Psychiatric Disorders During Pregnancy-General
Although pregnancy has typically been considered a time of emotional well being, recent studies suggest that up to 20% of women suffer from mood or anxiety disorders during pregnancy. Particularly vulnerable are those women with histories of psychiatric illness who discontinue psychotropic medications during pregnancy. Although data accumulated over the last 30 years suggest that some medications may be used safely during pregnancy, knowledge regarding the risks of prenatal exposure to psychotropic medications is incomplete. Thus, it is relatively common for patients to discontinue or to avoid pharmacologic treatment during pregnancy.
What are the risks of medication exposure?
Frequently women with histories of psychiatric illness seek consultations regarding the use of medications during pregnancy, either prior to conception or early in the course of pregnancy. In other cases, women present with recurrent or new onset of mood or anxiety symptoms during pregnancy. In both of these settings, the clinician faces certain challenges when making recommendations regarding the treatment of psychiatric illness during pregnancy.
All medications diffuse readily across the placenta, and no psychotropic drug has yet been approved by the Food and Drug Administration (FDA) for use during pregnancy. When prescribing medications during pregnancy, one must consider the following risks associated with prenatal exposure: risk of teratogenesis, risk of neonatal toxicity, and risk of long-term neurobehavioral sequelae.
Risk of Teratogenesis
The baseline incidence of major congenital malformations in newborns born in the United States is estimated to be between 2 and 4%. During the earliest stages of pregnancy, formation of major organ systems takes place and is complete within the first 12 weeks after conception. A teratogen is defined as an agent that interferes with this process and produces some type of organ malformation or dysfunction. Exposure to a toxic agent before two weeks of gestation does not typically result in a congenital malformation but is more likely to result in a non-viable blighted ovum. For each organ or organ system, there exists a critical period during which development takes place and is susceptible to the effects of a teratogen. For example, neural tube folding and closure, forming the brain and spinal cord, occur within the first four weeks of gestation. Formation of the heart and great vessels takes place from four to nine weeks after conception.
Risk of Neonatal Symptoms
Neonatal toxicity or perinatal syndromes refer to a spectrum of physical and behavioral symptoms observed in the acute neonatal period that can be attributed to drug exposure at or near the time of delivery. Recently attention has focused on a range of transient neonatal distress syndromes associated with exposure to (or withdrawal from) antidepressants in utero. These syndromes appear to affect about 25% of babies exposed to antidepressants in utero. Anecdotal reports that attribute these syndromes to drug exposure must be cautiously interpreted, and larger samples must be studied in order to establish a causal link between exposure to a particular medication and a perinatal syndrome.
Risk of Long-Term Effects
Although the data suggest that some medications may be used safely during pregnancy, our knowledge regarding the long-term effects of prenatal exposure to psychotropic medications is incomplete. Because neuronal migration and differentiation occur throughout pregnancy and into the early years of life, the central nervous system (CNS) remains particularly vulnerable to toxic agents throughout pregnancy. While insults that occur early in pregnancy may result in gross abnormalities, exposures that occur after neural tube closure (at 32 days of gestation) may produce more subtle changes in behavior and functioning.
Behavioral teratogenesis refers to the potential of a psychotropic drug administered during pregnancy to have long-term neurobehavioral effects. For example, are children who have been exposed to an antidepressant in utero at risk for cognitive or behavioral problems at a later point during their development? To date, few studies have systematically investigated the impact of exposure to psychotropic medications in utero on development and behavior in humans.
Antidepressants and Pregnancy
Although early case reports suggested a possible association between first trimester exposure to tricyclic antidepressants (TCAs) and limb malformation, three prospective and more than 10 retrospective studies have examined the risk of organ malformation in over 400 cases of first trimester exposure to TCAs. When evaluated on an individual basis and when pooled, these studies fail to indicate a significant association between fetal exposure to TCAs and risk for any major congenital anomaly. Among the TCAs, desipramine and nortriptyline are preferred since they are less anti-cholinergic and the least likely to exacerbate orthostatic hypotension that occurs during pregnancy.
Off all the antidepressants fluoxetine (Prozac) is the best characterized. Data collected from over 2500 cases indicate no increase in risk of major congenital malformation in fluoxetine-exposed infants. One prospective study of 531 infants with first trimester exposure to SSRIs (mostly citalopram, n=375) did not demonstrate an increased risk of organ malformation. Several meta-analyses combining studies with exposures to tricyclic antidepressants and SSRIs do not demonstrate an increase in risk of congenital malformation in children exposed to these antidepressants, with the exception of paroxetine. Recent reports have suggested that first trimester exposure to paroxetine is associated with an increased risk of cardiac defects including atrial and ventricular septal defects. Other published studies have not demonstrated increased teratogenicity of paroxetine. Even so, these findings prompted the FDA to change the category label of paroxetine from C to D.
Bupropion may be an option for women who have not responded to fluoxetine or a tricyclic antidepressant, as data thus far have not indicated an increased risk of malformations associated with bupropion use during pregnancy. The most recent information from the Bupropion Pregnancy Registry maintained by the manufacturer GlaxoSmithKline includes data from 517 pregnancies involving first trimester exposure to bupropion. In this sample, there were 20 infants with major malformations. This represents a 3.9% risk of congenital malformation that is consistent with what is observed in women with no known teratogen exposure. While this information regarding the overall risk of malformation is reassuring, earlier reports had revealed an unexpectedly high number of malformations of the heart and great vessels in bupropion-exposed infants. A retrospective cohort study including over 1200 infants exposed to bupropion during the first trimester did not reveal an increased risk of malformations in the bupropion-exposed group of infants nor did it demonstrate an increased risk for cardiovascular malformations. Further studies are required to assess the risk of neonatal symptoms in bupropion-exposed infants and to better evaluate the long-term neurobehavioral effects of bupropion exposure.
With regard to the other antidepressants, prospective data on 150 women exposed to venlafaxine during the first trimester of pregnancy suggest no increase in risk of major malformation as compared to non-exposed controls. In another prospective study, outcomes in 147 women taking either nefazodone (n=89) or trazodone (n-58) were enrolled during their first trimester of pregnancy were compared to two control groups of women exposed to either non-teratogenic drugs (n = 147) or to other antidepressants (n=147). There were no significant differences among exposed and non-exposed groups with regard to rates of congenital malformations. While these initial reports are reassuring, larger samples are required to establish the reproductive safety of these newer antidepressants. It is estimated that at least 500 to 600 exposures must be collected to demonstrate a two-fold increase in risk for a particular malformation over what is observed in the general population.
To date, the literature does not include prospective data on the use of mirtazapine (Remeron) or duloxetine (Cymbalta). Scant information is available regarding the reproductive safety of monoamine oxidase inhibitors (MAOIs), and these agents are generally not used in pregnancy as they may produce a hypertensive crisis when combined with tocolytic medications, such as terbutaline.
Several recent studies have suggested that exposure to SSRIs at the time of delivery may be associated with poor perinatal outcomes in about 25% of infants, with several studies reporting increased rates of admission to the special care nursery among SSRI-exposed infants. The most commonly reported symptoms in the newborns include tremor, restlessness, increased muscle tone, and increased crying. Several, but not all, studies have also reported slightly lower Apgar scores in SSRI-exposed infants. Reassuringly, these syndromes appear to be relatively benign and short-lived, resolving within 1 to 4 days after birth without any specific medical intervention.
These studies deserve careful consideration, yet one of the major shortcomings is that most have failed to use raters blinded to the mother’s treatment status. The decision to admit a newborn to a special care nursery may represent a reasonable precaution for an infant exposed to medication in utero and may not be an indication of a serious problem. Another limitation is that few studies have attempted to assess maternal mood during pregnancy or at the time of delivery. There is ample evidence to suggest that depression or anxiety in the mother may contribute to poor neonatal outcomes, including premature delivery and low birth weight, and it is important to evaluate the contribution of maternal mood to neonatal outcomes.
Another study has suggested that maternal SSRI use after the 20th week of gestation is associated with a higher than expected number of cases of persistent pulmonary hypertension of the newborn (PPHN). Although body mass index, diabetes, NSAID use, and smoking have been identified as maternal factors associated with PPHN, controlling for these potential confounders did not significantly attenuate the association between SSRI use and PPHN. Neither the use of SSRIs before the 20th week of gestation nor the use of non-SSRI antidepressants at any time during the pregnancy was associated with an increased risk of PPHN. If we assume that these findings are correct, the risk is still relatively small; the authors estimate the risk of PPHN to be less than 1% in infants exposed to SSRIs in utero. Further investigation is warranted to clarify the association between SSRI use and PPHN.
To date only two studies have systematically investigated the impact of exposure to antidepressants in utero on development and behavior in humans. The first of these studies followed a cohort of 135 children who had been exposed to either tricyclic antidepressants or fluoxetine (Prozac) during pregnancy (most commonly during the first trimester) and compared these subjects to a cohort of non-exposed controls. Results indicated no significant differences in IQ, temperament, behavior, reactivity, mood, distractibility, or activity level between exposed and non-exposed children followed up to 7 years of age. A more recent report from the same group that followed a cohort of children exposed to fluoxetine or tricyclic antidepressants for the entire duration of the pregnancy yielded similar results. The authors concluded that their findings support the hypothesis that fluoxetine and tricyclic antidepressants are not behavioral teratogens and do not have a significant effect on cognitive development, language or behavior.
For women with bipolar disorder, maintenance treatment with a mood stabilizer during pregnancy can significantly reduce the risk of relapse; however, many of the medications commonly used in this setting, including lithium and valproic acid, carry some degree of teratogenic risk. First trimester exposure to lithium has been associated with an increased risk of cardiovascular malformation estimated to be between 1 in 2000 (0.05%) and 1 in 1000 (0.1%). The anticonvulsant valproic acid carries a much higher risk of teratogenesis, with rates of neural tube defect ranging from 1 to 6%. Prenatal exposure to valproic acid has also been associated with characteristic craniofacial abnormalities, cardiovascular malformation, limb defects and genital anomalies, as well as other central nervous system structural abnormalities.
While other anticonvulsants are being used more frequently in the treatment of bipolar disorder, there is limited information on the reproductive safety of these newer anticonvulsants, specifically gabapentin (Neurontin), oxcarbazepine (Trileptal), topiramate (Topamax), tigabine (Gabitril), levetiracetam (Keppra), zonisamide (Zonegran).
However, there is a growing body of information the reproductive safety of lamotrigine (Lamictal), and this may be a useful alternative for some women. The International Lamotrigine Pregnancy Registry was created by GlaxoSmithKline (GSK) in 1992 to monitor pregnancies exposed to lamotrigine for the occurrence of major birth defects. Data from the Registry did not show an elevated risk of malformations associated with lamotrigine exposure. Other data from the North-American Anti-Epileptic Drug Registry indicates the prevalence of major malformations in a total of 564 children exposed to lamotrigine monotherapy was 2.7%; however, five infants had oral clefts, indicating a prevalence rate of 8.9 per 1000 births. In a comparison group of 221,746 unexposed births, the prevalence rate for oral clefts was 0.37/1000, indicating a 24-fold increase in risk of oral cleft in infants exposed to lamotrigine. However, other registries have not demonstrated such a significant increase in risk for oral clefts. It is important to put this risk into perspective. If we assume that the findings from the North American registry are true, the absolute risk of having a child with cleft lip or palate is about 0.9%. Clearly more data are essential to better evaluate the reproductive safety of lamotrigine; important questions regarding the safety of lamotrigine and other anticonvulsants might be best addressed by collaboration between multiple registries, including EURAP and the North-American Anti-Epileptic Drug Registry.
The consequences of prenatal exposure to benzodiazepines have been debated for over twenty years. Three prospective studies support the absence of increased risk of organ malformation following first trimester exposure to benzodiazepines. More controversial has been the issue of whether first trimester exposure to benzodiazepines increases risk for specific malformations. Although initial reports suggested that there may be an increased risk of cleft lip and cleft palate, more recent reports have shown no association between exposure to benzodiazepines and risk for cleft lip or palate. This risk– if it exists — is calculated to be 0.7%, approximately a ten-fold increase in risk for oral cleft over that observed in the general population. Nonetheless, the likelihood that a woman exposed to benzodiazepines during the first trimester will give birth to a child with this congenital anomaly, although significantly increased, remains less that 1%.
Currently, no systematic data are available on the reproductive safety of non-benzodiazepine anxiolytic agents such as buspirone and hypnotic agents zolpidem (Ambien) and zalepion (Sonata). Therefore, these medications are not recommended for use in pregnancy.
Recent studies have not demonstrated teratogenic risk associated with high- or medium-potency neuroleptic medications; however, a recent meta-analysis of the available studies noted a higher risk of congenital malformations after first trimester exposure to low-potency neuroleptic agents. In clinical practice, higher potency neuroleptic agents such as haloperidol (Haldol), perphenazine (Trilafon), and trifluoperazine (Stelazine) are recommended over the lower potency agents in managing pregnant women with psychiatric illness.
Information on the reproductive safety of the newer or “atypical” anti-psychotic medications is sparse but the body of data is growing. Thus far, most of the data on the reproductive safety of atypical agents has been limited to manufacturers’ accumulated case series and spontaneous reports. Among the 242 reports of olanzapine-exposed pregnancies collected by the manufacturer, there was no increase in risk of major malformations above baseline. Of 523 clozapine-exposed pregnancies, there were reported 22 “unspecified malformations.” In 151 reported quetiapine-exposed pregnancies, 8 infants were observed to have congenital anomalies. Eight malformations were reported among the infants born to approximately 250 women taking risperidone; however, pregnancy outcomes were not known in many of these cases reported to the manufacturer. Taken together, these reports do not suggest an increase in the risk of major malformation above the baseline 2% to 4% risk of malformations seen in the general population, nor do they indicate any specific pattern of abnormalities among drug-exposed infants.
The first published prospective study on the reproductive safety of the atypical agents provides reassuring data regarding the risk of malformations in infants exposed to these drugs. In this study, investigators prospectively followed a group of 151 women taking olanzapine, risperidone, quetiapine, or clozapine during pregnancy; all women had taken the medication during the first trimester. A comparison group of 151 healthy pregnant women were also followed. Rates of spontaneous abortion and therapeutic abortion were higher in the exposed group than in the comparison group, although this finding was not statistically significant. There were no differences between the two groups in terms of rates of major malformations, mean gestational age, birth weight, rates of complications at labor or neonatal complications. However, we can make only limited conclusions based on this type of information; larger numbers are needed to indicate safety. Atypical antipsychotics are best avoided if possible, although they are not absolutely contraindicated during pregnancy. Atypical antipsychotics should be reserved for use in more challenging clinical situations where treatment with more conventional agents has not been helpful.
Weighing the Risks
Women with histories of psychiatric illness frequently present for consultations regarding the use of psychotropic medications during pregnancy. Not infrequently, women present with the first onset of psychiatric illness while pregnant. Decisions regarding the initiation or maintenance of treatment during pregnancy must reflect an understanding of the risks associated fetal exposure to a particular medication but must also take into consideration the risks associated with untreated psychiatric illness in the mother. Psychiatric illness in the mother is not a benign event and may cause significant morbidity for both the mother and her child; thus, discontinuing or withholding medication during pregnancy is not always the safest option.
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