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Drugs and chemicals in human milk
Seminars in Fetal & Neonatal Medicine (2005) 10, 149e159
www.elsevierhealth.com/journals/siny
Drugs and chemicals in human milk Cheston M. Berlina,*, Gerald G. Briggsb,c,d,e a
Penn State Children’s Hospital, MS Hershey Medical Center, PO Box 850, 500 University Drive, Hershey, PA 17033-0850, USA b Miller’s Children’s Hospital e Women’s Pavilion, Long Beach Memorial Medical Center, Long Beach, CA, USA c University of California, San Francisco, USA d University of Southern California, LA, USA
KEYWORDS Breast milk; Drugs; Human milk; Lactation
Summary There is continuing emphasis by many professionals and organizations on the importance of breastfeeding as optimal infant nutrition. Pediatricians are frequently asked about the safety of medications taken by the nursing mother and the risk to the infant. Most drugs and many chemicals will be transferred into milk. For a vast majority of these compounds, there is no risk to the infant. It is almost always possible for the mother to continue nursing while taking the necessary medication. This article presents an introduction to the pharmacology of the transfer of drugs into milk, discusses the importance of the infant’s age in assessing safety and presents a number of maternal conditions for which drugs need to be used. ª 2004 Elsevier Ltd. All rights reserved.
Introduction The resurgence in the interest of pediatricians in breastfeeding is difficult to date precisely, but was almost certainly present with the publication in 1978 of the Healthy People 2000 goals to increase breastfeeding in 2000 to 75% in the period of early infancy and to 50% by 6 months of age.1 In 1978,
* Corresponding author. Tel.: C1 717 531 8006; fax: C1 717 531 0869. E-mail addresses: [email protected] (C.M. Berlin), [email protected] (G.G. Briggs). e Tel.: C1 562 933 2757; fax: C1 562 933 2759.
the rate of newborns being breastfed was 48.1%.1 At this time, concern was also expressed over the appearance in breast milk of drugs taken by the mother or chemicals to which the mother had been exposed in the environment. Early attempts to tabulate data concerning the excretion of drugs were undertaken by Knowles in 1965,2 Catz and Giacoia in 1973,3 and O’Brien in 1974.4 Before these review papers, many literature reports concerning effects on the nursing infant (occasionally adverse) were not supported by measurement of the drug in milk, and many were single-case reports. These review papers collected published studies in which milk concentrations were measured for certain drugs.
1744-165X/$ - see front matter ª 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2004.09.016
150 The Committee on Drugs of the American Academy of Pediatrics published the first comprehensive statement on the transfer of drugs and chemical into human milk in 1983.5 Succeeding editions of this statement were published in 1989,6 19947 and 2001.8 The more recent editions have relied on published reports (not personal communications or citations in the Physicians’ Desk Reference) in which the drug was measured. Many more recent reports are series of mothereinfant nursing pairs rather than single-case reports. An indication of the interest in this topic is illustrated by the increase in the number of references in the four AAP statements: from 175 in the 1983 version to 392 in the 2001 version (not all studies are referenced).
Why study drug excretion in milk? The first reason to study drug excretion in human milk is that the exclusively breastfed infant is unique among all children because she/he is solely dependent on human milk for nutrition. The infant is growing and developing rapidly, with corresponding maturation of many organs and physiologic processes. The presence of drugs or chemicals in milk may, if the concentration is high enough or if the infant is sensitive enough, interact at many possible physiological levels. There is a special concern about the vulnerability of the developing central nervous system. This concern with exogenous substances in the infant’s formula is not confined only to breast milk. A recent report from the Food and Nutrition Board of the Institute of Medicine of the National Academies presents many concerns (which are being considered) over the addition of a substance not already in infant formulas. One recent example of this is the addition of long-chain polyunsaturated fatty acids, such as arachidonic acid (ARA) and docosahexaenoic acid (DHA), to commercial formulas. The Food and Nutrition Board report discusses the background of food safety and the safety parameters to be considered when adding a substance new to infant formulas.9 The concepts presented in this report can also be applied to human milk with the maternal medication being the substances added. The second reason to study drug excretion in human milk is to obtain enough evidence to permit safe and effective maternal drug therapy. Over 90% of mothers could receive one or more drugs in the first week of postpartum.10 The percentage of women needing drug therapy at any time during lactation would seem to be equally high. Women should not stop breastfeeding just because they need to receive a drug; nor should they not take
C.M. Berlin, G.G. Briggs the drug just because they are breastfeeding. Even with reassurance that a medication is safe, some mothers elect either to not take the medical or to stop breastfeeding. Ito et al. reported on the follow-up of a cohort of women who called in for information concerning the safety of an antibiotic therapy while breastfeeding. In spite of assurances that it was safe to continue nursing and take the antibiotic, 15% did not initiate drug therapy and 7% stopped breastfeeding.11 More needs to be done to educate both patients and physicians on the safety of drugs during lactation.
Human milk and drug transport Human milk is a biological fluid synthesized in the mammary tissue by cellular mechanisms exquisitely designed to provide the infant with the precise quantitative and qualitative growth- and immune-enhancing factors, while at the same time enhancing motherechild bonding. The factors responsible for the transfer of drugs and other chemicals through the alveolar mammary cell and into milk have been reviewed.12e15 A brief summary will assist in discussing the use of drugs for maternal therapy. The transport of compounds across the mammary alveolar cells is thought to occur by a number of processes.16,17 The usual route is probably transcellular diffusion, in which small molecules (molecular weight 100e200) are dragged along with water flow (hydrostatic or osmotic pressure differences).18 Compounds of a larger molecular weight might enter milk through intercellular diffusion, thus avoiding the alveolar cell entirely. This could explain the presence in milk of maternal proteins such as cow milk antigen and various antibodies. Not only molecular weight but also the shape of the molecule will determine its passage. Passive diffusion could occur from interstitial water from the base of the cell. Ionophore diffusion might facilitate the transfer of charged ions and other substances that might be bound to carrier proteins. Lipidsoluble substances, as well as un-ionized compounds, are readily transported. This is reflected in the observation that lipid-soluble substances of a small molecular weight and no electrical charge will appear in milk at concentrations very similar to the simultaneous maternal plasma concentration; ethyl alcohol is a good example.19 The maternal plasma concentration of the drug is an important determinant of how much drug is available for excretion into milk. Because diffusion occurs along a concentration gradient, high maternal plasma/serum levels will produce high milk
Drugs and chemicals in human milk levels. The serum/plasma concentration is determined not only by the maternal dose but also by the mother’s ability to metabolize the drug. For example, the ability to metabolize a drug is genetically determined and there are many examples of ‘poor’ or ‘slow’ drug metabolizers in a given population. The ratio of ‘poor/slow’ to ‘normal’ metabolizers might be as high as 1e10 for some agents, so drug levels in milk in these individuals will be much higher than predicted. The typical daily amount of milk consumed by an infant is about 150 mL/kg/day. Many investigators use this value to estimate the weight-adjusted dose consumed by a nursing infant, so that a prediction can be made on the relative safety of a drug during breastfeeding. Ion trapping might occur during the transfer of a drug from maternal plasma to milk. Breast milk is slightly acidic (average pH 7.1) as compared to plasma (average pH 7.4), so the acid/base characteristics of a drug are important. All acid/base chemicals exist in equilibrium between their ionized and non-ionized forms. This equilibrium is an important determinant of how much drug will be present in milk. For example, the equilibrium for acidic drugs, such as penicillins and non-steroidal anti-inflammatory agents (NSAIDs), will favor ionization in the relatively alkaline plasma and, thus, less will be available for transport into milk. When transport does occur, the equilibrium obtained in milk will favor the non-ionized form because of the relatively acidic milk, so the drug will be transported back into the plasma. This reverse ‘ion trapping’ in plasma for acidic drugs will, in general, result in milk:plasma drug ratios that are !1.0. The reverse is true for basic drugs, such as betablockers. In this case, the relatively acidic milk shifts the equilibrium to the ionized form, thereby trapping the drug and, in general, producing drug milk:plasma ratios that are O1.0. This is why betablockers accumulate in milk. Because the milk concentrations for most drugs are less than or equal to the maternal plasma concentration, the total exposure of the nursing infant is usually less than 1% of the maternal dose.16 It is important to emphasize that these data are mostly from studies using a single maternal dose and do not reflect the quantitative transport in mothers on chronic drug therapy with steady-state plasma concentrations.
Risks to the nursing infant Very few drugs would be considered contraindicated during lactation. Reports of adverse effects
151 frequently do not include a measure of the drug in milk but report events that occur during lactation. Ito et al. reported on a cohort of 838 infants followed prospectively by the Motherisk Program at the Hospital for Sick Children in Toronto, Canada.20 All mothers were taking at least one drug (80%) and 20% were taking two or more drugs; nearly all infants (89%) were under 4 months of age. The follow-up telephone call occurred between 1 and 31 weeks from the initial inquiry by the mother as to the drug safety. The type of drug taken is important and is indicative of the type of exposure that can be expected by lactating women. The four most common groups were: analgesics 23.4%, antibiotics 19.8%, antihistamines 10.1% and sedatives 5.0%. It is possible that this division will be a different change for cohorts of nursing infants older than 4 months. Adverse events looked for were: diarrhea, drowsiness, irritability and others (rash, constipation, feeding difficulties, decrease in milk supply). There were 94 reports (11.2%) of minor adverse reaction in the nursing infant. Diarrhea in the infant of mothers taking antibiotics was the most common. Five of 26 women taking acetaminophen (paracetamol) with codeine reported drowsiness in their infant. There were no adverse events serious enough to require medical care. The authors recognize the limitations of this study in assigning reported symptoms to the mother’s use of the drug, including recall bias, third-party suggestions and concomitant mild infant illnesses. An important piece of data in this study is that of the initial 1110 mothers who called for advice, 54 women discontinued breastfeeding either permanently or during the maternal treatment period. In a further 218 cases, no drug was taken from the initial call to the follow-up call, presumably depriving the mother of needed therapy. Thus, in 30% of cases either the infant was deprived of breast milk or the mother was deprived of medical therapy. Anderson et al. have summarized the literature of 100 reported cases of adverse reactions in breastfed babies of mothers taking drugs.21 The distribution for the drug classes for these 100 cases was: antibiotics 17%, anticonvulsants 16%, antidepressants 13% and sedatives 13%. The relationship between maternal drug use and the adverse event was considered to be ‘definite’ in 0 cases, probable in 47% and possible in 53%. There were three deaths: a 23-day-old exposed to bromazepam (a benzodiazepine, not available in the USA), a 5-week infant exposed to methadone, but who also was malnourished, and a 1-month infant exposed to phenytoin and phenobarbital who also was smothered. The age of the infants is important: 37% were younger than 2 weeks and 63% were younger than
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1 month; only 4% of the reports were infants older than 6 months. It is important to emphasize that neonate and very young infants are at most risk for an adverse effect. Important factors for this observation are delayed development of hepatic drug-metabolizing enzymes and of glomerular filtration and renal tubular secretion.
Drugs to avoid in the newborn and in infants !6 months of age
pregnancy. Six of the 8 infants had measurable plasma concentrations of lithium ranging from 0.1 to 0.6 mmol/L. In 5 of the infants, the serum concentrations were between 18 and 65% of the maternal serum concentration.28 No adverse effects on the infants were described. It is not unusual for mothers who have been receiving such medication during pregnancy to become concerned after delivery and ask about the safety of breastfeeding. The topic of psychotropic medications is discussed later in this paper in detail under the selective serotonin reuptake inhibitors (SSRIs).
Beta-blocking agents Antineoplastic agents There are persuasive case reports of two betablocking agents, atenolol and acebutolol, causing symptoms of beta-blockade (hypotension, bradycardia, tachypnea) in very young infants.22,23 There is considerable variation of the percentage of the maternal dose potentially available to the nursing infant for members of the beta-blocking drug group.24 Previously, it was mentioned that the fraction of the maternal dose that might be transferred to the infant is usually less than 1%. The following are figures for certain beta-blockers24:
acebutolol: 3.5% atenolol: 5.7e19.2% labetalol: 0.07% propranolol: 0.2e0.9% sotalol: 22%
The figures of 19.2% for atenolol and 22% for sotalol are the highest potential percentage transfer of a drug from plasma to milk that has been reported in the literature.
Salicylates There is one report of salicylism occurring in a 16day-old infant whose mother was taking 650 mg aspirin every 4 h for arthritis.25 Mothers of very young infants needing an anti-inflammatory drug should take ibuprofen26 or naproxen.27
The exposure of the very young infant to these cytotoxic drugs presents a dilemma to the physician. Although there are no studies identifying cellular or organ damage, the rapidly dividing tissues of infants places them at risk. As the infant grows, the dose per body weight will decrease and any actual or theoretical risk will also decrease.
Drugs of abuse Nursing mothers should not use illicit drugs such as cocaine, narcotics, amphetamines, phencyclidine, and marijuana. They are hazardous to both the mother and the infant. Smoking by nursing mothers is discussed in the AAP statement.5 Whereas smoking is hazardous to the mother, a baby being breastfed might be at less risk for adverse events, such as respiratory illnesses, than a baby being bottle fed. A woman who is pregnant and planning to breastfeed should be encouraged and supported to stop smoking.
Treatment of maternal conditions The following are a number of common maternal conditions that usually require drug therapy, with a discussion of drug therapy during lactation.
Anticoagulation Lithium A discussion of the use of lithium both during pregnancy and in the postpartum period introduces the important subject of the use of any psychotropic medication (anxiolytics, antidepressants, antipsychotics), including antiepilepsy drugs. Schou and Amdisen published a series of 8 infants (7 under 4 weeks of age and 1 infant 10 weeks of age) whose mothers had received lithium during lactation and presumably during
Thrombophlebitis of any type is well known during pregnancy and the puerperium. The exact incidence is not known because of the difficulty of diagnosis for all cases. The range of estimates is 0.5e7/1000.29 Heparin is safe during nursing as it does not cross into milk because of its large molecular weight. Warfarin is also safe during lactation; it is highly bound to maternal plasma proteins (O99%) and is not detectable in milk or infant serum.30,31
Drugs and chemicals in human milk
Asthma The current emphasis on the treatment of asthma is the prevention of inflammation and subsequent bronchospasm with anti-inflammatory drugs. Inhaled corticosteroids (budesonide, beclomethasone) are now widely used. The dosage inhaled for budesonide is about 200e400 mg/day. The halflife is about 2e3 h, so that rapid disappearance from the maternal plasma is expected. Data concerning excretion in milk is not available for these steroids but the amount inhaled is so low that significant transfer across to milk would be expected to be very small. There are data available for the amount of a corticosteroid given either orally or intravenously that is transferred to milk. It is quite low; e.g. the amount of prednisolone secreted into milk is only 0.025% of a maternal intravenous dose of 50 mg. The peak milk concentration is only 200 ng/mL, so the exposure of the infant is exceedingly small.32 The amount by oral exposure is also small: a nursing mother receiving 120 mg per of prednisone excreted peak concentrations of 153 ng/mL of prednisone and 473 ng/mL of prednisolone at 2 h post-ingestion. Assuming the infant was nursed with 120 mL every 4 h, the total amount of glucocorticoid available for ingestion by the infant was 47 mg, an amount not likely to exert physiological effect.33 The amount available to be transferred from maternal plasma could be decreased by timing the inhalation so that it occurred just after a nursing period, so that when the next time to nurse arrives there would be a substantial decrease in the maternal plasma concentration. Beta-agonists such as albuterol are used as escape medications for active wheezing. Albuterol has not been measured in milk because it is widely used for respiratory conditions, even in young infants, it is unlikely that any transmitted milk will have an effect. Newer agents are drugs that block inflammation at the leukotriene level. The manufacturer of zafirlukast (Accolate) reports that nursing mothers receiving 50 mg/day orally had average steadystate concentrations in their milk of 50 ng/mL.34 Monteleukast has not been measured in milk but is given orally to children as young as 12 months in the treatment of asthma.
Anxiety and depression Anxiety and depression, either separate or together, are common during pregnancy and in the postpartum period.35 The incidence of postpartum depression might be as high as 1 in 8 women.36
153 Perhaps the most frequent inquiry physicians receive is concerning the safety of psychotropic drugs during lactation. These drugs can be placed in one of the four categories: anti-anxiety drugs, e.g. diazepam, alprazolam, clorazepate antidepressants, e.g. tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), bupropion antipsychotics, e.g. typical and atypical neuroleptics (haloperidol, risperidone, olanzapine), lithium central nervous stimulants, e.g. methylphenidate, amphetamine, atomoxetine
Anxiolytics Interest in the effect of psychotropic drugs on the infant began with the observation that diazepam administered to the mother was detectable both in her milk and in infant sera and urine.37e39 Active metabolites, desmethyldiazepam, oxazepam, and temazepam were also identified in maternal milk and infant sera.40,41 Although a majority of these infants were neonates, there was no discernable clinical effect on the infants. The persistence of diazepam and its desmethyl metabolite is illustrated by measurable levels in the infant serum 7 days after a single maternal dose.39 This emphasizes the slow metabolism and elimination of compounds by the neonate and very young infant.42,43 The interesting observation that there are naturally occurring benzodiazepine-like substances in human milk has not been extended.44 The concentration of these substances was in the range of 4 ng/mL, which is about 10 times lower than the concentration of benzodiazepines in milk after maternal administration of one of the drugs. Antidepressants The selective serotonin reuptake inhibitors (SSRIs) have become the drugs of choice for treatment of all types of depression, especially during pregnancy and the postpartum period. The tricyclic antidepressants are not widely used because of efficacy and toxicity concerns. The current group of SSRIs includes:
fluoxetine (Prozac) sertraline (Zoloft [Lustral in UK]) fluvoxamine (Luvox [Faverin in UK]) paroxetine (Paxil [Seroxat in UK]) citalopram (Celexa [Cipramil in UK]), also the single isomer, escitalopram (Lexapro [Cipralex in UK])
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There might be other trade names as these compounds go off patent. Although the mechanism of action is identical for each of the SSRIs, there might be significant interindividual variation in the response of patients to one of these drugs. The SSRIs have long plasma half-lives, ranging from 24 h for sertraline to 4e6 days for fluoxetine. Fluoxetine, sertraline, and citalopram also have active metabolites, although the metabolite of fluoxetine is the only one with significant activity. Many mothers take one of these drugs during pregnancy and then question the safety during breastfeeding. Others with postpartum depression have not been exposed to an antidepressant during pregnancy. It is now recognized that women who take a SSRI during pregnancy might have a neonate with a collection of symptoms that would indicate a withdrawal syndrome. Costei et al. reported on a group of 55 women who took paroxetine during the third trimester of pregnancy.45 Twelve infants had significant complications requiring prolonged hospitalization: 9 with respiratory distress, 2 with hypoglycemia and 1 with jaundice. Thirty-six of the 55 women continued to take the drug during breastfeeding and 8 reported symptoms in their infants: constipation, sleepiness and irritability. There were no symptoms in the control group of mothers (those mothers who used paroxetine only during the first or second trimester). Chambers et al. also reported increased adverse effects in newborns with third-trimester exposure to fluoxetine.46 These adverse effects included prematurity, admission to special care nurseries, and poor neonatal adaptation. Zeskind and Stephens reported adverse neonatal neurodevelopment behavior in a group of 17 infants with fetal exposure to SSRIs.47 These infants exhibited significant differences from the control group in tremulousness and measures of state and sleep organization. The question then arises whether postnatal exposure to these drugs could also alter shortand long-term infant neurodevelopment. All of the drugs in the above-mentioned classes work by altering neurotransmitters in the central nervous system. A review of the prenatal and/or postnatal administration of benzodiazepines summarizes the adverse effects on activity patterns and emotional/motivational responsiveness to environmental challenges in rats.48 Patel et al. have shown that reserpine given to pregnant rats alters cell proliferation in the offspring.49 Neurotransmitters may influence neuronal growth50 and development of synapses51 in animal models.
Of the 29 nursing pairs using tricylic antidepressants, only one pair showed transfer of drug (doxepin); all other assays were below the detectable limit.52 The infant with measurable concentrations of doxepin and its metabolite was the only infant having symptoms (sedation). Other reports have mentioned significant respiratory symptoms, poor feeding and hypotonia.
Tricyclic antidepressants Wisner et al. collected 15 published reports of maternal use of antidepressants during breastfeeding.
Fluvoxamine Fluvoxamine concentrations in 2 breastfeeding women were 425 ng/mL and 67 ng/mL.63 One
Fluoxetine There are case reports of adverse effects of maternal fluoxetine on nursing infants.53e55 These infants had feeding difficulties, sleepiness, irritability, excess crying, vomiting, and watery stools. Two infants were in the first week of life; the third was 6 weeks old. All three had measurable levels of either fluoxetine or its active metabolite, norfluoxetine. In one case, the symptoms returned after the child was challenged with breast milk that had been pumped and stored.55 In a series of lactating mothers reported by Taddio et al., milk concentrations of fluoxetine ranged from 23 to 189 ng/mL, and norfluoxetine concentrations ranged from 31 to 169 ng/mL.56 These assay numbers for milk concentrations are similar from study to study and also for the other SSRIs. Chambers et al. reported decreased growth curves among infants of mothers receiving fluoxetine compared with controls (fluoxetine during pregnancy, but not during lactation).57 These results were not confirmed by Moretti et al.58 Sertraline Stowe et al. reported a series of 11 infants nursing from mothers receiving sertraline. Milk concentrations of sertraline ranged from 8 to 92 ng/mL and for its active metabolite, desmethylsertraline, from 15 to 212 ng/mL.59 Three of 11 infants had plasma sertraline concentration of 2.7e3.0 ng/mL and 6 of 11 had plasma desmethylsertraline concentrations of 1.6e10 ng/mL. No adverse effects were observed in the infants. Paroxetine Stowe et al. studied 16 nursing pairs for the transfer of paroxetine.60 Milk concentrations ranged from 2 to 101 ng/mL but no drug was detected in the infants’ sera. Paroxetine use during lactating does not affect infant growth.61 Citalopram Citalopram exposure during breastfeeding did not cause a significant increase in infant adverse events.62 The drug has been found in milk.
Drugs and chemicals in human milk infant was 3 weeks old and the second one 26 months old. No drug was measurable in the infants’ plasma and there were no adverse events. Antipsychotics The following drugs used for psychiatric conditions have been identified in human milk after maternal administration: clozapine,64 haloperidol,65 chlorpromazine,65 trifluoperazine,65 and risperidone.66 Lithium is discussed above under drugs to avoid in very young infants. Yosdida et al. found haloperidol in all plasma and urine samples tested in infants whose mothers received the drug.65 This is an important report because none of the mothers had taken a neuroleptic drug while pregnant. While there were no reports of acute adverse effects, 3 of the 12 infants showed some decline in Bayley scores at 12e18 months. The report by Epperson et al. offers an important insight into the question of whether the small amount of any of the psychotropic drugs as discussed above will have significant pharmacodynamic effect on the nursing infant.67 Using the SSRI fluoxetine they were able to demonstrate the expected decline in maternal platelet concentrations of serotonin after starting therapy. Platelet serotonin is accumulated by a serotonin transporter (as is neuronal serotonin) and the use of a SSRI blocks this process, thus decreasing platelet serotonin in patients receiving a SSRI. All but one of the infants (n Z 11) exhibited no decline of platelet serotonin even though the mothers’ platelets showed the expected decline. This would also be an argument for lack of effect on neuronal transport as well. The one infant that did show a decline was the only infant to have a measurable blood fluoxetine concentration of 2.6 ng/mL. The same group has repeated this observation for sertraline.68 It would be important to identify other surrogate markers to predict possible effect on neuronal systems.
155 Transfer to the infant is confirmed for many drugs because of presence in the infant’s plasma and/or urine. Infants have a rapidly developing brain, including receptors involved in neurotransmission. Adverse events have occurred almost exclusively in the neonate or very young infant. The number of studies and the number of subjects in these studies is small. Long-term follow-up, especially for infants exposed to psychotrophic drugs only during lactation, is lacking. It might not be possible to assert, even with careful long-term studies, that neurodevelopmental problems during the school years are the result of exposure to these drugs. The decision to use psychotropic agents during lactation will be made after discussion between the mother and the infant’s physician. It must be emphasized that the mother’s health is very important and breastfeeding might be very therapeutic along with any medication. Many decisions in medicine have to be made with incomplete data.
Diabetes The management of maternal diabetes should be little altered by lactation.69,70 Insulin does not cross into milk; even if transferred, it would be hydrolyzed in the infant’s intestinal tract. The first-generation oral hypoglycemic agents are excreted into milk. A newer agent, metformin, appears in very low concentration.71 Metformin levels were below 0.3 mg/mL. Metformin should not cause hypoglycemia because its mechanism is to reduce insulin resistance. It would be prudent to monitor the infant’s blood sugars if the mother is taking an oral hypoglycemic agent.
Gastrointestinal disorders Summary for psychotropic drugs All psychotropic drugs studied to date appear in milk. The concentration is small, usually between 10 and 400 ng/mL for most drugs. The plasma half-life is long; brain half-life unknown. Choosing a psychoactive agent because it has a shorter half-life may not mean the brain half-life is also short. Many drugs have a biologically active metabolite.
The H2-blocking agents such as famotidine, raniditine, and cimetidine are safe. Not only are they excreted in very low amounts in milk but also they are given directly to infants in doses far exceeding any that might be transferred in milk. Many agents are available for the treatment of inflammatory bowel disease and many patients receive two of more drugs. Corticosteroid enemas, infliximab monoclonal antibody, and the salicylates such as mesalamine and olsalazine appear safe. If antimetabolites are used (6-mercaptopurine,
156 methotrexate), it might be prudent to monitor the infant’s hemogram and liver function. It might be possible, depending on the mother’s disease activity, to postpone using antimetabolites during the infant’s first few months.
Hypertension All diuretics appear to be safe. The beta-blocking agents are discussed above under drugs to avoid; some beta-blockers appear to be quite safe. Calcium channel blockers (nifedipine, verapamil, diltiazem) are excreted in very small amounts in milk; between 50 and 200 ng/mL at peak concentrations.72 No hypotensive episodes have been described in infants whose mothers take this drug. Note that some of these agents are also used to treat migraine and subarachnoid hemorrhage.
Infectious diseases All antibiotics can be used by the mother during lactation. Most antibiotics are given directly to the infant in doses far exceeding any dose that would be transferred through milk. However, questions have been raised about three antibiotics: Fluoroquinolones: this class of antibiotic has been reported to cause cartilage damage in the developing animal; this has not been observed in human, even in children treated for a prolonged period with therapeutic doses (e.g. cystic fibrosis). Metronidazole: this drug has been observed to cause chromosomal damage in the laboratory; not observed in human use. It is used in young infants and children to treat giardiasis and anaerobic infections. Tetracycline: this drug is listed frequently as causing dental staining in children as a result of maternal use during breastfeeding, although no case reports of this have been published. Dental staining is well known when given during pregnancy or directly to children under the age of 8 (enamel formation of unerrupted permanent teeth).
Migraine Many drugs are now used for the prophylaxis of migraine attacks, including calcium channel blockers, sertraline, propanolol, valproic acid and gabapentin. Sertraline, calcium channel blockers and SSRIs are discussed above. No adverse effects have
C.M. Berlin, G.G. Briggs been reported with the other agents. For the treatment of acute episodes, non-steroidal antiinflammatory agents, acetaminophen (paracetamol) and the triptan family are all safe. The amount of sumatriptan excreted in milk is exceedingly small e a total excretion of less than 15 mg following a maternal dose of 6 mg.73 It would be advisable to avoid the use of ergot alkaloids because of old reports of adverse effects.
Pain management Pain in the mother can be managed with acetaminophen (paracetamol) and non-steroidal antiinflammatory agents (both are given to infants in therapeutic doses). If a narcotic is needed, morphine is safe, especially in the perinatal period. However, prolonged high-dose use of morphine in the mother could lead to therapeutic plasma levels in the infant.74 Data are not available concerning the transfer of drug via transdermal patches such as the fentanyl patch.
Seizure disorders Phenobarbital and phenytoin are now rarely used as anti-epileptic agents. Data for the newer agents, carbamazepine, valproic acid, lamotrigine, tiagabine and gabapentin either are lacking or show transfer of small amount resulting in plasma levels in the infant of 1e5 mg/mL. An exception to this is lamotrigine in the young infant, who might accumulate enough drug to have a plasma concentration one-third of the maternal concentration.75 The mothers of these infants also received the drug during pregnancy. Monitoring the plasma level of an anticonvulsant in the infant should help to determine the exposure during breastfeeding.
Radioactive isotopes Most isotopes that a lactating woman could receive will be for diagnostic purposes and the isotope will have a reasonable short half-life. For example, the half-life of technectium 99 is about 5 h, and nearly all radioactivity is gone from pumped breast milk after 24 h. The safest way to ensure that the infant will not receive any radioactivity is for the mother to express her milk until the Radiology Department determines that the radioactivity is at background, when she can resume nursing. The expressed milk can be saved and the radioactivity will decay during storage. Use of isotopes with a long half-life (e.g.131I) and
Drugs and chemicals in human milk prolonged administration for therapeutic reason might preclude breastfeeding.
Thyroid conditions Drugs for the treatment of hypo- and hyperthyroid disease are safe during breastfeeding.
Herbs and dietary supplements Herbs and dietary supplements are widely used. One of three people uses them and it is a $22 billion dollar industry. The Dietary Supplement Act of 1994 by the US Congress removed these compounds from the same strict oversight by the Food and Drug Administration that is given to drugs. It permits the sale of all products sold before October 1994 without review/approval by any agency. For a new ingredient, the sponsor must notify the FDA and demonstrate it is safe. The burden of proof that a substance is not pure, is mislabeled, or causes adverse effects lies with the Federal Government (as was recently the case with Ephedra). Patients who inquire about using herbs or dietary supplements should be told the following: There is not the same oversight that exists with drugs. The active ingredient or ingredients in these substances is unknown. The purity of purported active ingredient is not guaranteed. Potential serious drug interactions have been described for many herbal products. Safety for the nursing infant cannot be assured.
Conclusion The goal of understanding drug excretion during lactation is twofold: ensure the safety of the infant and promote appropriate therapeutic intervention for maternal illness. Enough data have been collected to be able to give advice for a large number of compounds. For example, the AAP statement lists 171 drugs in a table entitled ‘Maternal medication usually compatible with breastfeeding’.5 It is imperative that continued research be done on newer compounds with the latest analytic methods to insure a knowledge base reflecting current practice. Long-term studies should be done to measure any possible neurobehavioral or developmental effects.
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Practice points Most drugs administered to the lactating mother will appear in milk in concentrations similar to maternal plasma concentrations Total daily exposure to the infant is usually less than 1% of the maternal dose Adverse events caused by such exposure are very rare and almost always occur in the infant less than 6 months of age For most maternal conditions, required drug therapy choices are available that will not cause adverse effects in the infant
Research directions Long-term follow-up of infants whose mothers received psychotropic drugs Measurement of new drugs as they enter into clinical use Determination of the effect of the newer oral contraceptive formulations on milk supply and growth and development of the offspring
References 1. Lawrence RA, Lawrence RM. Breastfeeding: a guide for the medical profession. 5th ed. St Louis: Mosby; 1999. p. 1e12. 2. Knowles JA. Excretion of drugs in milk e a review. J Pediatr 1965;66:1068e82. 3. Catz CS, Giacocia GP. Drugs and metabolites in human milk. In: Galli C, Jacini G, Pecile A, editors. Dietary lipid and postnatal development. New York: Raven Press; 1973. p. 247e55. 4. O’Brien TW. Excretion of drugs in human milk. Am J Hosp Pharm 1974;31:844e54. 5. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human breast milk. Pediatrics 1983;72:375e83. 6. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1989;84:924e36. 7. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137e50. 8. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and chemicals into human milk. Pediatrics 2001;108:776e89. 9. Committee on the Evaluation of the Addition of Ingredients New to Infant Formula. Food and Nutrition Board. Institute of Medicine. Washington D.C.: National Academies Press; 2004.
158 10. Matheson I, Kristensen K, Lunde PKM. Drug utilization in breast-feeding women: a survey in Oslo. Eur J Clin Pharmacol 1990;38:453e9. 11. Ito S, Koren G, Einarson TR. Maternal noncompliance with antibiotics during breastfeeding. Ann Pharmacother 1993; 27:40e2. 12. Wilson JT, Brown RD, Cherek DR, Dailey JW, Himan B, Jobe PC, et al. Drug excretion in human breast milk. Clin Pharmacokinet 1980;5:1e66. 13. Atkinson HC, Begg EJ, Darlow BA. Drugs in milk: clinical pharmacokinetic considerations. Clin Pharmacokinet 1988; 14:217e40. 14. Atkinson HC, Begg EJ. Reduction of drug distribution into human milk from physicochemical characteristics. Clin Pharmacokinet 1990;18:151e67. 15. Bailey B, Ito S. Breast-feeding and maternal drug use. Pediatr Clin North Am 1997;44:41e54. 16. Berlin CM. The excretion of drugs and chemicals in human milk. In: Yaffe SJ, Aranda JV, editors. Neonatal and pediatric pharmacology. 3rd ed. Philadelphia: Lippincott, Williams & Wilkins; 2004. p. 187e96. [chapter 16]. 17. Schanker LS. Passage of drugs across body membranes. Pharmacol Rev 1963;14:501e30. 18. Wilkinson GR. Pharmacokinetics. In: Hardman JG, Limbird LE, Gilman AG, editors. Goodman & Gilman’s pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill; 2001. p. 3e4. 19. Kesaniemi YA. Ethanol and acetaldehyde in the milk and peripheral blood of lactating women after ethanol administration. J Obstet Gynaecol Br Commonw 1974;81:301e10. 20. Ito S, Blajchman A, Stephenson M, Eliopoulos C, Koren G. Prospective follow-up of adverse reactions in breast-fed infants exposed to maternal medication. Am J Obstet Gynecol 1993;168:1393e9. 21. Anderson PO, Pochop SL, Manoguerra AS. Adverse drug reactions in breastfed infants: less than imagined. Clin Pediatr 2003;42:325e40. 22. Boutroy MJ, Bianchetti G, Dubruc C, Vert P, Morselli PL. To nurse when receiving acebutolol: is it dangerous for the neonate? Eur J Clin Pharmacol 1986.737e9. 23. Schmimmel MS, Eidelman AJ, Wilschanski MA, Shaw Jr D, Ogilvie RJ, Koren G. Toxic effects of atenolol consumed during breast feeding. J Pediatr 1989;114:476e8. 24. Atkinson H, Begg EJ. Concentration of beta-blocking drugs in human milk. J Pediatr 1990;115:156. 25. Clark JH, Wilson WG. A 16-day old breast-fed infant with metabolic acidosis caused by salicylate. Clin Pediatr 1981; 20:53e4. 26. Townsend RJ, Benedetti T, Erickson SH, Cengiz C, Gillespie WR, Gschwend J, et al. Excretion of ibuprofen into breast milk. Am J Ostet Gynecol 1984;149:184e6. 27. Jamali F, Stevens DR. Naproxen excretion in milk and its uptake by the infant. Drug Intell Clin Pharm 1983;17:393e6. 28. Schou M, Amdisen A. Lithium and pregnancy e III, lithium ingestion by children breast-fed by women on lithium treatment. BMJ 1973;2:1388. 29. Cunningham FG, Levano KJ, MacDonald PC, Gilstrap LC, Gant NF, Hankins GDV, et al, editors. Williams obstetrics. 20th ed. Stamford, CT: Appleton & Lange; 1997. p. 1112. 30. Orme ML, Lewis PJ, De Swiet M, Serlin MJ, Sibeon R, Baty JD, et al. May mothers given warfarin breast-feed their infants? BMJ 1977;1:1564e5. 31. De Swiet M, Lewis PJ. Excretion of anticoagulants in human milk. N Engl J Med 1977;297:1471. 32. Greenberger PA, Odeh YK, Frederiksen MD, Atkinson Jr AJ. Pharmacokinetics of prednisolone transfer to breast milk. Clin Pharmacol Ther 1993;53:324e8.
C.M. Berlin, G.G. Briggs 33. Berlin CM, Kaiser DG, Demers L. Excretion of prednisone and prednisolone in human milk. Pharmacologist 1979;21: 264. 34. Product information. Accolate, Physicians’ Desk Reference. 58 ed. Montvale NJ: Thompson PRD; 2004. p. 652. 35. Wisner KL, Peindl KP, Hanusa BH. Relationship of psychiatric illness to childbearing status: a hospital-based epidemiologic study. J Affect Disord 1993;28:39e50. 36. O’Hara MW, Swain AM. Rates and risk of postpartum depression: a meta analysis. Int Rev Psychiatry 1996;8: 37e54. 37. Patrick MJ, Tilstone WJ, Reavey P. Diazepam and breastfeeding. Lancet 1972;1:542e3. 38. Erikkola R, Kanto J. Diazepam and breast-feeding. Lancet 1972;1:1235e6. 39. Cole AP, Hailey DM. Diazepam and active metabolite in breast milk and their transfer to the neonate. Arch Dis Child 1975;50:741e2. 40. Dusci LJ, Good SM, Hall RW, Ilett KF. Excretion of diazepam and its metabolites in human milk during withdrawal from combination high dose diazepam and oxazepam. Br J Clin Pharmacol 1990;29:123e6. 41. Birnbaum CS, Cohen LS, Bailey JW, Grush LR, Robertson BA, Stowe ZN. Serum concentrations of antidepressants and benzodiazepines in nursing infants: a case series. Pediatrics 1999;104:e11. 42. Morselli PL, Principi N, Tognoni G, Reali E, Belvedere G, Standen SM, et al. Diazepam elimination in premature and full term infants and children. J Perinat Med 1973;1:133e41. 43. Rane A. Drug metabolism and disposition in infants and children. In: Yaffe SJ, Aranda JV, editors. Neonatal and pediatric pharmacology. 3rd ed. Philadelphia: Lippincott, Williams & Wilkins; 2005. p. 32e43. 44. Dencker SJ, Johansson G, Milsom I. Quantitation of naturally occurring benzodiazepine-like substances in human breast milk. Psychopharmacology 1992;107:69e72. 45. Costei AM, Kozer E, Ho T, Ito S, Koren G. Perinatal outcome following third trimester exposure to paroxetine. Arch Pediatr Adolesc Med 2002;156:1129e32. 46. Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnancy women taking fluoxetine. N Engl J Med 1996;335:1010e5. 47. Zeskind PS, Stephens LE. Maternal selective serotonin reuptake inhibitor use during pregnancy and newborn neurobehavior. Pediatrics 2004;113:368e75. 48. DeSalvia MA, Cagiano R, Lacomba C, Cuomo V. Neurobehavioral changes produced by developmental exposure to benzodiazepines. Dev Pharmacol Ther 1990;15:173e7. 49. Lewis PD, Patel AJ, Bendel G, Balazs R. Do drugs acting on the nervous system affect cell proliferation in the developing brain. Lancet 1977;1:399e401. 50. Lauder JM. Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends Neurosci 1993;16:233e40. 51. Whitaker-Azmitia PM, Druse M, Walker P, Lauder JM. Serotonin as a developmental signal. Behav Brain Res 1996;73:19e29. 52. Wisner KL, Perel JM, Findling RL. Antidepressant treatment during breast-feeding. Am J Psychiatry 1996;153:1132e7. 53. Hale TW, Shum S, Grossberg M. Fluoxetine toxicity in a breastfed infant. Clin Pediatr 2001;40:681e4. 54. Spencer MJ. Fluoxetine hydrochloride (Prozac) toxicity in a neonate. Pediatrics 1993;92:721e2. 55. Lester BM, Cucca J, Andreozzi L, Flanagan P, Oh W. Possible association between fluoxetine hydrochloride and colic in an infant. J Am Acad Child Adolesc Psychiatry 1993;32: 1253e5.
Drugs and chemicals in human milk 56. Taddio A, Ito S, Koren G. Excretion of fluoxetine and its metabolite, norfluoxertine, in human breast milk. J Clin Pharmacol 1996;36:42e7. 57. Chambers CD, Anderson PO, Thomas RG, Dick LM, Felix RJ, Fjohnson KA, et al. Weight gain in infants breastfed by mothers who take fluoxetine. Pediatrics 1999;104:e61. 58. Moretti ME, Sharma A, Bar-Oz B, Koren G, Ito S. Clin Pharmacol Ther 1999;65:141. 59. Stowe ZN, Owens MJ, Landry JC, Kilts CD, Ely T, Llewellyn A, et al. Sertraline and desmethylsertraline in human breast milk and nursing infants. Am J Psychiatry 1997;154:1255e60. 60. Stowe ZN, Cohen LS, Hostetter A, Ritchie JC, Owens MJ, Nemeroff CB. Paroxetine in human breast milk and nursing infants. Am J Psychiatry 2000;157:185e9. 61. Merlob P, Stahl B, Sulkes J. Paroxetine during breastfeeding: infant weight gain and maternal adherence to counsel. Eur J Pediatr 2004;163:135e9. 62. Lee A, Woo J, Ito S. Frequency of infant adverse events that are associated with citalopram use during breastfeeding. Am J Obstet Gynecol 2004;190:218e21. 63. Kristensen JH, Hackett LP, Kohan R, Paech M, Ilett. The amount of fluvoxamine in milk is unlikely to be a cause of adverse effects in breastfed infants. J Hum Lact 2002;18: 139e43. 64. Barnas C, Bergant A, Hummer M, Saria A, Fleischhacker WW. Clozapine concentration in maternal and fetal plasma, amniotic fluid, and breast milk. Am J Psychiatry 1994;151: 945. 65. Yoshida K, Smith B, Craggs M, Kumar R. Neuroleptic drugs in breast-milk: a study of pharmacokinetics and of possible adverse effects in breast-fed infants. Psychol Med 1998;28: 81e91. 66. Hill RC, McIgvor RJ, Wojnar-Horton RE, Hacket LP, Ilett KF. Risperidone distribution and excretion into human milk: case report and estimated infant exposure during breastfeeding. J Clin Psychopharmacol 2000;20:285e6. 67. Epperson CN, Jatlow PI, Czarkowski K, Anderson GM. Maternal fluoxetine treatment in the postpartum period:
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75.
effects on platelet serotonin and plasma drug levels in breastfeeding mothereinfant pairs. Pediatrics 2003;112: e425. Epperson CN, Anderson GM, McDougle CJ. Sertraline and breast-feeding. N Engl J Med 1997;336:1189e90. Riordan J, Auerbach KG. Women’s health and breastfeeding. In: Riordan J, Auerbach KG, editors. Breastfeeding and human lactation. 2nd ed. Sudbury: Jones and Bartlett; 1999. p. 541e3. Lawrence RA, Lawrence RM. Breastfeeding: a guide for the medical profession. 5th ed. St Louis: Mosby; 1999. p. 515e21. Gardiner SJ, Kirkpatrick CMJ, Begg EJ, Zhang M, Moore MP, Saville DJ. Transfer of metformin into human milk. Clin Pharmacol Ther 2003;73:71e7. Ehrenkrantz RA, Ackermnan BA, Hulse JD. Nifedipine transfer into human milk. J Pediatr 1989;114: 478e80. Wojnar-Horton RE, Hackett LP, Yapp P, Dusci, Paech M, Ilett KF. Distribution and excretion of sumatriptan in human milk. Br J Clin Pharmacol 1996;41:217e21. Robieux I, Koren G, Vandenbergh H, Schneiderman J. Morphine excretion in breast milk and resultant exposure of a nursing infant. J Toxicol 1990;28:365e70. Ohman I, Vitols S, Tomson T. Lamotrigine in pregnancy: pharmacokinetics during delivery, the neonate, and during lactation. Epilepsia 2000;41:709e13.
Sources for information AAP Statement. Transfer of drugs and chemicals into human milk. Pediatrics 2001;108:776e89 [4th ed.]. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 6th ed. Lippincott Williams & Wilkins; 2002. USPDI. Updated yearly. Rockville, Maryland: Published by the United States Pharmacopeia; 2004.
www.elsevierhealth.com/journals/siny
Drugs and chemicals in human milk Cheston M. Berlina,*, Gerald G. Briggsb,c,d,e a
Penn State Children’s Hospital, MS Hershey Medical Center, PO Box 850, 500 University Drive, Hershey, PA 17033-0850, USA b Miller’s Children’s Hospital e Women’s Pavilion, Long Beach Memorial Medical Center, Long Beach, CA, USA c University of California, San Francisco, USA d University of Southern California, LA, USA
KEYWORDS Breast milk; Drugs; Human milk; Lactation
Summary There is continuing emphasis by many professionals and organizations on the importance of breastfeeding as optimal infant nutrition. Pediatricians are frequently asked about the safety of medications taken by the nursing mother and the risk to the infant. Most drugs and many chemicals will be transferred into milk. For a vast majority of these compounds, there is no risk to the infant. It is almost always possible for the mother to continue nursing while taking the necessary medication. This article presents an introduction to the pharmacology of the transfer of drugs into milk, discusses the importance of the infant’s age in assessing safety and presents a number of maternal conditions for which drugs need to be used. ª 2004 Elsevier Ltd. All rights reserved.
Introduction The resurgence in the interest of pediatricians in breastfeeding is difficult to date precisely, but was almost certainly present with the publication in 1978 of the Healthy People 2000 goals to increase breastfeeding in 2000 to 75% in the period of early infancy and to 50% by 6 months of age.1 In 1978,
* Corresponding author. Tel.: C1 717 531 8006; fax: C1 717 531 0869. E-mail addresses: [email protected] (C.M. Berlin), [email protected] (G.G. Briggs). e Tel.: C1 562 933 2757; fax: C1 562 933 2759.
the rate of newborns being breastfed was 48.1%.1 At this time, concern was also expressed over the appearance in breast milk of drugs taken by the mother or chemicals to which the mother had been exposed in the environment. Early attempts to tabulate data concerning the excretion of drugs were undertaken by Knowles in 1965,2 Catz and Giacoia in 1973,3 and O’Brien in 1974.4 Before these review papers, many literature reports concerning effects on the nursing infant (occasionally adverse) were not supported by measurement of the drug in milk, and many were single-case reports. These review papers collected published studies in which milk concentrations were measured for certain drugs.
1744-165X/$ - see front matter ª 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2004.09.016
150 The Committee on Drugs of the American Academy of Pediatrics published the first comprehensive statement on the transfer of drugs and chemical into human milk in 1983.5 Succeeding editions of this statement were published in 1989,6 19947 and 2001.8 The more recent editions have relied on published reports (not personal communications or citations in the Physicians’ Desk Reference) in which the drug was measured. Many more recent reports are series of mothereinfant nursing pairs rather than single-case reports. An indication of the interest in this topic is illustrated by the increase in the number of references in the four AAP statements: from 175 in the 1983 version to 392 in the 2001 version (not all studies are referenced).
Why study drug excretion in milk? The first reason to study drug excretion in human milk is that the exclusively breastfed infant is unique among all children because she/he is solely dependent on human milk for nutrition. The infant is growing and developing rapidly, with corresponding maturation of many organs and physiologic processes. The presence of drugs or chemicals in milk may, if the concentration is high enough or if the infant is sensitive enough, interact at many possible physiological levels. There is a special concern about the vulnerability of the developing central nervous system. This concern with exogenous substances in the infant’s formula is not confined only to breast milk. A recent report from the Food and Nutrition Board of the Institute of Medicine of the National Academies presents many concerns (which are being considered) over the addition of a substance not already in infant formulas. One recent example of this is the addition of long-chain polyunsaturated fatty acids, such as arachidonic acid (ARA) and docosahexaenoic acid (DHA), to commercial formulas. The Food and Nutrition Board report discusses the background of food safety and the safety parameters to be considered when adding a substance new to infant formulas.9 The concepts presented in this report can also be applied to human milk with the maternal medication being the substances added. The second reason to study drug excretion in human milk is to obtain enough evidence to permit safe and effective maternal drug therapy. Over 90% of mothers could receive one or more drugs in the first week of postpartum.10 The percentage of women needing drug therapy at any time during lactation would seem to be equally high. Women should not stop breastfeeding just because they need to receive a drug; nor should they not take
C.M. Berlin, G.G. Briggs the drug just because they are breastfeeding. Even with reassurance that a medication is safe, some mothers elect either to not take the medical or to stop breastfeeding. Ito et al. reported on the follow-up of a cohort of women who called in for information concerning the safety of an antibiotic therapy while breastfeeding. In spite of assurances that it was safe to continue nursing and take the antibiotic, 15% did not initiate drug therapy and 7% stopped breastfeeding.11 More needs to be done to educate both patients and physicians on the safety of drugs during lactation.
Human milk and drug transport Human milk is a biological fluid synthesized in the mammary tissue by cellular mechanisms exquisitely designed to provide the infant with the precise quantitative and qualitative growth- and immune-enhancing factors, while at the same time enhancing motherechild bonding. The factors responsible for the transfer of drugs and other chemicals through the alveolar mammary cell and into milk have been reviewed.12e15 A brief summary will assist in discussing the use of drugs for maternal therapy. The transport of compounds across the mammary alveolar cells is thought to occur by a number of processes.16,17 The usual route is probably transcellular diffusion, in which small molecules (molecular weight 100e200) are dragged along with water flow (hydrostatic or osmotic pressure differences).18 Compounds of a larger molecular weight might enter milk through intercellular diffusion, thus avoiding the alveolar cell entirely. This could explain the presence in milk of maternal proteins such as cow milk antigen and various antibodies. Not only molecular weight but also the shape of the molecule will determine its passage. Passive diffusion could occur from interstitial water from the base of the cell. Ionophore diffusion might facilitate the transfer of charged ions and other substances that might be bound to carrier proteins. Lipidsoluble substances, as well as un-ionized compounds, are readily transported. This is reflected in the observation that lipid-soluble substances of a small molecular weight and no electrical charge will appear in milk at concentrations very similar to the simultaneous maternal plasma concentration; ethyl alcohol is a good example.19 The maternal plasma concentration of the drug is an important determinant of how much drug is available for excretion into milk. Because diffusion occurs along a concentration gradient, high maternal plasma/serum levels will produce high milk
Drugs and chemicals in human milk levels. The serum/plasma concentration is determined not only by the maternal dose but also by the mother’s ability to metabolize the drug. For example, the ability to metabolize a drug is genetically determined and there are many examples of ‘poor’ or ‘slow’ drug metabolizers in a given population. The ratio of ‘poor/slow’ to ‘normal’ metabolizers might be as high as 1e10 for some agents, so drug levels in milk in these individuals will be much higher than predicted. The typical daily amount of milk consumed by an infant is about 150 mL/kg/day. Many investigators use this value to estimate the weight-adjusted dose consumed by a nursing infant, so that a prediction can be made on the relative safety of a drug during breastfeeding. Ion trapping might occur during the transfer of a drug from maternal plasma to milk. Breast milk is slightly acidic (average pH 7.1) as compared to plasma (average pH 7.4), so the acid/base characteristics of a drug are important. All acid/base chemicals exist in equilibrium between their ionized and non-ionized forms. This equilibrium is an important determinant of how much drug will be present in milk. For example, the equilibrium for acidic drugs, such as penicillins and non-steroidal anti-inflammatory agents (NSAIDs), will favor ionization in the relatively alkaline plasma and, thus, less will be available for transport into milk. When transport does occur, the equilibrium obtained in milk will favor the non-ionized form because of the relatively acidic milk, so the drug will be transported back into the plasma. This reverse ‘ion trapping’ in plasma for acidic drugs will, in general, result in milk:plasma drug ratios that are !1.0. The reverse is true for basic drugs, such as betablockers. In this case, the relatively acidic milk shifts the equilibrium to the ionized form, thereby trapping the drug and, in general, producing drug milk:plasma ratios that are O1.0. This is why betablockers accumulate in milk. Because the milk concentrations for most drugs are less than or equal to the maternal plasma concentration, the total exposure of the nursing infant is usually less than 1% of the maternal dose.16 It is important to emphasize that these data are mostly from studies using a single maternal dose and do not reflect the quantitative transport in mothers on chronic drug therapy with steady-state plasma concentrations.
Risks to the nursing infant Very few drugs would be considered contraindicated during lactation. Reports of adverse effects
151 frequently do not include a measure of the drug in milk but report events that occur during lactation. Ito et al. reported on a cohort of 838 infants followed prospectively by the Motherisk Program at the Hospital for Sick Children in Toronto, Canada.20 All mothers were taking at least one drug (80%) and 20% were taking two or more drugs; nearly all infants (89%) were under 4 months of age. The follow-up telephone call occurred between 1 and 31 weeks from the initial inquiry by the mother as to the drug safety. The type of drug taken is important and is indicative of the type of exposure that can be expected by lactating women. The four most common groups were: analgesics 23.4%, antibiotics 19.8%, antihistamines 10.1% and sedatives 5.0%. It is possible that this division will be a different change for cohorts of nursing infants older than 4 months. Adverse events looked for were: diarrhea, drowsiness, irritability and others (rash, constipation, feeding difficulties, decrease in milk supply). There were 94 reports (11.2%) of minor adverse reaction in the nursing infant. Diarrhea in the infant of mothers taking antibiotics was the most common. Five of 26 women taking acetaminophen (paracetamol) with codeine reported drowsiness in their infant. There were no adverse events serious enough to require medical care. The authors recognize the limitations of this study in assigning reported symptoms to the mother’s use of the drug, including recall bias, third-party suggestions and concomitant mild infant illnesses. An important piece of data in this study is that of the initial 1110 mothers who called for advice, 54 women discontinued breastfeeding either permanently or during the maternal treatment period. In a further 218 cases, no drug was taken from the initial call to the follow-up call, presumably depriving the mother of needed therapy. Thus, in 30% of cases either the infant was deprived of breast milk or the mother was deprived of medical therapy. Anderson et al. have summarized the literature of 100 reported cases of adverse reactions in breastfed babies of mothers taking drugs.21 The distribution for the drug classes for these 100 cases was: antibiotics 17%, anticonvulsants 16%, antidepressants 13% and sedatives 13%. The relationship between maternal drug use and the adverse event was considered to be ‘definite’ in 0 cases, probable in 47% and possible in 53%. There were three deaths: a 23-day-old exposed to bromazepam (a benzodiazepine, not available in the USA), a 5-week infant exposed to methadone, but who also was malnourished, and a 1-month infant exposed to phenytoin and phenobarbital who also was smothered. The age of the infants is important: 37% were younger than 2 weeks and 63% were younger than
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1 month; only 4% of the reports were infants older than 6 months. It is important to emphasize that neonate and very young infants are at most risk for an adverse effect. Important factors for this observation are delayed development of hepatic drug-metabolizing enzymes and of glomerular filtration and renal tubular secretion.
Drugs to avoid in the newborn and in infants !6 months of age
pregnancy. Six of the 8 infants had measurable plasma concentrations of lithium ranging from 0.1 to 0.6 mmol/L. In 5 of the infants, the serum concentrations were between 18 and 65% of the maternal serum concentration.28 No adverse effects on the infants were described. It is not unusual for mothers who have been receiving such medication during pregnancy to become concerned after delivery and ask about the safety of breastfeeding. The topic of psychotropic medications is discussed later in this paper in detail under the selective serotonin reuptake inhibitors (SSRIs).
Beta-blocking agents Antineoplastic agents There are persuasive case reports of two betablocking agents, atenolol and acebutolol, causing symptoms of beta-blockade (hypotension, bradycardia, tachypnea) in very young infants.22,23 There is considerable variation of the percentage of the maternal dose potentially available to the nursing infant for members of the beta-blocking drug group.24 Previously, it was mentioned that the fraction of the maternal dose that might be transferred to the infant is usually less than 1%. The following are figures for certain beta-blockers24:
acebutolol: 3.5% atenolol: 5.7e19.2% labetalol: 0.07% propranolol: 0.2e0.9% sotalol: 22%
The figures of 19.2% for atenolol and 22% for sotalol are the highest potential percentage transfer of a drug from plasma to milk that has been reported in the literature.
Salicylates There is one report of salicylism occurring in a 16day-old infant whose mother was taking 650 mg aspirin every 4 h for arthritis.25 Mothers of very young infants needing an anti-inflammatory drug should take ibuprofen26 or naproxen.27
The exposure of the very young infant to these cytotoxic drugs presents a dilemma to the physician. Although there are no studies identifying cellular or organ damage, the rapidly dividing tissues of infants places them at risk. As the infant grows, the dose per body weight will decrease and any actual or theoretical risk will also decrease.
Drugs of abuse Nursing mothers should not use illicit drugs such as cocaine, narcotics, amphetamines, phencyclidine, and marijuana. They are hazardous to both the mother and the infant. Smoking by nursing mothers is discussed in the AAP statement.5 Whereas smoking is hazardous to the mother, a baby being breastfed might be at less risk for adverse events, such as respiratory illnesses, than a baby being bottle fed. A woman who is pregnant and planning to breastfeed should be encouraged and supported to stop smoking.
Treatment of maternal conditions The following are a number of common maternal conditions that usually require drug therapy, with a discussion of drug therapy during lactation.
Anticoagulation Lithium A discussion of the use of lithium both during pregnancy and in the postpartum period introduces the important subject of the use of any psychotropic medication (anxiolytics, antidepressants, antipsychotics), including antiepilepsy drugs. Schou and Amdisen published a series of 8 infants (7 under 4 weeks of age and 1 infant 10 weeks of age) whose mothers had received lithium during lactation and presumably during
Thrombophlebitis of any type is well known during pregnancy and the puerperium. The exact incidence is not known because of the difficulty of diagnosis for all cases. The range of estimates is 0.5e7/1000.29 Heparin is safe during nursing as it does not cross into milk because of its large molecular weight. Warfarin is also safe during lactation; it is highly bound to maternal plasma proteins (O99%) and is not detectable in milk or infant serum.30,31
Drugs and chemicals in human milk
Asthma The current emphasis on the treatment of asthma is the prevention of inflammation and subsequent bronchospasm with anti-inflammatory drugs. Inhaled corticosteroids (budesonide, beclomethasone) are now widely used. The dosage inhaled for budesonide is about 200e400 mg/day. The halflife is about 2e3 h, so that rapid disappearance from the maternal plasma is expected. Data concerning excretion in milk is not available for these steroids but the amount inhaled is so low that significant transfer across to milk would be expected to be very small. There are data available for the amount of a corticosteroid given either orally or intravenously that is transferred to milk. It is quite low; e.g. the amount of prednisolone secreted into milk is only 0.025% of a maternal intravenous dose of 50 mg. The peak milk concentration is only 200 ng/mL, so the exposure of the infant is exceedingly small.32 The amount by oral exposure is also small: a nursing mother receiving 120 mg per of prednisone excreted peak concentrations of 153 ng/mL of prednisone and 473 ng/mL of prednisolone at 2 h post-ingestion. Assuming the infant was nursed with 120 mL every 4 h, the total amount of glucocorticoid available for ingestion by the infant was 47 mg, an amount not likely to exert physiological effect.33 The amount available to be transferred from maternal plasma could be decreased by timing the inhalation so that it occurred just after a nursing period, so that when the next time to nurse arrives there would be a substantial decrease in the maternal plasma concentration. Beta-agonists such as albuterol are used as escape medications for active wheezing. Albuterol has not been measured in milk because it is widely used for respiratory conditions, even in young infants, it is unlikely that any transmitted milk will have an effect. Newer agents are drugs that block inflammation at the leukotriene level. The manufacturer of zafirlukast (Accolate) reports that nursing mothers receiving 50 mg/day orally had average steadystate concentrations in their milk of 50 ng/mL.34 Monteleukast has not been measured in milk but is given orally to children as young as 12 months in the treatment of asthma.
Anxiety and depression Anxiety and depression, either separate or together, are common during pregnancy and in the postpartum period.35 The incidence of postpartum depression might be as high as 1 in 8 women.36
153 Perhaps the most frequent inquiry physicians receive is concerning the safety of psychotropic drugs during lactation. These drugs can be placed in one of the four categories: anti-anxiety drugs, e.g. diazepam, alprazolam, clorazepate antidepressants, e.g. tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), bupropion antipsychotics, e.g. typical and atypical neuroleptics (haloperidol, risperidone, olanzapine), lithium central nervous stimulants, e.g. methylphenidate, amphetamine, atomoxetine
Anxiolytics Interest in the effect of psychotropic drugs on the infant began with the observation that diazepam administered to the mother was detectable both in her milk and in infant sera and urine.37e39 Active metabolites, desmethyldiazepam, oxazepam, and temazepam were also identified in maternal milk and infant sera.40,41 Although a majority of these infants were neonates, there was no discernable clinical effect on the infants. The persistence of diazepam and its desmethyl metabolite is illustrated by measurable levels in the infant serum 7 days after a single maternal dose.39 This emphasizes the slow metabolism and elimination of compounds by the neonate and very young infant.42,43 The interesting observation that there are naturally occurring benzodiazepine-like substances in human milk has not been extended.44 The concentration of these substances was in the range of 4 ng/mL, which is about 10 times lower than the concentration of benzodiazepines in milk after maternal administration of one of the drugs. Antidepressants The selective serotonin reuptake inhibitors (SSRIs) have become the drugs of choice for treatment of all types of depression, especially during pregnancy and the postpartum period. The tricyclic antidepressants are not widely used because of efficacy and toxicity concerns. The current group of SSRIs includes:
fluoxetine (Prozac) sertraline (Zoloft [Lustral in UK]) fluvoxamine (Luvox [Faverin in UK]) paroxetine (Paxil [Seroxat in UK]) citalopram (Celexa [Cipramil in UK]), also the single isomer, escitalopram (Lexapro [Cipralex in UK])
154
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There might be other trade names as these compounds go off patent. Although the mechanism of action is identical for each of the SSRIs, there might be significant interindividual variation in the response of patients to one of these drugs. The SSRIs have long plasma half-lives, ranging from 24 h for sertraline to 4e6 days for fluoxetine. Fluoxetine, sertraline, and citalopram also have active metabolites, although the metabolite of fluoxetine is the only one with significant activity. Many mothers take one of these drugs during pregnancy and then question the safety during breastfeeding. Others with postpartum depression have not been exposed to an antidepressant during pregnancy. It is now recognized that women who take a SSRI during pregnancy might have a neonate with a collection of symptoms that would indicate a withdrawal syndrome. Costei et al. reported on a group of 55 women who took paroxetine during the third trimester of pregnancy.45 Twelve infants had significant complications requiring prolonged hospitalization: 9 with respiratory distress, 2 with hypoglycemia and 1 with jaundice. Thirty-six of the 55 women continued to take the drug during breastfeeding and 8 reported symptoms in their infants: constipation, sleepiness and irritability. There were no symptoms in the control group of mothers (those mothers who used paroxetine only during the first or second trimester). Chambers et al. also reported increased adverse effects in newborns with third-trimester exposure to fluoxetine.46 These adverse effects included prematurity, admission to special care nurseries, and poor neonatal adaptation. Zeskind and Stephens reported adverse neonatal neurodevelopment behavior in a group of 17 infants with fetal exposure to SSRIs.47 These infants exhibited significant differences from the control group in tremulousness and measures of state and sleep organization. The question then arises whether postnatal exposure to these drugs could also alter shortand long-term infant neurodevelopment. All of the drugs in the above-mentioned classes work by altering neurotransmitters in the central nervous system. A review of the prenatal and/or postnatal administration of benzodiazepines summarizes the adverse effects on activity patterns and emotional/motivational responsiveness to environmental challenges in rats.48 Patel et al. have shown that reserpine given to pregnant rats alters cell proliferation in the offspring.49 Neurotransmitters may influence neuronal growth50 and development of synapses51 in animal models.
Of the 29 nursing pairs using tricylic antidepressants, only one pair showed transfer of drug (doxepin); all other assays were below the detectable limit.52 The infant with measurable concentrations of doxepin and its metabolite was the only infant having symptoms (sedation). Other reports have mentioned significant respiratory symptoms, poor feeding and hypotonia.
Tricyclic antidepressants Wisner et al. collected 15 published reports of maternal use of antidepressants during breastfeeding.
Fluvoxamine Fluvoxamine concentrations in 2 breastfeeding women were 425 ng/mL and 67 ng/mL.63 One
Fluoxetine There are case reports of adverse effects of maternal fluoxetine on nursing infants.53e55 These infants had feeding difficulties, sleepiness, irritability, excess crying, vomiting, and watery stools. Two infants were in the first week of life; the third was 6 weeks old. All three had measurable levels of either fluoxetine or its active metabolite, norfluoxetine. In one case, the symptoms returned after the child was challenged with breast milk that had been pumped and stored.55 In a series of lactating mothers reported by Taddio et al., milk concentrations of fluoxetine ranged from 23 to 189 ng/mL, and norfluoxetine concentrations ranged from 31 to 169 ng/mL.56 These assay numbers for milk concentrations are similar from study to study and also for the other SSRIs. Chambers et al. reported decreased growth curves among infants of mothers receiving fluoxetine compared with controls (fluoxetine during pregnancy, but not during lactation).57 These results were not confirmed by Moretti et al.58 Sertraline Stowe et al. reported a series of 11 infants nursing from mothers receiving sertraline. Milk concentrations of sertraline ranged from 8 to 92 ng/mL and for its active metabolite, desmethylsertraline, from 15 to 212 ng/mL.59 Three of 11 infants had plasma sertraline concentration of 2.7e3.0 ng/mL and 6 of 11 had plasma desmethylsertraline concentrations of 1.6e10 ng/mL. No adverse effects were observed in the infants. Paroxetine Stowe et al. studied 16 nursing pairs for the transfer of paroxetine.60 Milk concentrations ranged from 2 to 101 ng/mL but no drug was detected in the infants’ sera. Paroxetine use during lactating does not affect infant growth.61 Citalopram Citalopram exposure during breastfeeding did not cause a significant increase in infant adverse events.62 The drug has been found in milk.
Drugs and chemicals in human milk infant was 3 weeks old and the second one 26 months old. No drug was measurable in the infants’ plasma and there were no adverse events. Antipsychotics The following drugs used for psychiatric conditions have been identified in human milk after maternal administration: clozapine,64 haloperidol,65 chlorpromazine,65 trifluoperazine,65 and risperidone.66 Lithium is discussed above under drugs to avoid in very young infants. Yosdida et al. found haloperidol in all plasma and urine samples tested in infants whose mothers received the drug.65 This is an important report because none of the mothers had taken a neuroleptic drug while pregnant. While there were no reports of acute adverse effects, 3 of the 12 infants showed some decline in Bayley scores at 12e18 months. The report by Epperson et al. offers an important insight into the question of whether the small amount of any of the psychotropic drugs as discussed above will have significant pharmacodynamic effect on the nursing infant.67 Using the SSRI fluoxetine they were able to demonstrate the expected decline in maternal platelet concentrations of serotonin after starting therapy. Platelet serotonin is accumulated by a serotonin transporter (as is neuronal serotonin) and the use of a SSRI blocks this process, thus decreasing platelet serotonin in patients receiving a SSRI. All but one of the infants (n Z 11) exhibited no decline of platelet serotonin even though the mothers’ platelets showed the expected decline. This would also be an argument for lack of effect on neuronal transport as well. The one infant that did show a decline was the only infant to have a measurable blood fluoxetine concentration of 2.6 ng/mL. The same group has repeated this observation for sertraline.68 It would be important to identify other surrogate markers to predict possible effect on neuronal systems.
155 Transfer to the infant is confirmed for many drugs because of presence in the infant’s plasma and/or urine. Infants have a rapidly developing brain, including receptors involved in neurotransmission. Adverse events have occurred almost exclusively in the neonate or very young infant. The number of studies and the number of subjects in these studies is small. Long-term follow-up, especially for infants exposed to psychotrophic drugs only during lactation, is lacking. It might not be possible to assert, even with careful long-term studies, that neurodevelopmental problems during the school years are the result of exposure to these drugs. The decision to use psychotropic agents during lactation will be made after discussion between the mother and the infant’s physician. It must be emphasized that the mother’s health is very important and breastfeeding might be very therapeutic along with any medication. Many decisions in medicine have to be made with incomplete data.
Diabetes The management of maternal diabetes should be little altered by lactation.69,70 Insulin does not cross into milk; even if transferred, it would be hydrolyzed in the infant’s intestinal tract. The first-generation oral hypoglycemic agents are excreted into milk. A newer agent, metformin, appears in very low concentration.71 Metformin levels were below 0.3 mg/mL. Metformin should not cause hypoglycemia because its mechanism is to reduce insulin resistance. It would be prudent to monitor the infant’s blood sugars if the mother is taking an oral hypoglycemic agent.
Gastrointestinal disorders Summary for psychotropic drugs All psychotropic drugs studied to date appear in milk. The concentration is small, usually between 10 and 400 ng/mL for most drugs. The plasma half-life is long; brain half-life unknown. Choosing a psychoactive agent because it has a shorter half-life may not mean the brain half-life is also short. Many drugs have a biologically active metabolite.
The H2-blocking agents such as famotidine, raniditine, and cimetidine are safe. Not only are they excreted in very low amounts in milk but also they are given directly to infants in doses far exceeding any that might be transferred in milk. Many agents are available for the treatment of inflammatory bowel disease and many patients receive two of more drugs. Corticosteroid enemas, infliximab monoclonal antibody, and the salicylates such as mesalamine and olsalazine appear safe. If antimetabolites are used (6-mercaptopurine,
156 methotrexate), it might be prudent to monitor the infant’s hemogram and liver function. It might be possible, depending on the mother’s disease activity, to postpone using antimetabolites during the infant’s first few months.
Hypertension All diuretics appear to be safe. The beta-blocking agents are discussed above under drugs to avoid; some beta-blockers appear to be quite safe. Calcium channel blockers (nifedipine, verapamil, diltiazem) are excreted in very small amounts in milk; between 50 and 200 ng/mL at peak concentrations.72 No hypotensive episodes have been described in infants whose mothers take this drug. Note that some of these agents are also used to treat migraine and subarachnoid hemorrhage.
Infectious diseases All antibiotics can be used by the mother during lactation. Most antibiotics are given directly to the infant in doses far exceeding any dose that would be transferred through milk. However, questions have been raised about three antibiotics: Fluoroquinolones: this class of antibiotic has been reported to cause cartilage damage in the developing animal; this has not been observed in human, even in children treated for a prolonged period with therapeutic doses (e.g. cystic fibrosis). Metronidazole: this drug has been observed to cause chromosomal damage in the laboratory; not observed in human use. It is used in young infants and children to treat giardiasis and anaerobic infections. Tetracycline: this drug is listed frequently as causing dental staining in children as a result of maternal use during breastfeeding, although no case reports of this have been published. Dental staining is well known when given during pregnancy or directly to children under the age of 8 (enamel formation of unerrupted permanent teeth).
Migraine Many drugs are now used for the prophylaxis of migraine attacks, including calcium channel blockers, sertraline, propanolol, valproic acid and gabapentin. Sertraline, calcium channel blockers and SSRIs are discussed above. No adverse effects have
C.M. Berlin, G.G. Briggs been reported with the other agents. For the treatment of acute episodes, non-steroidal antiinflammatory agents, acetaminophen (paracetamol) and the triptan family are all safe. The amount of sumatriptan excreted in milk is exceedingly small e a total excretion of less than 15 mg following a maternal dose of 6 mg.73 It would be advisable to avoid the use of ergot alkaloids because of old reports of adverse effects.
Pain management Pain in the mother can be managed with acetaminophen (paracetamol) and non-steroidal antiinflammatory agents (both are given to infants in therapeutic doses). If a narcotic is needed, morphine is safe, especially in the perinatal period. However, prolonged high-dose use of morphine in the mother could lead to therapeutic plasma levels in the infant.74 Data are not available concerning the transfer of drug via transdermal patches such as the fentanyl patch.
Seizure disorders Phenobarbital and phenytoin are now rarely used as anti-epileptic agents. Data for the newer agents, carbamazepine, valproic acid, lamotrigine, tiagabine and gabapentin either are lacking or show transfer of small amount resulting in plasma levels in the infant of 1e5 mg/mL. An exception to this is lamotrigine in the young infant, who might accumulate enough drug to have a plasma concentration one-third of the maternal concentration.75 The mothers of these infants also received the drug during pregnancy. Monitoring the plasma level of an anticonvulsant in the infant should help to determine the exposure during breastfeeding.
Radioactive isotopes Most isotopes that a lactating woman could receive will be for diagnostic purposes and the isotope will have a reasonable short half-life. For example, the half-life of technectium 99 is about 5 h, and nearly all radioactivity is gone from pumped breast milk after 24 h. The safest way to ensure that the infant will not receive any radioactivity is for the mother to express her milk until the Radiology Department determines that the radioactivity is at background, when she can resume nursing. The expressed milk can be saved and the radioactivity will decay during storage. Use of isotopes with a long half-life (e.g.131I) and
Drugs and chemicals in human milk prolonged administration for therapeutic reason might preclude breastfeeding.
Thyroid conditions Drugs for the treatment of hypo- and hyperthyroid disease are safe during breastfeeding.
Herbs and dietary supplements Herbs and dietary supplements are widely used. One of three people uses them and it is a $22 billion dollar industry. The Dietary Supplement Act of 1994 by the US Congress removed these compounds from the same strict oversight by the Food and Drug Administration that is given to drugs. It permits the sale of all products sold before October 1994 without review/approval by any agency. For a new ingredient, the sponsor must notify the FDA and demonstrate it is safe. The burden of proof that a substance is not pure, is mislabeled, or causes adverse effects lies with the Federal Government (as was recently the case with Ephedra). Patients who inquire about using herbs or dietary supplements should be told the following: There is not the same oversight that exists with drugs. The active ingredient or ingredients in these substances is unknown. The purity of purported active ingredient is not guaranteed. Potential serious drug interactions have been described for many herbal products. Safety for the nursing infant cannot be assured.
Conclusion The goal of understanding drug excretion during lactation is twofold: ensure the safety of the infant and promote appropriate therapeutic intervention for maternal illness. Enough data have been collected to be able to give advice for a large number of compounds. For example, the AAP statement lists 171 drugs in a table entitled ‘Maternal medication usually compatible with breastfeeding’.5 It is imperative that continued research be done on newer compounds with the latest analytic methods to insure a knowledge base reflecting current practice. Long-term studies should be done to measure any possible neurobehavioral or developmental effects.
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Practice points Most drugs administered to the lactating mother will appear in milk in concentrations similar to maternal plasma concentrations Total daily exposure to the infant is usually less than 1% of the maternal dose Adverse events caused by such exposure are very rare and almost always occur in the infant less than 6 months of age For most maternal conditions, required drug therapy choices are available that will not cause adverse effects in the infant
Research directions Long-term follow-up of infants whose mothers received psychotropic drugs Measurement of new drugs as they enter into clinical use Determination of the effect of the newer oral contraceptive formulations on milk supply and growth and development of the offspring
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