General Principles
The emotional and medical benefits of breastfeeding to mother and infant are clear. Given the prevalence of psychiatric illness during the postpartum period, a significant number of women may require pharmacological treatment while nursing. Appropriate concern is raised, however, regarding the safety of psychotropic drug use in women who choose to breastfeed while using these medications. Efforts to quantify psychotropic medications and their metabolites in the breast milk of mothers have been reported. Serum of infants can also be assayed to assess more accurately actual neonatal exposure to medications. The data indicate that all psychotropic medications, including antidepressants, antipsychotic agents, lithium carbonate, and benzodiazepines, are secreted into breast milk. However, concentrations of these agents in breast milk vary considerably.
The amount of medication to which an infant is exposed depends on several factors: the maternal dosage of medication, frequency of dosing, and rate of maternal drug metabolism. Typically, peak concentrations in the breast milk are attained approximately 6 to 8 hours after the medication is ingested. Thus, the frequency of feedings and the timing of the feedings can influence the amount of drug to which the nursing infant is exposed. By restricting breastfeeding to times during which breast milk drug concentrations would be at their lowest (either shortly before or immediately after dosing medication) exposure may be reduced; however, this approach may not be practical for newborns who typically feed every 2 to 3 hours.
The nursing infant’s chances of experiencing toxicity are dependent not only on the amount of medication ingested but also on how well the ingested medication is metabolized. Most psychotropic medications are metabolized by the liver. During the first few weeks of a full-term infant’s life, there is a lower capacity for hepatic drug metabolism, which is about one-third to one-fifth of the adult capacity. Over the next few months, the capacity for hepatic metabolism increases significantly and, by about 2 to 3 months of age, it surpasses that of adults. In premature infants or in infants with signs of compromised hepatic metabolism (e.g., hyperbilirubinemia), breastfeeding typically is deferred because these infants are less able to metabolize drugs and are thus more likely to experience toxicity.
Antidepressants
Over the past 10 years, data have accumulated regarding the use of various antidepressant medications during breastfeeding. Available data on the use of tricyclic antidepressants (TCAs), fluoxetine, paroxetine, and sertraline during breastfeeding have been encouraging and suggest that the amounts of drug to which the nursing infant is exposed is low and that significant complications related to neonatal exposure to psychotropic medications in breast milk appear to be rare. Typically very low or non-detectable levels of drug have been detected in the infant serum, and one recent report indicates that exposure during nursing does not result in clinically significant blockade of serotonin (5-HT) reuptake in infants. Although less information is available on other antidepressants, serious adverse events related to exposure to these medications have not been reported.
There have been some case reports of adverse events in infants exposed to SSRIs in breastmilk, including jitteriness, irritability, excessive crying, sleep disturbance, and feeding problems. In many cases it has not been possible to establish a causal link between these events and exposure to drug. For the most part, no serious or life- threatening problems have been reported, although there was one report of a seizure that may have been related to exposure to bupropion (Wellbutrin). It is not clear, however, if the bupropion caused the seizure, and it should also be noted that neonatal seizures are relatively common, especially in the first 10 days of life. In addition, many of these reports concerning antidepressant exposure in breastmilk have been confounded by exposure to multiple medications and were not confirmed by unbiased observers.
Anti-Anxiety Agents
Given the prevalence of anxiety symptoms during the postpartum period, anxiolytic agents are often used in this setting. Data regarding the use of benzodiazepines have been limited; however, the available data suggest that amounts of medication to which the nursing infant is exposed are low. Case reports of sedation, poor feeding, and respiratory distress in nursing infants have been published; however, the data, when pooled, suggest a relatively low incidence of adverse events.
Mood Stabilizers
For women with bipolar disorder, breastfeeding may pose more significant challenges. First, on-demand breastfeeding may significantly disrupt the mother’s sleep and thus may increase her vulnerability to relapse during the acute postpartum period. Second, there have been reports of toxicity in nursing infants related to exposure to various mood stabilizers, including lithium and carbamazepine, in breast milk.
Lithium is excreted at high levels in the mother’s milk, and infant serum levels are relatively high, about one-third to one-half of the mother’s serum levels, thereby increasing the risk of neonatal toxicity. Reported signs of toxicity include cyanosis, hypotonia, and hypothermia. Although breastfeeding typically is avoided in women taking lithium, the lowest possible effective dosage should be used and both maternal and infant serum lithium levels should be followed in mothers who breastfeed. In collaboration with the pediatrician, the child should be monitored closely for signs of lithium toxicity, and lithium levels, thyroid stimulating hormone (TSH), blood urea nitrogen (BUN), and creatinine should be monitored every 6-8 weeks while the child is nursing.
Several recent studies have suggested that lamotrigine reaches infants through breast milk in relatively high doses, ranging from 20%-50% of the mother’s serum concentrations, which may be explained by poor neonatal metabolism of lamotrigine. In addition, maternal serum levels of lamotrigine increase significantly after delivery, which may also have contributed to the high levels found in nursing infants. None of these studies have reported any adverse events in breastfeeding newborns. One worry shared by clinicians and new mothers is the risk for Stevens-Johnson syndrome (SJS). This is a severe, potentially life-threatening rash, most commonly resulting from a hypersensitivity reaction to a medication, which occurs in about 0.1% of bipolar patients treated with lamotrigine. Thus far, there have been no reports of SJS in infants associated with exposure to lamotrigine. In fact, it appears that cases of drug-induced SJS are extremely rare in newborns. In a single case report, authors described a neonate developing the syndrome after exposure to the anticonvulsant phenobarbital.
Similarly, concerns have arisen regarding the use of carbamazepine and valproic acid. Both of these mood stabilizers have been associated in adults with abnormalities in liver function and fatal hepatotoxicity. Hepatic dysfunction associated with carbamazepine exposure in breast milk has been reported several times. Most concerning is that the risk for hepatotoxicity appears to be greatest in children younger than 2 years old; thus, nursing infants exposed to these agents may be particularly vulnerable to serious adverse events. Although the American Academy of Pediatrics has deemed both carbamazepine and valproic acid to be appropriate for use in breastfeeding mothers, few studies have assessed the impact of these agents on fetal well-being, particularly in nonepileptic mothers. In those women who choose to use valproic acid or carbamazepine while nursing, routine monitoring of drug levels and liver function tests is recommended. In this setting, ongoing collaboration with the child’s pediatrician is crucial.
Anti-Psychotic Agents
Information regarding the use of anti-psychotic drugs is limited and is particularly lacking for the newer atypical agents. While the use of chlorpromazine has been associated with adverse events including sedation and developmental delay, adverse events appear to be rare when medium- or high-potency agents are used. Less data, however, is available on the atypical anti-psychotic agents. Data on clozapine suggest that it may be concentrated in the breast milk; however, there are no data on infant serum levels, making it difficult to interpret the relevance of this finding. Given the severity of adverse events associated with clozapine exposure (i.e., decreased white blood cell count) the use of this medication should be reserved for those with treatment-refractory illness and monitoring of white blood cell counts in the nursing infant is mandatory. There is very limited data on the use of olanzapine, risperidone, and quetiapine during lactation, however the data that is available on these three medications suggest that the excretion of these medications in breast milk is low and that adverse effects appear to be rare. Monitoring of the infant is encouraged, as there has been a report of an infant who had sedation on a higher dose of olanzapine, which resolved after the dose was halved to 5mg/ day. To date, there are no reports of the use of the newer anti-psychotic medications, ziprasidone and aripiprazole, while breastfeeding.
Treatment Guidelines
Consultation about the safety of breastfeeding among women treated with psychotropic medications should include a discussion of the known benefits of breastfeeding to mother and infant and the possibility that exposure to medications in the breast milk may occur. Although routine assay of infant serum drug levels was recommended in earlier treatment guidelines, this procedure is probably not warranted; in most instances low or non-detectable infant serum drug levels will be evident and serious adverse side effects are rarely reported. This testing is indicated, however, if neonatal toxicity related to drug exposure is suspected. Infant serum monitoring is also indicated when the mother is nursing while taking lithium, valproic acid, or carbamazepine.