Treatment-resistant depression in pregnancy, the postpartum period, and transition to menopause

Introduction

The lifetime risk for depression is greater in women than men ( ) and is especially high during female reproductive events including the perimenstrual, peripartum, and perimenopausal phases. The increased depression prevalence in women during reproductive transitions is hypothesized to be due to psychological, social, and physiological changes including the unique temporal hormonal fluctuations associated with each transition. Treatments available for women suffering from depression during the reproductive life cycle are similar to those for the general population and include psychotherapy, pharmacotherapy, and neuromodulation. Limited data are available on treatment-resistant depression (TRD) during the peripartum and perimenopausal periods.

In this chapter, we will review the epidemiology, risk factors, symptomatology, and distinct treatment considerations for unipolar depression occurring during the peripartum and perimenopausal periods. We will also discuss the treatment of peripartum bipolar illness including data on the relative safety profiles of mood stabilizers and antipsychotics in pregnancy and lactation.

Unipolar peripartum depression

Diagnosis of unipolar peripartum depression

The Diagnostic and Statistical Manual Fifth Edition (DSM-5) defines peripartum depression as a major depressive episode with peripartum onset for patients whose symptoms arise during pregnancy or within 4 weeks of delivery ( ). Despite this narrow definition of the postpartum period, many clinicians and the World Health Organization (WHO) extend the definition of the postpartum period to up to 1 year after childbirth ( ). Peripartum depression is frequently distinguished by the presence of anxiety with excessive concern for the child’s health and fear of harming the child. A 2017 study isolated peripartum depressive symptom patterns that differed in severity, time of onset, and type of symptoms, and categorized these distinct presentations into the following five subtypes: severe anxious depression, moderate anxious depression, anxious anhedonia, pure anhedonia, and resolved depression ( ).

Epidemiology of unipolar peripartum depression

Peripartum depression is one of the most common complications of childbirth and is a serious public health problem. In 2018, the Centers for Disease Control and Prevention (CDC) estimated the overall prevalence of postpartum depression in the United States (U.S.) to be 13%, with a range of 9.7%–23.5% by state ( ). According to a 2019 CDC analysis, the rate of depression diagnosis at delivery increased sevenfold from 2000 to 2015 ( ). Among women with peripartum depression, 11.5% develop symptoms antenatally, 66.5% experience symptoms within 6 weeks of delivery, and 22% exhibit symptoms within 12 months of delivery ( ).

Despite the high prevalence of peripartum depression, it is frequently underdiagnosed and undertreated with resultant deleterious consequences to mothers and their offspring. Of women with antenatal depression, only 49.9% are identified in clinical settings, 13.6% receive treatment, 8.6% receive adequate treatment, and 4.8% achieve remission. Of women with postpartum depression, only 30.8% are identified in clinical settings, 15.8% receive treatment, 6.3% receive adequate treatment, and 3.2% achieve remission ( ).

The U.S. Preventive Services Task Force and the American Psychiatric Association (APA) recommend screening for depression in pregnant and postpartum women ( ; ). The APA recommends screening with a validated tool twice during pregnancy, once in early pregnancy and again later in the pregnancy, as well as postpartum during pediatric visits during the first 6 months as recommended by the American Academy of Pediatrics (AAP) ( ; ). The Edinburgh Postnatal Depression Scale (EPDS) and the Patient Health Questionnaire 9 (PHQ-9) are two self-rating screening tools that are validated to identify peripartum depression ( ); however, overreliance on peripartum depression screening tools may lead to misdiagnosis if screening is not followed by thorough psychiatric diagnostic evaluation. In women with an EPDS score > 11/30, 31.4% had major depressive disorder (MDD), 13.1% had bipolar disorder, 60.8% had an anxiety disorder ( ).

Untreated or undertreated antenatal depression can impair a mother’s ability to function and care for herself resulting in inadequate weight gain and is associated with nicotine, alcohol, and substance use ( ). Antenatal depression is also associated with increased risk of miscarriage ( ), pregnancy-induced hypertension, preeclampsia, preterm or operative delivery, fetal growth restriction ( ), low birth weight ( ), maternal–infant attachment difficulties ( ), and impaired lactation ( ). Additionally, offspring of depressed mothers are at increased risk of neurodevelopmental delay ( ) as well as emotional and behavioral problems, including depression ( ), hyperactivity, and conduct problems ( ). Tragically, maternal suicide is the leading cause of direct maternal mortality in the first postpartum year ( ).

Risk factors associated with unipolar peripartum depression

Numerous risk factors are associated with peripartum depression. Biological risk factors include personal or family history of psychiatric illness and smoking, alcohol or substance use ( ). Psychosocial risk factors include poor social support, stressful life events, adverse childhood experiences, domestic violence, and lifetime history of abuse ( ). Demographic and economic factors include young or advanced maternal age, African American or Latina race, single status, unemployment, and low education level or socioeconomic status ( ). Pregnancy-related factors include multiparity, unintended or unwanted pregnancy, present or past pregnancy complications, and pregnancy loss ( ).

Overview of treatment of unipolar peripartum depression

The treatment of depression in pregnant and postpartum women involves use of similar evidence-based psychological, pharmacotherapeutic, and neuromodulation interventions as in nonperipartum women, with some special considerations. When developing an individualized treatment plan for a peripartum patient, the provider should consider factors including gestational age (i.e., early, middle, or late gestation), plans for lactation or lactation status, psychiatric diagnoses, the severity of current and past symptoms, a suicidal and homicidal risk assessment, past psychiatric history particularly related to past pregnancies, efficacy of prior and current psychiatric treatments to determine level of treatment-resistance, medical comorbidities, family psychiatric history, patient preferences for treatment, and ability to adhere to the recommended treatment plan.

Psychotherapeutic treatment of unipolar peripartum depression

An APA taskforce recommends either psychotherapy or antidepressants as first-line treatment for mild-to-moderate peripartum depression ( ). Psychotherapy should also be considered as an adjunct to antidepressants in moderate-to-severe depression and in cases where women decline to take antidepressants. Both cognitive–behavioral therapy and interpersonal psychotherapy are evidence-based, effective forms of psychotherapy for peripartum depression ( ; ). For a comprehensive review of the evidence base for psychological interventions in peripartum depression, we refer the reader to Stuart and Koleva ( ).

Pharmacologic treatment of unipolar peripartum depression

Evaluating the safety and efficacy of antidepressant use for peripartum depression

Safety is an important consideration when choosing among psychopharmacotherapies for peripartum women. Past restrictions on randomized controlled trials (RCTs) of psychopharmacotherapies in pregnancy limited available data on safety and efficacy of even commonly used antidepressants. Most published pharmacotherapy studies are observational in design and therefore limited in accurate assessments of reproductive drug safety due to the potential for selection bias, recall bias, confounding, and exposure or outcome misclassification. While there are inconsistent data and quality of the literature, when evaluating the risk of antidepressant use during the peripartum period, it is crucial to ensure that the study adequately controlled for confounders, used a representative sample, and had results that have been replicated.

Antidepressants are indicated for moderate-to-severe peripartum depression, with selective serotonin reuptake inhibitors (SSRIs) typically considered first-line therapy. While there are no RCTs examining efficacy of antidepressants in antenatal depression, eight RCTs ( ; ; ; ; ; ; ; ) and four open-label studies ( ; ; ; ) have assessed use of SSRIs in treatment of postpartum depression. A meta-analysis of three studies comparing treatment with SSRIs with placebo for treatment of postpartum depression found that patients randomized to SSRIs were more likely to show response or remission of depressive symptoms at follow-up ( ). A systematic review reported that SSRIs, nortriptyline, and psychotherapy are effective for short-term treatment of postpartum depression, but there is not enough evidence to demonstrate clear superiority of either ( ). Despite limited evidence, there is consensus supporting the use of antidepressants in both antenatal and postpartum depression.

There are no RCTs evaluating use of selective norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, trazodone, nefazodone, tricyclic antidepressants (TCAs) (except nortriptyline), or monoamine oxidase inhibitors (MAOIs). Open-label studies support efficacy for venlafaxine ( ), desvenlafaxine ( ), bupropion ( ), and nefazodone ( ) in treatment of postpartum depression.

General considerations for the antenatal use of antidepressants

When possible, any changes to a medication regimen should be made prior to conception to ensure symptom stability and to minimize exposure to the fetus. Abrupt discontinuation of antidepressants in pregnant women with a history of depression is associated with high risk of relapse without known benefit ( ). Women with history of recurrent unipolar MDD or history of symptom recurrence associated with past reduction or discontinuation of pharmacotherapy should not discontinue their antidepressant during pregnancy. All psychotropic medications cross the placenta. When considering the use of antidepressants during pregnancy, it is preferable to prescribe those with a well-studied reproductive safety profile, often older antidepressants which have been studied over time, and to use a single antidepressant at the lowest effective dose rather than polypharmacy.

Treatment in pregnancy is complicated by physiologic and pharmacokinetic changes, including changes in gastrointestinal absorption, hepatic and renal blood flow, changes in glomerular filtration rate, and changes in both phase 1 (hepatic cytochrome P450) and phase 2 (uridine diphosphate glucuronosyltransferase) hepatic enzyme activities ( ). Changes in maternal drug pharmacokinetics in conjunction with placental transfer and fetal drug metabolism affect fetal psychotropic drug exposure ( ). Pregnancy-associated changes in absorption, distribution, metabolism, and elimination may lower psychotropic drug levels and possibly decrease treatment effects, particularly in late pregnancy. Furthermore, increased plasma volume and changes in protein binding may increase volume of distribution for lipophilic drugs ( ). Dose increases are often clinically necessary for citalopram, escitalopram, clomipramine and imipramine after 20 weeks’ gestation. In addition, antenatal dose requirements for fluoxetine, fluvoxamine, nortriptyline, paroxetine, and sertraline often increase in the third trimester ( ). Patients should be educated on the likely need for dose increases as gestation progresses, and symptoms should be monitored closely for changes in severity that would indicate need such increases.

While there is inadequate evidence to recommend routine therapeutic drug monitoring (TDM) of antidepressants other than TCAs during the peripartum period, measurement of serum drug levels when using TCAs to monitor efficacy and prevent toxicity is clinically necessary ( ). During pregnancy, we recommend monthly monitoring of TCA trough levels and frequent psychiatric symptom assessment. In the postpartum period, we recommend weekly monitoring of depressive symptoms and a review of systems to monitor for TCA side effects. The TCA dose often must slowly be decreased towards the preconception dose during the 2–6 weeks after delivery to reduce risk of TCA toxicity. We recommend checking a TCA blood level whenever adverse effects emerge in the early postpartum or at week six when nortriptyline level/dose ratios have been reported to peak.

When considering use of antidepressants during pregnancy, potential risk of under- or untreated depressive symptoms in both the mother and fetus must be weighed against the potential risk of antidepressant exposure for the following types of adverse events: (1) fetal organ malformation, (2) poor pregnancy and birth outcomes including spontaneous abortion, stillbirth, preterm birth, low birth weight and postpartum hemorrhage, (3) neonatal complications including poor neonatal adaptation syndrome and persistent pulmonary hypertension of the newborn, and (4) long-term neurobehavioral sequelae in the offspring. Regarding potential risks of antenatal antidepressant use, most studies have evaluated the safety of SSRIs and SNRIs, while less data are available on other antidepressants such as TCAs and MAOIs. For women with unipolar TRD who often do not achieve remission with nonpharmacotherapeutic interventions alone, the overall small absolute risks of antidepressant use during gestation often outweigh the risks of untreated depression. All women should be educated on the potential risks of pharmacotherapy during the peripartum period. The discussion of the risk/benefits/alternatives to treatment, the patient’s capacity to make the treatment decision, and ideally the partner’s agreement to treatment should be documented in the patient’s chart.

Risk of teratogenesis with antenatal antidepressant use

Birth defects affect 3% of infants born in the U.S. each year ( ). Any consideration of antidepressant effects on rate of teratogenesis must consider baseline rates. Most studies indicate that antidepressants are not associated with overall major congenital malformations ( ; ). While some studies have observed a correlation between antidepressant exposure and specific birth defects, (e.g., anencephaly, craniosynostosis, and omphalocele), only a small increase in the absolute risk (AR) has been observed ( ). Some studies have noted the potential for a small increase in AR for cardiovascular defects ( ), specifically septal defects, in antidepressant-exposed infants, particularly paroxetine; however, many other studies, after controlling for underlying maternal depressive illness and genetics, have found no association between antenatal antidepressant use and heart defects ( ; ; ).

Pregnancy and birth complications associated with antenatal antidepressant use

Risk of pregnancy loss

Miscarriage is a relatively common outcome of pregnancy, with most studies reporting 12%–15% loss among recognized pregnancies by 20 weeks’ gestation ( ). Across multiple studies, antenatal antidepressant use may contribute a small to nonexistent risk for spontaneous abortion after adjusting for potential confounders ( ; ). Antenatal antidepressant use does not appear to be associated with elevated risk of stillbirth, neonatal death or postneonatal death after controlling for potential confounders ( ).

Risk of preterm birth

There are mixed data regarding association between antenatal antidepressant use and preterm birth (PTB), defined as delivery at < 37 weeks of gestation. The PTB rate in U.S. infants is 10% ( ). A large national registry study which adjusted for potential confounding factors found that risk of PTB was lower in neonates with antenatal exposure to SSRIs than in unexposed neonates (4.7% vs 5.4%) ( ). A meta-analysis reported that depressed women with antenatal SSRI use had increased risk of PTB compared with controls (adjusted odds ratio (aOR) 1.24, 95% confidence interval (CI) 1.09–1.41) ( ). Control groups included both women with depression but without SSRI exposure and women without depression or SSRI exposure. In a subgroup analysis, risk of PTB remained significant when comparing depressed women with SSRI use with depressed women treated with psychotherapy alone (6.8% vs 5.8%; OR 1.17, 95% CI 1.10–1.25). Other studies indicate that antenatal antidepressant exposure may be associated with PTB ( ; ) but that the reduction in gestational age at birth (approximately 3 days shorter) may not be clinically significant.

Risk of low birth weight

Approximately 8.28% of neonates in the U.S. are born at a low birth weight (LBW), defined as < 2500 g ( ). There are mixed data regarding an association between antenatal SSRI exposure and LBW. A meta-analysis found that antenatal SSRI exposure was associated with LBW (relative risk (RR) 1.48, 95% CI 1.22–1.79) ( ); however, there was significant heterogeneity across studies and few studies adequately controlled for confounding factors. A larger meta-analysis observed that neonates exposed to antenatal antidepressants (mostly SSRIs) had lower birth weights than unexposed newborns ( ). However, the mean difference between exposed and unexposed babies was noted to be small (74 g) and unlikely to be clinically significant. Furthermore, when the control group was limited to neonates without antenatal antidepressant exposure born to depressed mothers, there was no longer a significant association between antidepressant exposure and lower birth weight. In summary, if there is an association, the AR increase for LBW appears to be small with antidepressant use, and studies have found that untreated antenatal depression is associated with LBW ( ).

Risk for postpartum hemorrhage

Postpartum hemorrhage (PPH), classically defined as an estimated blood loss ≥ 500 mL after vaginal birth or ≥ 1000 mL after cesarean delivery, has been estimated to occur in 1%–3% of U.S. deliveries ( ). Some studies have associated serotonergic antidepressant use with a small increased AR for PPH, hypothesized to be related to serotonin-induced inhibition of platelet aggregation ( ). A large U.S. Medicaid database study found an increased risk for PPH in women who used serotonergic antidepressants close to delivery, after adjustment for maternal illness (adjusted relative risk (aRR) 1.42, 95% CI 1.27–1.57) ( ). A significant study limitation was the inability to control for other potential confounders including alcohol, drug, and tobacco use or the use of over-the-counter medications. Other large studies have documented no increase in risk of PPH with antenatal serotonergic antidepressant use ( ).

Neonatal complications associated with antenatal antidepressant use

Poor neonatal adaptation syndrome

Antenatal exposure to antidepressants has been associated with poor neonatal adaptation syndrome (PNAS) in up to 30% of neonates ( ). PNAS is characterized by typically mild physical and neurobehavioral symptoms including abnormal irritability, sleep disturbances, lethargy, jitteriness, mild respiratory distress, hypothermia, feeding disturbances, altered muscle tone, tremor and rarely seizures ( ). PNAS is hypothesized to be due to a side effect of antidepressants persisting in the infant (antidepressant toxicity) or to antidepressant withdrawal in the neonate (discontinuation syndrome) ( ). PNAS is a transient condition, usually developing hours after birth and self-resolving within days to 2 weeks ( ). One study observed persistent PNAS signs in newborns at 1 month of age, but they were subtle and not clinically significant ( ). PNAS symptoms are typically managed with supportive care, rarely requiring neonatal intensive care unit (NICU) admission. One large national registry study found that 13.7% of infants with antenatal exposure to SSRIs were admitted to the NICU compared with 8.2% of unexposed babies in the general population (aOR 1.5, 95% CI 1.4–1.5) ( ); however, this study concluded that the AR for severe disease was low. It is not recommended to discontinue or lower the antidepressant dose before delivery because this approach does not reduce the risk of PNAS ( ) but may increase the relapse risk of maternal depression.

Risk for persistent pulmonary hypertension of the newborn

Some studies have identified an association between late gestation antidepressant use with persistent pulmonary hypertension of the newborn (PPHN) ( ; ), a serious but rare condition, characterized by failure of the neonatal cardiopulmonary transition to ensue, that occurs in 1.9 per 1000 live births in the general population ( ). Newborns with PPHN typically present within 24 h after birth with signs of respiratory distress and cyanosis that can progress to severe respiratory failure requiring intubation and mechanical ventilation ( ). Risk factors include increased maternal age, smoking, group B streptococcus infection, diabetes mellitus, hypertension, substance abuse, meconium aspiration, cesarean delivery, and prematurity and postmaturity ( ). Among other known causes of PPHN, the pathophysiology of PPHN may involve serotonin-induced damage to the neonatal lungs from antenatal antidepressant exposure characterized by vasoconstriction of pulmonary vessels, leading to increased vascular resistance ( ).

A 2014 meta-analysis reported an associated between late gestation SSRI use and increased risk of PPHN (OR 2.50, 95% CI 1.32–4.73) ( ); however, there was a moderate degree of heterogeneity across the studies. Furthermore, it is important to consider that since the frequency of PPHN in the general population is low, the AR increase related to late pregnancy antidepressant exposure must also be low. This meta-analysis estimated that the AR difference between late pregnancy SSRI exposure and no exposure in the development of PPHN was approximately 3 per 1000 infants and that approximately 350 women would have to be treated with SSRIs in late pregnancy to result in one additional case of PPHN. A study limitation included inadequate control for factors associated with PPHN that are also common in depressed women, including obesity, cesarean delivery, and PTB. Finally, a large observational study found that antenatal exposure to SSRIs was associated with a much lower risk of PPHN or no association at all ( ). In summary, there appears to be either a nonexistent or small increase in the AR for PPHN from 1.9 per 1000 in the general population to approximately 3 per 1000 with late gestation SSRI use.

Risk for psychopathology in offspring

Antenatal antidepressant exposure does not appear to be associated with increased risk for attention deficit hyperactivity disorder (ADHD) or autism in the offspring, based upon several studies which adjusted for potential confounders ( ; ). Antenatal antidepressant use may be associated with increased risk of depression in the offspring. A large national registry study which controlled for potential confounding factors found that the cumulative incidence of depression was greater in offspring (with antenatal SSRI exposure) by age 15, compared with offspring of women with psychiatric disorders without SSRI use (8% vs 2%) ( ). Additionally, depression occurred more in offspring with antenatal SSRI exposure compared with offspring of women who used SSRIs prior but not during pregnancy (8% vs 3%). The strength of these conclusions, however, are limited due to potential residual confounding in the study by maternal postpartum depression, which has been shown to be linked with an increased risk of depression in offspring by 16 years of age ( ).

Antenatal use of atypical antidepressants in unipolar depression

Bupropion

There is inconsistent evidence regarding whether antenatal exposure to bupropion is associated with teratogenesis. While a few studies have reported an association between antenatal bupropion exposure and congenital heart defects, the type of defect differs across studies. A retrospective case-control study, which adjusted for potential confounding factors, concluded that there was a greater likelihood of first trimester bupropion exposure in neonates with left ventricular outflow tract obstruction (LVOTO) compared to newborns without malformations (OR 2.6, 95% CI 1.2–5.7) ( ); however, the AR was small (2.1 per 1000 births). Additionally, bupropion was not associated with other cardiac malformations, such as ventricular septal defects (VSDs). More recently, a large registry case-control study, which did not control for potential confounding from maternal mental illness, found that there was a greater likelihood of first trimester bupropion exposure in infants with VSDs than neonates without malformations (aOR 2.5, 95% CI 1.3–5.0); however, bupropion was not associated with other congenital heart defects, such as LVOTO defects ( ). The studies are limited in that neither controlled for confounding by indication (using bupropion for depression or smoking), due to the small number of infants exposed to bupropion antenatally.

Several other studies have reported that bupropion is not a major teratogen. A large retrospective cohort study observed that first trimester bupropion exposure was not associated with an increased risk for overall congenital malformations or cardiac malformations ( ). A separate large U.S. Medicaid database study evaluating first trimester bupropion exposure found no increased risk for any congenital cardiac malformations, VSDs, or right ventricular outflow tract obstruction (RVOTO) after adjustment for maternal illness ( ).

Bupropion is often a treatment choice for women with peripartum depression and comorbid ADHD or nicotine dependence. One multistate insurance claims database study found that fetal exposure to bupropion, particularly in the second trimester, was strongly associated with an increased risk for ADHD ( ). While this study adjusted for some confounding factors (i.e., sex of the child, parental psychiatric diagnoses, and peripartum complications), it did not control adequately for tobacco, alcohol, or drug use, and there may have been confounding by undiagnosed parental ADHD. Future research is needed to evaluate the potential risk for ADHD in offspring exposed prenatally to bupropion.

Mirtazapine

Mirtazapine is not often used as a first-line therapy for antepartum depression as there is limited information available concerning its safety profile during pregnancy. The available data suggest that mirtazapine is not a major teratogen. In a systematic review of six observational studies, mirtazapine was not associated with increased incidence of major congenital malformations ( ). Unlike other antidepressants, mirtazapine has antiemetic properties that have used in the treatment of hyperemesis gravidarum ( ), which is frequently associated with severe anxiety and depression. As such, mirtazapine may be a particularly favorable choice for pregnant women suffering from severe nausea and comorbid depression or anxiety. For women who have failed traditional SSRI or SNRI pharmacotherapies, mirtazapine may additionally be a beneficial choice.

Trazodone and nefazodone

Trazodone and nefazodone are not used as first-line therapy for antepartum depression or insomnia as they do not have well-studied reproductive safety profiles. Limited data on the antenatal use of trazodone and nefazodone are reassuring regarding the risk of teratogenesis and major pregnancy complications. One small prospective observational study of found that first trimester exposure to trazodone or nefazodone ( n = 147) was not associated with major malformations, miscarriages, or stillbirths ( ), but larger studies powered to find rare adverse effects are not available in the literature.

Antenatal use of TCAs in unipolar depression

TCAs are generally not used as first- or second-line therapy for antepartum depression, as they can be poorly tolerated due to their anticholinergic side effect profile. In addition, data on the risks of antenatal exposure to TCAs are limited and includes smaller sample sizes compared to those of SSRIs. TCAs should be reserved for use in women with TRD who have not responded to a SSRI or SNRI. Desipramine and nortriptyline are favored TCAs as they are less anticholinergic, and thereby less likely to worsen orthostatic hypotension and constipation during pregnancy. Most studies have found that exposure to antenatal TCA use is not associated with congenital malformations, including cardiac malformations ( ; ). Although TCAs as a class are not thought to be teratogenic, some data suggest that antenatal exposure to clomipramine may be associated with a modestly elevated risk of total malformations (OR 1.36, 95% CI 1.07–1.72), cardiovascular defects as a group (OR 1.63, 95% CI 1.12–2.36), and VSDs and/or atrial septal defects (aOR 1.84, 95% CI 1.13–2.97) ( ). A main limitation is that the analysis did not control for maternal depression, illicit drug use, or other nonantidepressant medication, and the results may have been due to confounding by indication.

Antenatal use of MAOIs in unipolar depression

MAOIs are not used as first- or second-line therapy for antepartum depression because of the potential for interactions with foods and other drugs as well as vasoconstrictive effects. In addition, data on the risks of antenatal exposure to MAOIs are primarily limited to case reports ( ; ). One study that evaluated fetal exposure to MAOIs with other antidepressants did not identify adverse infant outcomes ( ). MAOIs should generally be avoided during pregnancy due to insufficient data regarding their reproductive safety profile and restrictions associated with their use. MAOIs may be considered for use in women with TRD who have not responded to other agents.

Antidepressant use during lactation

Antidepressant use should not discourage women from breastfeeding, as the overwhelming benefits of breastfeeding usually outweigh the low risks of antidepressant use in women suffering from postpartum depression. Furthermore, postpartum depression is associated with decreased lactation duration and increased breastfeeding difficulties ( ). Data about safety of infant exposure to antidepressants through breast milk are derived from small observational studies, as no RCTs have been performed. The relative infant dose (RID) is an estimate of infant drug exposure from breast milk derived from dividing the dose provided to the infant via breast milk (mg/kg/day) by the mother’s weight-adjusted dose (mg/kg/day). For most drugs, a RID from breast milk of < 10% of the weight-adjusted maternal dose is satisfactory while breastfeeding a healthy infant. Caution is required for drugs with a RID from breast milk of 10%–25% ( ).

Most antidepressants are transferred to breast milk in low concentrations, with few reaching 10% of the maternal weight-adjusted dose ( ). Paroxetine, sertraline, bupropion, duloxetine, fluvoxamine, and mirtazapine have RIDs < 3%, while citalopram, escitalopram, venlafaxine, and desvenlafaxine produce RIDs in breast milk closer to 10%. In contrast, fluoxetine has a RID slightly above the 10% guideline. Several TCAs may be used while breastfeeding because infant exposure has been found to be low and serious side effects in breastfed infants have not been observed, except for doxepin ( ). Nortriptyline is generally the preferred TCA for use with lactation due to its favorable safety profile. MAOIs are generally not used in breastfed infants as insufficient data are available about their use ( ). Limited data are available regarding the safety of serotonin modulators (trazodone, nefazodone, and vilazodone) in breastfed infants.

Nonspecific adverse signs to watch for in breastfed infants exposed to antidepressants include sedation, sleep disturbance, irritability, and poor feeding ( ). Strategies to limit infant exposure such as advising mothers to take antidepressants immediately after breastfeeding or discarding breast milk produced at the time of highest drug concentration are not recommended, as they can potentially make breastfeeding more stressful and are not evidence-based.

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