Antidepressants in pregnancy

17.1

Introduction

Depression is common among women during pregnancy, and although pregnancy is a time of increased health care utilization, it is likely as many as 66% of women affected during pregnancy are neither identified nor treated [ , ]. In an effort to accurately estimate the number of pregnant women with depressive disorders, Haight et al. (2019) examined US public databases to identify women admitted to inpatient facilities for the purpose of childbirth, who also had an ICD-9-CM diagnosis code for a depressive disorder as described in the Diagnostic and Statistical Manual of Mental Disorders , fifth Edition. In 2008, 4.1 women per 1000 had a diagnosis of depression; the rate increased to 28.7 per 1000 women in 2015 [ ]. Adding to the challenges of identifying depressive disorders during pregnancy is the fact that changes in appetite, sleep habits, energy level, and libido are normal symptoms during pregnancy, but may also be symptoms of depression [ ]. Women may avoid disclosing their feelings of depression for fear the baby may be removed from the mother's care [ ].

The size, complexity, and frequently inconsistent nature of the literature regarding the safety of psychotropic medications in pregnancy are daunting; consequently, many primary healthcare providers are reluctant to manage psychiatric illness during pregnancy. Untreated maternal depression may be associated with significant morbidity or even mortality for the mother–infant dyad [ ], and both psychiatric illness and psychotropic medication must be conceptualized as agents of fetal exposure [ ]. Prescribing psychiatric medication to pregnant women requires a complex risk–benefit calculus that balances the risks of untreated psychiatric illness to mother and fetus with the potential risks of medication use during pregnancy. This process ideally includes shared decision-making between the patient and psychiatric, obstetric, and primary care providers. However, significant shortages and uneven distribution of qualified behavioral health providers have resulted in many primary care providers being forced to assume sole management of treatment for depression during pregnancy [ ]. All health care providers who care for women during pregnancy need to be prepared to assess, diagnose, and treat the woman with depression in pregnancy. The goal of this chapter is to provide an overview of the management of depression during pregnancy and to summarize the most relevant issues impacting clinical decision-making.

Symptoms of depression include depressed mood or anhedonia for at least a 2-week period, accompanied by symptoms that include changes in sleep, appetite, energy, concentration, psycho-motor activity, feelings of guilt or worthlessness, and/or suicidal ideation [ ]. Diagnosis of depression in pregnant women is complicated by the similarity of normal symptoms of pregnancy to symptoms of depression; consequently, the presence of affective symptoms such as feelings of guilt or worthlessness, anhedonia, and thoughts of suicide may more strongly support a diagnosis of depression in pregnant women. Risk factors for developing perinatal depression encompass elements of a woman's genetics, hormonal/reproductive history, current stressors, and life experiences. Biologic factors that have consistently been associated with increased risk include a past history of depression or premenstrual dysphoric disorder and a family history of depression. Psychosocial factors, including stressful life events and lack of perceived social support, have consistently been found to predict perinatal depression [ ].

17.2

Effects of untreated perinatal depression on women and children

Untreated perinatal depression is associated with significant morbidity for mother–infant dyad via adverse obstetric outcomes related to poor maternal health, inadequate prenatal care, and postpartum depression [ ]. Poor nutrition, increased number of exposures to medications or herbal remedies, increased alcohol and tobacco use, and decreased compliance with prenatal care have been consistently associated with untreated psychiatric illness during pregnancy [ , ]. Data regarding specific adverse obstetric outcomes resulting from untreated depression during pregnancy are inconsistent. Miscarriage, fetal growth effects (low birth weight and intrauterine growth restriction), and preterm delivery have all been associated with untreated maternal depression. The strongest association appears to be with preterm birth; however, because of methodological limitations of the available data, it is not currently possible to draw definitive conclusions regarding associations between untreated maternal depression and these adverse reproductive outcomes [ , ].

In addition to the potential negative impact on pregnancy outcomes, perinatal depression is associated with increased irritability, decreased attentiveness, and decreased facial expressions in neonates. Children and adolescents born to depressed mothers are at risk for delayed cognitive and language development, lower IQ, and increased prevalence of psychiatric and emotional problems [ ]. Depression that begins during pregnancy frequently continues or worsens after delivery [ ].

17.3

Approach to treatment

Current guidelines created by a joint task force of the American Psychiatric Association (APA) and the American College of Obstetricians and Gynecologists (ACOG) recommend individual or group therapy as an initial treatment approach for pregnant women with mild to moderate depression [ ]. Additional nonpharmacologic interventions that may be recommended to women with mild depression include improved nutrition, exercise; eliminating nicotine, caffeine, and alcohol from the diet; good sleep hygiene; and reducing stressors and using relaxation techniques, support groups, and light therapy [ ].

For women who are unable to access or have not responded to nonpharmacologic interventions, who are experiencing an episode of moderate to severe depression during pregnancy, and/or who have a history of recurrent severe depression or suicidal ideation, initiation or maintenance of psychiatric medications is likely indicated [ ].

It is ideal to evaluate women with a history of psychiatric illness prior to pregnancy in order to generate an individualized treatment plan. However, since nearly 50% of pregnancies in US women ages 15–44 are unplanned, preconception evaluation is often not feasible in practice [ ]. Discontinuation of antidepressants during pregnancy is common and is associated with significant increase in relapse. In one large study, women who stopped antidepressants were five times as likely to have a relapse during pregnancy as women who continued their medication [ ]. Frequently, patient and physician concerns about potential teratogenesis or other negative neonatal outcomes overshadow consideration of the risks associated with untreated maternal psychiatric illness. This decision-making process is complicated by several factors, including varying fetal risks at different stages of gestation, inadequacy of the US Food and Drug Administration (FDA) medication categorization system, and limitations of currently available data regarding the safety of antidepressants in pregnancy [ ].

The approach to prescribing antidepressants in pregnancy can be guided by several general principles. The goal of treatment is remission of depressive symptoms, as inadequately treated depression subjects the fetus to risks associated with maternal illness and medication exposure. Choosing a medication with an established safety profile and a proven history of efficacy in the patient maximizes the potential for symptom response and minimizes potential risks to the fetus. One medication at higher dose is preferred to multiple medications at lower doses in order to decrease the total number of fetal exposures; pregnant women should receive the minimal effective dose of a single antidepressant [ , ].

Antidepressant dose requirements may increase across gestation as a consequence of induction of cytochrome enzymes 3A4 and 2D6 that increase drug metabolism in the second half of pregnancy [ , , ]. Although limited literature suggests levels of both tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) decrease in many women in late pregnancy, there is wide interpersonal variability in the pharmacokinetic changes of these medications across gestation. Currently, there are no evidence-based guidelines for altered dosing or therapeutic monitoring of antidepressants during pregnancy [ ]. Considering the possibility of increased antidepressant metabolism during pregnancy, women must be monitored closely for the re-emergence of depressive symptoms, especially during the third trimester. The possibility that some women may require higher doses of antidepressants in late pregnancy contradicts the clinical approach that advocates tapering antidepressants prior to delivery in hopes of mitigating potential adverse neonatal effects of medication use. Tapering antidepressants proximal to delivery has not been shown to decrease the potential risk of neonatal complications associated with medication use in late pregnancy [ ]. Discontinuing antidepressants has been associated with significant increase in relapse of depressive symptoms, and currently, neither the APA nor ACOG recommends tapering antidepressants prior to delivery [ , , ].

In addition to periodic assessment of antidepressant dose requirements across gestation, optimal management of perinatal mood and anxiety disorders includes recognizing the potential for postpartum illness. Women who are not already engaged in psychotherapy should be provided with referrals to begin depression-focused psychotherapy, specifically cognitive behavioral therapy (CBT) or interpersonal psychotherapy (IPT), both of which have been well studied for perinatal depression [ ]. Supportive dynamic psychotherapy has been less well studied in pregnancy but is a reasonable approach if CBT and IPT are not available [ ]. In addition to specific considerations regarding antidepressant use in pregnancy, prescribers should be familiar with current practice guidelines for the treatment of depression in general. There is no specific antidepressant that is better than another, and the choice of medication should be based on side effect profile, safety, tolerability, and previous response to medication in the individual patient [ ]. Antidepressants should be started at low dose and titrated over time to effectiveness; the speed of the titration depends upon the severity of associated side effects. Frequently, patients require 4–8 weeks of antidepressant treatment prior to experiencing moderate symptom reduction. Once remission of depression has been achieved, patients with fewer than three prior depressive episodes should be continued on antidepressants for a minimum of 4–9 months prior to considering discontinuation. Patients with three or more episodes of major depression may require maintenance antidepressant treatment indefinitely [ ]. Tapering antidepressants slowly over at least 2 weeks decreases both the risk of relapse of depressive illness and the severity of antidepressant discontinuation syndrome (flu-like symptoms, paresthesias, and insomnia) which is associated more strongly with SSRIs with short half-lives [ , ]. Decisions regarding tapering and discontinuation should be made in consultation with prescribing clinicians, if applicable, and patients should be monitored to assess for re-emergence of depressive symptoms.

17.4

Potential risks of selective serotonin reuptake inhibitor use during pregnancy

Due to their efficacy, tolerability, and safety profile, SSRIs are currently among the first-line pharmacologic treatments of major depression, and recent data suggest that up to 13% of US pregnancies have antidepressant exposure [ ]. All SSRIs indeed, all psychotropic medications, cross the placenta and are excreted in breast milk [ ]. The reproductive safety of SSRIs in pregnancy has been extensively studied. However, the data are often contradictory and limited by several factors, including the lack of randomized controlled trials, small sample sizes and limited power of many studies, the absence of information about disease state of the mother, and the failure to control for multiple confounding variables that impact reproductive outcomes [ ]. Currently available data in the major domains of reproductive toxicity will be summarized here.