American Academy of Neurology AAN
American Academy of Pediatrics AAP
American College of Obstetricians and Gynecologists ACOG
Antiepileptic drug AED
Anorexia nervosa AN
Bipolar disorder BD
Body mass index BMI
Bulimia nervosa BN
Cognitive behavioral therapy CBT
Concentration/dose (ratio) C/D
Confidence interval CI
Diagnostic and Statistical Manual of Mental Disorders DSM
Docosahexaenoic acid DHA
Edinburgh Postnatal Depression Scale EPDS
Electroconvulsive therapy ECT
Eicosapentaenoic acid EPA
Fetal alcohol syndrome FAS
Fetal alcohol spectrum disorder FASD
Food and Drug Administration FDA
Human immunodeficiency virus HIV
Intrauterine growth restriction IUGR
Low birthweight LBW
Major depressive episode MDE
Mood disorders questionnaire MDQ
Neonatal abstinence syndrome NAS
Nicotine replacement therapy NRT
Opioid agonist therapy OAT
Odds ratio OR
Postpartum depression PPD
Preterm birth PTB
Posttraumatic stress disorder PTSD
Randomized controlled trial RCT
Relative risk RR
Small for gestational age SGA
Selective serotonin reuptake inhibitor SSRI
Serotonin-norepinephrine reuptake inhibitor SNRI
Substance use disorder SUD
Sudden infant death syndrome SIDS
Thyroid-stimulating hormone TSH
Valproic acid VPA
“Mental health is fundamental to health.” This statement, made by Surgeon General David Satcher, emphasized the foundation that emotional well-being provides for health. 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 (version 5, or DSM-V ), a classification system that divides mental disorders into types based on criteria sets with defining features. This chapter covers the major categories of disorders that affect women of childbearing age. For the pregnant woman and her family, the capacity to function optimally, enjoy relationships, manage the pregnancy, and prepare for 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 outcome. Misra and colleagues presented a perinatal framework that integrates a life-span approach with multiple determinants ( Fig. 55-1 ). The model contains four levels that provide a paradigm for the determinants of perinatal health outcomes. The first level in the model is distal determinants, which focuses on distal (in time) risk factors that place a woman at greater susceptibility to proximal (current) risk factors. Distal determinants from biologic, physical, and social domains increase or decrease a woman’s likelihood of developing health problems, engaging in high-risk behaviors, or being exposed to potential toxins. Some of the most powerful influences on pregnancy outcome are related to historic women’s health factors that occur long before pregnancy, such as maltreatment during childhood. At the next level, proximal determinants, risk factors that have a direct impact on a woman’s health, are represented by biomedical and behavioral responses; for example, cigarette smoking. The interaction between distal and proximal risk factors determines an individual’s current overall health status. The relationship between a woman’s health status directly before conception and the demands of pregnancy affect perinatal health outcomes. The third level, processes, emphasizes the dynamic interaction of preconceptional, interconceptional, and intraconceptional factors on reproductive health. At the fourth level, outcomes, the model includes disease, function, and well-being, which provide a comprehensive view of health status.
Each patient comes to pregnancy with sets of malleable risks and assets. To the extent that biopsychosocial exposures with negative impact upon pregnancy outcome can be diminished, eliminated, or replaced with positive factors, pregnancy outcome can be improved. The role of the physician is to influence the patient’s exposures and behaviors to improve the probability of positive reproductive outcomes (see Fig. 55-1 ). Childbearing is an ideal time for health interventions because women have contact with professionals and access to health care coverage and are motivated toward positive behaviors to invest in the welfare of their offspring. The role of fathers has recently been identified as a research gap, and opportunity, in perinatal mental health. The father, partner, or a significant other can be engaged in interventions to reduce maternal stress, encourage prenatal care, and eliminate drug and alcohol use.
Our discussion of psychiatric disorders includes five major diagnostic categories that commonly occur in women of childbearing age: (1) mood, (2) anxiety, (3) eating disorders, (4) substance use disorders, and (5) schizophrenia. Our review focuses on the interrelationships among these disorders and their courses during pregnancy and postpartum and during lactation. The impact of childbearing on existing disorders or vulnerabilities in the female patient is reviewed along with episodes that are etiologically related to childbearing.
Major Depressive Episode
Diagnosis and Prevalence During Pregnancy and Postpartum
In the DSM-V, a major depressive episode (MDE) is defined as at least a 2-week period of either persistent depressed mood or loss of interest or pleasure in daily activities, so-called gatekeeper symptoms, plus four associated symptoms (three if both gatekeeper symptoms are present; see Box 55-1 ). Persistent means 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. It is possible to have a diagnosis of MDE without the symptom of depression. A woman could have persistent loss of interest or pleasure but no sadness and yet have four other symptoms noted in the DSM-V criteria for major depressive disorder. Note that appetite, sleep, and motor activity can be either decreased or increased relative to the woman’s norm. A fatigued woman who derives no pleasure from previously enjoyable activities, sleeps 15 hours per day, sits immobile for long periods, and is gaining weight has MDE. A guilt-ridden woman with sadness, 4 hours of sleep nightly, weight loss of 15 pounds, and pacing also has MDE, which may be episodic or chronic.
Over the last 2 weeks, most of the day nearly every day, five of the following (one symptom must be mood or interest) must cause marked distress or impairment in important areas of functioning:
Markedly diminished interest or pleasure
Significant weight loss or gain unrelated to dieting
Insomnia or hypersomnia
Fatigue or loss of energy
Feelings of worthlessness/guilt
Diminished ability to concentrate
Recurrent thoughts of death
Nearly twice as many women (12.0%) as men (6.6%) suffer from an MDE each year. Women are at the greatest risk for MDE between 25 and 44 years, the primary age for childbearing. The period prevalence of MDE is 12.7% during pregnancy (with 7.5% of women having a new episode), and 21.9% the year after parturition ; therefore, MDE is among the most common complications of childbearing. Mothers at increased risk are disadvantaged, have preterm infants, and are in adolescence. Depression persists from months to years after childbirth, with lingering limitations in physical and psychological functioning after recovery. Of women with postpartum MDE, 25% to 50% have episodes that last 7 months or more.
As predicted by the multiple determinants model (see Fig. 55-1 ), MDE has contributions from several risk factor domains. In women, the strongest predictors were stressful life events, genetic factors, history of an MDE, and high emotional sensitivity. Similarly, stressful life events and a history of MDE in the woman or her family are predictors of postpartum-onset MDE. Women with postpartum MDE are at increased risk (about 25% to 33%) for recurrence after a subsequent birth, and over 40% have nonpostpartum MDE.
The DSM-V allows the designation with peripartum onset to specify episodes that begin during pregnancy or within the first 4 weeks postpartum. Epidemiologists have defined the duration of postpartum based on data about the break point between elevated risk for psychiatric illness after birth and the baseline risk for episodes in childbearing-aged women. Kendell and Munk-Olsen and their colleagues found a significant peak in the rate of mood disorders in the 90-day period after childbirth. Although the definition of postpartum varies, the adverse effects of the disorder for the woman and her family are independent of time of onset.
The most commonly used measure to screen for MDE during childbearing is the Edinburgh Postnatal Depression Scale (EPDS; Fig. 55-2 ), which has been validated for use both during and after pregnancy. This self-report measure contains 10 items ranked from 0 to 3. Scored by simple addition, the EPDS is free to health care professionals and is available in 23 languages. A cutoff score of greater than or equal to 13 (the sensitivity for identifying MDE is 86%, specificity is 78%, positive predictive value is 73%) was recommended for screening for MDE in clinical settings. For pregnant women the recommended cutoff score is greater than or equal to 15. As with any screening tool, a positive test must be followed by diagnostic evaluation and treatment guidance. The differential diagnosis of MDE in the early postbirth period includes the “baby blues,” a transient syndrome that occurs in 80% of mothers that resolves by day 10 postpartum (see Chapter 23 ).
Natural History Across Childbearing
Periods of hormonal fluctuation—menstrual cycle, pregnancy, postpartum, and perimenopause—are associated with MDE. Investigators have suggested that the rapid change in gonadal steroid concentrations contributes to the etiology of postpartum-onset MDE. The neurobiology of women who develop postpartum depression (PPD) appears especially vulnerable to the mood-destabilizing effects of withdrawal from gonadal steroids.
Postpartum MDE does not differ from MDE at other periods during the childbearing years with respect to clinical presentation and duration of untreated episodes. However, aggressive obsessional thoughts occur more commonly in women who have postpartum-onset MDE compared with those whose depression falls outside the 1-year postbirth period. Delusions must be differentiated from the far more common obsessional thoughts in the context of depression. Obsessions are recurrent and persistent thoughts, impulses, or images that are experienced as intrusive and inappropriate and cause marked anxiety or distress. For example, some mothers have obsessional thoughts about drowning their baby and refuse to bathe the child. Women often have “what if” questions such as, What if I throw the baby over the banister? Obsessions differ from psychotic symptoms because the patient recognizes that the thoughts, impulses, or images are a product of her own mind (not imposed by an external force as might occur in psychosis). Additionally, obsessional visual images may occur but are brief and are perceived as being in the “mind’s eye” as opposed to an external hallucination. For example, a woman might have frightening images of her dead baby in a bathtub, but she is aware that the image does not reflect reality. The distinction is important clinically because women with obsessional thoughts are vigilant about preventing any action related to the thought content (e.g., insisting that all kitchen knives be locked away), whereas women with psychosis are at risk for taking action. Although these symptom sets are not mutually exclusive, co-occurrence is very rare.
The physiologic milieu created by MDE adversely impacts maternal function during pregnancy and postpartum. MDE is associated with poor prenatal care compliance, inadequate nutrition, obesity, smoking, alcohol and drug use, and suicide. A meta-analysis affirmed that MDE during pregnancy was associated with both low birthweight (LBW) and preterm birth (PTB). Offspring of pregnant women with MDE are at risk for insecure attachment and sleep and eating disorders. Children with in utero exposure to maternal MDE are four times more likely to be depressed at age 16 years.
Psychiatric illness during rapid development of the infant creates a new generation at risk. Maternal depression increases the risk for long-lasting adverse effects such as insecure attachment and poor cognitive performance. Other sequelae of maternal mental illness are increased rates of accidental injury, child abuse, neglect, and infanticide. Early identification and intervention for postpartum MDE has the potential to prevent negative sequelae for women and their families. The relationship between maternal MDE and multiple childhood problems is a continuum that often becomes apparent during pregnancy.
Treatment of Major Depressive Episode During Pregnancy
The emergence of MDE during childbearing compels a complete medical and family history, review of systems, and physical exam to assess for contributions to depressive symptoms, particularly thyroid abnormalities and anemia. Our experience is that MDE seldom remits with correction of hypothyroidism alone, and treatment for both is required. The use of prescribed and over-the-counter medications, herbal therapies, drugs, and alcohol must be assessed.
Although MDE is a highly prevalent condition, only 1 in 5 Americans receives any guideline-concordant intervention, and the rate is lower in pregnant women than in nonpregnant women. In nearly 6500 Medicaid recipients with established MDE treatment, women who became pregnant had a significantly greater drop in both outpatient psychotherapy visits and antidepressant prescription claims compared with matched nonpregnant women, and care did not resume after birth.
Evidence-based treatments for MDE are psychotherapy and antidepressants. Studies of interpersonal psychotherapy and pharmacotherapy document both reduced depressive symptoms and improved maternal function following treatment during pregnancy. Psychotherapy is the preferred treatment for most women ; however, it is not available in all practice settings, nor is it feasible for many mothers. Barriers to clinic-based depression care include the physical demands of pregnancy, transportation, childcare for other children, and cost. Adult outpatient settings do not typically offer flexible appointment schedules or allow children on site. If psychotherapy is not feasible, or the woman prefers pharmacotherapy, decision making tends to focus on the potential adverse effects of medication rather than the adverse effects of MDE. The result is often the choice by the woman or her physician to avoid or stop drug treatment to obviate fetal exposure without equal consideration of the risks of MDE to both the mother and fetus. For most pregnant women, the reality is that accessible and acceptable mental health treatment is very limited. Low treatment rates are a public health concern given accumulating evidence that MDE increases risk to the pregnant woman and fetus. Federally funded home visitation programs for disadvantaged women are potential adjuncts for collaborative care with obstetricians and mental health professionals to improve rates of depression treatment.
The risk-benefit decision-making process for treatment of MDE during pregnancy was described by representatives from the American Psychiatric Association. Individually tailored interventions are considered for their capacity to maximize maternal wellness while minimizing adverse effects for the maternal-fetal pair. The patient and physician both contribute expertise to the process, because the patient’s assignment of her own values dictates her choice. For example, some women will not consent to pharmacotherapy during pregnancy regardless of the impairment related to the MDE. Others choose pharmacotherapy because they are not confident that other treatments will be efficacious or because discontinuing medication invariably has been followed by recurrence with psychosocial consequences. The verbal informed consent process promotes the treatment alliance, recognizes the patient’s responsibility to make choices for herself and her baby, and provides an opportunity for ongoing assessment of the woman’s competence to make decisions.
Although used commonly, the word safe is problematic because it implies no possibility of an adverse effect. Confirming any exposure as harmless presents the impossible task of proving no effect on a monumental number of reproductive and developmental outcomes throughout the exposed offspring’s lifespan. What can be estimated from available studies is the magnitude of a subset of reproductive risks in antidepressant-treated women. The risks for multiple domains of reproductive toxicity considered in this chapter are miscarriage, intrauterine fetal demise, structural malformations, growth effects, neurobehavioral teratogenicity, and neonatal effects (see Chapter 8 ). A prominent observation from the literature is the methodologic difficulty of separating the reproductive effects of the drug exposure from the sequelae, both physiologic and psychosocial, of the underlying MDE.
Side Effects of Medical Treatment of Major Depressive Episode During Pregnancy
In a cohort study of all registered pregnancies in Denmark from 1997 to 2010, the adjusted hazard ratio for miscarriage after exposure to a selective serotonin reuptake inhibitor (SSRI) was 1.27 (95% confidence interval [CI], 1.22 to 1.33) compared with no exposure. However, women who discontinued SSRI treatment 3 to 12 months before pregnancy also had a similar increased hazard ratio of miscarriage (1.24; 95% CI, 1.18 to 1.30). In a population-based Danish cohort study, stillbirth and neonatal mortality were not associated with first-trimester SSRI use.
Studies of first-trimester SSRI exposure do not demonstrate consistent data to support an increased risk for structural malformations. Two large-scale case control studies revealed no increased risk rates overall for malformations, including cardiac anomalies, with SSRI exposure (combined drugs). Louik and colleagues compared the rates of malformation among 9849 cases and 5860 control infants. Analyses of the associations between individual SSRIs and specific defects showed significant associations between the use of sertraline and omphalocele (odds ratio [OR], 5.7; 95% CI, 1.6 to 20.7) and cardiac septal defects (OR, 2.0; 95% CI, 1.2 to 4.0) and between the use of paroxetine and right ventricular outflow tract obstruction defects (OR, 3.3; 95% CI, 1.3 to 8.8). At the same time, Alwan and colleagues published outcomes from 9622 infants with major birth defects and 4092 control infants born from the National Birth Defects Prevention Study. Maternal SSRI use was associated with anencephaly (OR, 2.4; 95% CI, 1.1 to 5.1); craniosynostosis (OR, 2.5; 95% CI, 1.5 to 4.0), and omphalocele (OR, 2.8; 95% CI, 1.3 to 5.7). In an accompanying editorial, Greene noted that the malformations reported in each study were different and that most had not been previously associated with SSRI exposure.
The relationship between SSRI use in pregnancy and cardiovascular defects has been the focus of recent studies. Bérard and colleagues conducted a population-based cohort study in Quebec of 18,493 depressed or anxious women who were exposed to sertraline ( n = 366), other SSRIs ( n = 1963), or a non-SSRI antidepressant ( n = 1296) and unexposed women in the first trimester. Sertraline use was not significantly associated with the risk of overall major malformations when compared with the no-exposure group. However, sertraline exposure was associated with an increased risk of atrial/ventricular defects (relative risk [RR], 1.34; 95% CI, 1.02 to 1.76) and craniosynostosis (RR, 2.03; 95% CI, 1.09 to 3.75). Exposure to SSRIs other than sertraline during the first trimester of pregnancy was associated with craniosynostosis (RR, 2.43; 95% CI, 1.44 to 4.11) and musculoskeletal defects (RR, 1.28; 95% CI, 1.03 to 1.58). Although analyses were adjusted for potential confounders, data on smoking, folic acid intake, alcohol use, and body mass index (BMI) were missing. Whereas the design included women with a history of depression or anxiety, antidepressant-treated women differ from unmedicated women, which is inherent in observational studies in which randomization is not used.
In a Danish study, the rate of congenital heart malformations was similar for pregnancies exposed to continuous SSRI use throughout the first trimester (OR, 2.01; 95% CI, 1.60 to 2.53) and for pregnancies in which SSRI treatment was paused during pregnancy (OR, 1.85; 95% CI, 1.07 to 3.20; P = .94). Similar risk estimates for specific cardiac malformations were found for individual SSRIs, and no dose-response relationship was observed. Similarly, in a recent American population-based cohort study, Huybrechts and colleagues found no increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester. A total of 64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6403 infants who were not exposed to antidepressants were born with a cardiac defect (72.3/10,000 infants), compared with 580 infants with exposure (90.1/10,000 infants). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. The relative risks of any cardiac defect with the use of SSRIs were 1.25 (95% CI, 1.13 to 1.38) in the unadjusted analysis, and markedly attenuated, 1.12 (95% CI, 1.00 to 1.26), in the analysis restricted to women with depression. Importantly, substantial differences in the characteristics of the patients who were treated, compared with untreated subjects, remained. Stratification according to propensity scoring achieved that comparisons were made between groups with almost identical characteristics. This strategy further attenuated the remaining positive association to 1.06 (95% CI, 0.93 to 1.22). No significant association was observed between the use of paroxetine and right ventricular outflow tract obstruction or between sertraline and ventricular septal defects. A similar pattern of increased risk was reported for cardiac malformations in unadjusted analyses, which became insignificant after adjustment was noted for tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion, and other antidepressants.
Preterm Birth and Growth Effects
In a meta-analysis, Grote and colleagues reported that maternal MDE or depressive symptoms during pregnancy increase the risk of PTB and LBW. The associations between antenatal depression and adverse outcome included PTB (RR, 1.13; 95% CI, 1.06 to 1.21) and LBW (RR, 1.18; 95% CI, 1.07 to 1.30) but not intrauterine growth restriction (IUGR). The magnitude of risk for PTB and LBW from gestational depression is comparable to the risk of smoking 10 or more cigarettes a day, but it is modest compared with the higher risks associated with black race and substance abuse. In a prospective study ( n = 238) of pregnant women with MDE, MDE with SSRI treatment, and controls with neither exposure, women with MDE who were either continuously treated with an SSRI (23%) or continuously exposed to MDE (21%) experienced PTB. The rates of late and early PTB were similarly distributed. Postnatal weight, head circumference, and length growth trajectories did not differ across the first year in infants exposed to a selective SNRI or to depression or to neither during pregnancy.
Behavioral teratogenicity refers to long-term postnatal effects on offspring behavior due to prenatal exposure to agents that affect the central nervous system. Cognitive function, temperament, and overall behavior were similar in children who were exposed prenatally to tricyclics or fluoxetine compared with controls. Few data about the postbirth development of individuals exposed in utero to SSRIs have been published; however, all converge on the finding that mental development is similar in exposed compared with unexposed children. Nulman and colleagues conducted intelligence testing on 3- to 7-year-old children who had been exposed in utero to an SSRI ( n = 62) or venlafaxine ( n = 62) or depression without medication ( n = 54) and controls ( n = 62). Exposure group, drug dose, and duration of drug treatment during pregnancy did not significantly affect cognitive function.
In a longitudinal study, 68 infants with prenatal SSRI ( n = 41) or MDE exposure ( n = 27) and 98 nonexposed controls were evaluated with the Bayley Scales of Infant Development. Neither prenatal exposure to an SSRI nor an MDD significantly impacted overall scores; however, SSRI exposure was associated with lower psychomotor development scores at 26 and 52 weeks compared with nonexposed infants, although this difference was no longer significant at 78 weeks. Although lower psychomotor scores were observed in the first year, the scores remained well within the normative range and were transient.
Direct serotonergic effects and/or withdrawal signs can occur in neonates after prenatal exposure to antidepressants. Compared with early gestational SSRI exposure or no exposure, late SSRI exposure incurs an overall risk ratio of 3.0 (95% CI, 2.0 to 4.4) for neonatal behavioral syndrome. Most SSRI-related neonatal case reports involve paroxetine and fluoxetine. Neonatal signs include central nervous system, motor, respiratory, and gastrointestinal signs that are usually mild and transient with resolution by 2 weeks of age. A severe syndrome that consists of seizures, dehydration, excessive weight loss, and hyperpyrexia is rare in full-term infants (1/313 cases). Based on the premise that neonatal signs are due to direct pharmacologic effects, tapering and discontinuation of the antidepressant over 10 days to 2 weeks before the delivery date with reintroduction of drug immediately after birth has been suggested ; however, data to demonstrate improved outcomes for mothers or newborns have not been published. If a woman has a history of rapid decompensation during antidepressant taper or discontinuation, this strategy is likely to carry more risk to the maternal-fetal pair than continued treatment.
Recommendations for Treatment During Pregnancy
The American College of Obstetricians and Gynecologists (ACOG) and the American Psychiatric Association developed a consensus document for antidepressant treatment during pregnancy. For mild cases of MDE in pregnant women, psychotherapy is the treatment of choice as the initial intervention. Depressed pregnant women treated with interpersonal psychotherapy had a significant symptomatic improvement compared with a parenting education control group, and 60% of women achieved remission criteria. Other focused, short-term therapies such as cognitive behavioral therapy (CBT) are also effective options for MDE and may be delivered by nonphysician professionals such as psychologists, psychiatric nurse clinicians, or licensed clinical social workers. The cost and accessibility of depression treatment also impacts treatment selection.
For moderate to severe MDE with marked functional impairment, antidepressant pharmacotherapy or combination therapy (medication and psychotherapy) is appropriate. Established efficacy and tolerability of any antidepressant for the individual woman is a strong consideration in drug choice during the risk-benefit decision-making process. Women with chronic or highly recurrent MDE may be on maintenance antidepressant medication when pregnancy occurs. Maintenance antidepressant treatment is recommended after three or more MDEs due to the near-certain likelihood of recurrence. For pregnant women studied in an academic setting, the risk of relapse for those who discontinued antidepressant usage proximate to conception was significantly greater than women who maintained treatment. Among 82 women who continued their medication, 21 (26%) relapsed compared with 44 (68%) of 65 women who discontinued medication. In contrast, Yonkers and colleagues found that pregnant women who continued antidepressants experienced the same rate of MDE recurrence as women who stopped in a community sample of obstetric patients. A predictive factor for recurrence in both studies were highly recurrent MDE (four or more episodes prior to pregnancy).
Dosage Changes Across Pregnancy
All TCAs and SSRIs are at least partially metabolized by cytochrome P450 (CYP) 2D6, which is induced in pregnancy and results in declining serum concentrations. In a publication about managing tricyclic dosages across pregnancy, a strategy to determine the minimum effective dose across gestation was suggested. The women selected a target depressive symptom that was most disturbing, typically insomnia or irritability. Women were asked to contact the physician each time the symptom emerged, and an incremental dose was added. The dosages increased during the second half of pregnancy and rapidly accelerated in the third trimester. The final dose near term was an average of 1.6 times the nonpregnant dose.
Similarly, the dose requirements and concentration-dose (C/D) ratios of the SSRIs fluoxetine, citalopram, escitalopram, and sertraline changed during pregnancy and postpartum. In the majority of women, the C/D ratios for the parent compound and primary metabolites decreased between 20 weeks’ gestation and delivery, which reflects increased drug metabolism. Pharmacogenetic characterization is not a standard of care for antidepressant therapy; however, Ververs and colleagues showed that CYP 2D6 genotypes predicted plasma paroxetine concentrations during pregnancy. Women who were extensive metabolizers ( n = 43) and ultrarapid metabolizers ( n = 1) showed steadily decreasing plasma paroxetine concentrations across pregnancy. In contrast, plasma paroxetine levels of intermediate metabolizers ( n = 25) and poor metabolizers ( n = 5) increased during pregnancy. Weight gain, maternal age, and smoking did not influence drug concentrations. In extensive and ultrarapid metabolizers, the depressive symptoms increased significantly during the course of pregnancy. Paroxetine is unique among the SSRIs in having 2D6 as the sole metabolic pathway. For TCAs and most SSRIs, dose requirements often increase during the second half of pregnancy to offset greater drug metabolism. Serial administration of a quantitative depression measure is recommended to identify early symptoms of relapse. The goal is to provide optimal drug dosing across the changing milieu of pregnancy to maximally reduce disease burden.
Known as a treatment for seasonal (winter) MDE, light therapy is also efficacious for nonseasonal MDE. Bright light, delivered as an early morning bolus of 10,000 lux illuminance with commercially available boxes, is an efficacious treatment for MDE. The light units conform to stringent standards, with illumination of a broad visual field, lighting from above to avoid glare, and ultraviolet screening. Light therapy for pregnant women with MDE was explored in a small randomized controlled trial (RCT) with bright white versus dim (inactive) arms. The response rates were significantly greater for bright compared with dim light after 5 weeks of 1 hour of early morning light and were comparable to antidepressant treatment. A clinician’s guide is available.
Manber and colleagues performed an RCT ( n = 150) of acupuncture treatment specific to MDE, acupuncture treatment targeted to a condition other than MDE, and a comparison group that received massage. Women who received acupuncture specific for MDE had a significantly greater response rate than those who received the other treatments; again, this response was comparable to that of standard MDE treatments.
Poor nutrition may contribute to the pathogenesis of MDE. Folate and vitamin B 12 are needed for single-carbon metabolism involved in the synthesis of serotonin and other monoamine neurotransmitters and catecholamines. Folate, B 12 , iron, zinc, and selenium deficiencies are more common among depressed than nondepressed persons. The depletion of nutrient reserves throughout pregnancy and lactation may increase a woman’s risk for MDE. Marginal or low folate status also increases the likelihood of nonresponse to antidepressant medication as well as the probability of relapse. Several RCTs have demonstrated that folic acid is an efficacious augmentation strategy for antidepressant medications.
Omega-3 fatty acids are essential long-chain polyunsaturated fatty acids found in nerve cell membranes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are derived primarily from fish. The American diet is relatively deficient in omega-3 compared with omega-6 fatty acids and other fats. Increased requirements during pregnancy raise the risk of deficiency and potentially of MDE. In cross-national studies, an inverse relationship has been shown between per capita fish intake and prevalence rates of MDE, postpartum MDE, and bipolar disorder. Supplementation with 1 gram of EPA and DHA has been recommended for patients with mood disorders. Omega-3 fatty acids have been used to treat perinatal MDE in small RCTs, but efficacy beyond placebo has not been convincingly demonstrated. However, DHA supplementation may attenuate the effects of maternal stress during late pregnancy and can reduce fetal exposure to glucocorticoids in women living in urban low-income environments. Women who received supplementation reported less stress and had lower levels of stress hormones in the third trimester than placebo-treated women. Omega-3 fatty acids have antiinflammatory effects that may contribute to the mechanism of action.
Treatment of Major Depressive Episode in the Postpartum Period
Medications effective for MDE in women outside of childbearing are effective during childbearing. In a randomized comparative efficacy trial, the tricyclic nortriptyline (NTP; n = 54) was compared with sertraline ( n = 55), and the response rates were equal. The dosing started with 10 mg for NTP and 25 mg sertraline for 2 days then 25 mg/day NTP and 50 mg/day sertraline thereafter, and it was increased every 2 weeks to a maximum of 150 and 200 mg/day, respectively. The total side effect burden for both drugs was similar, although the types differed for each drug. A major finding was that the dose of sertraline required for remission in this 8-week, double blind protocol was 100 mg/day or more, with many women requiring 150 to 200 mg/day. The starting dose of sertraline 50 mg/day was not efficacious in the majority of women, and dose adjustment should be anticipated approximately 2 weeks after treatment initiation. An RCT of sertraline versus placebo demonstrated efficacy for sertraline with a mean dose of 100 ± 54 mg/day.
In a small novel RCT of the efficacy of estradiol treatment, women with severe postpartum MDE were randomized to placebo or estradiol delivered by transdermal patch (200 µg/day) for 6 months. By 3 months, 80% of the estradiol-treated and 31% of the placebo-treated group responded. Endometrial changes were found in three participants at the end of the study, despite coadministration of dydrogesterone (10 mg/day, 12 days/month in the final 3 months of the RCT). The changes resolved at follow-up. The inclusion of women who took concurrent antidepressant medications limits the ability to discern an estradiol-specific effect. Little is known about estradiol secretion into breast milk; however, it was not detected in the milk of 18 women who used transdermal estradiol 50 to 100 µg/day for 12 weeks.
Prevention of Postpartum-Onset Major Depressive Episode
To reduce the risk for postpartum MDE, an interpersonal therapy-based group intervention was provided to pregnant women on public assistance. Within 3 months after delivery, 20% of the women in standard care developed postpartum MDE compared with 4% of women who received the intervention. Studies of antidepressants or hormones for the prevention of postpartum MDE are limited to three RCTs, with one small RCT demonstrating the efficacy of sertraline. Women with a history of MDE were treated with sertraline immediately following birth to prevent the onset of MDE. The dosing protocol was, in mg/day, 25 for 4 days, then 50 mg through week 4, and 75 thereafter. The duration of preventive treatment was a minimum of 6 months. The explanation for sertraline’s efficacy is based on its serotonergic impact; therefore, use of another serotonergic drug, particularly one to which the woman had previously responded, is appropriate. Although open studies supported that progesterone prevented recurrence, a placebo-controlled RCT of a synthetic progesterone increased the risk of depression after birth.
Treatment During Breastfeeding
The magnitude of antidepressant exposure through breast milk is substantially lower than during pregnancy ( Table 55-1 ). Comprehensive reviews of antidepressant drugs in maternal serum, breast milk, and infant serum have been published. Sertraline or paroxetine (among SSRIs) and nortriptyline (among TCAs) are agents of choice. These drugs are characterized by undetectable or very low breastfed-infant serum concentrations and no reports of adverse events. However, established efficacy of another drug for the woman must be considered strongly in the decision-making process. Although TCAs are reasonable treatments for postpartum MDE, they are second-line drugs due to their toxicity in overdose. More recently released antidepressants are second-line choices for breastfeeding women unless efficacy in prior episodes has been established.
|ANTIDEPRESSANT DRUG †||SERUM LEVEL RANGE IN BREASTFED INFANTS||TYPICAL MATERNAL DOSE RANGE (mg/day)|
|Nortriptyline *||Nortriptyline, below limit of quantifiability to 10 ng/mL||50-150; maternal therapeutic serum levels are 50 to 150 ng/mL|
|Nortriptyline metabolites||E-10-OH–nortriptyline = <4-16 ng/mL|
|Z-10-OH–nortriptyline = <4-17 ng/mL|
|Sertraline||Sertraline, below limit of quantifiability to 8 ng/mL||50-200|
|Sertraline metabolites||Norsertraline, below limit of quantifiability to 26 ng/mL|
|Paroxetine||Paroxetine, below limit of quantifiability||10-60|
|No active metabolites|
|Fluoxetine||Fluoxetine, below quantifiability to 340 ng/mL||20-60|
|Fluoxetine metabolite ‡||Norfluoxetine, below quantifiability to 265 ng/mL|
|Citalopram||Citalopram, below quantifiability to 12.7 ng/mL||20-40|
|Citalopram metabolite||Desmethylcitalopram, below quantifiability to 3.1 ng/mL|
|Venlafaxine||Venlafaxine, below quantifiability to 5 ng/mL||75-300|
|Venlafaxine metabolite||O-desmethylvenlafaxine, below quantifiability to 38 ng/mL|
|Bupropion||Average infant exposure expected to be 2% of the standard maternal dose on a molar basis; infant serum levels not measured in largest series ( n = 10) §||300|
The clinical condition of breastfed infants, particularly those who are sick or LBW, should be monitored to detect adverse effects that may be associated with the maternal drug (behavioral activation or sedation, new-onset feeding or sleeping problems; see Chapter 24 ). Routine laboratory measurement of serum drug levels in healthy full-term infants is not warranted; however, serum concentrations in preterm and sick infants have not been described and would be a welcome contribution to the literature.
Psychiatric Disorders and Suicidal Ideations
Oates performed an evaluation of the Confidential Enquiry into Maternal Deaths from the United Kingdom. Psychiatric disorder, and suicide specifically, was the leading cause of mortality and accounted for 28% of maternal deaths. Women also died of other complications related to psychiatric disorders and substance abuse, and they died violently. In a large scale study of 10,000 women screened with the EPDS, the proportions of response on item 10—“The thought of harming myself has occurred to me”—were for 0, or never, 96.81% ( n = 9681); for 1, or hardly ever, 2.46% ( n = 246); for 2, or sometimes, 0.65% ( n = 65); and for 3, or yes quite often, it was .08% ( n = 8). In this group of 10,000 women screened by phone, 3.2% of women had some degree of suicidal ideation.
Suicide assessment requires direct questioning of the patient about her desire to live or die, specific thoughts about killing herself, plans for carrying out the act, and access to and lethality of means. The American Psychiatric Association guidelines for the assessment of suicidal behaviors provide a comprehensive list of questions that help clinicians assess suicidal thoughts, plans, and behaviors. Initial questions address patients’ feelings about living (Have you ever thought that life was not worth living? Did you ever wish you could go to sleep and just not wake up?) and are followed by questions that address specific thoughts about death, self-harm, and suicide (Have things ever reached the point that you’ve thought of harming yourself?). If thoughts of self-harm are disclosed, clinicians should evaluate the details such as the intensity, frequency, timing, persistence, and circumstances. Physicians must also ask whether the patient has made a specific plan for self-harm. Ask about pills, household poisons, and firearms. Has the patient made preparations to enact the plan or for after her death (purchasing the means, writing a will, arranging for child care)? If the safety of the patient is at risk, emergency psychiatric consultation or involuntary commitment is indicated.
The practice guidelines identify situations in which suicide assessment is warranted: emergency department evaluation, an abrupt change in clinical symptoms, lack of improvement or worsening despite treatment, anticipation or experience of an interpersonal loss or stressor (divorce, loss of custody of children, financial loss, legal problems), or a physical illness associated with a threat to life, severe pain, or loss of function. Patients with increased risk are those with previous suicide attempts, major mood disorders (particularly bipolar disorder), schizophrenia, and substance use.
Diagnosis and Prevalence
The diagnosis of MDE is limited to the lifetime experience of normal mood with episodes of depression, whereas bipolar disorder (BD) includes normal, depressed, and elevated or irritable mood states (mania or its less intense form, hypomania). Changes in energy and activity levels parallel variations in mood. Mania is a persistent, abnormally euphoric, expansive or irritable mood state with inflated self-esteem, agitation, heightened energy, racing thoughts, pressured speech, impulsive behaviors, distractibility, and poor judgment for a minimum of 1 week. Impairment in function must be present. Hypomania is defined by a minimum of 4 continuous days of persistent increased creativity, productivity, and sociability or increased irritability that family or coworkers notice. The woman’s function may be enhanced by creativity and increased energy. In women, depression is the predominant mood state and is frequently mistaken for unipolar depression. Atypical depression—characterized by increased appetite, weight gain, hypersomnia, low energy, heaviness—is more common in women with BD and typically starts in the fall or winter and resolves in spring.
The lifetime prevalence of BD is 1% to 2%. BD type I, which affects women and men equally, is characterized by MDE and periods of mania or hypomania. Bipolar variants that are more common in women than men include BD type II (MDE and hypomania), mixed episodes (intermingled manic and depressive symptoms), and rapid cycling (four or more episodes of opposite polarity in one year). Women with BD often have comorbid anxiety disorders, alcohol or substance (especially Cannabis ) use disorders, bulimia nervosa, childhood or adult physical and/or sexual abuse, and medical problems that include migraines, metabolic syndrome, pain disorders, and hypothyroidism.
The differentiation of MDE from BD is a major challenge, and delays of 7 to 11 years until diagnosis of BD is common. Prescribing antidepressants without an antimanic drug can complicate treatment by increasing rapid cycling, mania, or mixed episodes. The most commonly used measure is the Mood Disorders Questionnaire (MDQ) shown in Figure 55-3 , which assesses lifetime history of mania with 13 yes/no symptoms and two questions: a yes/no query about whether symptoms occurred during the same time period and a designation of the magnitude of the resulting problems (none, minor, moderate, serious). A positive screen requires seven or more symptoms during the same period that caused moderate or serious problems. Our team studied use of the MDQ with the EPDS as a combined screening tool in a postpartum population with follow-up diagnosis by a research psychiatric interview. The addition of the MDQ to the EPDS identified BD in 50% of women with traditional scoring, and it reached almost 70% when the MDQ was scored without the impairment criterion. Based on this study, we recommend the MDQ or a diagnostic assessment for BD be given prior to prescribing antidepressants for a postpartum depressed woman.
Natural History Across Childbearing
The course of episodes is useful in evaluating recurrence risk during pregnancy. Women with episodes that occur only after delivery are not likely to relapse during pregnancy even without medication. However, women with a chronic course are likely to be symptomatic during pregnancy, and maintenance medication is appropriate. For women with chronic BD, discontinuation of drug treatment proximal to conception incurred a high risk for recurrence (86%) compared with patients who continued treatment (37%). After delivery, all women with BD are at high risk for recurrent mood episodes.
Postpartum psychosis is typically a manifestation of BD such as mania, mixed state, or depression with psychotic features . It occurs in 1 to 2 per 1000 births in the first month following delivery. Women are more vulnerable to psychosis in the post-birth period than at any other time during their lives. In the first 30 days after birth, a woman is 21.7 times more likely to develop psychosis than in the 2-year period prior to childbirth. If she has not had a child before, she is 35 times more likely to suffer psychosis than women who have children. The magnitude of these relative risks demonstrates that postpartum psychiatric morbidity is a major public health problem. The mechanism for the vulnerability of postpartum women with BD for decompensation and psychosis have not been elucidated. Sleep deprivation and marked interference with circadian rhythms related to labor are likely contributors to mood instability. Hormone elevations near the end of gestation and massive postpartum withdrawal also contribute to the risk. The clinical picture of postpartum psychosis is characterized by rapid onset of hectic mood fluctuations; marked cognitive impairment suggestive of delirium; bizarre behavior; insomnia; visual and auditory hallucinations, including unusual (tactile and olfactory) hallucinations; and impaired judgment and insight. Specific types of delusional thoughts are related to the risk for infanticide. Delusional altruistic homicide, often associated with maternal suicide, to save both mother and infant “from a fate worse than death” was reported in a review of filicides, that is, killing one’s son or daughter. Resnick observed that 40% of the perpetrators of filicide had seen physicians shortly before the tragedy. Sensitive, direct questions about thoughts of harm to the infant are imperative in the examination. Nonjudgmental inquiry can be made as follows: “Some new mothers have thoughts such as wishing the baby were dead or about harming the baby; has this happened to you?”
The risk for adverse pregnancy outcomes is increased in women with mental illness. A population cohort study demonstrated that women with BD had an increased frequency of placenta previa and antepartum hemorrhage compared with euthymic women.
Treatment of Bipolar Disorder During Childbearing
Medication maintenance is the mainstay of treatment for BD, although psychotherapy and education are also important. Early identification of BD and rapid initiation of treatment results in lower rates of relapse, increased time to recurrence, improved medication adherence, and better function. Because abrupt discontinuation of mood stabilizers increases the risk for recurrence, education about adherence and drug tapering for discontinuation is advisable.
Several classes of drugs are effective for the treatment of mania. Lithium, some antiepileptic drugs (AEDs), and atypical antipsychotic drugs are efficacious; however, these treatments provide response in only 36% to 50% of cases, and patients often receive more than one drug to manage their mood symptoms. To minimize fetal exposure, strategies include (1) use using the lowest effective doses, (2) minimizing the number of drugs taken, and (3) dividing daily doses to avoid high peak serum concentrations, unless compliance will be compromised.
Lithium is the standard drug for acute and maintenance therapy for BD. Before initiating lithium treatment, assessment of renal and thyroid function is necessary. The starting dose is 300 mg twice daily. Serum drug concentration and renal function tests should be repeated after 5 to 7 days of treatment. The target serum trough concentration is 0.4 to 1.0 mEq/L at 12 hours. Treatment response is usually achieved at 900 to 1200 mg daily. Due to the physiologic changes of pregnancy, monthly lithium levels are recommended in the first and second trimester with dose adjustment to achieve the prepregnancy concentration that was efficacious. In the final gestational and first postpartum month, weekly lithium levels may need to be measured. Common side effects of lithium include sedation, tremor, renal dysfunction, weight gain, nausea, vomiting, and diarrhea. Toxic effects are associated with somnolence, confusion, severe tremors, renal dysfunction, and intractable vomiting. Women with vomiting are especially vulnerable to toxicity due to fluid loss. Lithium toxicity is managed with drug discontinuation, rehydration therapy, and monitoring of fluid and electrolyte balance and renal function. Diuretics and nonsteroidal antiinflammatory drugs (NSAIDs), which can impair renal clearance, should be avoided in lithium-treated patients.
Lithium exposure during the first trimester was associated with an increased risk for Ebstein anomaly. Subsequent prospective studies demonstrated that the risk was overestimated due to voluntary reporting to a registry, which inflated the number of cases (numerator) and underestimated the magnitude of population exposed (denominator). The absolute risk of Ebstein anomaly with first-trimester exposure is 1/1000 to 1/2000, 20 to 40 times higher than in the general population. Lithium-exposed neonates are at risk for being large for gestational age and for hypotonia, feeding difficulties, depressed reflexes, cyanosis, apnea, bradycardia, hypothyroidism, and diabetes insipidus. The neonatal symptoms are temporary and are associated with maternal serum concentrations at delivery of greater than 0.64 mEq/L. The suspension of lithium dosing 24 to 48 hours before a scheduled delivery or at onset of labor reduces the risk for perinatal complications. Developmental milestones are normal in infants exposed in utero to lithium.
Valproic acid (VPA) was the first AED for mania approved by the Food and Drug Administration (FDA). The starting dose is 500 to 750 mg daily in divided doses, and therapeutic levels range from 50 to 125 µg/mL. Adverse effects include nausea, weight gain, fatigue, tremor, ataxia, diarrhea, abdominal pain, alopecia, hepatitis, thrombocytopenia, and pancreatitis.
Exposure to VPA is associated with increased risk for serious adverse outcomes that include all birth defects (OR, 10.7; 95% CI, 8.2 to 13.3), developmental delay, and fetal death compared with other AEDs (see Chapters 8 and 48 .) With exposure to multiple AEDs, women have a twofold to fivefold increased risk for major malformations and for having offspring with cognitive impairment compared with monotherapy. Rates of malformations from polytherapy were 6.0% compared with 3.7% for monotherapy. VPA is concentrated in the fetal compartment, and provision of the lowest effective dose in divided doses is recommended to avoid high single peak levels. Complications associated with VPA use near delivery include fetal decelerations and infant irritability, jitteriness, feeding difficulties, abnormal tone, hepatic toxicity, hypoglycemia, and reduction in neonatal fibrinogen levels. At birth, cord blood concentrations of VPA can reach twice the maternal levels.
Meador and colleagues evaluated the intelligence quotient (IQ) in 6-year-old children ( n = 224) who had been exposed to AEDs in utero, with adjustment for maternal IQ, AED drug type, standardized dose, gestational birth age, and use of periconceptional folate. The offspring IQs were lower after exposure to VPA (mean 97; 95% CI, 94 to 101) than after carbamazepine (mean 105; 95% CI, 102 to 108; P = .00015) or lamotrigine (mean 108; 95% CI, 105 to 110; P = .00003). A dose-response relationship was observed for VPA, but no other AED, with negative impact on offspring IQ, verbal and nonverbal ability, memory, and executive function. For all AED exposures, the mean IQs were higher in children whose mothers received folate (108; 95% CI, 106 to 111) than in the offspring of non–folate treated mothers (101; 95% CI, 98 to 104; P = .00009). Because over half of pregnancies are unplanned and the impact on neural tube development occurs 17 to 30 days postconception, women treated with maintenance VPA are exposed during this critical period, often before awareness of pregnancy. These findings dictate against use of VPA as a first-line drug for childbearing-aged women .
Carbamazepine and Oxcarbazepine
Carbamazepine (CBZ) is prescribed at doses between 400 and 1600 mg daily to achieve a target range of 4 to 12 µg/mL. Drug-induced toxicity is usually detectable from clinical symptoms, and the serum level provides objective evidence. During pregnancy, the total AED levels drop, but the amount of unbound bioavailable drug remains constant. Serum concentrations are useful in the assessment of patients with exacerbation of mood symptoms, side effects, and questionable treatment adherence. Hepatitis, leukopenia, thrombocytopenia, rash, sedation, and ataxia are CBZ side effects. Due to the additive effects on bone marrow suppression, combining CBZ and the antipsychotic clozapine is contraindicated.
The American Academy of Neurology (AAN) committee found no increased risk of major malformations in the offspring of women who received CBZ for epilepsy. However, infants exposed to CBZ had twice the risk for being small for gestational age (SGA) and to have low Apgar scores (<7) at delivery. Exposed children did not have reduced cognitive function on measures of IQ and developmental milestones compared with children who were not exposed to AEDs. Fetal serum levels of CBZ are 50% to 80% of maternal levels. Because adequate levels of vitamin K are necessary for normal midfacial growth and for the functioning of clotting factors, CBZ exposure in utero could increase the risk of neonatal bleeding. Some experts recommend treatment with vitamin K 20 mg/day throughout pregnancy and 1 mg intramuscularly to neonates.
Oxcarbazepine has been used to treat mania in divided doses totaling 600 to 1200 mg/day. The parent compound is rapidly metabolized to an active hydroxy metabolite, which undergoes hepatic glucuronidation and renal excretion. Adverse effects are hyponatremia, hypersensitivity reactions, and decreased thyroxine levels (without altered triiodothyronine or thyroid-stimulating hormone [TSH]). Side effects include headaches, dizziness, gait disturbance, fatigue, and concentration changes. In 55 infants exposed in utero to oxcarbazepine (20 combination therapy, 35 monotherapy), one cardiac malformation was reported in an infant also exposed to phenobarbital.
Lamotrigine (LTG) is indicated for bipolar depression maintenance therapy. Typical doses range from 50 to 200 mg/day, but doses up to 500 mg/day have been used for long-term treatment of patients with BD. Side effects include headaches, rash, dizziness, diarrhea, abnormal dreams, and pruritus. Aseptic meningitis is a rare but serious potential complication of treatment with LTG. The rash associated with LTG is maculopapular or erythematous in appearance and is associated with rapid dose escalation, combination with VPA, and treatment in adolescents. A retrospective analysis from 12 studies indicated that the rates of benign rash were 8.3% in LTG-treated and 6.4% in placebo-treated patients. In contrast, serious rash occurred in none of the LTG-treated and in only 0.1% of placebo-treated patients. One case of Stevens-Johnson syndrome occurred in an LTG-treated patient. Although this syndrome may be life threatening, the very low risk of serious rash must be weighed against the much more common risks associated with untreated BD.
Continuing LTG reduces the risk of recurrences in pregnant women with BD. Thirty percent of women who continued, versus all who stopped LTG, relapsed during pregnancy (OR, 23.2; 95% CI, 1.5 to 366). Patients who stopped treatment suffered relapses within 2 weeks. Because LTG clearance increases by 65% to 90% in the second and third trimesters compared with preconception, patients usually require higher doses during pregnancy. Guidelines for managing dosing across childbearing have been published. The LTG serum concentration that was efficacious before pregnancy is the target level to be maintained by dose adjustment throughout pregnancy. The metabolism of LTG returns to the prepregnancy state rapidly after birth. To avoid maternal toxicity (dizziness, tremor, and diplopia), the dose should be reduced by 20% to 25% within 3 days of birth and across the first weeks postpartum based on serum concentrations.
The rate of congenital malformations is similar in infants exposed in utero to LTG compared with the general population, but the rate increases when LTG is combined with other AEDs. The risk for orofacial cleft malformations is not increased in LTG-exposed offspring.
Antipsychotic drugs, including the first-generation agents (“typical,” such as haloperidol) and the second-generation agents (“atypical,” such as olanzapine) are effective treatments for BD and also for schizophrenia (see the discussion of atypical antipsychotics in the section “ Treatment Interventions for Women With Schizophrenia ” later in this chapter). Indications include maintenance therapy to prevent recurrence, bipolar depression (quetiapine and combined olanzapine-fluoxetine), and treatment-resistant depression. The usual daily dose ranges are 5 to 20 mg for olanzapine; 1 to 6 mg for risperidone; 100 to 400 mg, maximum 800 mg, for quetiapine; 80 to 160 mg for ziprasidone; 20 to 80 mg for lurasidone; and 5 to 30 mg for aripiprazole. The initial treatment is started at a lower dose and is titrated against response and tolerance.
The atypical agents are associated with fewer extrapyramidal side effects (tardive dyskinesia, tremor, rigidity, internal restlessness, slowed movements, and dystonia) compared with the older typical antipsychotic agents. Side effects include somnolence, increased hepatic transaminases, and hyperprolactinemia. In pregnancy, the metabolic side effects of the psychotropic drugs, particularly the atypical agents, are a major concern. Patients are at risk for weight gain, metabolic syndrome, elevated triglycerides, and glucose intolerance. Obesity is associated with complications that include gestational diabetes, preeclampsia, caesarean delivery, and large-for-gestational age (LGA) infants.
The reproductive risks of atypical antipsychotics have received minimal research attention. Pregnant women who received either typical or atypical drugs had increased risks for PTB, LBW, and major malformations compared with the general population, but these complications may reflect the effects of the underlying psychiatric disorder. Genetic liability and gene-environment interactions contribute to these outcomes, and maternal risk factors, substance abuse, nutritional status, and the biologic and behavioral concomitants of severe mental illness are likely to be the major determinants of increases in reproductive pathology. Rates of malformations, mainly atrial and ventricular septal defects, are variable. Some reports suggest that only infants with exposure to the typical agents were affected, whereas other data demonstrate an increased risk for malformations in women exposed to atypical antipsychotic drugs compared with controls (OR, 2.17; 95% CI, 1.20 to 3.91).
Rates of PTB are increased in patients treated with antipsychotics. However, infants with fetal exposure to the typical drugs weighed less (3158 g ± 440) than the infants exposed to the atypical (3391 g ± 446) or non-antipsychotic drugs (3382 g ± 384). Infants who were significantly LGA were born to mothers who received atypical (20%) compared with typical agents (2%) or non-antipsychotic drugs (3%). In addition, postnatal complications occurred significantly more often in infants prenatally exposed to atypical (15.6%) and typical (21.6%) antipsychotics compared with 4.2% of non–drug exposed women. The frequency of stillbirth or neonatal deaths was not increased compared with the baseline population.
A national pregnancy registry for atypical antipsychotics has been established ( womensmentalhealth.org/posts/pregnancy-registry ). As of December 2014, 303 women had completed the study and were eligible for inclusion in the analysis. Of 214 live births with first-trimester exposure to second-generation antipsychotics, three major malformations were confirmed. In the control group ( n = 89), one major malformation was confirmed. The absolute risk of major malformations was 1.4% for exposed infants and 1.1% for unexposed infants. The odds ratio for major malformations comparing exposed infants with unexposed infants was 1.25 (95% CI, 0.13 to 12.19), a nonsignificant difference but a small sample.
Alternate and Supplemental Treatment Options
An inverse correlation between omega-3 fatty acid consumption and the prevalence of BD has been demonstrated. An increased duration of remission in patients with BD who were randomized to fish oil versus placebo was reported. Electroconvulsive therapy (ECT) is highly effective for the management of treatment-resistant depression, acute mania, and severe mixed episodes. ECT involves delivering an electrical stimulus with a brief pulse device to induce a limited grand mal seizure blocked from peripheral expression by succinylcholine. During ECT, the patient receives short-acting anesthetic agents, which are not likely to cause adverse impact on the mother-infant pair.
Prevention of Bipolar Disorder Recurrence Postpartum
The risk for recurrence of mania, depression, or mixed states postpartum is the highest at any point in a woman’s life. In women who discontinued lithium therapy, the rates of recurrence in the postpartum period were almost three times that of the nonpregnant women over a similar time (70% vs. 24%). Moreover, among women who had previous postpartum psychosis, more than 40% experienced relapse after declining immediate postpartum lithium prophylaxis, and no woman who began medication immediately postpartum had a recurrence. The postpartum pharmacotherapy plan includes selection of the drug(s) of past response and educating partners to observe and report early symptoms to prevent episodes.
Breastfeeding for Women with Bipolar Disorder
The mother’s desire to breastfeed is an important consideration in the postpartum management (see Chapter 24 ). Successful lactation may be compromised by not breastfeeding through the night in the early postpartum period; however, sleep deprivation is a major factor in precipitating mania. If a partner or family member can provide support and feed the baby at night, sleep can be prioritized.
The American Academy of Pediatrics (AAP) and the AAN concluded that most medications used to treat BD produce breast milk concentrations less than 10% of the mother’s weight-adjusted concentrations. A multicenter longitudinal observational study of monotherapy of AEDs examined the impact of breastfeeding on IQ at 3 years age for CBZ, LTG, and VPA. Breastfed children did not differ from formula-fed children. However, the concentrations of LTG in breastfed infants averaged 30% to 35% of that of the mother. The risk for toxicity may be increased in breastfeeding infants of women who receive additional similarly metabolized agents such as lorazepam, aspirin, olanzapine, acetaminophen, and VPA.
Lithium treatment can be managed in breastfeeding women with education and close follow-up. In a case series of 10 mother-infant pairs, infant serum lithium concentrations were 25% of maternal levels. In another study of three infants, infant concentrations ranged from 10% to 17% of maternal levels. Caregivers should monitor the infant for signs of toxicity (poor feeding, lethargy, and hypotonia), especially in situations that increase the risk for dehydration (reduced feeding/oral intake, excessive fluid loss or fever). To avoid spuriously high levels of lithium, infant blood samples must be collected in tubes that do not contain lithium heparin as the stabilizing agent.
Diagnosis and Prevalence
Anxiety disorders include panic disorder, generalized anxiety disorder, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and agoraphobia and other phobias. Each of these disorders is distinct and is defined by specific diagnostic criteria according to DSM-V. Many individuals have subclinical anxiety symptoms . To meet criteria for the diagnosis of an anxiety disorder, the symptoms must cause impairment of functioning. In women, the lifetime prevalence of anxiety disorders is 5%; panic disorder, 5%; generalized anxiety disorder, 3%; OCD, 6%; social phobia and other specific phobias, 13%; and 10% for and PTSD. Multiple anxiety disorders are often present in an individual. Without treatment, anxiety disorders usually have a chronic course. Although rates of OCD are similar in men and women, all other anxiety disorders are 1.5 to 2 times more common in women. In addition, women with anxiety disorders have an increased risk for development of comorbid MDE.
Panic attacks are characterized by brief (5- to 15-minute) intense episodes of fear or discomfort that occur in many anxiety disorders and in healthy individuals exposed to acute stress. Symptoms include palpitations, sweating, shortness of breath, choking, nausea, abdominal discomfort, dizziness, unsteadiness, numbness or tingling, chills, hot flashes, or a fear of dying or losing control. Panic disorder is diagnosed when attacks are recurrent or associated with a fear of future attacks. The most disabling consequence of panic disorder is agoraphobia, which occurs in 30% to 40% of women with untreated panic disorder. Patients with agoraphobia restrict activities outside the home or insist on being accompanied by a trusted person due to fear of having a panic attack where help is unavailable.
Generalized anxiety disorder is characterized by excessive worrying about multiple problems. The issues of concern to persons with generalized anxiety disorder are realistic, but the level of worry is much more intense than appropriate. For example, a woman might worry for hours about whether a friend received a thank you note for a gift. Individuals with generalized anxiety disorder have symptoms associated with worry, such as muscle tension, fatigue, headache, nausea, diarrhea, or abdominal pain.
In contrast to generalized anxiety disorder, women with obsessive-compulsive disorder focus on more idiosyncratic and often unrealistic concerns. OCD is characterized by disturbing intrusive thoughts and performance of compulsions to temporarily relieve the distress generated by the intrusive thoughts. Obsessional thoughts usually focus on a few key themes: contamination, causing harm, offensive violent or sexual images, religious preoccupations, and urges for symmetry or ordering. Compulsions performed to relieve these intrusive worries include cleaning or washing, checking, repeating, ordering, hoarding, and mental rituals like counting and praying. During pregnancy and postpartum, contamination concerns and intrusive violent thoughts are particularly common. Differentiating obsessional thoughts and images from delusions and hallucinations can be challenging. New mothers with OCD may experience disturbing obsessions and mental images of harming their baby. They are highly distressed by these thoughts yet are not at increased risk of harming their infant.
Exposure to trauma in which a woman experienced or witnessed an event that involved actual or threatened death or serious injury is required for a diagnosis of posttraumatic stress disorder (PTSD). The traumatic event is persistently reexperienced in one or more of the following ways: (1) recurrent and intrusive distressing recollections, (2) recurrent distressing dreams, (3) acting or feeling as if the event were occurring in the present (flashbacks), (4) intense distress at cues that remind her of the event, (5) physiologic hyperarousal, and (6) exaggerated startle responses. Symptoms must persist for at least 1 month to meet diagnostic criteria for PTSD. Minimal study has been done about whether birth trauma can result in a new onset or recurrence of PTSD. Preliminary estimates suggest an incidence of 3% for delivery-related PTSD in community samples and as high as 15% in high-risk samples.
Separation anxiety is another type of anxiety focused on potential harm coming to self or others that would disrupt a close relationship. Women with separation anxiety can experience mental distress, nightmares, and physical anxiety symptoms associated with separation or the threat of separation.
Finally, excessive fear of a discrete object or situation constitutes a phobia. Social phobia refers to disabling fears of speaking or eating in public and fears of humiliation in social interactions. Other common specific phobias are body injury phobia (medical procedures), acrophobia (heights), arachnophobia (spiders), and claustrophobia (enclosed spaces). Individuals with panic disorder often have fear of situations from which they could not escape if they had a panic attack (airplanes). These fears are a feature of panic disorder and agoraphobia and would not warrant a diagnosis of phobia.
Fear of Labor and Delivery
Some women have intense fear of pregnancy and childbirth. About 5% to 10% of pregnant women have extreme fear of delivery, which may be considered a type of phobia. These women often request surgical deliveries to avoid labor. Risk factors for intense fear of delivery and requesting cesarean delivery include preexisting mental illness, history of abuse, poor social support, unemployment, and previous complicated delivery. Focused, short-term psychotherapy may enable these women to accept a vaginal delivery and improve the birth experience.
Natural History Across Childbearing
Pregnancy, delivery, and lactation produce profound changes in physiology, including changes in multiple hormonal and neurotransmitter systems that modulate anxiety symptoms. However, there has been relatively little study of the course of anxiety symptoms or anxiety disorders during pregnancy and postpartum. In one large prospective study, more women scored above threshold on an anxiety scale during weeks 18 and 32 of pregnancy compared with 8 weeks and 8 months postpartum, which suggests that nonspecific anxiety symptoms worsen during pregnancy. Antenatal anxiety symptoms and anxiety disorders are associated with an increased risk of postpartum depression, even after controlling for antenatal depression. Anxiety disorders are common comorbidities to MDE in the postpartum period. With respect to specific anxiety disorders, preliminary evidence suggests that panic disorder can improve during pregnancy but can recur postpartum. In addition, cessation of breastfeeding may precipitate relapse of panic disorder. Pregnancy and childbirth can trigger the onset of or an exacerbation of preexisting OCD. Obsessive-compulsive symptoms are very common in postpartum depression. Intrusive violent thoughts and contamination concerns are quite common in new mothers without psychiatric disorders. No information was found on the effects of pregnancy on the course of generalized anxiety disorder, phobias, or PTSD.
Beta-adrenergic agonists such as terbutaline may precipitate panic attacks and other anxiety symptoms during the treatment of premature labor. Hyperthyroidism is associated with panic attacks, and it and should be considered in the differential diagnosis of postpartum-onset anxiety episodes.
Effects of Anxiety During Childbearing
Anxiety symptoms and anxiety disorders are associated with an increased risk of preeclampsia and reduced birthweight. PTSD, an anxiety disorder associated with marked hyperarousal symptoms including severe insomnia has been associated with increased risk of PTB. Less is known about other anxiety disorders and their relationship to delivery complications. Psychosocial stress also has been linked to higher rates of PTB, and several physiologic pathways have been proposed to mediate the association, including autonomic arousal, elevated levels of cortisol and corticotropin-releasing hormone, and systemic inflammation. Lack of sleep, a common symptom of anxiety disorders, can increase inflammatory load and is associated with PTB.
Prenatal anxiety also has been associated with adverse effects on offspring. Fetuses of anxious women show increased heart rate reactivity to maternal stressors, and newborns of highly anxious mothers have reduced heart rate variability and poor autonomic regulation. Poor autonomic regulation of heart rate has been linked to impaired emotional regulation in older children and adults. In utero and as newborns, the offspring of anxious women spend more time in deep sleep and are more likely to cry excessively.
Maternal anxiety during pregnancy is associated with attention deficits, motor immaturity, and difficult temperament in offspring. In two large prospective longitudinal studies, anxiety during pregnancy increased the risk for hyperactivity, conduct disorder, and anxiety in childhood after controlling for obstetric and sociodemographic risks and for maternal depression. Research is needed to understand the contributions of genetic risk factors, parenting behaviors, and the altered uteroplacental milieu to developmental and psychiatric problems in the offspring of anxious mothers.
Treatment of Anxiety Disorders
The boundary between normal and pathologic anxiety cannot be drawn with great precision. When anxiety substantially impairs work, family, or social adjustment, mental health evaluation is indicated, and treatment is appropriate. Panic disorder responds to most antidepressant medications, which are first-line therapies for this disorder. Benzodiazepines are also effective but are associated with abuse and physical dependence in a subset of patients. Cognitive behavior therapy (CBT) is a time-limited, structured psychotherapy that is also effective for panic disorder.
In contrast, OCD is effectively treated specifically with serotonergic antidepressants. A behavioral therapy technique, exposure and response prevention, is also effective for OCD. Generalized anxiety disorder responds to a variety of antidepressant medications and to cognitive therapy. PTSD is partially responsive to antidepressants, but psychotherapy or combination treatment is often more effective. The first-line medication treatment for social phobia includes SSRIs and CBT. Specific phobias are treated with focused desensitization therapy rather than medication. An excellent patient educational workbook on anxiety disorders is available (see the resource list at the end of this chapter).
A risk-benefit evaluation for treatments during pregnancy must be individualized for the pregnant woman with anxiety disorder because, like MDE, anxiety can have a negative impact on pregnancy outcome (see Chapter 8 ). If psychotherapy treatment is refused, not available, or ineffective, pharmacologic treatment should be considered. The use of antidepressants in pregnancy and lactation has been reviewed in the section on major depression. Evidence from the available studies indicates that the teratogenic risk from benzodiazepine exposure, if any, is very small. However, less is known about the effect of benzodiazepines on neurodevelopment. At delivery, neonates exposed to higher doses can have withdrawal seizures or hypotonia.
Benzodiazepines enter breast milk but the concentration in milk varies by drug, dose, and frequency of use. Because alternative treatments are available for anxiety disorders, benzodiazepines often can be avoided or used to treat targeted symptoms for limited periods during pregnancy and lactation. Intermittent use of short half-life benzodiazepines is preferred because chronic use of long-acting benzodiazepines can result in infant sedation, and mothers must be educated to observe for drowsiness and poor feeding. Also, little is known about the degree to which benzodiazepines are absorbed into the circulation of breastfed infants.