A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) or (2)
(1) Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observation made by others (e.g., appears tearful)
(2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day
(3) Significant weight loss when not dieting or weight gain (e.g., a change of more than 5 % of body weight in a month), or decrease or increase in appetite nearly every day
(4) Insomnia or hypersomnia nearly every day
(5) Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down)
(6) Fatigue or loss of energy nearly every day
(7) Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick)
(8) Diminished ability to think or concentrate, or indecisiveness, nearly every day
(9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide
B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
C. The episode is not due to the physiological effects of a substance or a general medical condition
D. The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, delusional disorder, or other psychotic disorders
E. There has never been a manic episode or a hypomanic episode
Screening Measures
Depression during pregnancy is often measured by the Edinburgh Postnatal Depression Scale (EPDS) [2] or the Patient Health Questionnaire (PHQ-9) [3]. The EPDS (Table 3.2) is a 10-item self-report scale developed as a screen for postpartum depression (PPD); it is widely used during pregnancy as well. The top line of questions 1, 2, and 4 is scored “0,” the top line of the other questions is scored “3,” and the maximum possible score is 30. A score of 12 or above would warrant a clinical interview for depression. The EPDS includes questions about both mood and anxiety; it does not include questions about fatigue, oversleeping, or changes in appetite which can be common during pregnancy. The PHQ-9 (Table 3.3) is a 9-item self-report scale widely used in primary care settings as a screen for MDD [3]. The questions mirror the DSM-5 criteria for MDD. A score of 10 or above would warrant a clinical interview for depression. A positive answer on the question about suicidal ideation on either the EPDS or PHQ-9 would warrant further evaluation of suicidality.
In the past 7 days: 1. I have been able to laugh and see the funny side of things ___ As much as I always could ___ Not quite so much now ___ Definitely not so much now ___ Not at all 2. I have looked forward with enjoyment to things ___ As much as I ever did ___ Rather less than I used to ___ Definitely less than I used to ___ Hardly at all 3. I have blamed myself unnecessarily when things went wrong ___ Yes, most of the time ___ Yes, some of the time ___ Not very often ___ No, never 4. I have been anxious or worried for no good reason ___ No, not at all ___ Hardly ever ___ Yes, sometimes ___ Yes, very often 5. I have felt scared or panicky for not very good reason ___ Yes, quite a lot ___ Yes, sometimes ___ No, not much ___ No, not at all | 6. Things have been getting on top of me ___ Yes, most of the time I haven’t been able to cope at all ___ Yes, sometimes I haven’t been coping as well as usual ___ No, most of the time I have coped quite well ___ No, I have been coping as well as ever 7. I have been so unhappy that I have had difficulty sleeping ___ Yes, most of the time ___ Yes, sometimes ___ Not very often ___ No, not at all 8. I have felt sad or miserable ___ Yes, most of the time ___ Yes, quite often ___ Not very often ___ No, not at all 9. I have been so unhappy that I have been crying ___ Yes, most of the time ___ Yes, quite often ___ Only occasionally ___ No, never 10. The thought of harming myself has occurred to me ___ Yes, quite often ___ Sometimes ___ Hardly ever ___ Never |
PHQ-9 | Over the last 2 weeks, how often have you been bothered by any of the following problems? | Not at all | Several days | More than half the days | Nearly every day |
|---|---|---|---|---|---|
1. | Little interest or pleasure in doing things | 0 | 1 | 2 | 3 |
2. | Feeling down, depressed, or hopeless | 0 | 1 | 2 | 3 |
3. | Trouble falling or staying asleep or sleeping too much | 0 | 1 | 2 | 3 |
4. | Feeling tired or having little energy | 0 | 1 | 2 | 3 |
5. | Poor appetite or overeating | 0 | 1 | 2 | 3 |
6. | Feeling bad about yourself—or that you are a failure or have let yourself or your family down | 0 | 1 | 2 | 3 |
7. | Trouble concentrating on things, such as reading the newspaper or watching television | 0 | 1 | 2 | 3 |
8. | Moving or speaking so slowly that other people could have noticed or the opposite—being so fidgety or restless that you have been moving around a lot more than usual | 0 | 1 | 2 | 3 |
9. | Thoughts that you would be better off dead or of hurting yourself in some way | 0 | 1 | 2 | 3 |
Similar to the findings for screening for depression in adult populations in primary care, screening for depression during pregnancy in ob-gyn clinics does not necessarily lead to patient referral to treatment, patient access of treatment, or improvement in depression and anxiety. Barriers include availability of treatment, cost, child care, stigma of referral to a mental health clinician, as well as clinician time constraints and expertise with psychiatric disorders. Recent studies suggest that acceptance of and adherence to treatment is increased when mental health care is integrated in the ob-gyn or primary care setting.
Effect of Pregnancy on MDD Prevalence
Although the prevalence of MDD during pregnancy is the same as the prevalence in nonpuerperal women, pregnancy may be a time of risk of developing an episode in vulnerable women. It has been reported that rates of completed suicide may be lower in pregnant women; however, some studies report that rates of suicidal ideation may be higher compared to nonpuerperal women.
Risk Factors for MDD During Pregnancy
Previous MDD, poor social support, single status, adolescence, intimate partner violence, poor relationship quality, anxiety, life stress, unintended pregnancy, lower education, lower income, smoking, diabetes, high preconception body mass index, chronic medical conditions, previous miscarriage or stillbirth, obstetric risk.
Effect of MDD on Pregnancy
Women with MDD are reported to demonstrate poor health behaviors such as poor nutrition, lack of exercise, not taking prenatal vitamins and prescribed medications, poor compliance with prenatal care, increased smoking, and increased use of alcohol and over-the-counter and illicit drugs.
Effects of Untreated Prenatal MDD, Anxiety, and Stress on the Fetus
Altered fetal response to vibroacoustic stimulation, altered fetal heart rate variability, changed movement and sleep patterns, altered attention, delayed fetal head and overall growth, decreased maternal-fetal attachment, increased maternal and fetal cortisol- and corticotropin-releasing hormone (CRH), increase in C-reactive protein and pro-inflammatory cytokines, and possible epigenetic changes to placental glucocorticoid receptor promoter gene and 11-beta-hydroxysteroid dehydrogenase-2 gene.
Effects of Untreated Prenatal MDD, Anxiety, and Stress on Birth Outcome
Some of these effects are thought to be related in part to increased maternal and fetal cortisol levels, elevated fetal CRH, and increased norepinephrine. Low folate levels can add to the risk of depression on LBW and SGA.
Effects of Untreated Prenatal MDD, Anxiety, and Stress on the Infant and Child
Infant: Altered neonatal behavioral scores, altered cortisol reactivity, greater relative right frontal EEG asymmetry, decreased vagal tone, altered reactivity to pain or stress, altered temperament, altered attention, delayed neuromotor development, and sleep problems.
Toddler: Delayed motor and cognitive development, altered executive function, internalizing and externalizing disorders, and altered response to stress.
Child and Adolescent: Increased risk of depression, anxiety disorders, ADHD, psychosis, and altered response to stress.
Prenatal programming effects may be modified by postpartum caregiving and may be exacerbated by continued maternal depression or childhood adversity.
Antidepressant Use During Pregnancy
Approximately 7 % of women in the United States take an SSRI at some point during their pregnancy. Sertraline is currently the most prescribed antidepressant during pregnancy, followed by fluoxetine.
Many women discontinue their antidepressant once the pregnancy is recognized, either on their own or at the advice of a clinician. Discontinuation of antidepressants may lead to an increased risk of relapse of MDD, particularly in women with more previous episodes, longer length of illness, and an episode in the 6 months prior to conception. The risk of relapse is highest during the first trimester.
There is a risk of relapse of recurrent MDD even if antidepressants are maintained during pregnancy.
Pregnancy Outcomes with Antidepressant Use
Fetal exposure to antidepressants occurs through the umbilical cord, across the placenta by transporter genes, and through absorption from amniotic fluid. Antidepressant exposure in the fetus is influenced by the cord-to-maternal ratio of the antidepressant level; half-life of antidepressant; peak and trough levels of antidepressant; cytochrome P450 genetic polymorphisms in the mother, fetus, and placenta; and the unbound fraction of antidepressant in the fetus [5]. Adverse birth outcomes have not been clearly associated with timing of SSRI exposure (e.g., first vs. third trimester), length of SSRI exposure (e.g., part of pregnancy vs. throughout pregnancy), or dose of SSRI.
Spontaneous Miscarriage
Approximately 12 % of clinically recognized pregnancies under 20 weeks undergo spontaneous miscarriage, usually during the first trimester. Exposure to antidepressants during the first trimester increases the risk of spontaneous miscarriage by approximately 65 %. Maternal depression is a confounding factor in most studies to date.
Preterm Birth
PTB occurs in 12 % of births in the United States. Many cohort and case-control studies have reported an increased risk of PTB (pooled OR of 1.55) with prenatal exposure to selective serotonin reuptake inhibitors; [6] some studies have controlled for maternal depression but most have not. A recent review commented that the risk of PTB averages 3 days shorter gestational age, considered a small effect [6].
Birth Weight
LBW occurs in 8 % of births in the United States. Many cohort and case-control studies have reported an increased risk of LBW (pooled SMD of −0.10) with prenatal exposure to selective serotonin reuptake inhibitors; [6] some studies have controlled for maternal depression but most have not. A recent review commented that the risk of lowered LBW averages 2.6 ounces, considered a small effect [6].
Lower 1 min and 5 min Apgar scores with SSRIs have been reported [6]. PTB and LBW have also been reported with prenatal exposure to tricyclic antidepressants. The mechanism by which antidepressants might increase risk for PTB and LBW is not clear. Some studies suggest that the effects of antidepressants on birth outcome may be additive to the effects of untreated or underlying maternal depression and anxiety on birth outcome.
Congenital Malformations
Mixed results have been reported about increased risks of congenital malformations with first trimester exposure to antidepressants. If an increased risk does exist, it is a small increase in absolute risk (approximately 0.5 % with antidepressants vs. 0.3 % in unexposed pregnancies) and no consistent organ malformation has been reported with antidepressants as a class [7, 8]. There is a possibility of increased cardiac septal defects with paroxetine (1 % vs. 0.7 % in unexposed pregnancies) [9] and left outflow tract heart defects with bupropion [8]. The mechanism by which antidepressants might increase cardiac malformations is not clear, but altered serotonergic influence on cardiac development is hypothesized. Study results have been inconsistent, and the small absolute increased risks could be due to the antidepressant, the underlying illness, or unknown factors associated with either or both [8].
Persistent Pulmonary Hypertension of the Newborn
Persistent pulmonary hypertension of the newborn (PPHN) occurs in 1–2 infants per 1,000 live births. PPHN occurs when there is failure of the normal relaxation in the fetal pulmonary vascular bed during the circulatory transition that occurs shortly after birth. The elevated pulmonary hypertension causes right-to-left shunting of extrapulmonary blood through the ductus arteriosus and foramen ovale, which can lead to hypoxemia, respiratory distress, acidosis, and right heart failure. There is a 10–20 % mortality risk which varies with etiology.
Risk Factors: Meconium aspiration or other lung injury, prematurity, postmaturity, hypoglycemia, cold stress, inflammation, sepsis, pulmonary hypoplasia, nonsteroidal anti-inflammatory drug use, lower socioeconomic status, diabetes, urinary tract infections, tobacco use, smoking, cesarean section delivery, increased maternal weight, and fetal male gender.
Potential Etiologies: Increased vasoconstriction of smooth muscle cells and/or decreased production of nitric oxide, a potent vasodilator. SSRIs may influence serotonin effects on pulmonary vascular smooth muscle endothelium [10].
Increased Risk with SSRIs
Three of 6 studies have reported increased risk (risk ratio up to 5) of PPHN with SSRI use in the second half of pregnancy; the 3 studies reporting an increased risk have large sample sizes [11]. The absolute risk is approximately 0.3 % with SSRI use after week 20 of pregnancy [12]. This increased risk has been noted with fluoxetine, sertraline, paroxetine, and citalopram. PPHN may represent the severe end of a spectrum of respiratory difficulties with SSRI exposure.
The mortality rate with SSRIs (in the one study that had mortality from PPHN in babies exposed to SSRIs) was reported equal to the mortality rate without exposure to SSRIs [12].
In July 2006, the FDA issued a Public Health Advisory stating that in one study, PPHN was six times more common in babies whose mothers took an SSRI antidepressant after the 20th week of the pregnancy compared to babies whose mothers did not take an antidepressant. The FDA advised careful consideration of the potential benefits and risks of the medication for each individual pregnant patient.
In December 2011, the FDA issued a Safety Announcement advising health-care professionals not to alter their current clinical practice of treating depression during pregnancy due to conflicting findings of studies of SSRI use during pregnancy and the development of PPHN.
Postnatal Adaptation Syndrome
An FDA Alert in 2004 warned that neonates exposed to SSRIs or SNRIs late in the third trimester may develop complications following delivery requiring prolonged hospitalization, respiratory support, and tube feeding.
Neonatal symptoms include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.
Prevalence: 10–30 % of newborns exposed to SSRIs and SNRIs. Postnatal adaptation syndrome (PNAS) has been most frequently associated with fluoxetine, paroxetine, and venlafaxine third trimester exposure.
Potential Etiologies: Serotonin toxicity due to accumulation of antidepressant in the neonate, cholinergic overdrive, and discontinuation syndrome from abrupt discontinuation of neonate exposure to antidepressant [13].
Course: Symptoms usually transient with spontaneous resolution within 2 weeks.
Treatment: Observation of neonate and supportive treatment as needed; intensive care may be indicated for a few days. Although the FDA made a suggestion in 2004 to taper antidepressants prior to expected delivery, there is no evidence that tapering the dose of antidepressant prior to expected delivery lessens neonatal adaptation symptoms, and this strategy could increase the risk of postpartum depression (PPD).
Long-Term Effects on Child Development
SSRI use in pregnancy has been associated with mild developmental delays in motor development and attention in 1–3 yo children; these delays are within normal limits and seem to resolve with age.
Exposure to prenatal depression, not prenatal exposure to antidepressants, has been associated with problematic behaviors in 3–6 yo children.
SSRI use in pregnancy has been associated with 2–3 times increased risk of autism spectrum disorders in some but not all studies [14].
Continued exposure to untreated maternal depression beyond the first postpartum year continues to be a critical risk for cognitive and behavioral problems in childhood and contributes to long-term psychopathology in the child and adolescent.
Other Possible Negative Effects from Antidepressant Use During Pregnancy
New onset hypertension or preeclampsia
Prolonged QT interval in the newborn
Increased mortality in the first month or year of life
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