Contemporary management of unipolar depression in the perinatal period

Abstract

Introduction:

There is increasing recognition that antenatal depression and postpartum depression are highly prevalent and have significant impact on maternal and child health.

Areas Covered:

In the initial part of the manuscript, the authors review the epidemiology of antenatal and postpartum depression and its impact on maternal and child health. The later part of the manuscript reviews the current status of the medical management and psychosocial interventions targeting perinatal depression.

Expert Opinion:

Perinatal depression is the focus of several studies with increasing interest in developing effective interventions. While several psychosocial interventions targeting maternal depressive symptoms during pregnancy and postpartum are available, more studies are needed to address the need for safe and efficacious strategies for the use of antidepressant medication during pregnancy and in the postpartum period.

1. Introduction

Perinatal depression is described as a depressive episode occurring during pregnancy or till one year after childbirth or both. Some define perinatal depression as a non-psychotic mild or moderate depressive episode during the pregnancy or postpartum period [1]. Consensus definition of perinatal depression is maternal depression arising during any period from conception to the end of the first postpartum year [2,3]. Perinatal anxiety disorders are common and can occur as a comorbid condition with perinatal depression. This review focuses on contemporary management of unipolar depression during the perinatal period and includes both the use of antidepressant medications as well as psychosocial interventions.

According to a meta-analysis of 96 studies from both high income and low middle income countries (LMICs), the global prevalence of perinatal depression was 11.9% [2]. A recent meta-analysis noted that one in every four women in LMICs experienced depression during pregnancy [4]. While the World Health Organization (WHO) recommends screening of depression and other common mental disorders as part of routine antenatal care [5], identification of antenatal depression in LMICs is low. Lack of guidelines and protocols for identification and management of depression and paucity of culturally valid screening instruments complicate the picture in LMICs. US Preventative Service Task Force (USPSTF) recommends routine screening for depression in all pregnant and postpartum women in the US in the presence of existing treatment protocols and availability of expertise from clinicians in the management of depression. It aims at reduction of prevalence of depression to half among postpartum women [6].

Maternal depression is associated with several adverse health outcomes for both the mother and the child. Untreated antenatal depression can result in inadequate maternal weight gain during pregnancy, maternal malnutrition and irregular antenatal visits, antenatal hemorrhage, pre-term delivery and low birth weight [7]. It is also associated with an increased risk for pre-eclampsia and adverse cardiovascular outcomes in women [8,9]. Infants born to women with antenatal depression are at an increased risk for low birth weight, intrauterine growth retardation (IUGR), and premature delivery, and premature death of fetus [10,11]. In addition, antenatal depression is associated with adverse neurocognitive outcomes like receptive language deficit in infants [12] and an increased rate of childhood internalizing and externalizing disorders [10].

Postpartum depression is associated with an increased risk of suicide and intentional self-harm and is one of the leading causes of maternal mortality during the first year of the postpartum period [13]. Prevalence of suicidal ideation during the pregnancy and postpartum period is around 5 to 14% [14]. In addition, women with suicidal ideation during pregnancy or the postpartum period are at a higher risk of developing postpartum depression. Factors associated with suicidal ideation during the pregnancy and postpartum period include severe perinatal depression, past history of perinatal depression, unplanned pregnancy and younger maternal age [15].

Untreated postpartum depression adversely impacts child health that include among others non-adherence to immunization schedules, stunted growth [16], and increased rates of hospitalization due to diarrhea and pneumonia [17,18]. Postpartum depression can affect the initiation or duration of breast feeding [19]. In addition, postpartum depression is known to be associated with behavioral and temperamental difficulties in children [20,21]. Studies have also reported that postpartum depressive symptoms impair child’s learning, acquisition of milestones and overall cognitive and language development [22]. Children exposed to postpartum depression are at an increased risk of developing depression at an early age compared to children not exposed to postpartum depression [23]. Thus, antenatal and postpartum depression is associated with several adverse health consequences for both the mother and the offspring.

2. Epidemiology

In high income countries, the prevalence of antenatal and postpartum depression ranges from 8% to10% [2]. In LMICs, the prevalence of both antenatal depression and postpartum depression is much higher with reported prevalence of antenatal depression being 16 –26% and postpartum depression being 16–35%, respectively [24,25]. Overall pooled prevalence of perinatal depression across both high and low income countries is estimated to be 11.9% [2].

2.1. Risk factors

Several factors have been noted to increase the risk for the development of antenatal depression. These include unplanned and unwanted pregnancy, intimate partner violence, childhood sexual abuse, lack of empathy from partner, lower level of maternal education, poor physical health, lower socio economic status, poor social support, past history of a mental disorder, past history of obstetric complications, and more number of children in the family [25,26].

Risk factors linked to postpartum depression include perceived lack of support from spouse, previous history of psychiatric illness, antenatal depression, prenatal anxiety, lower level of maternal education, and adverse life events. In addition, adverse birth outcomes such as low birth weight and preterm delivery and poor infant health increase the risk for postpartum depression [27]. In LMICs, social factors like hostile in-laws, birth of a female child, role restrictions due to female gender, and restriction in autonomy of procreation is associated with an increased risk for postpartum depression [1,25].

3. Neurobiology of perinatal depression

Several gene candidates, neuroendocrine hormones, and neurotransmitters have been implicated in the pathophysiology of perinatal depression. Polymorphism in estrogen receptor gene ESR 2 [28], serotonin transporter gene 5HTT [29], MAO A gene [30], tryptophan hydroxylase 2 [31] and gene coding for oxytocin [32] have been described to be associated with an increased risk for postpartum depression. Others have suggested epigenetic modification of heterochromatin protein 1 and estrogen signaling molecule gene as possible biomarkers for postpartum depression [19,33].

Several neuroendocrine hormones like ovarian steroids have been implicated in the pathogenesis of perinatal depression. Reduced levels of gonadal steroids and oxytocin concentration in mid-gestation have been implicated in postpartum depression [34,35]. Exposure to oxytocin in the perinatal period increases the risk for postpartum depression [36]. Studies have reported decreased responsiveness to dexamethasone suppression test in women with postpartum depression suggesting dysfunction of HPA axis [37]. A recent study noted that plasma GABA levels were lower and progesterone and pregnanolone levels were higher in women at risk for postpartum depression compared to healthy controls and the interactions between GABA and neuroactive steroids may have a role in the pathophysiology of postpartum depression [38].

Functional neuroimaging studies done in women with postpartum depression have revealed decreased activity in orbitofrontal cortex, striatum, amygdala and anterior cingulate cortex in response to infant related stimuli or specific tasks [39,40]. Women with postpartum depression showed reduced activity in anterior cingulate cortex when they saw their infant’s distressed faces and decreased activity in insula and orbitofrontal cortex when they saw their infant’s happy faces [39]. Further studies are needed to elucidate neurobiological underpinnings of perinatal depression.

4. Clinical features

4.1. Antenatal depression

Women with antenatal depression present with loss of interest, low mood, reduced concentration, sleep disturbance and suicidal thoughts [41]. However, they also exhibit symptoms that overlap with symptoms of pregnancy like somatic symptoms, fatigue, reduced energy, changes in sleep and appetite [42]. Some studies have reported that depression is more common in the first and the last trimester of pregnancy compared to the second trimester [43]. While the increased rates of depression in the first trimester of pregnancy could be due to the new life event of becoming a mother, unplanned pregnancy is another risk factor for early occurrence of depression [44]. Antenatal depression also increases the risk for recurrence of depression in subsequent pregnancies [41].

4.2. Postpartum depression

The course and presentation of postpartum depression is highly heterogeneous. Postpartum blues are common in two thirds of women and they present with mild exhaustion, mood swings, anxiety, irritability and tearfulness. They typically begin 3–4 days after childbirth and resolve in few hours to few days. They generally do not require any intervention. One of the distinguishing features between postpartum depression and postpartum blues is that the latter is transient, while postpartum depression is persistent and longer lasting with adverse impact on child-care and the mother’s overall functioning. Some women with postpartum depression report suicidal ideation and are at an increased risk for suicide [45]. While in majority of women, postpartum depression improves within 3–6 months after childbirth, some longitudinal studies have shown that in about 30% of women, depression persists beyond the first postpartum year [46] and can even persist up to several years after child birth [47]. Poor marital relationship, inadequate maternal care, sexual abuse and financial constraints, and personality factors like trait anxiety, self- criticism and problems managing role demands were predictive of persistent depressive symptoms in the postpartum period [46]. In LMIC settings, poverty, lower level of education, having five or more children and lack of perceived support have been shown to be associated with persistent depression in the postpartum period [48].

The risk of developing depression is high during the first three months of the postpartum period [49,50] and risk of hospitalization for any mental disorder is highest between 10 and 19 days in the postpartum period [51]. Anxiety symptoms, in comparison to sad mood are more prominent in women with postpartum depression. They can also present with irritability, mood fluctuations, crying spells and insomnia [52]. Others have noted features like worries about baby’s well-being and ability to care for the newborn as being specific to postpartum depression [46]. Depression occurring during the postpartum period increases the risk for later occurrence of depression and bipolar affective disorder [53].

In summary, postpartum depression is highly prevalent and impacts both maternal and child health and in some women, postpartum depression is persistent and increases the risk for later development of depression. Thus, it is critical to provide prompt and appropriate intervention for women with post-partum depression.

5. Assessment and screening

Antenatal depression is missed frequently because physical symptoms like impaired sleep, appetite and fatigue are common during pregnancy. Women may not report depressive symptoms while they are expected to embrace pregnancy without any guilt due to the fear of being stigmatized [54]. Findings from the US Preventative Services Task Force study showed a reduction in new onset depression in the postpartum period by 45–64% through the introduction of routine screening for depression in the antenatal period, particularly in the presence of additional treatment support [6]. Screening of depression can be done during the first antenatal visit and then in the third trimester of pregnancy as antenatal depression is more common in the first and last trimester [43] and later at 6 weeks postpartum, as obstetrician routinely conduct health examinations and discuss family planning options at approximately 6 weeks after birth and this time period is well-positioned to identify postpartum depression [55]. However, screening of depressive symptoms among pregnant women can be impacted by fear of disclosure because of stigma and attitude to mental illness, and/or due to lack of awareness [56]. In addition, in several societies, motherhood is idealized leading to unrealistic expectations from pregnant or postpartum women [57]. In low resource settings, systemic factors such as lack of easy access to antenatal health services, cost associated with health care and child care needs may also act as significant barriers to seeking mental health care during the perinatal period [57,58]. In LMICs, overcrowded and busy antenatal healthcare services often do not have adequate time to screen for mental health problems during pregnancy [59]. Furthermore, lack of trained mental health personnel in antenatal services often result in low rates of screening [60]. In developed countries, collaborative care approaches that involve a close liaison between mental health professionals and antenatal health care providers were found to be useful in mitigating depressive symptoms and improving functioning among socially disadvantaged women [61]. In low resource settings, task shifting by training primary and community health workers in the screening and treatment of mental health disorders was found to be acceptable and feasible [62] and this approach has recently been extended to screening and treatment of perinatal depression [63,64].

5.1. Antenatal depression

American College of Obstetricians and Gynecologists have recommended several screening measures that can be used to identify depression during pregnancy. These include the Edinburgh Postnatal Depression Scale (EPDS) [65], the Patient Health Questionnaire-9 (PHQ-9) [66], the Beck Depression Inventory (BDI) [67], and the Center for Epidemiologic Studies Depression Scale (CES–D) [68]. Among these, EPDS is the most widely used screening tool [69] including in low resource settings and is validated for use among pregnant women [70,71]. The MINI (Mini International Neuropsychiatric Interview) plus [72] is one of the most widely used diagnostic tools to confirm a diagnosis of perinatal depression [73,74]. Others have used Structured Clinical Interview for DSM IV TR [75–77], Schedule for Clinical Assessment in Neuropsychiatry [78,79] and Schedule for Affective Disorders and Schizophrenia [80,81] to confirm psychiatric diagnosis in the perinatal period. However, administration of psychiatric diagnostic interviews is time-consuming and has a high rate of non-completion of interviews among less advantaged women during the perinatal period [77]. In addition, screening tools compared to structured diagnostic interviews are better able to identify functional impairment among women with perinatal depression. Further studies are needed to justify the routine use of diagnostic interview schedules to confirm a diagnosis of depression in the perinatal period.

Studies have reported associations between several chronic medical conditions such as diabetes and hypertension, and perinatal mental illnesses [8]. A systematic review also noted an association between elevated titers of thyroid autoantibodies in early and mid-pregnancy and an increased risk for depression [82]. Thus, it is important to screen for chronic medical conditions in women presenting with depressive symptoms during the perinatal period.

5.2. Postpartum depression

EPDS [65] or PHQ-9 [66] is the recommended screening tools for identifying postpartum depression [83]. However, there is no clear consensus about the timing of screening for depression in the postpartum period.

6. Medical management of depression during pregnancy

Clinical decision to initiate treatment with antidepressant medication for antenatal depression depends on multiple factors. Factors guiding the initiation of antidepressant treatment during pregnancy are current severity of depressive symptoms, past psychiatric history, past attempts at tapering medication in previous episodes, availability of resources for psychotherapy, presence of social support, and current risk of suicide [3,84]. Risk-benefit analysis of the use of antidepressant medication for treatment of antenatal depression is a critical first step before initiating treatment. Adverse consequences of in-utero exposure to antidepressants on fetus like congenital defects, neurodevelopmental sequel and unfavorable birth outcomes should be weighed against the impact that untreated maternal depression has on the fetus [10].

6.1. Effects of in-utero antidepressant exposure on the child

6.1.1. Congenital defects

Some studies have noted an association between the use of specific serotonin reuptake inhibitors (SSRI) during pregnancy and an increased risk of cardiovascular birth defects [85,86]. A population based study from Denmark showed a modest increase in Atrial Septal Defect (ASD) in children of women who were exposed to any SSRI except escitalopram during the first trimester of pregnancy. However, the risk was small in absolute terms (2 cases per 1000 births) [87]. Health register based data from Denmark, Finland, Norway and Sweden covering the period from 1996 to 2010 among 36,772 births showed that 3.7% of infants who were exposed to SSRI like fluoxetine, fluvoxamine, sertraline, citalopram and escitalopram, and specific norepinephrine reuptake inhibitor (SNRI) like venlafaxine during pregnancy had congenital malformation compared to 3.1% of infants in the non-exposed group [88]. Thus, the use of SSRI or SNRI was not associated with an increased risk for cardiovascular birth defects, or other congenital birth defects. Similarly, a recent meta-analysis did not show any significant association between SSRI exposure during pregnancy and the risk of congenital malformations in the newborn [89].

6.1.2. Neurodevelopmental sequelae

A recent systematic review noted that the use of antidepressants like SSRI, SNRI, and TCA in women during pregnancy was not associated with an increased risk for attention deficit hyperactivity in children [90]. Similarly, a review that included case control and cohort studies of women with history of antenatal depression did not find an increased risk for ADHD and autism spectrum disorder among children exposed to antidepressant during pregnancy [91]. Current evidence from available studies about the association between antidepressant exposure during pregnancy and an increased risk for disorders like autism and ADHD in children are limited by factors like total duration of exposure of antidepressants during pregnancy, the timing of initiation of antidepressant treatment during pregnancy and lack of information on various confounding factors like genetic vulnerability, environmental and lifestyle factors [92]. A meta-analysis that examined the association between antidepressant exposure in utero and motor development in children did not find any clinically significant difference on standardized measures of motor development between the exposed and non-exposed groups of children from birth to 6 years [93]. A recent systematic review examined the association between the use of SSRIs like sertraline and fluoxetine, and venlafaxine during pregnancy and short term outcomes in neonates like autonomic stability, reflexes, motor movements, and sleep in infants of 6–8 weeks and long term outcomes among children that included emotional difficulties, conduct symptoms, hyperactivity, attention and developmental milestones like motor and language acquisition [94]. The study concluded that there were no clinically significant differences in any of the short term and long-term outcomes between exposed and non- exposed group of children. However, majority of the studies that were included in the meta-analysis had small sample sizes and were not adequately powered.

7. Antidepressant exposure during pregnancy and maternal outcomes

Exposure to antidepressants during pregnancy may be associated with an increased risk of pre- eclampsia and eclampsia [95] and shorter period of gestation with an early onset of labor [96]. There seems to be an increased risk of pregnancy induced hypertension in women exposed to SSRI during the first 5 months of gestation [97]. In a prospective longitudinal study from Canada that recruited 6761 pregnant women with singleton pregnancies, 3.2% of women were exposed to antidepressant medication like SSRI, SNRI and TCA and/or anxiolytic medication like benzodiazepines before 16 weeks of pregnancy. Women who were exposed to antidepressants or anxiolytic medication during early pregnancy had an increased risk of pre-eclampsia (OR 3.41, 95% CI, 1.66,7.02) when compared to the non-exposed group of women (OR 1.60, 95% CI, 0.21,12.3) [98]. The use of antidepressants like amitriptyline and venlafaxine appear to increase the risk for gestational diabetes [99].There is a slightly increased risk of spontaneous abortion with antidepressants and this risk seems to be specifically associated with the use of paroxetine and venlafaxine during pregnancy [100,101]

8. Antidepressant exposure during pregnancy and birth outcomes

There is conflicting data regarding antidepressant exposure in utero and birth outcomes. A recent meta-analysis [102] found an association between antidepressant use and adverse birth outcomes like low birth weight, pre-term labor and increased rates of admissions to neonatal intensive care units (NICU). In a retrospective study of 2.2 lakhs deliveries in United States, 6% of the pregnant women were exposed to antidepressant medication [103]. All antidepressants were converted into fluoxetine equivalents and classified into 10 mg per day, 20 mg per day, 40 mg per day and 70 mg per day. Women who used fluoxetine dose equivalents of 40 mg or more showed an increase in preterm birth (risk ratio RR 1.78, 95% CI, 1.48, 2.14). These findings highlight the importance of limiting the exposure of pregnant women to the lowest effective dose of antidepressants [103]. In a registry based study from Sweden, among 7.4 lakhs pregnancies identified from 2006 to 2012, there was an increased risk of NICU admissions in infants exposed to SSRI compared to the non-exposed group (13.7% vs. 8.2%, odds ratio 1.5, 95% CI 1.4,1.5) [104]. While TCA use during pregnancy has been associated with an increased risk for pre- eclampsia and neonatal adaptation syndrome but the risk is less likely with amitriptyline and imipramine [10,105,106].

However, several other systematic reviews did not find any association between antidepressant exposure in utero and adverse birth outcomes [107,108]. A meta-analysis of 23 studies that assessed the link between exposure to SSRI, TCA and MAO Inhibitors during pregnancy and adverse birth outcomes like spontaneous abortion, low birth weight and low Apgar score did not find any significant differences between exposed and non-exposed group of newborns [107]. A recent systematic review included two types of studies, studies that focused on birth outcomes in women exposed to antidepressant medication in utero and studies involving birth outcomes of untreated depression in pregnant women, thereby arriving at a risk benefit analysis of exposure to antidepressants during pregnancy. Eleven cohort and case control studies were included and analysis showed that birth outcomes like low birth weight did not differ between the two groups. However, no definitive conclusions regarding preterm delivery and pregnancy loss could be drawn, due to small number of studies and modest effect sizes. The review concluded that if the women were receiving antidepressants during pregnancy, medications need not be discontinued due to concerns regarding birth outcomes [108].

There can be several possible reasons for the conflicting set of findings. Several of the studies included in systematic reviews had small sample sizes, were not adequately powered and most had small effect sizes. Data extracted from registries often do not have information on medication compliance and medical and psychiatric history before pregnancy. Most of the studies have used chemical classes such as SSRI as a unit of analysis rather than a specific antidepressant medication [10]. Studies have not accounted for several possible confounders like smoking, parity, maternal age, diabetes, and hypertension, and lifestyle factors during pregnancy and exposure to other medications like angiotensin converting enzyme inhibitors given for treating pre-eclampsia. There is significant heterogeneity across studies regarding selection criteria and the timing of exposure to antidepressants during pregnancy [92,93]. Furthermore, many studies have not taken into consideration severity of depressive symptoms during pregnancy [93]. Thus, more studies are needed to assess the risk and benefit of the use of antidepressants during pregnancy to ameliorate depression [108].

9. Initiation of antidepressant use during pregnancy

9.1. General principles

The goal of treatment is to use an individualized approach taking into consideration the risk-benefit analysis of initiating treatment with antidepressant medication during pregnancy, severity of depression, patient related risk factors and availability of social support [84]. Intervention should target mitigation of risk factors like smoking, alcohol use, optimal intake of nutrition and regular antenatal visits [109,110]. Antidepressants are indicated in patients with severe depression, reduced oral intake, vegetative symptoms and time constraints to attend psychotherapy [110]. The choice of antidepressant medication rests on its safety and efficacy profile during pregnancy [84]. While choosing an antidepressant medication to treat antenatal depression, it is important to consider its safety profile during breast feeding [111]. Informed consent should be obtained and lowest possible dose of antidepressant medication should be used. If a woman has had a good response to a particular antidepressant medication in previous episodes of depression, it is prudent to use the same medication, as this limits exposure to different types of antidepressant medication during pregnancy [84]. However, switching to another antidepressant medication is recommended if the pregnant women was on paroxetine or fluoxetine during the pre-pregnancy period as paroxetine use during pregnancy is associated with a higher risk of congenital malformations [112] and long half of fluoxetine secreted in the breast milk precludes its use in lactating women [113]. Issues regarding discontinuation of antidepressants during pregnancy are complex. Some investigators recommend discontinuation of antidepressants before labor to avoid neonatal adaptation syndrome [84], which can occur when there is a sudden withdrawal from antidepressant medication. Infants can have respiratory distress, cyanosis, apnea, hyperreflexia, hypotonia, tremors, irritability, jitteriness, and inconsolable crying on abrupt withdrawal of antidepressants. It is self-limiting and mild in majority of the cases [112]. However, discontinuation of antidepressant medication prior to the onset of labor needs to be weighed against the risk of relapse of depressive symptoms during the postpartum period [84].

9.2. Choice of specific antidepressant medication during pregnancy

Most protocols recommend the use of sertraline and citalopram as the first line of treatment for antenatal depression [3,10,84]. Paroxetine is to be avoided during pregnancy as its use during pregnancy is associated with an increased risk of cardiac malformations in the newborn [112]. Similarly, it is better to avoid clomipramine during pregnancy as in some studies it has been associated with an increased risk of congenital malformations such as cleft palate, open eyelids, ear defects and neck defects [114]. UK Teratology body recommends the use of amitriptyline and imipramine as the first line options for treatment of depression during pregnancy [10]. Benzodiazepines as a class of drugs should be avoided as some studies have noted its use to be associated with an increased risk for floppy infant syndrome, withdrawal signs in the newborn, congenital malformations such as esophageal atresia, microphthalmia and pulmonary valve stenosis [115] and impaired cognitive development in children [116]. There is limited evidence for safe and efficacious use of other antidepressant medications during pregnancy.

9.3. Monitoring of women on antidepressant medication during delivery

Hospital delivery is recommended for pregnant women on antidepressant medication. Neonatal adaptation syndrome is observed in infants exposed to TCA in utero [105] and SSRI, especially paroxetine and fluoxetine [117]. Infants have to be monitored for anticholinergic side effects like transient bowel obstruction and urinary retention if exposed to TCA in-utero [118]. Children exposed to SSRI like fluoxetine and paroxetine in utero have to be observed for primary pulmonary hypertension [119], although the association between SSRI exposure and primary pulmonary hypertension is very small according to the current evidence [119]. Among neonates exposed to antidepressants in utero, observation of neonates is recommended from 12 hours to 3 days following delivery.

9.4. Antidepressant medication during the postpartum period and breast feeding

Antidepressant use is an important aspect of management of postpartum depression and antenatal depression continuing into the postpartum period. In a systematic review, six trials that included 596 patients concluded that while SSRIs were significantly more effective than placebo for women with postpartum depression, the evidence base for this was very low owing to small sample sizes and high attrition rates [111]. More randomized controlled trials with larger sample sizes and longer follow ups are needed to establish efficacy for the use of antidepressant medications in the treatment of postpartum depression. However, in the presence of suicidal risk, refusal to eat, neurovegetative symptoms and past history of depression, use of antidepressant medications need to be considered [110].

Risks of untreated maternal depression should be weighed against continuing lactation and exposure of infants to antidepressants in the breast milk [120]. Continuing breastfeeding is strongly recommended even when the mother is on antidepressant medications [121]. Factors affecting the passage of medication into human milk include the rate of absorption of the antidepressants, its half-life, molecular size, solubility of the drug, and the volume of distribution [122,123]. In addition, the concentration of antidepressant medication in infants depends on the type of antidepressant medication, concentration of medication in the breast milk and the rate of metabolism of the medication by the infant [122]. Studies focusing on antidepressants safety in breast feeding include only case series with data on medication levels in the breast milk, milk to plasma ratio, and plasma medication levels in infants. Factors guiding the choice of antidepressants during breastfeeding depend on the past treatment response, favorable side effect profile and antidepressants with the largest number of studies on safety during breastfeeding [120,122]. Sertraline, nortryptiline and citalopram are recommended for the treatment of postpartum depression due to their effectiveness and safety in breastfeeding women as the infant serum concentrations of these medications are low [111]. Treatment with paroxetine can be initiated in the postpartum period as it is not detectable in infant serum [124]. Fluoxetine is to be avoided in lactating women due to high serum drug levels in infants [125]. There is very limited data on the safety of other antidepressants in lactating women.

9.5. Depression during the pre-conception and continuation of antidepressants during pregnancy

The decision to continue medication during pregnancy among women already on antidepressant medications is influenced by several factors. If depression was of severe intensity during the pre-conception period requiring inpatient admission, and/or associated with high suicidal risk, it is recommended that antidepressant medication be continued through pregnancy [84]. However, if the depression had been mild and/or women had been well for at least 3 months before pregnancy, the antidepressant medication can be tapered and stopped at the onset of pregnancy [84]. It is important to include women and their partners in the decision making regarding the continuation of antidepressants during pregnancy.

9.6. Prevention of postpartum depression

Few studies have examined the effect of antidepressant treatment in the prevention of recurrence of postpartum depression among high-risk women. In a randomized control trial that compared nortryptyline to placebo, no significant differences emerged between the two groups on the rate of recurrence of postpartum depression in high risk women [126]. In another randomized controlled study, sertraline was found to be better than placebo in preventing the recurrence of postpartum depression among high risk women [127]. It is difficult to draw any definitive conclusion as both these studies had small sample sizes.

10. Psychosocial interventions in perinatal depression

Several psychological therapies have been developed for the treatment of perinatal depression. Cognitive Behavior Therapy (CBT) and Interpersonal Therapy (IPT) are the two of the most widely used and researched therapeutic modalities [128]. Other psychological and psychosocial therapies include supportive groups [129], psycho-education [130] and psychodynamic psychotherapy [131]. The psychological interventions target depression during pregnancy [132], after childbirth [133] or at both time periods [134], and is administered either in group [135] or individual formats [133]. While psychological interventions are generally provided by trained mental health professionals [136], in resource poor settings, where mental health professionals are scarce, interventions by trained primary health care workers [134,136,137], community health care workers [138] or even peers [17] are effective in lowering depressive symptomatology. Stephens et al. [133] examined the effectiveness of psychological interventions in postpartum depression by undertaking a meta-analysis of 10 randomized control trials of patients from primary care with a diagnosed depressive episode. The studies used 14 psychological intervention arms which included cognitive behavioral therapy, interpersonal therapy, counseling and other interventions. It was seen that psychological interventions resulted in lower depressive symptomatology when compared to control both immediately after treatment (standardized mean difference = −0.38; 95% CI, −0.49,−0.27) and at 6 months of follow- up (standardized mean difference = −0.21; 95% CI, −0.37, −0.05). The study did not find any significant differences between the various types of therapy. The interventions also led to improvements in adjustment to parenthood, marital relationship, social support, stress, and anxiety. In a systematic review and meta-analysis to examine the efficacy of CBT for treating and preventing depression during the perinatal period [139],, forty randomized and quasi randomized control trials from the U.S.A., UK, and Australia were included. CBT resulted in significant reductions in depressive symptoms compared to control conditions in intervention studies, and in prevention studies it was found that women who received CBT during pregnancy had significantly lower rates of postpartum depressive episodes compared to control. It was also seen that interventions in the postpartum period were more effective than those in the antenatal period, and individually administered treatments were more effective than group interventions. In a recent systematic review and meta- analysis [140] of 28 studies assessing the efficacy of IPT for perinatal depression, IPT was effective in reducing depressive symptoms and the prevalence of depressive episodes. In treatment studies, IPT reduced symptoms of depression and anxiety and improved relationship quality, social adjustment and social support, though there were insufficient studies to evaluate the effects of IPT in preventing perinatal depression. In a recent systematic review [141] to evaluate the effectiveness of IPT interventions to treat perinatal psychological distress, 25 randomized controlled trials, 10 quasi-experimental studies, eight open trials and two single case studies were included. In 24 studies, the IPT intervention was delivered individually; in 17 studies IPT was delivered in a group setting and in two studies a combination of group and individual sessions were used. In 27 studies, interventions were initiated during pregnancy (60%), and in 18 (40%), during the postpartum period. IPT was found to be an effective intervention for the prevention and treatment of psychological distress in women during the perinatal period.

While traditionally, most studies have focused on reduction of maternal depressive symptoms [139,140], more recently, impact of interventions have also included child outcome measures [142,143]. In a study by Stein et al. [143], the effects of a parenting video-feedback therapy (VFT) intervention versus a control treatment of progressive muscle relaxation (PMR) on child outcomes at 2 years was examined. Both treatments were added to CBT for persistent postpartum depression. There were no group differences in child outcome, language development, behavior problems, attachment or security with both groups achieving scores similar to non-clinical norms on all outcomes. In a recent 5 year follow up study [142] of a previous CBT based pilot randomized controlled trial that included 54 pregnant women with depression, the effects of antenatal CBT for depression and anxiety on child buccal cell DNA-methylation, brain morphology, behavior and cognition were examined. Children from the CBT group had overall lower DNA-methylation compared to children from the TAU group. Children from the CBT group had a thicker right lateral occipital cortex and lingual gyrus on voxel based morphometry analysis.

While there is extensive research on the effectiveness of psychological therapies and psychosocial interventions in the West, few studies have examined the effectiveness of psychological interventions for perinatal depression in low and middle income countries. There is scarcity of trained mental health professionals to provide interventions in resource poor settings and hence, attempts have been made to train nonspecialist health workers to deliver psychosocial therapies. In a review of nine studies, Chowdhary et al. [1] examined the content and delivery of psychological interventions delivered by nonspecialist health workers in low and middle income countries. It was found that the interventions shared a number of key features, such as delivery provided within the context of routine maternal and child health care beginning in the antenatal period and extending to postpartum; focus of the intervention beyond the mother to include the child and involving other family members; and attention to social problems and a focus on empowerment of women. All interventions were adapted for contextual and cultural relevance. The review concluded that task shifting is feasible using non specialist health workers to deliver psychological interventions for perinatal depression in low-resource settings. The Thinking Healthy Program (THP) delivered by trained community health workers [144] is being used in many LMIC settings and has been found to be effective with very few cultural adaptations [134]. The THP includes an evidence-based approach to reduce prenatal depression through evidence- based cognitive-behavioral techniques, which included building an empathetic relationship, focusing on the here and now, behavior activation and problem solving. However, in a study done on 570 pregnant women in Pakistan using the THP, it was found that the program had no effect on symptom severity or remission from perinatal depression at 6 months after childbirth [138]. In a study conducted in Rawalpindi, Pakistan and Goa, India, using the Thinking Healthy Program delivered by trained peers, qualitative data was collected through 7 focus groups and 61 in-depth interviews [17]. Most women perceived the intervention to be acceptable, useful, and viewed the peers as effective delivery-agents, though a minority of them had concerns about confidentiality and stigma related to their condition, and some peers felt the role was emotionally challenging. In a study currently being conducted in Nigeria [137], a mobile delivered psychoeducation based intervention by midwives is being assessed under the expanding care for perinatal women with depression (EXPONATE) program.

Though there is a large volume of evidence on the effectiveness of psychosocial interventions to alleviate depressive symptoms during the perinatal period and prevent short term and long term negative consequences in developed countries, very few studies have examined these in low and middle income countries. In addition, studies are needed to examine the impact of psychosocial interventions targeting maternal depressive symptoms on infant and child health outcomes. Studies should also examine ways to prevent perinatal depression. Recent USPSTF recommendations suggest that counseling should be provided for all pregnant women at high-risk for perinatal depression [145]

Based on the afore-mentioned review of literature on treatment of perinatal depression, treatment algorithms for antenatal and postpartum depression are depicted in Figures 1 and 2, respectively.

Figure 1.

Flowchart for the management of antenatal depression.

Figure 2.

Flowchart for the management of new onset postpartum depression.

11. Expert opinion

There has been increasing call for universal screening of perinatal depression. Several professional organizations and the WHO have stressed the importance of integrating mental health assessments of women with antenatal services. This approach builds on existing evidence of both short and long term adverse health consequences, of untreated perinatal depression on maternal and child health. There has been significant progress in the development of efficacious psychosocial interventions for the treatment of perinatal depression. Recently, emerging studies from LMICs have adopted task shifting approach using trained community health workers and nurses to deliver psychosocial interventions targeting perinatal depression.

The risk of developing congenital defects in fetus and the newborn and adverse birth outcomes on exposure to antidepressants during pregnancy is relatively small. There is greater clarity on the factors that influence the choice of antidepressant medication for the treatment of perinatal depression. The literature does offer some guidelines on the use of antidepressant medications during pregnancy. However, the evidence is based on studies with small sample size and lacking adequate power. Studies that do have large data sets are primarily drawn from population based registers that often have other methodological lacunae such as non-availability of information on confounding factors that impact maternal and infant health.

There is growing consensus that for mild to moderate depression CBT and IPT based interventions are the treatment of choice for both depressive symptoms during pregnancy and in the postpartum period. Antidepressant medications are to be used for treatment of severe perinatal depression with profound vegetative symptoms and or with patients at high risk for suicide.

Longitudinal studies also seem to suggest that in some women, perinatal depression tends to last for several years after child birth. More studies with larger sample sizes and longer follow- ups are required to provide conclusive evidence for the effectiveness of use of antidepressants in postpartum depression. Studies that combine psychosocial interventions with the use of antidepressant medications may be more effective in ameliorating depressive symptoms in persistent perinatal depression. Thus, further studies are needed to establish clinical guidelines for the use of antidepressant medications in the treatment of perinatal depression. Such guidelines could inform the clinicians and public about safe and efficacious medical treatment of depression during the antenatal and postpartum period for the betterment of maternal and child health.

Article highlights.

• The authors briefly review the potential health effects of perinatal depression on maternal and child health.

• Comprehensive evaluation of perinatal depression includes assessment of severity of depression, associated suicidal risk, presence of vegetative symptoms, social support, and past history of depression, and resources available for treatment.

• The choice of antidepressant medication for the treatment of perinatal depression must be individualized and take into consideration patient related clinical factors and availability of resources.

• There is a need to integrate assessment and interventions targeting maternal depressive symptoms with antenatal services and child well- being clinics across the spectrum of health services.

• More research on the management of perinatal depression is needed from LMICs where the burden of perinatal depression is high and there is a scarcity of trained mental health professionals.