The Safety of Psychotropic Drug Use During Pregnancy: A Review

Abstract and Background

Abstract

A substantial number of women of childbearing age are prescribed psychotropic drugs, and because nearly 50% of pregnancies are unplanned, many women are still taking them upon becoming pregnant. This article reviews the various classes of psychotropic drugs that are commonly used to treat psychiatric disorders -- antidepressants, benzodiazepines, antipsychotics, antiepileptics, lithium and monoamine oxidase (MAO) inhibitors -- in terms of their safety during pregnancy. Evidence-based information from epidemiologic studies indicates that most psychotropic drugs are relatively safe for use during pregnancy. There is also an increasingly large body of evidence-based information in the literature indicating that it may be more harmful to both the mother and her baby if she is not treated appropriately when suffering from a severe psychiatric disorder. Therefore, it is important for women with psychiatric disorders and their healthcare providers to have access to evidenced-based information about the safety of these drugs when taken during pregnancy to ensure that women make an informed decision as to whether they should continue with the pharmacotherapy they have been using to treat their condition.

Background

Psychiatric disorders are common among women of childbearing age, and affected women are frequently prescribed psychotropic drugs. However, despite the fact that most recent studies have documented the relative safety of these medications during pregnancy, there remains a high level of anxiety regarding their safety among patients and healthcare providers alike. For every pregnancy, the baseline risk of a major congenital malformation is 1% to 3% of the population, so chance alone would account for a substantial number of children born with birth defects whose mothers consumed medications in early pregnancy. This concept is often misunderstood and, consequently, many of these birth defects have been attributed to the consumption of drugs.^[1]

In addition, some women believe that psychotropic drugs must be more harmful to take during pregnancy than other drugs because they act on the brain.^[2] Moreover, the media tend to exacerbate women's fears by frequently stressing positive associations between drug treatment and birth defects while ignoring the results of studies that show negative associations.^[3] Because of these factors as well as others -- such as well-meaning friends and family who advise women not to take any drugs during pregnancy^[2] -- it is not surprising that either their own fears or the advice of well-intentioned healthcare providers lead some women to decide to discontinue their psychotropic medications upon diagnosis of a pregnancy.^[4]

The objective of this review is to examine all of the information in the literature regarding the use of psychotropic drugs during pregnancy. This will provide women and their healthcare providers with evidence-based information about the safety of these drugs during pregnancy and help women make an empowered decision regarding pharmacotherapy during pregnancy.

Antidepressants

Major Malformations

To date, none of the antidepressants that have been studied in pregnancy have been found to increase the baseline rate of 1% to 3% for major malformations.^[5-11] In addition, a meta-analysis examined almost 1800 women who used the newer antidepressants during pregnancy in 7 prospective, comparative studies and found no increased risk for major malformations.^[12] There is little information on the safety of mirtazepine, which has a tetracyclic structure and is unrelated to any other antidepressant. Recently, a collaborative group examined 96 pregnancy outcomes of women exposed to mirtazepine.^[13] There were 3 groups of women in the study: group 1 was exposed to mirtazepine, group 2 was exposed to other antidepressants, and group 3 consisted of nondepressed, nonexposed women. There were no differences in the rates of malformations in the 3 groups.

Spontaneous Abortions

Most studies of antidepressant use during pregnancy report an increased rate of spontaneous abortions in the women exposed to antidepressants. To further examine this finding, our research team at The Motherisk Program, The Hospital for Sick Children, Toronto, Canada, conducted a meta-analysis to determine baseline rates of spontaneous abortions and whether antidepressants increase those rates.^[14] Rates of spontaneous abortions in women taking antidepressants compared with nondepressed women were combined into a relative risk (RR) using a random effects model. Of 15 potential articles, 6 cohort studies of 3567 women (1534 exposed, 2033 nonexposed) provided extractable data. All were matched on important confounders. The baseline spontaneous abortion rate (95% CI) was 8.7% (7.5% to 9.9%; n = 2033). For antidepressants, the rate was 12.4% (10.8% to 14.1%; n = 1534), significantly increased by 3.9% (1.9% to 6.0%); RR was 1.45 (1.19 to 1.77; n = 3567). No differences were found among antidepressant classes. Although the most recent study on mirtazepine was not included in the meta-analysis, the rate of spontaneous abortion was higher in the exposed group versus the nondepressed, nonexposed group (18% vs 10%).^[13] However, these results did not reach statistical significance because of the small sample size.

Long-term Neurodevelopmental Adverse Outcomes

A concern typically associated with the use of psychoactive medications during pregnancy, including antidepressants, is the possibility of adverse neurodevelopmental sequelae with exposure to these medications in utero. To address these concerns with respect to fluoxetine and tricyclic antidepressants (TCAs), a long-term assessment was conducted of temperament, mood arousability, activity level, distractibility, and, most importantly, global IQ and language development in children of 80 women exposed to TCAs and 55 women exposed to fluoxetine during the first trimester of pregnancy.^[15] Assessment of language development and IQ occurred between 16 and 86 months postnatal age. No significant differences between the groups were detected in any of the parameters examined. A second long-term neurodevelopmental follow-up, conducted by the same authors, examined the offspring of 40 women exposed to TCAs and 46 women exposed to fluoxetine throughout gestation and compared them with those of 36 non-teratogen-exposed women with respect to language development, global IQ, and temperament between 15 and 71 months postnatal age.^[16] In their analyses, these researchers also adjusted for the effects of duration and severity of maternal depression, duration of pharmacologic treatment, number of depression episodes after delivery, maternal IQ, socioeconomic status, cigarette smoking, and alcohol use. No association between gestational use of TCAs or fluoxetine and language development, global IQ, or temperament was observed. By contrast, global IQ was negatively associated with duration of depression, and language development was negatively correlated with the number of postnatal depressive episodes, suggesting that the children of depressed mothers have decreased global IQ and language development in comparison to the children prenatally euthymic women.

Poor Neonatal Adaptation

Recently, there have been a number of reports describing poor neonatal adaptation in some babies and documenting increased admission to the neonatal intensive care unit (NICU) in neonates exposed to antidepressants during the last trimester of pregnancy. Clinical manifestation of poor neonatal adaptation has included such symptoms as jitteriness, tachycardia, hypothermia, vomiting, hypoglycemia, irritability, constant crying, increased tonus, eating/sleeping difficulties, convulsions, and respiratory distress; these symptoms are usually transient and self-limiting. Unfortunately, because of the lack of epidemiologic studies, there is no definitive prevalence as to how often this actually occurs. However, after examining all of the reports, it seems that this pattern of symptoms may occur in up to 30% of all babies who have been exposed to selective serotonin reuptake inhibitors during late pregnancy. However, to put things into perspective, in studies that had comparative groups, this same pattern of symptoms was seen in 6% to 9% of babies who were not exposed.

Poor neonatal adaptation occurs when infants who were exposed in utero to various antidepressants in late pregnancy abruptly discontinue them -- that is, they were born and thus are no longer exposed to the antidepressant. If clinicians identify those cases with exposure to antidepressants during late pregnancy, it is important that the babies be observed for longer than the typical 1 to 2 days postpartum to detect neonatal symptomatology. Infants with symptoms are treated conservatively in the vast majority of cases, with observation in a NICU, and they do not appear to manifest any residual effects.^[17]

Untreated Depression During Pregnancy

Recently, researchers have been examining the possibility that not treating depression during pregnancy may have adverse effects for both the mother and child. Our group published a review on this topic and found that although there is a wide variability in reported effects, untreated depression during pregnancy appears to carry substantial perinatal risks, which include suicidal ideation; increased risk for miscarriages, hypertension, preeclampsia, and lower birth weight; and, importantly, an increased risk for postpartum depression.^[18] These may be direct risks to the fetus and infant or risks secondary to unhealthy maternal behaviors arising from the depression. Our conclusion was that untreated postpartum depression -- not treatment with antidepressants during pregnancy -- results in adverse perinatal outcomes.

In other research on depression during pregnancy and the postpartum period, a British study documented that maternal depression during pregnancy has been relatively neglected in favor of postnatal depression, even though it is more prevalent and approximately 25% of cases of postpartum depression actually began during pregnancy.^[19] In addition, as part of a large screening study of perinatal depression, an American group screened pregnant women for demographic, depression, and treatment variables in obstetrics clinics. Women taking antidepressant medication before conception were included in the sample, as the study aimed to document rates of antidepressant medication use and the relationship to depressive symptomatology. Among women who reported using antidepressant medications within 2 years prior to screening (n = 390, or 11% of all women), 22% reported current use of these medications. Women who reported using antidepressant medications (52%) and those who discontinued them (49%) had elevated depressive symptoms during pregnancy.^[20]

The Committee on Research on Psychiatric Treatments of the American Psychiatric Association identified treatment of major depression during pregnancy as a priority area in clinical management. On the basis of this recommendation, a position paper was published on the risk-benefit decision making for treatment of depression during pregnancy.^[21] The authors concluded that there was no evidence to implicate antidepressants as causing harm to an unborn baby and that a pregnant women should be treated so long as the benefits and possible risks are well explained to her.

Benzodiazepines

Despite the fact that benzodiazepines have been on the market for more than 40 years, the safety of their use during pregnancy remains controversial because there have been conflicting results regarding their teratogenicity, with some studies citing an increased risk and others not.^[23-25]

Major Malformations

The risk for congenital malformations with use of benzodiazepines during the first trimester of pregnancy was addressed by a meta-analysis that included 23 studies.^[25] Pooled data from the case-control studies revealed a significant increase in the risk of major malformations (odds ratio [OR] 3.01; 95% CI1.32-6.84) or oral cleft alone (OR 1.79; 95% CI1.13-2.82). It is important to note that the case-control studies included in the meta-analysis were heterogeneous, which decreases the reliability of the marginally significant results. Pooled data from the cohort studies, on the other hand, revealed no association between fetal exposure to benzodiazepines and the risk of oral clefts (OR 1.19; 95% CI 0.34 - 4.15) or any other major malformation (OR 0.90; 95% CI0.61-1.35).

In summary, there is insufficient evidence to prove that benzodiazepines are human teratogens. The absolute risk for clefts, if present, remains small (incidence of oral clefts in the general population is about 1/1000), so the 2-fold increase translates to 2/1000. If a woman requires a benzodiazepine in pregnancy or has been taking benzodiazepines prior to becoming pregnant, she should be advised of this conflicting information, and a level 2 ultrasound can be performed to rule out visible forms of oral clefts.

Poor Neonatal Adaptation

Babies of mothers should be watched carefully after birth for signs of abrupt discontinuation syndrome, which may include sedation, hypotonia, reluctance to suck, apnea, cyanosis, and impaired metabolic responses to cold stress. However, these effects are self limiting.^[26] Women who require a benzodiazepine during pregnancy must weigh the benefits with the possible risks and could decrease the dose during late pregnancy to minimize the discontinuation effects in the neonate.

Long-term Neurodevelopmental Adverse Effects

There have been no reports of long-term adverse effects on the IQ or neurodevelopment in children born to mothers taking benzodiazepines during pregnancy.^[26]

Antipsychotics

Conventional Antipsychotics

Conventional antipsychotic agents have been on the market for more than 40 years, and there is no evidence that, when used during pregnancy, they increase the rates of major malformations.

Major Malformations

The Collaborative Perinatal Project monitored 142 mother-child pairs who were exposed to chlorpromazine during the first trimester of pregnancy and did not find an increased risk for major malformations. Furthermore, perinatal mortality rates and birth weights were similar to those for the general population.^[27] Recently, a study was published that assessed the safety of the butyrophenone neuroleptics haloperidol and penfluridol during pregnancy.^[28] The rates of major malformations were compared between a cohort of pregnant women exposed to haloperidol or penfluridol during pregnancy and a nonexposed comparison group. Outcomes were ascertained for 215 pregnancies with exposure to haloperidol (n = 188) or penfluridol (n = 27) and compared with outcomes for 631 controls. The rates of major malformations did not differ between the haloperidol/penfluridol-exposed group and the control group.

Atypical Antipsychotics

There is little information on the safety of the newer, so-called atypical antipsychotics. A single study from our group was recently published that documented 151 pregnancy outcomes in women exposed to these drugs, including olanzepine (n = 60) risperidone (n = 49), quetiapine (n = 36), and clozapine (n = 6).^[29]

Among women exposed to an atypical antipsychotic, there were 110 live births (72.8%), 22 spontaneous abortions (14.5%), 15 therapeutic abortions (9.9%), and 4 stillbirths (2.6%). Among babies of women in this group, there was 1 major malformation (0.9%), and the mean birth weight ± standard deviation (SD) was 3341 ± 685 g. There were no statistically significant differences in any of the pregnancy outcomes of interest between the exposed and comparison groups, with the exception of the rate of low birth weight, which was 10% in exposed babies compared with 2% in the comparison group (P = .05). There was a higher rate of spontaneous abortions 22 (14.5%) in the exposed group vs 13 (8.6%) in the nonexposed group. Because of the small sample size, however, this did not reach statistical significance.

Long-term Neurodevelopmental Studies

In a prospective cohort study of 50,282 women and their offspring, intelligence quotients at 4 years of age in 1309 children of women exposed to phenothiazine drugs during the first 4 lunar months of pregnancy were similar to those of 48,973 children of women who were not exposed.^[27]

Possible Neonatal Adverse Effects

Infants who have been exposed to neuroleptics throughout pregnancy should be watched carefully after birth for any signs of extrapyramidal symptoms.^[30] A woman requiring antipsychotic medication during pregnancy should not change her treatment if she is well controlled, as it is important for her child that she be a well-functioning individual who can adequately interact with and take care of her baby.

Antiepileptics

The commonly used older anticonvulsants used to treat epilepsy are established human teratogens.

Major Malformations

The use of older anticonvulsants in pregnancy increases the rates of neural tube defects. At 1%, carbamazepine appears to have the lowest teratogenic effect of the older anticonvulsants. Phenytoin has higher overall rates of malformations, at approximately 10%. In the past, valproic acid was thought to have an approximately 2% risk.^[31] However, a recent study from the Antiepileptic Drug Pregnancy Registry in Boston documented a higher than previously known risk for valproic acid. Sixteen affected cases were identified among 149 women exposed to valproic acid (proportion: 10.7%; 95% CI: 6.3%-16.9%). The prevalence in the internal comparison group was 2.9% (95% CI: 2.0 to 4.1%; OR: 4.0, 95% CI: 2.1 to 7.4; P < .001). Assuming a 1.62% prevalence in the external comparison group, the relative risk of having an affected offspring for the exposed women was 7.3 (95% CI: 4.4 to 12.2; P < .001). Three babies in this group were born with neural tube defects, which is significantly higher than what would be expected for this sample size, as neural tube defects occur in 1/1000 births. Of note, all 3 women whose babies were born with a neural tube defect took the recommended amount of folic acid preconceptionally.^[32]

Newer Anticonvulsants

Increasing information on the newer anticonvulsants has come to light.

Major Malformations

Recently, the results of a pregnancy registry were published. Among 414 first-trimester exposures to lamotrigine monotherapy, 12 outcomes with major birth defects were reported (2.9%, 95% CI 1.6% to 5.1%). Among the 88 first-trimester exposures to lamotrigine polytherapy including valproate, 11 outcomes with major birth defects were reported (12.5%; 95% CI 6.7% to 21.7%). Among 182 first-trimester exposures to lamotrigine polytherapy excluding valproate, 5 outcomes with major birth defects were reported (2.7%, 95% CI 1.0% to 6.6%). No distinctive pattern of major birth defects was apparent among the offspring exposed to lamotrigine monotherapy or polytherapy.^[33]

Another study, which included 248 pregnancies with maternal exposure to oxcarbazepine monotherapy and 61 with exposure to oxcarbazepine adjunctive therapy cited 6 malformations among infants of the mothers in the monotherapy group, yielding a malformation rate of 2.4% (6/248), which is within the baseline range for the general population.^[34] There were 4 malformations associated with oxcarbazepine adjunctive therapy, yielding a malformation rate of 6.6% (4/61). These results suggest that monotherapy with this drug during pregnancy does not increase the risk for malformations.

Another registry assessed the safety of gabapentin exposure during pregnancy. Prospective and retrospective data on fetuses, including 3 twin gestations, were collected from 39 women with epilepsy and other disorders exposed to gabapentin during pregnancy.^[35] Gabapentin exposure during pregnancy did not lead to an increased risk for adverse maternal and fetal events, including major malformations.

Finally, the results of a Motherisk study did not support common belief that epilepsy per se represents a teratogenic risk.^[36] It is widely quoted that women with epilepsy have a higher than baseline risk for giving birth to a child with malformations, independent of the effects of antiepileptic drugs. Using a random effects model, we conducted a meta-analysis of all cohort and case-control studies reporting malformation rates in children of women with epilepsy exposed or not exposed to antiepileptic drugs and compared these with malformation rates for children of nonepileptic women. We found 10 studies reporting results of untreated epilepsy (n = 400) and their nonepileptic healthy controls (n = 2492); 9 out of 10 studies also reported results on 1443 patients exposed to antiepileptic drugs and their 2526 nonexposed healthy controls. The risk for congenital malformations in the offspring of women with untreated epilepsy was not higher than among nonepileptic controls (OR = 1.92; 95% CI 0.92-4.00). There was evidence of publication bias; thus, with bias removed the OR was 0.99 (95% CI 0.49-2.01). By contrast, the offspring of epileptic women who received antiepileptic drugs had higher incidences of malformation than controls (OR 3.26; 95% CI 2.15-4.93).

Neonatal Concerns

If phenobarbital, carbamazepine, or phenytoin is administered, maternal vitamin K supplementation may be given to the mother 4 to 6 weeks before the expected date of delivery and administered immediately after birth to the newborn. However, studies to date have not demonstrated a proven benefit in this practice. The neonate should be also be assessed carefully for epilepsy and anticonvulsant-associated dysmorphology.^[31]

Long-term Neurodevelopment

Motherisk prospectively collected and followed up 36 pregnant women who were exposed to carbamazepine and valproic acid monotherapy.^[37] We evaluated the relative fetal safety of carbamazepine and phenytoin for the treatment of maternal epilepsy. Children exposed in utero to carbamazepine did not differ from their controls in any of the administered neurobehavioral tests with respect to global IQ. However, the children in the phenytoin group scored 10 points lower in the global IQ and a significantly higher number of them scored less than 84. Another study that examined children into adolescence who had been exposed in utero to various antiepileptic drugs (monotherapy and polytherapy) found that maternal epilepsy and antiepileptic drug therapy during pregnancy appear to have long-term effects on the offspring well into adolescence, which manifest in EEG patterns, minor neurologic dysfunction, and intellectual performance.^[38] The severity of effects increased from control group to epilepsy/no-drug group, to monotherapy group, and was most marked in the polytherapy group.

Folic acid 4 mg/day should be taken 3 months before conception and during the first trimester to help prevent folic acid deficiency-induced malformations (neural tube defects). Prenatal management should include detailed ultrasound examination and levels of maternal serum alpha-fetoproteins. With proper preconceptional, prenatal, and postpartum management, up to 95% of these pregnancies have been reported to have favorable outcomes.^[31]

Lithium

Lithium has been on the market for many years and is commonly used to treat bipolar disorder.

Major Malformations

By 1983, there were a total of 225 case reports of children of mothers who took lithium during pregnancy in the International Registry of Lithium Exposed Babies. Evaluation of the registry at that time revealed that the number of cases of Ebstein's anomaly far exceeded the spontaneous occurrence in the general population.^[39] However, there were no population-based, prospective, controlled studies to ascertain the actual incidence. In 1992, a study conducted by Motherisk prospectively recruited and followed 148 women who took lithium during the first trimester of pregnancy. Pregnancy outcome was compared with that of controls matched for maternal age. There was complete follow-up of pregnancy outcome in 138 of 148 patients recruited. In the other 10, fetal echocardiograms were available but postnatal follow-up was not done. The mean daily dose of lithium was 927 mg (SD 340 mg). Rates of major congenital malformations did not differ between the lithium (2.8%) and control (2.4%) groups. However, 1 woman in the lithium group chose to terminate her pregnancy after Ebstein's anomaly was detected by a prenatal echocardiogram. These results indicated that lithium was not a major human teratogen and that the risk for Ebstein's anomaly is 0.5%, or 1/2000 babies whose mothers took lithium during pregnancy. To rule out this specific abnormality, the pregnant woman should undergo adequate screening tests, including detailed ultrasound and fetal echocardiography.^[40]

Neonatal Concerns

Lithium is frequently associated with perinatal complications and reversible neonatal toxicity. A review of the English literature published from 1978 to 2004 identified 30 babies who were exposed to lithium during gestation with adequate clinical description.^[41] A significant number of these babies presented with neurodevelopmental deficits and depressed neurologic status, including hypotonia, respiratory distress syndrome, cyanosis, lethargy, and weak suck and Moro reflexes during the neonatal period. However, the majority of these adverse effects resolved, and most babies made a full recovery. The newborn should be monitored carefully for possible lithium toxicity, which can include cyanosis, hypotonia, bradycardia, thyroid depression with goiter, atrial flutter, cardiomegaly, hepatomegaly, and diabetes insipidus. These toxic effects are usually self-limiting and resolve upon renal excretion of the drug within 1 to 2 weeks.

Long-term Neurodevelopment

There are no reports in the literature of any long-term adverse effects in children whose mothers took lithium in pregnancy.

MAO Inhibitors

There is very little information on the safety of the MAO inhibitors during pregnancy, probably because they are generally used as a "last resort drug"; consequently, few pregnant women are exposed to them. There are no prospective controlled studies on the safety of phenelzine, tranylcypromine, or the newer reversible MAO inhibitor moclobemide. However, there are a number of case reports and case series documenting no association with an increased risk for birth defects or other adverse effects.^[42-44]

If a woman becomes pregnant while being treated with an MAO inhibitor, she should be advised that there is little information about the safety of this drug during pregnancy and she should weigh the benefits vs unknown risks carefully.

Abrupt Discontinuation of Psychotropic Drugs

Pregnant women should be very cautious about discontinuing any psychotropic drugs abruptly. A study of women taking antidepressants and/or benzodiazepines, all of whom reported abrupt discontinuation of the drug for fear of harming their fetuses, was conducted at The Motherisk Program.^[4] In this study, 34/37 women discontinued the drugs abruptly and 3 patients used some form of tapering off. Almost one third of the patients reported suffering from suicidal ideation because of "unbearable" symptoms, 4 of whom required hospitalization. Another woman had a therapeutic abortion because she did not feel that she could go through the pregnancy because of the effects, and one woman who had abruptly discontinued a large daily dose of a benzodiazepine used alcohol to combat the abrupt discontinuation symptoms. Abrupt discontinuation of other psychotropic drugs also carries its own risk, not only the very uncomfortable physiologic effects but exacerbation of the illness. This exacerbation includes return of seizures (antiepileptics), return of psychosis (antipsychotics), and rapid recurrence of mania (lithium).

If, after receiving all of the evidenced-based information on the safety/risk of the drug, the woman still does not feel comfortable about exposing her fetus to the drug, the medication should be very gradually tapered off before discontinuing.^[45]

Concluding Remarks

The body of evidence in the literature to date suggests that psychotropic drugs as a group are relatively safe to take during pregnancy, and women and their healthcare providers should not be unduly concerned if a woman requires treatment. Just as important, it must also be noted that evidence is emerging that an untreated psychiatric disorder can exert its own risk -- not only on maternal health but also on the health of the infant. It is logical that a woman who is in optimal mental health will be the best mother she can be to her baby. The evidence-based information presented in this review can help women and their healthcare providers to make an informed decision on whether or not to use these medications during pregnancy.

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Authors and Disclosures

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Author

Adrienne Einarson, RN

The Motherisk Program, Division of Clinical Pharmacology/Toxicology, The Hospital for Sick Children, The University of Toronto, Ontario, Canada

Disclosure: Adrienne Einarson, RN, has disclosed no relevant financial relationships. Correspondence: einarson@sickkids.ca.

CME Author

Charles P Vega, MD

Associate Professor, Residency Director, Department of Family Medicine, University of California, Irvine

Disclosure: Charles Vega, MD, FAAFP, has disclosed that he has received grants for educational activities from Pfizer.

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