Am Fam Physician. 2008;78(6):772-778
Guideline source: American College of Obstetricians and Gynecologists
Literature search described? Yes
Evidence rating system used? Yes
Published source: Obstetrics & Gynecology, November 2007
Available at: http://www.greenjournal.org/content/vol110/issue5
An estimated 500,000 pregnancies in the United States each year involve women who have or who will develop psychiatric illness during the pregnancy. The use of psychotropic medications in these women is a concern because of the risks of adverse perinatal and postnatal outcomes. However, advising these women to discontinue medication presents new risks associated with untreated or inadequately treated mental illness, such as poor adherence to prenatal care, inadequate nutrition, and increased alcohol and tobacco use.
Ideally, decisions about psychiatric medication use during and after pregnancy should be made before conception. The use of a single medication at a higher dosage is preferred over multiple medications, and those with fewer metabolites, higher protein binding, and fewer interactions with other medications are also preferred. All psychotropic medications cross the placenta, are present in amniotic fluid, and can enter breast milk. The U.S. Food and Drug Administration has categorized medications according to risk during pregnancy (Table 1).
|Drug||FDA pregnancy category*||AAP rating||Lactation risk category†|
|Anxiolytics and hypnotics|
|Alprazolam (Xanax)||D||Unknown, of concern||L3|
|Diazepam (Valium)||D||Unknown, of concern||L3; L4 if used chronically|
|Lorazepam (Ativan)||D||Unknown, of concern||L3|
|Quazepam (Doral)||X||Unknown, of concern||L2|
|Temazepam (Restoril)||X||Unknown, of concern||L3|
|Nonbenzodiazepine anxiolytics and hypnotics|
|Zaleplon (Sonata)||C||Unknown, of concern||L2|
|Antiepileptics and mood stabilizers|
|Valproic acid (Depakene)||D||Compatible||L2|
|Tricyclics and heterocyclics|
|Amitriptyline||C||Unknown, of concern||L2|
|Amoxapine (Asendin)‡||C||Unknown, of concern||L2|
|Clomipramine (Anafranil)||C||Unknown, of concern||L2|
|Desipramine (Norpramin)||C||Unknown, of concern||L2|
|Doxepin (Sinequan)‡||C||Unknown, of concern||L5|
|Imipramine (Tofranil)||C||Unknown, of concern||L2|
|Nortriptyline (Pamelor)||C||Unknown, of concern||L2|
|Selective serotonin reuptake inhibitors|
|Escitalopram (Lexapro)||C||NA||L3 in older infants|
|Fluoxetine (Prozac)||C||Unknown, of concern||L2 in older infants; L3 in neonates|
|Fluvoxamine (Luvox)‡||C||Unknown, of concern||L2|
|Paroxetine (Paxil)||D||Unknown, of concern||L2|
|Sertraline (Zoloft)||C||Unknown, of concern||L2|
|Bupropion (Wellbutrin)||B||Unknown, of concern||L3|
|Trazodone (Desyrel)‡||C||Unknown, of concern||L2|
|Chlorpromazine (Thorazine)‡||C||Unknown, of concern||L3|
|Clozapine (Clozaril)||B||Unknown, of concern||L3|
|Haloperidol (Haldol)||C||Unknown, of concern||L2|
|Perphenazine (Trilafon)‡||C||Unknown, of concern||NA|
|Quetiapine (Seroquel)||C||Unknown, of concern||L4|
|Trifluoperazine (Stelazine)‡||C||Unknown, of concern||NA|
|Ziprasidone (Geodon)||C||Unknown, of concern||L4|
Ten to 16 percent of pregnant women meet diagnostic criteria for depression, and up to 70 percent of pregnant women have symptoms of depression. Studies have shown a relapse rate of 68 percent in women who discontinue antidepressant therapy during pregnancy. Untreated maternal depression is associated with increased rates of adverse outcomes (e.g., premature birth, low birth weight, fetal growth restriction, postnatal complications), especially when depression occurs in the late second to early third trimesters.
There is limited evidence of teratogenic effects from the use of antidepressants in pregnancy and adverse effects from exposure during breastfeeding. Exposure to selective serotonin reuptake inhibitors (SSRIs) late in pregnancy has been associated with transient neonatal complications; however, the potential risks associated with SSRI use must be weighed against the risk of relapse if treatment is discontinued. Treatment with SSRIs or selective norepinephrine reuptake inhibitors during pregnancy should be individualized.
Paroxetine (Paxil) should be avoided by pregnant women and women who plan to become pregnant, and fetal echocardiography should be considered for women exposed to paroxetine during early pregnancy. Because abrupt discontinuation of this drug is associated with withdrawal symptoms and a high rate of relapse, prescribing information about discontinuation of therapy should be followed carefully.
The combination of breastfeeding and SSRI use has not been studied extensively; however, medication exposure from breastfeeding is less than the exposure that occurs transplacentally. Isolated adverse effects have been reported, the most notable of which was an infant who had transient apnea after being exposed to citalopram (Celexa). Generally, no long-term neurobehavioral studies have been done in infants exposed to SSRIs through breast milk. Most tricyclic antidepressants seem to be safe during lactation except for doxepin (Sinequan), which reportedly led to an incident of infant respiratory depression.
Rates of postpartum relapse in women with bipolar disorder range from 32 to 67 percent. Perinatal episodes of the disorder tend to be depressive and are more likely to recur in subsequent pregnancies. The risk of postpartum psychosis is increased by as much as 46 percent in women with this disorder.
The use of lithium during pregnancy has been associated with congenital cardiac malformations, fetal and neonatal cardiac arrhythmias, hypoglycemia, premature delivery, and other adverse outcomes. However, neurobehavioral sequelae were not found in a five-year follow-up of 60 school-age children exposed to lithium during gestation. The decision to discontinue lithium therapy during pregnancy because of fetal risks should be weighed against the maternal risks of illness exacerbation.
The physiologic changes of pregnancy may affect the absorption, distribution, metabolism, and elimination of lithium, and close monitoring of lithium levels during pregnancy and the postpartum period is recommended. The following guidelines have been suggested for women with bipolar disorder who are taking lithium and plan to conceive:
Lithium therapy should be gradually tapered before conception in women who have mild, infrequent episodes.
Lithium therapy should be tapered before conception, but gradually restarted after organogenesis in women who have more severe episodes and are at moderate risk of short-term relapse.
Lithium therapy should be continued throughout the pregnancy in women who have severe, frequent episodes, and these patients should be counseled about the reproductive risks associated with therapy.
Fetal echocardiography should be considered in women exposed to lithium in the first trimester.
The use of lithium during breastfeeding has been associated with a number of adverse effects; however, only 10 maternal-infant dyads have been studied. Effects included lethargy, hypotonia, hypothermia, cyanosis, and electrocardiography changes. No long-term studies have examined the neurobehavioral consequences of lithium therapy during breastfeeding.
ANTIEPILEPTIC THERAPY FOR BIPOLAR DISORDER
Several antiepileptic drugs are used in the treatment of bipolar disorder, including valproic acid (Depakene), carbamazepine (Tegretol), and lamotrigine (Lamictal). However, data on the fetal effects of these drugs come primarily from studies of women with seizures. It is not clear whether the underlying pathology of epilepsy contributes to the teratogenic effect of these drugs on the fetus.
Exposure to valproic acid during pregnancy is associated with an increased risk of neural tube defects, craniofacial and cardiovascular anomalies, fetal growth restriction, and cognitive impairment. Carbamazepine exposure during pregnancy is associated with facial dysmorphism and fingernail hypoplasia. It is unclear whether carbamazepine use increases the risk of neural tube defects or developmental delay. Although these drugs are superior to lithium in the treatment of patients with mixed episodes or rapid cycling, they should be avoided during pregnancy.
The use of lamotrigine during pregnancy has not been associated with any major fetal anomalies and is an option for maintenance therapy in women with bipolar disorder.
Valproic acid use during lactation has been studied in 41 maternal-infant dyads; only one infant was adversely affected with thrombocytopenia and anemia. The American Academy of Pediatrics and the World Health Organization consider valproic acid safe in breastfeeding women. Carbamazepine is ruled “probably safe”; rare side effects include transient cholestatic hepatitis and hyperbilirubinemia.
Anxiety disorders are the most common psychiatric disorders, and some (e.g., panic disorder, generalized anxiety disorder, posttraumatic stress disorder, agoraphobia) are twice as likely to be diagnosed in women than in men. Anxiety and stress during pregnancy are associated with spontaneous abortion, preterm delivery, and delivery complications, although a direct causal relationship has not been established.
The use of benzodiazepines in women with anxiety disorders does not carry a significant teratogenic risk. Prenatal exposure to diazepam (Valium) increases the risk of oral cleft, but the absolute risk increases by only 0.01 percent (from six to seven in 10,000 infants). Maternal use of benzodiazepines shortly before delivery is associated with floppy infant syndrome (i.e., hypothermia, lethargy, poor respiratory effort, and feeding difficulties), and withdrawal syndromes may persist for several months after delivery in infants whose mothers took alprazolam (Xanax), chlordiazepoxide (Librium), or diazepam.
In general, use of benzodiazepines during breastfeeding affects the infant only if he or she has an impaired ability to metabolize the drug. In this situation, the infant may demonstrate sedation and poor feeding.
Adverse outcomes have been reported in women with schizophrenia, including preterm delivery, low birth weight, placental abnormalities, increased rates of congenital malformation, and a higher incidence of postnatal death. If left untreated during pregnancy, schizophrenia can have devastating effects on the mother and child.
Atypical antipsychotics have replaced typical agents as first-line therapy for psychotic disorders because these drugs are better tolerated and may be more effective in managing the negative symptoms of schizophrenia. The reproductive safety data on atypical antipsychotics are limited, but the use of olanzapine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel), and clozapine (Clozaril) has been associated with increased rates of low birth weight and therapeutic abortion. No long-term studies of children exposed to atypical antipsychotics during gestation have been conducted. Therefore, the routine use of these drugs during pregnancy and lactation is not recommended.
Typical antipsychotics have a larger reproductive safety profile; no significant teratogenic effect has been documented with chlorpromazine (Thorazine), haloperidol (Haldol), or perphenazine (Trilafon). Doses of typical antipsychotics should be minimized during the peri-partum period to limit the necessity of using additional medications to manage extrapyramidal side effects.
Data on antipsychotic use in breastfeeding women are limited. A small study of chlorpromazine use during breastfeeding showed no developmental deficits in children up to five years of age; however, a study of both chlorpromazine and haloperidol revealed developmental deficits in children 12 to 18 months of age.