About Course
Chapter 64. Psychopharmacology During Pregnancy and Lactation
PSYCHOPHARMACOLOGY DURING PREGNANCY AND LACTATION:
INTRODUCTION
The management of mental illness during pregnancy and lactation represents a unique and complex
clinical situation involving a minimum of two concomitant medical conditions (i.e., pregnancy and a
psychiatric disorder) and also demanding consideration of the welfare of at least two patients (i.e.,
mother and child), not to mention the potential impact of maternal illness on the family at large.
The American College of Obstetricians and Gynecologists Practice Bulletin on the use of
psychotropic medications during pregnancy and lactation acknowledges the potential adverse
impact of untreated or inadequately treated maternal mental illness (American College of
Obstetricians and Gynecologists 2007).
Given the high incidence of psychiatric disorders among women during the childbearing years, the
increasing proportion of women who plan to nurse, and the introduction of new psychotropic
medications that are less likely to interfere with female reproductive physiology (e.g.,
second-generation antipsychotics [SGAs]), clinicians will be more frequently confronted with this
complex dilemma. The most common scenarios in which physicians provide care for a patient with a
mental disorder while she is pregnant or nursing include the following:
Preconception consultation with a patient who wishes to have a baby but who has a history of a chronic
or recurrent psychiatric illness and/or who currently takes one or more psychotropic medications
Urgent consultation in early pregnancy with a patient who has inadvertently conceived during
treatment with one or more psychotropic medications
Provision of treatment to a patient who is experiencing an exacerbation of a preexisting mental illness
during pregnancy or the postpartum, often after having discontinued pharmacological treatment
proximate to conception
Provision of treatment to a patient who is experiencing the onset of a new mental illness during
pregnancy or the postpartum
Formulation of plans during pregnancy to provide prophylactic treatment at some juncture to a patient
who is at high risk for postpartum mental illness
Despite rapid advances, the extant literature regarding psychotropic therapy during pregnancy and
lactation remains hampered by a cadre of confounds that preclude definitive treatment guidelines.
Existing studies lack methodological consistency and are often without the requisite sample size or
study design necessary to establish a significant causal relation for deleterious effects of
psychotropic medications. Specific methodological concerns include 1) limited effort to control for
the concomitant effect of maternal illness on obstetrical and infant outcome; 2) limited effort to
control for the potentially confounding effects of other nonpsychotropic exposures that might
accompany maternal mental illness; 3) failure to provide objective confirmation of purported
exposures, with a tacit assumption of full maternal psychotropic compliance and disclosure of other
concomitant exposures (e.g., tobacco, alcohol); and 4) widespread reliance on retrospective recall
to document exposures and/or outcomes (even in many so-called prospective studies) months or
even years after delivery, with a potential for systematic recall bias. As early as 6 months after
delivery, maternal retrospective reports demonstrate systematically biased underreporting of
depression and use of nonpsychotropic agents during pregnancy, whereas use of psychotropic
agents is accurately reported (Newport et al. 2008b).Print: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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The proper assessment of the risk to offspring attributable to psychotropic exposure must consider
the baseline frequencies of obstetrical complications and developmental anomalies, the timeline of
embryonic and fetal development, the potential risks of exposure to nonpsychotropic medications,
and the potential risks associated with untreated maternal psychiatric illness. In the United States,
84.5% of pregnancies result in a live delivery (Kiely 1991; McBride 1972). Recent birth registry
data collectively comprising nearly 2.5 million deliveries in New York State and Sweden indicate
that 3%–4% of these infants will suffer from major malformations (New York State Department of
Health 2005; Swedish Centre for Epidemiology 2004). Most major malformations occur during the
embryonic period (i.e., the third through the eighth week of gestation), and most organ systems
(with the notable exception of the central nervous system [CNS]) are developed by the conclusion
of week 11 (Sadler 1985). Finally, it must be noted that medications are prescribed to up to 80% of
pregnant women (Cohen et al. 1989), and more than one-third take a psychotropic medication at
some point during pregnancy (Doering and Stewart 1978).
Because clinical experience indicates that the principal goal of both patient and clinician is to
minimize potentially harmful offspring exposure, we propose in this chapter a rational model for
developing perinatal treatment guidelines that is founded on the shared conviction that minimizing
infant exposure to the effects of both maternal illness and maternal treatment is the preeminent
objective. We subsequently review the available data regarding pharmacokinetic and
pharmacodynamic alterations during pregnancy and lactation and describe the clinical relevance of
these data for psychotropic dose management and forecasting of offspring exposure. We then
review the available data regarding the potential risks of pharmacotherapy during pregnancy or
lactation with specific psychotropic agents from various medication classes, including
antidepressants, mood stabilizers, antipsychotics, and anxiolytics. We conclude the chapter with a
review of the future directions for perinatal psychiatric research and a discussion of potential
modifications of previously suggested treatment guidelines, emphasizing the need for an
individualized risk–benefit assessment.
A MODEL FOR TREATMENT GUIDELINES DURING PREGNANCY AND
LACTATION: MINIMIZING OFFSPRING EXPOSURE
The clinical management of any medical condition during pregnancy and lactation is one of “relative
safety” that must consider the reproductive safety of available therapies, the likelihood of illness
relapse or exacerbation in the absence of continued treatment, and the potential impact of
untreated maternal illness. Minor ailments, including headaches, nausea, insomnia, and localized
infections, are routinely treated during pregnancy with medications that often have limited
reproductive safety data. Conversely, women with mental illness are often encouraged to
discontinue psychotropic medication during pregnancy and lactation. The underlying desire to avoid
offspring psychotropic exposure is laudable; however, such recommendations are often made with
limited knowledge of the potential adverse obstetrical effects of maternal mental illness and an
assumption that psychotropic medications are poorly represented in the reproductive safety
database. Comprehensive treatment guidelines for perinatal psychiatric illness must therefore
incorporate an appraisal of the clinical consequences of offspring exposure to both maternal illness
and available therapies.
When the clinician conducts a risk–benefit assessment for new or expectant mothers with mental
illness, it must first be acknowledged that the possibility of offspring exposure, to either treatment
or illness, is always present. Advising a pregnant or breast-feeding patient to discontinue
psychotropic medication does not eliminate offspring exposure; it simply exchanges the risks of
psychotropic exposure for the risks of untreated maternal illness. A thorough risk–benefit
assessment also requires an understanding of the pathways of offspring exposure. In the context of
perinatal psychiatric illness, fetal/neonatal exposure may occur either directly or indirectly (Stowe
et al. 2001). Direct exposure is imparted by any biological or pharmacological substrate that comes
into direct contact with the child. Indirect exposure is conferred by the influence of such a
substrate on the child’s environment.
Direct exposure to psychotropic agents is a given. All psychotropics studied to date cross thePrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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placenta (Hendrick et al. 2003b; Newport et al. 2005, 2007; Stowe et al. 1997), are present in
amniotic fluid (Hostetter et al. 2000), and are excreted into breast milk (Newport et al. 2002a).
Clinicians often assume that liability exists only for those direct exposures to medications that are
under their immediate control, but other exposures should engender concern. The fetus and
breast-feeding infant are also directly exposed to maternal illness via changes in the hormonal and
immunological constituents within the fetomaternal circulation (Wadhwa et al. 1998) and breast
milk (Cox et al. 2000). The magnitude and clinical significance of these direct exposures to the
substrates of maternal illness remain obscure.
Indirect exposures to illness or treatment are also possible, although less readily apparent. Indirect
effects of maternal psychiatric illness on offspring may be mediated by poor maternal compliance
with prenatal care, inadequate maternal nutrition, exposure to other prescription or
over-the-counter medications or herbal remedies, increased use of alcohol and tobacco, deficits in
mother–infant bonding, and disruptions within the family environment. Indirect exposure to
psychotropic therapy may be conferred by treatment-emergent side effects (e.g., somnolence,
alterations in appetite).
Assessing the risks of offspring exposure to maternal psychiatric illness must consider both the
likelihood that an episode of illness will occur and the evidence that the illness may be harmful to
the child. The clinician can estimate a patient’s likelihood of peripartum recurrence or exacerbation
by carefully synthesizing prevalence data from epidemiological studies with evidence from the
patient’s own history. Gathering comprehensive personal and family psychiatric histories is critical
to treatment planning. Patients with frequent episodes of psychiatric illness, a declining course, or
a history of prior perinatal illness are more likely to become ill in the current puerperium. Because
many psychiatric disorders are more prevalent in women than in men, and most begin early in life,
typically during or even before the reproductive years, clinicians routinely provide treatment to
women for mental illnesses during the childbearing years. Efforts to determine the precise
incidence of perinatal psychiatric illness are hindered by several factors: 1) the overlap of
symptoms between certain mental illnesses and the normal sequelae of pregnancy, 2) the reliance
on retrospective reports in many studies, and 3) the limited assessment of comorbid medical
disorders that could contribute to psychiatric symptoms (e.g., anemia, thyroid dysfunction)
(Pedersen et al. 1993).
PREVALENCE OF PSYCHIATRIC DISORDERS DURING PREGNANCY AND THE
POSTPARTUM PERIOD
Despite the clinical lore that pregnancy is a time of emotional well-being, rates of depression during
pregnancy are comparable to those of nonpuerperal depression (Buesching et al. 1988; Cutrona
1986; Kumar and Robson 1984; Manly et al. 1982; O’Hara et al. 1982; Watson et al. 1984). Two
large investigations, collectively comprising 122,400 women, found a 14%–20% incidence of major
depressive disorder during pregnancy (Marcus et al. 2003; Oberlander et al. 2006). In fact, more
than 11% of women presenting for evaluation of postpartum depression report symptom onset
during pregnancy (Stowe et al. 2005). Treatment discontinuation can be especially problematic. In
a recent study by our group, pregnant women with a history of depression who discontinued
antidepressant therapy proximate to conception were 2.6 times more likely to experience a relapse
before delivery in comparison with those who continued antidepressant treatment (68% vs. 26%)
(Cohen et al. 2006).
The perinatal course and management of bipolar disorder have come under increased scrutiny in
the past decade. In an initial retrospective study, Grof et al. (2000) described a benign course for
women with lithium-responsive bipolar disorder during pregnancy; however, most evidence
indicates that pregnant women with bipolar disorder are highly vulnerable to recurrence without
continued pharmacotherapy. For example, three retrospective studies have reported 45%–52%
bipolar disorder recurrence rates during pregnancy (Blehar et al. 1998; Freeman et al. 2000;
Viguera et al. 2000). More recently, we have reported, in two separate prospective samples, relapse
rates of 84%–100% among pregnant women with bipolar disorder who discontinue mood stabilizer
therapy versus 30%–38% among those who continue mood stabilizer therapy (Newport et al.Print: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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2008b; Viguera et al. 2007).
Psychotic disorders have also been observed to worsen during pregnancy (Glaze et al. 1991; McNeil
et al. 1984a, 1984b). Furthermore, women with schizophrenia have been reported to have high
rates of unplanned and unwanted pregnancies (Miller 1997; Miller and Finnerty 1996) that may
further escalate as SGAs with little impact on prolactin physiology (Dickson and Edwards 1997;
Kaplan et al. 1996) become mainstays of therapy.
Although perinatal data regarding obsessive-compulsive disorder (OCD) are limited, it is
noteworthy that 15%–39% of women with OCD report symptom onset during pregnancy (Neziroglu
et al. 1992; K. E. Williams and Koran 1997). The course of OCD during pregnancy appears to be
variable, with 73% of women reporting no symptom change, 14% reporting symptom exacerbation,
and 14% reporting symptom improvement (Jenike et al. 1990; K. E. Williams and Koran 1997). The
course of panic disorder during gestation is also highly variable, with 19% of patients experiencing
more frequent panic attacks, 30% having reduced attacks, and 51% showing no change (Hertzberg
and Wahlbeck 1999; Wisner et al. 1996a). Finally, a traumatic labor and delivery experience can
precipitate posttraumatic stress disorder (Allen 1998; Fones 1996).
Postpartum psychiatric illness has been documented for millennia and has been substantiated by
recent research. For example, a widely cited study by Kendler et al. (1993) reported a dramatic rise
in psychiatric hospitalizations during the first postpartum month. In fact, up to 13% of all
psychiatric admissions for women occur during the first postpartum year (Duffy 1983). Postpartum
depression affects between 10% and 22% of adult women and up to 26% of adolescent mothers
(Stowe and Nemeroff 1995; Troutman and Cutrona 1990). The postpartum is also a time of
heightened risk for women with bipolar disorder (Kendell et al. 1987; Targum et al. 1979).
Postpartum psychosis is thankfully a rare condition, occurring in only 1–2 of every 1,000 live births.
Most postpartum psychoses appear to be psychotic episodes of a mood disorder (McGorry and
Conell 1990).
EFFECT OF MATERNAL PSYCHIATRIC DISORDERS
Not only the likelihood but also the potential impact of maternal psychiatric illness on child
well-being must be considered in the risk–benefit assessment. A salient feature of most mental
disorders is impairment of function (American Psychiatric Association 2000), and intervention is
clearly warranted if the impairment precludes a woman’s participation in prenatal care or in some
other manner jeopardizes the pregnancy or infant.
Obstetrical and developmental outcomes have been best studied in women experiencing depressive
symptoms. For example, prenatal maternal depression may slow fetal growth (Hedegaard et al.
1996; Schell 1981), result in smaller infant head circumferences (Lou et al. 1994), increase the risk
of preterm delivery and other obstetrical complications (Korebrits et al. 1998; Oberlander et al.
2006; Orr and Miller 1995; Perkin et al. 1993; Steer et al. 1992), and even precipitate long-standing
behavioral changes in the offspring (Luoma et al. 2001, 2004; Meijer 1985; T. G. O’Connor et al.
2003; Stott 1973). Depressed gravidas are also more likely to abuse alcohol, engage in suicidal
behavior, neglect prenatal care, and receive inadequate nutrition (Zuckerman et al. 1989), causing
significant risk to the fetus (Perkin et al. 1993).
Maternal depression during pregnancy is also associated with neurobiological alterations in the
offspring. For example, elevated serum concentrations of cortisol and catecholamines in depressed
third-trimester gravidas are correlated with urinary concentrations of these substrates in their
infants 24 hours after delivery (Lundy et al. 1999).
Postnatal maternal depression also carries deleterious consequences for infant development. As
early as 3 months, infants of depressed mothers exhibit less facial expression, less head
orientation, less crying, and more fussiness than do infants of nondepressed mothers (Martinez et
- 1996). As they age, the children of depressed mothers display ineffective emotional regulation
(Downey and Coyne 1990), slowed motor development evident as early as 6 months (Galler et al.
2000), and poorly integrated interactions even when the children of depressed mothers arePrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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interacting with nondepressed mothers (Jameson et al. 1997), and these children also show lower
self-esteem beginning in preschool (Downey and Coyne 1990), more fear and anxiety (Lyons-Ruth
et al. 2000), more aggression (Jameson et al. 1997), and more insecure and disorganized
attachment behaviors (Martins and Gaffan 2000) than do children of nondepressed mothers.
Children of depressed mothers are ultimately more likely to experience emotional instability, to
have behavioral problems and suicidal behavior, and to require psychiatric treatment (Lyons-Ruth
et al. 2000; Weissman et al. 1984).
The effect of other maternal psychiatric disorders on infant and neonatal development is less well
investigated. Although formal studies are lacking, the poor judgment and reckless behavior that
characterize manic episodes of bipolar disorder inarguably convey a host of risks to the developing
child. The risks, if any, associated with maternal hypomania are less clear.
Perinatal exacerbation of schizophrenia and other psychotic illnesses also warrants concern.
Women with schizophrenia have a higher prevalence of substance abuse during pregnancy (Miller
and Finnerty 1996) and often exhibit bizarre ideas regarding contraception, pregnancy, and child
rearing that complicate their perinatal course (McEvoy et al. 1983). Left untreated, schizophrenia
during the peripartum can have devastating consequences for both mother and child. Cases exist of
maternal self-mutilation (Coons et al. 1986; Yoldas et al. 1996), infanticide (Bucove 1968), and
denial of pregnancy with consequent refusal of prenatal care (Slayton and Soloff 1981). In addition,
children born to mothers with schizophrenia are more likely to suffer from obstetrical complications
(Miller and Finnerty 1996), although a recent investigation did not confirm this finding (Bennedsen
et al. 2001). Maternal schizophrenia is also associated with a higher rate of perinatal death (Rieder
et al. 1975). Furthermore, mothers with schizophrenia often exhibit aberrant parenting styles that
may contribute to the development of avoidant behaviors in their children (Riordan et al. 1999).
The impact of anxiety disorders on obstetrical outcomes remains obscure. A case series of eight
women with OCD during pregnancy reported that two developed preeclampsia, three delivered
prematurely, and five underwent cesarean section (Maina et al. 1999).
The clinical data regarding the obstetrical and developmental consequences of maternal mental
illness are complemented by an extensive line of laboratory animal research bearing homology to
depression and other stress-related psychiatric disorders (for a review, see Newport et al. 2002b).
Consistent with the limited human database, animal research indicates that prenatal stress
adversely affects offspring growth (Herrenkohl and Gala 1979; Schneider et al. 1999), learning
ability (Jaiswal and Bhattacharya 1993; Smith et al. 1981; Weller et al. 1988), and postnatal
development (Fride and Weinstock 1984).
Furthermore, preclinical research indicates that certain biobehavioral aberrations induced by
prenatal stress may persist into adulthood. For example, prenatally stressed adult rats continue to
demonstrate depression-like behaviors (Secoli and Teixeira 1998), anxiety-like behaviors in novel
situations (Fride and Weinstock 1988; Poltyrev et al. 1996; Szuran et al. 1991; Vallee et al. 1997;
Weinstock et al. 1988), and exaggerated “emotional” responses to stress (Fride et al. 1986; Pfister
and Muir 1992; Wakshlak and Weinstock 1990). Prenatally stressed primates also exhibit
diminished exploratory behavior (Clarke and Schneider 1993; Schneider 1992).
These behavioral alterations are accompanied by lasting neurobiological alterations. In particular,
prenatally stressed animals demonstrate multiple alterations in hypothalamic-pituitary-adrenal
(HPA) axis function, including the following: 1) increased basal concentrations of plasma
corticosterone and adrenocorticotropic hormone (ACTH) (McCormick et al. 1995; Takahashi 1998;
Takahashi and Kalin 1991), 2) heightened production of corticotropin-releasing factor (CRF) in the
fetal hypothalamus (Fujioka et al. 1999), and 3) exaggerated corticosterone responses to
subsequent mild stressors (Fride and Weinstock 1984; Henry et al. 1994; Peters 1982; Weinstock et
- 1992). The activity of catecholamine (Alonso et al. 1994, 1997; Fride et al. 1985; Henry et al.
1995; Peters 1982, 1984) and serotonin (Hayashi et al. 1998; Peters 1982, 1986, 1988, 1990)
systems is also altered in prenatally stressed laboratory animals.Print: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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Laboratory paradigms that interfere with maternal care (e.g., maternal separation, variable
foraging) precipitate similar adverse biobehavioral outcomes in the offspring. Offspring from these
neonatal maternal stress protocols exhibit insecure attachment behaviors (Andrews and Rosenblum
1988, 1991, 1994; Rosenblum and Paully 1984), depression-like and anxiety-like behaviors (Levine
1967), and alterations in stress-respondent neurobiological systems (Coplan et al. 1996, 1998;
Pauk et al. 1986; Pihoker et al. 1993; Walker et al. 1991). Although direct correlations between
laboratory animal stress models and human psychiatric illness are difficult to sustain, these
preclinical data underscore the potential long-term effects of maternal stress during the
peripartum.
TREATMENT ISSUES DURING PREGNANCY AND LACTATION
An appraisal of the risks and benefits afforded by psychotropic treatment is the other major facet of
the perinatal risk–benefit assessment. The theoretical risks of fetal and neonatal medication
exposure may be classified as either acute or developmental adverse effects (Table 64–1). Acute
effects are typically immediately evident and are not dependent on the developmental window of
exposure. Examples of acute effects include drug toxicity, drug withdrawal, and drug–drug
interactions. Developmental effects are, by definition, dependent on the developmental window of
exposure and are often not evident until later. These effects include somatic teratogenesis (i.e.,
major and minor malformations) and so-called neurobehavioral teratogenesis (i.e., alterations in
brain development that affect the child’s subsequent behavior, cognitive abilities, and emotional
regulation). The window of vulnerability to somatic teratogenesis is limited to the embryonic phase
of development, but because CNS development continues long after delivery, the fetus and
breast-feeding infant are vulnerable to the theoretical risk of neurobehavioral teratogenesis.
TABLE 64–1. Risks of perinatal medication exposure
Acute Developmental
Pregnancy Neonatal toxicity
Neonatal withdrawal
Drug–drug interactions
Somatic teratogenesis
Neurobehavioral teratogenesis
Lactation
Infant toxicity
Drug–drug interactions
Neurobehavioral teratogenesis
The risks of psychopharmacological exposure can be averted by using nonpharmacological
treatment alternatives. Some of these therapies, including interpersonal psychotherapy (O’Hara et
- 2000; Spinelli 1997), cognitive-behavioral therapy (Appleby et al. 1997), sleep deprivation (B. L.
Parry et al. 2000), and electroconvulsive therapy (Miller 1994), have been used in the peripartum
and warrant consideration (Cohen et al. 1989; Miller 1991). These alternatives are not without
shortcomings. They are often costly or unavailable in the rapidly evolving managed care
environment, and they may take longer to work than psychotropic medications. Any delay in
therapeutic benefit thus extends the child’s exposure to the risks associated with maternal mental
illness. A recent meta-analysis that the treatment effect of perinatal psychotherapy is less than that
of antidepressant pharmacotherapy, although synergistic effects can be achieved with concomitant
administration of antidepressants and psychotherapy (Bledsoe and Grote 2006). Consequently,
psychotropic medications remain the principal treatment offering for many, if not most, women
with perinatal mental illness.
Deciding whether to use psychotropic medication during pregnancy and/or lactation carries
complicated clinical, ethical, and potentially legal ramifications. A rapidly expanding data set
regarding the reproductive safety of psychotropic medications has in part addressed many of these
concerns, but these data span a broad literature in psychiatry, obstetrics, pediatrics, and basic
science journals, limiting the ease of availability. In addition, the current literature regarding
psychotropic medications during pregnancy and lactation reveals numerous methodologicalPrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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problems. The most glaring deficiency is the absence of an appropriate control group for
comparison; therefore, psychotropic outcome studies are subject to the confounding effects of
maternal psychiatric illness that may be misinterpreted as medication effects. Despite these
limitations, ethical considerations preclude the possibility that well-controlled clinical trials will
ever be conducted for psychotropic medication among pregnant or lactating women.
The use of psychotropic medications during pregnancy and lactation continues to generate
considerable debate, and a final consensus is unlikely to be forthcoming. Adequately controlled
studies to resolve these issues are equally unlikely. The pregnancy and lactation reproductive
safety database for psychotropic medications is therefore composed of a diverse conglomeration of
isolated case reports, case series by pharmaceutical companies and academic centers, birth
registries, retrospective surveys, reports from teratology or poison control centers, more extensive
clinical and preclinical pharmacokinetic investigations, an increasing array of review articles
summarizing data from these primary sources, the American Academy of Pediatrics (2001)
breast-feeding rating system, and the U.S. Food and Drug Administration (FDA) pregnancy rating
system (Table 64–2). In the absence of controlled trials, it is not surprising that the FDA has not to
date approved any psychotropic medication for use during pregnancy or lactation. The FDA
pregnancy rating system is not without shortcomings. One potential confounder of this system is
that medications that have been available longer are more likely to have accrued a greater number
of adverse case reports than newer, less studied medications. Similarly, it is often difficult to track
the process that actually contributes to the individual category ratings.
TABLE 64–2. U.S. Food and Drug Administration (FDA) use-in-pregnancy ratings
Category Interpretation
A
Controlled studies show no risk: Adequate, well-controlled studies in pregnant women have
failed to demonstrate risk to the fetus.
B
No evidence of risk in humans: Either animal findings show risk, but human findings do not; or,
if no adequate human studies have been done, animal findings are negative.
C
Risk cannot be ruled out: Human studies are lacking, and animal studies are either positive for
fetal risk or lacking as well. However, potential benefits may justify the potential risk.
D
Positive evidence of risk: Investigational or postmarketing data show risk to the fetus.
Nevertheless, potential benefits may outweigh risks.
X
Contraindicated in pregnancy: Studies in animals or humans, or investigational or
postmarketing reports, have shown fetal risk that clearly outweighs any possible benefit to the
patient.
Source. Physicians’ Desk Reference 2007.
Reviewing the reproductive safety database is only one aspect of assessing the relative utility of
psychopharmacological treatment. A meticulous review of the patient’s clinical history is also
important. Obtaining comprehensive medical and obstetrical histories, particularly screening for a
history of placental insufficiency, preeclampsia, and urinary or gastrointestinal disorders, is
imperative. Early identification of probable perinatal comorbidities may guide the selection of
psychotropic agents. For example, psychotropics with potent antihistaminic properties may
complicate the course of overt or gestational diabetes during pregnancy, whereas other
psychotropic agents (e.g., selective serotonin reuptake inhibitors [SSRIs]) may actually improve
glycemic control. Potential drug interactions with medications used to manage medical
comorbidities or with analgesic and anesthetic medications used at delivery should also be
considered. Obtaining the patient’s psychiatric history and family psychiatric history is also
important, not only for clarifying the psychiatric diagnosis but also for providing documentation of
responses to previous therapeutic trials of psychotropic medications. Regardless of the volume of
reproductive safety data, a medication that has been poorly tolerated or ineffective for a particular
patient is of little value.Print: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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PHARMACOKINETICS AND PHARMACODYNAMICS OF PREGNANCY AND
LACTATION: IMPLICATIONS FOR DOSE MANAGEMENT
When the decision is made to use a psychotropic medication during pregnancy or lactation, it is
important to administer the minimum effective dose. Clinicians commonly reduce the dose of
psychotropic medication upon learning that a patient is pregnant, in a well-meaning effort to
reduce fetal medication exposure. However, indiscriminate dosage reduction also increases the
patient’s vulnerability to relapse. Inadequate dosing therefore unduly exposes the child to the risks
of both medication and maternal illness, yet administering doses higher than those necessary to
achieve and sustain remission is equally inadvisable. Inordinately high doses expose the child to
unnecessarily high medication concentrations. The therapeutic goals of psychopharmacological
treatment during pregnancy and lactation are 1) to eliminate the child’s exposure to maternal
illness by achieving clinical remission while 2) minimizing the child’s exposure to psychotropic
medication. To accomplish these concomitant goals, dose management during pregnancy and
lactation must be informed by an understanding of the factors governing the placental passage and
breast milk excretion of psychotropic medications as well as of the impact of the physiological
changes of pregnancy on the pharmacological effects of these medicines.
It is well recognized that dosage adjustments are often required to maintain the therapeutic
efficacy of medications during pregnancy. For example, it may be necessary to increase the dose of
tricyclic antidepressants (TCAs) to approximately 1.6 times the preconception dose to maintain
therapeutic concentrations in late pregnancy (Altshuler et al. 1996; Wisner et al. 1993). Similar
increases may be required with SSRIs during the early third trimester to sustain euthymia
(Hostetter et al. 2000). However, the pattern of dose adjustment during gestation is not uniform for
all medications. For example, among anticonvulsant/mood-stabilizing medications, serum
concentrations of lamotrigine (I. Ohman et al. 2000; Pennell et al. 2000; Tran et al. 2002) and
valproic acid (Otani 1985; Philbert et al. 1985) decline steadily across gestation, whereas
carbamazepine concentrations (Bardy et al. 1982b; Battino et al. 1982; Bologa et al. 1991; Dam et
- 1979; Lander et al. 1980; Omtzigt et al. 1993; Otani 1985; Tomson et al. 1994; Yerby et al.
1985) exhibit smaller changes that are primarily evident only in late pregnancy. Increasing
evidence indicates that these alterations in drug concentrations and dosing requirements are a
consequence of the impact of the physiological changes of pregnancy on the pharmacokinetics
(Boobis and Lewis 1983; Frederiksen 2001; Little 1999; Wyska and Jusko 2001), and possibly the
pharmacodynamics (Wyska and Jusko 2001), of psychotropic medications.
Each of the four generally recognized phases of the pharmacokinetic sequence—absorption,
distribution, metabolism, and excretion—is affected by pregnancy. Several factors serve to increase
the absorption of orally administered medications during gestation. Decreases in the rate of gastric
emptying (Hunt and Murray 1958) and intestinal motility (E. Parry et al. 1970) lengthen the transit
time of oral medications and thus increase the time for absorption across the intestinal mucosa. In
addition, heightened blood flow to the digestive tissues (Mattison 1986) increases the rate of
absorption.
Drug distribution is also altered during gestation. Both plasma volume (Lund and Donovan 1967;
Mattison et al. 1991) and extracellular fluid volume (Mattison et al. 1991; Petersen 1957; Plentl and
Gray 1959) increase dramatically. In addition, increases in body fat during pregnancy (Mattison et
- 1991) further expand the volume of distribution for psychotropic medications, which are almost
uniformly highly lipophilic compounds. The dilutional effect of the increased volume of distribution
is offset somewhat by decreased concentrations of circulating plasma proteins such as albumin
(Frederiksen et al. 1986; Mendenhall 1970; Perucca and Crema 1982), serving to increase the
distribution of many compounds into the bioavailable free fraction. However, plasma concentrations
of some plasma proteins are relatively unchanged (e.g., 1-acid glycoprotein [Wood and Wood
1981]) or even increased (e.g., sex hormone–binding globulin [Perucca and Crema 1982]) during
pregnancy. Alterations in the unbound fraction arising from gestational changes in plasma protein
concentrations impact the availability of medications not only for bioactivity but also for metabolic
degradation.Print: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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Rates of drug metabolism during pregnancy are also affected by other mechanisms. First, tissue
delivery of medication is increased during pregnancy by the increase (up to 50%) in cardiac output
(Lees et al. 1967), but a smaller percentage of this heightened cardiac output is delivered to the
liver as more blood is diverted to the uterus and other organs (Robson et al. 1990). Second,
pregnancy is associated with numerous changes in the activity of various hepatic and extrahepatic
enzymes. The activity of the hepatic cytochrome P450 (CYP) 3A4 (Bologa et al. 1991; Homma et al.
2000) isoenzyme is increased during gestation but that of CYP1A2 (Bologa et al. 1991; Tsutsumi et
- 2001) is decreased. CYP2D6 activity is increased during pregnancy in all women except those
who are pharmacogenetically poor CYP2D6 metabolizers (Wadelius et al. 1997). Many CYP
isoenzymes are also present in placental tissue, although the activity of the placental enzymes
appears to be considerably lower than that of their hepatic counterparts (Hakkola et al. 1996).
Finally, drug elimination during pregnancy is affected by increases in renal blood flow (Metcalfe et
- 1955) and glomerular filtration rate (Davison and Hytten 1974; Dunlop 1981). In summary, the
pharmacokinetic alterations of pregnancy are governed by a complex set of interdependent
variables that remain obscure but may ultimately provide a basis from which to construct rational
models for dosing guidelines during gestation.
Dose management during the peripartum may also be affected by alterations in the
pharmacodynamics of psychotropic agents. Even less is known regarding the impact of the
physiology of pregnancy on pharmacodynamics, but indications that postpartum depression is
associated with alterations in the binding affinity of platelet serotonin transporters for radiolabeled
imipramine and paroxetine (Hannah et al. 1992; Newport et al. 2004) lend credence to the
existence of puerperal pharmacodynamic alterations. Pharmacodynamic indirect response models
and signal transduction models (Wyska and Jusko 2001) offer plausible mechanisms whereby drug
activity is altered during gestation. Additional candidate models of pharmacodynamic alterations
during pregnancy remain to be explored.
The extent of fetal psychotropic exposure is the other principal consideration when administering
medication during gestation. Fetal psychotropic exposure is largely dictated by placental passage of
the medication, and all psychotropic medications are presumed to cross the placenta. Rates of
placental transfer can be grouped into three categories (Pacifici and Nottoli 1995):
Type I: complete transfer—Medication concentrations rapidly equilibrate between the maternal and
fetal compartments.
Type II: excessive transfer—Fetal concentrations are greater than maternal concentrations.
Type III: incomplete transfer—Fetal concentrations are less than maternal concentrations.
Although there is no immediate evidence of placental filtering of psychotropic medications, there
are significant differences in the rates of placental passage among antidepressants (Hendrick et al.
2003b) and antipsychotics (Newport et al. 2007). The primary mechanism of placental transport is
simple diffusion, and its rate largely depends on the physicochemical properties of the particular
medication. The major determinants of a medication’s rate of diffusion across the placenta are
molecular weight, lipid solubility, degree of ionization, and protein binding (Audus 1999; W. M.
Moore et al. 1966; Pacifici and Nottoli 1995); however, the relative importance and critical
thresholds for the respective physicochemical properties are yet to be delineated. At least one
transplacental active transport mechanism has been identified. Placental glycoprotein (PGP)
actively transports substrates from the fetal circulation back to the maternal circulation.
Consequently, medications with greater affinity for PGP should be associated with relatively lower
fetal-to-maternal medication ratios, as we recently demonstrated in an investigation of
antipsychotic placental passage (Newport et al. 2007). Further clarification of the pharmacological
attributes governing placental passage may ultimately contribute to the identification and
development of efficacious psychotropic agents with minimal rates of placental transfer (Wang et
- 2007).
Fetal plasma concentrations are not, however, the ultimate measure of functional psychotropic
exposure and may even underestimate the more critical measure, fetal brain concentration. CertainPrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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physiological attributes of the human fetus, including high cardiac output, increased blood–brain
barrier permeability, low plasma protein concentrations and plasma protein binding affinity, and
low hepatic enzyme activity (Bertossi et al. 1999; Morgan 1997; Oesterheld 1998), may result in
higher fetal CNS concentrations of psychotropic medications than might be anticipated from
circulating levels. Preclinical investigations from our group have demonstrated that transplacental
passage results in high levels in fetal brain tissues and significant binding at neurotransmitter
uptake sites (A. D. Fisher et al. 2001; Graybeal et al. 2002; Owens et al. 1997).
Similar considerations apply when endeavoring to minimize the psychotropic exposure of infants
whose mothers are receiving psychiatric medication during lactation. After delivery, the neonate
continues to exhibit unique physiological characteristics, including relatively low activity of hepatic
enzymes. Hepatic maturation in the infant appears to occur at a highly variable rate (Warner 1986)
and is more delayed in premature infants. Both glucuronidation and oxidation systems are initially
immature at birth (as low as 20% of adult levels). The latter system typically matures by age 3
months (Atkinson et al. 1988). In addition, rates of glomerular filtration and tubular secretion are
relatively low in neonates—30%–40% and 20%–30% lower than adult levels, respectively (Welch
and Findlay 1981). Hence, the potential that psychotropic exposure may be higher than anticipated
remains a consideration for breast-fed infants.
Because medications predominantly enter breast milk by passive diffusion of the nonionized,
unbound fraction (J. T. Wilson et al. 1980), the pH gradient between maternal serum and breast
milk plays a significant role in the amount of medication that is excreted into breast milk.
Medications may in certain instances become ion-trapped in milk. The lower pH of human milk may
alter the molecular structure of a medication, preventing its reperfusion into the maternal
circulation (Agatonovic-Kustrin et al. 2002). In addition, active secretory mechanisms also exist
that can further concentrate drugs in breast milk (Kari et al. 1997; Oo et al. 1995; Toddywalla et al.
1997). A model to predict rates of breast milk excretion from descriptive characteristics of the
molecular structure of candidate medications has recently been proposed (Agatonovic-Kustrin et al.
2002).
One purpose of such models is to provide a means to forecast infant exposure without performing
invasive procedures on the child. Most familiar approaches utilize maternal serum concentrations
and/or breast milk concentrations to calculate a milk-to-plasma ratio that is in turn used to
calculate the infant’s “daily dose” acquired through breast-feeding. Unfortunately, many existing
studies calculate the milk-to-plasma ratio from a single random breast milk sample. This simplistic
approach ignores the pharmacokinetics of medication excretion in breast milk and may thus provide
an inaccurate prediction of infant exposure.
Accurately forecasting the level of infant exposure via lactation necessitates consideration of two
well-described excretion gradients: distribution gradient and time gradient (Stowe et al. 1997,
2000). First, a distribution gradient of medication concentration in human milk exists during the
course of a single feeding. As a rule, psychotropic medications are highly lipophilic and therefore
present in higher concentrations in the fatty hindmilk. Consequently, a milk–plasma ratio calculated
from an isolated random milk sample can vary widely between foremilk and hindmilk collections. In
addition, a dose-to-dose time gradient for psychotropic excretion into breast milk also exists. The
time course of psychotropic excretion into breast milk is largely consistent with the gastrointestinal
absorptive phase of these medications and thus can largely be predicted by their known
pharmacokinetics. For example, peak breast milk concentrations of sertraline occur at about 8
hours after the last dose, whereas the nadir occurs just prior to the next dose. Accurate prediction
of daily infant dose via breast-feeding requires a model that acknowledges these excretion
gradients. Utilizing this type of model, our group completed a detailed study of both the
pharmacokinetics of excretion and infant serum measures for sertraline demonstrating that the
maximum calculated infant dose is typically less than 1/500 of the maternal dose (Stowe et al.
1997).
ANTIDEPRESSANTSPrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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Antidepressant medications are used to treat a variety of neuropsychiatric illnesses. Commonly
prescribed antidepressants are listed in Table 64–3. According to recent reports, 6.6% of pregnant
women receive a prescription for an antidepressant at some point during pregnancy (Andrade et al.
2008).
TABLE 64–3. Antidepressant medications
Generic name Trade name Daily dose
(mg/day)a
Risk
categoryb
American Academy of Pediatrics
ratingc
Selective serotonin uptake inhibitors
Citalopram Celexa 20–60 C Unknown, but of concern
Escitalopram Lexapro 5–20 C N/A
Fluoxetine Prozac 20–60 C Unknown, but of concern
Fluvoxamine Luvox 50–300 C Unknown, but of concern
Paroxetine Paxil 20–50 D Unknown, but of concern
Sertraline Zoloft 50–200 C Unknown, but of concern
Tricyclic antidepressants
Amitriptyline Elavil, Endep 150–300 D Unknown, but of concern
Amoxapine Asendin 150–400 Cm
Unknown, but of concern
Clomipramine Anafranil 150–250 Cm
Unknown, but of concernd
Desipramine Norpramin 150–300 C Unknown, but of concern
Doxepin Sinequan,
Adapin
150–300 C Unknown, but of concern
Imipramine Tofranil 150–300 D Unknown, but of concern
Maprotiline Ludiomil 140–225 Bm
N/A
Nortriptyline Pamelor,
Aventyl
75–150 D N/A
Protriptyline Vivactil 15–60 C N/A
Monoamine oxidase inhibitors
Isocarboxazid Marplan 30–60 C N/A
Phenelzine Nardil 45–90 C N/A
Tranylcypromine Parnate 30–60 C N/A
Other antidepressants
Bupropion Wellbutrin 150–450 C Unknown, but of concern
Duloxetine Cymbalta 30–90 C N/A
Mirtazapine Remeron 15–45 C N/A
Nefazodone Serzone 300–600 C N/A
Trazodone Desyrel 200–300 C Unknown, but of concern
Venlafaxinee
Effexor 150–375 C N/A
Note. N/A = not available.
aDosing strategies adapted from Schatzberg and Cole 1991; Kaplan and Sadock 1993; and, for newer
medications, the manufacturers’ package inserts.
bRisk category adapted from Briggs et al. 2005 and/or Physicians’ Desk Reference 2007; “m” subscript Print: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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indicates data taken from the manufacturer’s package insert.
cAmerican Academy of Pediatrics 2001.
dOriginal committee report 1994 listed as “compatible,” and a correction was later published.
eNot listed in Briggs et al. 1994. Risk category taken from Physicians’ Desk Reference (1992, 1993, 1994, and
1996 editions).
Selective Serotonin Reuptake Inhibitors
SSRI antidepressants, among the best-studied medications in pregnancy and the single
best-studied class of medications in lactation, have emerged as first-line agents for treating
depression during pregnancy and lactation.
Prospective reports of first-trimester SSRI use currently consist of 4,679 fluoxetine exposures
resulting in 126 (2.7%) children with major malformations (Briggs et al. 2005; Chambers et al.
1996; GlaxoSmithKline 2005; Goldstein et al. 1997; Hallberg and Sjöblom 2005; McElhatton et al.
1996; Pastuszak et al. 1993; Wilton et al. 1998), 3,393 sertraline exposures with 66 (1.9%) major
malformations (GlaxoSmithKline 2005; Hallberg and Sjöblom 2005; Kulin et al. 1998; Wilton et al.
1998), 2,688 citalopram exposures with 73 (2.7%) major malformations (Ericson et al. 1999;
GlaxoSmithKline 2005; Hallberg and Sjöblom 2005; Heikkinen et al. 2002; Sivojelezova et al. 2005),
2,687 paroxetine exposures with 94 (3.5%) major malformations (GlaxoSmithKline 2005; Hallberg
and Sjöblom 2005; Kulin et al. 1998; McElhatton et al. 1996; Wilton et al. 1998), 235 escitalopram
exposures with 8 (3.4%) major malformations (GlaxoSmithKline 2005), 147 fluvoxamine exposures
with 1 (0.7%) major malformation (GlaxoSmithKline 2005; Kulin et al. 1998; McElhatton et al.
1996; Wilton et al. 1998), and 395 exposures to unspecified SSRIs with 6 (1.5%) major
malformations (Einarson et al. 2001; Ericson et al. 1999; Hendrick et al. 2003a; Simon et al. 2002;
Sivojelezova et al. 2005). The 2.6% (n = 374) overall SSRI malformation rate among these 14,224
pregnancies is consistent with rates reported in the general population (New York State
Department of Health 2005; Rimm et al. 2004; Swedish Centre for Epidemiology 2004).
Despite these reassuring and voluminous data, some concerns have been raised. For example, a
preliminary analysis of a managed care database demonstrated a statistically higher odds ratio for
major malformations, particularly cardiovascular malformations, after first-trimester paroxetine
exposure in comparison to exposure to other antidepressants (GlaxoSmithKline 2005), leading the
FDA to reclassify paroxetine’s pregnancy category (U.S. Food and Drug Administration 2005).
Although the FDA deemed the data sufficiently compelling to alter the pregnancy classification,
definitive conclusions are precluded by numerous limitations in this data set (e.g., there is no
nonexposed control group, the paroxetine malformation rates reported in this study approximate
population norms, and the significant finding in one arm of the study is eliminated when those with
exposure to other known teratogens are excluded).
Three recent large-scale case–control studies of first-trimester SSRI exposure have likewise
produced generally reassuring results, although some concerns have emerged. One of these studies
comparing 9,622 cases (infants with malformations) and 4,092 controls (infants without
malformations) found no evidence to suggest that SSRI exposure was associated with higher rates
of cardiovascular defects but did report small increases in the risk for three uncommon
malformations—anencephaly (odds ratio [OR] = 2.4), craniosynostosis (OR = 2.5), and
omphalocele (OR = 2.8) (Alwan et al. 2007). Conversely, a study comparing 9,489 cases and 5,860
controls found no evidence of increased risk for heart defects of these other three malformations
with first-trimester SSRI exposure (Louik et al. 2007). Analysis of individual antidepressants in the
second study did demonstrate an increased risk for omphalocele (OR = 5.7) and septal defects (OR
= 2.0) with sertraline exposure, and for right ventricular outflow tract obstruction defects (OR =
3.3) with paroxetine exposure. Finally, a nested case–control study of 1,403 infants, including 101
with major malformations, found no evidence that SSRI or paroxetine use was associated with an
increased risk for cardiovascular or other major malformations, unless women were administered
25 mg of paroxetine per day, in which case their infants were at higher risk for cardiovascular
malformations (OR = 3.1) and overall malformations (OR = 2.2).Print: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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The first investigation of the neurobehavioral impact of prenatal SSRI exposure is a landmark study
by Nulman et al. (1997a) of children exposed in utero to antidepressant medications (55
fluoxetine-exposed children, 80 TCA-exposed children, 84 children with no antidepressant
exposure). Children between 16 months and 7 years of age were evaluated with an extensive
battery of neurodevelopmental tools measuring global intelligence quotient (IQ), language
development, temperament, mood, activity level, and behavior. No significant differences on any of
the neurodevelopmental measures were detected among the three groups of children in the study.
Furthermore, global IQ and language development were nearly identical among all the groups. In
conclusion, there was no apparent neurobehavioral impact of prenatal exposure to fluoxetine or
TCAs on children of preschool or early elementary school age.
To date, few studies have systematically assessed child development after prenatal antidepressant
exposure. The first two reports, from the same group, assessed children between 15 and 86 months
of age, collectively comparing 126 children exposed prenatally to a TCA and 90 children exposed to
fluoxetine with 120 children of women with no history of depression. Using age-adjusted rating
instruments, they found no differences with respect to global cognition, psychomotor development,
or language development (Nulman et al. 1997a, 2002). The third study, assessing children between
6 and 40 months of age, compared 13 children whose mothers were depressed but did not take
antidepressant medication during pregnancy with 31 children who were prenatally exposed to an
SSRI (Casper et al. 2003). Like the Nulman et al. studies, this group also found no differences in
global cognition; however, lower psychomotor scores were reported for the SSRI-exposed children.
Unfortunately, limitations of these three studies render their implications speculative at best. First,
children were not age-matched in any of these studies. Although the authors reported age-adjusted
index scores, the predictive validity of these indices across child developmental stages has not been
established (Black and Matula 2000). Consequently, groupwise differences in the ages of the
children might confound the results. Second, the Casper et al. (2003) study is further confounded
by the fact that 29% of the participants were enrolled after delivery. This inclusion of a
retrospective (postnatally enrolled) sampling could result in an overrepresentation of children with
developmental abnormalities.
Another recent investigation (Oberlander et al. 2004) evaluated children at fixed time points (2
months and 8 months of age), thereby eliminating the age adjustment confound. This study
reported no difference between 46 SSRI-exposed infants and 23 children of healthy volunteers with
respect to either cognitive or motor development. Finally, a recent assessment of externalizing and
attentional behaviors in 4-year-old children found no evidence that prenatal SSRI exposure affected
these outcomes (Oberlander et al. 2007).
Although evidence regarding the developmental effects of SSRI exposure has been reassuring, data
on the impact of prenatal antidepressant exposure on vulnerability to miscarriage, preterm
delivery, and/or low birth weight are decidedly mixed. Some investigators have reported an
association with such outcomes (Chambers et al. 1996; Chun-Fai-Chan et al. 2005; Oberlander et al.
2006; Pastuszak et al. 1993; Simon et al. 2002), whereas others have not (Einarson et al. 2001,
2003; Kulin et al. 1998; Sivojelezova et al. 2005). This is further complicated by yet other studies
reporting an association of prenatal maternal stress and/or depression with prematurity and low
birth weight (Orr et al. 2002; Steer et al. 1992). As such, no definitive conclusions can be drawn as
to whether antidepressant use during gestation conveys an adverse impact on fetal growth or the
timing of parturition.
Finally, a transient self-limited syndrome of neonatal symptoms, most commonly respiratory
difficulty and tremulousness/jitteriness, associated with fetal exposure to serotonergic
antidepressants proximate to delivery has drawn increasing attention (Moses-Kolko et al. 2005).
Most controlled prospective studies suggest that there may be an association between SSRI
exposure and poor neonatal adaptation (Chambers et al. 1996; Costei et al. 2002; Källén 2004;
Laine et al. 2003; Oberlander et al. 2004, 2006; Sivojelezova et al. 2005; Zeskind and Stephens
2004), although one recent study found no such association (Maschi et al. 2008) and closer scrutinyPrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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of these reports reveals a cadre of methodological shortcomings. Little effort has been made to
mask those evaluating the neonates as to fetal antidepressant exposure, only one study
(Oberlander et al. 2006) has endeavored to control for the impact of maternal mental illness, and
key confounding exposures such as gestational age at delivery, maternal smoking, and/or maternal
use of other medications have been either ignored altogether or controlled in the crudest fashion
(as dichotomous variables derived from unconfirmed maternal self-report). The most recent and
arguably best designed of these studies (Oberlander et al. 2006) reported a significant association
of SSRI exposure with neonatal respiratory difficulty and small-for-gestational-age birth weight;
however, the authors failed to highlight the significant associations in their data of maternal
depression during pregnancy with cesarean section delivery, preterm delivery, longer duration of
neonatal hospital stay, and neonatal feeding problems.
A putative mechanism for SSRI-associated neonatal respiratory difficulty has been suggested by a
recent retrospective case–control study (Chambers et al. 2006) reporting an overrepresentation of
SSRI exposure after gestational week 20 among neonates with persistent pulmonary hypertension
(PPHN) (OR = 6.1). However, the fact that only 3.7% of the neonates with PPHN were exposed to
an SSRI in late pregnancy, coupled with the recognition that PPHN is itself a relatively rare
condition affecting approximately 0.19% of newborns (Greenough and Khetriwal 2005), raises
questions as to whether this statistically significant finding is as clinically meaningful as the
authors contend.
Another recent case–control study, comparing the exposures of neonates who “required
observation” with those of “healthy” neonates (Misri et al. 2004), further highlights the importance
of controlling for confounding factors. In this study, in which all neonates (n = 46) were exposed to
antidepressants and born to mothers who fulfilled diagnostic criteria for major depressive disorder,
the mothers of infants who required observation had significantly higher scores on the Hamilton
Rating Scale for Depression (21.7 vs. 16.2) and the Hamilton Anxiety Scale (21.1 vs. 13.6), were
significantly more likely to have a comorbid anxiety disorder (92.8% vs. 53.1%), and were on
average exposed to higher doses of clonazepam (0.43 mg/day vs. 0.14 mg/day).
Pharmacokinetic data regarding the placental passage of SSRI antidepressants remain limited. A
recent study by Hendrick et al. (2003b) demonstrated that mean fetal–maternal ratios of the
plasma concentrations of several SSRIs (i.e., fluoxetine, fluvoxamine, paroxetine, and sertraline)
and their active metabolites are uniformly less than 1, although considerable differences exist
between medications. Data on in vivo placental passage of citalopram are not yet available.
Investigations that will enable the elaboration of comprehensive pharmacodynamic models to guide
SSRI dose management throughout gestation are currently under way.
Published reports pertaining to SSRIs and lactation now exceed the published literature for any
other class of medications, encompassing numerous exposures to sertraline (Altshuler et al. 1995;
Birnbaum et al. 1999; Dodd et al. 2000; C. Epperson et al. 1997; N. Epperson et al. 2001; Hendrick
et al. 2001; Kristensen et al. 1998; Mammen et al. 1997; Stowe et al. 1997, 2000; Wisner et al.
1998), fluoxetine (Birnbaum et al. 1999; Burch and Wells 1992; Nonacs and Cohen 2002;
Kristensen et al. 1999; Lester et al. 1993; Taddio et al. 1996; Yoshida et al. 1998a), paroxetine
(Birnbaum et al. 1999; Hendrick et al. 2001; R. Ohman et al. 1999; Spigset et al. 1996; Stowe et al.
2000), escitalopram (Rampono et al. 2006), fluvoxamine (Hendrick et al. 2001; Piontek et al. 2001;
Wright et al. 1991), and citalopram (Jensen et al. 1997; Schmidt et al. 2000; Spigset et al. 1997).
Although infant follow-up data are limited, only a few isolated cases of adverse effects have been
reported. Long-term neurobehavioral studies of infants exposed to SSRI antidepressants during
lactation have not been conducted, although a study of 12 infants exposed to sertraline during
nursing detected no adverse effects on growth or achievement of developmental milestones
(Llewellyn et al. 1997).
Pharmacokinetic studies of SSRIs in lactation constitute a confusing array of investigations
employing varying assay sensitivities and inconsistent collection methods that complicate efforts to
compare rates of breast milk excretion between compounds. The pharmacokinetic profiles of breastPrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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milk excretion, including delineation of distribution gradients and time gradients, are best defined
for sertraline (Stowe et al. 1997; Hendrick et al. 2003b), paroxetine (Stowe et al. 2000), and
fluoxetine (Suri et al. 2002). Collectively, findings from these studies indicate that quantitative
infant SSRI exposure during lactation is considerably lower than transplacental exposure to these
same medications during gestation.
Tricyclic Antidepressants
TCAs have been available in the United States since 1963 and were widely used during pregnancy
and lactation before the proliferation of reproductive safety data regarding the SSRIs. No clear
association has been demonstrated between TCA exposure and congenital malformations. Early
studies suggested that TCA exposure might be associated with limb anomalies (Barson 1972; Elia et
- 1987; McBride 1972), but a meta-analysis by Altshuler et al. (1996) of 14 studies representing
more than 300,000 live births identified a congenital malformation incidence of only 3.14% (n =
13) among 414 infants exposed to a TCA during the first trimester. A review of data from the
European Network of Teratology Information Services revealed similar rates of malformation after
TCA exposure (McElhatton et al. 1996). These rates are well within the normal baseline incidence of
2%–4%. Furthermore, the landmark study by Nulman et al. (1997a) involving 80 children exposed
to a TCA during gestation found no evidence that prenatal exposure to these medications is
associated with adverse neurobehavioral effects.
Few data exist regarding the acute effects of TCA exposure on fetal and neonatal well-being. There
are case reports of fetal tachycardia (Prentice and Brown 1989) and numerous neonatal symptoms,
including tachypnea, tachycardia, cyanosis, irritability, hypertonia, clonus, and spasm (Eggermont
1973; Miller 1991; Webster 1973). A small (n = 18) prospective study identified no evidence of
increased complications during labor and delivery but did report transient withdrawal symptoms
among TCA-exposed neonates (Misri and Sivertz 1991).
In a pharmacokinetic investigation addressing nortriptyline dose management during gestation,
Wisner et al. (1993) reported that dose increases approximately 1.6 times higher than the
preconception dose might be required in late pregnancy to maintain therapeutic serum
concentrations and thereby sustain clinical benefit.
TCAs also have been widely used during lactation. The only adverse event reported to date is
respiratory depression in a nursing infant exposed to doxepin, leading the authors to conclude that
doxepin should be avoided but that most TCAs are safe for use during breast-feeding (Matheson et
- 1985). This clinical finding is paralleled by the pharmacokinetic data regarding TCAs in which all
TCAs are evident in breast milk, but infant plasma concentrations are considerably higher for
doxepin than for other TCAs (for a review, see Wisner et al. 1996b). The time gradient for excretion
also has been reported, with peak breast milk concentrations occurring 4–6 hours after an oral dose
of both amitriptyline (Pittard and O’Neal 1986) and desipramine (Stancer and Reed 1986).
Monoamine Oxidase Inhibitors
Although the monoamine oxidase inhibitors (MAOIs) were introduced more than 40 years ago,
clinical data regarding their use during pregnancy and lactation are limited. The currently available
MAOIs (i.e., isocarboxazid, phenelzine, and tranylcypromine) are all FDA Category C medications;
however, a small prospective study (Heinonen et al. 1977) suggested that prenatal tranylcypromine
exposure is associated with increased risk for fetal malformations. Laboratory animal studies also
have reported teratogenic potential from embryonic exposure to MAOIs (Poulson and Robson
1964). The utility of MAOIs during pregnancy and lactation is severely limited by the potential for
hypertensive crisis, which necessitates dietary constraints and avoidance of numerous medications
that are commonly used during pregnancy (e.g., pseudoephedrine) or labor and delivery (e.g.,
meperidine). These restrictions can be avoided, at least in part, with the so-called reversible MAOIs
(i.e., brofaromine and moclobemide). The reversible MAOIs are not currently available in the United
States. The single published case report regarding moclobemide exposure during gestation reported
no perinatal complications and indicated that the child demonstrated normal somatic and motoricPrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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development up to 14 months of age (Rybakowski 2001).
Other Antidepressants
Reproductive safety data are considerably more limited for most of the agents comprising the
heterogeneous assortment of other antidepressants, including bupropion, duloxetine, mirtazapine,
nefazodone, trazodone, and venlafaxine.
Prospective reports of first-trimester use of these agents consist of 2,550 bupropion exposures
producing 56 (2.2%) children with major malformations (Boshier et al. 2003; Briggs et al. 2005;
Chun-Fai-Chan et al. 2005; Cole et al. 2007; GlaxoSmithKline 2005), 771 venlafaxine exposures
with 14 (1.4%) major malformations (Einarson et al. 2001; GlaxoSmithKline 2005), 404 trazodone
exposures with 10 (2.5%) major malformations (Briggs et al. 2005; GlaxoSmithKline 2005;
McElhatton et al. 1996), 140 nefazodone exposures with 2 (1.4%) major malformations
(GlaxoSmithKline 2005), 125 mirtazapine exposures with 2 (1.6%) major malformations (Djulus et
- 2006; GlaxoSmithKline 2005), and an additional combined report of 121 nefazodone or
trazodone exposures with 2 (1.7%) major malformations (Einarson et al. 2003). There are no
published data on first-trimester duloxetine exposure.
Pharmacokinetic data during pregnancy are available only for venlafaxine. The pharmacokinetic
study by Hendrick et al. 2003b reported that fetal–maternal plasma ratios for both venlafaxine and
its active metabolite, O-desmethylvenlafaxine, are greater than 1. This higher rate of placental
passage may be a consequence of certain physicochemical properties of venlafaxine, including its
relatively low molecular weight and low binding to plasma proteins.
Data regarding the use of atypical antidepressants during lactation are likewise extremely limited.
The existing literature includes reports of one infant exposed to bupropion (Briggs et al. 1993) and
three infants exposed to venlafaxine (Ilett et al. 1998). No adverse effects were reported for any of
these four children. Bupropion was undetectable in the plasma of the infant whose mother was
taking that antidepressant (Briggs et al. 1993), but the plasma concentration of
O-desmethylvenlafaxine was higher in one of the venlafaxine-exposed infants than in her mother
(Ilett et al. 1998).
MOOD-STABILIZING MEDICATIONS
The perinatal management of bipolar disorder has received considerable attention and continues to
be one of the most difficult challenges of modern psychiatric practice. The current mainstays of
treatment for bipolar disorder are lithium, valproate, carbamazepine, and lamotrigine (Table 64–4).
TABLE 64–4. Mood-stabilizing and antiepileptic medications
Generic name Trade name Daily dosage
(mg/day)a
Risk
categoryb
American Academy of
Pediatrics ratingc
Carbamazepine Tegretol 400–1,600 Cm
Compatible
Clonazepam Klonopin 0.5–10 C N/A
Gabapentin Neurontin 900–1,800 C N/A
Lamotrigine Lamictal 300–500 C Unknown, but of concern
Levetiracetam Keppra 500–3,000 C N/A
Lithium
carbonate
Eskalith, Lithobid,
Lithonate
900–2,100 D Contraindicated
Oxcarbazepine Trileptal 600–1,200 C Unknown, but of concern
Tiagabine Gabatril 160–320 C N/A
Topiramate Topamax 200–800 C Unknown, but of concernPrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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Generic name Trade name Daily dosage
(mg/day)a
Risk
categoryb
American Academy of
Pediatrics ratingc
Valproic acid Depakote (divalproex
sodium)
750–1,500 D Compatible
Note. N/A = not available.
aDosing strategies adapted from Schatzberg and Cole 1991; Kaplan and Sadock 1993; and for newer
medications, the manufacturers’ package inserts.
bRisk category adapted from Briggs et al. 2005 and/or Physicians’ Desk Reference 2007; “m” subscript
indicates data taken from the manufacturer’s package insert.
cAmerican Academy of Pediatrics 2001.
Lithium
Used routinely since the 1950s, lithium remains the cornerstone of the available pharmacotherapies
for bipolar disorder. Early reports of congenital malformations following in utero lithium exposure
led to the establishment of the Danish Registry of Lithium Babies in 1969. Additional registries
were later established in Canada and the United States, culminating in the International Register of
Lithium Babies.
Early retrospective data suggested that lithium exposure was associated with a 400-fold increase in
the vulnerability to congenital heart disease, with particular susceptibility to a malformation of the
tricuspid valve known as Ebstein’s anomaly (Nora et al. 1974; Weinstein and Goldfield 1975), but a
subsequent meta-analysis of the available data calculated the risk ratio for cardiac malformations
to be 1.2–7.7 and the risk ratio for overall congenital malformations to be 1.5–3.0 (Cohen et al.
1994). Altshuler et al. (1996) estimated that the risk for Ebstein’s anomaly after prenatal lithium
exposure rises from 1 in 20,000 to 1 in 1,000. A series of more recent yet small studies also failed
to confirm the early estimates regarding the teratogenic potential of lithium (Friedman and Polifka
2000; Jacobsen et al. 1992; Källén and Tandberg 1983), although these studies had limited
statistical power. Laboratory animal studies had indicated that neurobehavioral alterations also
might be a concern for prenatal lithium exposure, but a 5-year follow-up of 60 school-age children
exposed to lithium during gestation found no overt evidence of adverse neurobehavioral sequelae
(Schou 1976).
Preconception counseling with a psychiatrist, obstetrician, and perhaps a genetic counselor should
be the standard of care for women with bipolar disorder. Cohen et al. (1994) suggested the
following treatment guidelines for women who are maintained on lithium and plan to conceive: 1)
lithium should be gradually (>2 weeks) tapered prior to conception in women who experience mild
and infrequent episodes of illness; 2) lithium should be tapered prior to conception but reinstituted
after organogenesis in women who have more severe episodes but are only at moderate risk for
relapse in the short term; 3) lithium should be continued throughout gestation for women who have
especially severe and frequent episodes of illness in conjunction with counseling regarding
reproductive risks. Prenatal assessment for fetal anomalies, including a fetal echocardiogram
between weeks 16–18 of gestation, should be performed for women treated with lithium during the
first trimester. In the event of unplanned conception during lithium therapy, the decision to
continue or discontinue lithium should also be informed by the severity and course of the patient’s
illness as well as the time point in gestation when the exposure comes to attention. Discontinuing
lithium therapy after cardiogenesis is complete at approximately 9–11 weeks gestation may be ill
advised.
In addition to the developmental consequences of exposure, lithium’s low therapeutic index also
raises concerns regarding acute perinatal toxicities. Lithium exposure later in gestation can
produce fetal and neonatal cardiac arrhythmias (N. Wilson et al. 1983), hypoglycemia and
nephrogenic diabetes insipidus (Mizrahi et al. 1979), reversible changes in thyroid function
(Karlsson et al. 1975), polyhydramnios, premature delivery, and a “floppy infant syndrome” similarPrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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to that witnessed with benzodiazepine exposure (Llewellyn et al. 1998). The neonate may exhibit
signs of lithium toxicity at serum concentrations lower than maternal concentrations. Neonatal
symptoms of lithium toxicity, including flaccidity, lethargy, and poor suck reflexes, may persist for
more than 7 days (Woody et al. 1971).
In a pooled analysis of lithium placental passage and neonatal outcomes (Newport et al. 2005), we
determined that 1) higher neonatal lithium concentrations were associated with significantly lower
Apgar scores, longer hospital stays, and higher rates of CNS and neuromuscular complications; 2)
umbilical cord (i.e., fetal) plasma concentrations were uniformly equivalent to maternal
concentrations, suggesting that lithium rapidly equilibrates across the placenta; and 3) withholding
lithium therapy for 24–48 hours prior to delivery resulted in a 0.28 mEq/L reduction in maternal
(and presumably fetal) lithium concentrations, thereby likely improving neonatal outcomes.
Consequently, scheduled deliveries, which afford opportunity for temporary suspension of lithium
therapy for 24–48 hours, are advised for women taking lithium during late gestation.
The physiological alterations of pregnancy are of particular importance in the perinatal
management of lithium. Changes in renal clearance across pregnancy and the potential for abrupt
volume changes during delivery due to copious diaphoresis and the loss of blood and amniotic fluid
mandate careful monitoring of lithium levels during pregnancy and especially at delivery.
Furthermore, nonsteroidal anti-inflammatory drugs, which inhibit renal clearance of lithium, should
be avoided in mother and infant alike during the early postpartum period.
The existing database regarding lithium and lactation encompasses 21 maternal–infant nursing
dyads (Fries 1970; Schou and Amdisen 1973; Skausig and Schou 1977; Sykes et al. 1976;
Tunnessen and Hertz 1972; Viguera et al. 2007; Weinstein and Goldfield 1969; Woody et al. 1971).
Adverse events, including lethargy, hypotonia, hypothermia, cyanosis, electrocardiogram changes,
and elevated thyroid-stimulating hormone level, were reported in 4 (19%) of these children
(Skausig and Schou 1977; Tunnessen and Hertz 1972; Viguera et al. 2007; Woody et al. 1971),
including 1 infant who developed frank lithium toxicity with a serum concentration of 1.4 mEq/L,
which was double the maternal level (Skausig and Schou 1977). The American Academy of
Pediatrics (2001) discourages the use of lithium during lactation. The largest pharmacokinetic
study of lithium in lactation demonstrated a milk-to-plasma ratio of 0.53 and an infant-to-maternal
plasma ratio of 0.24 (Viguera et al. 2007). In other studies, nursing infants have exhibited lithium
concentrations generally ranging from 5% to 65% of maternal levels (Fries 1970; Kirksey and
Groziak 1984; Schou and Amdisen 1973; Sykes et al. 1976; Tunnessen and Hertz 1972; Weinstein
and Goldfield 1969), excluding the lone infant whose serum concentration was 200% of the
maternal concentration (Skausig and Schou 1977). Because dehydration can increase the
vulnerability to lithium toxicity, the hydration status of nursing infants of mothers taking lithium
should be carefully monitored (Llewellyn et al. 1998). There are no available reports regarding the
long-term neurobehavioral sequelae of lithium exposure during lactation.
Valproate (Valproic Acid)
Several anticonvulsants, including valproate, lamotrigine, and carbamazepine, are now used in the
treatment of bipolar disorder. The widespread use of valproate raises serious concerns for the
reproductive safety of women with bipolar disorder. Prenatal exposure to valproate has been
associated with numerous congenital malformations, including neural tube defects (Bjerkedal et al.
1982; Centers for Disease Control 1992; Jager-Roman et al. 1986; Lindhout and Schmidt 1986);
craniofacial anomalies, including craniosynostosis (Assencio-Ferreira et al. 2001; Lajeunie et al.
1998, 2001; Paulson and Paulson 1981); limb abnormalities (Rodriguez-Pinilla et al. 2000); and
cardiovascular anomalies (Dalens et al. 1980; Koch et al. 1983; Sodhi et al. 2001).
Valproate exposure prior to neural tube closure, during the fourth week of gestation, confers a
1%–2% risk for spina bifida, which is 10–20 times greater than the prevalence in the general
population (Bjerkedal et al. 1982; Centers for Disease Control 1992; Rosa 1991). One meta-analysis
placed the risk for neural tube defects even higher, at 3.8%, with particular vulnerability for the
infants of women whose daily dose exceeds 1,000 mg (Samrén et al. 1997). Other studies supportPrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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this dose–response relationship (Canger et al. 1999; Kaneko et al. 1999; Omtzigt et al. 1992;
Samrén et al. 1999), leading one group to recommend that daily dosages not exceed a maximum of
1,000 mg and that maternal serum concentrations not exceed a maximum of 70 g/mL to reduce
the risk for malformations (Kaneko et al. 1999). In a case–control study examining the incidence of
limb malformations in a cohort of more than 44,000 children, 67 of whom were exposed to
valproate in the first trimester, Rodriguez-Pinilla et al. (2000) reported an odds ratio of 6.17 for
limb abnormalities among children exposed to valproate and estimated the risk of limb
abnormalities from valproate exposure at 0.42%.
A fetal valproate syndrome was initially reported by Di Liberti et al. (1984) and subsequently
confirmed by other investigators (Ardinger et al. 1988; Martinez-Frias 1990; Winter et al. 1987).
The phenotypic attributes of fetal valproate syndrome include stereotypical facial features such as
bifrontal narrowing, midface hypoplasia, a broad nasal bridge, a short nose with anteverted nares,
epicanthal folds, micrognathia, a shallow philtrum, a thin upper lip, and a thick lower lip (McMahon
and Braddock 2001; S. J. Moore et al. 2000). Many of the congenital malformations previously
associated with valproate exposure, including neural tube defects, congenital heart defects, cleft
lip, cleft palate, limb abnormalities, urogenital defects, and abdominal wall defects, have been
recognized as components of the fetal valproate syndrome (McMahon and Braddock 2001).
Whereas the association between neural tube defects and folate deficiency is well established,
valproate’s antagonistic effect on folate may also underlie the full spectrum of fetal valproate
syndrome. A case–control study comparing 57 children with fetal anticonvulsant syndromes, 46 of
whose mothers were treated with valproate, with 152 control children found a significantly higher
rate of a homozygosity for a mutation in the gene for methylenetetrahydrofolate reductase
(MTHFR), a key enzyme in folate metabolism (Dean et al. 1999).
Neurodevelopmental outcomes associated with prenatal valproate exposure are equally concerning.
A review indicated that developmental delay is evident in 20% and mental retardation in 10% of
children exposed to valproate monotherapy prenatally (Kozma 2001). An interim report from a
prospective multicenter investigation of the neurodevelopmental effects of prenatal antiepileptic
drug exposure indicated that 24% of 2-year-olds with prenatal valproate exposure had mental
developmental indexes of less than 70, more than doubling the rate of other antiepileptic drugs
(Meador et al. 2006). Retrospective reports indicate that varying degrees of cognitive impairment
may be present in children manifesting the physical sequelae of fetal valproate syndrome (Adab et
- 2001; Gaily et al. 1990; S. J. Moore et al. 2000). Fetal valproate syndrome has also been
associated with pervasive developmental disorders, including autism (Bescoby-Chambers et al.
2001; S. J. Moore et al. 2000; G. Williams et al. 2001; P. G. Williams and Hersh 1997) and
Asperger’s syndrome (S. J. Moore et al. 2000).
Valproate exposure during gestation is also associated with risks for numerous fetal and neonatal
toxicities, including hepatotoxicity (Kennedy and Koren 1998), coagulopathies (Mountain et al.
1970), and neonatal hypoglycemia (Ebbesen et al. 2000; Thisted and Ebbesen 1993). Ten of 13
infants who demonstrated neonatal hypoglycemia after prenatal valproate exposure developed
withdrawal symptoms—including irritability, jitteriness, hypertonia, seizures, and vomiting—that
began 12–24 hours after delivery and lasted up to 1 week (Ebbesen et al. 2000).
Pharmacokinetic studies in women with epilepsy indicate that maternal valproate concentrations
steadily decline across pregnancy, reaching levels up to 50% lower than preconception
concentrations (Yerby et al. 1990, 1992). Consistent findings from other studies demonstrate that
valproate is more rapidly cleared during gestation, and especially during the final month of
pregnancy (Nau et al. 1982b; Otani 1985; Philbert et al. 1985). Dosage increases during pregnancy
may therefore be required to maintain therapeutic concentrations. Valproate readily crosses the
human placenta, with fetal concentrations at delivery equal to or slightly higher than maternal
concentrations (Froescher et al. 1984b; Philbert et al. 1985; Yerby et al. 1990, 1992).
The published literature regarding valproate and lactation includes 41 mother–infant nursing dyads
(Alexander 1979; Bardy et al. 1982a; Dickinson et al. 1979; Froescher et al. 1981; Nau et al. 1981;Print: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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Piontek et al. 2000; Stahl et al. 1997; Tsuru et al. 1988; von Unruh et al. 1984; Wisner and Perel
1998). From these cases, only one adverse event, thrombocytopenia and anemia in an infant, has
been reported (Stahl et al. 1997). The pharmacokinetic data indicate that valproate milk-to-plasma
ratios are uniformly low and that serum concentrations of nursing infants are 2%–40% of maternal
concentrations (Alexander 1979; Bardy et al. 1982a; Piontek et al. 2000; Stahl et al. 1997; von
Unruh et al. 1984; Wisner et al. 1996b). Studies of the neurobehavioral effects of valproate
exposure during lactation have not been conducted.
In summary, among all psychotropic agents, valproate bears the greatest burden for fetal risk,
leading the principal investigator of the multicenter Neurodevelopmental Effects of Antiepileptic
Drugs study, Kimford Meador, M.D., to conclude that it “should never be used as a first-line choice
in women of childbearing age” (Cassels 2006). If valproate must be used during pregnancy, its risk
may be reduced by being careful not to exceed 1,000 mg per day or a serum concentration of 70
g/ml. Folate supplementation (4–5 mg per day) is also recommended, although there is no
evidence that this reduces the risk of valproate-associated anomalies. Because nearly half of
pregnancies in the United States are unplanned, and women with unplanned pregnancies typically
first recognize that they are pregnant during the sixth week of gestation or even later (2 full weeks
after neural tube closure), all women of childbearing potential who are treated with valproate
should receive concomitant folate supplementation, regardless of whether they plan to conceive.
The preliminary evidence that aspects of fetal valproate syndrome other than neural tube defects
may be associated with valproate’s antagonism of folate metabolism suggests that folate
supplementation should be administered not only in the first trimester but also throughout
gestation. Because of the potential for valproate-associated neonatal coagulopathies, oral vitamin K
supplementation (10–20 mg per day) may be considered during the final month of gestation.
Prenatal surveillance for congenital abnormalities should include maternal serum -fetoprotein,
fetal echocardiography, and a level 2 ultrasound at approximately 16–18 weeks’ gestation. Finally,
genetic screening of women taking valproate for mutations in the MTHFR gene warrants future
consideration but cannot yet be recommended for routine clinical practice.
In contrast to the marked risks of its use during pregnancy, valproate therapy during lactation
appears to be well tolerated by nursing infants. Nevertheless, periodic assays of platelet count and
serum liver enzymes of nursing infants are recommended because of the risks for
thrombocytopenia and hepatotoxicity associated with valproate therapy.
Carbamazepine
Carbamazepine is associated with many of the same risks as valproate during gestation, although in
many cases with less frequency or severity. For example, first-trimester carbamazepine exposure is
associated with a risk for neural tube defects, although the 0.5%–1.0% risk in
carbamazepine-exposed infants (Rosa 1991) is approximately half that seen with valproate
exposure (Lindhout and Schmidt 1986; Rosa 1991). A meta-analysis of five prospective studies
encompassing 1,255 prenatal exposures indicated that carbamazepine exposure in utero is
associated with an increased risk of neural tube defects, cleft palate, cardiovascular abnormalities,
and urinary tract anomalies (Matalon et al. 2002). An epidemiological study indicated that
periconceptional folate supplementation was associated with a lower rate of neural tube defects
among the children of women taking carbamazepine during pregnancy (Hernandez-Diaz et al.
2001).
A fetal carbamazepine syndrome manifested by a short nose, long philtrum, epicanthal folds,
hypertelorism, upslanting palpebral fissures, and fingernail hypoplasia has also been described
(Jones et al. 1989) but has received considerably less attention than fetal valproate syndrome. A
subsequent study found the phenotypic characteristics of fetal carbamazepine syndrome evident in
6 of 47 children exposed to carbamazepine monotherapy during gestation (Ornoy and Cohen 1996).
Other investigations have confirmed this association with facial anomalies (S. J. Moore et al. 2000;
Nulman et al. 1997b; Scolnick et al. 1994; Wide et al. 2000), but one of these studies demonstrated
similar facial abnormalities among children born to women with epilepsy who were untreatedPrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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during pregnancy (Nulman et al. 1997b). This fetal carbamazepine syndrome has also been
associated with developmental delay in up to 20% of exposed children (Jones et al. 1989; S. J.
Moore et al. 2000; Ornoy and Cohen 1996), although other investigators have failed to demonstrate
evidence of cognitive dysfunction in carbamazepine-exposed children (Gaily et al. 1990, 2004;
Meador et al. 2006; Scolnick et al. 1994; van der Pol 1991; Wide et al. 2000).
Potential fetal/neonatal toxicities associated with carbamazepine exposure include blood
dyscrasias, coagulopathies, skin reactions, and hepatotoxicity. Most of these risks remain
theoretical, although neonatal hepatotoxicity has been reported in a carbamazepine-exposed infant
(Frey et al. 2002).
Pharmacokinetic studies of carbamazepine clearance during gestation have yielded mixed results.
Some investigators have reported statistically significant increases in carbamazepine clearance
during the third trimester (Battino et al. 1982; Dam et al. 1979; Lander et al. 1980), but others
have found no changes in carbamazepine clearance (Bardy et al. 1982b; Otani 1985; Yerby et al.
1985). Placental pharmacokinetic studies indicate that the placental transfer of carbamazepine is
lower than that of other anticonvulsants (Nau et al. 1982a; Yerby et al. 1990, 1992), with
fetal-to-maternal plasma ratios equaling 0.5–0.8 (Nau et al. 1982a).
The literature on carbamazepine and lactation includes 12 published reports and 144 mother–infant
nursing pairs (Brent and Wisner 1998; Frey et al. 1990, 2002; Froescher et al. 1984a; Kaneko et al.
1982; Kok et al. 1982; Kuhnz et al. 1983; Merlob et al. 1992; Niebyl et al. 1979; Pynnonen and
Sillanpaa 1975; Pynnonen et al. 1977; Wisner and Perel 1998), representing the most extensive
data set for any mood stabilizer in lactation. This includes 8 reports of adverse events: 1 drowsy,
irritable infant with an undetectable serum concentration of carbamazepine (Kok et al. 1982); 2
“hyperexcitable” infants in whom carbamazepine levels were not reported (Kuhnz et al. 1983); 2
infants with cholestatic hepatitis in whom carbamazepine levels were not reported (Frey et al.
1990, 2002); 1 infant with poor nursing effort (Froescher et al. 1984a); 1 infant with an increased
serum concentration of -glutamyl transpeptidase (GGT) but no overt clinical sequelae whose
serum concentration was 33% of the maternal concentration (Merlob et al. 1992); and 1 infant with
a “seizurelike” phenomenon whose carbamazepine level was 8% of the maternal level (Brent and
Wisner 1998). Serum carbamazepine concentrations in the 8 nursing infants in whom these levels
were assessed ranged from undetectable to 65% of the maternal level (Brent and Wisner 1998; Kok
et al. 1982; Merlob et al. 1992; Pynnonen and Sillanpaa 1975; Pynnonen et al. 1977; Wisner and
Perel 1998).
Although the risks associated with in utero carbamazepine exposure are marginally better than
those for valproate exposure, the clinical recommendations are quite similar. Carbamazepine
should be avoided in pregnancy, especially during the first trimester. Folate supplementation (4–5
mg/day) is also recommended not only during gestation but also throughout the reproductive years
because of the high prevalence of inadvertent conception in the United States. Women taking
carbamazepine during gestation should receive prenatal surveillance for congenital abnormalities,
including maternal serum -fetoprotein, fetal echocardiography, and a level 2 ultrasound at
approximately 16–18 weeks’ gestation. Carbamazepine has by far the most extensive database for
mood stabilizers in lactation, but reports of hepatic dysfunction in nursing infants certainly raise
concern. Periodic assays of blood counts and serum liver enzymes of nursing infants are
recommended in light of the risks for blood dyscrasias and hepatotoxicity associated with
carbamazepine therapy.
Lamotrigine
Reproductive safety data regarding lamotrigine have rapidly accrued during the past decade and
compare favorably with safety data for other agents available in the treatment of bipolar disorder.
The overall risk of major fetal malformations following first-trimester prenatal exposure to
lamotrigine is 2.6% (83 per 3,176 exposures, including 0.32% [8 per 2,537 exposures] for midline
cleft formations) (Dominguez-Salgado et al. 2004; GlaxoSmithKline 2007; Holmes et al. 2006;
Meador et al. 2006; Morrow et al. 2006; Sabers et al. 2004; Vajda et al. 2003), rates that are withinPrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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the range of births not involving drug exposures. A recent report by the North American Pregnancy
Registry (Holmes et al. 2006) noted a relatively high rate of midline facial clefts (0.89% of 564
exposures); however, the collective rate of orofacial clefts in the other registries was only 0.15%
(2 per 1,937 exposures) (Dominguez-Salgado et al. 2004; GlaxoSmithKline 2007; Meador et al.
2006; Morrow et al. 2006; Sabers et al. 2004; Vajda et al. 2003). Furthermore, a forthcoming
case–control study by the European Surveillance of Congenital Anomalies (EUROCAT),
encompassing 5,511 children with orofacial clefts and 80,052 children without clefts, reports an
adjusted odds ratio of 0.67 for clefts with lamotrigine exposure (Dolk et al. 2008). The United
Kingdom Epilepsy and Pregnancy Register reported a higher risk of malformations at maternal daily
doses exceeding 200 mg (Morrow et al. 2006), although this was not confirmed in a subsequent
analysis of the manufacturer’s registry (GlaxoSmithKline 2007). Despite these reassuring findings,
folate supplementation is recommended for all women of childbearing age taking any antiepileptic
drug, including lamotrigine. Prospective neurodevelopmental data have also been favorable among
children with prenatal lamotrigine exposure (Meador et al. 2006).
The pharmacokinetics of lamotrigine during pregnancy are well studied, with numerous studies
consistently reporting that lamotrigine clearance steadily increases across gestation (de Haan et al.
2004; Pennell et al. 2004; Petrenaite et al. 2005; Tran et al. 2002). Indeed, seizure control in
pregnant women with epilepsy can be maximized by regular monitoring of plasma concentrations
and periodic dose changes as necessary (Pennell et al. 2008). These studies are limited by the
cotherapy of lamotrigine with other anticonvulsants, which are known to alter the metabolism of
lamotrigine. It is unclear whether similar dose changes would be necessary to maintain mood
stability in patients with bipolar disorder and whether the common adjunctive agents used to treat
bipolar disorder would have similar effects on lamotrigine metabolism. Studies in epilepsy patients
taking lamotrigine also reveal that its rate of clearance abruptly declines after delivery (I. Ohman
et al. 2000; Pennell et al. 2004; Tran et al. 2002). Therefore, dosage reductions may be necessary
after delivery to avoid maternal symptoms of lamotrigine toxicity, such as dizziness, nausea and
vomiting, and diplopia (Tran et al. 2002).
Published reports are also available regarding the placental passage of lamotrigine with a series of
small studies to indicate that lamotrigine concentrations in fetal circulation at delivery are equal to
maternal concentrations (Myllynen et al. 2003; I. Ohman et al. 2000; Sathanandar et al. 2000;
Tomson et al. 1997). There have been no reports of acute adverse events observed in neonates
exposed to lamotrigine.
Reports regarding lamotrigine and lactation (GlaxoSmithKline 2007; Liporace et al. 2004; Newport
et al. 2008b; I. Ohman et al. 2000; Page-Sharp et al. 2006; Rambeck et al. 1997; Tomson et al.
1997) collectively encompass 55 maternal–infant nursing dyads. There have been no adverse
events observed in these breast-fed infants, although 7 infants were observed to have a benign
thrombocytosis (Newport et al. 2008a). In the largest (n = 30) of these studies (Newport et al.
2008a), the mean milk-to-plasma ratio was 41.3%, the relative infant dose equaled 9.2%, and the
infant-to-maternal plasma ratio equaled 18.3%. Long-term neurobehavioral outcomes have not
been studied in nursing infants exposed to lamotrigine.
Other Anticonvulsants
Other antiepileptic drugs (gabapentin, levetiracetam, zonisamide) may be utilized in the treatment
of mental illnesses, although efficacy trials for these agents have not been impressive.
Clinicians should be aware that more pharmaceutical companies are initiating postmarketing
surveillance registries for antiepileptic drugs.
Second-Generation Antipsychotics
The older first-generation antipsychotics (FGAs) such as haloperidol and chlorpromazine have
historically been used to manage the agitated behavior that often accompanies a manic episode;
however, these agents are not effective mood stabilizers. Recent interest has focused on the
mood-stabilizing utility of the SGAs (i.e., aripiprazole, clozapine, olanzapine, paliperidone,Print: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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quetiapine, risperidone, and ziprasidone). With the exception of the newest of these agents,
paliperidone, all SGAs now carry an FDA indication for one or more phases of bipolar disorder
management.
The reproductive safety database for the SGAs, which is reviewed in the following section, contains
scant data. Given this paucity of information, the SGAs cannot yet be recommended as first-line
agents for the management of bipolar disorder during the peripartum. However, a risk–benefit
assessment after inadvertent conception by a patient who is taking an SGA to manage bipolar
disorder may indicate that continuing the SGA is preferable to switching to another mood stabilizer.
ANTIPSYCHOTICS
Second-Generation Antipsychotics
The advent of SSRIs in the 1980s revolutionized the treatment of depression, and a similar
revolution has now taken place in the treatment of psychosis. The psychopharmacological
armamentarium available to treat psychotic disorders has expanded beyond the traditional FGAs
(e.g., haloperidol, chlorpromazine) to include a growing array of SGAs.
Commonly prescribed antipsychotic medications, as well as agents used to treat the side effects of
FGAs, are listed in Table 64–5. The SGAs currently available in the United States are aripiprazole,
clozapine, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. Compared with the
older FGAs, these new agents are less likely to produce tardive dyskinesia and extrapyramidal side
effects (EPS) and arguably more effective in managing the negative symptoms of schizophrenia.
The SGAs have consequently supplanted the FGAs as first-line medications for psychotic disorders
and are being increasingly used for other psychiatric indications, including bipolar disorder, OCD,
and treatment-resistant depression. Despite these agents’ rapidly expanding use, the reproductive
safety database regarding SGAs remains extremely limited.
TABLE 64–5. Antipsychotic medications
Generic name Trade
name
Daily dosage
(mg/day)a
Risk
categoryb
American Academy of
Pediatrics ratingc
First-generation
antipsychotics
Chlorpromazine Thorazine 200–800 C Unknown, but of concern
Fluphenazine Prolixin 5–10 C N/A
Haloperidol Haldol 5–10 Cm
Unknown, but of concern
Loxapine Loxitane 20–80 C N/A
Mesoridazine Serentil 100–400 C Unknown, but of concern
Molindone Moban 20–80 C N/A
Perphenazine Trilafon 8–32 C Unknown, but of concern
Pimozided
Orap 1–10 C N/A
Thioridazine Mellaril 200–600 C N/A
Thiothixene Navane 10–40 C N/A
Trifluoperazine Stelazine 10–40 C Unknown, but of concern
Second-generation
antipsychotics
Aripiprazole Abilify 10–30 Cm
N/A
Clozapine Clozaril 100–800 Bm
Unknown, but of concern
Olanzapine Zyprexa 5–20 Cm
N/APrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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Generic name Trade
name
Daily dosage
(mg/day)a
Risk
categoryb
American Academy of
Pediatrics ratingc
Paliperidone Invega 3–12 Cm
N/A
Quetiapine Seroquel 25–800 C Unknown, but of concern
Risperidoned
Risperdal 1–16 C N/A
Ziprasidone Geodon 40–160 C Unknown, but of concern
Medications for side
effects
Amantadine Symmetrel 100–400 Cm
N/A
Benztropine Cogentin 0.5–6.0 C N/A
Diphenhydramine Benadryl 25–150 Bm
N/A
Propranolol Inderal 20–120 Cm
Compatible
Trihexyphenidyl Artane 2–15 C N/A
Note. N/A = not available.
aDosing strategies adapted from Schatzberg and Cole 1991; Kaplan and Sadock 1993; and for newer
medications, the manufacturers’ package inserts.
bRisk category adapted from Briggs et al. 2005 and/or Physicians’ Desk Reference 2007; “m” subscript
indicates data taken from the manufacturer’s package insert.
cAmerican Academy of Pediatrics 2001.
dNot listed in Briggs et al. 1994. Risk category taken from Physicians’ Desk Reference (1992, 1993, 1994, and
1996 editions).
Clozapine
The extant literature regarding the reproductive safety of clozapine, the oldest of the SGAs, is
limited to case reports (Barnas et al. 1994; Di Michele et al. 1996; Kornhuber and Weller 1991;
Waldman and Safferman 1993), case series (McKenna et al. 2005; Stoner et al. 1997; Tenyi and
Tixler 1998), and a retrospective review (Dev and Krupp 1995), collectively encompassing 79
children exposed to clozapine during pregnancy and/or lactation. Adverse sequelae associated with
perinatal clozapine therapy include maternal gestational diabetes (Dickson and Hogg 1998);
several minor anomalies, including cephalohematoma, hyperpigmentation folds, and a coccygeal
dimple, in an infant (Stoner et al. 1997); transient low-grade fever at delivery in an infant whose
was mother receiving lithium cotherapy (Stoner et al. 1997); and floppy infant syndrome in a
newborn whose mother was taking clozapine and lorazepam during gestation (Di Michele et al.
1996). In a review of 61 children exposed to clozapine perinatally, Dev and Krupp (1995) reported
5 cases of congenital malformations and 5 cases of neonatal syndromes, although many of these
mothers were taking other psychotropic medications during pregnancy. The lone case report of
clozapine use during lactation reported no adverse impact on the nursing infant (Kornhuber and
Weller 1991).
The only investigation of the perinatal pharmacokinetics of clozapine demonstrated similar
medication concentrations in maternal serum and amniotic fluid but markedly higher
concentrations in fetal serum and breast milk (Barnas et al. 1994), leading the authors to conclude
that clozapine accumulates in the fetal circulation and breast milk. Although no cases of
agranulocytosis have been reported in infants of women taking clozapine during pregnancy or
lactation, this theoretical risk and the consequent requirement for monitoring of leukocyte counts
in newborns and nursing infants limit the utility of clozapine during the peripartum.
Olanzapine
Of the remaining SGAs, the earliest reproductive safety data were reported for olanzapine. APrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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published birth registry of 23 prospectively ascertained olanzapine-exposed pregnancies and 2
retrospectively ascertained cases of olanzapine lactation exposure from the Lilly Worldwide
Pharmacovigilance Safety Database reported no major congenital malformations, 13% spontaneous
abortions, 5% preterm deliveries, and 5% rate of fetal demise (Goldstein et al. 2000). A
prospective study comparing outcomes among 151 pregnant women with SGA exposure
(olanzapine, n = 60; risperidone, n = 49; quetiapine, n = 36; clozapine, n = 6) to 151 pregnant
control subjects reported no differences in rates of spontaneous abortion, stillbirth, major
malformations, prematurity, or low birth weight (McKenna et al. 2005). In this study, only one
SGA-exposed child (olanzapine) was observed to have any major malformations (a series of midline
defects including an oral cleft, encephalocele, and aqueductal stenosis).
In a recent study of antipsychotic placental passage rates and neonatal outcomes (Newport et al.
2007), umbilical cord concentrations in olanzapine-exposed neonates (n = 14) were 72.1% of
maternal concentrations (higher than rates for haloperidol, risperidone, and quetiapine). In this
study, there were trends toward higher rates of low birth weight (30.8%; P <0.06) and neonatal
intensive care unit admission (30.8%; P <0.09) among neonates exposed to olanzapine than those
exposed to the other agents.
Case reports of 16 infants exposed to olanzapine during lactation with no evidence of infant toxicity
currently appear in the literature (Croke et al. 2002; Friedman and Rosenthal 2003; Gardiner et al.
2003; Goldstein et al. 2000; Kirchheiner et al. 2000). Pharmacokinetic studies of olanzapine
exposure during lactation have reported that plasma concentrations were undetectable in infants
during nursing (Gardiner et al. 2003; Kirchheiner et al. 2000) and that the median infant daily dose
via breast-feeding was approximately 1.0%–1.6% of the maternal dose (Ambresin et al. 2004;
Croke et al. 2002; Gardiner et al. 2003).
There are no available data regarding the neurodevelopmental effects of olanzapine exposure
during pregnancy or lactation.
Risperidone
There are two prospective reports of pregnancy outcome for women with first-trimester risperidone
exposure. In the first, an assessment of the collective outcomes for several SGAs (McKenna et al.
2005) included 49 women with risperidone exposure. There were no children born with major
malformations in this sample. The second study, including 68 women with first-trimester exposure
and known outcomes, reported 9 (13.2%) spontaneous abortions, 1 (1.5%) stillbirth, and 2 (2.9%)
children with major malformations (Coppola et al. 2007). The reproductive safety literature for
risperidone encompasses 49 women and is limited to a single case report.
In our recent analysis of antipsychotic placental passage, risperidone concentrations in neonates (n
= 6) were 49.2% of maternal levels (Newport et al. 2007). Pharmacokinetic studies of risperidone
excretion into breast milk have reported milk-to-plasma ratios of less than 0.5 for both risperidone
and 9-hydroxyrisperidone (R. C. Hill et al. 2000; Ilett et al. 2004) and infant doses ranging from
2.3% to 4.7% of the maternal dose (Ilett et al. 2004).
There are no available data regarding the neurodevelopmental effects of risperidone exposure
during pregnancy or lactation.
Quetiapine
The reproductive safety literature for first-trimester quetiapine exposure is limited to the McKenna
et al. (2005) study, which reported no major malformations among 36 infants exposed to
quetiapine. In the Newport et al. (2007) study of antipsychotic placental passage, quetiapine
concentrations among neonates (n = 21) were 23% of maternal concentrations. To our knowledge,
this is the lowest placental passage rate ever reported for a psychotropic agent.
A single case of quetiapine use during lactation following use during pregnancy estimated the
nursing infant dose at 0.09% of the maternal daily dose (Lee et al. 2004).Print: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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There are no available data regarding the neurodevelopmental effects of quetiapine exposure
during pregnancy or lactation.
Aripiprazole
There are currently no reports regarding the use of aripiprazole during pregnancy or lactation.
Paliperidone
There are currently no reports regarding the use of paliperidone during pregnancy or lactation.
Ziprasidone
There are currently no reports regarding the use of ziprasidone during pregnancy or lactation.
First-Generation Antipsychotics
In contrast to the SGAs and most other classes of psychotropic medications, the FGAs have a large
reproductive safety database that addresses concerns of both somatic and neurobehavioral
teratogenicity. Furthermore, the widespread use of phenothiazines to treat pregnancy-associated
emesis (typically at low doses) aids in separating the effects of psychiatric illness and antipsychotic
drugs on pregnancy outcome. Chlorpromazine, haloperidol, and perphenazine have received the
greatest scrutiny, with no significant associations between these compounds and major congenital
malformations forthcoming (Goldberg and DiMascio 1978; R. M. Hill and Stern 1979; Nurnberg and
Prudic 1984).
In a study of 100 women treated with haloperidol (mean dosage = 1.2 mg/day) for hyperemesis
gravidarum, no differences in gestational duration, fetal viability, or birth weight were noted (Van
Waes and Van de Velde 1969). In a large prospective study encompassing nearly 20,000 women
treated primarily with phenothiazines for emesis, Milkovich and Van den Berg (1976) found no
significant association with neonatal survival rates or severe anomalies after controlling for
maternal age, medication, and gestational age at exposure. Similar results have been obtained in
several retrospective studies of women treated with trifluoperazine for repeated abortions and
emesis (Moriarty and Nance 1963; Rawlings et al. 1963). In contrast, Rumeau-Rouquette et al.
(1977) reported a significant association of major anomalies with prenatal exposure to aliphatic
side-chain phenothiazines but not with piperazine- or piperidine-class agents. Reanalysis of the
data obtained by Milkovich and Van den Berg (1976) did find a significant risk of malformations
associated with phenothiazine exposure in weeks 4 through 10 of gestation (Edlund and Craig
1976).
Clinical neurobehavioral outcome studies encompassing 203 children exposed to FGAs during
gestation detected no significant differences in IQ scores at 4 years of age (Kris 1965; Slone et al.
1977), although relatively low antipsychotic doses were used by many women in these studies.
Conversely, several laboratory animal studies (Hoffeld et al. 1968; Ordy et al. 1966; Robertson et
- 1980), although not all (Dallemagne and Weiss 1982), have demonstrated persistent deficits in
learning and memory among offspring prenatally exposed to FGA medications.
Beyond the teratogenic potential of the FGAs lies the possibility of fetal and infant toxicities such as
neuroleptic malignant syndrome (James 1988) and EPS manifested by heightened muscle tone and
increased rooting and tendon reflexes persisting for several months (Cleary 1977; R. M. Hill et al.
1966; M. O. O’Connor et al. 1981). Furthermore, prenatal exposure to SGAs has been reported to
produce neonatal jaundice (Scokel and Jones 1962) and postnatal intestinal obstruction (Falterman
and Richardson 1980).
In our recent study of antipsychotic placental passage, neonatal haloperidol (n = 13)
concentrations were 66% of maternal concentrations (Newport et al. 2005).
In lactation, chlorpromazine is the most widely studied typical antipsychotic, with 7 infants
exposed to chlorpromazine during nursing exhibiting no developmental deficits at 16-month and
5-year follow-up evaluations (Kris and Carmichael 1957). However, 3 infants in another studyPrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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whose mothers were prescribed both chlorpromazine and haloperidol exhibited evidence of
developmental delay at 12–18 months (Yoshida et al. 1998b). Pharmacokinetic investigations of
FGAs during lactation, including haloperidol (Stewart et al. 1980; Whalley et al. 1981; Yoshida et al.
1998b), trifluoperazine (J. T. Wilson et al. 1980; Yoshida et al. 1998b), perphenazine (J. T. Wilson
et al. 1980), thioxanthenes (Matheson and Skjaeraasen 1988), and chlorpromazine (Yoshida et al.
1998b), have uniformly reported milk-to-plasma ratios of less than 1, although adequate control for
distribution and time gradients is lacking in these studies. One group postulated that the
physicochemical properties of perphenazine could lead it to become “trapped” in breast milk (J. T.
Wilson et al. 1980).
Fetal and infant exposure to any of the various agents available for the management of EPS (e.g.,
diphenhydramine, benztropine, amantadine) also raises concern. Results of the Collaborative
Perinatal Project indicate that first-trimester exposure to diphenhydramine, the best studied of
these medications, is associated with major and minor congenital anomalies (Miller 1991; Wisner
and Perel 1988). A case–control study demonstrated a significantly higher rate of prenatal
diphenhydramine exposure among 599 infants with oral clefts than among 590 control infants
(Saxén 1974). Clinical studies of the teratogenic potential of benztropine and amantadine are
lacking, although laboratory animal studies indicate that amantadine is associated with an elevated
risk of congenital malformations (Hirsch and Swartz 1980). Perinatal toxicities, including neonatal
intestinal obstruction after gestational exposure to benztropine (Falterman and Richardson 1980)
and a possible neonatal diphenhydramine withdrawal syndrome manifested by tremulousness and
diarrhea (Parkin 1974), also warrant concern.
In summary, FGAs have been widely used for almost 50 years, and the paucity of data linking these
agents to either teratogenic or toxic effects suggests that the risk associated with these
medications is minimal. In particular, piperazine phenothiazines (e.g., trifluoperazine,
perphenazine) may have especially limited teratogenic potential (Rumeau-Rouquette et al. 1977).
Given the greater perinatal risks associated with anticholinergic medications, their use should be
avoided if possible. Consequently, FGAs used during the peripartum should be kept at the lowest
effective dose to minimize the need for adjunctive medications to manage EPS.
Early data regarding the teratogenic potential of the SGAs have been reassuring; however, the
limited volume of SGA data to date precludes definitive conclusions regarding their reproductive
safety. Therefore, the routine use of SGAs during pregnancy and lactation cannot yet be
recommended. Nonetheless, if a woman who is taking an SGA inadvertently conceives, a
comprehensive risk–benefit assessment may indicate that continuing the SGA (to which the fetus
has already been exposed) during gestation is preferable to switching to an FGA (to which the fetus
has not yet been exposed). Monitoring of blood glucose and weight gain should be an integral
aspect of clinical management during pregnancy.
ANXIOLYTICS
Benzodiazepines and antidepressants are the most commonly used medications for the treatment of
anxiety disorders. Benzodiazepines have a wide spectrum of clinical indications, including the full
array of anxiety disorders, insomnia, alcohol detoxification, muscle relaxation, adjunctive treatment
of seizure disorders, and conscious sedation during invasive medical procedures. A retrospective
survey of Medicaid prescription records for more than 100,000 pregnant women between 1980 and
1983 found that at least 2% were prescribed a benzodiazepine during gestation (Bergman et al.
1992). Table 64–6 lists the benzodiazepine and nonbenzodiazepine anxiolytics and
sedative-hypnotics used in the treatment of anxiety disorders and insomnia.
TABLE 64–6. Anxiolytic and hypnotic medications
Generic name Trade
name
Daily dosage (mg/
day)a
Risk
categoryb
American Academy of
Pediatrics ratingc
BenzodiazepinesPrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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Generic name Trade
name
Daily dosage (mg/
day)a
Risk
categoryb
American Academy of
Pediatrics ratingc
Alprazolam Xanax 0.5–6.0 Dm
Unknown, but of concern
Chlordiazepoxide Librium 15–100 D N/A
Clonazepam Klonopin 0.5–10 C N/A
Clorazepate Tranxene 7.5–60 D N/A
Diazepam Valium 2–60 D Unknown, but of concern
Estazolamd
ProSom 1–2 X N/A
Flurazepam Dalmane 15–30 Xm
N/A
Halazepamd
Paxipam 60–160 N/A N/A
Lorazepam Ativan 2–6 Dm
Unknown, but of concern
Oxazepam Serax 30–120 D N/A
Prazepamd
Centrax 20–60 D Unknown, but of concern
Quazepamd
Doral 7.5–30 Xm
Unknown, but of concern
Temazepam Restoril 15–30 Xm
Unknown, but of concern
Triazolam Halcion 0.125–0.25 Xm
N/A
Nonbenzodiazepines
Buspironed
BuSpar 20–30 Bm
N/A
Chloral hydrate Noctec 500–1,500 Cm
Compatible
Eszopiclone Lunesta 2–6 C N/A
Ramelteon Rozerem 8 C N/A
Zaleplon Sonata 5–20 C Unknown, but of concern
Zolpidem tartrated
Ambien 5–10 C N/A
Note. N/A = not available.
aDosing strategies adapted from Schatzberg and Cole 1991; Kaplan and Sadock 1993; and for newer
medications, the manufacturers’ package inserts.
bRisk category adapted from Briggs et al. 2005 and/or Physicians’ Desk Reference 2007; “m” subscript
indicates data taken from the manufacturer’s package insert.
cAmerican Academy of Pediatrics 2001.
dNot listed in Briggs et al. 1994. Risk category taken from Physicians’ Desk Reference (1992, 1993, 1994, and
1996 editions).
The earliest studies of benzodiazepine-associated teratogenic effects reported an increased risk of
oral clefts after in utero exposure to diazepam (Aarskog 1975; Saxén 1975; Saxén and Saxén
1974), but later studies failed to confirm this association (Entman and Vaughn 1984; Rosenberg et
- 1984; Shiono and Mills 1984). Prospective studies of first-trimester alprazolam exposure
encompassing approximately 1,300 pregnancies demonstrated no excess of oral clefts or other
congenital anomalies (Barry and St. Clair 1987; Schick-Boschetto and Zuber 1992; St. Clair and
Schirmer 1992). A subsequent meta-analysis by Altshuler et al. (1996), which pooled data from
several studies, demonstrated 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 consistent with the findings of a recent case–control study that reported no
difference in the rate of prenatal benzodiazepine exposure between more than 38,000 infants with
congenital anomalies and nearly 23,000 control children without congenital defects (Eros et al.
2002).Print: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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Longitudinal follow-up studies to evaluate the neurobehavioral effects of prenatal benzodiazepine
exposure are urgently needed. A “benzodiazepine exposure syndrome,” including growth
retardation, dysmorphism, and both mental and psychomotor retardation in infants exposed
prenatally to benzodiazepines (Laegreid et al. 1987), has been reported, although other
investigators have disputed this finding (Gerhardsson and Alfredsson 1987; Winter 1987). A second
group found no differences in the incidence of behavioral abnormalities at age 8 months or in IQ
scores at age 4 years among children exposed to chlordiazepoxide during gestation (Hartz et al.
1975). Nevertheless, a series of laboratory animal studies continues to raise concerns that prenatal
benzodiazepine exposure may be associated with long-term deficits in memory and learning ability
(Frieder et al. 1984; Hassmannova and Myslivecek 1994; Myslivecek et al. 1991).
Although the data regarding the teratogenic effects of benzodiazepine exposure remain somewhat
controversial, the occurrence of neonatal toxicity and withdrawal syndromes is well documented.
Numerous groups have described a floppy infant syndrome characterized by hypothermia, lethargy,
poor respiratory effort, and feeding difficulties after maternal use of benzodiazepines shortly before
delivery (Erkkola et al. 1983; J. N. Fisher et al. 1985; Haram 1977; Kriel and Cloyd 1982; McAuley et
- 1982; Sanchis et al. 1991; Speight 1977; Woods and Malan 1978). In a study of 53 infants born
to women who were administered lorazepam prior to delivery, term infants whose mothers had
taken oral lorazepam (up to 2.5 mg three times daily) showed no evidence of toxicity other than a
minimal delay in establishing feeding, but preterm infants and term infants whose mothers had
received larger intravenous doses of lorazepam exhibited a constellation of symptoms consistent
with floppy infant syndrome (Whitelaw et al. 1981). Neonatal withdrawal syndromes characterized
by restlessness, hypertonia, hyperreflexia, tremulousness, apnea, diarrhea, and vomiting have been
described in infants whose mothers were taking alprazolam (Barry and St. Clair 1987),
chlordiazepoxide (Athinarayanan et al. 1976; Bitnum 1969; Stirrat et al. 1974), or diazepam
(Backes and Cordero 1980; Mazzi 1977). Symptoms of these neonatal syndromes have been
reported to persist for as long as 3 months after delivery (for a review, see Miller 1991).
Pharmacokinetic studies during pregnancy indicate that benzodiazepines as a class readily traverse
the placenta and that some of these drugs may accumulate in the fetus after prolonged
administration (Mandelli et al. 1975; Shannon et al. 1972). For example, the fetal–maternal ratio of
plasma diazepam concentrations at delivery is generally greater than 1 (Erkkola et al. 1974), likely
a result, at least in part, of the fact that the fetal rate of metabolizing diazepam is considerably
slower than the adult rate (Mandelli et al. 1975). In addition, particularly high concentrations of
diazepam are sequestered in lipophilic fetal tissues, including the fetal brain, lungs, and heart
(Mandelli et al. 1975). A study reporting that fetal–maternal ratios of lorazepam are typically less
than 1 (Whitelaw et al. 1981) suggests that placental transfer of lorazepam is lower than that of
other benzodiazepines. Neonatal clearance of lorazepam is slow, with detectable levels evident 8
days after delivery (Whitelaw et al. 1981), and the clearance of chlordiazepoxide appears to be
even slower (Athinarayanan et al. 1976).
Buist et al. (1990) concluded that benzodiazepines at relatively low doses present no
contraindication to nursing. However, infants with an impaired capacity to metabolize
benzodiazepines may exhibit sedation and poor feeding even with low maternal doses (Wesson et
- 1985). Overall, benzodiazepines exhibit lower milk-to-plasma ratios than other classes of
psychotropics. For example, Wreitland (1987) found a milk-to-plasma ratio of 0.1–0.3 for oxazepam
and calculated that the infant daily dose via lactation is 1/1,000 of the maternal dose. The
percentage of the maternal dose of lorazepam to which a nursing infant is exposed has been
estimated to be 2.2% (Summerfield and Nielsen 1985).
In summary, benzodiazepines do not appear to carry a significant risk of somatic teratogenesis, but
neurobehavioral sequelae remain obscure. Because benzodiazepines are associated with a risk for
neonatal toxicity and withdrawal syndromes, these drugs should be tapered prior to delivery when
possible. Benzodiazepines should not, however, be abruptly withdrawn during pregnancy.
Clonazepam (FDA Category C) appears to have minimal teratogenic risks (Sullivan and McElhatton
1977). Because lorazepam and oxazepam are less dependent on hepatic metabolism, theyPrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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theoretically have less potential for fetal accumulation during pregnancy. Finally, when judicious
doses are utilized, benzodiazepines can be safely administered during lactation. However,
breast-feeding should be discontinued if an infant exhibits sedation or other signs of
benzodiazepine toxicity, regardless of maternal dose.
Recently, newer agents, including buspirone, a nonbenzodiazepine anxiolytic, and zolpidem and
zaleplon, nonbenzodiazepine hypnotics, have been added to the psychotropic armamentarium.
There are no published reports of the use of these agents in pregnancy or lactation.
FUTURE DIRECTIONS AND GENERAL RECOMMENDATIONS
The development of treatment guidelines for mental illness during pregnancy and lactation
continues to be hampered by the haphazard accrual of research data with inconsistent
methodologies. Whereas there are limited clinical data to support the contention that most
psychotropic medications are teratogenic, laboratory animal studies, which typically attain
maternal concentrations markedly higher than those achieved in clinical care, demonstrate clear
somatic and neurobehavioral teratogenic effects (Elia et al. 1987). Such discrepancies between the
clinical and preclinical data hinder efforts to construct reliable treatment recommendations.
Because pregnant and nursing women are generally excluded from clinical trials of pharmacological
agents, definitive clarification is unlikely to be forthcoming in the near future.
This raises questions about the future of clinical research in pregnancy and lactation. Some
investigators have argued that conducting clinical trials in pregnant and nursing women is on its
face unethical (Kerns 1986). Although such a view is understandable, the failure to conduct such
studies may deprive some women of available treatment and may over time increase the overall
risk to women and their infants. Alternative ethical positions regarding perinatal clinical research
have been raised. In an investigation of alternative interventions following evidence of in utero
failure to thrive, obstetrical researchers have advocated application of the uncertainty principle
(Peto and Baigent 1998) to the ethical question of clinical research during gestation (Vail et al.
2001). The uncertainty principle mandates that a patient, even a pregnant patient, should be
ethically eligible to participate in a randomized clinical trial if the preferred clinical course of action
is uncertain. Because the relative risks to fetus and infant of exposure to maternal psychiatric
illness compared with exposure to maternal psychotropic medication are often unclear, the
uncertainty principle may be equally applicable to the study of psychiatric treatment during
pregnancy and lactation. These questions must be deliberated so that perinatal psychiatric research
can be advanced in an ethically responsible, yet expeditious, manner.
Meanwhile, given the current state of our knowledge, a thorough risk–benefit analysis should be
completed for each woman presenting with concerns of psychiatric illness during pregnancy and
lactation. This risk–benefit analysis should consider factors such as maternal psychiatric history,
the potential deleterious effects of untreated illness on both the mother and her infant, and the
potential adverse effects of offspring exposure to different classes of psychotropic medications
within particular developmental windows. Table 64–7 and Table 64–8 summarize the basic
risk–benefit assessments for pregnancy and lactation, which should be individualized according to
the patient’s history and treatment goals.
TABLE 64–7. Risk–benefit assessment for pregnancy: summary of facts
Known
85% of all pregnancies produce live births.
7%–14% of deliveries are preterm.
2%–4% of live births result in infants with significant malformations, and up to 12% have minor anomalies.
>60% of all women take at least one prescription medication during pregnancy.
In the ideal pregnancy, as defined by the Centers for Disease Control and Prevention, maternal weight is
±15% of ideal body weight, and the mother was taking prenatal vitamins with folic acid for 6 weeks beforePrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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conception.
Most women learn of pregnancy at 5–8 weeks’ gestation and therefore may be past the window of risk for
fetal anomalies associated with psychotropic medications.
Pregnancy is not protective against psychiatric illness.
Increasing data
Major depressive episodes occur with similar incidence during pregnancy as during nongravid periods.
Obsessive-compulsive disorder may have its onset or may worsen during pregnancy.
The incidence of psychotic disorders varies throughout pregnancy; there are limited data suggesting a need
to decrease dosage of antipsychotic medications.
The teratogenic risk of psychotropic medications has been historically overestimated.
Increasing data on obstetrical outcome and follow-up of infants of mothers taking psychotropic medications
are comparable in study sample sizes to data on most other prescription drugs.
Untreated maternal mental illness may adversely affect obstetrical outcome and infant development.
Unknown
The long-term neurobehavioral effects of in utero exposure to psychotropic medications are unknown,
although initial studies have not reported adverse effects for several medications.
TABLE 64–8. Risk–benefit assessment for lactation: summary of facts
Known: postpartum
>60% of women plan to breast-feed.
5%–17% of all nursing women take a prescription medication during breast-feeding.
12%–20% of nursing women smoke cigarettes.
Breast-feeding is supported by numerous professional organizations as the ideal form of nutrition for the
infant.
The postnatal period is a high-risk time for onset or relapse of psychiatric illness.
All psychotropic medications studied to date are excreted in breast milk.
Increasing data
Untreated maternal mental illness has an adverse effect on mother–infant attachment and later infant
development.
The adverse effects of psychotropic agents on infants are limited to case reports.
The nursing infant’s daily dose of psychotropic agents is less than the maternal daily dose.
The nursing infant’s exposure to psychotropic medications is less than the fetal exposure.
Psychotropic medications are excreted in breast milk with a specific individual time course, allowing the
minimization of infant exposure with continuation of breast-feeding.
Unknown
The long-term neurobehavioral effects of infant exposure to psychotropic medications through breast-feeding
are unknown.
Initial Treatment Approach for Women of Reproductive Age
When treating women of reproductive age, it is advisable to assume at all times that pregnancy is
imminent. More than 50% of pregnancies in the United States are unplanned; however, it is not
cost effective to screen for pregnancy at all routine outpatient psychiatric visits.
By factoring reproductive safety considerations into all treatment decisions for women ofPrint: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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child-bearing age, whether or not the patient is pregnant or actively trying to conceive, clinicians
can maximize reproductive safety when inadvertent conception occurs.
Assuming that the clinician has already exhausted reasonable nonpharmacological interventions,
we offer the following general treatment recommendations for the care of a patient with a mental
disorder during pregnancy and lactation.
Informed Consent
It is impossible to provide an exhaustive list of all the risks for any given psychotropic medication,
but the evidence (or lack thereof) for adverse activational effects (e.g., toxicity, withdrawal) and
organizational effects (e.g., somatic teratogenesis, neurobehavioral teratogenesis) of each
medication should be reviewed. It is equally important to discuss with the patient the risks of the
untreated illness to both the mother and the infant. Finally, it is important to document that other
treatment modalities have been attempted or considered.
Choice of Medication
When the decision is made to use a psychotropic medication, the goal is to maximize efficacy so
that offspring exposure to maternal mental illness can most reliably be eliminated while avoiding
offspring exposure to multiple medications. The most important factor in choosing a medication is
therefore treatment history. If a patient has a history of a positive response to a particular
medication, a novel agent should not be started during pregnancy or lactation. Such an approach
only increases the risk of offspring exposure to multiple medications and continued maternal
illness. Prior offspring exposures also warrant consideration. If a patient was taking a particular
medication earlier in gestation (and it was efficacious), continuing or restarting that medication is
usually preferable to switching to a new medication. Switching medications in this manner
automatically increases the child’s number of medication exposures and may extend the duration of
maternal illness. In addition to data from the treatment history, medications with the following
characteristics should be sought:
Greatest reproductive safety database—Medications with some published pregnancy and/or lactation
safety data are preferred. Being the first to use a particular medication in pregnancy or nursing is not
advisable. Medications that have been available for a longer time usually have a larger database.
Lower FDA risk category (B > C > D)—The FDA is empirically conservative and has access to the
greatest amount of pre- and postmarketing data. Although this rating may be controversial for some
medications, medicolegal considerations support this approach.
Few or no metabolites—Data from both pregnancy and lactation suggest that drug metabolites, which
typically have longer elimination half-lives relative to the parent drug, may achieve higher steady-state
levels in both fetal circulation and nursing infant serum. The issue of active versus inactive metabolites
is unresolved with respect to teratogenic effects.
Fewer side effects and drug interactions—Medications with fewer hypotensive and anticholinergic side
effects are preferable. Additionally, the effect on seizure threshold and potential interaction with
commonly used obstetrical anesthetic and analgesic agents should be minimized.
Concordant data—Medications with conflicting data should be avoided; a clinically comparable
alternative should be used, if available. Adherence to this recommendation also should reduce any
potential legal liability.
Dosage
The goal of treatment during pregnancy and lactation is adequate treatment for syndrome
remission. Partial treatment only enhances risk by continuing to expose mother and infant to both
illness and medications. The minimum effective dose should be maintained throughout treatment,
and the clinician should remain mindful that dosage requirements might change during pregnancy.
To minimize the potential for neonatal withdrawal and maternal toxicity after delivery, careful
monitoring of side effects and serum concentrations may be indicated. Adjusting the feeding and
dose schedule and discarding the peak breast milk concentrations for several agents can minimize
exposure of nursing infants.Print: Chapter 64. Psychopharmacology During Pregnancy and Lactation http://www.psychiatryonline.com/popup.aspx?aID=437201&print=yes…
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Communication With Other Physicians
It is highly recommended that the psychiatrist discuss the medication and potential interactions
with both the patient’s obstetrician and, if the patient chooses to nurse, her infant’s pediatrician.
Monitoring Exposure of Nursing Infants
Most clinical laboratory assays lack the sensitivity necessary to detect the typical serum
concentrations of nursing infants, and even detectable infant serum concentrations are
uninterpretable; therefore, infant serum monitoring is not routinely indicated for most psychotropic
medications. One noteworthy exception is the child who is exhibiting potential medication side
effects. A small proportion of breast-feeding children may be metabolic outliers for a particular
medication and thus may accumulate especially high serum concentrations. If there is a reasonable
index of suspicion that the child’s symptoms represent a medication effect, then breast-feeding
should be discontinued, regardless of infant serum concentration. Consequently, we recommend
checking an infant’s serum concentration when the child is suspected to be experiencing a
medication side effect. Furthermore, infant serum concentrations and other laboratory studies (e.g.,
blood counts, electrolytes, hepatic profiles) should be monitored when nursing mothers are taking
medications (e.g., certain anticonvulsants) with low therapeutic indices or known systemic
toxicities.
CONCLUSION
The use of pharmacological therapies during pregnancy and lactation will continue to be a complex
clinical endeavor that will certainly generate anxiety among patients and clinicians. There is a
propensity in the medical literature and the news media to emphasize adverse outcomes, whereas
negative study results seldom garner much attention. This is true for both medication and illness
exposures. Consequently, clinicians must practice with access to incomplete information.
Thoughtful consideration of “pregnancy potential” in the treatment planning for women of
reproductive capacity serves to reduce the consternation precipitated by a positive pregnancy test.
By inquiring routinely about birth control during all visits when treating women during the
reproductive years, clinicians can provide a conduit for discussion and treatment planning that aims
to reduce risk for mother and child.
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Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.
Course Content
Introduction to Medication Safety in Pregnancy and Lactation
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Understanding the Basics of Medication Safety
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Pharmacokinetics and Pharmacodynamics in Pregnancy
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Common Medication Risks During Pregnancy
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Quiz on Medication Safety Basics
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Guidelines for Medication Use in Lactation
Understanding Pharmacokinetics and Pharmacodynamics During Pregnancy
Identifying and Managing Risks: Teratogenic and Lactogenic Medications
Safe Medication Guidelines and Best Practices for Healthcare Providers
Case Studies and Practical Applications in Pregnancy and Lactation
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