Depression During Pregnancy
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Even though pregnancy is a period of emotional well-being, in some women, when pregnant, experience their first depressive episode, whereas others, with a history of depression, are at risk for its recurrence, suggesting that pregnant women show the same risk for depression as other women of child-bearing age. Women are 1.7 times more likely than men to experience major depression, and are at greatest risk between ages 25-44 years, childbearing age (1). Pregnancy is a stressor that may be associated with an increased incidence and severity of depressive episodes. Gestational depression is a widespread problem that often goes undiagnosed and untreated. In medical practice, we compartmentalize symptoms and diseases into manageable units; however, the patient comes as an integrated whole. The effect of pathology in any part of the body affects the entire patient. Psychiatric disorders are defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), a categorical classification that divides mental disorders into types based on criteria sets with defining features. A depressed woman is more likely not to comply with her prenatal care, to self-medicate with tobacco, alcohol, and illicit drugs, and to commit suicide, all of which underscore a pressing need for appropriate treatment. Depression in response to stressful life situations occurs only in some women; in others, episodes occur without extraordinary stressful events.
The purpose of this document is to address the maternal and neonatal risks of both depression and antidepressant medication exposure. It focuses on periconceptional and antenatal management. For the pregnant woman, the capacity to function optimally, enjoy relationships, manage pregnancy, and prepare for the infant's birth is critical. Perinatal health can be conceptualized within a model that integrates the complex social, psychological, behavioral, environmental and biologic forces that shape pregnancy. Antenatal depression affects the health and well-being of the mother, baby, and family.
About 14% to 23% of pregnant women will experience a depressive disorder with pregnancy (2). Studies also suggest that depressive symptoms are highly prevalent during late pregnancy and postpartum period; about 50% of pregnant women in the third trimester had depressive symptomatology. A meta-analysis found depression rates of 12% and 14% in the second and third trimester (3). According to the Agency for Healthcare Research and Quality, depression affects between 14% and 23% of pregnant women and from 11% to 32% of women in the first 3 months postpartum. Moreover, as new American College of Obstetricians and Gynecologists (ACOG) guidelines also reiterate, many postpartum episodes begin in pregnancy. The incidence of depression (minor and major) during pregnancy and/or the postpartum period is approximately 10%. A woman has a 10% to 25% risk of being diagnosed with major depressive disorders at some point in her life, with the greatest risk occurring during the childbearing years (4). These prevalence rates are comparable among different countries. Approximately 3% to 5% of women experience major depression during pregnancy (2). If untreated, 50% of these women will experience a postpartum exacerbation, which can confer a risk of attempted suicide of up to 15% (5). Thus, the importance of recognizing and treating depression during pregnancy cannot be understated. Women with a history of major depression are at high risk for relapse during pregnancy, especially if they discontinue medications (6). In a study of 201 women who were not depressed at conception, 68% of those who discontinued their medication during pregnancy relapsed, compared with only 26% of those who continued; the hazard ratio was 5.0 (95% CI, 2.8-9.1) (5). And because even staying on the drugs does not completely protect pregnant patients against relapse, these women require close monitoring.
Identifying Depression in Pregnancy
In the DSM-IV, a major depression episode is defined as at least a 2-week period of either persistent depressed mood or loss of interest or pleasure in daily activities (the "gatekeeper" symptoms) plus four associated symptoms (or three if both gatekeeper symptoms are present). Persistent is operationalized as the symptom must be present for most of the day nearly every day. The patient also must have impairment of function in interpersonal relationships or work. Note that it is possible to have a diagnosis of major depressive episode without the symptom of depression. A woman could have persistent loss of interest or pleasure but no depressed mood and four other symptoms from the following list: appetite disturbance or significant weight change, sleep loss/excess, psychomotor agitation/retardation, fatigue or energy loss, feeling of worthless or guilt, impaired thinking or concentration, and suicidal ideation. Note that appetite, sleep and motor activity can be either decreased or increased. Since there is no separate category for perinatal depression, be aware of the American Psychiatric Association criteria for diagnosing major depression, which requires a patient to have experienced at least five of nine possible symptoms over the previous 2 years (1). To make the diagnosis, one of these five must be present, either:
The other seven symptoms to look for, which should be occurring nearly daily, are:
Depression identified within the first postpartum year is considered postpartum depression (5)(7). Clinicians and patients often misattribute the symptoms of depression such as insomnia, lack of energy, and changes in appetite and weight, to the expected changes in pregnancy. Sad, blue, hopeless, or helpless mood are symptoms of a possible mood disorder, and thinking about suicide is never normal. Women feel guilty about being depressed during pregnancy, so many suffer in silence. When a woman does complain, she should be evaluated.
Hidden symptoms: depressed pregnant women may not feel bonded to the fetus and may have obsessional (illogical intrusive) thoughts about harming the fetus, which they rarely reveal. Asking a patient about "scary thoughts" may enable the patient to reveal them. Depressed women can also have other obsessive compulsive symptoms or panic attacks (8). Both anxiety and depressive symptoms need diagnosis and treatment during pregnancy. The differential diagnosis also includes bipolar depression, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, and eating disorder. Screening tools such as the Edinburgh Postnatal Depression Scale (EPDS) (available athttp://www.fresno.ucsf.edu/pediatrics/downloads/edinburghscale.pdf), the postpartum Depression Screening Scale, and the Beck Depression Inventory can help detect antenatal depression (5)(9)(14). Depressive symptoms can be associated with lower health-related quality of life in late pregnancy. Few studies have quantified the effect of depressive symptoms in early pregnancy or among a racially and economically diverse group. In this study (10), women with depressive symptoms had significantly lower health-related quality of life scores in all domains except Physical Functioning. After adjustment for sociodemographic, clinical , and social support factors, depressive symptoms were associated with health-related quality of life scores that were 30 points lower in Role-Physical, 19 points lower in Bodily Pain, 10 points lower in General Health, and 56 points in Role-Emotional. The study concluded; women in early pregnancy with depressive symptoms have poor health-related quality of life. Early identification and management of depressive symptoms in pregnant women may improve their sense of well-being (10).
A complete psychiatric evaluation includes a urine-toxicology screen and baseline labs (thyroid-stimulating hormone, comprehensive metabolic profile, complete blood count). Also ask the patient if she is taking nutriceuticals, herbal medications, or over-the-counter and other medications; these may produce mood changes or interfere with psychotherapeutic drugs. Obstetricians and gynecologists should refer severe cases to a psychiatrist as soon as possible.
When depressed patients present prior to conception for evaluation, her provider should determine whether the patient has moderate to severe symptoms. If the evaluation is conducted by an obstetrical provider and the patient has suicidal or acute psychotic symptoms, she should be promptly referred to a psychiatrist for aggressive treatment. In such instances, it is judicious for the patient to wait a period of time after she has achieved euthymia before she attempts to conceive. Whether the patient has an evaluation with an obstetrician or a psychiatrist, if she has moderate to severe symptoms, her clinician should strongly consider evaluation and optimization of her antidepressant medication. It is prudent to counsel the patient to wait for a period of time prior to conceiving in this instance as well. While it is difficult to specify an exact or optimal length of time for all patients, guidelines such as those from the Agency for Healthcare Quality and Research, suggest that antidepressant treatment for a first, acute episode of depression should endure at least 6-12 months (11).
Patients with mild or no symptoms for 6 months or longer may be candidates for medication taper and discontinuation prior to conception. The patient's psychiatrists and obstetrician can collaborate with the patient to make the decision regarding a hiatus from pharmacotherapy. Generally, if a woman is a candidate for stopping pharmacological treatment, slow taper such as 25% reduction in dose every 1-2 weeks with close monitoring for relapse or discontinuation symptoms is preferable. Patients with a history of severe, recurrent major depressive disorders (MDD), psychosis, bipolar illness, psychiatric comorbidity that requires pharmacotherapy, or history of a serious suicide attempt may not be candidates for medication discontinuation. These individuals should continue psychotropic medication and her obstetrician and psychiatrist, if available, should coordinate her care so that she has optimal prophylaxis from psychiatric illness relapse but also appropriate obstetrical care. Some women may also benefit from referral to a therapist who can provide psychotherapy. While cognitive behavioral therapy (CBT) or interpersonal psychotherapy (IPT) is preferable, other types of counseling may be helpful if empiric-based therapies are not available. A previous study suggests that in nonpregnant women, minor depression may represent a prodromal or a residual phase of major depression (12). In the current study (13), this condition was infrequent, because most women with minor depression, depressive symptoms occurred independently from a major depression episode. Nevertheless, during the third trimester, some women with minor depression were still depressed at the last evaluation, supporting the hypothesis that the minor depression symptoms may represent a prodromal phase of a major depression to occur in the postpartum period, which frequently begins during pregnancy.
Depression Screening Tools (14):
Maternal Depression and Adverse Reproductive Outcomes
Both depressive symptoms and antidepressant exposure are associated with fetal growth changes and shorter gestations, but the majority of studies that evaluated antidepressant risks were unable to control for the possible effects of depressive disorder. Short-term neonatal irritability and neurobehavioral changes are also linked with maternal depression and antidepressant treatment (15).
Miscarriage: Reasons for miscarriage, especially early events, are difficult to obtain because prospective data collection must begin with pregnancy, typically after 6 weeks gestation, only occurs in about 8% of women and large sample sizes are needed to assess differences among exposures associated with this outcome. Accordingly, there is a paucity of information about depression and spontaneous pregnancy loss. We found existing studies problematic because of small sample sizes and other methodological limitations, which preclude definitive conclusions (16).
Fetal Growth Restriction (IUGR): Fetal growth effects are typically manifested as delivery of low birth weight (LBW), born <2,500 g or small for gestational age (SGA), typically birth weight <10% of age-adjusted weight infants. Depressive symptoms in mother have been linked with an increased risk for delivery of a LBW or SGA infant in some but not in all studies (17). Only the latter negative reports included structured diagnostic assessments for depression but the numbers of women with major depressive disorders were small in both studies. The current state of information does not support or refute and association between major depressive disorders and LBW or SGA delivery.
Preterm Delivery (PTD): These are deliveries that occur prior to 37 completed weeks of gestation. Several studies report an association between depressive symptoms or a depressive disorder and shorter gestations, including preterm delivery (PTD), although findings are not consistent (18). The same limitations discussed above apply to the outcomes of PTD and gestational age, and thus, available data neither support nor refute a link between MDD and these outcomes.
Neonatal Effects: There are no studies in literature that link maternal depression to congenital anomalies in their infants. However, neonates born to mothers with a depressive disorder have increased risk for irritability, less activity and attentiveness, and fewer facial expressions compared to offspring born to mothers without depression (18). This suggests that either genetic and/or other perinatal factors have an impact on infant behavior. In small studies, newborns of depressed women have physiologic profiles that parallel those of their mothers and include elevated cortisol, decreased peripheral levels of dopamine and serotonin, greater relative right frontal electroencephalogram activation and lower vagal tone (18).
Long-term Effects on Offspring: Surprisingly, little research has looked at the specific effects of antenatal depression on late neonatal or post-neonatal development in children although maternal depression after delivery has received extensive attention. In general, depressive symptoms in the mother, rather than a diagnosis of a maternal depressive disorder, have been the exposure of interest in few existing studies. One large cohort study attempted to assess the specific effects of depressive symptoms, according to the Edinburgh Postnatal Depression Scale (EPDS), in mothers during pregnancy although child performance was based upon maternal report only and potential bias cannot be excluded (19). In this study, children exposed to maternal depressive symptoms at 18 and 32 weeks gestation, but not postnatally, showed greater development delay at 18 months than children with mothers who were not depressed in pregnancy. The odds ratio (OR) for developmental problems for offspring born to a mother with depressive symptoms according to cutoff of 12 on the EPDS was 1.34 (95% CI=1.01-1.78; P=.043). The possibility of bias and existence of studies that do not agree support the need for more work to determine the degree of slow developmental risk conferred to a child when mother is depressed in pregnancy.
Management of Pregnant Woman with Depression
Behavioral Treatments for Mood Disorders
Many patients with mild-to-moderate depression can be treated by psychosocial approaches including individual and group psychotherapy in lieu of medication. Patients with residual symptoms, those at high risk of relapse, those with comorbid conditions such as panic disorder and those who prefer to avoid medication may benefit from psychotherapy. This is an especially critical option for women preparing for conception or currently pregnant since a large percentage of women may plan to avoid medication. Cognitive behavioral therapy (CBT) or interpersonal psychotherapy (IPT) has been shown to be effective for depression in pregnant women (20). Web and computer based cognitive behavioral therapy are options if there are few behavioral therapists in a patient's area or she has monetary limitations. While evidence for supportive and psychodynamic psychotherapy is limited, these approaches are also reasonable if IPT and CBT are unavailable.
Novel Treatments: exposure to bright morning light has been established as an efficacious treatment of major depressive episode (MDE). The responsivity of depressed pregnant women to bright light therapy has been studied in two small studies. In a pilot randomized clinical trial of the MDE women, significant improvement of depressive symptoms was demonstrated (21). Omega-3 fatty acids are long-chain polyunsaturated fatty acids recognized as critical nutrients that the body cannot make. An inverse relationship between omega-3 fatty acid and depressive symptoms is general populations has been demonstrated. The efficacy and safety of omega-3 fatty acids for depression during pregnancy is being evaluated in a randomized, placebo-controlled study (21). However, an open trial of seven women treated with nearly 3 g of fish oil in the final trimester of pregnancy failed to prevent postpartum depression in four out of seven women.
Use of Psychiatric Medications during Pregnancy
The best time to decide whether to give pregnant woman antidepressants is before she gets pregnant, given that 49% of all pregnancies are unplanned, it may not be possible in many patients. Drugs are usually first-line of treatment for a woman with a history of medication-responsive depression or for one who has moderate-to-severe depression. Patients fall into three groups:
Drug of choice is guided by a woman's history of response, the family history of response (especially in the drug-naļve patient), the safety data in pregnancy and lactation, and side effects. In general, it is better to avoid recently released drugs until safety data have accumulated. All psychotropic medications studied to date cross the placenta, are present in amniotic fluid, and can enter human breast milk (22). The leading choices for antenatal depression are the selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, sertraline, citalopram, and paroxetine) and venlafaxine, a serotonin/norepinephrine reuptake inhibitor (SNRI), in that they have the most safety data in pregnancy and lactation. Although ACOG does not currently recommend paroxetine in pregnancy, its use is justified in some situations: for example, in already pregnant patient who is doing well on it and in a woman with a relapse who has responded very well to paroxetine in the past. However, a woman should not necessarily be started on or switched to an SSRI or SNRI just because she is planning to become pregnant or is already pregnant. If a patient is uniquely responsive to an older drug (such as nortriptyline) or a less-studied drug (and has failed trials of SSRIs), then the benefits of that drug to the mother may outweigh the less well-characterized risks to the fetus.
Safety and Efficacy of Treatment for Depression during Pregnancy
Based on a Swedish national registry and a U.S. insurance claims database that have raised concerns about a 1.5 to 2-fold increased risk of congenital cardiac malformations (atrial and ventricular septal defects) associated with first-trimester paroxetine exposure (22). The manufacturer subsequently changed paroxetine's pregnancy FDA category from C to D. Recently, the teratogenic effect of SSRI use during the first trimester of pregnancy was examined in two large case-control studies from multi-site surveillance programs. In the National Birth Defects Prevention Study, no significant associations were found between SSRI use overall and congenital heart defects (23). However, an association was found between SSRI use (particularly paroxetine) during early pregnancy and anencephaly, craniosynostosis, and omphalocele. Importantly, these risks were found only after more than 40 statistical tests were performed. Even if findings were not the result of chance, the absolute risks associated with SSRI use identified in this study were small. For example, a 2-fold to 3-fold increase in birth defects would occur for omphalocele (1 in 5,000 births), craniosynostosis (1 in 1,800 births) and anencephaly (1 in 1,000 births). In contrast, in the Slone Epidemiology Center Birth Defects Study no increased risk of craniosynostosis, omphalocele, or heart defects associated with SSRI use overall during early pregnancy was found (22). An association was seen between paroxetine and right ventricular septum defects. The current data on SSRI exposure during early pregnancy provide conflicting data on the risk for both overall and specific malformations. Some investigators have found a small increased risk of cardiac defects, specifically with paroxetine exposure. The absolute risk is small and generally not greater than two per 1,000 births; hence, these agents are not considered major teratogen. Exposure to SSRIs late in pregnancy has been associated with transient neonatal complications, including jitteriness, mild respiratory distress, and transient tachypnea of the new born, weak cry, poor tone, and neonatal intensive care unit admission (24).
A more recent FDA public health advisory highlighted concerns about the risk of an unconfirmed association of newborn persistent pulmonary hypertension with SSRI use (22). The potential risk of SSRI use in pregnancy must be considered in the context of the risk of relapse of depression if treatment is discontinued. Factors associated with relapse during pregnancy include a long history of depressive illness (more than 5 years) and a history of recurrent relapses (more than 4 episodes). Therefore, treatment with all SSRIs or SNRI or both during pregnancy should be individualized. At this time, paroxetine use in pregnant women and women planning pregnancy should be avoided, if possible. Fetal echocardiography should be considered for women exposed to paroxetine in early pregnancy. Because abrupt discontinuation of paroxetine has been associated with withdrawal symptoms, discontinuation of this agent should occur according to the product's prescribing information.
Tricyclic antidepressants (TCAs) have been available in the United States since 1963 and were widely during pregnancy and lactation before the introduction of SSRIs. Results from initial studies, which suggested that TCA exposure might be associated with limb anomalies, have not been confirmed with subsequent studies. Neonatal neurobehavioral effects from fetal exposure have not been reported (25). Acute effects associated with TCA exposure include case reports of fetal tachycardia, neonatal symptoms such as tachypnea, tachycardia, cyanosis, irritability, hypertonia, clonus and spasm, and transient withdrawal symptoms. In more recent studies, a significant link between prenatal exposure to TCAs and perinatal problems has not been documented. Atypical antidepressants are non-SSRI and non-TCA antidepressants that work by distinct pharmacodynamic mechanisms. The atypical antidepressants include bupropion, duloxetine, mirtazapine, nefazodone, and venlafaxine. The limited data of fetal exposure to these antidepressants, do not suggest an increased risk of fetal anomalies or adverse pregnancy events (26). In the one published study of bupropion exposure in 136 patients, a significantly increased risk of spontaneous abortion, but not an increased risk of major malformations, was identified (26). In contrast, the bupropion registry maintained at GlaxoSmithKline has not identified any increased risk of spontaneous abortion, although these data have not undergone peer review. Antidepressant medication is the mainstay of treatment for depression, although considerable data show that structured psychotherapy, such as interpersonal psychotherapy or cognitive behavioral therapy, are effective treatments for mild to moderate depression and are beneficial adjuncts to medication.
Electroconvulsive Therapy during Pregnancy
Electroconvulsive therapy has long been regarded as a safe and effective treatment for severe depression in pregnancy, especially when the depressive disorder is life threatening or fails to respond to antidepressant drugs. There is little evidence that it is harmful to the woman or fetus when both are carefully monitored (27). Patients who have not responded to antidepressant therapy or who are psychotic, suicidal or severely disabled are candidates for electroconvulsive therapy. Other patients with severe depression may prefer electroconvulsive therapy because of the rapidity of response to this modality.
Acupuncture for Depression during Pregnancy
When properly implemented, acupuncture has relatively mild and transient, if any, side effects and therefore holds promise as a safe alternative to antidepressant medications for treatment of depression during pregnancy. In this evaluator-blinded, randomized controlled trial efficacy of acupuncture for treatment of depression during pregnancy was studied (29). A total of 150 pregnant women who met Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria for major depressive disorder were randomized to receive either acupuncture specific for depression or one of two active controls: control acupuncture or massage. Treatments lasted 8 weeks (12 sessions). Junior acupuncturists, who were not told about treatment assignment, needled participants at points prescribed by senior acupuncturists. All treatments were standardized. The primary outcome was the Hamilton Rating Scale for Depression, administered by masked raters at baseline and after 4 and 8 weeks of treatment. Continuous data were analyzed using mixed effects models and by intent to treat. The short acupuncture protocol demonstrated symptom reduction and a response rate comparable to those observed in standard depression treatments of similar length and could be a valuable treatment option for depression during pregnancy.
Breastfeeding has clear benefits for both mother and infant, and in making the decision to recommend breastfeeding, these benefits should be weighed against the risks to the neonate of medication exposure while breastfeeding. Most medications are transferred through breast milk, although most are found at very low levels and likely are not clinically relevant for the neonate. For women who breastfeed, measuring serum levels in the neonate is not recommended. In results from studies, it has been shown that, quantitatively, medication exposure during lactation is considerably lower than transplacental exposure to SSRIs during gestation (22)(28). Only a few isolated cases of adverse effects have been reported, although infant follow-up data are limited. The package insert for citalopram does report a case of an infant who experienced a transient apneic episode. Long-term neurobehavioral studies of infants exposed to SSRI antidepressants during lactation have not been conducted. The TCAs also have been widely used during lactation. The only adverse event reported to date is respiratory depression in a nursing infant exposed to doxepin, which led to the conclusion that doxepin use should be avoided but that most TCAs are safe for use during breastfeeding. Data regarding the use of atypical antidepressants during lactation are limited to the use of venlafaxine and bupropion (30).
Certain considerations should be addressed before initiation of antidepressants while breast feeding: 1) consider behavioral treatments as first-line interventions, particularly for mild to moderate depression; 2) obtain thorough informed consent and provide a risk-benefit analysis to the mother and her family; 3) moderate to severe major depressive disorder are appropriately treated by antidepressants; and 4) clinical factors, such as previous history of treatment response, should drive the selection of antidepressant (32). Intensive postpartum support provided by a health professional such as a public health nurse or midwife is the most effective intervention for mitigating the onset of a postpartum mood disorder. These results may be bolstered by the benefit related to community care. More recent evidence suggests that peer support via the telephone also may be effective in the prevention of postpartum depression.
Depression is very common during pregnancy and the postpartum period. At this time there is insufficient evidence to support a firm recommendation for universal antepartum or postpartum screening (30). Incidence of 14.5% of depression during pregnancy and the same rate in the first 3 postpartum months are seen in many studies, although higher rates have been reported among inner city women, mothers of preterm infants, and adolescent mothers (31). Depression persists from months to years after childbirth, with lingering limitations in physical and psychological functioning following recovery from depressive episodes. 25 to 50% of women who experience depression in the postpartum period have episodes that last 7 months or longer. The most significant factor in the duration of the depression is delay in receiving treatment.
Whenever possible, multidisciplinary management involving the patient's obstetrician, mental health clinician, primary health care provider, and pediatrician is recommended to facilitate care. Use of single medication at a higher dose is favored over the use of multiple medications for the treatment of psychiatric illness during pregnancy. Advising a pregnant or breastfeeding woman to discontinue medication exchanges the fetal or neonatal risks of medication exposure for the risks of untreated maternal illness. Maternal psychiatric illness, if inadequately treated or untreated, may result in poor compliance with prenatal care, inadequate nutrition, exposure to additional medication or herbal remedies, increased alcohol and tobacco use, deficits in mother-infant bonding, and disruptions with the family environment. For known teratogens, knowledge of gestational age is helpful in the decision about drug therapy because the major risk of teratogenesis is during embryogenesis (i.e., during third through the eighth week of gestation). Electronic resources for information related to the fetal and neonatal effects of psychotropic drug therapy in pregnancy and breast feeding include Reprotox (www.reprotox.org) and TERIS (http://depts.washington.edu//terisweb). There are also insufficient data to recommend how often screening should be done. However, screening for depression has the potential to benefit a woman and her family and should be strongly considered. Women with positive assessment require follow-up evaluation and treatment if indicated. Medical practices should have a referral process for identified cases. Women with current depression or a history of major depression warrant particularly close monitoring and evaluation. Further study is needed to determine whether the assessment and treatment of depressive symptoms in early pregnancy can reduce depressive symptoms in later in pregnancy and postpartum period. Further studies might prospectively evaluate the effect of depressive symptoms on biologic mechanisms of pregnancy and perinatal outcomes.
Funding: The reviews to improve and promote Maternal and Child Mental Health are funded by WHEC Initiative for Global Health. We thank our partners in health for their contributions.