Shona L. Ray-Griffith, M.D.
D. Jeffrey Newport, M.D.
Zachary N. Stowe, M.D.
The management of mental illness during pregnancy and lactation is a complicated clinical challenge encompassing two concomitant medical conditions (i.e., pregnancy and a psychiatric disorder) that requires consideration of the welfare of at least two patients (i.e., mother and child). Various nonpharmacological treatment options for maternal mental illnesses during the antepartum and postpartum periods are beyond the scope of this chapter. Viable treatment options must be available, accessible, affordable, and effective for the illness, and in many cases, this may involve pharmacotherapy. Unfortunately, definitive treatment guidelines for perinatal psychotropic medications remain unavailable. In the two decades since the initial iteration of this chapter, there has been an enormous expansion in the reproductive safety literature focusing on psychotropic medications.
In this chapter, we posit that minimizing infant exposure to the purported risks of both maternal mental illness and psychotropic medications is the preeminent clinical objective. Investigations and reviews focusing on reproductive safety of psychotropic medications typically provide only cursory information about the effect of illness, rely on maternal self-report to address concomitant fetal exposures, and use extensive statistical interrogation that may not have meaningful clinical import.
Space limitations preclude a comprehensive review of each class of psychotropic medications; rather, we review the available data with an emphasis on providing the clinician with the requisite components to interpret and apply medication reproductive safety data in the clinical decision. Also included are data regarding pharmacokinetic alterations during pregnancy and lactation and the potential clinical relevance of these data for psychotropic dosage management. The chapter concludes with a series of potential modifications of previously suggested treatment guidelines to optimize clinical decisions and a list of resources.
The clinical management of any medical condition during pregnancy and lactation must consider the reproductive safety of available therapies, the likelihood of illness recurrence without continued treatment, and the potential effect of untreated maternal illness. Minor ailments, such as headaches and nausea, are routinely treated during pregnancy with medications that often have limited reproductive safety data. Recent data indicate that 90% of pregnant women take one medication and that more than 50% take four or more medications (Ayad and Costantine 2015; Mitchell et al. 2011), confounding the ability to isolate the effect of an individual medication. Women with mental illness are frequently encouraged to discontinue psychotropic medication during pregnancy, and pregnancy is associated with high rates of both antidepressant discontinuation (Petersen et al. 2011) and nonadherence to prescribed psychiatric medications (Lupattelli et al. 2015). The desire to avoid offspring exposure to psychotropic medication is laudable; however, recommendations to discontinue medication are often made with limited knowledge of the potential risk of recurrent illness and of the effect of maternal illness on obstetrical and child outcomes.
An assessment of 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 experiencing illness recurrence or exacerbation by carefully synthesizing prevalence data from epidemiological studies with evidence from the patient’s own history. Patients with frequent episodes of psychiatric illness, a declining course, or a history of perinatal illness are more likely to become ill in the current pregnancy or the postpartum period.
Investigations of the incidence and course of maternal mental illness have found no evidence that mental illness lies quiescent during pregnancy and considerable evidence that the postpartum period entails heightened vulnerability. The incidence of depression during the perinatal period is comparable to that in other populations (Buesching et al. 1986; Cutrona 1983; Kumar and Robson 1984; Manly et al. 1982; O’Hara et al. 1982; Watson et al. 1984). Two large studies, collectively comprising 122,400 women, found a 14%–20% incidence of prenatal major depressive disorder (MDD) (Marcus et al. 2003; Oberlander et al. 2006). In fact, 11% of women presenting for evaluation of postpartum depression report symptom onset before delivery (Stowe et al. 2005). Discontinuation of treatment during pregnancy in women with histories of MDD or bipolar disorder increases the risk of episodes during pregnancy (Cohen et al. 2006; Newport et al. 2008c; Viguera et al. 2007b). However, one group failed to identify an increase in depression with antidepressant discontinuation (Yonkers et al. 2011).
Psychotic disorders also may worsen during pregnancy (Glaze et al. 1991; McNeil et al. 1984a, 1984b). The course of obsessive-compulsive disorder (OCD) appears to be variable during pregnancy, with 14%–33% of patients experiencing exacerbation (Guglielmi et al. 2014; Jenike et al. 1990; Williams and Koran 1997). Women with OCD who continued pharmacotherapy throughout the perinatal period did not have a significant change in symptoms (House et al. 2016). Panic disorder during gestation is also variable, with 19% of patients experiencing more frequent panic attacks and 30% having less frequent attacks (Hertzberg and Wahlbeck 1999; Wisner et al. 1996a). Finally, obstetrical trauma and pregnancy loss can precipitate posttraumatic stress disorder (PTSD) (Allen 1998; Engelhard et al. 2001; Fones 1996), with PTSD symptoms following stillbirth persisting into the next pregnancy (Turton et al. 2001).
Postpartum mental illness has been documented for millennia and is substantiated by modern research. Early studies reported that psychiatric hospitalization rates increased during the first postpartum month (Kendler et al. 1993) and noted that up to 12.5% of all psychiatric admissions for women occurred during the first postpartum year (Duffy 1983). Postpartum depression affects 10%–22% of adult mothers and up to 26% of adolescent mothers (Stowe and Nemeroff 1995; Troutman and Cutrona 1990). Women with bipolar disorder also face considerable postpartum risks (Kendell et al. 1987; Targum et al. 1979). Postpartum OCD, often manifested by violence and contamination obsessions, may affect 9%–16% of new mothers (Miller et al. 2013; Zambaldi et al. 2009), with one-third experiencing new-onset OCD symptoms during the postpartum period (Miller et al. 2013). Nearly one-half of women with preexisting OCD report an exacerbation of symptoms during the postnatal period (Guglielmi et al. 2014). Thankfully, postpartum psychosis, the most severe postpartum syndrome, is a rare condition; however, its prevalence is at least 100-fold higher among women with bipolar disorder than among those with other affective or psychotic disorders (Brockington et al. 1982; Kendell et al. 1987).
Not only the likelihood but also the potential effect of maternal mental illness on maternal and child well-being must be considered. Most studies focusing on obstetrical and developmental outcomes have focused on the effect of maternal depression, anxiety, and stress. Often these terms are used interchangeably, with most previous investigations focusing on maternal symptoms rather than diagnosis. Given the high rate of comorbidity of mood and anxiety disorders in women, the distinction between maternal depression and maternal anxiety may not have clinical import. The effect of maternal unipolar versus bipolar depression during gestation remains unexplored. Maternal depression during pregnancy has been associated with slower fetal growth (Hedegaard et al. 1996; Schell 1981; Uguz et al. 2013); increased risk of preterm delivery and other obstetrical complications (Korebrits et al. 1998; Liu et al. 2016; Oberlander et al. 2006; Orr and Miller 1995; Perkin et al. 1993; Steer et al. 1992; Uguz et al. 2013; Venkatesh et al. 2016); and long-standing cognitive, behavioral, and emotional changes in the offspring (Luoma et al. 2001, 2004; Meijer 1985; Nulman et al. 2002; O’Connor et al. 2003; Søndergaard et al. 2003; Stott 1973). Similarly, prenatal panic disorder is associated with higher rates of preterm birth and low birth weight (Uguz et al. 2013), and maternal anxiety is associated with higher rates of attentional problems (Van den Bergh and Marcoen 2004). Depressed pregnant women are less compliant with prenatal vitamins and obstetrical care; receive poorer nutrition; and have greater use of prescription opiates, hypnotics, alcohol, tobacco, and illicit substances (Newport et al. 2012; Zuckerman et al. 1989). Finally, depressed pregnant women, and those with PTSD, often experience suicidal thoughts (Newport et al. 2007b; Smith et al. 2006) and may engage in suicidal behavior.
Postpartum depression also carries deleterious consequences for infant development. As early as 3 months, infants of depressed mothers show less facial expression, less head orientation, less crying, and more fussiness compared with infants of nondepressed mothers (Martinez et al. 1996). As they age, the children of depressed mothers show ineffective emotional regulation (Downey and Coyne 1990), delayed motor development (Galler et al. 2000), poor interpersonal skills (Jameson et al. 1997), lower self-esteem (Downey and Coyne 1990), increased 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). Children of depressed mothers are ultimately more likely to experience emotional instability, to have behavior problems and suicidal behavior, and to require psychiatric treatment (Lyons-Ruth et al. 2000; Weissman et al. 1984).
Antepartum 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; Taylor et al. 2015) and may have bizarre ideas about contraception, pregnancy, and child rearing that complicate their perinatal course (McEvoy et al. 1983; Riordan et al. 1999). Maternal schizophrenia has been associated with elevated rates of obstetrical complications (Bennedsen et al. 2001; Miller and Finnerty 1996) and fetal and neonatal death (Rieder et al. 1975).
The clinical data regarding the obstetrical and developmental consequences of maternal mental illness are supported by an extensive line of laboratory animal research. Preclinical studies across a variety of species indicate that stress during pregnancy and the early postpartum period adversely affects offspring growth, learning ability, and postnatal development, producing a range of biobehavioral aberrations that may persist into adulthood (for a review, see Newport et al. 2002).
Clinical decisions during pregnancy and the postpartum period must consider the risks of fetal and neonatal medication exposure. These risks may be broadly classified as acute or developmental adverse effects (Table 57–1). Acute effects are typically immediately evident and are not dependent on the developmental window of exposure. Examples 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 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 central nervous system (CNS) development continues long after delivery, the fetus and breast-feeding infant are equally vulnerable to the theoretical risks of neurobehavioral teratogenesis.
Acute |
Developmental |
|
Pregnancy |
Neonatal toxicity |
Somatic teratogenesis |
Neonatal withdrawal |
Neurobehavioral teratogenesis |
|
Drug–drug interactions |
||
Lactation |
Infant toxicity |
Neurobehavioral teratogenesis |
Drug–drug interactions |
A decision to use psychotropic medication during pregnancy and/or lactation will carry complicated clinical, ethical, and potentially legal consequences. Although a rapidly expanding base of reproductive safety data has begun to address many of these concerns, review of the current literature reveals numerous methodological problems. The most glaring deficiencies are a frequent lack of appropriate control groups and an overreliance on retrospective data collection—deficiencies shown to introduce systematic biases that potentially lead to overestimation of the effect of psychotropic exposure (Newport et al. 2008a). In particular, most studies report outcomes of “depressed–treated women compared with nondepressed–untreated women,” eliminating any opportunity to disentangle treatment and illness effects on outcomes (McDonagh et al. 2014). Despite these limitations, ethical considerations preclude implementation of randomized controlled trials to evaluate psychotropic efficacy and safety during pregnancy and lactation. Therefore, the reproductive safety database for psychotropic medications is composed of a diverse conglomeration of case reports, case series by pharmaceutical companies and academic centers, birth registries, retrospective surveys, reports from teratology or poison control centers, clinical and preclinical pharmacokinetic investigations, review articles summarizing data from these sources, and the U.S. Food and Drug Administration (FDA) medication safety rating systems (Table 57–2).
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. |
|
In addition to the available reproductive safety data, the patient’s clinical history is important in treatment selection. If the rationale for psychotropic therapy during pregnancy is to protect the mother and the child from the harmful sequelae of maternal mental illness, then a history of treatment response or nonresponse is critical. Regardless of the favorability of its reproductive safety profile, a medication that has been ineffective for or poorly tolerated by a particular patient is of little value during the reproductive period.
On June 30, 2015, the FDA’s new Pregnancy and Lactation Labeling Rule became effective, with a plan for staggered implementation over the following 3–5 years. The new labeling rule eliminates the pregnancy letter category previously used (see Table 57–2) and provides the following information for the use of medications in pregnancy and delivery when available: 1) pregnancy exposure registry, 2) narrative risk summary, 3) clinical considerations, and 4) data description of supporting evidence. Specifically, the clinical considerations are as follows: disease-associated maternal and embryo/fetal risk, dosage adjustment, maternal adverse reactions, fetal/neonatal adverse reactions, and labor or delivery. Two new sections also summarize evidence for lactation and evidence for males and females of reproductive potential. The labeling will be updated as evidence emerges but is required only for medications receiving FDA approval after June 30, 2001. Medications approved prior to this date are strongly encouraged to comply with the new recommendations but are not required to do so.
The result of these changes is two unintegrated systems for reproductive safety ratings that present a challenge for clinicians. Similarly, the rate of accrual for reproductive safety information in humans is variable and all obtained postmarketing. The new safety ratings will arguably have greater clinical import, because the older system often provided more favorable ratings to newer medications with very limited information and was often overvalued in clinical decisions. For example, a clinician may be tempted to use buspirone (Category B) over clonazepam (Category D) for panic disorder despite the very limited information underlying buspirone’s preferable pregnancy rating and its lack of efficacy for panic disorder. Similarly, lurasidone (Category B) may be used in lieu of lithium (Category D) for bipolar depression despite the virtual absence of human data on lurasidone’s safety during gestation and the lack of published clinical experience in the antepartum and postpartum periods.
Prescribing the minimal effective dosage is especially important during pregnancy and lactation. On learning that a patient is pregnant, clinicians and patients often instinctively lower psychotropic dosages in an effort to reduce fetal exposure, but indiscriminate dosage reduction may increase the vulnerability to relapse. If the therapeutic objective is to eliminate the child’s exposure to maternal illness while minimizing the child’s psychotropic exposure, then dosage management must be informed by an understanding of the factors governing the alterations in drug disposition across gestation, the placental passage, and excretion into breast milk.
Dosage adjustments may be required to maintain medication efficacy during pregnancy. For example, it may be necessary to increase the dosage of tricyclic antidepressants (TCAs) to approximately 1.6 times the preconception dosage to maintain therapeutic concentrations in late pregnancy (Altshuler et al. 1996; Wisner et al. 1993). Small studies examining selective serotonin reuptake inhibitors (SSRIs) have reported clearance changes over the course of pregnancy and the necessity for dosage adjustments in response to increased maternal symptoms (Freeman et al. 2008; Hostetter et al. 2000; Sit et al. 2008). However, the pattern of dosage adjustment during gestation is not uniform for all medications. For example, among anticonvulsant and mood-stabilizing medications, serum concentrations of lamotrigine (Ohman et al. 2000; Pennell et al. 2004; Polepally et al. 2014; Tran et al. 2002) and valproate (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 al. 1979; Lander et al. 1981; Omtzigt et al. 1993; Otani 1985; Tomson et al. 1994; Yerby et al. 1985) undergo smaller changes that are primarily evident only in late pregnancy. These alterations in drug concentrations and dosing requirements likely result from effects 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. Ultimately, an improved understanding of the factors governing perinatal pharmacokinetic and pharmacodynamic alterations may enable the development of personalized dosing strategies during gestation.
The level of fetal psychotropic exposure is another key consideration. All psychotropics studied to date cross the human placenta; yet there are significant differences in placental passage rates. Bidirectional placental transfer is mediated primarily by simple diffusion, and determinants of the transplacental diffusion rate include molecular weight, lipid solubility, degree of ionization, and protein-binding affinity (Audus 1999; W.M. Moore et al. 1966; Pacifici and Nottoli 1995). In addition, placental P-glycoprotein (P-gp), which actively transports substrates from the fetal to the maternal circulation, is likely a key determinant of fetal psychotropic exposure. Consequently, medications with greater affinity for P-gp should be associated with lower fetal-to-maternal medication ratios, which, in fact, has been confirmed in an investigation of antipsychotic placental passage (Newport et al. 2007a). Furthermore, clarification of the factors governing placental passage may ultimately contribute to the development of psychotropic agents with minimal rates of placental transfer (Wang et al. 2007).
Fetal plasma concentrations are not, however, the ultimate measure of functional psychotropic exposure and may even underestimate the more critical measure of fetal brain concentration. Certain physiological attributes of the human fetus, including high cardiac output, increased blood–brain barrier permeability, low plasma protein concentrations and plasma protein binding affinities, and low hepatic enzyme activity (Bertossi et al. 1999; Morgan 1997; Oesterheld 1998), may produce higher-than-anticipated fetal CNS concentrations of psychotropic medications than might be anticipated from circulating levels. Preclinical investigations from our group have found that transplacental passage of psychotropic drugs results in high levels in fetal CNS tissues and significant binding at neurotransmitter receptor and transporter sites (Capello et al. 2011).
Similar considerations apply when endeavoring to minimize the psychotropic exposure of nursing infants. Because the neonate has relatively low hepatic enzyme activity (Warner 1986) and low glomerular filtration and tubular secretion rates (Welch and Findlay 1981), psychotropic exposure may be higher than anticipated for breast-fed infants. A model to predict rates of breast-milk excretion from characteristics of the molecular structure of candidate medications has been proposed (Agatonovic-Kustrin et al. 2002). Such models may allow clinicians to estimate a nursing infant’s exposure without subjecting the infant to invasive procedures.
The use of antidepressant medications in pregnancy has been extensively reviewed (McDonagh et al. 2014; Yonkers et al. 2014), and multiple meta-analyses have found no association between antidepressant use in pregnancy and congenital malformations and/or major malformations (Einarson and Einarson 2005; Grigoriadis et al. 2013). We include an overview of the individual categories of antidepressants in this section.
Reproductive safety data on the SSRIs have rapidly accrued over the past two decades. A recent meta-analysis investigating SSRIs found no overall association with birth defects (Reefhuis et al. 2015). Despite overall reassuring data, some concerns with specific SSRIs have emerged. Reefhuis et al. (2015) found an increased risk of anencephaly, atrial septal defects, right ventricular outflow tract obstruction, gastroschisis, and omphalocele with paroxetine and an increased risk of right ventricular outflow track obstruction defects and craniosynostosis with fluoxetine. Analysis of a managed care database identified a higher odds ratio (OR) for cardiovascular malformations with exposure to paroxetine compared with other antidepressants (GlaxoSmithKline 2005). Three large case–control studies of SSRI exposures (Alwan et al. 2007; Bérard et al. 2007; Louik et al. 2007) reported largely reassuring results, although with some concerns. The first (Alwan et al. 2007) reported small increases in the risk of three uncommon malformations—anencephaly (OR=2.4), craniosynostosis (OR=2.5), and omphalocele (OR=2.8) associated with use of fluoxetine, sertraline, or paroxetine. The second study (Louik et al. 2007) reported an increased risk of omphalocele (OR=5.7) and septal defects (OR=2.0) with sertraline exposure and of right ventricular outflow tract obstruction defects (OR=3.3) with paroxetine exposure. The third study (Bérard et al. 2007) found no evidence of increased risk of cardiovascular or other malformations with SSRI use, unless women were taking paroxetine at daily dosages of 25 mg or greater, in which case their infants were at an increased risk of cardiovascular (OR=3.1) and overall malformations (OR=2.2). In the Medicaid Analytic eXtract (MAX) database, Huybrechts et al. (2014a) found an overall adjusted risk of 1.06 (95% confidence interval [CI]=0.93–1.22) for any cardiac defect with use of an SSRI in the first trimester; a risk of 1.07 (95% CI=0.59–1.93) for a right ventricular outflow tract obstruction with use of paroxetine; and a risk of 1.04 (95% CI=0.76–4.41) for a ventricular septal defect with use of sertraline.
A handful of studies have systematically assessed child development after prenatal exposure to antidepressants. Two studies (Nulman et al. 1997a, 2002) assessed children (ages 15–86 months) who had been prenatally exposed to fluoxetine (n=90) or TCAs (n=126), collectively comparing them with nonexposed children (n=120). No differences were observed with respect to global cognitive, psychomotor, or language development. The same research group compared children exposed to SSRIs in utero with children of mothers without depression or SSRI use and found no difference in IQ or behavior (Nulman et al. 2012). A similar study that compared children (ages 6–40 months) with prenatal SSRI exposure (n=31) and children without antidepressant exposure (n=13) observed no differences in global cognition but reported lower psychomotor scores for the SSRI-exposed children (Casper et al. 2003).
Unfortunately, limitations of these studies render their implications speculative at best. Children were not age-matched in any of these studies, and the predictive validity of measured indices across child developmental stages has not been established (Black and Matula 2000). In addition, the Casper et al. (2003) study was confounded by the fact that 29% of the participants were enrolled after delivery, which could have resulted in an overrepresentation of children with developmental abnormalities.
A study of 69 (46 SSRI-exposed; 23 nonexposed) children that eliminated the age confound by examining the children at two fixed time points—ages 2 months and 8 months—reported no differences between the exposed and the nonexposed children in cognitive or motor development (Oberlander et al. 2004). Finally, an assessment of 4-year-old children found no evidence that prenatal SSRI exposure affected externalizing or attentional behaviors (Oberlander et al. 2007). It is noteworthy that several of these developmental studies involved a significant overlap in the cohort of children, thereby limiting further the cumulative sample size of extant follow-up studies.
Multiple studies have examined the association between maternal antidepressant use and autism spectrum disorders in offspring. The results were mixed, with four studies finding an association between antidepressant exposure and autism (Boukhris et al. 2016; Croen et al. 2011; El Marroun et al. 2014; Gidaya et al. 2014) and six finding no such association (Castro et al. 2016; Clements et al. 2015; Harrington et al. 2014; Hviid et al. 2013; Rai et al. 2013; Sørensen et al. 2013). In addition, close inspection reveals evidence of probable detection bias in at least some of these studies, with nonminority children of well-educated mothers overrepresented in the autism case subjects (Croen et al. 2011). These discordant and arguably flawed data preclude definitive conclusions regarding any autism risk attributable to prenatal antidepressant exposure.
Data regarding the effect of prenatal antidepressant exposure on rates of miscarriage, preterm delivery, and low birth weight are decidedly mixed. Some investigators have reported an association between antidepressant exposure and such outcomes (Chambers et al. 1996; Chun-Fai-Chan et al. 2005; Oberlander et al. 2006; Pastuszak et al. 1993; Ross et al. 2013; Simon et al. 2002), whereas others have not (Einarson et al. 2001, 2003; Kulin et al. 1998; Sivojelezova et al. 2005; Venkatesh et al. 2016). Multiple recent meta-analyses found an association between prenatal antidepressant exposure and preterm delivery (Huang et al. 2014; Huybrechts et al. 2014b; Ross et al. 2013) and low birth weight (Huang et al. 2014; Ross et al. 2013). Interpretation is complicated by other reports that link prenatal maternal stress and/or depression with prematurity and low birth weight (Orr et al. 2002; Steer et al. 1992). As a result, no definitive conclusions can be drawn as to whether antidepressant use during gestation conveys an adverse effect on fetal growth or the timing of parturition.
Finally, concerns have been expressed regarding neonatal SSRI syndromes, typically manifested by transient symptoms including respiratory difficulty and tremulousness (Moses-Kolko et al. 2005). Most controlled prospective studies suggest that SSRI exposure is associated with 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 study found no such association (Maschi et al. 2008). Closer scrutiny of these reports identified a cadre of methodological shortcomings. Limited effort was made to mask those evaluating the neonates as to exposure status, only one study (Oberlander et al. 2006) controlled for the effect of maternal mental illness, and key confounding factors such as gestational age at delivery and maternal use of other medications and/or habit-forming substances were either ignored altogether or controlled only in a rudimentary manner.
A case–control study comparing the exposures of neonates who “required observation” with those of “healthy” neonates (Misri et al. 2004) underscores the importance of controlling for confounding factors. In this study of antidepressant-exposed neonates (n=46) born to mothers with MDD, the mothers of infants who required observation had more severe symptoms of depression and anxiety, were more likely to have a comorbid anxiety disorder, and were exposed to higher dosages of clonazepam.
Debate has also focused on a more serious neonatal concern—a possible connection between late-pregnancy SSRI exposure and persistent pulmonary hypertension of the neonate (PPHN). A case–control study (Chambers et al. 2006) of 1,213 neonates (377 with PPHN) reported data supporting an association between SSRI exposure and PPHN (OR=6.1). However, a similar study of 1,104 SSRI-exposed neonates and 1,104 matched control subjects found no association (Andrade et al. 2009). A case–control study (Källén and Olausson 2008) of more than 831,000 neonates (of whom 506 were diagnosed with PPHN) from the Swedish Medical Birth Register observed a more modest association (OR=2.9). The overall rate of PPHN in this population-wide study was approximately 1 in 2,000, and the rate of PPHN with SSRI exposure was approximately 1 in 600. In the largest study to date, involving more than 3 million women, the adjusted odds of PPHN, after controlling for depression, was 1.10 (95% CI=0.77–1.35) for SSRI use and 1.14 (95% CI=0.74–1.74) for non-SSRI antidepressant use (Huybrechts et al. 2015). Finally, a study concluded that PPHN was associated not with SSRI exposure but rather with cesarean delivery prior to onset of labor (Wilson et al. 2011), underscoring the importance of controlling for all potential confounding factors. Overall, the SSRI-PPHN data are mixed, with a very low absolute rate of PPHN.
Pharmacokinetic data regarding the placental passage of SSRI antidepressants remain limited. However, existing studies have found that mean fetal-to-maternal ratios for numerous SSRIs and their active metabolites are uniformly less than 1.0, although considerable differences exist among agents (Hendrick et al. 2003; Rampono et al. 2009).
Published reports pertaining to SSRIs and lactation now encompass the largest data set for medications during breast feeding, including infant serum measures, breast milk concentrations, and pharmacokinetic studies of excretion. There are now published investigations for all of the SSRIs, including sertraline (Altshuler et al. 1995; Birnbaum et al. 1999; Dodd et al. 2000; Epperson et al. 1997, 2001; Hendrick et al. 2001a; Kristensen et al. 1998; Mammen et al. 1997; Stowe et al. 1997, 2003; Wisner et al. 1998), fluoxetine (Birnbaum et al. 1999; Burch and Wells 1992; Goldstein et al. 1997; Hendrick et al. 2001b; Kristensen et al. 1999; Lester et al. 1993; Suri et al. 2002; Taddio et al. 1996; Yoshida et al. 1998a), paroxetine (Birnbaum et al. 1999; Hendrick et al. 2001a; Ohman et al. 1999; Spigset et al. 1996; Stowe et al. 2000), escitalopram (Rampono et al. 2006), fluvoxamine (Hendrick et al. 2001a; Piontek et al. 2001; Wright et al. 1991), and citalopram (Heikkinen et al. 2002; 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 warrant continued examination. The pharmacokinetic profiles of breast milk excretion, including delineation of distribution gradients and time gradients, are best defined for sertraline (Stowe et al. 1997, 2003), paroxetine (Stowe et al. 2000), and fluoxetine (Suri et al. 2002). These studies indicate that quantitative infant SSRI exposure during lactation is considerably lower than transplacental exposure.
Reproductive safety data are more limited for other classes of antidepressants, including bupropion, desvenlafaxine, duloxetine, mirtazapine, nefazodone, trazodone, venlafaxine, vilazodone, and vortioxetine. Prospective reports of first-trimester use of these agents have included 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), 862 venlafaxine exposures with 91 (10.6%) major malformations (Einarson et al. 2001; GlaxoSmithKline 2005; Polen et al. 2013), 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), 508 mirtazapine exposures with 14 (2.8%) major malformations (Djulus et al. 2006; GlaxoSmithKline 2005; Smit et al. 2015; Winterfeld et al. 2015), and a combined report of 121 nefazodone or trazodone exposures with 2 (1.7%) major malformations (Einarson et al. 2003). For duloxetine, there have been 165 exposures with 3 (1.8%) major malformations (Einarson et al. 2012). The only reported case of vilazodone use in pregnancy resulted in a full-term, healthy neonate (Morrison 2014). No published data are yet available for prenatal vortioxetine exposure.
A single study that followed an infant until 9 months after in utero exposure to duloxetine reported normal infant cognitive, language, motor, and psychomotor development (Bellantuono et al. 2013). Likewise, children exposed to venlafaxine in utero showed no differences in IQ or behavior compared with children of nondepressed mothers (Nulman et al. 2012).
A recent study found that prenatal exposure to serotonin-norepinephrine reuptake inhibitor antidepressants after the 20th week of gestation was associated with an increased risk of hypertensive disorders of pregnancy (OR=2.57; 95% CI=1.34–4.93), with an even higher (sixfold) increase among those receiving venlafaxine at dosages exceeding 187.5 mg/day (Newport et al. 2016).
Prenatal pharmacokinetic data are limited. High rates of placental transfer (i.e., umbilical cord concentrations in excess of maternal concentrations) have been reported for venlafaxine (Hendrick et al. 2003) and for its active metabolite desvenlafaxine (Hendrick et al. 2003; Rampono et al. 2009). Duloxetine has a single case report of a cord-to-maternal serum concentration ratio of 0.12, which suggests a low rate of placental transfer (Boyce et al. 2011).
Lactation data also remain limited. Best studied are venlafaxine/desvenlafaxine, for which three studies (Ilett et al. 1998; Newport et al. 2009; Rampono et al. 2011) encompassing 26 mother–infant nursing dyads have reported infant dosages that were 6.8%–8.1% of maternal dosages, which is within the notional 10% presumed safety level (Hendrick et al. 2003; Rampono et al. 2009). A single case report and a small case series of six women receiving duloxetine therapy during lactation described relative infant doses of less than 1% (Boyce et al. 2011; Lobo et al. 2008). The sole report of bupropion in nursing infants noted that the drug could not be detected in the plasma of a nursing infant (Briggs et al. 1993). Five studies totaling 55 neonates exposed to mirtazapine have reported no adverse outcomes and a low relative infant dose (Aichhorn et al. 2004; Klier et al. 2007; Kristensen et al. 2007; Smit et al. 2015; Tonn et al. 2009). No lactation data have been published for vilazodone or vortioxetine.
Before the introduction of the SSRIs, TCAs were widely used during pregnancy and lactation. No clear association has been established between TCA exposure and congenital malformations. Early studies raised concerns about limb anomalies (Barson 1972; Elia et al. 1987; McBride 1972), but a meta-analysis by Altshuler et al. (1996) identified a congenital malformation incidence of only 3.14% (n=13) among 414 infants exposed to a TCA during the first trimester. A data review from the European Network of Teratology Information Services and the United Kingdom’s General Practice Research Database found similar rates of malformation after TCA exposure (McElhatton et al. 1996; Vasilakis-Scaramozza et al. 2013). Moreover, no adverse neurodevelopmental effects were reported in two studies involving 126 children with prenatal TCA exposure (Nulman et al. 1997a, 2002).
Few data exist regarding the acute effects of TCA exposure on fetal and neonatal well-being. There are case reports of fetal tachycardia and neonatal symptoms including tachypnea, tachycardia, cyanosis, irritability, hypertonia, clonus, and spasm (Eggermont 1973; ter Horst et al. 2012). A small (n=18) prospective study found no evidence of increased complications during labor and delivery but did report transient withdrawal symptoms among TCA-exposed neonates (Misri and Sivertz 1991).
TCAs 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 al. 1985). This clinical finding is paralleled by pharmacokinetic data indicating that whereas all TCAs are excreted in breast milk, infant plasma concentrations are considerably higher for doxepin than for other TCAs (for a review, see Wisner et al. 1996b).
Although the monoamine oxidase inhibitors (MAOIs) were introduced almost 50 years ago, reproductive safety data are sparse. 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).
Early retrospective data suggested that lithium exposure was associated with a 400-fold increase in cardiac malformations—specifically, a defect of the tricuspid valve known as Ebstein’s anomaly (Nora et al. 1974; Weinstein and Goldfield 1975). However, a subsequent meta-analysis calculated the risk ratio for cardiac malformations as 1.2–7.7 and the risk ratio for overall congenital malformations as 1.5–3.0 (Cohen et al. 1994). Altshuler et al. (1996) estimated that the risk of Ebstein’s anomaly after prenatal lithium exposure rises from 1 in 20,000 to 1 in 1,000. A recent study indicated that lithium exposure in utero is associated with a higher rate of cardiovascular malformations but not of all major congenital malformations (Diav-Citrin et al. 2014). Additional studies (albeit small ones) also failed to confirm the early estimates regarding lithium’s teratogenic potential (Friedman and Polifka 2000; Jacobson et al. 1992; Källén and Tandberg 1983). Laboratory animal studies had indicated that neurobehavioral alterations also might be a concern for prenatal lithium exposure, but two studies of school-age children exposed to lithium during gestation found no evidence of adverse neurobehavioral sequelae (Schou 1976; van der Lugt et al. 2012).
The continued recommendation for prenatal assessment for fetal anomalies in women taking lithium includes a fetal echocardiogram between weeks 18 and 20 of gestation. In the event of unplanned conception during lithium therapy, the decision to continue or discontinue lithium should be informed by the severity and course of the patient’s illness and 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.
Lithium’s low therapeutic index raises concerns about acute perinatal toxicities. Lithium exposure later in gestation can result in fetal and neonatal cardiac arrhythmias (Wilson et al. 1983), hypoglycemia and nephrogenic diabetes insipidus (Mizrahi et al. 1979), thyroid dysfunction (Karlsson et al. 1975), polyhydramnios, premature delivery, and floppy infant syndrome (Llewellyn et al. 1998). 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.
The physiological alterations of pregnancy are of particular importance in the perinatal management of lithium. Changes in renal clearance over the course of pregnancy and the potential for abrupt volume changes during delivery as a result of 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 25 mother–infant nursing dyads (Bogen et al. 2012; Fries 1970; Schou and Amdisen 1973; Skausig and Schou 1977; Sykes et al. 1976; Tunnessen and Hertz 1972; Viguera et al. 2007a; Weinstein and Goldfield 1969; Woody et al. 1971). Adverse events, including lethargy, hypotonia, hypothermia, cyanosis, electrocardiogram changes, poor feeding, slow growth, gross and fine motor delay, and elevated thyroid-stimulating hormone levels, were reported in five (16%) of these children (Bogen et al. 2012; Skausig and Schou 1977; Tunnessen and Hertz 1972; Viguera et al. 2007a; Woody et al. 1971), including one 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 (American Academy of Pediatrics Committee on Drugs 2001) discourages the use of lithium during lactation. The largest pharmacokinetic study of lithium in lactation reported a milk-to-plasma ratio of 0.53 and an infant-to-maternal plasma ratio of 0.24 (Viguera et al. 2007a). In other studies, nursing infants have had lithium concentrations generally ranging from 5% to 65% of maternal levels (Bogen et al. 2012; 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 vulnerability to lithium toxicity, the hydration status of nursing infants of mothers taking lithium should be carefully monitored (Llewellyn et al. 1998).
Prenatal exposure to valproate has been associated with numerous congenital malformations (rate of 6.7% for overall congenital malformations; Campbell et al. 2014), including neural tube defects (Bjerkedal et al. 1982; Centers for Disease Control 1992; Jäger-Roman et al. 1986; Lindhout and Schmidt 1986), craniofacial anomalies (Assencio-Ferreira et al. 2001; Lajeunie et al. 1998, 2001; Paulson and Paulson 1981), limb abnormalities (Rodríguez-Pinilla et al. 2000), cardiovascular anomalies (Dalens et al. 1980; Koch et al. 1983; Sodhi et al. 2001; Veiby et al. 2014), and hypospadias (Veiby et al. 2014). Valproate exposure prior to neural tube closure, during the fourth week of gestation, confers a 1%–2% risk of spina bifida, which is 10–20 times greater than the risk in the general population (Bjerkedal et al. 1982; Centers for Disease Control 1992; Rosa 1991). One meta-analysis placed the risk of neural tube defects even higher, at 3.8%, with particular vulnerability for the infants of women whose daily dosage exceeded 1,000 mg (Samrén et al. 1997). Other studies support this dose–response relationship (Canger et al. 1999; Kaneko et al. 1999; Omtzigt et al. 1992; Samrén et al. 1999; Tomson et al. 2011, 2015), leading one group to recommend that daily dosages not exceed 1,000 mg and that maternal serum concentrations not exceed 70 μg/mL to reduce the risk of 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, Rodríguez-Pinilla et al. (2000) reported an OR 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 DiLiberti et al. (1984) and subsequently confirmed by other investigators (Ardinger et al. 1988; Martínez-Frías 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 have been recognized as attributes of fetal valproate syndrome (McMahon and Braddock 2001). Valproate’s antagonism of folate activity may underlie the risk of both spina bifida and fetal valproate syndrome. A case–control study comparing 57 children with fetal anticonvulsant syndromes, 46 of whose mothers were given valproate, with 152 control children found a significantly higher rate of homozygosity for a mutation in the gene for methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, in the valproate-exposed children (Dean et al. 1999).
Neurodevelopmental outcomes associated with prenatal valproate exposure are equally of concern. A review found that developmental delay was evident in 20% and intellectual disability 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 noted that 24% of 2-year-olds with prenatal valproate exposure had mental developmental indexes of less than 70, more than double the rate associated with other antiepileptic drugs (Meador et al. 2006). More recent studies have consistently shown deleterious neurodevelopmental effects from prenatal valproate exposure (Baker et al. 2015; Cohen et al. 2013; Meador et al. 2009, 2013; Shallcross et al. 2011; Veiby et al. 2013), with particular consequences for verbal cognition (McVearry et al. 2009; Meador et al. 2011; Nadebaum et al. 2011a, 2011b). Retrospective reports indicate that varying degrees of cognitive impairment may be present in children manifesting the physical sequelae of fetal valproate syndrome (Adab et al. 2001; Gaily et al. 1990; Moore et al. 2000). Fetal valproate syndrome also has been associated with autism spectrum disorders (Bescoby-Chambers et al. 2001; Christensen et al. 2013; Moore et al. 2000; Williams and Hersh 1997; Williams et al. 2001; Wood et al. 2015).
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 had 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 have reported that maternal valproate concentrations steadily decline over the course of pregnancy, falling to levels as much as 50% lower than preconception concentrations (Yerby et al. 1990, 1992). Consistent findings from other studies indicate 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 therefore may be required to maintain therapeutic efficacy. Valproate readily crosses the human placenta, with umbilical cord 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 database 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; 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). In a study of the neurobehavioral effects of valproate exposure during lactation, Meador et al. (2014) found no adverse effects on cognitive functions.
In summary, prenatal valproate use raises grave safety concerns. In women of childbearing age, valproate should never be used except as a treatment of last resort. If valproate must be used during pregnancy, its risk may be reduced by being careful not to exceed 1,000 mg/day or a serum concentration of 70 μg/mL. Folate supplementation (4–5 mg/day) is also recommended, although no definitive evidence indicates that it reduces the risk of valproate-associated anomalies. 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/day) may be considered during the final month of gestation. Prenatal surveillance for congenital abnormalities should include maternal serum α-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.
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 counts and serum liver enzymes in nursing infants are recommended because the neurodevelopmental effect of nursing exposure to valproate is unclear.
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 0.5%–1.0% risk of neural tube defects (Rosa 1991), which 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). The European Surveillance of Congenital Anomalies (EUROCAT) study (Jentink et al. 2010), a large case–control investigation, reported that carbamazepine exposure was associated with an increased risk of spina bifida (OR=2.6) only. The Australian Register of Antiepileptic Drugs in Pregnancy showed that carbamazapine exposure in utero was associated with renal tract abnormalities (Vajda et al. 2013). 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 (Hernández-Díaz et al. 2001).
A fetal carbamazepine syndrome—manifested by a short nose, long philtrum, epicanthal folds, hypertelorism, upslanting palpebral fissures, and fingernail hypoplasia—has been described (Jones et al. 1989), and in one study, the phenotypic characteristics of this syndrome were observed in 6 of 47 children prenatally exposed (Ornoy and Cohen 1996). Other studies have confirmed the association with facial anomalies (Moore et al. 2000; Nulman et al. 1997b; Scolnik et al. 1994; Wide et al. 2000), but one of these studies found similar facial abnormalities among children born to women with epilepsy who were untreated during pregnancy (Nulman et al. 1997b). There has been an isolated case report of phocomelia (i.e., absence or underdevelopment of limbs) in an infant with in utero exposure (Dursun et al. 2012).
Data regarding the neurodevelopmental sequelae of prenatal carbamazepine exposure have been mixed. Some studies reported developmental delay in up to 20% of children with fetal carbamazepine syndrome (Jones et al. 1989; Meador et al. 2011; Moore et al. 2000; Ornoy and Cohen 1996; Veiby et al. 2013), but others did not find that association (Gaily et al. 1990; Scolnik et al. 1994; van der Pol et al. 1991; Wide et al. 2000). Recent systematic studies generally have found no evidence of developmental delay in children exposed to carbamazepine in utero (Baker et al. 2015; McVearry et al. 2009; Meador et al. 2006, 2009, 2011; Nadebaum et al. 2011b).
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 significant increases in carbamazepine clearance during the third trimester (Battino et al. 1982; Dam et al. 1979; Lander et al. 1981), but others have found no changes in clearance (Bardy et al. 1982b; Johnson et al. 2014; Otani 1985; Reisinger et al. 2013; 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 umbilical cord–to–maternal plasma ratios of 0.5–0.8 (Nau et al. 1982a).
The literature on carbamazepine and lactation encompasses 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; Pynnönen and Sillanpää 1975; Pynnönen et al. 1977; Wisner and Perel 1998), representing the most extensive data set for any mood stabilizer in lactation. Included are 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 γ-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; Pynnönen and Sillanpää 1975; Pynnönen et al. 1977; Wisner and Perel 1998).
Although the risks associated with prenatal 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 α-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. Thus, periodic assays of blood counts and serum liver enzymes of nursing infants are recommended.
Reproductive safety data for lamotrigine have rapidly accrued during the past decade and compare favorably with safety data for other mood stabilizers. The overall risk of major fetal malformations following first-trimester prenatal exposure to lamotrigine is 2.6% (207 per 7,951 exposures) (Campbell et al. 2014; Cunnington et al. 2011; Dominguez-Salgado et al. 2004; GlaxoSmithKline 2007; Holmes et al. 2006; Meador et al. 2006; Mølgaard-Nielsen and Hviid 2011; Morrow et al. 2006; Sabers et al. 2004; Vajda et al. 2003), a risk that is within the range associated with births not involving drug exposures. A 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 0.10% (3 per 2,956 exposures) (Dominguez-Salgado et al. 2004; GlaxoSmithKline 2007; Meador et al. 2006; Mølgaard-Nielsen and Hviid 2011; Morrow et al. 2006; Sabers et al. 2004; Vajda et al. 2003). Furthermore, the EUROCAT case–control study, encompassing 5,511 children with orofacial clefts and 80,052 children without clefts, reported an adjusted OR of 0.67 for clefts with lamotrigine exposure (Dolk et al. 2008). The U.K. Epilepsy and Pregnancy Register reported a higher risk of malformations at maternal dosages exceeding 200 mg/day (Morrow et al. 2006), although this finding was not confirmed in subsequent analyses (GlaxoSmithKline 2007; Mølgaard-Nielsen and Hviid 2011). Despite these reassuring findings, folate supplementation is recommended for all women of childbearing age taking any antiepileptic drug, including lamotrigine. Prospective neurodevelopmental data have been consistently favorable among children with prenatal lamotrigine exposure (Baker et al. 2015; McVearry et al. 2009; Meador et al. 2006, 2009, 2011; Nadebaum et al. 2011b).
Numerous pharmacokinetic studies have reported that lamotrigine clearance steadily increases across gestation (de Haan et al. 2004; Fotopoulou et al. 2009; Franco et al. 2008; Pennell et al. 2004, 2008; Petrenaite et al. 2005; Polepally et al. 2014; Reisinger et al. 2013; Tran et al. 2002). These studies are limited by polytherapy with other anticonvulsants, which are known to alter the metabolism of lamotrigine. It is unclear whether dosage changes would be necessary to maintain mood stability in patients with bipolar disorder and whether the adjunctive agents commonly used in the treatment of bipolar disorder would have similar effects on lamotrigine metabolism. Studies in patients taking lamotrigine also report that its rate of clearance abruptly declines after delivery (Ohman et al. 2000; Pennell et al. 2004; Polepally et al. 2014; 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 on the placental passage of lamotrigine indicate that lamotrigine concentrations in fetal circulation at delivery are equal to maternal concentrations (Myllynen et al. 2003; Ohman et al. 2000; Paulzen et al. 2015; 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 (Clark et al. 2013; GlaxoSmithKline 2007; Liporace et al. 2004; Newport et al. 2008c; Nordmo et al. 2009; Ohman et al. 2000; Page-Sharp et al. 2006; Rambeck et al. 1997; Tomson et al. 1997) collectively encompass 60 mother–infant nursing dyads. The only reported adverse event was an apneic episode in a nursing infant whose mother was taking lamotrigine 850 mg/day (Nordmo et al. 2009). Seven other infants were observed to have a benign thrombocytosis (Newport et al. 2008b). In the largest (n=30) of these studies (Newport et al. 2008b), 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.
Commonly prescribed antipsychotic medications, as well as agents used to treat the side effects of first-generation antipsychotics (FGAs), are covered in Chapters 24–35. The second-generation antipsychotics (SGAs) have supplanted the FGAs as first-line medications for psychotic disorders and are also used for other psychiatric indications, including bipolar disorder, anxiety disorders, and treatment-resistant depression. Despite rapidly expanding use, the reproductive safety database regarding SGAs remains limited. A recent study that used a national pregnancy registry for SGAs reported an OR of 1.25 (95% CI=0.13–12.13) for major malformations in exposed infants compared with nonexposed infants (Cohen et al. 2015). A neurobehavioral outcome study identified a transient delay in cognitive, motor, social-emotional, and adaptive behavior in SGA-exposed infants that resolved by age 12 months (Peng et al. 2013).
Even though some data have been reassuring, the small volume of SGA data to date precludes definitive conclusions about 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).
Reproductive safety data for clozapine, the oldest of the SGAs, are limited to case reports (Barnas et al. 1994; Di Michele et al. 1996; Kornhuber and Weller 1991; Moreno-Bruna et al. 2012; 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 80 children exposed to clozapine during pregnancy and/or lactation. Adverse sequelae associated with in utero 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); delayed peristalsis (Moreno-Bruna et al. 2012); transient low-grade fever in an infant also exposed to lithium (Stoner et al. 1997); and floppy infant syndrome in a newborn also exposed to lorazepam (Di Michele et al. 1996). In a review of 61 children exposed to clozapine prenatally, Dev and Krupp (1995) reported 5 cases of congenital malformations and 5 cases of neonatal syndromes; however, many of these mothers were taking other psychotropic medications during pregnancy. A recent study of neurodevelopmental consequences of prenatal exposure to SGAs reported higher rates of developmental delay at ages 2 months and 6 months among clozapine-exposed infants compared with infants exposed to other SGAs (Shao et al. 2015). The only reported case of clozapine use during lactation noted no adverse effects on the nursing infant (Kornhuber and Weller 1991).
The only investigation of the perinatal pharmacokinetics of clozapine found elevated concentrations in fetal serum and breast milk compared with concentrations in maternal serum and amniotic fluid (Barnas et al. 1994), leading the authors to conclude that clozapine accumulates in fetal circulation and breast milk. Although no cases of agranulocytosis have been reported in clozapine-exposed infants, this potential risk and the requisite laboratory monitoring limit the utility of clozapine during the peripartum.
A published birth registry of 23 prospectively ascertained olanzapine-exposed pregnancies from the Lilly Worldwide Pharmacovigilance Safety Database reported no major malformations, 13% spontaneous abortions, 5% preterm deliveries, and 5% fetal deaths (Goldstein et al. 2000). In a subsequent examination of the same database, 610 prospectively identified pregnancies exposed to olanzapine resulted in 10% premature births, 9% spontaneous abortions, 8% perinatal conditions (i.e., an adverse event occurring within 7 days of birth), and 4% congenital anomalies (Brunner et al. 2013). A prospective study comparing outcomes among 151 pregnant women with SGA exposure (olanzapine, n=60; risperidone, n=49; quetiapine, n=36; clozapine, n=6) with outcomes among 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, one SGA-exposed child (olanzapine) was observed to have major malformations (a series of midline defects including an oral cleft, encephalocele, and aqueductal stenosis). A recent meta-analysis reported a malformation rate of 3.5% among 1,090 olanzapine-exposed infants, a rate that compares favorably to rates with other SGAs (Ennis and Damkier 2015).
In a study of antipsychotic placental passage rates and neonatal outcomes (Newport et al. 2007a), umbilical cord concentrations in olanzapine-exposed neonates (n=14) were 72.1% of maternal concentrations. In this study, there was a trend 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 compared with those exposed to the other antipsychotics.
Case reports of 39 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; Gilad et al. 2011; Goldstein et al. 2000; Kirchheiner et al. 2000; Whitworth et al. 2010). The Lilly Safety Database reported on 62 breast-feeding mother–infant dyads with a 15.6% rate of adverse events, identified as somnolence, irritability, tremors, and insomnia (Brunner et al. 2013). 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; Stiegler et al. 2014) and that the median infant daily dosage via breast feeding was approximately 0.7%–1.8% of the maternal dosage (Ambresin et al. 2004; Aydin et al. 2015; Brunner et al. 2013; Croke et al. 2002; Gardiner et al. 2003).
Prospective data on pregnancy outcomes following first-trimester risperidone exposure include a collective study of outcomes for several SGAs (McKenna et al. 2005) reporting no major malformations among 49 risperidone-exposed infants and a recent meta-analysis reporting a 5.1% malformation rate among 432 risperidone-exposed infants (Ennis and Damkier 2015). An additional study in 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). No data on the neurodevelopmental effects of risperidone exposure during pregnancy or lactation are available.
Pharmacokinetic studies have reported placental passage concentrations among neonates (n=6) of 49.2% (Newport et al. 2007a), milk-to-plasma ratios of less than 0.5 for risperidone and less than 0.88 for 9-hydroxyrisperidone (Hill et al. 2000; Ilett et al. 2004; Weggelaar et al. 2011), and infant plasma concentrations ranging from 2.3% to 4.7% of maternal levels (Ilett et al. 2004; Weggelaar et al. 2011).
The reproductive safety literature for first-trimester quetiapine exposure is limited to a case series of two successive pregnancies (Grover and Madan 2012), which reported healthy, full-term deliveries, and the McKenna et al. (2005) study, which reported no major malformations among 36 infants exposed to quetiapine. In the Newport et al. (2007a) 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. No data are available on the neurodevelopmental effects of quetiapine exposure during pregnancy or lactation.
Three cases of quetiapine use during lactation following use during pregnancy estimated the nursing infant dosage at 0.09%–7.3% of the maternal daily dosage (Lee et al. 2004; Van Boekholt et al. 2015).
Reproductive safety data for aripiprazole include a case series of 86 mother–infant dyads that showed an increased risk of premature birth and fetal growth retardation but no increased risk of congenital malformations, miscarriages, preeclampsia, or gestational diabetes (Bellet et al. 2015). In addition, a recent meta-analysis reported a 5.0% malformation rate among 100 infants with first-trimester aripiprazole exposure (Ennis and Damkier 2015). A single case report indicated poor respiratory effort at birth (Watanabe et al. 2011), and two case reports and a case series showed no adverse obstetrical or neonatal outcomes (Gentile et al. 2011; Lutz et al. 2010; Windhager et al. 2014).
Of the three case reports of aripiprazole use during lactation, the milk excretion profiles were questionable in two (Lutz et al. 2010; Schlotterbeck et al. 2007), and the other reported a milk-to-plasma ratio of 0.051 (Watanabe et al. 2011). Placental transfer was 53.3%–54.7%, as shown in two reports of four mother–infant dyads (Watanabe et al. 2011; Windhager et al. 2014).
Information about the use of other SGAs is scant. Use of ziprasidone, brexpiprazole, lurasidone, iloperidone, or asenapine during pregnancy has not been reported. A lone case report of use of paliperidone palmitate, the long-acting injectable formulation of paliperidone, during pregnancy (haloperidol was also used) indicated no adverse obstetrical outcomes (Özdemir et al. 2015).
Data concerning lactation were limited to a single case report of ziprasidone use during lactation that reported a milk-to-plasma ratio of 0.06 (Schlotterbeck et al. 2009).
In contrast to the SGAs, the FGAs have an extensive reproductive safety database addressing both somatic and neurobehavioral teratogenicity. Furthermore, the historical use of phenothiazine antipsychotics to treat pregnancy-associated emesis 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 malformations (Goldberg and DiMascio 1978; Hill and Stern 1979; Nurnberg and Prudic 1984).
In a study of 100 women taking 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 prospective study encompassing nearly 20,000 women receiving primarily 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 taking 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 phenothiazines but not to 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 1984).
Neurobehavioral outcome studies encompassing 203 children exposed to FGAs during gestation detected no significant differences in IQ scores at age 4 years (Kris 1965; Slone et al. 1977), although relatively low antipsychotic dosages were used by many women in these studies. Conversely, several laboratory animal studies (Hoffeld et al. 1968; Ordy et al. 1966; Robertson et al. 1980), although not all (Dallemagne and Weiss 1982), have identified 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 extrapyramidal side effects (EPS) manifested by heightened muscle tone and increased rooting and tendon reflexes persisting for several months (Cleary 1977; Hill et al. 1966; O’Connor et al. 1981). Furthermore, prenatal exposure to FGAs has been associated with neonatal jaundice (Scokel and Jones 1962) and postnatal intestinal obstruction (Falterman and Richardson 1980).
In our study of antipsychotic placental passage, neonatal haloperidol (n=13) concentrations were 66% of maternal concentrations (Newport et al. 2007a).
In lactation, chlorpromazine is the most widely studied typical antipsychotic, with 7 infants exposed to chlorpromazine during nursing showing no developmental deficits at 16-month and 5-year follow-up evaluations (Kris and Carmichael 1957). However, 3 infants in another study whose mothers were prescribed both chlorpromazine and haloperidol showed 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 (Wilson et al. 1980; Yoshida et al. 1998b), perphenazine (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 1.0, although adequate control for distribution and time gradients was lacking in these studies. One group postulated that the physicochemical properties of perphenazine could lead it to become “trapped” in breast milk (Wilson et al. 1980); however, this speculation is unconfirmed.
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 indicated that first-trimester exposure to diphenhydramine, the best studied of these medications, was associated with major and minor congenital anomalies (Miller 1991; Wisner and Perel 1988). A case–control study found a significantly higher rate of prenatal diphenhydramine exposure among 599 infants with oral clefts than among 590 control infants (Saxén 1974). Despite these data, diphenhydramine is routinely used during pregnancy. Clinical studies of the teratogenic potential of benztropine and amantadine are lacking, although laboratory animal studies indicated 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 more than 40 years, and the paucity of data linking these agents to either teratogenic or toxic effects suggests that their risks are minimal. In particular, piperazine phenothiazines (e.g., trifluoperazine, perphenazine) may have especially low teratogenic potential (Rumeau-Rouquette et al. 1977). Given the greater fetal risks associated with anticholinergic medications (e.g., diphenhydramine), their use should be avoided if possible. Consequently, FGAs used during the antepartum period should be kept at the lowest effective dosage to minimize the need for adjunctive medications to manage EPS.
Pharmacotherapy for anxiety disorders includes antidepressants, benzodiazepines, buspirone, and certain atypical antipsychotics.
A retrospective analysis of more than 100,000 women found that at least 2% were prescribed a benzodiazepine during gestation (Bergman et al. 1992). The earliest benzodiazepine teratogenicity studies reported an increased risk of oral clefts after in utero diazepam exposure (Aarskog 1975; Saxén 1975; Saxén and Saxén 1975), but later studies failed to confirm this association (Ban et al. 2014; Entman and Vaughn 1984; Rosenberg et al. 1983; Shiono and Mills 1984). Prospective studies of first-trimester alprazolam exposure encompassing approximately 1,300 pregnancies indicated no excess of oral clefts or other birth defects (Barry and St Clair 1987; Schick-Boschetto and Zuber 1992; St Clair and Schirmer 1992), and a recent study of first-trimester exposure to diazepam and temazepam echoed this finding (Ban et al. 2014). A meta-analysis found that prenatal benzodiazepine exposure does confer an increased risk of oral clefts, although the absolute risk increased by only 0.01% (Altshuler et al. 1996). This conclusion is consistent with the findings of a later case–control study that found no difference in rates of prenatal benzodiazepine exposure between more than 38,000 infants with congenital anomalies and nearly 23,000 control children (Eros et al. 2002).
Although benzodiazepine teratogenicity data are somewhat mixed, benzodiazepine neonatal syndromes are well documented. Numerous groups have described a floppy infant syndrome characterized by hypothermia, lethargy, poor respiratory effort, and feeding difficulties following benzodiazepine exposure in late pregnancy (Erkkola et al. 1983; Fisher et al. 1985; Haram 1977; Källén and Reis 2012; Kriel and Cloyd 1982; McAuley et al. 1982; Sanchis et al. 1991; Speight 1977; Woods and Malan 1978). In a study of 53 infants with late-pregnancy lorazepam exposure, term infants whose mothers had taken oral lorazepam showed no evidence of toxicity other than a brief delay in establishing feeding, whereas preterm infants and term infants whose mothers had received larger intravenous doses of lorazepam had 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; Bitnun 1969; Stirrat et al. 1974), or diazepam (Backes and Cordero 1980; Mazzi 1977). Benzodiazepine 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 readily traverse the placenta and with prolonged administration may accumulate in the fetus (Mandelli et al. 1975; Shannon et al. 1972). For example, fetal concentrations of diazepam at delivery are typically higher than maternal concentrations (Erkkola et al. 1974). Because benzodiazepine metabolism is slower in the fetus than in the mother, it is understandable that an agent like diazepam (which has multiple active metabolites) might accumulate in the fetus. In addition, high concentrations of diazepam are sequestered in lipophilic fetal tissues, such as the brain, lungs, and heart (Mandelli et al. 1975). In contrast, fetal-to-maternal ratios of lorazepam (which has no active metabolites) are typically less than 1.0 (Whitelaw et al. 1981). Yet 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).
Studies evaluating the neurobehavioral effects of prenatal benzodiazepine exposure are needed. A benzodiazepine exposure syndrome—consisting of growth retardation, dysmorphism, and mental and psychomotor retardation in infants (Laegreid et al. 1987)—has been reported, although some investigators have disputed this finding (Gerhardsson and Alfredsson 1987; Winter 1987). One 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), and another group found no correlation between antenatal exposure and language competence at age 3 years (Odsbu et al. 2015). Nevertheless, a series of laboratory animal studies raised concerns that prenatal benzodiazepine exposure may produce deficits in memory and learning ability (Frieder et al. 1984; Hassmannova and Myslivecek 1994; Jaiswal and Bhattacharya 1993; Myslivecek et al. 1991).
Buist et al. (1990) concluded that benzodiazepines at low dosages present no contraindication to nursing. A recent retrospective cohort study found a sedation rate of 1.6% in infants exposed to benzodiazepines while breast feeding, but there was no association with maternal dosage (Kelly et al. 2012). Infants with impaired metabolic capacity may show sedation and poor feeding even with low maternal dosages (Wesson et al. 1985). Overall, benzodiazepines are associated with lower milk-to-plasma ratios than are other classes of psychotropics. For example, Wretlind (1987) found a milk-to-plasma ratio of 0.1–0.3 for oxazepam and calculated that the infant daily dosage via lactation is 1/1,000th of the maternal dosage. The percentage of the maternal dosage 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 neonatal risks, they should be used judiciously and tapered before delivery if possible. Benzodiazepines should not be abruptly withdrawn during pregnancy. Because lorazepam and oxazepam are less dependent on hepatic metabolism, they theoretically have less potential for fetal accumulation during pregnancy. Finally, benzodiazepines can be safely administered, in judicious doses, during lactation. However, breast feeding should be discontinued if an infant experiences sedation or other signs of benzodiazepine toxicity.
Buspirone has garnered a unique, and arguably illogical, position within the psychotropic armamentarium. Although buspirone is labeled FDA Category B, published data are extremely limited. The only report of prenatal administration of buspirone identified 1 infant born with a major malformation among 14 infants with first-trimester buspirone exposure (Wilton et al. 1998). No published reports exist regarding buspirone’s safety during lactation.
The development of prenatal and postnatal treatment guidelines is hampered by the haphazard accrual of clinical research data with inconsistent methodologies. Whereas clinical data have confirmed the teratogenic potential for only a few psychotropic agents, animal studies, which commonly use maternal concentrations exponentially higher than those seen in clinical care, show clear somatic and neurobehavioral teratogenicity (Elia et al. 1987). Such inconsistencies between clinical and preclinical data further confound efforts to construct reliable treatment recommendations. Similarly, advances in statistical methods and the accrual of data from a variety of sources have identified statistical findings that may have limited relevance to clinical decision making (Ranganathan et al. 2015). Because pregnant and nursing women are generally excluded from clinical trials of pharmacological agents, definitive clarification with proper control groups is unlikely to be forthcoming in the near future. Consequently, clinical treatment decisions are made on the basis of incomplete or uncertain information.
Obtaining informed consent in the clinical decision cannot be overemphasized. Informed consent should include the following:
Agreement on the primary treatment objective, which typically is to minimize potential harm to the fetus (Acceptance of and adherence to this objective will help reduce the potential for subsequent maternal self-recrimination.)
Discussion of the availability, affordability, accessibility, and potential efficacy of nonpharmacological treatments
Consideration of the likelihood and severity of illness without continued pharmacotherapy
Review of the potential risks of untreated mental illness to the fetus and mother
Review of the potential risks of fetal psychotropic exposure
Acknowledgment that no risk-free alternative is available other than deciding not to conceive
Acknowledgment that the understanding of risks remains incomplete (Ultimately, it is impossible to provide an exhaustive list of all risks for any given psychotropic agent, but the evidence—or lack of evidence—for adverse effects should be reviewed.)
Nonpsychotropic treatments should focus on maximizing maternal health during pregnancy, such as prenatal vitamins; adequate hydration; daily exercise; and avoidance of alcohol, tobacco, caffeine, and illicit substances. Good evidence indicates that concomitant exposures, such as to tobacco, increase both obstetrical and neonatal risk. Nonpsychotropic treatment strategies also include psychotherapy alternatives appropriate during pregnancy and the postpartum period.
Medication selection requires several steps. Initial treatment planning for reproductive-age women with mental illness should include the potential pregnancy and future family planning. Notably, more than 45% of the pregnancies in the United States are unplanned, and knowledge of conception is often well into the organogenesis (Finer and Zolna 2016; Kost 2015). Choosing initial pharmacotherapy with this in mind supports “new and improved=limited data.”
Psychotropic therapy is administered after knowledge of conception only when the clinician and patient agree that the risks to the fetus of untreated mental illness likely exceed the risks of fetal psychotropic exposure. Consequently, both the safety and the efficacy of the psychotropic regimen are important considerations. A psychotropic agent is preferred if 1) it has previously been effective for the patient; 2) it has previously been well tolerated by the patient; 3) the fetus has already been exposed to it (i.e., the patient was taking the agent at knowledge of conception); and 4) it has a favorable reproductive safety profile. It is important to emphasize the potential hazards of switching agents during pregnancy or lactation. Changing medications generally should be avoided (unless well-defined risks are associated with the current regimen), because medication changes increase the number of medications to which the infant has been exposed, limit the clinician’s ability to apply available safety information (e.g., virtually no data exist on concomitant or tandem multiple medication exposures), and may heighten the mother’s vulnerability to illness.
Maintaining maternal emotional well-being is the goal of psychotropic treatment in the antepartum and postpartum periods. Partial or subtherapeutic treatment heightens risk by continuing to expose the mother and infant to both illness and medications. The minimum effective dosage should be maintained throughout treatment, and the clinician should remain mindful that dosage requirements may change during pregnancy. Similarly, clinicians and patients should be aware that dosage adjustment may not significantly alter fetal exposure during pregnancy (i.e., the fetus is exposed to the maternal plasma concentration, not the maternal dosage). To minimize the potential for neonatal withdrawal and maternal toxicity after delivery, careful monitoring of side effects and serum concentrations may be indicated.
Because clinical laboratory assays typically lack the sensitivity to detect the serum concentrations of nursing infants, infant plasma monitoring for psychotropic medications is not routinely indicated. If there is an index of suspicion that a child is experiencing an adverse effect from nursing exposure to a psychotropic medication, breast feeding should be discontinued. However, routine laboratory monitoring (e.g., blood counts, electrolytes, hepatic profiles) is required when nursing mothers are taking medications (e.g., lithium, valproate, carbamazepine) with low therapeutic indices or known systemic toxicities.
For clinicians involved in the care of numerous women in their reproductive years, a valuable resource that includes an interactive e-book is Drugs in Pregnancy and Lactation by G.G. Briggs and R.K. Freeman.
Additional online resources include the following:
Centers for Disease Control and Prevention—www.cdc.gov/pregnancy/meds/treatingfortwo
InfantRisk Center—www.infantrisk.com
LactMed—https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm
Organization of Teratology Information Specialists: MotherToBaby—www.mothertobaby.org
Reprotox—www.reprotox.com
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