). Animal reproduction data, if available, confirm the risk. The drug should not be used in pregnancy.

No (Limited) Human Data—No Relevant Animal Data
There are no human pregnancy data or relevant data in animals, or the human pregnancy experience, that may or may not include the 1st trimester, is limited. The risk in pregnancy cannot be assessed.

Human Data Suggest Risk in 1st Trimester
Evidence (for the drug or similar drugs) suggests that there may be an embryo–fetal risk for developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) in the 1st trimester but not in the 2nd and 3rd trimesters. The human pregnancy data outweigh any animal reproduction data.

Human Data Suggest Risk in 1st and 3rd Trimesters
Evidence (for the drug or similar drugs) suggests that there may be an embryo–fetal risk for developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) in the 1st and 3rd trimesters but not in the 2nd trimester. The human pregnancy data outweigh any animal reproduction data.

Human Data Suggest Risk in 2nd and 3rd Trimesters
Evidence (for the drug or similar drugs) suggests that there may be a fetal risk for developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) in the 2nd and 3rd trimesters but not in the 1st trimester. The human pregnancy data outweigh any animal reproduction data.

Human Data Suggest Risk in 3rd Trimester
Evidence (for the drug or similar drugs) suggests that there may be a fetal risk for developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) in the 3rd trimester, or close to delivery but not in the 1st or 2nd trimesters. The human pregnancy data outweigh any animal reproduction data.

Human (and Animal) Data Suggest Risk
The human data for the drug or drugs in the same class or with the same mechanism of action, and animal reproduction data if available, suggest that there may be a risk for developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) throughout pregnancy. Usually, pregnancy exposure should be avoided, but the risk may be acceptable if the maternal condition requires the drug.

 

Infant Doses and Plasma Concentrations of Newer Antidepressants after Excretion in Breast Milk

Drug

Approximate Number of Mother/Infant Pairs Studied

Absolute Infant Dose (mg/d)

Relative Infant Dose (%)

Absolute Infant Plasma Concentrations (ng/ml)

Relative Infant Plasma Concentrations (%)

Selective serotonin reuptake inhibitors

Citalopram

80

0.14

3-10

Negligible

Up to 10

Escitalopram

12

0.04

3-6

< 5

< 4

Fluoxetine

149

0.14

< 12

Up to 100

Up to 80

Fluvoxamine

12

0.12

< 2

Not detected

-

Paroxetine

119

0.03

0.5-3

Not detected

-

Sertraline

145

0.04

0.5-3

Not detected

-

Other antidepressants

Venlafaxine

23

0.50

6-9

Up to 40

Up to 30

Duloxetine

6

< 0.03

< 1

Not detected

-

Bupropion

20

0.20

2

Not detected

-

Mirtazapine

11

0.04

0.5-3

0.2

<1

 

References:

Berle JO, Spigset O. Antidepressant Use During Breastfeeding. Curr Womens Health Rev. 2011;7(1):28-34.

 

Maternal Use of Specific Antidepressant Medications During Early Pregnancy and the Risk of Selected Birth Defects

Design

Population-based, multicenter case-control National Birth Defects Prevention Study (n= 30,630 case mothers)

Objective

To examine associations between individual antidepressants and specific birth defects with and without attempts to partially account for potential confounding by underlying conditions.

Study Groups

Case mothers (n= 30,630)

Control mothers (n= 11,478)

Inclusion Criteria

Included cases with selected birth defects who were identified from surveillance systems; controls were randomly sampled live-born infants without major birth defects. 

Exclusion Criteria

N/A

Methods

The NBDPS was a US population-based, multisite (Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah) case-control study that examined risk factors for major structural birth defects. Cases with selected birth defects were identified from surveillance systems using standard case definitions and included live births (all sites), stillbirths (all sites but New York before 2000 and New Jersey), and terminations (all sites except Georgia before 1999, Massachusetts before 2011, New York before 2000, and New Jersey).

Clinical data were abstracted from medical records and classified by clinician geneticists and other clinicians. Sites collected data on pregnancies ending on or after October 1, 1997, through those with an estimated date of delivery (EDD) on or before December 31, 2011. Infants with known single-gene disorders or chromosomal abnormalities were excluded. Controls were randomly sampled live-born infants without major birth defects identified via vital records or hospital birth logs from the same birth months and state- or county level (depending on the site) geographic catchment area as cases.

Mothers participated in a computer-assisted telephone interview 6 weeks to 24 months after the EDD, with a median time to interview of 11 months for case and 9 months for control mothers (67% case and 65% control mother participation, respectively). Women were considered unexposed if they reported no antidepressant use during the 3 months before conception through their pregnancy’s end. Women were considered exposed only outside of early pregnancy if they reported exposure to any antidepressant, but solely during the 2 to 3 months before conception and/or pregnancy months 4 to 9.

Duration

October 1997–December 2011

Outcome Measures

 Comparison of early pregnancy antidepressant-exposed women with those without antidepressant exposure. 

Patient

Characteristics

 Early pregnancy antidepressant use was reported by 1562 cases (5.1%) and 467 control mothers (4.1%); among control mothers, the most common (≥ 0.2% monotherapy prevalence) antidepressants were sertraline, fluoxetine, paroxetine, citalopram, escitalopram, venlafaxine, and bupropion. Sertraline, fluoxetine, citalopram, and escitalopram use during early pregnancy increased over the study years.

Results

Data presented in supplemental material where raw odds ratio (OR) values for individual outcomes/defects were not listed; i.e. presented as a figure. Key findings by authors identified below:

There were no elevated adjusted odds ratios (aORs) between escitalopram and specific birth defects.

Mothers who used paroxetine or fluoxetine in early pregnancy had the highest proportion of elevated aORs with specific birth defects among the SSRIs examined, followed by citalopram and sertraline.

Mothers who used venlafaxine had elevated aORs for most examined defects; some were relatively high (ie, aORs 3.34 [95% CI, 1.69-6.60]–5.26 [95% CI, 1.96-14.12]).

Adverse Events

Common Adverse Events: Not applicable

Serious Adverse Events: Not applicable 

Percentage that Discontinued due to Adverse Events: Not applicable

Study Author Conclusions

Our results indicated venlafaxine had the highest proportion of elevated birth defect risks while escitalopram had the fewest. For women who require antidepressants during pregnancy, relative differences in the safety of specific medications may be useful to consider in risk-benefit decision-making. Fully informed decision-making requires balancing the risks and benefits of any proposed intervention against the maternal and fetal risks of untreated depression or anxiety, mindful that with every pregnancy an underlying risk of a birth defect exists regardless of antidepressant treatment.

InpharmD Researcher Critique

Patients with more severe depression may have selected treatment based upon the previous success or clinician experience. Underlying conditions or confounders may be at play to create artificial associations. 



References:

Anderson KN, Lind JN, Simeone RM, et al. Maternal Use of Specific Antidepressant Medications During Early Pregnancy and the Risk of Selected Birth Defects. JAMA Psychiatry. 2020;77(12):1246-1255. doi:10.1001/jamapsychiatry.2020.2453

 

Safety of SSRIs During Pregnancy: a Controlled Study

Design

Open-label, comparative, controlled study

N= 56

Objective

To analyze the efficacy and the safety of selective serotonin reuptake inhibitors (SSRIs) during pregnancy focusing on fetal weight, ultrasonography parameters, Apgar score, and admission to the neonatal intensive care unit

Study Groups

Pregnant women treated with SSRIs (n= 30)

Pregnant women with no SSRIs (n= 26)

Methods

SSRIs prescribed from the first visit (52% first trimester, 19% second and 28% third trimester) to the depressed pregnant women (n= 30) were: citalopram 20-30 mg/day (n= 8), escitalopram 10-15 mg/day (n= 2), fluoxetine 20-30 mg/day (n= 2), paroxetine 20-40 mg/day (n= 8) and sertraline 50-100 mg/day (n= 10). These women were compared to a group of pregnant women who did not take any SSRIs.

Duration

May, 2009 to July, 2009

Outcome Measures

Adverse outcomes in pregnancy related to SSRI use

Baseline Characteristics

  
  SSRI (n= 30) No SSRI (n= 26)

Age, years

 35.54 ± 4.64 33.23 ± 5.88

Caucasian

 100% 100%

Parity

 1.57 ± 0.75 1.5 ± 0.70

Gravidity

 3.54 ± 0.71 2.41 ± 0.42

Results 

All women had full‐term deliveries. There was no significant difference in the birth weight observed between women treated with SSRIs and the control with no SSRIs (2961.25 ± 388.54 g vs 2920.00 ± 246.47 g, respectively).

There were no statistically significant differences in any of the pregnancy outcomes of interest between the SSRI group and control group. There was no statistically significant association in newborns of women treated with an SSRI and the control group in the first and fifth minute Apgar score, and no newborns were admitted to neonatal ICU.

Adverse Events

Common Adverse Events: N/A

Study Author Conclusions

No definitive association between use of SSRIs during pregnancy and an increased risk of birth defects or other adverse outcomes could be found. A significant clinical improvement in anxiety and depression was observed in patients during psychopharmacological treatment with a significant amelioration between first and third trimester.

InpharmD Researcher Critique

Due to the small sample size, this study was underpowered to detect increased risks during pregnancy. Potential long‐term effects of these drugs on newborns were not evaluated.



References:

Altamura AC, De gaspari IF, Rovera C, Colombo EM, Mauri MC, Fedele L. Safety of SSRIs during pregnancy: a controlled study. Hum Psychopharmacol. 2013;28(1):25-8.

 

Use of Selective Serotonin-Reuptake Inhibitors in Pregnancy and the Risk of Birth Defects
Design

Case-controlled study

N= 13,714
Objective

To evaluate the relationship between maternal selective serotonin-reuptake inhibitors (SSRIs) use in early pregnancy and the occurrence of selected birth defects
Study Groups

Infants with major birth defects (n= 9,622)

Control infants (n= 4,092)
Methods

Data was collected for infants born with birth defects using the National Birth Defects Prevention Study (NBDPS). Information on the infants in each defect category was reviewed by clinical geneticists who were unaware of the infants’ exposure status, who confirmed case eligibility and classified the cases as isolated (no additional major unrelated defect) or multiple (more than one major unrelated birth defect).

The mothers were asked whether they had taken any of three specific SSRIs, identified by brand name Prozac (fluoxetine), Zoloft (sertraline), and Paxil (paroxetine) during and before pregnancy, and when each medication was taken. Exposure was defined as reported use of any SSRI from 1 month before to 3 months after conception.  Women were considered unexposed if they did not take an SSRI at any time during pregnancy or during the 3 months before conception.  Women who took non-SSRI antidepressants were included in the unexposed group.
Duration

1997 to 2002
Primary Outcome Measure Occurrence of selected birth defects with infants exposed to SSRI’s during early pregnancy
Baseline Characteristics               

 

 Mothers of Case Infants (n= 9,622) Mothers of Control Infants (n= 4,092)
 

No./total no. (%)

Race or ethnic group

    

Non-Hispanic white

 5,861/9,603 (61.0%)   2,454/4,081 (60.1%)  

Non-Hispanic black

 978/9,603 (10.2%)   491/4,081 (12.0%)  

Hispanic

 2,238/9,603 (23.3%) 931/4,081 (22.8%)  

Other

 526/9,603 (5.5%)     205/4,081 (5.0%)  

Age

    

< 35 years

 8,057/9,622 (83.7%)   3,508/4,092 (85.7%)  

≥ 35 years

 1,565/9,622 (16.3%)     584/4,092 (14.3%)  

Alcohol use

    

No

 5,899/9,622 (61.3%)   2,501/4,092 (61.1%)  

Yes

 3,723/9,622 (38.7%)   1,591/4,092 (38.9%)  

Exposure to non-SSRI antidepressants

    

No

 9,229/9,302 (99.2%)   3,954/3974 (99.5%)  

Yes

 73/9,302 (0.8%)   20/3,974 (0.5%)  

Exposure to SSRIs

    

No

 9,320/9,550 (97.6%) 3979/4,065 (97.9%)

Yes

 230/9,550 (2.4%) 86/4,065 (2.1%)
Results

There were no significant associations between maternal use of SSRIs overall during early pregnancy and congenital heart defects or most other categories or subcategories of birth defects. Maternal SSRI use was associated with anencephaly (214 infants, 9 exposed; adjusted odds ratio, 2.4; 95% confidence interval [CI], 1.1 to 5.1), craniosynostosis (432 infants, 24 exposed; adjusted odds ratio, 2.5; 95% CI, 1.5 to 4.0), and omphalocele (181 infants, 11 exposed; adjusted odds ratio, 2.8; 95% CI, 1.3 to 5.7).
Adverse Events

Common Adverse Events: N/A
Study Author Conclusions

This study did not show an increased risk of most birth defects, and SSRI exposure was present in only a small number of cases of certain defects. The absolute risks associated with SSRIs appear small in comparison with the baseline risks of birth defects that exist in every pregnancy. Maternal stress and depression during pregnancy have been associated with adverse reproductive outcomes, and discontinuation of antidepressant treatment in pregnant women with serious depressive illness may have adverse effects on the mother and her baby. Thorough assessment of the potential risks and benefits of SSRI use is necessary to allow women of reproductive age to make informed decisions about such therapy.
InPharmD Researcher Critique

This study was unable to differentiate between potential effects from the SSRI drug itself and the effects of the patients' underlying depression. Information regarding risk factors and medication usage were reported by patients, increasing the risk of mistakes or omissions. 
References:

Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med. 2007;356(26):2684-92.