   INTRODUCTION

has topped the 4 million mark annually; approximately 50% of these pregnancies represent inadvertent
conception; women hav...
persistent avoidance of stimuli associated with the trauma 5. In women, the event often includes sexual or
physical abuse ...
involving depression during pregnancy is limited. Recent investigations show that depression occurs at the same
frequency ...
manifests itself as sexually inappropriate behavior and indiscretion 62. Although schizophrenia occurs in
approximately on...
postpartum period seems to be potentially more problematic.

The data on the incidence, course, and impact of the psychiat...

The overlap in the potential treatment options for various psychiatric il...
exposures [103–110], 364 citalopram exposures 109, 309 paroxetine exposures [109–112], 225 sertraline
exposures [109,110,1...
of antidepressants proximate to delivery, although admitting they were unsure if this was a toxic or withdrawal

from 1 in 20,000 to 1 in 1000. A series of more recent yet small studies also fails to confirm the early estimates
neural tube defects in carbamazepine-exposed infants 198 is significantly less than the rate with valproate
exposure [171,...
there are increasing reports of and FDA approval for such medications in the treatment of BPD. Many clinicians
have forgot...
the total number of exposures; that is, if choosing to treat, patients should be kept well by adjusting and
monitoring med...
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47. [47]Steer RA, Scholl TO, Hediger ML, Fischer RL. Self-reported depression and negative pregnancy
outcomes. J Clin Epid...
67. [67]Bennedsen B, Mortensen P, Olesen A, Henriksen T, Frydenberg M. Obstetric complications in women
with schizophrenia...
87. [87]Treasure J, Russell G. Intrauterine growth and neonatal weight gain in babies of women with anorexia
nervosa. BMJ....
106. [106]McElhatton P, Hanneke M, Elefant E, Vial T, Bellemin B, Mastroiacovo P, et al.. The outcome of
pregnancy in 689 ...
123. [123]Kaufman M, Henry M, Frederick B, Hennen J, Villafuerte R, Stoddard E, et al.. Selective serotonin
reuptake inhib...
144. [144]Woods D, Malan A. Side effects of maternal diazepam on the newborn infant. S Afr Med J.

145. [145]...
163. [163]Wilson N, Forfar J, Godman M. Atrial flutter in the newborn resulting from maternal lithium
ingestion. Arch Dis ...
offspring of women with epilepsy: a prospective study. Epilepsia. 1999;40:1231–1236.

182. [182]Kaneko S, Battino D, Ander...
200. [200]Matalon S, Schechtman S, Goldzweig G, Ornoy A. The teratogenic effect of carbamazepine: a meta-
analysis of 1255...
epilepsy. Epilepsia. 2000;41:200.

218. [218]Sathanandar S, Blesi K, Tran T, Leppik I. Lamotrigine clearance increases mar...
236. [236]Schou M. Lithium treatment at 52. J Affect Disord. 2001;67:21–32.

237. [237]Stowe Z, Calhoun K, Ramsey C, Sadek...
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Talking psychiatry...Psychiatric disorders in pregnancy


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Talking psychiatry...Psychiatric disorders in pregnancy

  1. 1. INDEX  INTRODUCTION  PSYCHIATRY DISORDERS IN PREGNANCY  MANAGEMENT OF PSYCHIATRY DISORDERS IN PREGNANCY INTRODUCTION The course and treatment of illnesses during pregnancy can generate considerable clinical anxiety as the clinician assesses the risks and benefits of intervention against a backdrop of limited information and myriad review articles that provide less than definitive direction. This clinical decision is complicated further by the mandate of do no harm and the desire of many women to protect the child at all costs. There is widespread acceptance that some conditions warrant treatment secondary to the potential adverse impact of the illness (eg, hyperemesis, hypertension, infection, and epilepsy). In contrast, the treatments for some illnesses are continued in absence of evidence that such conditions pose a significant risk to the pregnancy (eg, allergies and insomnia). The location of psychiatric illnesses along this continuum of medical severity or risk is unclear, complicated further by the lack of objective tests and the subjective nature of many of the symptoms, thereby leading to reliance on clinical judgment with respect to the need for intervention. Given the high rate of psychiatric morbidity in women of reproductive years, it is important to clarify the course, potential impact, and treatment options for psychiatric illnesses during pregnancy. The importance of extending this information to all subspecialties is evident: the birth rate in the United States
  2. 2. has topped the 4 million mark annually; approximately 50% of these pregnancies represent inadvertent conception; women have higher rates of several anxiety disorders (eg, panic disorder [PD], post-traumatic stress disorder [PTSD], and generalized anxiety disorder), major depression, and eating disorders (EDs) compared with men; the reproductive years represent the greatest window of risk for psychiatric morbidity; psychiatric comorbidity with other medical conditions is common and often complicates treatment planning; and the treatment of psychiatric illness increasingly has fallen under the auspices of various clinical subspecialists, including nurse practitioners and physician's assistants. Conservatively, more than 500,000 pregnancies each year involve women who have psychiatric illnesses that either predate or emerge during the pregnancy, and half of these are unplanned. This estimate underscores the need to treat women of reproductive capacity clinically, like they are pregnant from the very first visit, and to be familiar with the extant literature on the course of illness in pregnancy and the impact of illness or treatment on obstetric outcome. The literature on the impact of psychiatric illness or treatment on obstetric outcome is highly confounded. Clinical and basic science investigators routinely use measures of anxiety, stress, and depression almost interchangeably and in the absence of validation of such measures in pregnancy. The overlap and relationship between anxiety, stress, and depression may be intuitive but formally remain obscure. Similarly, treatment outcome investigations rely on retrospective reporting, poison control centers, and case series. To date, no obstetric outcome study of in utero psychotropic medication exposure has controlled prospectively for tobacco, alcohol, or drug use; concomitant medications; or psychiatric symptoms during pregnancy. Given the limitations of the current literature, this review addresses salient questions to aid the clinician in a better understanding of where psychiatric illness and its treatments lie in the continuum of risk to the patient, pregnancy, and child. Broadly, these questions are: (1) Do women experience psychiatric illness in pregnancy? (2) Does psychiatric illness improve during pregnancy? (3) Does psychiatric illness pose a risk to pregnancy outcome? and (4) Which psychiatric treatment options are the best choices for pregnancy? PSYCHIATRY DISORDERS IN PREGNANCY Historically, pregnancy has been perceived as a time of emotional well-being. There is limited data, however, to support such a contention. There are few investigations of the incidence or prevalence of psychiatric illnesses during pregnancy. There are even fewer studies that have looked at the course of pre-existing psychiatric illness across pregnancy. Although depression has received the most investigative attention, it is not the most common psychiatric illness in women.  Anxiety disorders Anxiety disorders include PD, obsessive-compulsive disorder (OCD), generalized anxiety disorder, PTSD, social anxiety disorder, and phobias. They are the most commonly occurring psychiatric disorders, with approximately 13.3% of Americans aged 18 to 54 years meeting diagnostic criteria. Women are two times as likely to be diagnosed than men, and almost one third of women experience a variant of an anxiety disorder during their lifetime [1–3]. Unfortunately, general practitioners, who usually see patients more often than those in other medical disciplines, miss a large proportion of diagnosable psychiatric disorders, with anxiety disorders missed most often 4. PD is characterized by recurrent panic attacks, which come out of the blue and include an intense discomfort or fear. Symptoms include palpitations, sweating, trembling, shortness of breath, choking feelings, chest pain, nausea, dizziness, a detached dream-like state of derealization, fear of dying, and fear of losing control 5. The incidence of PD during pregnancy is unknown. Retrospective studies suggest that pregnancy is protective against panic attacks [6–8], with one group theorizing that alterations in the Pco2 during the course of pregnancy reduce the physiologic trigger of anxiety 8. In contrast, a recent prospective study fails to corroborate these findings and finds that the severity of the disorder before pregnancy predicts the course of the disorder during pregnancy 9. The literature includes a total of 260 pregnancies in women who have had PD, and indicates that 30% of women experience symptom improvement, whereas 19% worsen [10,11]. PTSD occurs after the experience of a traumatic event, which evokes intense fear or helplessness. Recurrent, intrusive, distressing recollections or dreams or a reliving of the experience follows the event. There often is
  3. 3. persistent avoidance of stimuli associated with the trauma 5. In women, the event often includes sexual or physical abuse either of themselves or their children [12,13]. The incidence and course of PTSD in pregnancy are unknown. In some cases, pregnancy and childbirth may exacerbate symptoms of PTSD, particularly if the pregnancy is a result of rape or if the pregnancy experience triggers memories of sexual trauma [14,15]. Several investigators suggest that the experience of childbirth itself may precipitate PTSD [16–18], with a resultant fear of pregnancy, referred to as tocophobia. A phenomenon only recently begun to be studied is the idea of pretraumatic stress, an intense fear of the upcoming birth 19. Some women report a fear of vaginal birth in general, resulting in a rise in the number of cesarean sections requested. This fear is associated with personality traits that predispose women to anxiety and their and their partner's dissatisfaction with their relationship and the life they are living 20. Although nearly 20% of women report being afraid of childbirth 20, 2.3% meet full diagnostic criteria for PTSD. Predictors of this pretraumatic stress include previous psychiatric problems or previous psychiatric counseling for childbirth, high trait anxiety scores, and depressive symptomatology. Risk factors include a previous traumatic birth experience or previous traumatic experiences in general, poor stress coping skills, and low perceived social support 19. A single investigation suggests that PTSD might be associated with a higher risk for obstetric complications, such as ectopic pregnancy, spontaneous abortion, hyperemesis, preterm contractions, and excessive fetal growth 21. OCD is characterized by the occurrence either of obsessions or compulsions. Obsessions are recurrent, persistent, intrusive and inappropriate thoughts, impulses, or images that cause marked anxiety or distress. Compulsions are repetitive behaviors or mental acts that an individual is driven to perform in response to an obsession, which are aimed at preventing or reducing distress 3. The incidence of OCD in pregnancy is unknown. Despite limited formal investigation, most clinicians and researchers agree that pregnancy seems to be a potential trigger of OCD symptom onset with more than 30% of the women in a specialized OCD clinic experiencing symptom onset during pregnancy 22. Given the potential similarities between OCD and maternal behaviors (eg, baby proofing), such data is not surprising. It generally is accepted that OCD worsens in the postpartum period and that obsessions are a common component of postpartum depression [23,24]. One group proposes that hormonal alterations are a risk factor for exacerbation of OCD symptoms 25. The impact of OCD on obstetric outcome is limited to a single study. An investigation of eight women who had OCD found that two had pre- eclampsia, three delivered preterm, and five had cesarean section 26. Elevated levels of prenatal maternal anxiety and stress are shown to be one of many factors that cause poor pregnancy outcomes 27, such as forcep deliveries, prolonged labor, precipitate labor, clinical fetal distress 28, preterm delivery [29,30], and spontaneous abortion 31; a direct causal relationship, however, is not established. Increased levels of maternal cortisol, often seen in response to stress, late in pregnancy are associated with lower developmental scores in early infancy 32; increased levels of adrenocorticotropic hormone at 24 weeks' gestation are associated with inadaptability early in infancy 32; and maternal anxiety in late pregnancy independently predicts slowed mental development in 2-year-old children 33. Pre-eclampsia, a severe complication in pregnancy, although not associated with raised salivary cortisol and pregnancy-associated maternal stress 34, may be associated with the presence of maternal depression and anxiety 35. Research in this area is emerging, but some investigators believe stress hormones may increase levels of oxidative stress circulating in the mother's system and impair uteroplacental blood flow, creating a higher vascular resistance index in blood flow through the placenta 34. Despite the high incidence of anxiety disorders in women, there is limited information about the incidence and clinical course of these disorders during pregnancy and, for some disorders, such as generalized anxiety disorder, there is no data. These investigations fail to demonstrate any clear palliative effects of pregnancy on anxiety disorders, and the obstetric complications from maternal anxiety and stress can be significant. In comparison, there is considerably more information on mood disorders in pregnancy.  Mood disorders The most common mood disorder is major depression and it is characterized by a depressed or irritable mood, diminished interest or pleasure in activities, weight loss or gain, appetite and sleep changes, and loss of energy, among other symptoms 5. Women are two times more likely as men to experience a major depressive episode at some point in their lives 36, and despite the Diagnostic and Statistical Manual, Fourth Edition's 5 assertion that women are most likely to experience their first depressive episode during their childbearing years, research
  4. 4. involving depression during pregnancy is limited. Recent investigations show that depression occurs at the same frequency in gravid women as it does in nongravid women; approximately 10% to 16% fulfill diagnostic criteria for a major depressive episode during pregnancy, whereas approximately 70% of pregnant women report experiencing depressive symptoms [36–39]. Many symptoms of depression, including weight gain, changes in appetite, sleep disturbance, loss of libido, and fatigue, also are associated with pregnancy and often are dismissed by professionals and laypersons [36,40]. Additionally, many pregnant women never are assessed for other medical disorders that potentially can contribute to depressive symptoms, such as anemia, gestational diabetes, and thyroid dysfunction 41. These factors make an accurate diagnosis of a depressive disorder in a pregnant woman challenging. The course of depression during pregnancy has received limited attention. In the authors' initial study of women taking antidepressants at conception, more than 60% experienced depressive symptoms during pregnancy 42. A recently completed collaborative prospective study of 207 pregnant women who had a history of depression and were taking antidepressants proximate to conception demonstrates that 68% of women who discontinued medications experienced a depressive episode in pregnancy 43. More than 25% of the women in this study who continued antidepressant medication experienced relapse. Maternal depression is associated with problems not only for the mother but also for the developing fetus. There is a greater incidence of premature birth, very low birth weight, and postnatal complications in mothers suffering from depression 44 and increased life stress; decreased social support; poor weight gain; or tobacco, alcohol, and drug use 45, all of which demonstrate an adverse effect on obstetric outcome. The relationship between poor pregnancy outcomes and depression becomes much stronger when the mother is depressed during the late second to early third trimester 46, and the relative risk for poor pregnancy outcomes rises 5% to 7% for each point increase in the mother's score on the Beck Depression Inventory 47. In addition to the problems noted previously, maternal depression also is associated with decreased fetal growth 46, raised newborn cortisol and catecholamine levels 48, and newborns who cry more and are more difficult to console 49. Later in life, children of depressed mothers are more prone to suicidal behavior, conduct problems, and emotional instability and require psychiatric care more often [50,51]. Bipolar disorder (BPD), historically called manic-depressive disorder, is a serious psychiatric disorder affecting 1.5% of Americans. BPD is characterized by distinct periods of abnormally and persistently elevated, expansive, or irritable mood, during which the following can occur: inflated self-esteem or grandiosity, decreased need for sleep, pressured speech, flight of ideas or racing thoughts, distractibility, increase in goal-directed activity or psychomotor agitation, and excessive involvement in pleasurable activities that have a high potential for painful consequences (unrestrained buying sprees, sexual indiscretions, or foolish business investments) 5. It typically is recurrent, usually begins in adolescence or early adulthood, and tends to cause a significant amount of distress and dysfunction. BPD often is accompanied by substance abuse disorders and has high mortality rates because of high suicidality [52,53]. The incidence of BPD in pregnancy is unknown. The course of illness typically has been investigated as a risk for relapse with medication discontinuation. A single study indicates that lithium- responsive pregnant women have a recurrence rate during pregnancy lower than predicted 54. In contrast, a larger body of research suggests that pregnancy is a time of substantial risk of relapse, particularly after discontinuation of pharmacologic treatment [55–58], the majority of these relapses being depressive episodes 55. An expert panel recently completed an extensive review of BPD and its treatment during pregnancy 59. The data on mood disorders clearly indicates there is minimal evidence of improvement and that the clinical course through pregnancy in the context of medication discontinuation is laden with relapse. The obstetric complications of maternal depression can be acute and have a long-lasting adverse impact on infant development, temperament, and behavior. Although the obstetric impact of BPD is unknown, it can be assumed to have an adverse impact as the majority of episodes in pregnancy are depressive.  Schizophrenia and psychosis Schizophrenia is a severe and persistent mental illness characterized by psychotic symptoms, such as delusions and hallucinations; residual negative symptoms, such as flat affect; and significant occupational and social dysfunction 5. Gender differences in the clinical expression of schizophrenia have been reported for some time. Research shows that men have greater negative symptoms, worse level of functioning, and an earlier age of onset compared with women 60, whereas women report a higher occurrence of auditory hallucinations 61 and higher levels of paranoia, depressed mood, obsessional thinking and behavior, and impulsivity, which generally
  5. 5. manifests itself as sexually inappropriate behavior and indiscretion 62. Although schizophrenia occurs in approximately only 1% to 2% of women, the most common age of initial onset is during a woman's childbearing years 63, giving physicians cause for concern. The incidence in pregnancy is unknown and there is sparse information about the course of illness that is confounded by alterations in pharmacotherapy and unreported pregnancies. With regard to the high risk of decompensation during pregnancy and post partum, continuous antipsychotic medication often is warranted 64. Data indicates that women who have psychoses neither improve during pregnancy nor require smaller doses of maintenance medication while pregnant. Women who have schizophrenia experience more obstetric complications than women who do not have mental illness 65. One study finds that they also have high rates of poverty and substance abuse and are less likely to receive consistent prenatal care 66. In contrast, a recent investigation does not confirm this data 67. Maternal schizophrenia also is associated with a higher rate of perinatal death 68. Mothers who have schizophrenia are significantly more likely to deliver a low birth weight (LBW) newborn [69,70], are at increased risk for preterm delivery 71, and are more likely to require interventions during delivery 67 than mothers who do not have a diagnosis of schizophrenia. Women admitted to the hospital for acute psychotic episodes during pregnancy seem to be at the greatest risk for adverse pregnancy outcomes, including stillbirth and infant death 72. Untreated schizophrenia during the postpartum period can have disastrous consequences for mother and child. There are cases of maternal self-mutilation [73,74], infanticide 75, and denial of pregnancy, resulting in the patient's refusal of prenatal care 76.  Eating disorders EDs seldom are screened for in nonpsychiatric clinics. EDs, including anorexia nervosa and bulimia, affect more than 5% of Americans, and 90% of these are women of childbearing age [5,77]. In addition, almost half of the women who have anorexia exhibit bulimic behaviors, and 30% to 80% of women who have bulimia have a history of anorexia 78. Anorexia is defined as the failure to maintain body weight at 85% of the norm for one's height. Weight loss is accompanied by extreme fear of gaining weight and distortions of body image. Dieting, self- induced vomiting, extreme exercising, laxatives, diuretics, and thyroid hormone can be used to cause weight loss. Bulimia is defined as recurrent episodes of binge eating, characterized by lack of control of eating and recurrent inappropriate, compensatory behavior to prevent weight gain, such as self-induced vomiting; misuse of laxatives, diuretics or enemas; fasting; and excessive exercise 5. Although fertility is reduced markedly in women who suffer from anorexia nervosa, women do conceive despite maintaining suboptimal weight and not menstruating 79. There may be a protective value of pregnancy against EDs. One study reports that pregnant women who have EDs were less concerned with weight than nonpregnant women, had lower dietary restraint, and attempted to lose weight less frequently 80. Although many women show substantial improvement in bulimic symptoms during pregnancy, possibly because of societal approval of weight gain during pregnancy and cultural pressures to care for the fetus [81,82], there are cases reported in which the symptoms worsen 83. Furthermore, patients who have bulimia seem to have a higher risk of affective disorders after delivery, including postpartum depression [81–83]. There is conflicting obstetric outcome data in women who have EDs. The majority of women in one study had reasonably good outcome with a 6.1% rate of birth defects, but more than one third experienced postpartum depression 84. In contrast, other studies find higher rates of pregnancy complications in women who have EDs, including prematurity, LBW, and higher rate of miscarriage and cesarean section [85–87]. Stewart et al discovered that women whose ED was in remission at conception gained more weight during pregnancy and had babies with higher birth weights and 5-minute Apgar scores 88. Furthermore, babies of women who have EDs post partum are at increased risk for food deprivation and inadequate weight gain and growth 89. There is evidence that children born to mothers who have EDs also are at risk for EDs. This may begin as feeding problems in infancy and continue through adolescence and adulthood as a result of mothers who have EDs restricting food 90, not eating in front of their children 91, and demonstrating other behaviors associated with the disorder. One study shows 50% of the children of mothers who had EDs also had other psychiatric disorders, including OCD, antisocial and oppositional defiant disorder, and eneuresis. EDs or a history of EDs seldom is assessed in the nonpsychiatric clinical setting. Although there is evidence that EDs may have a more benign course in pregnancy compared with other psychiatric illnesses, the comorbidity with depression and anxiety warrants concerns for obstetric outcome. Similarly, the impact of EDs in the
  6. 6. postpartum period seems to be potentially more problematic. The data on the incidence, course, and impact of the psychiatric illnesses discussed previously are summarized in Table 1 and include the most common Food and Drug Administration (FDA)–approved treatment options. These data focus on pregnancy, and there is general consensus that the postpartum period represents considerable risk for the majority of psychiatric illnesses. Table 1. Summary of incidence, course, and impact of psychiatric illnesses in pregnancy Adverse Incidence in Impact on Incidence in Course in impact of Diagnosis general obstetric Treatment options pregnancy pregnancy illness on population outcome children Anxiety 13.3% overall Unknown Limited LBW, SGA, Yes CBT, IPT disorders rate of any evidence of premature Antidepressants anxiety improvement for delivery, Benzodiazepines disorder PD OCD decreased fetal probably growth worsens Major 12% in 10% No LBW, SGA, Yes CBT, IPT depression women, 6.6% –16% improvement premature Antidepressants ECT in men 70% delivery, Light therapy experience decreased fetal depressive growth symptoms High rate of relapse with medication discontinuation Bipolar 1.2% Unknown No Unknown Unknown Mood stabilizers ECT disorder improvement Antipsychotics High rate of relapse with medication discontinuation Schizophrenia 1.1% Unknown No LBW, SGA, Unclear, Antipsychotics improvement reduced head confounded circumference, by premature birth, medication higher rates of exposures stillbirth and infant death Eating 0.5% Unknown Seem to LBW, inadequate Yes Psychotherapy disorders –3.7% improve during or excessive Behavioral of women pregnancy and weight gain, programsAntidepressants suffer from potentially miscarriage, anorexia, 1.1% worsen post hyperemesis – 4.2% partum gravidarum, suffer from premature bulimia delivery, cesarean delivery, and low Apgar scores Abbreviation: SGA, small for gestational age.
  7. 7. MANAGEMENT OF PSYCHIATRY DISORDERS IN PREGNANCY The overlap in the potential treatment options for various psychiatric illnesses during pregnancy and lactation warrant their discussion by category rather than by illness. There are limited studies of the efficacy of any specific treatment during pregnancy, as the literature focuses on the reproductive safety of such treatments. There is no data to suggest that a treatment is less effective in pregnancy than in nongravid conditions.  Psychotherapy Use of nonpharmacologic treatment alternatives, such as cognitive-behavioral therapy (CBT) 92 and interpersonal psychotherapy (IPT) [93,94], for the treatment of psychiatric illnesses during pregnancy is underinvestigated dramatically. Myriad studies show such structured psychotherapies to be effective in the treatment of anxiety disorders and depression. IPT is associated with greater improvement in mood than a parent education program during the prenatal period in one study 95. An elegant study of manual development demonstrates the efficacy of IPT for depression in the postpartum period 94. There are case reports of the efficacy of CBT in the treatment of PD in pregnancy. In one study, women in a postpartum prevention group, who received one session of CBT during hospitalization in the days immediately after the birth, had significantly more reductions in the frequency of depression than the control group 96.  Light therapy The use of light therapy in the treatment of depression, in particular seasonal affective disorder, demonstrates efficacy. A single open-label trial of light therapy found it beneficial in reducing depressive symptoms during pregnancy 97. Additional study is warranted and caution should be exercised in the use of such therapies if there is diagnostic uncertainty.  Electroconvulsive therapy Electroconvulsive therapy (ECT) is an effective treatment of major depression and BPD that has few side effects and may pose fewer risks than untreated mood episodes or pharmacotherapy with a teratogenic agent. There are reports of congenital malformations in offspring exposed to ECT in utero 98, although confirmation of a causal relationship is lacking. Overall, the reported complications of ECT during pregnancy are uncommon and transient 99. The risk of fetal cardiac arrhythmias can be minimized by avoiding atropine, ensuring adequate oxygenation, avoiding excessive hyperventilation, and elevating the right hip. Fetal cardiac monitoring during ECT allows detection of arrhythmias and correction of any contributory problems. There are limited reports of uterine contractions after ECT 100 but no risk of premature labor 99. Although nonpharmacologic treatments seem promising, there is limited availability and funding to cover such interventions, leaving many clinicians with the potential use of medications during pregnancy. The use of psychotropic medications in pregnancy and lactation has been reviewed extensively 101.  Antidepressants A Medline search conducted in February 2004 of antidepressants in pregnancy yielded 26 journal articles with a total of 4556 participants. Information is derived from myriad sources, including birth registries, retrospective surveys, case reports, case series, reports from poison control and teratology centers, and controlled observational studies. Despite the capacious amount of reproductive safety information available on this class of drugs, absolute numbers in each study are small, making definitive conclusions elusive. On the whole, findings regarding pregnancy outcomes after the use of antidepressants in pregnancy are favorable. Antidepressants have been in use for more than 4 decades with no confirmed reports of birth defects associated with in utero exposure. A comprehensive meta-analysis in 1996 failed to identify any risk for in utero exposure to antidepressants 102, and data on tricyclic antidepressants (TCAs) have not advanced significantly since that report. The selective serotonin uptake inhibitors (SSRIs) have moved to the forefront of treating depression and anxiety. To date, published retrospective and prospective reports of SSRI use during gestation consist of 1241 fluoxetine
  8. 8. exposures [103–110], 364 citalopram exposures 109, 309 paroxetine exposures [109–112], 225 sertraline exposures [109,110,112], and 80 fluvoxamine exposures [106,112]. No published reports regarding prenatal exposure to the new enantiomeric compounds, duloxetine and escitalopram, currently are available. Collectively, these data provide no evidence that prenatal SSRI exposure is associated with an increased incidence of congenital malformations. Recent additions to the available regimen of antidepressants include a heterogeneous assortment of antidepressants that work by distinct pharmacodynamic mechanisms. Antidepressants that do not fit into the major categories include bupropion, mirtazapine, nefazodone, and venlafaxine. A recent report demonstrates no adverse effects of fetal exposure to venlafaxine 113. Despite the paucity of data, physicians in the United States increasingly are prescribing bupropion to treat depression during pregnancy, apparently as a consequence of its inclusion by the FDA in the B risk category for pregnancy. The manufacturer of bupropion has maintained a pregnancy registry for the compound since 1997; this registry, however, has not been submitted for publication or peer review; as such, there are no published data regarding its safety or tolerability during gestation. Likewise, there are no published reports regarding the use of mirtazapine or nefazodone during pregnancy. Recent pharmacokinetic studies [110,114] demonstrate that antidepressants do cross the placenta, and rodent investigations from the authors' group 115 indicate significant central nervous system exposure. Similarly, additional studies indicate that during the course of pregnancy there are significant alterations in the clearance of TCAs and SSRIs that may warrant dose adjustments [102,116,117]. In contrast, there are reports that attribute adverse obstetric outcome to antidepressant exposure. One study finds that third-trimester exposure to fluoxetine is associated with higher rates of prematurity, admissions to special care nurseries, poor neonatal adaptation, shorter birth length, and lower birth weight compared with exposure during the first or second trimesters 105. Cohen et al 118 finds no significant differences in gestational age at delivery, birth weight, Apgar scores, or timing of maternal-infant discharge between early and late exposed infants; there were twofold and threefold increases, however, in neonatal complications and admissions to special care nurseries between the two groups, respectively. One cohort study also finds higher rates of spontaneous abortions in women exposed to TCAs (n=74) or fluoxetine (n=128) compared with matched control subjects 103. Other groups have failed to come up with similar findings, reporting that no differences existed between groups [108,112,119]. Because none of the studies that report associations between in utero antidepressant exposure and poor pregnancy outcome controlled for maternal depression, concomitant medication exposure, or alcohol and tobacco use, these results are provisional at best. Two landmark studies conducted by Nulman et al [108,119] find that in utero exposure to TCA or fluoxetine did not affect children's global IQ; temperament; or language, cognitive, and behavioral development; uncontrolled depression in the latter study, however, was associated with lower cognitive and language achievements 119. Most commonly, results are mixed, leaving the question of the safety of antidepressant medications during pregnancy unanswered. Simon et al 120 conducted a study comparing pregnancy outcomes in patients exposed to TCAs and SSRIs with those in control subjects. They found no significant differences between those exposed to TCAs and control subjects in gestational age at birth, Apgar scores, birth weight, or head circumference; those exposed to SSRIs, however, showed significantly lower Apgar scores, gestational age at birth, and birth weight 120. A similar finding of lower birth weight associated with high doses of fluoxetine in later pregnancy raises questions regarding the impact of these medications on birth weight 114. Recently, much attention has been paid to selective serotonin discontinuation syndrome, a set of adverse effects emerging after cessation of antidepressants (SSRIs and venlafaxine) [121–123]. Concern has emerged over whether or not neonates suffer from discontinuation syndrome after delivery when exposure to SSRIs is stopped abruptly at birth. Costei et al 124 find a high rate of neonatal complications, in particular respiratory distress, in infants whose mothers took paroxetine (22%) throughout pregnancy compared with control infants (6%). Earlier studies found that neonatal withdrawal symptoms occurred after third-trimester exposure to paroxetine and were evident in the first days after birth for up to 1 month [125,126]. Symptom characteristics included irritability, constant crying, shivering, increased tonus, eating and sleeping difficulties, convulsions, jitteriness, poor gaze control, necrotising enterocolitis, vomiting, myclonus, and lethargy [125,126]. Although evidence for perinatal serotonin discontinuation syndrome seems compelling, research in this area is confounded by the presence of maternal smoking, polypharmacy, maternal health problems, and pregnancy and delivery complications. Despite the limitations of these case reports, the FDA recently issued a warning concerning the use
  9. 9. of antidepressants proximate to delivery, although admitting they were unsure if this was a toxic or withdrawal effect. As discussed previously, a major potential confound to these adverse reports is the overlap in reported adverse outcomes related to antidepressant exposure (eg, LBW) and the data indicating that untreated maternal depression and anxiety are associated with the same finding. Further research is needed to support existing findings before definitive conclusions can be drawn.  Benzodiazepines Benzodiazepines have a wide spectrum of clinical indications, including the full array of anxiety disorders, insomnia, alcohol detoxification, muscle relaxation, adjunctive use for seizure disorders, and conscious sedation during invasive medical procedures. A retrospective survey of Medicaid prescription records from 1980 to 1983 for more than 100,000 pregnant women found that at least 2% were prescribed a benzodiazepine during gestation 127. Initial studies of benzodiazepine-associated teratogenic effects report an increased risk of oral clefts after in utero exposure to diazepam [128–130], but later studies fail to confirm this association [131–133]. Studies of first-trimester alprazolam exposure encompassing approximately 1300 pregnancies demonstrate no excess of oral clefts or other congenital anomalies [134–136]. A subsequent meta-analysis by Altshuler et al 102, pooling data from several studies, demonstrates that prenatal benzodiazepine exposure does confer an increased risk of oral cleft, although the absolute risk increased by only 0.01%, from 6 in 10,000 to 7 in 10,000. This conclusion is confirmed in a recent case control study of benzodiazepine exposure in more than 38,000 infants compared with nearly 23,000 control children 137 that demonstrates no difference in the rate of congenital anomalies. Longitudinal follow-up studies describe a benzodiazepine exposure syndrome, including growth retardation, dysmorphism, and mental and psychomotor retardation in infants exposed prenatally to benzodiazepines 138, although other investigators dispute this finding [139–141]. Although the data regarding the teratogenic effects of benzodiazepine exposure remain controversial, the occurrence of neonatal toxicity and withdrawal syndromes are well documented. Many groups describe a floppy infant syndrome, characterized by hypothermia, lethargy, poor respiratory effort, and feeding difficulties after maternal use of benzodiazepines shortly before delivery [142–149]. Neonatal withdrawal syndromes, characterized by restlessness, hypertonia, hyperreflexia, tremulousness, apnea, diarrhea, and vomiting, are described in infants whose mothers were taking alprazolam 134, chlordiazepoxide [150–152], or diazepam [153,154]. Symptoms of these neonatal syndromes are reported to persist for as long as 3 months after delivery 155. These data fail to confirm the excessive concern for direct teratogenic effects but underscore the need to be mindful of neonatal symptoms when benzodiazepines are used proximate to delivery.  Mood stabilizers The management of BPD has received considerable attention and continues to be one of the most difficult challenges of modern psychiatric practice 59. The current FDA-approved treatments of BPD include mood stabilizers and atypical antipsychotic agents. Given the audience, an exhaustive review of the reproductive safety data on anticonvulsants has been abbreviated. All mood stabilizers cross the placental barrier and demonstrate complete placental passage 156.  Lithium Since the 1950s, lithium has emerged as the cornerstone of the available pharmacotherapies for BPD. Early reports of congenital malformations after in utero lithium exposure led to the establishment in 1969 of the Danish Registry of Lithium Babies. Additional registries were established in Canada and the United States, culminating in the International Register of Lithium Babies, a physician-reporting registry. Early data suggested that lithium exposure was associated with a 400-fold increase in the vulnerability for congenital heart disease, in particular Epstein's anomaly [157,158], but a subsequent meta-analysis of the available data calculated the risk ratio for cardiac malformations to be 1.2 to 7.7 and the risk ratio for overall congenital malformations to be 1.5 to 3.0 159. Altshuler et al 102 estimates that the risk for Epstein's anomaly after prenatal lithium exposure rises
  10. 10. from 1 in 20,000 to 1 in 1000. A series of more recent yet small studies also fails to confirm the early estimates regarding the teratogenic potential of lithium [160–162]. Lithium's low therapeutic index also raises concerns regarding acute perinatal toxicities. Lithium exposure later in gestation is associated with fetal and neonatal cardiac arrhythmias 163, hypoglycemia and nephrogenic diabetes insipidus 164, reversible changes in thyroid function 165, polyhydramnios, premature delivery, and a floppy baby syndrome similar to that witnessed with benzodiazepine exposure 166. Neonatal symptoms of lithium toxicity, including flaccidity, lethargy, and poor suck reflexes, may persist for more than 7 days 167. A recent study by the authors' group 156 demonstrates that stopping lithium within 48 hours of delivery significantly reduces neonatal complications without compromising maternal emotional well-being. The physiologic alterations of pregnancy are of particular importance in the management of lithium therapy during the peripartum, warranting careful monitoring of lithium serum concentrations, although lithium is not effective for all variants of BPD and the long-term sequelae of lithium exposure has given way to the increased use of antiepileptic medications (AEDs). Arguably, the majority of the data for AEDs has been obtained from women who have epilepsy and there is limited data on the outcomes of AEDs in women who have BPD, a fact noted more than 2 decades ago 168. Conservative clinical management, however, warrants extension of these data to women who have BPD pending additional investigations.  Valproic acid (valproate) Several anticonvulsants are used in the treatment of BPD. Foremost among these are valproate and carbamazepine, which are superior to lithium for patients who experience mixed episodes or rapid cycling. Anticonvulsants, however, with the possible exception of lamotrigine, have limited efficacy in the treatment of bipolar depression. A major problem in psychiatric clinics with the use of AEDs is the limited appreciation of risk for inadvertent conception and the need to treat women of reproductive capacity as though they are pregnant from the first visit (eg, document birth control, educate about risk of medications, and provide supplemental folic acid). Despite these potential problems, valproate and, to a lesser extent, carbamazepine increasingly are preferred as first-line mood stabilizers by many clinicians. Briefly, prenatal exposure to valproate is associated with many congenital malformations, including neural tube defects [169–172], craniofacial anomalies 173, limb abnormalities 174, and cardiovascular anomalies [175–177]. A recent meta-analysis places the risk for neural tube defects at 3.8%, with particular vulnerability for the infants of women whose daily dose exceeds 1000 mg 178. Additional studies support this dose-effect relationship [179–182]. Fetal anticonvulsant syndromes are reported for several AEDs [182,183] and valproate is no exception. An initial report 184, confirmed by other investigators [185–187], demonstrates a broad array of anomalies associated with valproate exposure. Although there are some conflicting reports on exactly which features are part of this syndrome, there is consensus that valproate exposure is responsible. Of concern also are retrospective reports indicating various degrees of cognitive impairment in children who have fetal valproate syndrome [188–190]. A recent review indicates that developmental delay is evident in 20% and mental retardation in 10% of children exposed to valproate monotherapy prenatally 191. Pharmacokinetic studies in women who have epilepsy indicate that maternal serum valproate concentrations decline steadily across pregnancy, reaching levels up to 50% lower than preconception concentrations [192,193]. Consistent findings from other studies demonstrate that valproate is cleared more rapidly during gestation, especially during the final month of pregnancy [194–196]. Recent data from the authors' group confirms this effect in women who have epilepsy and BPD 197.  Carbamazepine Carbamazepine is another mood stabilizer, although the efficacy in BPD has limited its widespread acceptance as a first-line pharmacotherapy. Carbamazepine is associated with many of the same risks as valproate during gestation, although in many cases with less frequency or severity. For example, exposure to carbamazepine, like valproate, during the first trimester is associated with a risk for neural tube defects, but the 0.5% to 1% risk for
  11. 11. neural tube defects in carbamazepine-exposed infants 198 is significantly less than the rate with valproate exposure [171,198]. A recent epidemiologic study indicates that periconceptional folate supplementation is associated with a lower rate of neural tube defects among the children of women taking carbamazepine during pregnancy 199. A recent meta-analysis of five prospective studies encompassing 1255 prenatal exposures indicates that carbamazepine exposure in utero is associated with an increased risk of neural tube defects, cleft palate, cardiovascular abnormalities, and urinary tract anomalies 200. As with valproate, a fetal carbamazepine syndrome is described 201 but has received considerably less attention than fetal valproate syndrome. A subsequent study finds the phenotypic characteristic of fetal carbamazepine syndrome evident in 6 of 47 children exposed to carbamazepine monotherapy during gestation 202. Other investigations confirm this association with facial anomalies [190,203–205], but one of these studies demonstrates similar facial abnormalities among children born to women who had epilepsy and were untreated during pregnancy 204. There are conflicting reports regarding the relationship of the fetal carbamazepine syndrome to developmental delays [188,190,201–203,205–207]. In contrast to other AEDs, the pharmacokinetic studies of carbamazepine clearance during gestation and placental passage have produced mixed results. Some investigators report statistically significant increases in carbamazepine clearance during the third trimester [208–210], but others find no changes in carbamazepine clearance [195,211,212]. Placental passage investigations indicate that carbamazepine is lower than other anticonvulsants [192,193,213], with fetal-maternal plasma ratios equaling 0.5 to 0.8 213. The clinical import of the data on carbamazepine in light of the efficacy limitations in the treatment of BPD is unclear, particularly regarding recent data on lamotrigine.  Lamotrigine Several investigations demonstrate that lamotrigine is efficacious in the treatment of BPD. Similarly, prescribing trends indicate that lamotrigine is emerging rapidly as a first-line treatment of epilepsy and BPD during pregnancy. One potentially unique facet of lamotrigine is demonstrated in clinical trials that indicate efficacy for the depressed and manic phases of illness in BPD. Data from the Lamotrigine Pregnancy Registry maintained at GlaxoSmithKline (Triangle Park, North Carolina) include United States and United Kingdom reports of pregnancy exposure and have obstetric outcome for more than 500 cases. The results to date are reassuring, with a risk of less than 2% for fetal malformation after first-trimester lamotrigine exposure. The registry has not undergone the peer review process in its entirety 214 and clinicians are encouraged to request the information. Although clinical data to date do not indicate a higher rate of neural tube defects among lamotrigine-exposed infants, the Physicians' Desk Reference reports that premarketing laboratory animal data demonstrate that lamotrigine is associated with decreased circulating folate concentrations 215. Consequently, routine folate supplementation (4 to 5 mg/d) is recommended for all women of reproductive age, pregnant or not, who are taking lamotrigine. The pharmacokinetics of lamotrigine use during pregnancy have been scrutinized; the reliance on glucyronidation, which changes dramatically during pregnancy, has generated considerable interest with respect to how to use lamotrigine effectively during pregnancy. Several reports indicate collectively that lamotrigine clearance steadily increases across gestation [216–220], necessitating periodic dose changes during pregnancy to maintain seizure control in patients who have epilepsy. A series of small studies indicate that lamotrigine concentrations in fetal circulation at delivery are equal to maternal concentrations [218,221–223]. Studies also indicate that its rate of clearance declines abruptly after delivery [219,222]. Therefore, dose reductions typically are necessary after delivery to avoid maternal symptoms of lamotrigine toxicity, such as dizziness, nausea and vomiting, and diplopia 219. Lamotrigine use during breastfeeding continues to generate concerns, although investigations are under way and preliminary reports fail to demonstrate any adverse effects.  Antipsychotic medications The introduction of the atypical antipsychotic drugs has proved efficacious in the treatment of schizophrenia and
  12. 12. there are increasing reports of and FDA approval for such medications in the treatment of BPD. Many clinicians have forgotten that the original clinical use of the phenothiazines was to treat first-trimester nausea and that promethazine (Phenergan), a commonly prescribed antiemetic in pregnancy, is a phenothiazine. Phenothiazines are useful as antipsychotic medications but also are used for their antiemetic, antinauseant, and antihistamine effects 224. These medications are useful during labor and delivery because of their ability to potentiate the effects of analgesics, sedatives, and general anesthetics 224. Of the typical antipsychotic medications, chlorpromazine, haloperidol, and perphenazine have received the greatest scrutiny, as they produce no significant increase in major congenital malformations [225–227]. In a study 228 of 100 women treated with haloperidol (mean dose 1.2 mg/d) for hyperemesis gravidarum, no differences in gestational duration, fetal viability, or birth weight were observed. In a large prospective study encompassing nearly 20,000 women treated primarily with phenothiazines for emesis, Milkovich and Van den Berg 229 find no significant association with neonatal survival rates or severe anomalies after controlling for maternal age, medication, and gestational age at exposure. In contrast, one group 230 reports a significant association of major anomalies with prenatal exposure to phenothiazines with aliphatic side chains but not with piperazine or piperidine class agents. Reanalysis of the data obtained by Milkovich and Van den Berg 229 does find a significant risk of malformations associated with phenothiazine exposure in weeks 4 through 10 of gestation 231. A meta-analysis 102 confirms an association between phenothiazines with aliphatic side chains in lip and palate anomalies. One study examining 12 mothers who received antipsychotic medication during the final trimester of pregnancy finds that at 3 and 14 days of age, the infants of these women showed poor neonatal motor functioning on the Brazelton Neonatal Behavioral Assessment Scale 232, indicating symptoms of withdrawal syndrome, including tremulousness, hypertonicity, and poor motor maturity 233. A similar study followed 16 women and their infants throughout pregnancy and up to 7 years post partum. All 16 of these women took phenothiazines throughout pregnancy; no apparent adverse effects of the medication were found, however 234. Although the atypical antipsychotic medications are emerging as the treatment of choice for psychosis, there also is increasing use of such agents in refractory major depression. The data on these medications is limited. The largest data set comes from several case reports (n=73) on clozapine 156 and there is no evidence of increased birth defects. The second largest data set is derived from postmarketing surveillance at Eli Lilly (Indianapolis, Indiana) for olanzapine (n=23). These women did not experience increased risk of spontaneous abortion, stillbirth, or prematurity, and the newborns did not seem to be at greater risk for major malformations as a result of the prenatal exposure to olanzapine 235. There is limited or no information on the remaining atypical antipsychotic medications. A clinical concern for use in pregnancy is that several of these medications are implicated in glucose metabolism alterations; therefore, the authors' group emipirically recommends conducting the glucose tolerance test earlier in pregnancy for these women. In summary, with respect to medication use during pregnancy, there is considerable variability in the potential impact of medications on obstetric outcome and neonatal well-being. The clinician is forced to balance the risk of such medications with the risk of the illness being targeted. Often, pharmaceutical companies and the FDA render warnings and provide little support for the use of such treatments during pregnancy and lactation. A quotation germane to the issues encountered, credited to Dr. Schou, one of the original authors of the lithium registry, summarizes the usefulness of such warnings and cautions: “When manufacturers and official agencies warn against drug treatment during pregnancy, their warnings serve to protect themselves and are of little use to clinically responsible physicians” 236. SUMMARY This review, although not exhaustive, provides information on the potential impact of psychiatric illness on obstetric outcome. There is clear evidence that psychiatric illness poses a risk to pregnancy outcome. The reproductive safety data on many of the available treatments fail to demonstrate a clear risk from treatment. The medications with clear teratogenic, neonatal, and developmental risks are, not surprisingly, those used to treat some of the most severe and debilitating psychiatric illnesses. Even the amount of information available is inadequate without some straightforward clinical guidelines. A model of risk for illness and treatments of illnesses during pregnancy developed by the authors' group 237 reminds clinicians that nonexposure does not exist. Rather, the decision is which type of exposure is in the best interest of the patient and family—exposure to illness or exposure to treatment. Regardless of the choice, clinicians are encouraged to think in terms of reducing
  13. 13. the total number of exposures; that is, if choosing to treat, patients should be kept well by adjusting and monitoring medications—partial treatment simply provides exposure to illness and treatment. Guidelines to accomplish the goal of minimizing exposures include: 1. Treating women of reproductive capacity from the first visit as if they are pregnant: choosing treatments with reproductive safety information (eg, new and improved=no data) and providing supplemental folic acid for all women (800 µg), with higher doses for those treated with anticonvulsants (3 to 4 mg). 2. For women who conceive while taking a medication, and if it was efficacious for them, then the majority of decisions for medication selection should be considered already made for pregnancy and lactation (eg, do not switch medications once pregnant or for breastfeeding, as that simply exposes the baby to a second medication and the data previously discussed do not apply). 3. Because the serum concentration of most medications decreases during pregnancy, establishing criteria a priori for increasing the maternal daily dose; as a general rule, sleep patterns are good markers of psychiatric illnesses. 4. Always preferring monotherapy to two medications. 5. Obtaining up-to-date information at (a website with links to many support groups, reproductive safety registries) or other women's health websites. These basic guidelines can help decrease the number of exposures and aid in conducting clinical care with at least some reproductive safety data. References 1. [1]NIMH. The numbers count: mental disorders in America. [Pub. No. 01-4584] Bethesda, MD, 2001. Available at: . Accessed 2004. 2. [2]Kessler R, McGonagle K, Zhao S, Nelson C, Hughes M, Eshleman S, et al.. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorder in the United States: results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51:8–19. 3. [3]Regier D, Narrow W, Rae D. The epidemiology of anxiety disorders: the Epidemiologic Catchment Area (ECA) experience. J Psychiatr Res. 1990;2:3–14. 4. [4]Ormel J, Koeter M, Van den Brink W, Van de Willige G. Recognition, management, and course of anxiety and depression in general practice. Arch Gen Psychiatry. 1991;48:700–706. 5. [5]American Psychiatric Association . Diagnostic and statistical manual of mental disorders. 4th edition. Washington, DC: American Psychiatric Association; 1994;. 6. [6]Villeponteaux V, Lydiard R, Laraia M, Stuart G, Ballenger J. The effects of pregnancy on preexisting panic disorder. J Clin Psychol. 1992;53:201–203. 7. [7]Norcott C, Stein M. Panic disorder in pregnancy. J Clin Psychol. 1994;55:539–542. 8. [8]Klein D, Skrobala A, Garfinkel R. Preliminary look at the effects of pregnancy on the course of panic disorder. Anxiety. 1994/1995;1:227–232. 9. [9]Cohen L, Sichel D, Dimmock J, Rosenbaum J. Impact of pregnancy on panic disorder: a case series. J Clin Psych. 1994;55:284–292.
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