CLINICAL REPORT

The Transfer of Drugs and Therapeutics Into HumanBreast Milk: An Update on Selected Topics

abstractMany mothers are inappropriately advised to discontinue breastfeedingor avoid taking essential medications because of fears of adverse effectson their infants. This cautious approach may be unnecessary in manycases, because only a small proportion of medications are contraindi-cated in breastfeedingmothers or associated with adverse effects on theirinfants. Information to inform physicians about the extent of excretion fora particular drug into human milk is needed but may not be available.Previous statements on this topic from the American Academy of Pediat-rics provided physicians with data concerning the known excretion of spe-cific medications into breast milk. More current and comprehensiveinformation is now available on the Internet, as well as an applicationfor mobile devices, at LactMed (http://toxnet.nlm.nih.gov). Therefore, withthe exception of radioactive compounds requiring temporary cessationof breastfeeding, the reader will be referred to LactMed to obtain themost current data on an individual medication. This report discussesseveral topics of interest surrounding lactation, such as the use ofpsychotropic therapies, drugs to treat substance abuse, narcotics, gal-actagogues, and herbal products, as well as immunization of breastfeed-ing women. A discussion regarding the global implications of maternalmedications and lactation in the developing world is beyond the scope ofthis report. The World Health Organization offers several programs andresources that address the importance of breastfeeding (see http://www.who.int/topics/breastfeeding/en/). Pediatrics 2013;132:e796–e809

INTRODUCTION

Lactating women can be exposed to medications or other therapeutics,either on a limited or long-term basis, depending on the need to treatacute or chronic conditions. Many women are advised to discontinuenursing or avoid taking necessary medications because of concerns aboutpossible adverse effects in their infants.1 Such advice is often not basedon evidence, because information about the extent of drug excretion intohuman milk may be unavailable, and for many drugs, information islimited to data from animal studies, which may not correlate with humanexperience. In addition, not all drugs are excreted in clinically significantamounts into human milk, and the presence of a drug in human milkmay not pose a risk for the infant. To weigh the risks and benefits ofbreastfeeding, physicians need to consider multiple factors. These fac-tors include the need for the drug by the mother, the potential effects of

Hari Cheryl Sachs, MD, FAAP* and COMMITTEE ON DRUGS

KEY WORDhuman milk

ABBREVIATIONSAAP—American Academy of PediatricsFDA—Food and Drug AdministrationHBV—hepatitis B vaccineHPV—human papillomavirus vaccineNSAID—nonsteroidal antiinflammatory drug

This document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authorshave filed conflict of interest statements with the AmericanAcademy of Pediatrics. Any conflicts have been resolved througha process approved by the Board of Directors. The AmericanAcademy of Pediatrics has neither solicited nor accepted anycommercial involvement in the development of the content ofthis publication.

The guidance in this report does not indicate an exclusivecourse of treatment or serve as a standard of medical care.Variations, taking into account individual circumstances, may beappropriate.

*The recommendations in this review are those of the authorsand do not represent the views of the US Food and DrugAdministration.

www.pediatrics.org/cgi/doi/10.1542/peds.2013-1985

doi:10.1542/peds.2013-1985

All clinical reports from the American Academy of Pediatricsautomatically expire 5 years after publication unless reaffirmed,revised, or retired at or before that time.

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2013 by the American Academy of Pediatrics

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the drug on milk production, theamount of the drug excreted into hu-man milk, the extent of oral absorptionby the breastfeeding infant, and poten-tial adverse effects on the breastfeedinginfant. The age of the infant is also animportant factor in the decision-makingprocess, because adverse events asso-ciated with drug exposure via lactationoccur most often in neonates youngerthan 2 months and rarely in infantsolder than 6 months.2 In the nearfuture, pharmacogenetics may also pro-vide important guidance for individu-alized decisions.

In large part because of efforts byCheston Berlin, Jr, MD, a statement bythe American Academy of Pediatrics

(AAP) on the transfer of drugs andchemicals into human milk was firstpublished in 19833 and underwentseveral subsequent revisions,4,5 themost recent of which was publishedin 2001.6 Previous editions wereintended to list drugs potentially usedduring lactation and to describe pos-sible effects on the infant and/or onlactation. Revisions for the statementcan no longer keep pace with therapidly changing information availablevia the Internet, published studies,and new drug approvals. A morecomprehensive and current databaseis available at LactMed (http://toxnet.nlm.nih.gov). LactMed includes up-to-date information on drug levels in

human milk and infant serum, possi-ble adverse effects on breastfeedinginfants, potential effects on lactation,and recommendations for possiblealternative drugs to consider. Com-mon herbal products are also in-cluded. For this reason, with theexception of radioactive compoundsthat require temporary or permanentcessation of breastfeeding, the readerwill be referred to LactMed to obtainthe most current data on an individualmedication.

This statement reviews proposedchanges in US Food and Drug Admin-istration (FDA) labeling that are de-signed to provide useful informationto the physician and to outline general

LactMed is part of the National Library of Medicine’s Toxicology Data Network (TOXNET)

Each record includes the following information:

� Generic name: refers to US-adopted name of active portion of the drug

� Scientific name: genus and species of botanical products (when applicable)

� Summary of use during lactation (includes discussion of conflicting recommendations and citations)

� Drug levels

▫ Maternal levels: based on studies that measure concentration in breast milk; includes relative infant dose(weight-adjusted percentage of maternal dose) when possible

▫ Infant levels: serum or urine concentrations from the literature� Effects in breastfed infants: adverse events with Naranjo* assessment of causality (definite, probably, possibly,

unlikely)

� Possible effects on lactation: if known, including effects on infants that may interfere with nursing (eg, sedation)

� Alternative drugs to consider: may not be comprehensive

� References

� Chemical Abstracts Service Registry Number

� Drug class

� LactMed record number

� Last revision date

Primary Author: Philip O. Anderson, PharmD

Contributor: Jason Sauberan, PharmD

Peer Review Panel:

Cheston M. Berlin, Jr, MDShinya Ito, MDKathleen Uhl, MDSonia Neubauer, MD

* The Naranjo probability scale is a method used to estimate the probability that an adverse event is caused by a drug.7

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considerations for individual risk/benefit counseling. An update re-garding the use of antidepressants,anxiolytics, and antipsychotics in thelactating woman is also provided, be-cause the use of psychotropic agentsduring lactation is still debated. Sincepublication of the last statement, nu-merous questions have been raisedregarding the use of methadone in thelactating woman. For this reason,therapies for substance abuse andsmoking cessation are discussed. Giventhe finding that codeine use may beassociated with toxicity in patients, in-cluding neonates with ultrarapid me-tabolism, a brief review of alternativeagents to treat pain in the lactatingwoman is provided. The use of gal-actagogues is also reviewed becausemore women now endeavor to breast-feed adopted infants or preterm neo-nates. The increasing use of herbalproducts has invited a discussion ofthe merits of these alternative thera-pies in the nursing woman. Finally,immunization of breastfeeding womenand their infants will be reviewed toassist pediatricians in encouragingimmunization when needed in lactat-ing women and addressing parentalreluctance to immunize breastfedinfants.

GENERAL CONSIDERATIONS

Several factors should be consideredwhen advising a woman regarding adecision to breastfeed her infant whileshe is on drug therapy. The benefits ofbreastfeeding for both the infant andmother need to be weighed against therisks of drug exposure to the infant (orto the mother, in the case of agentsintended to induce lactation). Manyfactors affect the individual risk/benefitdecision, including specific informationabout chemical and pharmacologicproperties of the drug, which may beavailable from resources such asLactMed and in product labeling. In

general, chemical properties of a drug,such as lack of ionization, small mo-lecular weight, low volume of distri-bution, low maternal serum proteinbinding, and high lipid solubility, facil-itate drug excretion into human milk.Drugs with long half-lives are morelikely to accumulate in human milk, anddrugs with high oral bioavailability aremore easily absorbed by the infant.8

The adverse event profile of the drug isanother property that affects the in-dividual risk/benefit ratio. Use ofa drug with a significant adverse effectin a lactating woman (such as an ar-rhythmia) may be acceptable to treata serious illness in the mother; how-ever, use of the same drug to increasemilk production would not be accept-able. For drugs with an adverse eventprofile that correlates with increasingdosage, higher maternal doses may beassociated with greater neonataltoxicity. In addition, the timing of ex-posure and the duration of therapyare other important considerations.A decision to breastfeed when con-tinuing treatment with an agent forwhich in utero exposure also hasoccurred differs from a decision toinitiate a novel therapy in the earlypostpartum period. Similarly, therisks of a single-dose therapy orshort-term treatment may differ fromthose of a chronic therapy.

In addition to pharmacokinetic orchemical properties of the drug, theinfant’s expected drug exposure isinfluenced by infant and maternal fac-tors beyond basic known pharmacoki-netic and chemical properties of thedrug itself. For example, the risk ofadverse reactions in a preterm infantor an infant with underlying chronicmedical conditions may be higher thanthat for a more mature or healthierinfant. Certain drugs may accumulatein the breastfed infant because of re-duced clearance or immaturity of met-abolic pathways. However, for other

drugs (eg, acetaminophen), the imma-turity of these same pathways mayprotect an infant from toxic drugmetabolites. Similarly, patients withspecific genotypes may experiencedrug toxicity, as evidenced by fatalitiesobserved in individuals who demon-strate ultrarapid metabolism of co-deine.9 Finally, certain infant conditions,such as metabolic diseases, and ma-ternal health conditions may precludenursing (eg, HIV) or require multipletherapies that are particularly toxic(eg, cancer treatment).

CHANGES IN DRUG LABELING

In the past, the lactation section in FDA-approved labeling was often limited tostatements that advise caution orcontain an admonition to discontinuebreastfeeding or discontinue therapy,depending on the importance to themother. In 2008, the FDA publisheda proposed revision to the regulations,which affects the pregnancy and lac-tation sections of labeling. The agencyis currently working on the final rule,which is intended to provide a clini-cally oriented framework for place-ment of pregnancy and lactationinformation into drug labeling and topermit the patient and physician toexplore the risk/benefit on the basis ofthe best available data. Under theproposed rule, the current NursingMothers section is replaced by a sec-tion called Lactation. The Lactationsection of labeling will contain 3subsections: Risk Summary, ClinicalConsiderations, and Data. The RiskSummary section will include a sum-mary of what is known about the ex-cretion of the drug into human milkand potential effects on the breastfedinfant, as well as maternal milk pro-duction. The Clinical Considerationssection will include methods to mini-mize exposure of the breastfed infantto the drug when applicable, as well asinformation about monitoring for

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expected adverse drug effects on theinfant. The Data component will pro-vide a detailed overview of the existingdata that forms the evidence base forthe other 2 sections.

In addition to the proposed rule, theFDA published “Guidance for Industry:Clinical Lactation Studies: Study De-sign, Data Analysis, and Recom-mendations for Labeling.”10

Along with outlining recommendationsregarding lactation study design aswell as the timing and indications forthese studies, this draft guidanceincludes advice on parameters (sev-eral of which are used in LactMed) thatcan be used to inform physiciansabout the extent of drug exposure.Using these parameters, drug expo-sure to the infant may be measureddirectly in infant serum or estimatedon the basis of pharmacokinetic pa-rameters. These estimates of infantexposure (for example, relative infantdose) can be expressed as a percent ofweight-adjusted maternal or, whenknown, weight-adjusted pediatric dose.

ANTIDEPRESSANTS, ANXIOLYTICS,AND ANTIPSYCHOTICS

Previous statements from the AAP cat-egorized the effect of psychoactive drugson the nursing infant as “unknown butmay be of concern.” Although new datahave been published since 2001, in-formation on the long-term effects ofthese compounds is still limited. Mostpublications regarding psychoactivedrugs describe the pharmacokineticsin small numbers of lactating womenwith short-term observational studiesof their infants. In addition, interpre-tation of the effects on the infant fromthe small number of longer-term stud-ies is confounded by prenatal treat-ment or exposure to multiple therapies.For these reasons, the long-term ef-fect on the developing infant is stilllargely unknown.11,12

Many antianxiety drugs, antide-pressants, and mood stabilizers appearin low concentrations in human milk,with estimated relative infant dosesless than 2% of weight-adjusted ma-ternal dose and/or milk-plasmaratios less than 1.13 However, the per-centage of maternal doses that ap-proach clinically significant levels (10%or more) have been reported forbupropion,14 diazepam,13 fluoxetine,15

citalopram,16 lithium,17 lamotrigine,18

and venlafaxine.19 Data on drug ex-cretion in human milk are not avail-able for up to one-third of psychoactivetherapies.13

Because of the long half-life of some ofthese compounds and/or their metab-olites, coupled with an infant’s imma-ture hepatic and renal function,nursing infants may have measurableamounts of the drug or its metabolitesin plasma and potentially in neuraltissue. Infant plasma concentrationsthat exceed 10% of therapeutic ma-ternal plasma concentrations havebeen reported for a number of selec-tive serotonin reuptake inhibitors,

antipsychotics, anxiolytics, and moodstabilizers (see Table 1).

Mothers who desire to breastfeedtheir infant(s) while taking theseagents should be counseled about thebenefits of breastfeeding as well as thepotential risk that the infant may beexposed to clinically significant levelsand that the long-term effects of thisexposure are unknown. Considerationshould be given to monitoring growthand neurodevelopment of the infant.

DRUGS FOR SMOKING CESSATIONOR TO TREAT SUBSTANCE ABUSE/ALCOHOL DEPENDENCE

Although many women are appropri-ately advised to refrain from smoking,drinking, and using recreational drugsduring and after pregnancy, in partbecause of adverse effects on theirinfants (see Table 2), some are unableto do so and may seek assistance afterdelivery. Maternal smoking is not anabsolute contraindication to breast-feeding.31 Nonetheless, for multiplereasons, including the association ofsudden infant death syndrome with

TABLE 1 Psychoactive Drugs With InfantSerum Concentrations Exceeding10% of Maternal PlasmaConcentrationsa

Agent Reference

Citalopram Weissman 200420

Clomipramine Schimmell 199121

Diazepam Wesson 198522

Doxepin Moretti 200916

Fluoxetine Weissman 2004,20 productlabeling

Fluvoxamine Weissman 200420

Lamotrigine Newport 2008,18

Fotopoulou 200923

Lithium Viguerra 2007,24

Grandjean 2009,25

Bogen 201226

Mirtazapine Tonn 200927

Nortriptyline Weissman 200420

Olanzapine Whitworth 200828

Sertraline Hendrick 2001,29 Stowe 200330

Venlafaxine Newport 200919

a Based on individual maternal-infant pair(s); may in-clude active metabolites.

ESTIMATES OF DRUG EXPOSURE

Daily Infant Dosage (mg/day)=Pðdrug  concentration  in  each milk 

collection× expreesed  volume in 

each milk  collectionÞOR

Cmilk½average  drug  concentration  in milkðmg=mLÞ�× Vmilkðvolume  in mL of  milk  ingested  in  24  hoursÞ

Note :   Vmilk   is  typically  estimated  to  be  150 mL=kg=day

Relative Infant Dose

%  Maternal  Dose¼ ½Daily  Infant  Dosage ðmg=kg=dayÞ÷Maternal  Dose ðmg=kg=dayÞ�× 100

%  Infant  or  Pediatric  Dose¼ ½Daily  Infant Dosage  ðmg=kg=dayÞ ÷ Infant or Pediatric doseðmg=kg=dayÞ�× 100

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tobacco exposure,32,33 lactating womenshould be strongly encouraged to stopsmoking and to minimize secondhandexposure. Exposure to alcohol or rec-reational drugs may impair a mother’sjudgment and interfere with her careof the infant and can cause toxicity tothe breastfeeding infant (see Table 2).

Limited information is available re-garding the use of medications inlactating women to treat substanceabuse or alcohol dependence or forsmoking cessation. However, the pres-ence of behaviors, such as continuedingestion of illicit drugs or alcohol, andunderlying conditions, such as HIV in-fection, are not compatible with breast-feeding.49,50 Patients also require ongoingpsychosocial support to maintainabstinence.48

Methadone, buprenorphine, and nal-trexone are 3 agents approved by theFDA for use in the treatment of opioiddependence. Continued breastfeedingby women undergoing such treatmentpresumes that the patient remainsabstinent, is HIV negative, and is en-

rolled in and closely monitored by anappropriate drug treatment programwith significant social support.48,51

Potential adverse effects on breast-feeding infants from methadone(according to product labeling) andbuprenorphine include lethargy, re-spiratory difficulty, and poor weightgain.52 The long-term effects of meth-adone in humans are unknown. None-theless, methadone levels in humanmilk are low, with calculated infantexposures less than 3% of the maternalweight-adjusted dose.53,54 Plasma con-centrations in infants are also low (lessthan 3% of maternal trough concen-trations) during the neonatal periodand up to 6 months postpartum.55,56

For these reasons, guidelines from theAcademy of Breastfeeding Medicineencourage breastfeeding for womentreated with methadone who are en-rolled in methadone-maintenance pro-grams.48

Buprenorphine is excreted into humanmilk and achieves a level similar to thatin maternal plasma.57 Infant exposure

appears to be up to 2.4% of the ma-ternal weight-adjusted dose.55,56,58

However, buprenorphine can be abused,and although the significance in humansis unknown, labeling for buprenor-phine and buprenorphine/naloxonecombinations states that use is notadvised by lactating women, becauseanimal lactation studies have showndecreased milk production and via-bility of the offspring. FDA labelingalso advises caution for use of nal-trexone in nursing infants of opioid-dependent women. Of note, publishedinformation on naltrexone is limited to1 case report that estimates infantexposure to be low (7 μg/kg/d, or0.86% of the maternal weight-adjusteddose).59

Transferred amounts of methadoneor buprenorphine are insufficient toprevent symptoms of neonatal absti-nence syndrome.49,60 Neonatal absti-nence syndrome can occur afterabrupt discontinuation of metha-done.51,61 Thus, breastfeeding shouldnot be stopped abruptly, and gradual

TABLE 2 Drugs of Abuse for Which Adverse Effects on the Breastfeeding Infant Have Been Reporteda

Drug Reported Effect or Reason for Concern Reference

Alcohol Impaired motor development or postnatal growth, decreasedmilk consumption, sleep disturbances.

Koren 2002,34 Backstrand 2004,35 Mennella 200736

Note: Although binge drinking should be avoided, occasional,limited ingestion (0.5 g of alcohol/kg/d; equivalent to 8 ozwine or 2 cans of beer per day) may be acceptable.

National Academy of Sciences 199137

Amphetamines Hypertension, tachycardia, and seizures. Product labelingIn animal studies of postnatal exposure, long-term behavioraleffects, including learning and memory deficits and alteredlocomotor activity, were observed.

Benzodiazepines Accumulation of metabolite, prolonged half-life in neonate orpreterm infant is noted; chronic use not recommended.

Jain 2005,38 Malone 200439

Apnea, cyanosis, withdrawal, sedation, cyanosis, and seizures.Cocaine Intoxication, seizures, irritability, vomiting, diarrhea,

tremulousness.Chasnoff 1987,40 Winecker 200141

Heroin Withdrawal symptoms, tremors, restlessness, vomiting, poorfeeding.

vandeVelde 200742

LSD Potent hallucinogen.Methamphetamine Fatality, persists in breast milk for 48 h. Ariagno 1995,43 Bartu 200944

Methylene dioxy-methamphetamine (ecstasy)

Closely related products (amphetamines) are concentrated inhuman milk.

Marijuana (cannabis) Neurodevelopmental effects, delayed motor development at 1 y,lethargy, less frequent and shorter feedings, high milk-plasma ratios in heavy users.

Djulus 2005,45 Campolongo 2009,46 Garry 201047

Phencyclidine Potent hallucinogen, infant intoxication. AAP 2001,6 Academy of Breastfeeding Medicine48

a Effect on maternal judgment or mood may affect ability to care for infant.

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weaning is advised if a decision ismade to discontinue breastfeeding.

Limited information is available for di-sulfiram and naltrexone, agents thatare used to treat alcohol dependence.As noted previously, a low relative infantdose (<1%) was observed in a singlecase report of naltrexone exposure ina 6-week-old breastfed infant.59 FDAlabeling discourages use of disulfiramand both the injectable and oral formof naltrexone in lactating women.

Only one-third of women successfullydiscontinue smoking without pharma-cologic aids.62 Nicotine replacementtherapy, bupropion, and varenicline areagents indicated for use as aids tosmoking cessation treatment. Nicotinereplacement therapy is compatiblewith breastfeeding as long as the dose(assuming a cigarette delivers ∼1 mgof nicotine) is less than the number ofcigarettes typically smoked, becausenicotine passes freely into human milkand is orally absorbed as nicotine.Cotinine concentrations are lower thanthose related to tobacco use. Short-acting products (eg, gum or lozenges)are recommended.62 Infant exposuredecreases proportionally with mater-nal patch doses.63

In contrast, bupropion is excreted intohuman milk with exposures that mayexceed 10% (range, 1.4%–10.6%) of thematernal dose.14 Although infant levelswere not measured, there is a casereport of a seizure in a 6-month-oldbreastfed infant potentially related tobupropion.64 Limited published in-formation is available for varenicline,but the varenicline label includesa boxed warning for serious neuro-psychiatric adverse events, includingsuicidal ideation or behavior. FDA la-beling discourages use of both theseagents in lactating women.

PAIN MEDICATIONS

Rarely, normal doses of codeine givento lactating women may result in

dangerously high levels of its activemetabolite morphine in breastfeedinginfants. A fatality has been noted in aninfant of a mother with ultrarapidmetabolism.65 In this infant, the post-mortem level of morphine (87 ng/mL)greatly exceeded a typical level ina breastfeeding infant (2.2 ng/mL), aswell as the therapeutic range forneonates (10–12 ng/mL). In addition,unexplained apnea, bradycardia, cya-nosis, and sedation have been repor-ted in nursing infants of mothersreceiving codeine.2,66 Hydrocodone isalso metabolized via the CYP2D6pathway. On the basis of pharmacoki-netic data, infants exposed to hydro-codone through human milk mayreceive up to 9% of the relative ma-ternal dose.67 Given the reducedclearance of hydrocodone in neonatesand the adverse events observed inultrarapid metabolizers of codeine,caution is advised for use of codeineand hydrocodone in both the motherand nursing infant. Close monitoringfor signs and symptoms of neonatal aswell as maternal toxicity is recom-mended. A commercial test to identifyultrarapid metabolizers is not yetwidely available. The incidence of thisspecific CYP2D6 genotype varies withracial and ethnic group as follows:Chinese, Japanese, or Hispanic, 0.5% to1.0%; Caucasian, 1.0% to 10.0%; AfricanAmerican, 3.0%; and North African,Ethiopian, and Saudi Arabian, 16.0% to28.0%.68

For these reasons, when narcoticagents are needed to treat pain in thebreastfeeding woman, agents otherthan codeine (eg, butorphanol, mor-phine, or hydromorphone) are pre-ferred. Clinically insignificant levels ofbutorphanol are excreted into humanmilk. Morphine appears to be toler-ated by the breastfeeding infant, al-though there is 1 case report of aninfant with plasma concentrationswithin the therapeutic range.69 Clear-

ance of morphine is decreased ininfants younger than 1 month andapproaches 80% of adult values by 6months of age.70 Limited data suggestthat use of hydromorphone for briefperiods may be compatible withbreastfeeding71,72; however, FDA label-ing discourages use. Regardless ofthe choice of therapy, to minimizeadverse events for both the motherand her nursing infant, the lowestdose and shortest duration of therapyshould be prescribed. Drug deliveryvia patient-controlled anesthesia oradministration by the epidural routemay also minimize infant exposure.

Other narcotic agents, such as oxy-codone, pentazocine, propoxyphene, andmeperidine, are not recommended in thelactating mother. Relatively high amountsof oxycodone are excreted into humanmilk, and therapeutic concentrationshave been detected in the plasma ofa nursing infant.73 Central nervous sys-tem depression was noted in 20% ofinfants exposed to oxycodone duringbreastfeeding.74 Thus, use of oxycodoneshould be discouraged. Limited pub-lished data are available about pentaz-ocine. However, respiratory depressionand apnea occur frequently in infants,particularly in neonates or in preterminfants, who are treated with pentazo-cine. Propoxyphene has been associatedwith unexplained apnea, bradycardia,and cyanosis, as well as hypotonia innursing infants.75,76 Moreover, pro-poxyphene was withdrawn from themarket because significant QT pro-longation occurred at therapeuticdoses.77 Meperidine use is associatedwith decreased alertness of the infantand is likely to interfere with breast-feeding.71 Although estimates of meper-idine exposure are low (approximately2% to 3% of the maternal weight-adjusted dose), the half-life of the activemetabolite for meperidine is prolonged,and it may accumulate in infant bloodor tissue.71,72

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When narcotics are not required torelieve mild to moderate pain, otheranalgesic agents can be used. Pre-suming that pain relief is adequate,short-acting agents, such as ibuprofenand acetaminophen, are acceptable.78

Although the half-life of ibuprofen maybe prolonged in neonates, particularlyin preterm infants (according toproduct labeling), minimal amounts ofibuprofen are excreted into humanmilk.72 Despite reduced clearance ofacetaminophen,79 hepatotoxicity isless common in neonates than inolder infants, in part because of lowlevels of certain cytochrome P-450enzymes, which convert acetamino-phen into toxic metabolites.80 Acet-aminophen is available for both oraland intravenous administration.

Although all nonsteroidal antiinflam-matory drugs (NSAIDs) carry a boxedwarning regarding gastrointestinalbleeding and potential long-term cardiactoxicity, according to their product la-beling and Gardiner et al,81 celecoxib,flurbiprofen, and naproxen are consid-ered to be compatible with breastfeed-ing, because less than 1% is excretedinto human milk. In addition, a breast-feeding infant would receive less than1% of the relative pediatric dose of cel-ecoxib prescribed for a 2-year-old(according to product labeling). How-ever, long-term use of naproxen is notrecommended because of the drug’slong half-life and case reports of gas-trointestinal tract bleeding and emesis.Avoiding NSAIDs in breastfeeding infantswith ductal-dependent cardiac lesionsmay be prudent.

Limited published data on otherNSAIDs (etodolac, fenoprofen, melox-icam, oxaprozin, piroxicam, sulindac,and tolmetin) are available, and FDAlabeling discourages their use fora variety of reasons. Although theimplications for humans are unknown,meloxicam concentrations in milk oflactating animals exceed plasma con-

centrations. Diflunisal has a long half-

life and is not recommended because

of potential adverse events, including

cataracts and fatality, in neonatalanimals. Similarly, mefenamic acid hasa prolonged half-life in preterm infants.Injectable and oral forms of ketorolacare contraindicated in nursing women,according to product labeling, becauseof potential adverse effects related toclosure of the ductus arteriosus inneonates. Less than 1% of ketorolacnasal spray is excreted into humanmilk, and unlike the oral and in-travenous forms of ketorolac, use is notcontraindicated (product labeling).

Carisoprodol and its active metabolite,meprobamate, are concentrated inhuman milk (2–4 times maternalplasma concentrations). Impaired milkproduction has been observed, andanimal studies suggest maternal usemay lead to less effective infant feeding(because of sedation) and/or de-creased milk production (according toproduct labeling).

Low doses (75–162 mg/d) of aspirinmay be acceptable82; however, use ofhigh-dose aspirin therapy duringbreastfeeding is not advised, becausethe serum concentration of salicylatein breastfeeding infants has beenreported to reach approximately 40%of therapeutic concentrations. Adverseevents, such as rash, platelet abnor-malities, bleeding, and metabolic aci-dosis have also been reported.71

GALACTAGOGUES

Galactagogues, or agents to stimulatelactation, are often used to facilitatelactation, particularly for mothers ofpreterm infants. They also may be usedto induce lactation in an adoptivemother. However, evidence to supportthese agents, including use of dopa-mine antagonists, such as domper-idone and metoclopramide; herbaltreatments; and hormonal manipula-tion, is lacking.83

Although a placebo-controlled study(n = 42) suggested that domperidonemay increase milk volume in mothersof preterm infants,84 maternal safetyhas not been established. The FDAissued a warning in June 2004 re-garding use of domperidone in breast-feeding women because of safetyconcerns based on published reportsof arrhythmia, cardiac arrest, andsudden death associated with intrave-nous therapy. Furthermore, treatmentwith oral domperidone is associatedwith QT prolongation in children andinfants.85,86 Domperidone is not anapproved product in the United States,and labeling for oral formulationsmarketed outside the United States donot recommend use during lactation.

Several small trials (each with fewerthan 25 subjects) published before1990 suggested that metoclopramideincreases prolactin concentrationsand/or milk production in mothers ofboth term and preterm infants.87

However, more recent controlledstudies do not replicate this finding.88,89

Human milk concentrations of meto-clopramide are similar to therapeuticconcentrations in adult plasma,88 andmeasurable amounts can be detectedin breastfeeding infants.90 Clearance ofmetoclopramide in neonates is pro-longed, which may result in excessiveserum concentrations and the risk ofconditions associated with overdose,such as methemoglobinemia. Of concern,prolactin concentrations were increasedin 4 of 7 infants exposed to metoclopra-mide via human milk.90 The safety profilefor metoclopramide includes adversereactions, such as dystonia, depression,suicidal ideation, and gastrointestinaltract disturbances, as well as a boxedwarning about the risk of tardive dyski-nesia. These risks to the mother limit theusefulness of this therapy.

Although a pilot study in 8 lactatingwomen performed decades ago sug-gested that oxytocin nasal spray

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increased human milk production,a larger placebo-controlled trial in 51women has not confirmed that ob-servation.91 Oxytocin nasal spray is nolonger marketed in the United States.Similarly, anecdotal reports supportingthe use of the herb fenugreek to facil-itate lactation have not been confirmedby controlled studies.92,93 Fenugreekcontains coumarin, which may interactwith NSAIDs.94 Use of fenugreek in lac-tating women also is associated withmaple-syrup odor in infants.95 Availabledata do not support the routine use ofother herbal products, such as fennel,to facilitate lactation.96

In summary, galactagogues have a lim-ited role in facilitating lactation and havenot been subject to full assessments ofsafety for the nursing infant. Nursingmothers should seek consultation witha lactation specialist and use non-pharmacologic measures to increasemilk supply, such as ensuring propertechnique, using massage therapy, in-creasing the frequency of milk expres-sion, prolonging the duration of pumping,and maximizing emotional support.

COMMONLY USED HERBALPRODUCTS

Despite the frequent use of herbalproducts in breastfeeding women (upto 43% of lactating mothers in a 2004survey),97 reliable information on thesafety of many herbal products islacking. Herbal products are not sub-ject to the same standards formanufacturing and proven effective-ness and safety as are drug productsbefore they are marketed.98 In fact,the use of several herbal productsmay be harmful, including kava andyohimbe. For example, the FDA hasissued a warning that links kavasupplementation to severe liver dam-age.99 Breastfeeding mothers shouldnot use yohimbe because of reports ofassociated fatalities in children.100 Inaddition, from 2008 through 2010, the

FDA recalled 10 or more dietary sup-plements each year because of thepresence of potentially toxic un-declared ingredients in the supple-ment.101 Similarly, the US GovernmentAccountability Office found that 16 of40 common herbal dietary supple-ments obtained from retail storescontained pesticide residues.102

Safety data are lacking for many herbscommonly used during breastfeeding,such as chamomile,103 black cohosh,104

blue cohosh,105 chastetree,106 echina-cea,107 ginseng,108 gingko,109 Hypericum(St John’s wort),110,111 and valerian.112

Adverse events have been reported inboth breastfeeding infants and moth-ers. For example, St John’s wort maycause colic, drowsiness, or lethargy inthe breastfed infant even though milkproduction and infant weight do notappear to be adversely affected110 andrelative maternal dose and infantplasma concentrations are low.113

Prolonged use of fenugreek may re-quire monitoring of coagulation statusand serum glucose concentrations.114

For these reasons, these aforemen-tioned herbal products are not rec-ommended for use by nursing women.

Although supplementation of nursingmothers with iron and vitamins is safeas long as recommended daily allow-ances are not exceeded, the use of othernutritional supplements may not be. Forinstance, L-tryptophan has been associ-ated with eosinophilic myositis.115 There-fore, physicians should inquire aboutthe use of herbal products and dietarysupplements in lactating women anddiscuss the need for caution becauseof the paucity of data available.

DIAGNOSTIC IMAGING

When feasible, elective imaging pro-cedures should be delayed untila woman is no longer breastfeeding.For most radiopharmaceuticals, breast-feeding should be interrupted for atime period based on the rate of de-

cline of the agent and dosimetry toavoid infant exposures greater than 1mSv (100 mrem). For agents that maybe concentrated in breast tissue, closecontact of the mother with the infantand, consequently, nursing may needto be avoided for a period of time,although expressed milk that has beenrefrigerated until the radioactivity hasdecayedmay be safe. General guidelinesbased on Nuclear Regulatory Commis-sion regulations and International Com-mission on Radiologic Protectionguidelines116 are cited in Tables 3 and4. However, because there is consid-erable variability in milk radioactivity,and close contact with an infant mayresult in additional exposure, consulta-tion with a radiologist should be sought.If deemed necessary, individualizedtesting of expressed milk may be per-formed to ensure that radioactivity hasreached background levels beforebreastfeeding is resumed.117

Notably, because radiolabeled iodin-ated products are concentrated in thedeveloping thyroid and radioactivitypersists after imaging with most 131Iand 125I radiopharmaceuticals (with theexception of 125I- hippurate), breast-feeding should be interrupted for aminimum of 3 weeks. Similarly, 22Naand 67Ga (gallium) administration alsorequire a prolonged (3-week) interrup-tion in breastfeeding. Because the lac-tating breast has a greater 131I affinitythan does the nonlactating breast,women should cease breastfeeding atleast 4 weeks before whole-body pro-cedures with 131I and should discontinuebreastfeeding thereafter. Doing so willreduce the radiation dose and potentialcancer risk to maternal breast tissue.

Traditionally, lactating women receivingintravascular gadolinium or iodinatedcontrast (as opposed to radiolabeled io-dine) are advised to discontinue nursingfor 24 hours. However, a minimal amount(0.04%) of the intravenous dose reacheshuman milk, and, of that, less than 1% to

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2% is absorbed by the infant. Therefore,breastfeeding can be continued withoutinterruption after the use of iodinatedcontrast or gadolinium.118

BREASTFEEDING AND VACCINES

With rare exceptions, maternal immu-nization does not create any problemsfor breastfeeding infants, althoughquestions concerning 2 topics oftenarise regarding lactation and immuni-zation: the effect of lactation on theinfant’s immune response to a vaccineand a potential adverse effect on theinfant from maternal immunization.Breastfeeding does not interfere with

the infant’s immune response to mostroutine immunizations (eg, diphtheriaand tetanus toxoids and acellular per-tussis vaccine, inactivated poliovirusvaccine, and hepatitis B vaccine [HBV]),121

despite the presence of maternalantibodies in human milk. Seroconver-sion rates are also similar betweenbreastfed and formula-fed infants re-ceiving rotavirus vaccine; however,vaccine efficacy for severe rotavirusgastroenteritis appears to be higher informula-fed infants compared with ex-clusively breastfed infants, particularlyduring the second season (98% vs 88%)when breastfeeding has been dis-continued.122 Nonetheless, protection

during the first year is similar. Moreover,breastfeeding enhances the antibodyresponse to pneumococcal and Haemo-philus influenzae type b vaccines.123

Breastfeeding may also decrease theincidence of fever after infant immuni-zation.124 Therefore, the timing of infantfeeding (including human milk) relativeto immunization is not restricted, evenfor live vaccines, such as rotavirus.

Lactating women may need to be im-munized. Inactivated vaccines (such astetanus toxoid, reduced diphtheriatoxoid, and acellular pertussis vaccine;inactivated poliovirus vaccine; influ-enza; hepatitis A vaccine; HBV; or humanpapillomavirus vaccine [HPV]) given to

TABLE 3 Radioactive Compounds That May Require Temporary Cessation of Breastfeeding: Recommendations of the International Commission onRadiologic Protection

Compound Examples Example of Procedures Recommended Time forCessation of Breastfeeding

Comments

14C-labeled Triolein, glycocholic acid, urea Helicobacter pylori breath test None No approved US products99mTc-labeled DMSA, DTPA, phosphonates

(MDP), PYP, tetrofosminMultiple: imaging of kidney,

bone, lung, heart, tumors0 to 4 h, as long as no freepertechnetate

Consider discarding at least 1meal after procedure

Microspheres, pertechnetate, WBC 12–24 h Range depends on doseSulfur-colloids, RBC in vivo 6 h

I-labeled 123I, 125I or 131I-iodo hippurate Thyroid imaging 12 h Note: whole-body irradiationwith 131I requires prolongedcessation

Others 11C- 11N or 11O-labeled PET scans None Short physical half-life57Co-labeled vitamin B12 Schilling test 24 h Pomeroy 200511918F-FDG PET scans None, first feeding

should be expressed breastmilk to avoid direct contact120

Use alternatives for 10 half-lives(10×109 min= 18 h)a

51Cr-EDTA Renal imaging None81mKr-gas Pulmonary imaging None No approved US products82Rb chloride PET scan of myocardium May resume 1 h after

last infusionHalf-life 75 sa

111In-octreotide SPECT, neuroendocrine tumors None111In -WBC 1 wk Depends on dose133Xe Cardiac, pulmonary, and

cerebral imagingNone Half-life 5 da

DMSA, dimercaptosuccinic acid; DTPA, diethylenetriaminepentaacetate; EDTA, ethylenediaminetetraacetic acid; FDG, fludeoxyglucose; PET, positron emission tomography; PYP, pyrophosphate;RBC, red blood cell; SPECT, single-photon emission computed tomography; WBC, white blood cell.a FDA-approved drug labeling.

TABLE 4 Radioactive Compounds Requiring Prolonged Cessation of Breastfeeding

Compound Examples Example of Procedures Recommended Time forCessation of Breastfeeding

Comments

I-labled 123I- BMIPP, -HSA, -IPPA, -MIBG, -NaI, or -HSA Imaging of tumors Greater than 3 wk Essentially need tostop breastfeeding131I-MIBG or -NaI

Others 201Tl-chloride Cardiac imaging 48 h to 2 wk Half-life 73 ha67Ga-citrate Imaging of tumors 1 wk to 1 mo Depends on dose22Na, 75Se Greater than 3 wk Essentially need to

stop breastfeeding

Use of expressed human milk recommended because of exposure via direct contact.120 BMIPP, β-methyl-p-iodophenyl-pentadecanoic acid; HSA, human serum albumin; IPPA, iodophe-nylpentadecanoic; MIBG, metaiodobenzylguanidine; NaI, sodium iodide.a FDA-approved drug labeling.

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a nursing mother do not pose a risk tothe breastfeeding infant. Several vac-cines, such as tetanus toxoid, reduceddiphtheria toxoid, and acellular per-tussis vaccine and influenza vaccine,are recommended for the motherduring the postpartum period to pro-tect the infant as well as the mother.Other routine or catch-up vaccines,such as HPV, hepatitis A vaccine, andHBV, can be given to the lactatingmother. HPV immunization is recom-mended for women younger than 27years. The incidence of adverse reac-tions in nursing infants within 30 daysof maternal immunization with HPV wassimilar to nursing infants of womenreceiving the control except for acuterespiratory illness (according to Gar-dasil labeling). Hence, caution is war-ranted when immunizing mothers ofinfants who are vulnerable to re-spiratory illnesses (eg, preterm infants,infants with congenital heart disease orchronic respiratory problems).

Most live vaccines are not associatedwith virus secretion in human milk. Forexample, despite maternal serocon-version, neither the varicella virus norantibody to varicella DNA has beendetected in breastfeeding infants.125

Although attenuated rubella can besecreted into human milk and trans-mitted to breastfed infants, infectionsare usually asymptomatic or mild.Consequently, postpartum immuniza-tion with measles-mumps-rubella vac-cine is recommended for women wholack immunity, especially to rubella.126

In contrast, infants are considered tobe at high risk of developing vaccinia

after exposure to smallpox vaccine orencephalitis after yellow fever vaccine.Two cases of meningoencephalitis innursing infants whose mothers hadbeen immunized against yellow feverare documented in the literature.127,128

Therefore, most vaccines, with the ex-ception of smallpox or yellow-fevervaccine, which are contraindicated innonemergency situations, may be ad-ministered during lactation.

SUMMARY

The benefits of breastfeeding outweighthe risk of exposure to most thera-peutic agents via human milk. Althoughmost drugs and therapeutic agents donot pose a risk to the mother or nursinginfant, careful consideration of the in-dividual risk/benefit ratio is necessaryfor certain agents, particularly thosethat are concentrated in human milk orresult in exposures in the infant thatmay be clinically significant on thebasis of relative infant dose or detect-able serum concentrations. Caution isalso advised for drugs and agents withunproven benefits, with long half-livesthat may lead to drug accumulation,or with known toxicity to the mother orinfant. In addition, specific infants maybe more vulnerable to adverse eventsbecause of immature organ function(eg, preterm infants or neonates) orunderlying medical conditions. Severalexcellent resources are available forthe pediatrician, including product la-beling and the peer-reviewed database,LactMed. Consultation with a specialistmay be indicated, particularly when the

use of radiopharmaceuticals, oncologicdrugs, or other therapies not ad-dressed by LactMed is contemplated.Additional information about topicsoutside the scope of this report, such asenvironmental agents, can be obtainedfrom the third edition of the AAP text-book Pediatric Environmental Health.129

LEAD AUTHORHari Cheryl Sachs, MD, FAAP

COMMITTEE ON DRUGS, 2012–2013Daniel A. C. Frattarelli, MD, FAAP, ChairpersonJeffrey L. Galinkin, MD, FAAPThomas P. Green, MD, FAAPTimothy Johnson, DO, FAAPKathleen Neville, MD, FAAPIan M. Paul, MD, MSc, FAAPJohn Van den Anker, MD, PhD, FAAP

FORMER COMMITTEE MEMBERSMark L. Hudak, MD, FAAPMatthew E. Knight, MD, FAAP

LIAISONSJohn J. Alexander, MD, FAAP – Food and DrugAdministrationSarah J. Kilpatrick, MD, PhD – American Collegeof Obstetricians and GynecologistsJanet D. Cragan, MD, MPH, FAAP – Centers forDisease Control and PreventionMichael J. Rieder, MD, FAAP – Canadian Pedi-atric SocietyAdelaide Robb, MD – American Academy ofChild and Adolescent PsychiatryHari Cheryl Sachs, MD, FAAP – Food and DrugAdministrationAnne Zajicek, MD, PharmD, FAAP – NationalInstitutes of Health

CONTRIBUTORAshley Moss, MD, FAAP

STAFFTamar Haro, JDRaymond J. Koteras, MHA

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