General information on drug use in breastfeeding: psychotropic drugs

Prescribing psychotropic drugs in breastfeeding: risk/benefit analysis

Box 11.2 can provide a framework for the practitioner to address the decision of whether or not to prescribe a psychotropic drug during breastfeeding. It can also guide discussion with the woman and, preferably, also her partner.

A categorisation of harmful effects to the infant has been developed utilising 2 classes: short-term toxicity (class 1) and long-term neurodevelopmental effects ('behavioural toxicity') (class 2). The risk of short-term toxicity (class 1) depends on a variety of complex factors, in addition to the drug itself. These include timing of dose in relation to breastfeeding, differing concentration in foremilk versus hindmilk, the weight of both the mother and the infant, as well as their ability to metabolise and/or excrete the drug and its active metabolites. It is this complexity that accounts, in part, for the conflicting findings regarding the extent of transmission of psychotropic drugs into breast milk. Nevertheless, most psychotropic drugs are excreted only to a minimal extent in breast milk, and in most cases the dose to which the infant is ultimately exposed is low and below that which would be expected to have any significant clinical effects. For this reason, there are few drugs that are totally contraindicated while breastfeeding. A significant number of findings of infant adverse reactions attributed to breastfeeding are confounded by exposure in utero. However, particular caution is required in the case of premature infants, or other infants whose ability to metabolise and/or excrete drugs may be impaired.

Infants whose mothers are taking psychotropic drugs should be monitored for gastrointestinal dysfunction (eg colic, poor feeding), as well as for excessive sedation, irritability and agitation. Given the high incidence of some of these problems in infants in general, the practitioner should be cautious about attributing these to medication. If severe, a trial of decreased dose or cessation may be appropriate. For drugs given in a once-daily dose, feeding just before dosing and avoidance of breastfeeding for 4 to 6 hours after ingestion may warrant consideration.

Class 2 is largely unexplored, but should not deter prescribing where this is otherwise indicated. The relevance of the unknown risk in class 2 is to impress on the practitioner that no psychotropic can be considered 100% safe in lactation, nonpharmacological interventions always warrant consideration and unnecessarily high doses and duration of treatment should be avoided. In addition, caution is warranted in prescribing only on the basis of prevention of recurrence of a condition (especially unipolar postnatal depression) that is not currently present. Nevertheless, prophylactic use of mood stabilisers in bipolar patients, especially if there have been previous serious postpartum relapses, is sometimes appropriate.

Important pharmacological determinants for the transfer of drugs into breast milk include plasma protein binding (PB), oral bioavailability (OB) and adult half-life of the drug. High protein binding restricts the diffusion into breast milk (eg olanzapine PB = 93%; sertraline PB = 98%). OB shows what percentage of the drug, from the breast milk swallowed by the baby, is absorbed (eg lithium OB = 50%). Shorter maternal half-life drugs are recommended over those with long half-lives.

Risk/benefit analysis for psychotropic drug prescribing during breastfeeding (Box 11.2)

Antipsychotic drugs

Second-generation antipsychotics

Definitive information is lacking for the second-generation antipsychotics (amisulpride, aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone and ziprasidone). Preliminary data suggest that olanzapine and risperidone have low infant doses relative to the maternal weight-adjusted dose and, given the lower adverse effects in the mother, these drugs are being increasingly used during lactation in preference to first-generation antipsychotics. However, additional studies are required to definitively establish safety, and the association of olanzapine with some (reversible) adverse effects in a small series of breastfed babies has led the manufacturer to recommend against breastfeeding if the mother is on this drug. Clozapine should not be used in breastfeeding (due to high concentration in breast milk and the risk of agranulocytosis) unless strongly indicated for maternal wellbeing. Use of more than one antipsychotic appears to substantially increase the likelihood of adverse infant reactions.

First-generation antipsychotics

The first-generation antipsychotics, especially at high dose, have occasionally been associated with adverse reactions in breastfed infants (eg urinary retention, dystonic reactions). In lower dose, ie less than 10 mg haloperidol daily or equivalent, they are usually regarded as safe.

Depot antipsychotics

Depot preparations should not be used, if possible. If the infant suffers an adverse reaction to a depot preparation, cessation of breastfeeding will be necessary.

Antidepressants

General information

Postnatal depression affects some 10% to 20% of mothers. Unfortunately, the literature still mainly comprises case reports or very small studies, and the presence of active metabolites is not always taken into account. However, more methodologically sound studies have started to emerge.

Selective serotonin reuptake inhibitors and other newer antidepressants

In the case of selective serotonin reuptake inhibitors (SSRIs), most studies suggest that infant plasma concentrations are either low or not detected, with the exception of fluoxetine where clinically significant concentrations have been measured. Fluoxetine and its metabolites with long half-lives have the potential to accumulate in the breastfed infant, and this drug has been associated with low weight gain, irritability, difficulty settling and infant gastrointestinal dysfunction in several studies. There are now several published studies on sertraline, citalopram, fluvoxamine and paroxetine that show acceptably low relative infant doses, and minimal class 1 adverse effects in breastfed infants. From published data, sertraline and paroxetine appear to have the lowest transmission and fluoxetine and citalopram the highest. Venlafaxine has a higher mean relative infant dose than the SSRIs; however, some experts consider it to be compatible with breastfeeding if other antidepressants are ineffective.

Where infants breastfed by mothers taking SSRIs or venlafaxine have been assessed neurologically or developmentally, no adverse outcomes have been noted. However, isolated cases of irritability, sleep disturbance and colic, which remitted when breastfeeding or the antidepressant was ceased, have been reported. The vast majority of these involved infants under two months and use of fluoxetine.

Moclobemide has very low transfer into breast milk and is probably safe. Desvenlafaxine, duloxetine, mirtazapine and reboxetine have not been adequately studied.

Older antidepressants

Breast milk transfer of tricyclic antidepressants (TCAs) is low, and they are generally considered safe during breastfeeding; however, compared with newer antidepressants they have a less favourable adverse effect profile for the mother, and much higher lethality in overdose. The use of doxepin is not recommended because there have been isolated case reports of sedation and respiratory depression in the infants.

Nortriptyline is sometimes recommended on the grounds that maternal serum concentration can be monitored.

As regards neurodevelopmental toxicity, the only data are for dothiepin (15 infants followed for four years). No adverse sequelae were found.

Mianserin and the irreversible nonselective monoamine oxidase inhibitors (MAOIs) have not been adequately studied.

Drugs used in bipolar disorder

General information

Drugs used in the treatment of bipolar disorder include lithium, sodium valproate, carbamazepine and lamotrigine, as well as second-generation antipsychotics. Discontinuation of these drugs in bipolar patients is associated with a significant risk of relapse. The risks versus benefits must be carefully weighed, taking into account the following sections on lithium and antiepileptics.

Lithium

Renal clearance of lithium may be reduced in the young infant and high infant serum concentrations have been reported. If possible, lithium should be avoided due to reports of infant sedation, dehydration, hypothyroidism and respiratory depression. If used, regular monitoring of infant serum concentration, thyroid function and electrolytes is recommended, but this is an invasive procedure. Moreover, the interpretation of infant serum lithium concentration, in terms of safety, may be difficult. The American Academy of Paediatrics states lithium is contraindicated in breastfeeding. However, the authors of a study of 10 such infants have advocated reassessment of current recommendations as they found low infant serum concentration and no ill effects. Some reported adverse reactions are confounded by intrauterine exposure.

Antiepileptics

No serious adverse reports have been associated with sodium valproate, and this may be the mood stabiliser of choice in breastfeeding. Hepatotoxicity has been reported in children under two years who have been prescribed sodium valproate, but this was via ingestion, not transmission in breast milk.

Occasional reports associate carbamazepine with infant jaundice and hepatic dysfunction. However, most guidelines regard it as compatible with breastfeeding. Monitoring of infant liver function and white cell count is probably worthwhile if the woman is taking either valproate or carbamazepine.

Unlike lithium, the American Academy of Paediatrics does not regard these two antiepileptics as contraindicated.

The safety of lamotrigine is questionable. Potentially serious skin conditions have been reported in young children treated with this drug. Lamotrigine has relatively high transmission and slow elimination in the neonate.

Anxiolytics and hypnotics

'Floppy infant syndrome', with symptoms of hypotonia, lethargy and reduced suckling, has been reported with the long-acting benzodiazepines (eg diazepam) since they may accumulate in the infant during chronic use. If a benzodiazepine hypnotic is needed during breastfeeding, then those with a shorter half-life are preferable.

Particular caution should be exercised in the first 3 or 4 postnatal days, especially if the infant has physiological jaundice.

There are no data relating to the use of zopiclone or zolpidem in breastfeeding.

Drugs for opioid dependence

Methadone is considered relatively safe to use during breastfeeding. It would appear the concentration in breast milk is low, regardless of maternal dose. Symptoms of withdrawal may occur in the first week in 60% of infants born to mothers on methadone maintenance. The concentration of methadone in breast milk is insufficient to prevent this. Infants in withdrawal are often very difficult to breastfeed (irritable and hypertonic with poor suck and swallow coordination) and involvement of a lactation consultant is desirable. On balance, provided there are no maternal medical contraindications, women on methadone should be encouraged to breastfeed. There are no longer-term follow-up studies of infants breastfed during methadone treatment.

Buprenorphine has not been associated with adverse effects on the breastfed infant in a small number of reports, and transmission to breast milk is low. More data are required to establish safety.

Revised October 2008. ©Therapeutic Guidelines Limited (etg35demo, November 2011)