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Guidance for the Clinician in Rendering Pediatric Care

CLINICAL REPORT The Transfer of Drugs and Therapeutics Into Human : An Update on Selected Topics

Hari Cheryl Sachs, MD, FAAP* and COMMITTEE ON DRUGS abstract KEY WORD Many are inappropriately advised to discontinue human milk or avoid taking essential medications because of fears of adverse effects ABBREVIATIONS on their . This cautious approach may be unnecessary in many AAP—American Academy of cases, because only a small proportion of medications are contraindi- FDA—Food and Drug Administration HBV— B vaccine cated in breastfeeding mothers or associated with adverse effects on their HPV—human papillomavirus vaccine infants. Information to inform physicians about the extent of excretion for NSAID—nonsteroidal antiinflammatory drug a particular drug into human milk is needed but may not be available. This document is copyrighted and is property of the American Previous statements on this topic from the American Academy of Pediat- Academy of Pediatrics and its Board of Directors. All authors rics provided physicians with data concerning the known excretion of spe- have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through cific medications into breast milk. More current and comprehensive a process approved by the Board of Directors. The American information is now available on the Internet, as well as an application Academy of Pediatrics has neither solicited nor accepted any for mobile devices, at LactMed (http://toxnet.nlm.nih.gov). Therefore, with commercial involvement in the development of the content of this publication. the exception of radioactive compounds requiring temporary cessation of breastfeeding, the reader will be referred to LactMed to obtain the The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. most current data on an individual medication. This report discusses Variations, taking into account individual circumstances, may be several topics of interest surrounding , such as the use of appropriate. psychotropic therapies, drugs to treat , narcotics, gal- *The recommendations in this review are those of the authors actagogues, and herbal products, as well as of breastfeed- and do not represent the views of the US Food and Drug Administration. ing women. A discussion regarding the global implications of maternal medications and lactation in the developing world is beyond the scope of this report. The World Health Organization offers several programs and resources 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 treat www.pediatrics.org/cgi/doi/10.1542/peds.2013-1985 acute or chronic conditions. Many women are advised to discontinue doi:10.1542/peds.2013-1985 or avoid taking necessary medications because of concerns about All clinical reports from the American Academy of Pediatrics possible adverse effects in their infants.1 Such advice is often not based automatically expire 5 years after publication unless reaffirmed, on evidence, because information about the extent of drug excretion into revised, or retired at or before that time. human milk may be unavailable, and for many drugs, information is PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). limited to data from animal studies, which may not correlate with human Copyright © 2013 by the American Academy of Pediatrics experience. In addition, not all drugs are excreted in clinically significant amounts into human milk, and the presence of a drug in human milk may not pose a risk for the . To weigh the risks and benefits of breastfeeding, physicians need to consider multiple factors. These fac- tors include the need for the drug by the , the potential effects of

e796 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 30, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS the drug on milk production, the (AAP) on the transfer of drugs and human milk and infant serum, possi- amount of the drug excreted into hu- chemicals into human milk was first ble adverse effects on breastfeeding man milk, the extent of oral absorption published in 19833 and underwent infants, potential effects on lactation, by the breastfeeding infant, and poten- several subsequent revisions,4,5 the and recommendations for possible tial adverse effects on the breastfeeding most recent of which was published alternative drugs to consider. Com- infant. The age of the infant is also an in 2001.6 Previous editions were mon herbal products are also in- important factor in the decision-making intended to list drugs potentially used cluded. For this reason, with the process, because adverse events asso- during lactation and to describe pos- exception of radioactive compounds ciated with drug exposure via lactation sible effects on the infant and/or on that require temporary or permanent occur most often in neonates younger lactation. Revisions for the statement cessation of breastfeeding, the reader than 2 months and rarely in infants can no longer keep pace with the will be referred to LactMed to obtain older than 6 months.2 In the near rapidly changing information available the most current data on an individual future, pharmacogenetics may also pro- via the Internet, published studies, medication. vide important guidance for individu- and new drug approvals. A more This statement reviews proposed alized decisions. comprehensive and current database changes in US Food and Drug Admin- In large part because of efforts by is available at LactMed (http://toxnet. istration (FDA) labeling that are de- Cheston Berlin, Jr, MD, a statement by nlm.nih.gov). LactMed includes up-to- signed to provide useful information the American Academy of Pediatrics date information on drug levels in to 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, MD Shinya Ito, MD Kathleen Uhl, MD Sonia Neubauer, MD * The Naranjo probability scale is a method used to estimate the probability that an adverse event is caused by a drug.7

PEDIATRICS Volume 132, Number 3, September 2013 e797 Downloaded from www.aappublications.org/news by guest on September 30, 2021 considerations for individual risk/ general, chemical properties of a drug, drugs (eg, acetaminophen), the imma- benefit counseling. An update re- such as lack of ionization, small mo- turity of these same pathways may garding the use of antidepressants, lecular weight, low volume of distri- protectaninfantfromtoxicdrug anxiolytics, and antipsychotics in the bution, low maternal serum metabolites. Similarly, patients with lactating woman is also provided, be- binding, and high lipid solubility, facil- specific genotypes may experience cause the use of psychotropic agents itate drug excretion into human milk. drug toxicity, as evidenced by fatalities during lactation is still debated. Since Drugs with long half-lives are more observed in individuals who demon- publication of the last statement, nu- likely to accumulate in human milk, and strate ultrarapid metabolism of co- merous questions have been raised drugs with high oral bioavailability are deine.9 Finally, certain infant conditions, regarding the use of methadone in the more easily absorbed by the infant.8 such as metabolic diseases, and ma- lactating woman. For this reason, The adverse event profile of the drug is ternal health conditions may preclude therapies for substance abuse and another property that affects the in- nursing (eg, HIV) or require multiple smoking cessation are discussed. Given dividual risk/benefit ratio. Use of therapies that are particularly toxic the finding that codeine use may be a drug with a significant adverse effect (eg, cancer treatment). associated with toxicity in patients, in- in a lactating woman (such as an ar- cluding neonates with ultrarapid me- rhythmia) may be acceptable to treat CHANGES IN DRUG LABELING tabolism, a brief review of alternative a serious illness in the mother; how- agents to treat pain in the lactating ever, use of the same drug to increase In the past, the lactation section in FDA- woman is provided. The use of gal- milk production would not be accept- approved labeling was often limited to actagogues is also reviewed because able. For drugs with an adverse event statements that advise caution or more women now endeavor to breast- profile that correlates with increasing contain an admonition to discontinue feed adopted infants or preterm neo- dosage, higher maternal doses may be breastfeeding or discontinue therapy, nates. The increasing use of herbal associated with greater neonatal depending on the importance to the products has invited a discussion of toxicity. In addition, the timing of ex- mother. In 2008, the FDA published the merits of these alternative thera- posure and the duration of therapy a proposed revision to the regulations, pies in the nursing woman. Finally, are other important considerations. which affects the pregnancy and lac- immunization of breastfeeding women Adecisiontobreastfeedwhencon- tation sections of labeling. The agency and their infants will be reviewed to is currently working on the final rule, tinuing treatment with an agent for assist pediatricians in encouraging which is intended to provide a clini- which in utero exposure also has immunization when needed in lactat- cally oriented framework for place- occurred differs from a decision to ing women and addressing parental ment of pregnancy and lactation initiate a novel therapy in the early reluctance to immunize breastfed information into drug labeling and to . Similarly, the infants. permit the patient and physician to risks of a single-dose therapy or explore the risk/benefit on the basis of short-term treatment may differ from the best available data. Under the GENERAL CONSIDERATIONS those of a chronic therapy. proposed rule, the current Nursing Several factors should be considered In addition to pharmacokinetic or Mothers section is replaced by a sec- when advising a woman regarding a chemical properties of the drug, the tion called Lactation. The Lactation decision to breastfeed her infant while infant’s expected drug exposure is section of labeling will contain 3 she is on drug therapy. The benefits of influenced by infant and maternal fac- subsections: Risk Summary, Clinical breastfeeding for both the infant and tors beyond basic known pharmacoki- Considerations, and Data. The Risk mother need to be weighed against the netic and chemical properties of the Summary section will include a sum- risks of drug exposure to the infant (or drug itself. For example, the risk of mary of what is known about the ex- to the mother, in the case of agents adverse reactions in a preterm infant cretion of the drug into human milk intended to induce lactation). Many or an infant with underlying chronic and potential effects on the breastfed factors affect the individual risk/benefit medical conditions may be higher than infant, as well as maternal milk pro- decision, including specific information that for a more mature or healthier duction. The Clinical Considerations about chemical and pharmacologic infant. Certain drugs may accumulate section will include methods to mini- properties of the drug, which may be in the breastfed infant because of re- mize exposure of the breastfed infant available from resources such as duced clearance or immaturity of met- to the drug when applicable, as well as LactMed and in product labeling. In abolic pathways. However, for other information about monitoring for

e798 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 30, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS

expected adverse drug effects on the ANTIDEPRESSANTS, ANXIOLYTICS, TABLE 1 Psychoactive Drugs With Infant infant. The Data component will pro- AND ANTIPSYCHOTICS Serum Concentrations Exceeding 10% of Maternal Plasma vide a detailed overview of the existing a Previous statements from the AAP cat- Concentrations data that forms the evidence base for egorized the effect of psychoactive drugs Agent Reference the other 2 sections. 20 on the nursing infant as “unknown but Citalopram Weissman 2004 In addition to the proposed rule, the Clomipramine Schimmell 199121 may be of concern.” Although new data 22 FDA published “Guidance for Industry: Diazepam Wesson 1985 have been published since 2001, in- Doxepin Moretti 200916 Clinical Lactation Studies: Study De- formation on the long-term effects of Fluoxetine Weissman 2004,20 product sign, Data Analysis, and Recom- labeling these compounds is still limited. Most 20 mendations for Labeling.”10 Fluvoxamine Weissman 2004 publications regarding psychoactive Newport 2008,18 Along with outlining recommendations drugs describe the pharmacokinetics Fotopoulou 200923 24 regarding lactation study design as in small numbers of lactating women Lithium Viguerra 2007, Grandjean 2009,25 well as the timing and indications for with short-term observational studies Bogen 201226 these studies, this draft guidance of their infants. In addition, interpre- Mirtazapine Tonn 200927 includes advice on parameters (sev- Nortriptyline Weissman 200420 tation of the effects on the infant from 28 eral of which are used in LactMed) that Olanzapine Whitworth 2008 the small number of longer-term stud- Sertraline Hendrick 2001,29 Stowe 200330 can be used to inform physicians ies is confounded by prenatal treat- Venlafaxine Newport 200919 about the extent of drug exposure. ment or exposure to multiple therapies. a Based on individual maternal-infant pair(s); may in- clude active metabolites. Using these parameters, drug expo- For these reasons, the long-term ef- sure to the infant may be measured fect on the developing infant is still directly in infant serum or estimated largely unknown.11,12 on the basis of pharmacokinetic pa- antipsychotics, anxiolytics, and mood rameters. These estimates of infant Many antianxiety drugs, antide- stabilizers (see Table 1). exposure (for example, relative infant pressants, and mood stabilizers appear Mothers who desire to breastfeed dose) can be expressed as a percent of in low concentrations in human milk, their infant(s) while taking these weight-adjusted maternal or, when with estimated relative infant doses agents should be counseled about the known, weight-adjusted pediatric dose. less than 2% of weight-adjusted ma- benefits of breastfeeding as well as the ternal dose and/or milk-plasma potential risk that the infant may be ratios less than 1.13 However, the per- exposed to clinically significant levels centage of maternal doses that ap- ESTIMATES OF DRUG EXPOSURE and that the long-term effects of this proach clinically significant levels (10% exposure are unknown. Consideration Daily Infant Dosage (mg/day)= or more) have been reported for should be given to monitoring growth P bupropion,14 diazepam,13 fluoxetine,15 ðdrug concentration in each milk and neurodevelopment of the infant. citalopram,16 lithium,17 lamotrigine,18 collection × expreesed volume in and venlafaxine.19 Data on drug ex- each milk collectionÞ cretion in human milk are not avail- DRUGS FOR SMOKING CESSATION OR able for up to one-third of psychoactive OR TO TREAT SUBSTANCE ABUSE/ Cmilk½average drug concentration in DEPENDENCE therapies.13 milkðmg=mLÞ × V ðvolume in mL milk Although many women are appropri- of milk ingested in 24 hoursÞ Because of the long half-life of some of these compounds and/or their metab- ately advised to refrain from smoking, Note: Vmilk is typically estimated to be 150 mL=kg=day olites, coupled with an infant’simma- drinking, and using recreational drugs ture hepatic and renal function, during and after pregnancy, in part Relative Infant Dose nursing infants may have measurable because of adverse effects on their amounts of the drug or its metabolites infants (see Table 2), some are unable % Maternal Dose¼½Daily Infant Dosage in plasma and potentially in neural to do so and may seek assistance after ðmg=kg=dayÞ ÷ Maternal Dose tissue. Infant plasma concentrations delivery. Maternal smoking is not an ðmg=kg=dayÞ × 100 that exceed 10% of therapeutic ma- absolute contraindication to breast- % Infant or Pediatric Dose¼½Daily Infant ternal plasma concentrations have feeding.31 Nonetheless, for multiple Dosage ðmg=kg=dayÞ ÷ Infant or Pediatric been reported for a number of selec- reasons, including the association of doseðmg=kg=dayÞ × 100 tive serotonin reuptake inhibitors, sudden infant death syndrome with

PEDIATRICS Volume 132, Number 3, September 2013 e799 Downloaded from www.aappublications.org/news by guest on September 30, 2021 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, decreased Koren 2002,34 Backstrand 2004,35 Mennella 200736 milk consumption, sleep disturbances. Note: Although binge drinking should be avoided, occasional, National Academy of Sciences 199137 limited ingestion (0.5 g of alcohol/kg/d; equivalent to 8 oz wine or 2 cans of beer per day) may be acceptable. Amphetamines Hypertension, tachycardia, and seizures. Product labeling In animal studies of postnatal exposure, long-term behavioral effects, including learning and memory deficits and altered locomotor activity, were observed. Benzodiazepines Accumulation of metabolite, prolonged half-life in neonate or Jain 2005,38 Malone 200439 preterm infant is noted; chronic use not recommended. Apnea, cyanosis, withdrawal, sedation, cyanosis, and seizures. Cocaine Intoxication, seizures, irritability, vomiting, diarrhea, Chasnoff 1987,40 Winecker 200141 tremulousness. Heroin Withdrawal symptoms, tremors, restlessness, vomiting, poor vandeVelde 200742 feeding. LSD Potent hallucinogen. Fatality, persists in breast milk for 48 h. Ariagno 1995,43 Bartu 200944 Methylene dioxy- Closely related products (amphetamines) are concentrated in methamphetamine (ecstasy) human milk. Marijuana () Neurodevelopmental effects, delayed motor development at 1 y, Djulus 2005,45 Campolongo 2009,46 Garry 201047 lethargy, less frequent and shorter feedings, high milk- plasma ratios in heavy users. 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. tobacco exposure,32,33 lactating women rolled in and closely monitored by an appears to be up to 2.4% of the ma- should be strongly encouraged to stop appropriate drug treatment program ternal weight-adjusted dose.55,56,58 smoking and to minimize secondhand with significant social support.48,51 However, buprenorphine can be abused, exposure. Exposure to alcohol or rec- Potential adverse effects on breast- and although the significance in humans reational drugs may impair a mother’s feeding infants from methadone is unknown, labeling for buprenor- judgment and interfere with her care (according to product labeling) and phine and buprenorphine/ of the infant and can cause toxicity to buprenorphine include lethargy, re- combinations states that use is not the breastfeeding infant (see Table 2). spiratory difficulty, and poor weight advised by lactating women, because Limited information is available re- gain.52 The long-term effects of meth- animal lactation studies have shown garding the use of medications in adone in humans are unknown. None- decreased milk production and via- lactating women to treat substance theless, methadone levels in human bility of the offspring. FDA labeling abuse or alcohol dependence or for milk are low, with calculated infant also advises caution for use of nal- smoking cessation. However, the pres- exposures less than 3% of the maternal trexone in nursing infants of opioid- ence of behaviors, such as continued weight-adjusted dose.53,54 Plasma con- dependent women. Of note, published ingestion of illicit drugs or alcohol, and centrations in infants are also low (less information on naltrexone is limited to underlying conditions, such as HIV in- than 3% of maternal trough concen- 1 case report that estimates infant fection, are not compatible with breast- trations) during the neonatal period exposure to be low (7 μg/kg/d, or feeding.49,50 Patients also require ongoing and up to 6 months postpartum.55,56 0.86% of the maternal weight-adjusted psychosocial support to maintain For these reasons, guidelines from the dose).59 abstinence.48 Academy of Breastfeeding Medicine Transferred amounts of methadone Methadone, buprenorphine, and nal- encourage breastfeeding for women or buprenorphine are insufficient to trexone are 3 agents approved by the treated with methadone who are en- prevent symptoms of neonatal absti- FDA for use in the treatment of opioid rolled in methadone-maintenance pro- nence syndrome.49,60 Neonatal absti- dependence. Continued breastfeeding grams.48 nence syndrome can occur after by women undergoing such treatment Buprenorphine is excreted into human abrupt discontinuation of metha- presumes that the patient remains milk and achieves a level similar to that done.51,61 Thus, breastfeeding should abstinent, is HIV negative, and is en- in maternal plasma.57 Infant exposure not be stopped abruptly, and gradual

e800 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 30, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS is advised if a decision is dangerously high levels of its active ance of morphine is decreased in made to discontinue breastfeeding. metabolite morphine in breastfeeding infants younger than 1 month and Limited information is available for di- infants. A fatality has been noted in an approaches 80% of adult values by 6 sulfiram and naltrexone, agents that infant of a mother with ultrarapid months of age.70 Limited data suggest are used to treat alcohol dependence. metabolism.65 In this infant, the post- that use of hydromorphone for brief As noted previously, a low relative infant mortem level of morphine (87 ng/mL) periods may be compatible with dose (<1%) was observed in a single greatly exceeded a typical level in breastfeeding71,72; however, FDA label- case report of naltrexone exposure in a breastfeeding infant (2.2 ng/mL), as ing discourages use. Regardless of a 6-week-old breastfed infant.59 FDA well as the therapeutic range for the choice of therapy, to minimize labeling discourages use of disulfiram neonates (10–12 ng/mL). In addition, adverse events for both the mother and both the injectable and oral form unexplained apnea, bradycardia, cya- and her nursing infant, the lowest of naltrexone in lactating women. nosis, and sedation have been repor- dose and shortest duration of therapy Only one-third of women successfully ted in nursing infants of mothers should be prescribed. Drug delivery discontinue smoking without pharma- receiving codeine.2,66 Hydrocodone is via patient-controlled anesthesia or cologic aids.62 Nicotine replacement also metabolized via the CYP2D6 administration by the epidural route therapy, bupropion, and varenicline are pathway. On the basis of pharmacoki- may also minimize infant exposure. agents indicated for use as aids to netic data, infants exposed to hydro- Other narcotic agents, such as oxy- smoking cessation treatment. Nicotine codone through human milk may codone, pentazocine, propoxyphene, and replacement therapy is compatible receive up to 9% of the relative ma- meperidine, are not recommended in the with breastfeeding as long as the dose ternal dose.67 Given the reduced lactating mother. Relatively high amounts (assuming a cigarette delivers ∼1mg clearance of hydrocodone in neonates of oxycodone are excreted into human of nicotine) is less than the number of and the adverse events observed in milk, and therapeutic concentrations cigarettes typically smoked, because ultrarapid metabolizers of codeine, have been detected in the plasma of nicotine passes freely into human milk caution is advised for use of codeine a nursing infant.73 Central nervous sys- and is orally absorbed as nicotine. and hydrocodone in both the mother temdepressionwasnotedin20%of Cotinine concentrations are lower than and nursing infant. Close monitoring infants exposed to oxycodone during those related to tobacco use. Short- for signs and symptoms of neonatal as breastfeeding.74 Thus, use of oxycodone acting products (eg, gum or lozenges) well as maternal toxicity is recom- should be discouraged. Limited pub- are recommended.62 Infant exposure mended. A commercial test to identify lished data are available about pentaz- decreases proportionally with mater- ultrarapid metabolizers is not yet ocine. However, respiratory nal patch doses.63 widely available. The incidence of this and apnea occur frequently in infants, In contrast, bupropion is excreted into specific CYP2D6 genotype varies with particularly in neonates or in preterm human milk with exposures that may racial and ethnic group as follows: infants, who are treated with pentazo- exceed 10% (range, 1.4%–10.6%) of the Chinese, Japanese, or Hispanic, 0.5% to cine. Propoxyphene has been associated maternal dose.14 Although infant levels 1.0%; Caucasian, 1.0% to 10.0%; African with unexplained apnea, bradycardia, were not measured, there is a case American, 3.0%; and North African, and cyanosis, as well as hypotonia in report of a seizure in a 6-month-old Ethiopian, and Saudi Arabian, 16.0% to nursing infants.75,76 Moreover, pro- breastfed infant potentially related to 28.0%.68 poxyphene was withdrawn from the bupropion.64 Limited published in- For these reasons, when narcotic market because significant QT pro- formation is available for varenicline, agents are needed to treat pain in the longation occurred at therapeutic but the varenicline label includes breastfeeding woman, agents other doses.77 Meperidine use is associated a boxed warning for serious neuro- than codeine (eg, butorphanol, mor- with decreased alertness of the infant psychiatric adverse events, including phine, or hydromorphone) are pre- and is likely to interfere with breast- suicidal ideation or behavior. FDA la- ferred. Clinically insignificant levels of feeding.71 Although estimates of meper- beling discourages use of both these butorphanol are excreted into human idine exposure are low (approximately agents in lactating women. milk. Morphine appears to be toler- 2% to 3% of the maternal weight- ated by the breastfeeding infant, al- adjusted dose), the half-life of the active PAIN MEDICATIONS though there is 1 case report of an metabolite for meperidine is prolonged, Rarely, normal doses of codeine given infant with plasma concentrations and it may accumulate in infant blood to lactating women may result in within the therapeutic range.69 Clear- or tissue.71,72

PEDIATRICS Volume 132, Number 3, September 2013 e801 Downloaded from www.aappublications.org/news by guest on September 30, 2021 When narcotics are not required to centrations. Diflunisal has a long half- Although a placebo-controlled study relieve mild to moderate pain, other life and is not recommended because (n = 42) suggested that analgesic agents can be used. Pre- of potential adverse events, including may increase milk volume in mothers 84 suming that pain relief is adequate, cataracts and fatality, in neonatal of preterm infants, maternal safety short-acting agents, such as ibuprofen animals. Similarly, mefenamic acid has has not been established. The FDA and acetaminophen, are acceptable.78 a prolonged half-life in preterm infants. issued a warning in June 2004 re- Although the half-life of ibuprofen may Injectable and oral forms of ketorolac garding use of domperidone in breast- be prolonged in neonates, particularly are contraindicated in nursing women, feeding women because of safety in preterm infants (according to according to product labeling, because concerns based on published reports product labeling), minimal amounts of of potential adverse effects related to of arrhythmia, cardiac arrest, and ibuprofen are excreted into human closure of the ductus arteriosus in sudden death associated with intrave- milk.72 Despite reduced clearance of neonates. Less than 1% of ketorolac nous therapy. Furthermore, treatment acetaminophen,79 hepatotoxicity is nasal spray is excreted into human with oral domperidone is associated less common in neonates than in milk, and unlike the oral and in- with QT prolongation in children and older infants, in part because of low travenous forms of ketorolac, use is not infants.85,86 Domperidone is not an levels of certain cytochrome P-450 contraindicated (product labeling). approved product in the United States, enzymes, which convert acetamino- Carisoprodol and its active metabolite, and labeling for oral formulations 80 phen into toxic metabolites. Acet- meprobamate, are concentrated in marketed outside the United States do aminophen is available for both oral human milk (2–4timesmaternal not recommend use during lactation. and intravenous administration. plasma concentrations). Impaired milk Several small trials (each with fewer Although all nonsteroidal antiinflam- production has been observed, and than 25 subjects) published before matory drugs (NSAIDs) carry a boxed animal studies suggest maternal use 1990 suggested that metoclopramide warning regarding gastrointestinal may lead to less effective infant feeding increases concentrations bleeding and potential long-term cardiac (because of sedation) and/or de- and/or milk production in mothers of toxicity, according to their product la- creased milk production (according to both term and preterm infants.87 beling and Gardiner et al,81 celecoxib, product labeling). However, more recent controlled fi 88,89 flurbiprofen, and naproxen are consid- Low doses (75–162 mg/d) of aspirin studies do not replicate this nding. ered to be compatible with breastfeed- may be acceptable82;however,useof Human milk concentrations of meto- ing, because less than 1% is excreted high-dose aspirin therapy during clopramide are similar to therapeutic into human milk. In addition, a breast- breastfeeding is not advised, because concentrations in adult plasma,88 and feeding infant would receive less than the serum concentration of salicylate measurable amounts can be detected 1% of the relative pediatric dose of cel- in breastfeeding infants has been in breastfeeding infants.90 Clearance of ecoxib prescribed for a 2-year-old reported to reach approximately 40% metoclopramide in neonates is pro- (according to product labeling). How- of therapeutic concentrations. Adverse longed, which may result in excessive ever, long-term use of naproxen is not events, such as rash, platelet abnor- serum concentrations and the risk of recommended because of the drug’s malities, bleeding, and metabolic aci- conditions associated with overdose, long half-life and case reports of gas- dosis have also been reported.71 such as methemoglobinemia. Of concern, trointestinal tract bleeding and emesis. prolactin concentrations were increased Avoiding NSAIDs in breastfeeding infants in 4 of 7 infants exposed to metoclopra- 90 fi with ductal-dependent cardiac lesions Galactagogues, or agents to stimulate mide via human milk. The safety pro le may be prudent. lactation, are often used to facilitate for metoclopramide includes adverse Limited published data on other lactation, particularly for mothers of reactions, such as dystonia, depression, NSAIDs (etodolac, fenoprofen, melox- preterm infants. They also may be used suicidal ideation, and gastrointestinal icam, oxaprozin, piroxicam, sulindac, to induce lactation in an adoptive tract disturbances, as well as a boxed and tolmetin) are available, and FDA mother. However, evidence to support warning about the risk of tardive dyski- labeling discourages their use for these agents, including use of dopa- nesia. These risks to the mother limit the a variety of reasons. Although the mine antagonists, such as domper- usefulness of this therapy. implications for humans are unknown, idone and metoclopramide; herbal Although a pilot study in 8 lactating meloxicam concentrations in milk of treatments; and hormonal manipula- women performed decades ago sug- lactating animals exceed plasma con- tion, is lacking.83 gested that nasal spray

e802 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 30, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS increased human milk production, FDA recalled 10 or more dietary sup- cline of the agent and dosimetry to a larger placebo-controlled trial in 51 plements each year because of the avoid infant exposures greater than 1 women has not confirmed that ob- presence of potentially toxic un- mSv (100 mrem). For agents that may servation.91 Oxytocin nasal spray is no declared ingredients in the supple- be concentrated in breast tissue, close longer marketed in the United States. ment.101 Similarly, the US Government contact of the mother with the infant Similarly, anecdotal reports supporting Accountability Office found that 16 of and, consequently, nursing may need the use of the herb fenugreek to facil- 40 common herbal dietary supple- to be avoided for a period of time, itate lactation have not been confirmed ments obtained from retail stores although expressed milk that has been by controlled studies.92,93 Fenugreek contained pesticide residues.102 refrigerated until the radioactivity has contains coumarin, which may interact Safety data are lacking for many herbs decayed may be safe. General guidelines with NSAIDs.94 Use of fenugreek in lac- commonly used during breastfeeding, based on Nuclear Regulatory Commis- tating women also is associated with such as chamomile,103 black cohosh,104 sion regulations and International Com- maple-syrup odor in infants.95 Available blue cohosh,105 chastetree,106 echina- mission on Radiologic Protection data do not support the routine use of cea,107 ginseng,108 gingko,109 Hypericum guidelines116 are cited in Tables 3 and other herbal products, such as fennel, (St John’s wort),110,111 and valerian.112 4. However, because there is consid- to facilitate lactation.96 Adverse events have been reported in erable variability in milk radioactivity, In summary, galactagogues have a lim- both breastfeeding infants and moth- and close contact with an infant may ited role in facilitating lactation and have ers. For example, St John’swortmay result in additional exposure, consulta- not been subject to full assessments of cause colic, drowsiness, or lethargy in tion with a radiologist should be sought. safety for the nursing infant. Nursing the breastfed infant even though milk If deemed necessary, individualized mothers should seek consultation with production and infant weight do not testing of expressed milk may be per- a lactation specialist and use non- appear to be adversely affected110 and formed to ensure that radioactivity has pharmacologic measures to increase relative maternal dose and infant reached background levels before milk supply, such as ensuring proper plasma concentrations are low.113 breastfeeding is resumed.117 technique, using massage therapy, in- Prolonged use of fenugreek may re- Notably, because radiolabeled iodin- creasing the frequency of milk expres- quire monitoring of coagulation status ated products are concentrated in the sion, prolonging the duration of pumping, and serum glucose concentrations.114 developing thyroid and radioactivity and maximizing emotional support. For these reasons, these aforemen- persists after imaging with most 131I tioned herbal products are not rec- and 125I radiopharmaceuticals (with the COMMONLY USED HERBAL ommended for use by nursing women. exception of 125I- hippurate), breast- PRODUCTS Although supplementation of nursing feeding should be interrupted for a mothers with and is safe minimum of 3 weeks. Similarly, 22Na Despite the frequent use of herbal as long as recommended daily allow- and 67Ga (gallium) administration also products in breastfeeding women (up ances are not exceeded, the use of other to 43% of lactating mothers in a 2004 require a prolonged (3-week) interrup- nutritional supplements may not be. For tion in breastfeeding. Because the lac- survey),97 reliable information on the instance, L-tryptophan has been associ- 131 fi safety of many herbal products is tating breast has a greater Iafnity ated with eosinophilic myositis.115 There- lacking. Herbal products are not sub- than does the nonlactating breast, fore, physicians should inquire about ject to the same standards for women should cease breastfeeding at the use of herbal products and dietary manufacturing and proven effective- least 4 weeks before whole-body pro- supplements in lactating women and 131 ness and safety as are drug products cedures with I and should discontinue discuss the need for caution because before they are marketed.98 In fact, breastfeeding thereafter. Doing so will of the paucity of data available. the use of several herbal products reduce the radiation dose and potential may be harmful, including kava and cancer risk to maternal breast tissue. DIAGNOSTIC IMAGING yohimbe. For example, the FDA has Traditionally, lactating women receiving issued a warning that links kava When feasible, elective imaging pro- intravascular gadolinium or iodinated supplementation to severe liver dam- cedures should be delayed until contrast (as opposed to radiolabeled io- age.99 Breastfeeding mothers should a woman is no longer breastfeeding. dine) are advised to discontinue nursing not use yohimbe because of reports of For most radiopharmaceuticals, breast- for 24 hours. However, a minimal amount associated fatalities in children.100 In feeding should be interrupted for a (0.04%) of the intravenous dose reaches addition, from 2008 through 2010, the time period based on the rate of de- human milk, and, of that, less than 1% to

PEDIATRICS Volume 132, Number 3, September 2013 e803 Downloaded from www.aappublications.org/news by guest on September 30, 2021 TABLE 3 Radioactive Compounds That May Require Temporary Cessation of Breastfeeding: Recommendations of the International Commission on Radiologic Protection Compound Examples Example of Procedures Recommended Time for Comments Cessation of Breastfeeding 14C-labeled Triolein, glycocholic acid, Helicobacter pylori breath test None No approved US products 99mTc-labeled DMSA, DTPA, phosphonates Multiple: imaging of , 0 to 4 h, as long as no free Consider discarding at least 1 (MDP), PYP, tetrofosmin bone, lung, heart, tumors pertechnetate meal after procedure Microspheres, pertechnetate, WBC 12–24 h Range depends on dose Sulfur-colloids, RBC in vivo 6 h I-labeled 123I, 125Ior131I-iodo hippurate Thyroid imaging 12 h Note: whole-body irradiation with 131I requires prolonged cessation Others 11C- 11Nor11O-labeled PET scans None Short physical half-life 57 119 Co-labeled B12 Schilling test 24 h Pomeroy 2005 18F-FDG PET scans None, first feeding Use alternatives for 10 half-lives should be expressed breast (10×109 min= 18 h)a milk to avoid direct contact120 51Cr-EDTA Renal imaging None 81mKr-gas Pulmonary imaging None No approved US products 82Rb chloride PET scan of myocardium May resume 1 h after Half-life 75 sa last infusion 111In-octreotide SPECT, neuroendocrine tumors None 111In -WBC 1 wk Depends on dose 133Xe Cardiac, pulmonary, and None Half-life 5 da cerebral imaging 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, . a FDA-approved drug labeling.

TABLE 4 Radioactive Compounds Requiring Prolonged Cessation of Breastfeeding Compound Examples Example of Procedures Recommended Time for Comments Cessation of Breastfeeding I-labled 123I- BMIPP, -HSA, -IPPA, -MIBG, -NaI, or -HSA Imaging of tumors Greater than 3 wk Essentially need to 131I-MIBG or -NaI stop breastfeeding Others 201Tl-chloride Cardiac imaging 48 h to 2 wk Half-life 73 ha 67Ga-citrate Imaging of tumors 1 wk to 1 mo Depends on dose 22Na, 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 ; IPPA, iodophe- nylpentadecanoic; MIBG, metaiodobenzylguanidine; NaI, iodide. a FDA-approved drug labeling.

2% is absorbed by the infant. Therefore, the infant’s immune response to most during the first year is similar. Moreover, breastfeeding can be continued without routine (eg, diphtheria breastfeeding enhances the interruption after the use of iodinated and tetanus toxoids and acellular per- response to pneumococcal and Haemo- contrast or gadolinium.118 tussis vaccine, inactivated poliovirus philus influenzae type b vaccines.123 vaccine, and hepatitis B vaccine [HBV]),121 Breastfeeding may also decrease the despite the presence of maternal incidence of fever after infant immuni- BREASTFEEDING AND VACCINES in human milk. Seroconver- zation.124 Therefore, the timing of infant With rare exceptions, maternal immu- sion rates are also similar between feeding (including human milk) relative nization does not create any problems breastfed and formula-fed infants re- to immunization is not restricted, even for breastfeeding infants, although ceiving rotavirus vaccine; however, for live vaccines, such as rotavirus. questions concerning 2 topics often vaccine efficacy for severe rotavirus Lactating women may need to be im- arise regarding lactation and immuni- gastroenteritis appears to be higher in munized. Inactivated vaccines (such as zation: the effect of lactation on the formula-fed infants compared with ex- tetanus toxoid, reduced diphtheria infant’s immune response to a vaccine clusively breastfed infants, particularly toxoid, and acellular pertussis vaccine; and a potential adverse effect on the during the second season (98% vs 88%) inactivated poliovirus vaccine; influ- infant from maternal immunization. when breastfeeding has been dis- enza; hepatitis A vaccine; HBV; or human Breastfeeding does not interfere with continued.122 Nonetheless, protection papillomavirus vaccine [HPV]) given to

e804 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 30, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS a nursing mother do not pose a risk to after exposure to smallpox vaccine or use of radiopharmaceuticals, oncologic the breastfeeding infant. Several vac- encephalitis after yellow fever vaccine. drugs, or other therapies not ad- cines, such as tetanus toxoid, reduced Two cases of meningoencephalitis in dressed by LactMed is contemplated. diphtheria toxoid, and acellular per- nursing infants whose mothers had Additional information about topics tussis vaccine and influenza vaccine, been immunized against yellow fever outside the scope of this report, such as are recommended for the mother are documented in the literature.127,128 environmental agents, can be obtained during the postpartum period to pro- Therefore, most vaccines, with the ex- from the third edition of the AAP text- tect the infant as well as the mother. ception of smallpox or yellow-fever book Pediatric Environmental Health.129 Other routine or catch-up vaccines, vaccine, which are contraindicated in such as HPV, hepatitis A vaccine, and nonemergency situations, may be ad- LEAD AUTHOR HBV, can be given to the lactating ministered during lactation. Hari Cheryl Sachs, MD, FAAP mother. HPV immunization is recom- COMMITTEE ON DRUGS, 2012–2013 mended for women younger than 27 SUMMARY Daniel A. C. Frattarelli, MD, FAAP, Chairperson years. The incidence of adverse reac- fi Jeffrey L. Galinkin, MD, FAAP tions in nursing infants within 30 days The bene ts of breastfeeding outweigh Thomas P. Green, MD, FAAP of maternal immunization with HPV was the risk of exposure to most thera- Timothy Johnson, DO, FAAP similar to nursing infants of women peutic agents via human milk. Although Kathleen Neville, MD, FAAP most drugs and therapeutic agents do Ian M. Paul, MD, MSc, FAAP receiving the control except for acute John Van den Anker, MD, PhD, FAAP respiratory illness (according to Gar- not pose a risk to the mother or nursing dasil labeling). Hence, caution is war- infant, careful consideration of the in- FORMER COMMITTEE MEMBERS ranted when immunizing mothers of dividual risk/benefit ratio is necessary Mark L. Hudak, MD, FAAP infants who are vulnerable to re- for certain agents, particularly those Matthew E. Knight, MD, FAAP that are concentrated in human milk or spiratory illnesses (eg, preterm infants, LIAISONS result in exposures in the infant that infants with congenital heart disease or John J. Alexander, MD, FAAP – Food and Drug chronic respiratory problems). may be clinically significant on the Administration Most live vaccines are not associated basis of relative infant dose or detect- Sarah J. Kilpatrick, MD, PhD – American College able serum concentrations. Caution is of Obstetricians and Gynecologists with virus secretion in human milk. For – also advised for drugs and agents with Janet D. Cragan, MD, MPH, FAAP Centers for example, despite maternal serocon- Disease Control and Prevention version, neither the varicella virus nor unproven benefits, with long half-lives Michael J. Rieder, MD, FAAP – Canadian Pedi- antibody to varicella DNA has been that may lead to drug accumulation, atric Society Adelaide Robb, MD – American Academy of detected in breastfeeding infants.125 or with known toxicity to the mother or fi Child and Adolescent Psychiatry Although attenuated rubella can be infant. In addition, speci c infants may Hari Cheryl Sachs, MD, FAAP – Food and Drug secreted into human milk and trans- be more vulnerable to adverse events Administration mitted to breastfed infants, infections because of immature organ function Anne Zajicek, MD, PharmD, FAAP – National Institutes of Health are usually asymptomatic or mild. (eg, preterm infants or neonates) or underlying medical conditions. Several Consequently, postpartum immuniza- CONTRIBUTOR excellent resources are available for tion with measles-mumps-rubella vac- Ashley Moss, MD, FAAP cine is recommended for women who the pediatrician, including product la- lack , especially to rubella.126 beling and the peer-reviewed database, STAFF In contrast, infants are considered to LactMed. Consultation with a specialist Tamar Haro, JD be at high risk of developing vaccinia may be indicated, particularly when the Raymond J. Koteras, MHA

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