Prescribing drug therapy for pregnant bipolar women requires psychiatrists to balance the potential for neonatal malformations against the high risk of relapse when patients discontinue their medications.1 To help you achieve this balance, we offer an evidence-based approach that includes:
- analysis of the FDA’s teratogenicity categories for psychotropics
- review of the safety profiles of drugs used in mood stabilization
- an algorithm for managing patients who are considering conception or are pregnant.
PSYCHOTROPIC RISKS TO OFFSPRING
All psychotropic medications diffuse across the placenta, which exposes the fetus to some degree. Risks include teratogenicity, obstetrical complications, perinatal syndromes, and long-term postnatal behavioral sequelae.
Teratogenicity. A medication is considered teratogenic when prenatal exposure significantly increases the risk of congenital deformities over the baseline risk, which is 2% in the United States.2 The cause of most congenital malformations is unknown. Risk for teratogenicity occurs in the first 12 weeks of gestation, as organs are formed.
Table 1
FDA Use-in-Pregnancy ratings for medications The FDA system weighs the degree to which research findings have ruled out risk to the fetus
| Category | Interpretation |
|---|---|
| A | Controlled studies show no risk |
| B | No evidence of risk in humans |
| C | Risk cannot be ruled out |
| D | Positive evidence of risk |
| X | Contraindicated in pregnancy |
| Source: Physicians’ Desk Reference. Montvale, NJ: Medical Economics Co., 2003. | |
Obstetrical complications include preterm delivery, low birth weight, and delivery complications such as low Apgar scores or behavioral effects requiring intensive care.
Perinatal syndromes include physical and behavioral symptoms noticed shortly after birth (such as jitteriness). These consequences are putatively related to drug use at or near birth and have limited duration.
Postnatal behavioral sequelae include long-term neurobehavioral abnormalities in children who were exposed to psychotropics in utero.
BALANCING RISKS
Risks with medication. The FDA’s “use in pregnancy” rating system (Table 1) uses available data to assess the degree of teratogenic risk. These guidelines can be confusing and are one of many tools to use when considering a possible drug treatment.
Most psychotropics are category “C” or “D,” which imply a chance of harm to the exposed fetus. Category “B” drugs would appear safer, but this rating could simply indicate a lack of adequate human data or that no data have shown harm in animals.
Moreover, a category “D” drug may be chosen more often during pregnancy than a category “C” drug. This may occur when more human data exist on using the category “D” drug in patients with a particular disorder (such as using lithium versus valproate or olanzapine in pregnant bipolar women).
No psychotropics are classified as “A,” meaning either some risks are associated with every psychotropic or the risk of some agents has not been adequately explored. Furthermore, no psychotropics are FDA-approved for use during pregnancy.
Risks without medication. Teratogenicity notwithstanding, psychotropic intervention is the most effective treatment for women with bipolar disorder. Patients who discontinue mood-stabilizing medication after conception increase their risk of relapse into depression or mania,3 either of which could lead to complications and untoward effects on the fetus.
Depression during pregnancy has been linked to low birth weight and preterm delivery.4,5 These effects may be mediated by the illness itself or by other factors that indirectly affect birth outcomes. For example, depression during pregnancy is associated with decreased appetite, substance use and abuse, and lower use of prenatal care.6
Untreated mania may also be associated with perinatal risks, as a pregnant patient in a manic state may engage in impulsive, high-risk behaviors that endanger her and the fetus.7
MOOD STABILIZERS
The FDA categorizes as “D” the three most commonly used mood stabilizers: lithium, valproate, and carbamazepine (Table 2). This rating implies that studies have demonstrated fetal risk but the drug’s potential benefit may still outweigh the risk.
Lithium. The International Registry of Lithium reported increased rates of cardiovascular malformations— such as Ebstein’s anomaly—in children whose mothers took lithium during pregnancy.
Relative risk for Ebstein’s anomaly in children with fetal exposure to lithium may be 20 times higher than the risk in unexposed children, although the absolute risk with lithium exposure remains low (1 in 1,000 births).1,8
No significant neurobehavioral teratogenicity has been reported in infants exposed in utero to lithium, although few cases have been studied. One study reported that 22 lithium-exposed infants attained developmental milestones at a pace comparable to that of unexposed controls.9
“Floppy baby” syndrome, in which infants experience hypotonicity and cyanosis, is the most recognized adverse effect in infants exposed to lithium in utero.10 Its frequency is unknown, but rare. Neonatal hypothyroidism and nephrogenic diabetes insipidus have also been documented.
Anticonvulsants. To date, no studies have examined the outcomes of children whose mothers took anticonvulsants for bipolar disorder during pregnancy, though the research concerning epileptic mothers is extensive.