Perinatal depression, which includes a depressive disorder during pregnancy or up to 1 year postpartum, affects approximately 1 in 7 women and is considered the most common complication of pregnancy and childbearing.1 In the United States, the prevalence of major depressive disorder during the perinatal period ranges from 8% to upward of 40% in the first year postpartum, with variability largely based on age, race/ethnicity, and other sociodemographic characteristics.2

The World Health Organization defines social determinants of health as nonmedical factors that impact health equity such as income, education, food insecurity, housing, early childhood development, social inclusion, and access to healthcare services.3 Using population-based data, researchers have demonstrated the risk of postpartum depression is significantly higher among younger women, those of American Indian/Alaska Native or Asian/Pacific Islander race/ethnicity, those with less than a high school education, as well as those without partner support.4,5 Other risk factors include a history of depression, a history of intimate partner violence, an unintended or unwanted pregnancy, lack of social support, and complications during pregnancy or in the neonatal period.6-9 The COVID-19 pandemic has further exacerbated these risks, with studies showing higher rates of psychiatric conditions (including depression, anxiety, and posttraumatic stress disorder) in perinatal women.10 Not only has the infection of COVID-19 carried a risk for adverse health outcomes but also social isolation protocols have required distancing from important social support networks and reduced access to care.10

Extant research has established the adverse sequelae of perinatal depression on maternal, neonatal, and early childhood outcomes. During pregnancy, depressive disorder is associated with lower levels of maternal-fetal attachment, inadequate gestational weight gain, and increased rates of substance use.11-13 Perinatal depression is also associated with an increased risk of preterm birth, low birth weight, and small for gestational age, known risk factors for neonatal morbidity and mortality.14 Infants born to women with perinatal depression are less likely to be breastfed, more likely to have inadequate preventive health services or safe practices, and more likely to exhibit cognitive and socioemotional delays.15-17 The influence of perinatal depression on early childhood development is largely due to poor maternal and infant bonding, less sensitive parenting practices, or a reduced ability to perceive and respond to the infant's behavioral signals.18-20

Despite the high prevalence and known adverse outcomes, perinatal depression often goes underdiagnosed and untreated. Research suggests that nearly 60% of women with depressive symptoms do not receive a clinical diagnosis, and half of women diagnosed with major depressive disorder do not receive any treatment.21 Multiple policies advocating for depression care within obstetric healthcare settings exist; yet, screening rates for depression remain low. The United States Preventive Services Task Force (USPSTF) recommends screening for all adults, including pregnant and postpartum women.22 Relatedly, the American College of Obstetricians and Gynecologists (ACOG) recommends universal screening for depression at least once during pregnancy and in the postpartum period, noting that screening alone is insufficient and treatment options must be discussed.23 Recognizing the risks of perinatal depression on childhood health, the American Academy of Pediatrics recommends screening for postpartum depression in pediatric primary care settings.24

Both the American Psychiatric Association (APA) and the ACOG outline treatment options for perinatal depression, including psychotherapy or antidepressant pharmacotherapy as initial treatment of mild to moderate perinatal depression.23 Research suggests that most women, during the perinatal period, prefer nonpharmacological approaches for the treatment of depression, largely due to conflicting information about the safety of antidepressant medications during pregnancy and the fear of being stigmatized.25 Research has demonstrated pregnancy to be a period associated with high rates of discontinuation of antidepressants due to concerns of effects of medications on fetal development.26 In addition, researchers have shown, through qualitative research, that women making decisions about pharmacotherapy for depression during the perinatal period experience high rates of decisional conflict including shame and guilt regarding the use of antidepressant medications.27

The decision to initiate or continue pharmacotherapy for perinatal depression should be made in close collaboration with pregnant and postpartum women. Specifically, a careful review of the potential obstetric and neonatal risks of untreated depressive symptoms against the risk of medication exposure is necessary. The purpose of this article is to discuss common treatments of perinatal depression, including potential risks and benefits associated with antidepressant medications during the perinatal period, and to review clinical guidelines provided by the ACOG, the APA, and the USPSTF.

Nonpharmacological therapies for perinatal depression

When perinatal depression is mild to moderate, the risk-benefit ratio often leans in favor of nonpharmacological treatments as reflected by guidelines worldwide.28 Many nonpharmacological therapies are beneficial for perinatal depression, including cognitive behavioral therapy (CBT) and interpersonal therapy (IPT). CBT and IPT are the most widely used nonpharmacological therapies for major depression and are empirically supported for perinatal depression.29 Specifically, CBT and IPT can be effectively provided for high-risk pregnant women, including those in minority and low-income populations.30,31 The USPSTF recommends providers refer pregnant and postpartum women for counseling services if they have 1 or more of the following risk factors: a history of depression, current depressive symptoms, and/or socioeconomic risk factors such as low income, recent intimate partner violence, elevated anxiety, or a history of significant negative life events.32

CBT can be used to treat many conditions including depression, anxiety, and obsessive-compulsive disorders.33 It is problem focused and aims to find behavioral solutions for distress. CBT encourages a person to consider his or her own thoughts, attitudes, expectations, and behaviors and to identify negative thought patterns and maladaptive behaviors.33 Techniques are then learned in order to change the unwanted thought patterns and behavioral habits. CBT has been widely utilized as treatment of women with perinatal depression, with variations in strategies that focus on behavioral and/or cognitive components.

"Third-wave" cognitive behavioral therapies, such as acceptance and commitment therapy, mindfulness-based cognitive therapy, and problem-solving therapy, emphasize specific aspects of mental health including an individual's relationship with his or her own thoughts and adaptive skills for problem solving. A meta-analysis of CBT use for prevention and treatment of perinatal depression found that CBT was effective, particularly during the postpartum period and for first-time postpartum women who may have difficulty applying skills learned during pregnancy.34 In addition, though individual therapy was found to be more effective than group interventions for reducing symptoms of depression, group interventions were noted to be a source of social support for women during pregnancy and postpartum and can provide a cost-effective way for accessing mental healthcare.34

IPT focuses on improving social functioning and interpersonal relationships to help reduce stress.35 An example of a strategy used in IPT may focus on reviewing a woman's symptoms of depression and relating these symptoms to recent conflicts or disputes with a significant other. In addition, patterns of conflict in relationships or difficulties associated with recent role changes may be discussed.36 IPT can be well suited for perinatal women, with evidence showing a reduction in depressive symptoms and an improvement in relationship quality.37 Specifically, IPT has been reported to improve communication in relationships, which can play an important role in marital satisfaction.37 Nonpharmacological therapies, including CBT and IPT, can be effective for perinatal depression, with evidence demonstrating the greatest benefit in reducing depressive symptoms occurs in therapies with an interpersonal component.30,38-40

Antidepressant medications for perinatal depression

Antidepressant medication is recommended as first-line treatment of moderate to severe depression and may also be prescribed for mild depression if a woman declines psychological therapy, prefers medication treatment, or has a history of severe unipolar depression.41 Selective serotonin reuptake inhibitors (SSRIs), serotonin/norepinephrine reuptake inhibitors (SNRIs), and norepinephrine/dopamine reuptake inhibitors (NDRIs) are most frequently prescribed and work by inhibiting the reuptake of monoamines (ie, serotonin, norepinephrine, dopamine) by their respective monoamine transporters.42 The monoamine hypothesis posits the pathophysiological basis of depression is a depletion of serotonin, norepinephrine, and/or dopamine within the central nervous system (CNS).43 Although the exact mechanism of depression is unknown, blocking the reuptake of monoamines by antidepressant agents appears to significantly reduce symptoms of depression and has led to the development of the monoamine hypothesis.43 Tricyclic antidepressants (TCAs) block the reuptake of serotonin and norepinephrine and have been effective for reducing symptoms of depression; however, these medications are prescribed less frequently due to the potential for toxicity.42 In cases of severe refractory depression, second-generation antipsychotic (SGA) medications can be used as an adjunctive therapy, but caution is advised during the perinatal period.

All psychotropic medications appear to cross the placenta and have raised concern regarding fetal exposure.44 In 2015, the US Food and Drug Administration (FDA) published the "Pregnancy and Lactation Labeling Rule" (PLLR), which required changes to the format on all prescription drug labels to allow healthcare providers to better assess and discuss the benefits and risks of medication use during pregnancy and lactation.45 The PLLR replaced the letter categories A, B, C, D, and X, with subsections including "Pregnancy," "Lactation," and "Females and Males of Reproductive Potential." These subsections include a risk summary, current safety data, and clinical considerations that are important for providers to discuss with their patients. The following section reviews common classes of antidepressants used during the perinatal period and discusses findings within the literature regarding potential obstetric and neonatal risks associated with specific medications from each drug class (see Table 1).

Table 1. Antidepressant medications for perinatal depression

Selective serotonin reuptake inhibitors

SSRIs have dramatically transformed psychopharmacology and are commonly used as first-line medication therapy for major depressive disorder.41 Many healthcare providers prescribe SSRIs because they are well tolerated by patients in comparison with older antidepressant medications.46 The SSRI drug class consists of 6 medications including fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram. Each medication has unique secondary pharmacological characteristics; however, all SSRIs share the same major benefit to inhibit serotonin reuptake selectively and potently.42

Many studies have examined obstetric and neonatal risks associated with SSRI exposure; however, findings have been mixed.47 Studies reporting adverse obstetric outcomes such as preeclampsia, preterm birth, and postpartum hemorrhage have raised significant concern regarding use of SSRIs during pregnancy.48-50 However, a large cohort study of 100 942 pregnant women with depression did not find an association between SSRIs and preeclampsia but rather determined a higher risk among women who used SNRIs and tricyclic medications as monotherapy during pregnancy.51 A large meta-analysis also determined that the risk for preterm birth was no longer significant when compared with newborns of women with untreated depression during pregnancy.52

Regarding adverse neonatal outcomes, evidence of persistent pulmonary hypertension of the newborn (PPHN), low birth weight, and congenital defects has been inconsistent and may differ on the basis of the timing of gestation.53-56 Specifically, data show that SSRI use in the second half of pregnancy is associated with an increased risk of PPHN.53 In 2015, the Centers for Disease Control and Prevention (CDC) found 5 birth defects (anencephaly, atrial septal defects, right ventricular outflow tract obstruction defects, gastroschisis, and omphalocele) associated with the use of paroxetine and 2 birth defects (right ventricular outflow tract obstruction defects and craniosynostosis) associated with the use of fluoxetine during early pregnancy.54 The CDC reported reassuring evidence, however, that birth defects were not associated with most SSRIs.54 In a large cohort study of 64 389 women who used an SSRI medication in their first trimester, Huybrechts and colleagues55 reported no significant association between right ventricular outflow tract obstruction and paroxetine or ventricular septal defects and sertraline. Other studies examining offspring neurobehavioral outcomes, such as autism spectrum disorder and attention-deficit/hyperactivity disorder (ADHD), have been inconclusive and additional rigorous research is needed.57

The risk for adverse neonatal events during breastfeeding is generally low with the use of SSRI medications; however, differences exist in the transferability of these medications through breast milk. Sertraline is considered to have favorable pharmacokinetics that make this drug one of the preferred SSRI medications during breastfeeding.58 Conversely, fluoxetine is found to have a higher infant dose through breast milk as compared with other SSRI medications and is not considered as favorable during this time.58 Citalopram and escitalopram are considered intermediate between sertraline and fluoxetine and have been linked to adverse effects including excessive somnolence, decreased feeding, and infant weight loss.58,59 Although SSRI medications are thought to be generally safe during pregnancy and lactation, providers should discuss potential risks with their patients as described on FDA medication labels.

Serotonin/norepinephrine reuptake inhibitors

SNRIs are often second-line treatment of depression if SSRIs have not been effective. They inhibit the reuptake of both serotonin and norepinephrine, allowing for increased concentration of these monoamines at the synaptic cleft.42 Commonly used SNRI medications include venlafaxine, duloxetine, and desvenlafaxine, and tolerability varies by each drug.57 SNRIs are a newer antidepressant group; thus, recommendations during pregnancy are often extended from knowledge of SSRI use.

In a few studies involving SNRIs, adverse obstetric outcomes of gestational hypertension and preeclampsia have been examined. Specifically, De Ocampo and colleagues60 found that continued use of SNRIs after 20 weeks' gestation to be significantly associated with gestational hypertension. Women using 2 or more antidepressants were also at a higher risk for preeclampsia.60 The authors found no elevated risk of gestational hypertension or preeclampsia for those who discontinued treatment before 20 weeks' gestation.60

Regarding adverse neonatal outcomes, findings have been mixed. Some studies have reported no association between SNRI use during pregnancy and outcomes of neonatal maladaptation and congenital malformations,61,62 while 2 studies have found adverse neonatal outcomes associated with the use of venlafaxine and duloxetine during pregnancy.63,64A study by Anderson and colleagues63 demonstrated birth defects associated with the use of venlafaxine, while Marks and colleagues64 found higher rates of maladaptation and neonatal intensive care unit admissions for use of duloxetine early in pregnancy. Nonteratogenic effects have also been associated with venlafaxine and desvenlafaxine use during pregnancy and lactation including transient outcomes of respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.65 Long-term neurodevelopmental outcomes (such as offspring ADHD) are considered unlikely; however, elevated risk throughout childhood and adolescence needs to be further elucidated.66

During lactation, moderate amounts of SNRI drugs can be found in breast milk and warrant caution during this time.67 Findings show desvenlafaxine has a higher concentration in breast milk than venlafaxine, though no serious adverse effects are reported.58 Research demonstrates a few cases of drowsiness and agitation with the use of venlafaxine or desvenlafaxine during breastfeeding.68 Limited data show infant serum concentrations of duloxetine to be lower than those of venlafaxine and desvenlafaxine and adverse reactions have not been reported.58

Norepinephrine/dopamine reuptake inhibitors

NDRIs, such as bupropion, are not often prescribed as first- or second-line therapy but are considered if other antidepressants have not been effective.69 A systematic review of bupropion use during pregnancy found an elevated risk of cardiovascular defects in the first trimester, although the absolute risk for these outcomes was generally low and confounding effects (eg, use for smoking cessation) were noted.70 No significant associations were found regarding outcomes of low birth weight and preterm birth; however, higher rates of spontaneous abortion were noted in a few studies.70 One case of seizures is reported in a 6-month-old infant68,71; however, plasma concentrations of bupropion in breast milk are considered to be generally low to undetectable.68,72 The FDA recommends caution with the use of NDRIs during pregnancy and the lactation period and careful review of the data regarding potential adverse effects.

Tricyclic antidepressants

TCAs have been used to treat depression for decades and were particularly effective in treating melancholic depression beginning in the late 1950s. TCAs, such as amitriptyline, amoxapine, doxepin, nortriptyline, and clomipramine, were commonly prescribed as first-line treatment of depression before the introduction of SSRIs in 1987. These medications work by blocking the reuptake of serotonin and norepinephrine, which helps improve mood and concentration.42 Because of a narrow therapeutic index, there are concerns regarding toxicity with the use of these medications. Particularly, TCA use has been associated with higher rates of overdose, hospitalizations, and fatalities than with other antidepressants.73

During pregnancy, TCA use has been associated with an increased risk for preeclampsia. Specifically, Tran and colleagues74 reported an increased risk for late-onset preeclampsia or preeclampsia occurring after 34 weeks of gestation. Regarding adverse neonatal outcomes, findings have been mixed. One study reported outcomes of congenital eye, ear, face, neck, and digestive defects75 with use of TCAs during pregnancy and another found Clomipramine to be particularly associated with more severe outcomes of neonatal cardiac defects.76 On the other hand, a recent systematic review of TCA uses during pregnancy found no substantial evidence to suggest significant negative effects on fetal development including congenital anomalies or long-term neurodevelopmental problems.77

During breastfeeding, less research has been done to understand the effects of TCAs in comparison to other medications such as SSRIs. TCA dose in breastmilk appears to be consistent among these drugs and are generally low to undetectable in infant serum.58 Limited data shows adverse effects may occur with amitriptyline and doxepin and should be considered with caution.68 Per Uguz,78 amitriptyline can be associated with extreme drowsiness and should be monitored. Doxepin is often avoided during breastfeeding as studies have reported an 8 week old infant pale, limp, and somnolent after a maternal doxepin dose was increased from 10mg daily to 25mg three times per day and a 9 day old breastfed infant with poor sucking and swallowing, hypotonia, vomiting and weight loss after maternal dose of 35mg of doxepin daily at bedtime.68 Most TCAs are considered moderately safe during breastfeeding, however, careful review of the data and potential adverse effects with use of specific medications is warranted.

Second-Generation antipsychotics (SGAs)

SGAs (e.g. aripiprazole, quetiapine, olanzapine, risperidone) can be used as an adjunctive treatment for refractory major depression; however, during pregnancy, these medications are initiated or continued with caution as there is still a large gap in data regarding their reproductive safety. In review of SGA use during pregnancy, findings demonstrate an increased risk for obstetric outcomes including pregnancy hypertension and shorter gestation.79 Additionally, adverse neonatal outcomes have been examined including congenital malformations, lower birth weight, neonatal maladaptation and admissions.79,80 Specifically, authors have reported adverse neonatal complications including congenital cardiac malformations and lower birth weight with use of risperidone and paliperidone.80 Evidence also suggests an increased risk of lower birth weight and higher rates of neonatal admissions with use of aripiprazole during pregnancy.79

All SGA medications have been found in breast milk though direct adverse effects of infant exposure are rare.68 Maternal doses of olanzapine up to 20mg daily have shown low to undetectable medication levels in infant serum; however, in some cases, infant sedation has occurred.68 Due to obstetric and neonatal adverse outcomes reported in human studies, caution is advised with use of SGAs during pregnancy and in the lactation period.

Guidelines from leading organizations

The ACOG defines perinatal depression as at least one major or minor depressive episode during pregnancy or in the first year after delivery.23 Current practice guidelines from the ACOG recommend obstetric care providers screen women for depression and anxiety at least once during the perinatal period using a standardized, validated screening tool such as the Edinburgh Postnatal Depression Scale (EPDS), the Patient Health Questionnaire 9, the Beck Depression Inventory and/or the Center for Epidemiologic Studies Depression Scale. The EPDS is used most frequently in clinical practice settings since it is often quick for patients to complete and has been translated into over 50 languages.23 The EPDS also assesses symptoms of anxiety which is a common comorbid condition. In addition to an initial screening, the ACOG recommends providers complete a comprehensive assessment of maternal mood and emotional well-being during a postpartum visit.

The ACOG and the APA developed guidelines for treatment of perinatal depression including behavioral therapies and antidepressant treatment. For women with mild to moderate perinatal depression, treatment with psychosocial approaches including individual and/or group psychotherapy is recommended.41 The ACOG and APA recognize cognitive behavioral therapy, and interpersonal psychotherapy as effective options for treatment of perinatal depression particularly for women with residual symptoms, those at high risk of relapse, those with comorbid conditions and those who prefer to avoid medication therapy.41 The USPSTF also recommends counseling services for women at risk for perinatal depression.81 In review of current evidence, the USPSTF concluded there is a moderate benefit of counseling interventions in preventing perinatal depression and this benefit should be discussed in clinical settings with pregnant and postpartum women.81

Regarding antidepressant treatment, the ACOG and APA provide recommendations for use of antidepressant therapy during preconception, pregnancy, and postpartum. For women presenting with symptoms of depression prior to conception, providers are recommended to screen for the severity of depression and to determine if the symptoms are moderate to severe.41 For instances in which aggressive antidepressant treatment is required, women are recommended to wait until a euthymic mood is achieved prior to attempting to conceive.41 Continued use of an antidepressant medication for at least six months after remission is recommended to prevent relapse and treatment failure.82 Women who have improved with medication treatment and show mild to no symptoms of depression for at least six months may be candidates for a medication taper with close monitoring for relapse.82 For those with recurrent depression, providers are recommended to continue psychotropic medication and coordinate care to achieve optimal prophylaxis during the perinatal period.41

If starting an antidepressant during pregnancy, providers are recommended to start with the lowest possible dose and avoid the use of newer antidepressant therapies in the first trimester due to a lack of conclusive safety information about these agents during pregnancy.41 The treatment of choice should depend on the safety profile of the medication, the stage of gestation, medication history, and the desired therapeutic effect. For pregnant women continuing use of an antidepressant prescribed prior to pregnancy, the ACOG and APA recommend providers discuss the risks and benefits of the antidepressant medication and consider whether it is more beneficial to continue using the medication or if a substitute medication should be initiated.41 If the patient desires to discontinue treatment in favor of nonpharmacological methods, providers should consider an appropriate taper regimen and monitor the patient closely for symptoms of relapse.

Breastfeeding continues to be promoted by all major organizations throughout the first year of a child's life to promote health and reduce adverse outcomes.83 Transferability of most antidepressant medications through breastmilk is considered low to undetectable, however, providers should discuss the risk-benefit ratio with patients for informed decision making.84

DISCUSSION

Perinatal depression is a common complication of pregnancy and childbirth and has the potential for serious consequences including obstetric complications and adverse neonatal health outcomes. Health care providers should screen all pregnant and postpartum women for depression as recommended by leading health care organizations and provide women with information regarding appropriate treatment options. Moreover, health care providers must understand the impact of stigma as a potential barrier to mental health discussions in the clinical setting. Stigma, whether internal (e.g. self-identification as a failure) or external (e.g. being perceived as a "bad mother"), may be viewed by women as a consequence for disclosing symptoms of perinatal depression.85,86 Studies suggest women may fear disrespect or judgement by health care providers as well as the possibility of losing their child (or children) to child protective services.87-90 Stigma and perceived consequences of treatment are important hindering factors that can lead to poor engagement in mental health services and, in turn, adverse obstetric and child health outcomes.91

To provide optimal care for women with perinatal depression, Kimmel and colleagues92 suggest further development of research guidelines and best practices is crucial to meet the needs of diverse populations. Specifically, the authors suggest the development of standardized frameworks by diverse stakeholders is necessary to better characterize perinatal depression and optimize treatment.92 In addition to guidelines provided by ACOG, APA and USPSTF, the Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN) recommends mental health screening tools be made available in every clinical setting and a response protocol be established based on local resources.93 Further, the American College of Nurse-Midwives recognizes perinatal depression as an important public health issue and maintains public health policies should resolve disparities among racial and socioeconomic groups.94

CONCLUSION

Health care providers are recommended to review current guidelines and provide women with support and information regarding treatment options for perinatal depression. Discussions regarding treatment should be patient centered with consideration for the risk of untreated depression, symptom severity, the stage of gestation and maternal preference. Nonpharmacological therapies, including CBT and interpersonal therapy, are recommended as first line treatment for women with symptoms of mild to moderate perinatal depression.41 In cases of moderate to severe depression, patients and providers should discuss the risks and benefits of medication use and an appropriate plan of care. Evidence regarding adverse effects of antidepressant medication during the perinatal period is inconsistent, thus, recommendations are to weigh the pros and cons of medication therapy during this time.

References