Effects of Antimanic Mood-Stabilizing Drugs on Fetuses, Neonates, and Nursing Infants

Mohammad Masud Iqbal, MD, MPH, MSPH, DTM; Sai Prakash Gundlapalli, MD, William G. Ryan, MD, Thad Ryals, MD, Birmingham, Ala; Terry E. Passman, MD, Department of Psychiatry and Behavioral Neurobiology, the Regional Neonatal Intensive Care Unit, and the Department of Epidemiology and International Health, University of Alabama at Birmingham School of Medicine; and the Harbor Unit, Thomas Hospital, Fairhope, Ala

South Med J. 2001;94(3) 

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The ability of drugs to pass from the mother to the fetus and the nursing infant must be considered when administering antimanic drugs. High levels of lithium, VPA, and carbamazepine and low levels of folate in the maternal blood are risk factors for teratogenesis in animals and humans during pregnancy. In utero exposure to these agents and to clonazepam during the first trimester of pregnancy increases the risk of major and minor anomalies. Adverse effects include intrauterine growth retardation, prenatal and postnatal internal bleeding, increased perinatal mortality, apnea, premature labor, neurologic toxicity, developmental delay, hypoglycemia, and psychomotor and mental retardation. Although some studies have shown that lithium can be used safely during pregnancy, these antimanic drugs should be avoided if possible, especially during the sensitive phase of organogenesis (days 18 through 55 after conception).

To date, there is insufficient research to establish whether the new second-generation anticonvulsants (gabapentin, lamotrigine, and topiramate), conventional antipsychotics (chlorpromazine, haloperidol, fluphenazine, and thiothixene), and atypical antipsychotics (clozapine, risperidone, and olanzapine) have any teratogenic effects on the fetus or nursing infant.

Although pregnancy for women with bipolar disorder is considered a high-risk obstetric condition, most women with this disease can have safe pregnancies and healthy babies. To achieve this goal, several steps must be taken. Prenatal counseling should begin at least 3 months before conception. It is necessary to make sure that a woman understands the concept of teratogenic risk and the perinatal risk of nursing associated with treatment of her medical condition. A woman with manic-depressive disorder treated with lithium, VPA, or carbamazepine in the first trimester will need to understand not only the increased risk of fetal cardiac and neurologic anomalies associated with these drugs, but also the increased genetic risk of bipolar illness in her child. Antimanic drug dosage adjustments should be based on symptoms as well as on serum drug concentrations. Prenatal examinations should include a fetal structural level 2 ultrasound examination at 18 to 20 weeks' gestation. If the anticonvulsant drugs cannot be avoided during pregnancy, monotherapy with the lowest possible dosage is recommended. Electroconvulsive therapy (ECT) may be used for patients who need immediate stabilization of their bipolar condition, those with suicidal thoughts, and those who cannot tolerate or do not respond to medications. The literature contains more than 300 reports of ECT used during pregnancy with no clear evidence of teratogenic effects.[211]

Monotherapy is preferable because of the higher risk of congenital malformation associated with combination therapy. If lithium, VPA, or carbamazepine is used, the daily dose should be divided into three or four doses to minimize peak serum levels, since evidence shows that teratogenicity of these drugs is dose-dependent. Folate supplementation of 4 mg/day beginning at 3 months before conception and continuing through 12 weeks of gestation reduces the risk of neural tube defects, especially for those taking any anticonvulsant (particularly VPA or carbamazepine). Although there is no conclusive proof that periconceptional folate supplementation in women using anticonvulsant drugs prevents neural tube defects, we believe that by following these guidelines more than 90% of pregnant women using VPA and carbamazepine today can expect normal infants.[212]

The antimanic drugs that can be prescribed safely during pregnancy are chlorpromazine, haloperidol, fluphenazine, and clozapine. The remainder have been associated with some adverse effects during pregnancy and are obviously not recommended unless specifically indicated. Whether the new second-generation anticonvulsant drugs, such as gabapentin, lamotrigine, and topiramate, are good choices for the pregnant woman with bipolar disorder remains to be seen. The limited number of human pregnancy exposures to date do not signal a significant number or particular type of adverse outcomes.

Caution should be exercised when antimanic drugs are given to a nursing mother. All products ingested by the mother are excreted in some form in human milk. The antimanic drug therapy may be discontinued temporarily if it is not essential. The lowest possible dosages may be used in limited time frames with adequate supervision of the infant. Factors that should be considered when prescribing a drug to a nursing mother include the potential acute toxicity of the drug, dosage and duration of therapy, age of the infant, quantity of milk consumed, experience with the drug in infants, pharmacokinetics in the infant, potential long-term effects, and possible interference with lactation. In general, nursing women receiving medication should stop nursing if the drug is known to be harmful to the infant or when using a drug that is so potent that even small amounts could be harmful.

On the basis of data about infant serum levels and reported adverse effects, only VPA and carbamazepine may be used during breast feeding. Other drugs such as thiothixene, risperidone, olanzapine, and clonazepam can be used with caution. Lithium, gabapentin, lamotrigine, topiramate, haloperidol, fluphenazine, and clozapine should be used only when the potential benefits justify the possible risks to the infant.


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