PEDIATRICS Vol. 105 No. 4 April 2000, pp. 880-887

AMERICAN ACADEMY OF PEDIATRICS:
Use of Psychoactive Medication During Pregnancy and Possible Effects on the Fetus and Newborn

Committee on Drugs

	ABSTRACT

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Psychoactive drugs are those psychotherapeutic drugs used to modify emotions and behavior in the treatment of psychiatric illnesses. This statement will limit its scope to drug selection guidelines for those psychoactive agents used during pregnancy for prevention or treatment of the following common psychiatric disorders: schizophrenia, major depression, bipolar disorder, panic disorder, and obsessive-compulsive disorder. The statement assumes that pharmacologic therapy is needed to manage the psychiatric disorder. This decision requires thoughtful psychiatric and obstetric advice.

The primary literature on use of these drugs during pregnancy has been extensively reviewed in the past decade.^1-13 The serious consequences to the mother and fetus of not using these drugs during pregnancy also have been addressed.^4,6,8,11,13 The Food and Drug Administration (FDA) classifies drugs for teratogenic risk as shown in Table 1.^14,15 Friedman et al¹⁶ and the Public Affairs Committee of the Teratology Society¹⁷ have challenged these "Use-in-Pregnancy Ratings." These authors believe that the ratings do not provide sufficient useful therapeutic guidance to physicians and that the default assignment of agents to FDA category C is misleading to many practitioners who consider this rating to indicate some degree of risk (ie, more risk than that of category B) rather than a lack of information from studies in humans. They recommend FDA ratings be replaced by narrative statements that summarize and interpret available data regarding hazards of developmental toxicity and provide estimates of teratogenic risk. The Committee on Drugs is encouraged to note that an FDA subcommittee is actively working on this issue assisted by the Office of Research on Women's Health of the National Institutes of Health.¹⁸

Estimates of risk for drugs used during pregnancy are derived largely from case reports or retrospective cohort epidemiologic studies. These types of studies are often biased or flawed because of possible reporting bias and the many confounding variables, such as nutritional and health status; maternal age; use of alcohol, tobacco, or illicit drugs; environmental toxins; history of miscarriages and stillbirths; genetic history; use of multiple drugs including nonprescription drugs; gestational age at time of drug exposure; compliance; total dose; and the effects of the psychiatric illness or other illnesses present. Our knowledge will remain limited because prospective, randomized, and well-controlled investigational studies on the risks of exposure to psychoactive drugs during pregnancy are neither feasible nor ethical.¹⁹ When psychoactive drugs are medically indicated during pregnancy, this exposure could provide an opportunity to conduct prospectively controlled comparisons of the fetal effects of these drugs to carefully matched controls. Recent prospective, well-controlled epidemiologic studies have lessened, to some extent, the concerns that lithium and fluoxetine are teratogenic.^20-22 Guidelines published in 1996²³ for the use of anticonvulsants during pregnancy are available.

With these limitations in mind, this statement provides literature-based guidelines to assist physicians with appropriate drug selection for women who contemplate pregnancy or are pregnant and who have psychiatric disorders that require drug treatment. Information about the effects of those drugs on the fetus and newborn is also provided. Detailed advice regarding drug selection is provided in the accompanying tables. The determination of which drug treatment to use entails the following: 1) physician and informed patient (family) risk-benefit analysis; 2) an assessment of risk for the fetus and the breastfed newborn²⁴; 3) consideration of skip-generation or first filial (F1) generation risk (eg, epidemiologic evidence of the development of vaginal cancer in the offspring of a mother exposed to diethylstilbestrol)²⁵; and 4) the family medical history, especially a history of psychoactive drug treatment that was effective.

	BENEFITS AND RISKS OF DRUG TREATMENT

Because of the potential for teratogenesis and other adverse events in the fetus or newborn, varying degrees of concern exist when any drug is prescribed during pregnancy. Avoidance of pregnancy and avoidance of drug therapy during pregnancy are commonly suggested strategies to prevent fetal drug exposure. However, these strategies are often not possible. It frequently becomes necessary to contemplate pharmacotherapy following counseling of a pregnant woman who has a serious psychiatric illness, because the benefit of appropriate psychoactive drug treatment has been clearly established.²⁶

Drug treatment is indicated if psychotherapy is inadequate or inappropriate for the patient's severity of illness. Once a decision to offer pharmacotherapy is made, important factors in drug selection for the mother include efficacy of the drugs available, the anticipated response of the individual patient, and the overall toxicity profile of the drug for the mother and fetus.

Potential adverse effects for the fetus and the neonate include: 1) structural malformations, 2) acute neonatal effects including intoxication and neonatal abstinence syndromes, 3) intrauterine fetal death, 4) altered fetal growth, and 5) neurobehavioral teratogenicity. Neurobehavioral teratogenicity encompasses long-term central nervous system defects that result in delayed behavioral maturation, impaired problem solving, and impaired learning.²⁷ Physical malformations do not necessarily accompany the functional deficits. Chronic in utero exposure to drugs may result in intoxication or tolerance postnatally.²⁸ Neonatal drug withdrawal symptoms may occur when drug exposure ceases at birth.²⁹ Specific and supportive therapy may be required if the newborn displays signs of continued drug effects or withdrawal. Long-term developmental and neurologic follow-up is appropriate, including consideration for referral to centers for national databases (eg, Teratology Information Services and Motherisk Program).

	GENERAL DOSING RECOMMENDATIONS

Before it is possible to predict potential adverse events based on pharmacokinetic data, considerable pharmacokinetic studies will be required in infants and children. Adverse drug events are often linked to the pharmacokinetic variations in maternal, placental, fetal, or neonatal drug absorption, distribution, metabolism, and elimination.^30,31 Some of these alterations are likely to increase or decrease the dose necessary for many drugs during pregnancy, thus increasing or decreasing the risk for fetal exposure. The change in dose can be complex depending on the trimester(s) of exposure. For example, to maintain serum levels within the therapeutic range, particularly in the third trimester, the dose of tricyclic antidepressant must be increased 1.6 times the mean does required when the patients are not pregnant.³² In addition, some drugs tend to concentrate in the fetus, and their effects may be prolonged even after delivery.¹ It is advisable to monitor the effectiveness of treatment throughout pregnancy to achieve the lowest effective dose of any agent.

Depending on severity of the disorder and opinion of the attending physician in consultation with other physicians (eg, psychiatrist, pediatrician, or obstetrician), it may be advisable to discontinue psychoactive drug(s) by tapering the dose, especially for anti-anxiety drugs, ~2 weeks before the estimated delivery date to minimize neonatal effects. However, cessation of drug treatment is usually inappropriate for patients with severe disease, and it may be associated with discontinuation syndromes or recurrence of signs and symptoms.

	SCHIZOPHRENIA

Comments on the common fetal, neonatal, and teratogenic effects of antipsychotic drugs, and guidelines for drug selection appear in Table 2. The continuum from lower to higher potency not only reflects the dose but also the differing adverse reaction profiles of these agents. Maternal side effects of the lower potency agents include sedation (antihistaminergic), gastrointestinal dysfunction, tachycardia (anticholinergic), hypotension (-antiadrenergic), hyperprolactinemia, and, rarely, extrapyramidal reactions and cholestatic jaundice. Side effects of the higher potency agents consist of extrapyramidal reactions, such as acute dystonia, akathisia, parkinsonism, and tardive dyskinesia.

Newer agents include: 1) a low-potency antipsychotic agent, clozapine (Clozaril), which produces minimal extrapyramidal reactions in adult patients, but infrequently causes agranulocytosis (cumulative incidence: 0.8% at 12 months of treatment and 0.91% at 18 months of treatment³³); 2) a high-potency antipsychotic agent, olanzapine (Zyprexa); and 3) risperidone (Risperdal), a high-potency agent pharmacologically similar to haloperidol. The use of these newer agents is increasing rapidly; however, almost no systematic studies in pregnant women are available.

	DEPRESSION

The principal drugs used to treat major depression are listed in Table 3. Comments on their neonatal and possible teratogenic effects and guidelines for drug selection are included in the table.

The frequency of seizures is increased in pregnant women receiving maprotiline compared with other tricyclic antidepressants. Because equally effective drugs for depression are available, maprotiline should be avoided during pregnancy, particularly in patients with hypertension and seizure disorders.³⁴

Monoamine oxidase inhibitors are not frequently recommended or used in pregnancy, because they can exacerbate hypertension, and their drug and food interaction profile is extensive and often complicates treatment. No maternal or fetal adverse complications were noted in 2 women taking phenelzine throughout pregnancy.^35,36

Unlike the tricyclics, fluoxetine therapy does not result in maternal sedative, anticholinergic, hypotensive actions, and cardiotoxicity. Compared with tricyclics, serious acute reactions are less likely after large doses. Common side effects include nausea, somnolence, insomnia, sexual dysfunction, headache, tremor, dyspepsia, abdominal pain, and nervousness.

	BIPOLAR DISORDER

Mood stabilizing drugs used to treat the manic phase of bipolar disorder include lithium, carbamazepine, and valproic acid. Benzodiazepines with weakly active, short-lived, or inactive metabolites (eg, alprazolam and lorazepam) are also given occasionally in conjunction with antipsychotic agents to control agitation. Carbamazepine and valproic acid are used alone or in combination with lithium for maintenance therapy in patients who do not respond adequately to lithium.

The principal mood stabilizing drugs and comments on their major fetal and teratogenic effects and guidelines for drug selection are listed in Table 4. If an antipsychotic, antidepressant, or benzodiazepine drug needs to be added to the regimen for management of bipolar disorder, see the guidelines section in Tables 2, 3, and 5, respectively.

	PANIC DISORDER

Most patients with panic disorder can be managed by cognitive behavioral techniques except when anxiety is sufficiently severe to produce social dysfunction, depression, and suicidal ideation.³⁷ The treatment of choice for panic disorder is an antidepressant; however, benzodiazepines may be used in the initial stages of treatment for an acute attack because antidepressants do not have an immediate clinical effect. Imipramine, phenelzine, or fluoxetine can be used for preventive therapy. Although alprazolam is the only benzodiazepine approved for treatment and prevention of panic disorder, lorazepam, clonazepam, and diazepam have similar efficacy.³⁸ Antidepressants, especially selective serotonin re- uptake inhibitors, are preferred to benzodiazepines for preventive therapy.

The principal drugs used in the prevention and treatment of panic disorder and comments on their major neonatal and possible teratogenic effects, as well as guidelines for drug selection are listed in Table 5. See Table 3 for additional information on the tricyclics, the monoamine oxidase inhibitors, and the selective serotonin re-uptake inhibitors.

	OBSESSIVE-COMPULSIVE DISORDER

Obsessive-compulsive disorder is now recognized as common, developing in 1% to 2% of the general population.^39,40 Patients who are severely affected require both behavioral and pharmacologic therapy.⁴¹ Symptoms of both anxiety and depression are quite common and may require drug therapy.

The tricyclic with the most selective serotonergic re-uptake inhibitory action, clomipramine, and the selective serotonin re-uptake inhibitors, fluoxetine and fluvoxamine,⁴² are approved for patients with this disorder. Although the data are more limited, fluvoxamine, paroxetine and sertraline are acceptable alternatives that seem to lack teratogenic effects.⁴³

The antiobsessional agents used to manage obsessive-compulsive disorder and comments on their major neonatal and possible teratogenic effects, as well as guidelines for drug selection are listed in Table 6.

	CONCLUSION

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After counseling of the pregnant woman, severe psychiatric illness may compel drug treatment. To minimize the risk of fetal and neonatal toxicity, including an abstinence syndrome, the physician should prescribe the lowest dosage that provides adequate control of the woman's illness. The neonate must be monitored for evidence of persistent drug effect or development of an abstinence syndrome. The Committee encourages long-term research on prospective studies of structural malformations and neurobehavioral teratogenicity.

The recommendations in this policy statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate.⁴⁴

	OTHER RESOURCES

An on-line clinical automated teratology database, TERIS, is available by subscription from the Office of Teratology Information Services for a fee of $1000 at the following Web site address: http://weber.u.washington.edu/terisweb/teris/index.html. Summaries in this database include timely data on teratogenicity, transplacental carcinogenesis, embryonic or fetal death, and fetal and perinatal pharmacologic effects of drugs and selected environmental agents. Another database is available from the National Library of Medicine at: http://www.index.nlm.nih. gov/sitemap.html. Additional references provided in Teratogenic Effects of Drugs: A Resource for Clinicians,⁴⁵ Catalog of Teratogenic Agents,⁴⁶ Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risks,⁷ and Chemically Induced Birth Defects⁴⁷ are also recommended.

	ACKNOWLEDGMENT

The Committee on Drugs wishes to acknowledge the invaluable assistance provided by the American Psychiatric Association and the American College of Obstetricians and Gynecologists for their technical support in reviewing this policy.

COMMITTEE ON DRUGS, 1998-1999
Robert M. Ward, MD, Chairperson
Brian A. Bates, MD
D. Gail McCarver, MD
Daniel A. Notterman, MD
Philip D. Walson, MD
Douglas N. Weismann, MD
John T. Wilson, MD

LIAISON REPRESENTATIVES
Owen R. Hagino, MD
  American Academy of Child and Adolescent Psychiatry
Donald R. Bennett, MD, PhD
  American Medical Association/United States Pharmacopeia
Joseph Mulinare, MD, MSPH
  Centers for Disease Control and Prevention
Richard Depp III, MD
  American College of Obstetricians and Gynecologists
John Siegfried, MD
  Pharmaceutical Research and Manufacturers of America
Siddika Mithani, MD
  Health Protection Branch, Canada
Stuart M. MacLeod, MD, PhD
  Canadian Paediatric Society
Therese Cvetkovich, MD
  Food and Drug Administration
Sumner J. Yaffe, MD
  National Institutes of Health

AAP SECTION LIAISONS
Charles J. Coté, MD
  Section on Anesthesiology
Stanley J. Szefler, MD
  Section on Allergy and Immunology

CONSULTANT
Katherine L. Wisner, MD

	FOOTNOTES

The recommendations in this statement do not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.

	ABBREVIATIONS

FDA, Food and Drug Administration.

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