Antidepressant use during pregnancy: the benefit-risk ratio

doi:10.1016/j.ajog.2012.02.009

American Journal of Obstetrics and Gynecology

Volume 207, Issue 3, September 2012, Pages 157-163

https://doi.org/10.1016/j.ajog.2012.02.009 Get rights and content

Antidepressants are used commonly in pregnancy. Physicians who provide health care for pregnant women with depression must balance maternal well-being with potential fetal risks of these medications. Over the last decade, scores of original and review articles have discussed whether selective serotonin reuptake inhibitors–selective serotonin norepinephrine reuptake inhibitors possess risks to the fetus; however, very little has been done to integrate these potential risks, if they exist, into an overall context of a benefit:risk ratio. This review aims at presenting an updated analysis of fetal and maternal exposure to selective serotonin or norepinephrine reuptake inhibitors to allow an evidence-based benefit:risk ratio. When a psychiatric condition necessitates pharmacotherapy, the benefits of such therapy far outweigh the potential minimal risks of cardiac malformations, primary pulmonary hypertension of the newborn infant, or poor neonatal adaptation syndrome.

Section snippets

Congenital malformations

Over the first 2 decades after the introduction of fluoxetine into practice, both dysmorphologic and neurobehavioral human studies did not detect consistent risks of congenital malformations with the drug itself or with newer SSRIs and SNRIs.3, 8, 9, 10 Because of the relatively limited sample size of the initial studies, the common statement that described the fetal safety of these drugs was that they “do not appear to constitute major human teratogens.”

This school of thought changed with a

Pregnancy-induced pharmacokinetic and pharmacodynamic changes

In late pregnancy, there is an increased bodyweight that effectively decreases the dose per kilogram of antidepressants. Importantly, there is increased activity of several cytochrome enzymes, most notably CYP450 3A4 and CYP450 2D6, which catalyzes the metabolism of most SSRIs and SNRIs.⁵⁹ Although this may lower serum concentrations of antidepressants, it is important to remember that often the drug is converted into an active metabolite, as in the case of venlafaxine and fluoxetine;

The risks of untreated depression

Uncontrolled depression in pregnancy has been associated with the increased risk of miscarriages, prematurity, and low birthweight.⁶⁰ Critically, the strongest predictor of the life-threatening postpartum depression is depression in late pregnancy. Women who discontinue their antidepressants “cold turkey” because of fears of teratogenic effects exhibit higher rates of morbidity and hospitalization, which include suicide ideations and attempts and impaired adherence to medical therapy and

Monitoring depression symptoms in pregnancy

Although the depressed pregnant woman optimally should be treated by a psychiatrist, the obstetrician can have a unique opportunity to screen her for depressive symptoms. While in the waiting room for her appointment, the woman can complete the 5-minute Edinburgh Scale for depressive symptom (found online at http://www.fresno.ucsf.edu/pediatrics/downloads/edinburghscale.pdf). This 10-item questionnaire allows an estimation of depressive symptoms with high predictive values toward diagnosis

Perception of teratogenic risk

Pregnant women tend to perceive their teratogenic risk of medications as significantly higher than the true risk.⁶⁵ Even in cases of exposure to nonteratogenic agents, women believe that their own child's risk for malformation is in the range of 25%, which is in the range of risk that was caused by thalidomide.⁶⁵ Not surprisingly, it is common for pregnant women to avoid therapy, even for life-threatening medical conditions, or even to consider termination of otherwise wanted pregnancies.⁶⁶

Benefit:risk ratio

Although over the last decade scores of original and review articles have discussed whether SSRIs-SNRIs possess a risk for congenital malformations (Table), very little has been done to integrate these potential risks, if they exist, into an overall context of benefit:risk ratio. Herein we will synthesize the components of risks and benefits of antidepressant use in pregnancy that should be considered in each case when the decision is being made to use or to avoid antidepressants during

Antidepressants during breastfeeding

Because they are molecules of relatively small molecular weight, all SSRIs-SNRIs cross the mammary gland to some extent into milk. In general, the extent to which a drug crosses into breast milk is quantified as the ratio of the dose per kilogram that is offered to the suckling baby through milk divided by the dose per kilogram that is taken by the mother.⁷² In the case of SSRIs-SNRIs, the relative infant dose is <5%, which makes it unlikely to cause adverse effects.⁷³ In the context of

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Mediterranean Diet Adherence and Depressive Symptoms among a Nationally Representative Sample of Pregnant Women in the United States
2023, Journal of Nutrition
Prenatal depression affects ∼12% of pregnant women in the United States and is associated with an increased risk of adverse birth outcomes and maternal mortality. Adherence to a healthy dietary pattern may reduce and/or protect against depressive symptoms.
To investigate the relationship between adherence to a Mediterranean diet and depressive symptoms among pregnant women in the United States.
We used data from the National Health and Nutrition Examination Survey (2005–2018, N = 540) and included pregnant women aged 18–44 y with a positive urine pregnancy test. The Mediterranean diet score (aMED) was calculated from 1 24-h recall; aMED typically ranges from 0–9, but in these analyses, it ranged from 0–8 because alcohol was not included. The aMED score was dichotomized as high (>3) compared with low (≤3). The Patient Health Questionnaire-9 (PHQ-9), which measures depressive symptoms, was dichotomized as lower compared with higher (PHQ-9 score ≥10), based on the clinical cutoff for patient referral. Our primary model employed logistic regression to investigate the association between aMED adherence and high depressive symptoms when controlling for socio-demographics (age, racial/ethnicity, education, poverty, and relationship status), total calories, and prepregnancy body mass index (kg/m²). We also modeled the PHQ-9 score as a continuous variable using a random-effects model.
About 5% of pregnant women had moderate to severe depressive symptoms, and 45% were highly adherent to a Mediterranean diet. Higher adherence to a Mediterranean diet was associated with lower odds of depressive symptoms (odds ratio: 0.31, 95% confidence interval: 0.10, 0.98). Results were not significant for the continuous PHQ-9 score (β: –0.30; 95% confidence interval: –0.90, 0.30).
Adherence to a Mediterranean diet may have the potential to lower depressive symptoms among pregnant women; however, these results should be interpreted with caution. Nevertheless, considering the public health significance of promoting mental wellness among pregnant women, this relationship merits further examination using experimental designs.
Maternal antenatal depression's effects on child developmental delays: Gestational age, postnatal depressive symptoms, and breastfeeding as mediators
2023, Journal of Affective Disorders
Maternal antenatal depression experienced around conception or during pregnancy may adversely affect child development. This study explores three potential mechanisms of the effects of antenatal depression on children's developmental delays at 2–3 years: gestational age of the child, continued depressive symptoms postnatally, and interrupted breastfeeding practices.
Mothers (N = 2888) of 3450 children, including 2303 singletons and 1147 multiples from the Upstate KIDS cohort provided data. Linked hospital discharge data was combined with mothers' reports to identify women with moderate to severe antenatal depression. Gestational age was extracted from birth certificates. Mothers completed a depression screener at 4 months postpartum, reported about their breastfeeding practices from 4 to 12 months postpartum, and completed a developmental delay screener when children were 24, 30, and 36 months.
In unadjusted path analysis models, mothers with antenatal depression had more postnatal depressive symptoms and breastfed fewer months, which translated into children being more likely to have developmental delays. Gestational age was not a mediator. Effects were similar across girls and boys and singletons and twins, and largely held when adjusting for covariates.
Main limitations were the relatively advantaged sample and reliance on maternal report.
Maternal antenatal depression may impact child development through continued depressive symptoms in the postpartum period and through reduced breastfeeding duration suggesting additional targets for intervention.
Antidepressant use during pregnancy and development of preeclampsia: A focus on classes of action and specific transporters/receptors targeted by antidepressants
2022, Journal of Psychiatric Research
The association between antidepressants and preeclampsia has been inconsistently reported. Given the compound-specific variable affinity for different transporters/receptors, their effect on preeclampsia risk could differ. Our study examined the risk of preeclampsia (and its subtypes) following exposure to different classes of antidepressants, also accounting for specific transporters/receptors targeted by antidepressants.
We conducted a cohort study, combining data from the Netherlands Perinatal Registry and the PHARMO Database Network. Exposure to antidepressants was examined from conception to week 20 of gestation; extended use thereafter was also studied. Antidepressants were categorized according to classes [selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and other antidepressants] and according to target transporters/receptors. Women not using any antidepressants during 15 months before delivery were included as reference.
We included 2,103 exposed and 95,376 reference women. Preeclampsia occurred in 70 exposed women (15 early-onset, 55 late-onset) and in 2,582 reference women (387 early-onset, 2,195 late-onset). TCA monotherapy (214 women) was associated with an increased risk of preeclampsia (n = 15, RR 2.46, 95% CI 1.51–4.02) and late-onset preeclampsia (n = 12, RR 2.41, 95% CI 1.39–4.17, early-onset could not be evaluated). No association was detected with SSRIs, SNRIs and MAOIs. We did observe an increased risk of early-onset preeclampsia following exposure to 5-HT2A antagonizing antidepressants (6/405 women, excluding TCA users, RR 3.56, 95% CI 1.60–7.94).
Our results support an increased risk of preeclampsia and the late-onset subtype among TCA users. The association between 5-HT2A antagonists and the early-onset subtype needs to be interpreted with caution based on the relatively small number of exposed cases.
Automated quantification of opioid withdrawal in neonatal rat pups using Ethovision® XT software
2021, Neurotoxicology and Teratology
Chronic prenatal exposure to opioids often causes fetal opioid dependence that leads to neonatal opioid withdrawal syndrome (NOWS) shortly after delivery. Rat models of NOWS often require quantifying neonatal withdrawal behaviors using time-consuming, labor-intensive manual scoring methods. The goal of this study was to automate quantification of opioid withdrawal in neonatal rat pups. Accordingly, we used the animal behavior software Ethovision® XT to analyze archived videos of rat pups subjected to precipitated opioid withdrawal testing on postnatal day 0. We compared results obtained from Ethovision® XT with those previously obtained from manual scoring. Two endpoints reported by Ethovision® XT, Distance Moved (cm) and Movement Duration (s), had strong positive linear relationships with manually derived global withdrawal scores (GWS; R² > 0.73). Sensitivity and specificity of each endpoint to discriminate presence and absence of low-grade withdrawal were assessed by receiver operator characteristic curve analysis, which indicated that Distance Moved and Movement Duration had excellent accuracy (AUC > 0.90). Finally, we analyzed main and interaction effects of prenatal treatment (with vehicle or mu opioid receptor full agonists) and postnatal challenge (with saline or an opioid receptor antagonist) on each endpoint and determined they were similar for the manual and automated methods. These results show that Ethovision® XT software can reliably quantify opioid withdrawal in neonatal rat pups with non-inferiority to manual scoring even in videos that were not originally purposed and optimized for Ethovision® XT analysis. This faster and less labor-intensive method of analysis is expected to accelerate progress in preclinical studies of NOWS.
Emerging issues and questions on peripartum depression prevention, diagnosis and treatment: a consensus report from the cost action riseup-PPD
2020, Journal of Affective Disorders
Peripartum depression [PPD] is a public health problem which has been widely studied. Nonetheless, study findings and clinical guidelines for PPD treatment differ among countries and the condition is still underdiagnosed and undertreated, suggesting the importance of a global understanding of PPD. The Riseup-PPD Cost Action aims to establish a Pan-European and multidisciplinary network of researchers dedicated to the global understanding of PPD.
A literature search was performed in different databases (e.g., Medline, PsychInfo) including a combination of terms related with PPD diagnosis, prevention, treatment and cost-effectiveness of its management. A narrative synthesis of the literature, together with a critical overview of the current issues/questions to be addressed within the topic of PPD were performed.
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The main limitation is the non-systematic nature of the literature search.
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2019, Hormones and Behavior
Maternal depression and treatment with selective serotonin reuptake inhibitors (SSRIs), the most common form of pharmaceutical intervention, can both have an impact on infant development. As such, it is difficult for healthcare providers to recommend a course of treatment to expectant mothers suffering from depression, or to women on antidepressant medication prior to pregnancy. This review will discuss the existing research on the developmental impacts of maternal depression and its treatment with SSRIs, with a particular focus on contributing factors that complicate our attempt to disentangle the consequences of maternal depression and its treatment such as the timing or severity of the depression. We will explore avenues for translational animal models to help address the question of “Trick or Treat”, i.e.: which is worse for offspring development: exposure to maternal depression, or the SSRI treatment? Further, we will explore sex-dependent outcomes for the offspring in human and animal studies as male and female offspring may react differently to the presence of maternal depression or antidepressant treatment. Without more clinical and preclinical data, it remains difficult for women to make an informed decision regarding their depression treatment before, during, and after their pregnancy.

View all citing articles on Scopus

: The authors report no conflict of interest.

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Expert reviewObstetricsAntidepressant use during pregnancy: the benefit-risk ratio

Section snippets

Congenital malformations

Pregnancy-induced pharmacokinetic and pharmacodynamic changes

The risks of untreated depression

Monitoring depression symptoms in pregnancy

Perception of teratogenic risk

Benefit:risk ratio

Antidepressants during breastfeeding

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Reprod Toxicol

Mayo Clin Proc

Reprod Toxicol

Clin Ther

Semin Perinatol

Paediatr Respir Rev

J Obstet Gynaecol Can

Am J Obstet Gynecol

Am J Obstet Gynecol

Cohort study of depressed mood during pregnancy and after childbirth

BMJ

Drugs in pregnancy

N Engl J Med

Comparative efficacy of antidepressants

Drugs

Trends in antidepressant overdoses

Pharmacoepidemiol Drug Saf

Selective serotonin-reuptake inhibitors and persistent pulmonary hypertension of the newborn

N Engl J Med

Neurodevelopment of children exposed in utero to antidepressant drugs

N Engl J Med

Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac)

JAMA

Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study

JAMA

Selective serotonin reuptake inhibitors in human pregnancy: to treat or not to treat

Obstet Gynecol Int

Evaluation of the risk of congenital cardiovascular defects associated with use of paroxetine during pregnancy

Am J Psychiatry

Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn

N Engl J Med

Birth outcomes in pregnant women taking fluoxetine

N Engl J Med

The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England

BJOG

Delivery outcome after the use of antidepressants in early pregnancy

Eur J Clin Pharmacol

Birth outcomes among pregnant women taking paroxetine (Paxil): OTIS 14th Annual Meeting Proceedings

Teratology

Risks associated with selective serotonin reuptake inhibitors in pregnancy

Obstet Gynecol

Maternal use of selective serotonin reuptake inhibitors and risk of congenital malformations

Epidemiology

Congenital malformations after antidepressant medication with paroxetine in early pregnancy?

Hum Reprod

Paroxetine and congenital malformations: a prospective comparative study

Drug Saf

Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations

Birth Defects Res A Clin Mol Teratol

Risks of congenital malformations and perinatal events among infants exposed to antidepressant medications during pregnancy

Pharmacoepidemiol Drug Saf

First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage

Birth Defects Res B Dev Reprod Toxicol

Use of selective serotonin-reuptake inhibitors in pregnancy and risk of birth defects

N Engl J Med

Expert review
Obstetrics
Antidepressant use during pregnancy: the benefit-risk ratio