Introduction

This chapter will present a selected review of studies about the course and treatment of psychiatric disorders through pregnancy. The research on the influence of untreated psychiatric disorders and symptoms on birth outcome will be described. The potential adverse effects on the fetus and neonate from psychotropic medications will be reviewed. Management of the pregnant woman with a psychiatric disorder should consider the consequences of fetal exposure to untreated maternal psychiatric illness, fetal exposure to psychotropic medications, and available alternative treatments [1]. Unfortunately, there are no risk-free decisions for pregnant women with a psychiatric disorder. However, the evidence predominantly supports present practice that ongoing treatment of psychiatric disorders in pregnancy is preferable to withholding treatment during gestation. Postpartum blues and postpartum depression (PPD) are in the section on depression. Postpartum psychosis is discussed in the section on bipolar disorder.

Major depressive disorder

Specific agents in each of these classes are listed in Table 21.1. The response rate to any of these classes of medications is typically around 50–60% in a primary care setting with most of the responders having improved by 6–7 weeks after initiation of treatment. There are no data to clearly show that one of these agents is more effective than another and treatment decisions outside pregnancy are usually based on side effect profile, previous response to medication, price and reproductive plans. Unlike TCA and MAOI, intentional overdoses of SSRI and SNRI have the advantage that they are unlikely to lead to a successful suicide.

Table 21.1 Antidepressant medications with some pregnancy-specific recommendations

Nonpharmacologic treatments of MDD during pregnancy

Pregnant women with depression often prefer psychosocial treatments to antidepressant medications [65]. The systematic evaluation of psychotherapy in pregnant women has been minimal. Interpersonal psychotherapy (IPT) is an established treatment for PPD [66], and depressed pregnant women similarly can benefit from the exploration of role transitions and interpersonal issues. A randomized controlled study (RCT) reported that IPT administered in a group format was superior to a parenting education program in improving mood in pregnant women with depression [67]. A recent study reported positive results with CBT started during pregnancy for depressed women that continued into the postpartum months. In this study, CBT administered by community-based primary health workers improved maternal mood up to 1 year compared to enhanced routine care [68]. Although effective, and from a safety standpoint ideal for pregnancy, use of psychotherapy is hampered by both limited access to trained psychotherapists and the logistic difficulties that many women face in committing to 12–16 weekly sessions of therapy when it is available.

Randomized controlled trials have reported efficacy with acupuncture [69,70], massage [71], and bright light therapy [72] for prenatal depression. Moderate exercise has been reported to improve maternal well-being without adverse effects on birth outcomes although exercise has not been specifically studied in depressed pregnant women [73]. RCT with omega-3 supplementation have yielded positive [74] and negative results [75,76] for depression during pregnancy. The use of these modalities for treatment of anything more than mild depression would generally be discouraged.

Women with severe depression not responsive to pharmacotherapy or nonpharmacologic treatments may need electroconvulsive therapy (ECT). Although ECT has been used safely in pregnancy, there are specific maternal and fetal precautions [77]. Of concern are recent case reports of fetal cerebral infarcts, fetal cardiac arrhythmias and premature birth with ECT during pregnancy [77–79].

Antidepressant treatment of MDD during pregnancy

Treatment of MDD during pregnancy should follow the general guidelines for the treatment of MDD in the nongravid woman. The ACOG has recommended that preferred medications in pregnancy are those with the best safety data, fewer metabolites, higher protein binding to decrease placental passage, and fewer interactions with other medications [1]. Desipramine and nortriptyline are the TCA recommended in pregnancy because they are less anticholinergic and less likely to precipitate orthostatic hypotension [80]. However, SSRI and SNRI have generally replaced TCA as first-line treatments for depression. Up to one-quarter of pregnant women in North America and Europe take a SSRI at some point during their pregnancy [81–85]. SSRI and their metabolites have been detected in both umbilical cord blood [86] and amniotic fluid [87]. Fetal drug exposure may be determined by fetal genotypes for drug metabolism and transporter proteins located in the placenta in addition to the concentration of medication found in the mother’s serum, umbilical cord blood and amniotic fluid [88,89].

Antidepressants and miscarriage

One meta-analysis of studies reported that exposure to antidepressant medication was associated with a 1.45 relative risk of miscarriage compared to nonexposure; however, the miscarriage rate of 12.4% with exposure was within range of normal population rates [90]. Another meta-analysis of studies reported a significant odds ratio of 1.7 for miscarriage with SSRI use [91]. Two studies conducted subsequent to these meta-analyses also reported increased miscarriage rates with bupropion [92], mirtazapine and other antidepressants [93]. Many of the studies included in both of these meta-analyses did not control for confounding variables such as age, smoking and underlying depression.

Antidepressants and birth outcome

Recent studies have reported an increased risk of PTD with in utero exposure to TCA and SSRI [94,95] as well as SNRI [96]. A retrospective review conducted in a Canadian population cohort reported that maternal use of SSRI increased the risk of LBW, PTD, fetal death and neonatal seizures compared to nonexposed infants [97]. LBW, younger gestational age at birth, and lower Apgar scores have been reported with third-trimester exposure of fluoxetine compared to first- or second-trimester exposure [98] and with SSRI exposure compared to TCA exposure or no exposure [99]. LBW has been associated with higher doses of fluoxetine compared to lower doses or use of other SSRI [100]. However, other studies have failed to find birthweight differences between SSRI-exposed and nonexposed infants [101,102] or between early and late SSRI-exposed infants [103,104]. Another study reported that birthweight, gestational age, premature birth and 5-minute Apgar scores did not differ between neonates exposed to various antidepressants and nonexposed neonates, although 1-minute Apgar scores were lower in exposed neonates [105]. Many of the studies examining birth outcomes with antidepressant exposure have not controlled for untreated prenatal maternal depression, concomitant medications, maternal age or other sociodemographic variables, smoking, alcohol or drug use. These potential confounding factors could underlie the mixed results from studies evaluating the effect of SSRI exposure on pregnancy outcomes.

Two studies have controlled for untreated prenatal depression. One study reported that compared to birth outcomes of untreated women with depression and healthy controls, prenatal SSRI use was associated with an increased risk of PTD and lower gestational age at birth, but not with LBW or lower Apgar scores [30]. Another study examining more than 119,000 births compared birth outcomes of infants of depressed mothers treated with SSRI, depressed mothers not treated with SSRI, and nonexposed control mothers, while controlling for maternal depression severity [83]. Although not a RCT, this large study used linked population health data and propensity score matching. Compared to infants of depressed mothers not treated with SSRI, infants of depressed mothers treated with SSRI were more likely to have LBW, younger gestational age, and a higher proportion born earlier than 37 weeks. Longer prenatal SSRI exposure increased these risks [106]. Both maternal depression and SSRI use were significantly associated with increased risk of birthweight below the 10th percentile when maternal illness severity was controlled for in the analyses. These results suggest (but do not prove – a large randomized control trial would be necessary for this) that exposure to SSRI adds to the negative birth outcomes due to the effect of exposure to underlying depression alone (LBW and younger gestational age) [83].

Antidepressants and congenital malformations

Studies examining the prevalence of congenital malformations with first-trimester exposure to antidepressants have yielded mixed results. Two meta-analyses reported that newer antidepressants were not associated with an increased risk of major or minor malformations above the 1–3% population baseline risk [91,107]. Studies have reported a lack of increased congenital malformation rates with fluoxetine exposure [98,100,108–110] and with exposure to sertraline, paroxetine, fluvoxamine or citalopram [95,100,101,110–113]. No increased risk of congenital malformations has been reported with trazodone and nefazodone [114], bupropion [92,115], mirtazapine [93], venlafaxine [116], and TCA [117].

Two large case–control studies reported an association of sertraline with omphalocele and of paroxetine with right ventricular outflow tract obstruction defects [118], and an association of omphalocele, craniosynostosis, and anencephaly with several SSRI [119]. These results suggested a very small increase in absolute risk and a lack of specific malformations linked to specific antidepressants. A study conducted in Denmark reported an adjusted relative risk of 1.34 for congenital malformations (cardiovascular, gastrointestinal, muscle and bone) in infants born to mothers who took SSRI early in pregnancy compared to nonexposed infants [120]. A recent prospective study reported increased cardiovascular abnormalities in infants exposed to fluoxetine compared to paroxetine or no exposure [113]. The risk of congenital malformations was recently reported to not be associated with the duration of antidepressant use during the first trimester [121]. Most of the studies of congenital malformations have not controlled for underlying maternal psychiatric disease. A recent study that did control for maternal illness variables reported that the risk of cardiovascular malformations is increased with first-trimester combined SSRI and benzodiazepine use [122].

In 2005, a retrospective analysis of GlaxoSmithKline data reported an adjusted odds ratio of 2.08 for cardiovascular malformations (mostly ventricular septal defects) and an adjusted odds ratio of 2.2 for overall major congenital malformations with paroxetine use compared to other antidepressants. The FDA issued a public health advisory about paroxetine use in pregnancy in December 2005 and paroxetine’s FDA pregnancy category was changed from “C” to “D.” Subsequently, the elevated risk of cardiac malformations with first-trimester use of paroxetine was confirmed by a meta-analysis [123] and a retrospective cohort study from Sweden [124]. A large study of a healthcare organization database reported a slight increase in the prevalence of several congenital malformations with paroxetine compared to exposure with other antidepressants [125]. However, a recently published study of prospective cohorts reported that first-trimester paroxetine use was not associated with an increased risk of cardiovascular defects [126]. In addition, a recent meta-analysis [127] reported a lack of increased cardiovascular abnormalities with first-trimester paroxetine use. The ACOG has advised that paroxetine not be used during pregnancy and that the use of SSRI should be individualized [128].

In summary, the relationship between congenital malformations and antidepressants, including paroxetine, is unclear. If first-trimester antidepressant exposure does increase the risk of congenital malformations, the magnitude of the increase is not large and the use of these agents to treat major depression in pregnancy is justifiable when potential risks of treatment are weighed against the potential risks of untreated depression.

Antidepressants and poor neonatal adaptation

Exposure to antidepressants at the end of the third trimester may lead to a poor neonatal adaptation (PNA), also described as neonatal behavioral syndrome, neonatal toxicity or neonatal abstinence syndrome. PNA includes poor muscle tone, jitteriness, respiratory distress, weak or absent cry, hypoglycemia, poor temperature regulation, low Apgar score and seizures [95,129–131]. The symptoms are usually mild and transient, but supportive care in special care nurseries may be necessary [103,105,111,132,133]. PNA has been reported to occur in up to 30% of exposed neonates [134]. A comprehensive review reported that third-trimester SSRI exposure carried an overall risk ratio of 3.0 compared to first-trimester exposure or no exposure [132]. Even with control for severity level of maternal prenatal depression, the risk for respiratory distress at birth was greater with exposure to SSRI during pregnancy compared to nonexposure [83] and with longer gestational exposure to SSRI [106].

An increased risk of PNA with third-trimester use of paroxetine and fluoxetine has been reported in seminal studies [132,135]. Subsequent cases of neonatal symptoms have been reported with third-trimester use of paroxetine [136], citalopram [111,137], venlafaxine [96,133,138,139], mirtazapine [96,140], and duloxetine [141]. A recent study reported a prolonged neonatal QTc interval with SSRI use prior to delivery [142]. Neonatal jitteriness, irritability, respiratory difficulties, poor suck reflex, urinary retention, functional bowel obstruction, and, rarely, seizures have also been described with third-trimester TCA use [95,143]. In 2005, the FDA issued an advisory about the potential for neonatal symptoms with late third-trimester use in the prescribing information of antidepressants.

The signs and symptoms of the PNA have not been systematically defined, but they have similarities with some of the signs and symptoms of adult serotonin toxicity, SSRI discontinuation syndrome and cholinergic overdrive [129–132,144,145]. Future studies of PNA need to include use of a validated neonatal behavioral symptom scale, assessments of infants by evaluators blind to maternal SSRI use, control for maternal psychiatric and other variables, and follow-up to evaluate long-term sequelae [146].

Antidepressants and persistent pulmonary hypertension of the newborn

A case–control study reported an association between SSRI use after week 20 of pregnancy and an increased risk of persistent pulmonary hypertension of the newborn (PPHN) after controlling for maternal Body Mass Index, diabetes, smoking and nonsteroidal anti-inflammatory drug (NSAID) use [84]. The absolute risk was small (7/1000), and compares to the risk of PPHN in unexposed newborns (1/700). Although all f the cases of PPHN observed in this study were relatively mild and self-limited, PPHN can be fatal in 10–20% of newborns. The FDA issued an alert about the increased risk of PPHN with SSRI use in the second half of pregnancy in July 2006. A subsequent study from Sweden confirmed a smaller increased risk of PPHN with SSRI late in pregnancy [147]. However, two recent studies failed to find an association between SSRI use in pregnancy and PPHN [148, 149]. It has been suggested that SSRI may promote pulmonary artery constriction after birth by direct effects on pulmonary smooth muscle cells or by inhibiting the vasodilator nitric oxide [84]. In utero fluoxetine exposure induced pulmonary hypertension in rats by an increase in pulmonary artery smooth muscle proliferation [150]. PPHN may fall at the severe end of the spectrum of respiratory problems that can occur after third-trimester SSRI use [84,147].

Long-term effects of antidepressants during pregnancy

Few long-term studies exist that have followed the cognitive, neurologic and behavioral development of children exposed to antidepressant medications or untreated disease during pregnancy. A review of studies about the long-term development of children with prenatal and postpartum SSRI exposure reported that most studies (involving 306 children) have demonstrated no impairment with exposure, while two studies (involving 81 children) have suggested mild adverse effects of motor control and development [151]. Normal neurodevelopment at 1 year was reported in a prospective study of infants with fetal exposure to citalopram compared to nonexposed infants [152]. Normal neurodevelopment, language development and IQ were also reported in prospective cohorts of children up to age 5 exposed to TCA or fluoxetine, compared to no exposure [153,154]. Two more recent studies reported that in a cohort of 4-year-old children, concurrent maternal depression, but not exposure to SSRI during pregnancy, was associated with externalizing (aggression and increased activity) behaviors [155] and internalizing (withdrawal, depression, emotional reactivity, anxiety) behaviors [156]. Since both untreated illness and medication exposure pose risks to the fetus, there is a critical need for future systematic studies of long-term developmental effects of exposure to both untreated illness and antidepressant medication during each trimester.

Treatment dilemmas for pregnant women with depression

A pregnant woman with depression faces significant treatment dilemmas given the growing evidence that fetal risk exposure occurs with depression, stress, and anxiety as well as psychotropic medications (see Box 21.5). The decision about how to treat psychiatric illness in pregnancy involves the woman, her partner, her clinician, and an ongoing discussion about research results of medication versus untreated disease exposure. However, patients, their partners and clinicians must rely on results from observational, cohort and administrative database studies in the absence of definitive studies [157]. Moreover, the results of these studies are difficult to interpret due to the confounding effects of medication, underlying illness and unhealthy behaviors due to illness Also, there is minimal evidence-based research suggesting efficacy of psychotherapies or alternative treatments for MDD during pregnancy. Treatment options are governed by the current severity of symptoms, psychiatric history and response to treatment, clinician presentation of treatment choices with their risks and benefits, patient perception of the risks and benefits of treatment choices, cultural expectations, and plans for breastfeeding. A recent study of pregnant women with depression identified cost, lack of transportation, distrust of mental health clinicians, and lack of knowledge of available resources as barriers to pursuing psychiatric care [158].

A woman who is euthymic on her antidepressant may wish to taper her medication prior to a planned conception, or following conception, in an effort to decrease the exposure of the fetus to medication. However, the risk for relapse of MDD is significant and there are clear risks of exposure to untreated depression. If a pregnant woman decides to start, restart or continue medication, monotherapy and the minimum effective dosage of an antidepressant without known teratogenicity should be used. At the time of writing, the SSRI sertraline and the TCA nortriptyline would appear to be the “safest” medication choices for treatment of depression when initiating therapy in pregnancy or changing antidepressant medication in preparation for (or early on during) a pregnancy. However, the literature suggests that some risk likely exists with any antidepressant use during pregnancy. The risk of miscarriage is increased slightly with first-trimester exposure compared to nonexposure. Antidepressants are not considered major teratogens and, overall, they are not linked to significantly increased rates of specific congenital malformations [1]. However, a controversy exists as to whether first-trimester exposure to paroxetine increases the risk of cardiovascular malformations. Exposure to SSRI in the second half of pregnancy does appear to increase the risk of PPHN.

Neonatal symptoms due to antidepressant toxicity or withdrawal are generally mild and transient, but deserve systematic study. The tapering of antidepressant medication approximately 2 weeks prior to delivery in an attempt to decrease possible PNA is currently controversial and it is not our present practice to do so [159]. Although PNA symptoms might be decreased, the timing of delivery cannot be predicted, a taper could predispose a woman to MDD prior to delivery as well as post partum, and a decrease in PNA following a taper has not been confirmed [132,160].

The long-term effects of exposure to antidepressants during pregnancy, as well as to untreated psychiatric symptoms, are largely unstudied to date. Thus, pregnant women with depression must choose the risks of exposure to untreated disease or to medication without clear data about the long-term effects of both on the development of their infant and child. Table 21.1 lists the presently available antidepressant medications and offers some practical advice about their use in pregnancy. Although these data are up to date at the time of writing, the reader should be aware that the literature on the use of antidepressants in pregnancy is rapidly evolving.

Treatment of postpartum depression

The treatment of PPD is assumed to be similar to the treatment of MDD at nonpuerperal periods. However, a new infant brings about significant role change with new demands, sleep loss and fatigue, each of which can exacerbate depressive symptoms. In addition, women who are breastfeeding need to consider potential exposure of the infant to psychotropic medications through breast milk. Breastfeeding mothers with PPD may prefer psychotherapy to medications [161–163]. Systematic reviews report that psychotherapies have at least moderate efficacy for PPD [164,165], an example of which is IPT which addresses role change, social support, the marital relationship, and life stressors [66].

Women with PPD may choose antidepressant medication or may need to add it to psychotherapy if improvement does not occur. Two placebo-controlled RCT demonstrated superiority of paroxetine [166] and fluoxetine [167]. Two active comparator RCT reported that sertraline and nortriptyline were equally effective [168] and that both paroxetine and combined paroxetine/CBT were effective in women with PPD and co-morbid anxiety disorders [169]. Antidepressant studies in PPD to date have not uniformly included breastfeeding women and have not systematically assessed adverse effects in breastfeeding infants. Other treatments studied in PPD have included estrogen, exercise, and light therapy [170]. Two recent RCT failed to demonstrate superiority of fish oil over placebo in PPD [75,76].

Breastfeeding

The breastfeeding woman with PPD must take into account the known negative effects of not treating her depression on child development and the potential risks of exposure of her infant to antidepressant medication through breast milk. In addition to potential short-term adverse effects, the long-term effects of antidepressant exposure through breast milk on child cognitive, motor, neurologic and behavioral development are unknown [149]. Reviews of antidepressants and breastfeeding suggest that sertraline, paroxetine and nortriptyline usually yield undetectable infant serum levels and an absence of adverse effects in infants, while adverse effects have been reported with fluoxetine, citalopram and doxepin [171–173]. Lactation risk categories currently exist [174], and the FDA has suggested a future reclassification [175]. Breast milk analysis and measurement of infant antidepressant serum levels are not routinely obtained in clinical care [1], and adverse effects in the infant may not correlate with milk-to-plasma ratios [176]. Administration of an antidepressant should include a low initial dose followed by gradual titration of the dose while monitoring the infant for adverse effects such as irritability, sedation, poor weight gain or a change in feeding patterns [172,177]. If adverse effects in the infant are noted, the pediatrician should be consulted, and the options include decreasing the dose, changing to partial or full bottlefeeding or changing the medication. If a postpartum woman is already doing well on an antidepressant that may be associated with potential adverse effects or high infant serum levels, carefully monitoring the infant rather than switching the antidepressant may be indicated [172,177].

Bipolar disorder

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