OBJECTIVE: The objective of this study was to review the existing literature on the use of various classes of psychotropic medications during breastfeeding to provide information about infant exposure levels and reported adverse events in breastfed infants.
METHODS: A bibliographic search in the Medline (1967 through July 2008), Embase (1975 through July 2008), and PsycINFO (1967 through July 2008) databases was conducted for studies on breastfeeding and psychotropic medications for a total of 96 drugs. References of retrieved articles, reference books, and dedicated Web sites were also checked. The manufacturers were contacted for drugs without published information. Original articles and review articles that provide pharmacokinetic data on drug excretion in breast milk and infant safety data were considered, to estimate the “compatibility level” of each drug with breastfeeding.
RESULTS: A total of 183 original articles were eligible for analysis. Documentation was retrieved for 62 (65%) drugs. In all, 19 (31%) psychotropic drugs can be used during lactation according to an evidence-based approach. For 28 drugs, the available data do not permit an evaluation of the drug's safety profile during breastfeeding and, for an additional 15 drugs, the exposure dose or observed adverse effects make their use unsafe.
CONCLUSIONS: Although most drugs are considered safe during breastfeeding, compatibility with breastfeeding has not been established for all psychotropic drugs. There is a need for additional research and accumulation of experience to guarantee a more rational use of psychotropic drugs during breastfeeding.
Breastfeeding is essential for the physical and psychological health of both mother and child, and its benefits are well documented.1–6 The World Health Organization recommends exclusive breastfeeding for at least the first 4 to 6 months of life and its continuation for 1 to 2 years thereafter.7,8 In the past few years, several initiatives have been launched to promote breastfeeding, which have led to an increase in this first-choice form of nutrition worldwide. Despite the increased attention toward breastfeeding, however, information on breast milk drug excretion and knowledge of the adverse effects on the infant are often unavailable or still limited for many drugs that frequently are used by women of childbearing age, and misinformation abounds.9
Worldwide, more than half of breastfeeding women take some type of drug,10 and the concern about potential harm to the nursing infant from maternal medications is often cited as a reason to stop lactation,11 even if discontinuing breastfeeding is often the wrong decision. The Summary of Product Characteristics should not be considered a reliable source of breastfeeding information; it often indicates that a drug is not recommended during lactation, suggesting that it be avoided or that breastfeeding be interrupted. The warnings are not necessarily related to observed or reported adverse effects; they are often used as a defensive measure on the part of the manufacturer when the drug's safety information is not available.
It is important that women be informed as to whether they can safely breastfeed while taking their medication.12 Information on how to deal with drugs in lactation therefore seems indispensable in efforts to promote breastfeeding.13 Concerns that also attributable to a scarcity of available knowledge about drug safety during lactation are common for all drugs,14 but for a few therapeutic classes such as psychotropic agents, they are relevant.15
Psychiatric disorders represent a considerable public health problem that affects a significant number of pregnant and lactating women and can have substantial negative physical and psychological sequelae for mother and child. Because of these serious consequences, early diagnosis and treatment interventions are imperative for the health and well-being of the mother and the child.16
Given the prevalence of psychiatric disorders in the perinatal period, a significant number of women may require pharmacologic treatment.17–19 It has been estimated that, each year, more than 500000 pregnancies in the United States are complicated by psychiatric disorders such as depression, anxiety, and psychosis, which often develop, recur, and/or worsen during and after pregnancy. Furthermore, 13% of all psychiatric hospital admissions for women occur during the first postpartum year.20
Depression is the most frequent mental disorder in the perinatal period: ∼10% to 16% of pregnant women fulfill diagnostic criteria for major or minor depression, but up to 70% report symptoms of depression.21 Furthermore, ∼7% to 20% of women receive a diagnosis of postpartum depression in the first year after delivery.22 Untreated depression and anxiety can have a negative impact on pregnancy,23 and adverse short-term and long-term effects can have a negative impact on the developing infant and child.24,25
The evidence on psychotropic medication use in breastfeeding mothers is limited: for many drugs only case reports or very small studies are available (often only pharmacokinetic data and not with respect to safety), whereas for other drugs on which more information is available, the reviews are not complete and updated. This lack of data makes it difficult to formulate any generalizations regarding the safety of these medications26–29; therefore, there is a need to collect and evaluate systematically the available information on the risks of psychotropic drugs during breastfeeding. This article reviews the literature to provide more complete and updated information on infant exposure levels and reported adverse events in the various psychotropic medication classes.
Original articles and review articles on breastfeeding and mother and newborn infant exposure to 96 psychotropic drugs were considered. The drugs were classified according to the International Anatomic Therapeutical Classification system in antipsychotics (N05A), anxiolytics (N05B), hypnotics and sedatives (N05C), antidepressants (N06A), psychostimulants (N06B), and antiepileptics (N03; Table 1). Drug combinations and drugs without indications for women of childbearing age were excluded.
A bibliographic search in the Medline (1967 through July 2008), Embase (1975 through July 2008), and PsycINFO (1967 through July 2008) databases was performed. The searches performed were as follows: [drug name] and [breastfeeding or lactation or breast milk or drug milk level], limiting to [human].
To make the search more complete, the terms were searched for in the databases' dictionaries as well as through a free text search of the key words in the articles' titles and abstracts. Manual searches of bibliographies were also conducted to identify additional pertinent studies. All of the references were then analyzed.
Moreover, secondary sources, specialist manuals, reference books, and dedicated Web sites (eg, LactMed, The MotherRisk Program–Hospital for Sick Children, American Academy of Pediatrics, Martindale, Meyler's Side Effects of Drugs) were consulted. Other information was found in the DRUGDEX database (Micromedex), a Web site that reports data on drugs from the medical literature, and REPROTOX (Reproductive Toxicology Center, Columbia Hospital for Women Medical Center, Washington, DC), a database of references on reproductive risk that also contains a section with studies related to drug use during breastfeeding. For drugs for which no studies were identified through the procedures described, the manufacturers were contacted directly. The references retrieved were collected and analyzed using the software program Reference Manager 11 (Institute for Scientific Information, Berkeley, CA).
To fit the selection criteria, studies had to provide 2 types of information:
pharmacokinetic data on drug excretion in breast milk and
adverse effects reported in breastfed infants who were exposed to the drug through maternal breast milk.
The following data were extracted and tabulated from each study:
Maternal dosage: the treatment dosage was usually specified in mg/d. When the treatment dose was specified in mg/kg per day, the value was multiplied by 60 kg, the standard weight of an adult woman.30 When the studies involved several patients who were taking different therapeutic dosages, the range between the minimum and the maximum was reported in a table.
Number of mother–infant pairs for which pharmacokinetic data on drug excretion in breast milk were available was also reported.
Milk-to-plasma ratio (M/P): the concentration of the drug in the mother's milk divided by the concentration of the drug in the mother's plasma measured at the same moment: milk concentration/plasma concentration = Cm/Cp. Table 1 reports the range between the minimum and maximum M/P. When the studies reported the average concentration of the drug in plasma and milk only or when a single determination of the drug was conducted, Table 1 indicates a single value.
Relative infant dosage (% dose): the daily dosage of drug received by an infant through breast milk, expressed as a percentage of the weight-adjusted maternal daily dosage. It is calculated as follows30: (Cm [mg/mL] × 900)/maternal daily dose (mg/kg) = %. When possible, the percentage of drug received by the infant relative to the maternal dosage, as an interval between a minimum and maximum of the calculated values, was reported. When the study reported the average concentration of the drug in milk or when a single determination of the drug in milk was conducted, a single value was indicated. When the study also reported the concentration of the active metabolite(s) in milk, the values for drug and metabolite(s) were added together in the equation.
Infant safety data: the incidence of adverse effects reported in breastfed infants who were exposed to the drug through maternal breast milk, expressed as a ratio of number of breastfed infants, and the type of the observed effects.
Estimation of the Compatibility Level
The “compatibility level” of each drug with breastfeeding was estimated taking into account the following:
pharmacokinetic characteristics of the drug;
data on drug excretion in breast milk;
number of treatment days at sampling, according to acute and chronic administration; and
incidence and type of adverse effects reported in breastfed infants.
Each drug was considered as follows:
Compatible: the drug's use during breastfeeding is considered safe because the relative infant dosage is <10% of the maternal dosage30 and no relevant adverse effects were reported in breastfed infants.
To be used with caution: the available data do not allow an evaluation of the safety profile of the use of the drug during breastfeeding (eg, small number of mother–infant pairs, relevant infant adverse effects) or because of the possible accumulation of the drug with prolonged use (eg, benzodiazepines).
Contraindicated: the drug's use during breastfeeding is contraindicated because the relative infant dosage is >10% of the maternal dosage and relevant adverse effects were reported in breastfed infants.
The bibliographic search produced 183 original articles that were eligible for analysis (Table 1). Documentation was available for 62 (65%) of 96 drugs; for the remaining 34 (35%) drugs, even the manufacturer was unable to provide information on use during breastfeeding (Table 2). Twelve drugs resulted in exposure levels in breastfed infants that were higher than 10% of the maternal therapeutic dosages, and their use is therefore contraindicated (Table 3). These drugs were antiepileptics (7 of 14), anxiolytics (1 of 8), selective serotonin reuptake inhibitors (SSRIs; 2 of 6), and antipsychotics (2 of 11). Adverse effects among breastfed infants were reported for 21 (34%) of 62 drugs (Table 4). Thus, for 34 psychotropic drugs, the information is unavailable, and for an additional 15, their use is unsafe because of exposure dosage or observed adverse effects. A total of 19 (31%) psychotropic drugs can be used during lactation according to an evidence-based approach, whereas for 28 drugs, the available data do not allow an evaluation of their safety profile during breastfeeding.
Among the drugs with available studies on breastfeeding, antidepressants had a greater number of studies (SSRIs more than tricyclic antidepressant). For 20 (87%) of the 23 antidepressants considered, 60 pharmacokinetic studies (concerning a total of 342 mother–infant pairs) and 75 articles that reported infant adverse effects (31 reported of 612 monitored) were found. Data on use during breastfeeding were unavailable only for ademethionine, oxytriptan, and trimipramine.
In particular, among the antidepressants, sertraline, paroxetine, and fluvoxamine are the first-choice drugs for treatment of depression in breastfeeding mothers because they have the lowest degree of excretion into human breast milk. Considering the high relative infant dosage, their long half-life, and the reported adverse effects in infants, the use of citalopram, escitalopram, and fluoxetine are contraindicated during breastfeeding.
SSRIs were better documented than tricyclic antidepressants, especially regarding their safety profile in breastfed infants; however, the major concern with exposing infants to SSRIs through breast milk is whether long-term exposure to low dosages of these medications may have long-term neurobehavioral effects. Most of the considered studies were short-term studies; there have been no studies on infants' long-term exposure to very low dosages of antidepressants. Some studies, however, showed that the platelet serotonin uptake was not decreased in breastfed infants who were exposed to sertraline or fluoxetine through breast milk. By inference, breastfeeding exposure to these drugs therefore should not affect serotonin metabolism in the infant brain; however, this aspect needs additional investigation.31,32 In any case, if a mother wishes to breastfeed her infant while taking an SSRI, then she should be advised to monitor the infant and to inform the pediatricians promptly if the infant experiences sedation, nausea, reduced suckling, or other sign of drug toxicity.
Antipsychotics are the class with the smallest number of studies concerning use during breastfeeding. For 11 (50%) of the 22 antipsychotics considered, 29 pharmacokinetic studies (concerning a total of 146 mother–infant pairs) and 29 articles on infant adverse effects (11 reported of 162 monitored) were found.
Chlorpromazine and olanzapine could be considered the first-choice drugs for treatment of psychotic disorders in breastfeeding mothers because they have the lowest degree of excretion into human breast milk and scant adverse effects in breastfed infants. Considering the high relative infant dosage and the reported adverse effects in infants, the use of clozapine, lithium, and sulpiride is contraindicated during breastfeeding.
Because psychosis requires long-term treatment and because the data on safety of antipsychotics during lactation are limited, the benefits of breastfeeding may be weighed against the potential risks of medication. All antipsychotic drugs are sedating and have relatively long half-lives, so the infants should be observed for lethargy, sedation, and appropriate development.
Hypnotics and Anxiolytics
The available data regarding the use of hypnotic and anxiolytic agents during breastfeeding are scant. For 16 (57%) of the 28 hypnotics and anxiolytics considered, 23 pharmacokinetic studies (concerning a total of 122 mother–infant pairs) and 13 articles on infant adverse effects (6 reported of 57 monitored) were retrieved. The available data suggest that the amounts of these medications to which the nursing infant is exposed are not very high; however, they must be used with caution by breastfeeding mothers, taking into account that neonates metabolize benzodiazepines more slowly than adults and that these drugs are usually used for long-term periods, so they may accumulate in breastfed infants and produce infant sedation, nausea, and poor feeding.
The use of long-acting benzodiazepines, such as diazepam and clobazam, is therefore contraindicated in breastfeeding mothers. If a benzodiazepine is needed during breastfeeding, then a short-acting one, such as midazolam, oxazepam, pinazepam, or lormetazepam, should be used. Moreover, the minimum dosage required for symptom relief should be used, and the infant should be monitored regularly. If an infant experiences sedation, nausea, reduced suckling, or other signs of toxicity, then breastfeeding should be discontinued. Single doses of benzodiazepines do not require any limitation on breastfeeding.
The antiepileptic therapeutic group is the most investigated during breastfeeding. Data are available for 14 (70%) of the 20 drugs considered: 47 pharmacokinetic studies (concerning a total of 255 mother–infant pairs) and 43 articles on infant adverse effects (26 reported of 220 monitored) were found.
Valproic acid and carbamazepine are the first-choice drugs for treatment of mothers with epilepsy during breastfeeding because of their low degree of excretion into human breast milk and limited reported adverse effects in infants. Considering the high relative infant dosage and the reported adverse effects in infants, the use of 6 drugs (ethosuximide, phenobarbital, lamotrigine, primidone, topiramate, and zonisamide) is contraindicated during breastfeeding.
Because antiepileptics are used in long-term treatment, the most appropriate therapy in childbearing women with epilepsy should be evaluated before pregnancy and during the breastfeeding period considering the potential harm of the medication on the fetus and breastfed newborn. If the mother is on therapy with 1 of the contraindicated drugs (eg, phenobarbital), then the infant should be observed for lethargy, sedation, and appropriate development. Although the routine monitoring of infant serum drug levels is not warranted, the infant serum can also be assayed to assess actual neonatal exposure to medication more accurately.
Studies are available only for methylphenidate (2 studies on pharmacokinetics in 2 pairs and no adverse effects in 1 infant). Methylphenidate shows an M/P that varies from 1.1 to 2.7 and a relative infant dosage that is 0.2% of the maternal dosage; however, the available information is too scant to permit an evaluation of the safety profile of the drug.
No data are available on the use during breastfeeding of one third of psychotropic drugs. For the other two thirds, available information varies widely. Although many psychotropic drugs are considered safe during breastfeeding because they are excreted to a low extent into breast milk (relative infant dosage <10% of the therapeutic maternal dosage) and no serious adverse events related to exposure to these medications through breast milk have been reported, there are documented differences between drugs within the same class and there is no class action in relation to breastfeeding. Furthermore, for each therapeutic category, there are drugs with minimal infant exposure via breastfeeding. For these drugs, the dosage to which the infant is exposed is very low and well below what would be expected to have any significant clinical effects. For this reason, they are considered first choice for the treatment of breastfeeding mothers (sertraline, chlorpromazine, lormetazepam, and carbamazepine), whereas a few drugs are contraindicated (citalopram, clozapine, diazepam, and phenobarbital).
Although antiepileptics and antidepressants have been studied extensively, to date, less information regarding the use of antipsychotics, anxiolytics and hypnotics, and psychostimulants while breastfeeding is available. The existing literature is often limited to a small number of studies based on a few cases or case reports, making it difficult to formulate any generalizations regarding their safety profile in lactation.26–29 These drugs are being used more frequently and need additional investigation.
Mothers are increasingly encouraged to nurse, but breastfeeding while taking psychotropic medications is an important issue that has not received the attention that it deserves.29 Women with postpartum psychiatric disorders are understandably anxious about any uncertainties surrounding the safety of their medications in their infants and often face the dilemma of whether to use psychotropic medication while continuing to breastfeed their infants. Quite often, the first reaction is to stop breastfeeding or to stop any psychotropic medications entirely. Moreover, many physicians have been hesitant to prescribe psychotropic medication to women who choose to breastfeed. What is easily forgotten are the risks of untreated psychiatric disorders in the postpartum period.33 In such cases, it is important to safeguard the mental health of the mother while at the same time optimizing the emotional and physical well-being of the infant.34 In general, these medications should not be prescribed without careful consideration, but neither should they be automatically avoided.
The decision to prescribe psychotropic agents to breastfeeding mothers should depend on an individual risk/benefit analysis: the known benefits of breastfeeding and medication use for both mother and infant must be weighed against the risk of untreated maternal illness or the risk of infant exposure to medications through breast milk.35 There are immediate risks (eg, hypersensitivity reactions, adverse central nervous system effects such as lethargy and reduced feeding) and risks of long-term effects on the developing brain.28 This analysis requires up-to-date knowledge on safety of psychotropic medication use during breastfeeding.24
The strength of this review is the systematic approach used to collect the available information on psychotropic medication use during breastfeeding. The result is a more complete, accurate, and updated review of the evidence, and this can represent an important tool for health professionals for promoting the rational use of psychotropic drugs in breastfeeding mothers. The major objective of this review is to be a reliable source of evidence-based information for current problems in daily clinical practice, especially for psychiatrists, pediatricians, family physicians, and obstetrician-gynecologists, who often play an important role in women's decision to start or continue breastfeeding while taking psychotropic medications.
If treatment is deemed appropriate, then the smallest number of medications at the lowest possible dosage consistent with control of the mental illness should be prescribed,17 and a drug with a proven favorable safety/efficacy profile should be preferred.24 All psychotropic drugs are excreted into breast milk, but concentrations and effects may vary considerably. The amount of medication to which an infant is exposed through lactation depends on several factors: the maternal dosage, frequency of dosing, rate of absorption into maternal circulation, diffusion from maternal circulation into breast milk, rate of maternal drug metabolism, and absorption of the drug by the infant. Moreover, the frequency and 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 levels or by taking medication immediately after breastfeeding, the infant exposure to the drug may be reduced. As with all drugs taken while breastfeeding, it is prudent to monitor carefully the clinical status of infants for signs of drug-related toxicity and adverse effects (generally sedation; irritability; and changes to sleep, feeding, and growth). It is also essential that mothers be properly educated about this matter and advised to discontinue a medication if their infant develops signs of toxicity or adverse effects.20 In this setting, ongoing collaboration with the pediatrician is crucial.
If a mother is on therapy with 1 of the contraindicated drugs because she is affected by postpartum affective illness that responds only to a particular drug (this is common for epilepsy), then it is advisable to keep her on that drug rather than to switch. In addition, the woman should be kept on the lowest possible effective dosage of medication, and the infant should be observed for possible adverse effects. Although the routine monitoring of infant serum drug levels is not warranted, if neonatal toxicity related to drug exposure through breast milk is suspected or when the mother is nursing while taking a drug that is contraindicated during breastfeeding, then infant serum can also be assayed to assess neonatal exposure to medication more accurately.37
The use of psychotropic drugs during lactation will continue to be a controversial topic. Given the possible occurrence of psychiatric illness during the postpartum period, a significant number of women may require pharmacologic treatment. The nutritional, immunologic, and psychological benefits of breastfeeding have been well documented. Conversely, it is clear from this review that, given the limited data, it is difficult to reach a conclusion on the safety profile of many psychotropic drugs during breastfeeding. There is a need for additional research and reported experience. In particular, a long-term monitoring of the neurocognitive development of breastfed infants is needed; however, certain medications can safely be used by mothers who are planning to breastfeed, even if it is also widely known (but parents must to be informed) that no drug is completely free of adverse effects. All psychotropic drugs should be viewed with caution during breastfeeding, taking into account the known benefits of breastfeeding to mothers and infants as well as the possibility that infant exposure to clinically significant levels in breast milk may occur.
We thank Dr Benedetta Schiavetti for help with the preparation of this article.
- Accepted April 23, 2009.
- Address correspondence to Filomena Fortinguerra, PharmD, Public Health Department, Laboratory for Mother and Child Health, “Mario Negri” Institute for Pharmacological Research, Via Giuseppe La Masa 19, 20156 Milan, Italy. E-mail:
Financial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject:
The evidence on psychotropic medication use during breastfeeding is limited for many drugs, in particular for antipsychotics, hypnotics, and anxiolytics. This lack of data makes it difficult to formulate any generalizations regarding the safety of these medications.
What This Study Adds:
We systematically collected and evaluated the available information on the safety of psychotropic medication use during breastfeeding to provide physicians with updated and evidence-based information for current problems in daily clinical practice.
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- Horta BL, Bahl R, Martines JC, Victora CG. Evidence on the Long-term Effects of Breastfeeding. Systematic Reviews and Meta-analyses. Geneva, Switzerland: World Health Organization; 2007. Available at: http://libdoc.who.int/publications/2007/9789241595230_eng.pdf. Accessed April 8, 2009
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- ↵WHO/UNICEF. Global Strategy for Infant and Young Child Feeding. Geneva, Switzerland: World Health Organization; 2003. Available at: www.who.int/nutrition/publications/gs_infant_feeding_text_eng.pdf. Accessed April 8, 2009
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- ↵Musters C, McDonald E, Jones I. Management of postnatal depression. BMJ.2008;337 :a736
- ↵American College of Obstetricians and Gynecologists. ACOG practice bulletin No. 87 November 2007: use of psychiatric medications during pregnancy and lactation [published corrections appear in Obstet Gynecol. 2007;110(6):1424 and Obstet Gynecol. 2008;111(2 pt 1):454]. Obstet Gynecol.2007;110 (5):1179– 1198
- ↵Sivertz K, Kostaras X. The use of psychotropic medications in pregnancy and lactation. B C Med J.2005;47 (3):135– 138
- ↵Kohen D. Psychotropic medication and breastfeeding. Adv Psychiatr Treat.2005;11 :371– 379
- ↵Bennett PN. Use of the monograph on drugs. In: Bennett PN. Drugs and Human Lactation. 2nd ed. Amsterdam, Netherlands: Elsevier; 1996:67–74
- ↵Epperson N, Jatlow PI, Czarkowski K, Anderson GM. Maternal fluoxetine treatment in the postpartum period: effects on platelet serotonin and plasma drug levels in breastfeeding mother-infant pairs. Pediatrics.2003;112 (5). Available at: www.pediatrics.org/cgi/content/full/112/5/e425
- ↵Turner KM, Sharp D, Folkes L, Chew-Graham C. Women's views and experiences of antidepressants as a treatment for postnatal depression: a qualitative study. Fam Pract.2008;25 (6):450– 455
- ↵Einarson A, Portnoi G, Koren G. Update on motherisk updates: seven years of questions and answers. Can Fam Physician. 2002;48 :1301– 1304
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