- Email: [email protected]
Breastfeeding Maternal Medication Use
JOGNN
CLINICALISSUES
Breastfeeding and Maternal Medication Use Kathleen G. Auerbach, PhD, IBCLC
=
Drug therapy during lactation requires recognition of several elements, including drug properties, the status of the infant, the mother’s milk production, and what is known about particular drugs. It is important to consider the various properties of a drug when evaluating its possible effects in the breastfeeding infant. In addition, the volume of milk the infant receives and its composition can influence exposure levels. Other factors of importance include the infant’s age, frequency of feedings, recommended drug dosage, and whether the drug is short- or long-acting. Suggestions are offered for appropriate drug therapy when the mother is breastfeeding, including the safety of drugs commonly administered during lactation and questions to ask when a mother seeks assistance about suggested medication use. JOGNN, 28, 554-563;
1999. Accepted: May 1999
Too often, the breastfeeding mother is told she must not combine medication use with breastfeeding. This proscription often is followed by a recommendation to wean her infant from the breast. If she follows this advice, her infant has an increased risk of acute and chronic illnesses because bottle feeding provides no protection against viral or bacterial pathogenic organisms. This situation need not occur if the health provider acknowledges the value of breastfeeding and its continuation, asks relevant questions, and checks appropriate references that provide current information. Three principles govern discussions of drug therapy during lactation: (a) most drugs adminis554 JOGNN
tered to the lactating woman pass into her breastmilk; (b) most medications can be found in very small amounts in breastmilk; and (c)few drugs are contraindicated during lactation. Failure to consider each of these facts may contribute to inappropriate recommendations, which may have adverse effects on the health of the breastfeeding infant, the lactating woman, and the breastfeeding course.
Two Common Myths About Drugs and Breastfeeding Misconceptions about medications taken by pregnant and lactating women have contributed to confusion and inappropriate recommendations to women during the perinatal period. One such myth is that the drugs a mother receives during labor have little or no effect on the neonate. In most cases, this is untrue. When the woman is given a labor analgesic medication, the drug in question eventually can be found in her plasma compartment. Because her placenta is still nourishing the fetus, these same drugs are passed to the fetus. These drugs go to various fetal organs, including the brain (if the drug in question is lipophilic) and the liver. The clinical effects observed depend on the timing of the dose to the mother and on the half-life of the drug in specific organ compartments. For example, fentanyl has been reported to cause respiratory depression in the neonate (Carrie, O’Sullivan, & Seegobin, 1981). In some cases, more drug (such as fentanyl) is found in the infant, even if the dose to the woman was delivered shortly before the infant’s birth (Loftus, Hill, & Cohen, 1995).
Volume 28, Number 5
In other cases (such as meperidine), more drug is found in the fetus when the drug was given to the woman 90 minutes to 3 hours in advance of the infant’s birth (Spigset, 1994). The fetal liver slowly eliminates the drug in question. Observant care providers note that the short-lived effect of the analgesic on the woman appears to be manifested considerably longer in the infant. Knowing the half-life of a drug in the woman does not accurately predict the half-life of the same drug in the fetus or neonate (see Table 1). Because information on drugs and their effect on pregnant women, their fetuses, and their neonates sometimes is confusing, the health provider must assist the woman to balance her desire not to compromise her infant’s status while seeking pain relief should she conclude she will function better with such assistance. In most cases, the shorter the period between delivery of an analgesic or anesthetic and the infant’s birth, the less effect the medication has on the neonate. Many lactation consultants and other health providers have observed that the infants of women who have received a variety of labor medications seem to be unaccountably sleepy or difficult to rouse or have trouble coordinating complex motor activities, such as suckling. These observations reflect the degree to which medications given to the laboring woman have been transmitted to the fetus; sometimes the effects of such drugs are noticeable for many hours or days after birth. These effects include diminished alertness, poorer muscle tone, and poor or ineffective feeding behaviors (Crowell, Hill, & Humenick, 1994; Loftus et al., 1995; Matthews, 1989; Murray, Dolby, Nation, & Thomas, 1981; Sepkoski, Lester, Ostheimer, & Brazelton, 1992; Thorp & Breedlove, 1996; Youngstrom, Baker, & Miller, 1996). Even in cases in which the mother controls her own medication after delivery, such as when a patient-controlled analgesic pump is used for pain relief after cesarean section, similar outcomes have been observed, particularly with meperidine (Wittels et al., 1997).
A second myth says that an infant is exposed to as much medication through breastfeeding as a fetus would be through the placenta. Most health providers caution women against using medications unnecessarily or self-medicating during pregnancy on the grounds that the teratogenicity of the particular compound may contribute to fetal anomalies or other adverse outcomes. Such advice is appropriate, for the placenta is a far more effective route of transmission of drugs and their metabolites than is the breast and its productbreastmilk. However, drugs that should be avoided during pregnancy may pose little or no risk to the breastfeeding neonate or older infant. Operating under the same cautions appropriate when a woman is pregnant unnecessarily restricts the options available should a mother need drug therapy after the infant’s birth. In addition, the inappropriate cross-referencing of drug information in pregnancy to lactation may result in unnecessarily recommending interruption or cessation of breastfeeding.
D r u g s that should be avoided during pregnancy may pose little or no risk to the breastfeeding neonate or older infant.
Knowing the medications most likely to result in a delay in appropriate infant behaviors is essential to providing information about intrapartal analgesia to the pregnant woman and her family. Ideally, the information should be provided antenatally so the parturient couple can make a fully informed decision (Dillon et al., 1997). After the delivery, health care providers in the maternal-neonatal unit should observe infant behavior, provide additional support if the infant is experiencing
TABLE 1
-
Half-life of Selected Opioid Aiialgesics Often Given lliiriiig Labor
Agent
Morphine Meperidine (Demerol) Normeperidine Fentanyl Sufentanil Alfentanil
Adult Half-life (hrs)
Pediattic Half-life (hrs)
1.5-2 3.2 14-21 24 2-3 1-2
13.9 6-32 20-63 3-13 13-19
5-4
From: Hale, T. (1998, June). Anesthetic medications and breastfeeding mothers. Paper presented at Breastfeeding Support Consultants 2nd Annual North American Conference, Scottsdale, AZ.
SeptembedOctober 1999
JOG”
555
adverse effects of the maternally administered medication, and offer an explanation and reassurance to the mother that these effects are transitory.
Properties of the Drug Knowing certain characteristics about drugs and their diffusion in the body can be helpful in identifying the relative risk of giving a breastfeeding mother a drug. For example, all drugs enter breastmilk unless their molecular weight is so high (>800) that they cannot penetrate the cellular barrier. An example is heparin, which if given to the mother is not found in the breastmilk or in the breastfeeding infant. In the 1st few days of breastfeeding, the cells in the milk compartment are somewhat more permeable than they are 14 days later. In addition, some elements (such as bovine milk proteins) can enter the milk between the cellular junctions that otherwise would form a barrier. This early permeability explains why some infants may exhibit signs of milk sensitivity later in life, after a single exposure to such proteins in the 1st days of life (Lifschitz, Hawkins, Guerra, & Byrd, 1988). The milk compartment also is bidirectional: what gets in can get out. Thus, a drug that peaks in milk after several minutes also may leave the milk compartment and be undetectable sometime later. Pumping and dumping in an effort to more rapidly reduce the amount of drug in the breastmilk is neither necessary nor effective (Dillon et al., 1997). Breastfeeding when the drug is in a trough in the mother’s plasma results in markedly reduced infant exposure to the drug. Is the drug lipid or protein bound? Transcellular diffusion is the means by which drugs, particularly if lipid soluble and of low molecular weight, can enter the milk compartment. However, if a drug is highly protein bound, the amount of drug present in the breastmilk is low because it is trapped in the mother’s plasma compartment. Warfarin is an example of a drug that is highly protein bound. Thus, the amount that is found in the breastmilk is low. If the drug binds to lipids, the potential load in the breastmilk is higher, particularly after the 1st postpartum week, when mature milk production is well-established. Lipid soluble drugs also easily move through the lipid membranes. Mature human milk, in contrast to colostrum, has a high lipid load. Fluoxetine is an example of a drug that is highly lipid bound; thus, levels in the milk tend to be high. The mi1k:plasma (M:P) ratio can indicate whether the drug concentrates in human milk. Many care providers use the M:P ratio as a guide when determining whether to recommend the use of one drug, rather than another drug. Although the M:P ratio is helpful information, it does not provide a complete picture. In some cases, the M:P ratio of a given drug may be high, but if the absolute quantity of the drug is low, the in-
556 JOGNN
fant’s exposure will be low. Morphine is a good example. Although the M:P ratio ranges from 1.1 to 3.6, its absolute quantity in the infant is low. For example, if the total amount of morphine in the breastmilk is 0.5 mg/L, and it concentrates to even three times that level in the infant, the amount available to the infant is 4 0 g/L, an amount so low as to be of little clinical consequence (Hale, 1998). The means by which the infant is exposed to a given drug taken by the mother has many steps: the drug must first get into the mother’s plasma and then into the breastmilk. The infant must ingest the milk, which delivers the drug into the infant’s gastrointestinal tract, where it may be destroyed. If so, the drug will not be found in the infant’s plasma. (One example of such a drug is insulin.) If the drug is destroyed in the infant’s gastrointestinal tract, it is not bioavailable to the infant. The route of drug administration to the mother also is important. In general, a topical application is less likely to expose the infant to the same amount of drug administered orally. Intravenous or intramuscular administration of a drug increases the amount of the drug in human milk compared with oral administration of the drug. If the medication is to be given for an acute condition, the duration and dosing of the medication is likely to be such that the drug can be taken between breastfeedings or at times when the infant is unlikely to be feeding. In addition, the total potential time an infant is exposed to the drug through breastmilk is short. However, if the drug is being given to assist in the management of a chronic condition, the potential exposure may be higher and for a longer period. In addition, if more than one pharmaceutical preparation is prescribed, the interaction of the drugs must be considered. Unfortunately, the interaction effect of multidrug therapy in the breastfeeding infant is unknown in most cases.
Milk Composition and Volume The pH of colostrum (7.45) is somewhat higher than that of transitional milk and mature milk (7.0-7.1) (Bailey & Ito, 1997). As a result, basic drugs, as opposed to weak acids, concentrate more in colostrum than in mature milk. In contrast, lipophilic drugs are present in higher amounts in mature milk because it is higher in fat than is colostrum. Thus, fat-binding drugs given during the early postpartal period are present in breastmilk at lower levels during that period than when given 2 weeks later, when the breastmilk has a higher cream content. Fat content is somewhat lower in foremilk than in hindmilk. Because this concentration of cream in human milk varies by the timing in a given feeding and
Volume 28, Number 5
by the timing of a feeding throughout the day, breastfeeding at different times during the day or evening when the drug is at its peak represents a varying level of potential exposure to the infant. The milk production or milk volume also must be considered. A drug found in the milk compartment may be present in larger amounts if the mother is making a lot of milk and in smaller amounts if the mother is actively weaning and breastfeeding less frequently.
Infant Considerations In addition to the properties of the drug and considerations pertaining to breastmilk, one must consider the following about the infant. How old is the infant? The potential effect in a neonate is higher than in an older infant, when kidney function is more effective. A premature infant is more likely to have immature liver and renal systems that metabolize the drug more slowly than is a healthy 2month-old infant born at term. How often is the infant breastfeeding and how long are these breastfeeding? The infant who is suckling frequently and for long periods (which is typical during the early neonatal phase) is more likely to be exposed to maternal drugs taken frequently than is the infant who breastfeeds infrequently or for short periods, a pattern typical of the toddler or older infant or one who is receiving solid foods in addition to breastmilk. The gastric emptying time of breastfed infants is considerably shorter than that for bottle-fed infants (Cavell, 1981; Widstrom et al., 1987). This potentially reduces the exposure time of a drug that is not destroyed in the infant’s gastrointestinal tract. In addition, gastric acid secretion likely destroys many drugs, thus rendering moot their presence in the breastmilk. Drugs destroyed in the infant’s gastrointestinal tract will not be found in the infant’s plasma. Thus, knowing the amount of drug found in milk is only part of the story and may suggest a higher likelihood of infant exposure than would be the case if the infant’s serum is checked for the presence of the drug in question.
Other Considerations What is the recommended dosage and how often is the mother asked to take the medication? In most cases, dosing can be scheduled around breastfeeding episodes so the infant can be fed when the drug is at a trough, rather than a peak, level. For example, feeding the infant immediately before taking the drug would not expose the infant. Feeding the infant within the first 60 minutes after ingestion of the drug likely would expose the infant when the drug is at its peak in the mother’s system (including her milk compartment). Is the drug a SeptemberlOctober 1999
short- or long-acting preparation? In most cases, drugs are short-acting; that is, they peak soon after ingestion and trough quickly. These drugs pose a lesser risk for the breastfeeding infant than do long-acting drugs that are taken using a dosing pattern designed to increase
I n most cases, dosing can be scheduled around breastfeeding episodes so the infant can be fed when the drug i s at a trough, rather than a peak, level.
drug concentrations. However, if the drug in question is long-acting and protein bound, the amount the infant receives is lower than if the mother is given a short-acting lipid bound drug, particularly if she must take it several times a day. Can the drug in question be given to infants? If so, it is highly unlikely the amount available to the infant through the breastmilk exceeds the appropriate routinely prescribed therapeutic pediatric dose. Such drugs can be considered safe for use by the lactating mother for her breastfeeding infant or young child. Examples include the many antibiotics that are given to lactating women for mastitis and other acute conditions (see Tables 2 and 3).
Drugs Considered Safe During Breastfeeding Antibiotics Mothers continue to report being told to stop breastfeeding when they are prescribed an antibiotic. This advice is inappropriate. In most all cases, very low levels of antibiotics can be found in human milk. The antibiotics in the penicillin/cephalosporin and erythromycin classes are considered safe. If side effects are observed in the infant, they tend to be limited to the time when the drug is being taken and usually include minor gastrointestinal flora changes, resulting in a more odorous stool or in a diarrhea-like stool (Ito, Blajchman, Stephenson, Eliopoulos, & Koren, 1993). Particularly if the mother is being treated for mastitis, the antibiotic drug of choice should be one that has an antistaphylococcal action, such as cephalexin, dicloxacillin, or Augmentin. These drugs reduce the risk of abscess secondary to mastitis. An exception is the fluoroquinolones, which should be used with caution because it has been found to adversely affect the joints in young laboratory animals (Stoukides, 1991). See examples of drugs in Table 4.
JOG”
557
-
TABLE 2
Qirustioirs to Ash i k / i > wik,qiiiiiirig Drirg Tlwrsrpy ii r L Z Hrurrstfc.c.tiirrK Mother 1. What is the status of the infant (for example, is
the neonate preterm, ill, on an apnea monitor, a healthy toddler?): The age and status of the infant is a key element when considering maternal drug therapy. 2. Is the drug necessary to maintain the mother's health? 3. How long will the mother need the drug? At what doses? 4. What is known about the pharmacokinetics of the drug in breastfeeding women? 5. What is known about the drug concentration in human milk? 6. Can the drug have an adverse effect on the mother's milk supply? 7. Is this drug commonly used for treating pediatric patients? If so, the amount available from human milk is likely to be well below therapeutic levels and thus not a concern. 8. Is the drug bioavailable in the breastfeedmg infant, or is it destroyed in the infant's gastrointestinal tract? If bioavailable, what pharmacokinetic information is known about the drug in infants? 9. Have any known toxicities been reported from the drug in nursing infants? 10. Have any long-term effects been reported to occur in nursing infants or children? 11. What alternative drugs are available that a. do not appear in breastmilk? b. are found in breastmilk in lower concentraions? c. produce fewer (potentiallactual)adverse effects in breastfeeding infants?
Derived in part frm:!%graves, R. (1997). Drugs in breast milk: a scientific explanation. J o d of Pediam.c Hcaltb Core, 1 1 ; 230-237.
Vaccines Vaccines have heen clearcd h y the Centers for Disease Control and the American Academy of Pediatrics (AAI') for use i n breastfeeding women with few restrictions. Such clearcd vaccines include rabies, influenza, and other killed virus vLiccines. Breastfeeding is not a reason f o r delaying vaccinations of the infant. Breastfeeding Infants havc been found to develop and maintain highcr titers after vnccination than d o bottle-fcd infants (Hahn-Zoric et al., 1990; lirogh et al., 1989; I"1hst & Spady, 1930).
Antibacterial Agents I t the mother necds treatment, this is not the time t o stop breastfeeding. For example, the most effective dose for Tricliomonas is metronidazole in a 7-8 dose or
558 JOG"
7.50 nig three times a day for 10 days. However, the AAP Committee on Drugs ( 1994) recommends the breastfeeding woman piimp and discard for 24 hours after the last dose of nietronidazole. This recommendation has received criticism because it is difficult t o substantiate the reasoning. N o significant increases in adverse effects have been noted i n infants whose mothers received 400 mg of nictronidazole three times a day.
-
TABLE 3
issues L i HseListfec>dirrgA lotlwr- Slmirltl 13e Eircorriqqeti to Disc-irss W i t h Her- P r - i i i r t r q ~ C r 7 re Pro iiiticu 1. Select a route that will minimize potential drug ex-
2.
3.
4. 5.
6.
7.
8.
9.
posure to the infant. (Topical medications are less likely than drugs given orally to be found at high levels in the mother's milk; intravenously administered drugs likely will be higher than those given orally.) Select a drug that does not easily distribute into breastmilk. How new is the drug? Was the suggested drug one recently brought to the care provider's attention by a sales representative? If so, information about its effects during lactation on the mother or her neonate may be limited. Consider an appropriate alternative that has been available for a longer period and for whose during lactation are known. Consider a short-acting drug, rather than a longacting drug. Can the dosing schedule be adjusted so that feedings occur at troughs, rather than at peak drug concentration times? In many cases, a potential adverse reaction in the infant if exposed to the drug at peak levels can be avoided if breastfeedings occur at penods when the drug level is at a trough. Monitor the infant for signdsymptomsof drug toxicity. Obtain infant serum or urine drug concentrations if there is concern about infant toxicity. (This information cannot be determined from information about how much drug potentially may be in the mother's milk.) If a contraindicated drug must be used, what is the potential adverse effect on the breastfeeding infant and the lactating mother of interrupting breastfeeding for as long as four to five halflife periods before resuming breastfeeding?The mother will need instruction and access to appropriate equipment to express her breastmilk during this period. The neonate can be given previously expressed milk. Delay drug therapy until the infant is weaned if this is anticipated within an appropriate time period.
Detived in part from: Sagraves, R. (1997).Drugs in breast milk: A scientific explanation. ]onma1 of Pediatric Health Cure, 11;230-237.
The mean milk-to-plasma (M/P) ratio was 0.9 (less than 1) in this same study. In addition, the dose available through the milk is approximately 3 to 5 mg/kg, which is far less than the usual recommended pediatric therapeutic dose of 10 to 20 mg/kg for term infants. This is the drug of choice for pediatric Giardia; if the drug can be given to the infant in therapeutic doses, it is highly unlikely exposure through breastmilk will affect the infant (Passmore, McElnay, Rainey, & D'Arcy, 1988).
Analgesics
Drugs That Are Contraindicated During Breastfeeding The continuation of breastfeeding is a highly valued preventive health choice. Although some drugs are contraindicated during the lactation course, in nearly all
T h e continuation of breastfeeding is a
highly valued preventive health choice.
Analgesics include codeine, morphine, ibuprofen, and acetaminophen. These drugs tend to short-acting and likely appear in low levels in milk in most cases (Hale, 1999).
cases, appropriate alternatives are available that pose less risk to the mother or infant.
Serotonin Reuptake Inhibitors
Estrogen-Containing Birth Control Products
Serotonin reuptake inhibitors, such as fluoxetine, sertraline, paroxetine, to control symptoms of depression are increasingly used because postpartum depression can interfere with optimal parenting. Infants cared for by depressed mothers often show signs of depression (Cohen & Tronick, 1983). Although fluoxetine appears to work well during pregnancy, its metabolite has a long half-life, so another drug should be used after the infant's birth. Sertraline is becoming the drug of choice after delivery, in large part because concentrations of the drug in breastmilk are quite low. In many infants, plasma levels of sertraline were below the limit of detection (<2 ng/mL) (Kristensen et al., 1998; Stowe et al., 1997).
Radiocontrast Agents Radiocontrast agents (such as those used for magnetic resonance imaging and computed tomography scanning) are considered safe. The average half-life of these agents is 50 minutes or less. Mothers concerned about their infants being exposed through breastmilk could wait 5 half-lives (about 3 hours) and be assured that virtually none of the agents remain in the milk (Hale, 1998). If the mother becomes uncomfortably full while waiting to breastfeed, she can express her milk during the interim.
All estrogen-containing birth control products suppress milk production and are most likely to do so during the 1st month of lactation, when production is being established. Low-dose combination oral contraceptives can be given after 6 weeks, after milk production is well established (Kennedy, 1999). Encouraging their use during the first 6 weeks of lactation places some infants at risk of inadequate milk transfer and subsequent poor growth. If a minipill is prescribed, it should be a progestin-only preparation. If milk production is adversely affected, this medication can be stopped immediately to recover adequate milk production. Medroxyprogesterone has been observed to adversely affect some women when it is injected earlier than 6 weeks after delivery. In addition, its removal is more problematic than discontinuing an oral contraceptive (Kennedy, 1999, pp. 697-698).
Nonsteroidal Anti-inflammatoy Agents Nonsteroidal anti-inflammatory agents generally are considered safe for breastfeeding women. However, preparations such as naproxen that have long half-lives are considered somewhat less appropriate than other preparations. However, the AAP (1994) considers Advil, Motrin, and Nuprin safe for use by breastfeeding women.
Antianxiety Drugs and Sedatives Methadone Therapy Methadone therapy should be continued in the mother who is receiving it as an alternative to heroin addiction. The infant appears to be unharmed by receiving methadone through breastmilk (Hansen & Moore, 1989). The methadone received through breastmilk theoretically prevents the infant from experiencing painful withdrawal symptoms as a result of withdrawal of the drug after birth (Geraghty, Graham, Logan, & Weiss, 1997). SeptemberlOctober 1999
Long-term use of diazepam and possibly lorazepam can increase the risk of drug concentration in the infant. Products with a shorter half-life, such as alprazolam or midazolam are considered safer alternatives.
Radioactive Compounds Radioactive compounds, such as 1-125 (which has a half-life of 60.1 days) and 1-131 (which has a half-life of 8.2 days) should be avoided. Expressing milk and not using it for the equivalent decay time of 5 half-lives
JOG"
559
Dn4g class Analgesics Codeine Meperidine (Demerol) Oxycodone (Percodan) Propoxyphene (Darvon) Antibiotics Amoxicillin (Amoxil) Dicloxicillin (Dynapen) Cephalexin (Keflex) Ciprofloxacin (Cipro) Metronidazole (Flagyl)
saf;?
Con&a-
Caution
indicated
X X X
X
X X
X X
Ofloxacin (Floxin) Antidepressants and Antianxiety drugs Alpramlam (Xanax) Diazepam (Valium)
X
Fluoxetine (Prozac) Lorazepam (Ativan) Midazolam (Versed)
X X
X Paroxetine (Paxil) X Sertraline ( a l o f t ) Antifungals X Fluconazole (Diflucan) X Miconazole (Monistat) X Nystatin (Mycostatin) Antihistamines Bromphenaramine (Dimetane) Diphenhydramine (Benadryl) Hexofenadine (Allegra) X Loratidine (Claritin) X Terfenadine (Seldane) X Antihypertensives Atenolol (Tenormin) X Nifedipine (Adalat)
Sumatriptan (Imitrex) Verapamil (Isoptin)
Use with
X X
Additional Notes Use short-term in single doses Neurobehavioral depression in newborns Use short-term in single doses Use short-term in single doses Preferred for treatment of otitis media and Lyme disease in mothers and infants Preferred if mother has mastitis Minimal amounts found in milk Modest dose is preferred for no longer than 1 week Single dose preferred to reduce time of interrupted breastfeeding Modest dose is preferred for no longer than 1 week
Irritability after withdrawal has been noted in some infants The metabolite is longer lasting than the drug; infant should be monitored if drug is used long-term Colic, restlessness in infant Very low levels in milk Minimal amounts in milk, particularly after 4 h after administration Maximum dose to infant 1/3 that of mother Very low concentrations in infant Approved for use in neonates Poorly absorbed in topical form Not found in milk May cause drowsiness May cause drowsiness Nonsedating; no adverse effects on infants reported Nonsedating; no adverse effects on infants reported Undetectable in milk Avoid in a neonate when high doses are required Very low levels in milk; preferred for treatment of nipple vasospasm Milk concentration levels are low Not detected in infant serum (Continues)
560 JOGNN
Volume 28, Number 5
TABLE 4
-
Drug Classes a i d Kecoiiiii2eiinntioiis Pei+tniiiiiig to TIwir Use by n Lnctntiiig Mother (Coritinirecl)
Drug class
Use with Safe
Caution
Contraindicated
Additiml Notes
Bronchodilators X Cromolyn (Intal) Epinephrine (Primatene) x Theophylline (Aminophylline)x Nonsteroidal Antiinflammatories (NSAIJIs) Acetaminophen (Tylenol) X X Ibuprofen (Advil, Motrin) Naproxen (Aleve) X Steroids Prednisone (Meticorten) X Vaccines X Influenza Measles X MMR (measlesX mumps-rubella) Oral polio X Rabies (Imovax) Varicella (chicken pox) Radiocontrast agents Ga-67 1-123 1-125 1-131
Tc-99m Drugs of abuse Cocaine Heroin Marijuana Nicotine Phencyclidine (PCP)
Destroyed in infant gut Destroyed in infant gut Less than 1% in infant
Very low levels in milk Is used for infants Very low levels in milk Minimal amwnts in milk
No problems reported No problems reported Not to be given to a pregnant woman Do not give to mother if her infant is younger than 6 weeks Considered unlikely to produce untoward effects Avoid if infandyoung child is immunocompromised
X X
Half-life is 3.26 days Half-life is 13.2 h Half-life is 12 days Half-life up to 14 days Half-life 6.02 h
X X X X X
Intoxication in infant Tremors, poor feeding, restlessness, vomiting None reported Vomiting, diarrhea, decreased milk production Maternal hallucinations
X X X
X X
Infomution compiled fiom: AAP, 1994; Hale, 1999; Riordan & Auerbach, 1997.
is preferred to avoid exposing the infant to the compounds in question. In some cases, the period of interrupted breastfeeding may result in weaning the infant. Alternatives, such as technetium (with a half-life of 6.02 hours) and 1-123 (with a half-life of 13.2 hours) pose a lesser risk to the breastfeeding course because the interruption of breastfeeding is substantially shorter (Hale, 1998, p. 714).
Drugs of Abuse These drugs adversely affect the maternal ability to nurture in addition to their potential effects on the infant
SeptembedOctober 1999
exposed through breastmilk. Women whose toxicology screening tests are positive for heroin, cocaine, or similar drugs should be counseled regarding the adverse effects of these drugs on their infants and themselves.
Where to Seek Appropriate Information The Physicians Desk Reference is a fine reference if one is seeking information about the properties of a given pharmaceutical preparation. However, it is considered a poor source for information about the potential effects on the lactating mother or her breastfeeding infant. The
lOGNN 561
information contained within its pages is designed to prevent a lawsuit against the pharmaceutical firm. The standard recommendation for virtually all drugs includes proscriptions against their use by pregnant or lactating women. This caution is not necessarily based on the known effects of the drug on the woman or fetushnfant during pregnancy or lactation. Other sources are more helpful if one is seeking specific information and recommendations based on clinical studies and observations. For example, the American Academy of Pediatrics (AAP, 1994) document is easily obtained. Briggs, Freeman, and Yaffe (1998) and the related quarterly updates are an excellent resource on newer drugs. Hale’s Medications und Mothers’ Milk (1999) is considered an essential resource for identifying key properties of given drugs to make case-by-case decisions about drug therapy. This book is updated annually. No single document should be considered complete when contemplating drug therapy. It is always wise to check more than one source before providing information about a drug. In this manner, the information provided is more likely to be accurate.
Summary Few drugs represent a problem of such magnitude that the infant will experience sequelae as a result of exposure through breastfeeding. Health providers need to confirm for their patients that preservation of the breastfeeding experience is important, primary preventive health care. Within that frame of reference, any necessary drug therapy selected ideally would not interfere with continued breastfeeding. The plethora of drug preparations available nearly always offers numerous alternatives from which to choose. Selection of drugs for which the potential and observed effects on the breastfeeding infant are known is nearly always a more appropriate choice than a sample preparation that has appeared on the market and about which little clinical information is available. In situations in which safe, alternative drug therapy is unavailable, the mother has the right to choose whether to accept use of a contraindicated drug, one for which adverse effects on her infant are unknown, or to temporarily or permanently discontinue breastfeeding.
REFERENCES American Academy of Pediatrics, Committee on Drugs. (1994). The transfer of drugs and other chemicals into human milk. Pediatrics, 93, 137-150. Bailey, B., & Ito, S. (1997). Breast-feeding and maternal drug use. Pediatric Clinics of North America, 44, 41-54. Briggs, G. G., Freeman, R. K., & Yaffe, S. J. (Eds.). (1998). Drugs in pregnancy and lactation (5th ed.). Baltimore: Williams & Wilkins.
562 JOG”
Carrie, L. E. S., 0 Sullivan, G. M., & Seegobin, R. (1981). Epidural fentanyl in labour. Anaesthesia, 36, 965-969. Cavell, B. (1981).Gastric emptying in infants fed human milk or infant formula. Acta Paediatrica Scandinavica, 70, 639-64 1. Cohen, J. F., & Tronick, E. Z. (1983). Three-month-old infants’ reaction to simulated maternal depression. Child Development, 54, 185-193. Crowell, M. K., Hill, P. D., & Humenick, S. S. (1994). Relationship between obstetric analgesia and time of effective breastfeeding. Journal of Nurse-Midwifery, 39, 150-156. Dillon, A. E., Wagner, C. L., Wiest, D., & Newman, R. B. (1997). Drug therapy in the nursing mother. Obstetric and Gynecological Clinics of North America, 24, 675-696. Geraghty, B., Graham, E. A., Logan, B., & Weiss, E. L. (1997). Methadone levels in breast milk. Journal of Human Lactation, 13,227-230. Hahn-Zoric, M., Fulcoris, F., Minoli, I., Moro, G., Carlsson, B., Bottiger, M., Raiha, N., & Hanson, L. A. (1990). Antibody responses to parenteral and oral vaccines are impaired by conventional and low protein formulas as compared to breast-feeding. Acta Paediatrica Scandinavica, 79, 1137-1142. Hale, T. (1999). Medications and mothers’ milk (8th ed.). Amarillo, TX: Pharmasoft Medical Publishing. Hansen, B., & Moore, L. (1989).Recreational drug use by the breastfeeding woman. Part 1: Illicit drugs. Journal of Human Lactation, 5, 178-180. Ito, S., Blajchman, A., Stephenson, M., Eliopoulos, C., & Koren, G. (1993). Prospective follow-up of adverse reactions in breast-fed infants exposed to maternal medication. American Journal of Obstetrics and Gynecology, 168, 1393-1399. Kennedy, K. I. (1999). Fertility, sexuality, and contraception during lactation. In Riordan, J., & Auerbach, K. G. (Eds.), Breastfeeding and human milk (2nd ed.) (pp. 675-705). Boston: Jones and Bartlett Publishers, Inc. Kristensen, J. H., Ilett, K. F., Dusci, L. J., Hackett, L. P., Yapp, P., & Wojnar-Horton, R. E. (1998). Distribution and excretion of sertraline and N-desmethylsertraline in human milk. British Journal of Clinical Pharmacology, 45,453-457. Krogh, V., Duffy, L. C., Wong, D., Rosenband, M., Riddlesberger, K. R., & Ogra, P. L. (1989).Postpartum immunization with rubella virus vaccine and antibody response in breast-feeding infants. Journal of Laboratory and Clinical Medicine, 113, 695-699. Lifschitz, C. H., Hawkins, H. K., Guerra, C., & Byrd, N. (1988). Anaphylactic shock due to cow’s milk protein hypersensitivity in a breast-fed infant. Journal of Pediatric Gastroenterology and Nutrition, 7, 141-144. Loftus, J. R., Hill, H., & Cohen, S. E. (1995).Placental transfer and neonatal effects of epidural sufentanil and fentanyl administered with bupivacaine during labor. Anesthesiology, 83, 300-308. Matthews, M. K. (1989). The relationship between maternal labour analgesia and delay in the initiation of breastfeeding in healthy neonates in the early neonatal period. Midwifery, 5, 3-10.
Volume 28, Number 5
Murray, A. D., Dolby, R. M., Nation, R. C., & Thomas, D. B. (1981). Effects of epidural anesthesia on newborns and their mothers. Child Development, 52, 71-82. Pabst, H. F., & Spady, D. W. (1990). Effect of breast-feeding on antibody response to conjugate vaccine. Lancet, 336, 269-270. Passmore, C. M., McElnay, J., Rainey, E. A., & D’Arcy, P. F. (1988).Metronidazole excretion in human milk and its effect on the suckling neonate. British Journal of Clinical Pharmacology, 26, 45-51. Riordan, J., & Auerbach, K. G. (1997). Pocket guide to breastfeeding and human lactation. Boston: Jones and Bartlett Publishers, Inc. Sagraves, R. (1997). Drugs in breast milk: A scientific explanation. Journal of Pediatric Health Care, 1 1 , 230-237. Sepkoski, C. M., Lester, B. M., Ostheimer, G. W., & Brazelton, T. B. (1992). The effects of maternal epidural anesthesia on neonatal behavior during the first month. Developmental Medicine and Child Neurology, 34, 1072-1 080. Spigset, 0. (1994). Anaesthetic agents and excretion in breast milk. Acta Anaesthesiologica Scandinavica, 38, 94-103. Stoukides, C. A. (1991). Quinolone antibiotics and breastfeeding. Journal of Human Lactation, 7, 143-144. Stowe, Z . N., Owens, M. J., Landry, J. C., Kilts, C. D., Ely, T., Llewellyn, A., & Nemeroff, C. B. (1997).Sertraline and desmethylsertraline in human breast milk and nursing infants. American /ournal of Psychiatry, 154, 1255-1260.
SeptemberlOctober 1999
Thorp, J. A., & Breedlove, G. (1996). Epidural analgesia in labor: An evaluation of risks and benefits. Birth, 23, 63-83. Widstrom, A-M, Ransjo-Arvidson, A. B., Christensson, K., Matthiesen, A-S., Winberg, J., & Uvnas-Moberg, K. (1987). Gastric suction in healthy newborn infants. Acta Paediatrica Scandinavica, 76, 566-572. Wittels, B., Glosten, B., Foure, E. A. M., Moawad, A. H., Ismail, M., Hibbard, J., Senal, J. A., Cox, S. M., Blackman, s. C., Karl, L., & Thistad, R. A. (1997). Postcesarean analgesia with both epidural morphine and intravenous patient-controlled analgesia: Neurobehavioral outcomes among nursing neonates. Anesthesia and Analgesia, 85, 600-606. Youngstrom, P. C., Baker, S. W., & Miller, J. L. (1996). Epidurals redefined in analgesia and anesthesia: A distinction with a difference. J O G N N , 25, 350-354.
Kathleen G. Auerbach maintains a private lactation consulting practice at The Parent Center in Ferndale, WA, and is a frequent presenter at conferences and workshops. She is an Adjunct Professor in the School of Nursing at the University of British Columbia in Vancouvev, British Columbia, Canada. Address for correspondence: Kathleen G. Auerbach, PhD, IBCLC, The Parent Centev, 6145 North Beulah Avenue, Ferndale, WA 98248.
JOGNN 563
CLINICALISSUES
Breastfeeding and Maternal Medication Use Kathleen G. Auerbach, PhD, IBCLC
=
Drug therapy during lactation requires recognition of several elements, including drug properties, the status of the infant, the mother’s milk production, and what is known about particular drugs. It is important to consider the various properties of a drug when evaluating its possible effects in the breastfeeding infant. In addition, the volume of milk the infant receives and its composition can influence exposure levels. Other factors of importance include the infant’s age, frequency of feedings, recommended drug dosage, and whether the drug is short- or long-acting. Suggestions are offered for appropriate drug therapy when the mother is breastfeeding, including the safety of drugs commonly administered during lactation and questions to ask when a mother seeks assistance about suggested medication use. JOGNN, 28, 554-563;
1999. Accepted: May 1999
Too often, the breastfeeding mother is told she must not combine medication use with breastfeeding. This proscription often is followed by a recommendation to wean her infant from the breast. If she follows this advice, her infant has an increased risk of acute and chronic illnesses because bottle feeding provides no protection against viral or bacterial pathogenic organisms. This situation need not occur if the health provider acknowledges the value of breastfeeding and its continuation, asks relevant questions, and checks appropriate references that provide current information. Three principles govern discussions of drug therapy during lactation: (a) most drugs adminis554 JOGNN
tered to the lactating woman pass into her breastmilk; (b) most medications can be found in very small amounts in breastmilk; and (c)few drugs are contraindicated during lactation. Failure to consider each of these facts may contribute to inappropriate recommendations, which may have adverse effects on the health of the breastfeeding infant, the lactating woman, and the breastfeeding course.
Two Common Myths About Drugs and Breastfeeding Misconceptions about medications taken by pregnant and lactating women have contributed to confusion and inappropriate recommendations to women during the perinatal period. One such myth is that the drugs a mother receives during labor have little or no effect on the neonate. In most cases, this is untrue. When the woman is given a labor analgesic medication, the drug in question eventually can be found in her plasma compartment. Because her placenta is still nourishing the fetus, these same drugs are passed to the fetus. These drugs go to various fetal organs, including the brain (if the drug in question is lipophilic) and the liver. The clinical effects observed depend on the timing of the dose to the mother and on the half-life of the drug in specific organ compartments. For example, fentanyl has been reported to cause respiratory depression in the neonate (Carrie, O’Sullivan, & Seegobin, 1981). In some cases, more drug (such as fentanyl) is found in the infant, even if the dose to the woman was delivered shortly before the infant’s birth (Loftus, Hill, & Cohen, 1995).
Volume 28, Number 5
In other cases (such as meperidine), more drug is found in the fetus when the drug was given to the woman 90 minutes to 3 hours in advance of the infant’s birth (Spigset, 1994). The fetal liver slowly eliminates the drug in question. Observant care providers note that the short-lived effect of the analgesic on the woman appears to be manifested considerably longer in the infant. Knowing the half-life of a drug in the woman does not accurately predict the half-life of the same drug in the fetus or neonate (see Table 1). Because information on drugs and their effect on pregnant women, their fetuses, and their neonates sometimes is confusing, the health provider must assist the woman to balance her desire not to compromise her infant’s status while seeking pain relief should she conclude she will function better with such assistance. In most cases, the shorter the period between delivery of an analgesic or anesthetic and the infant’s birth, the less effect the medication has on the neonate. Many lactation consultants and other health providers have observed that the infants of women who have received a variety of labor medications seem to be unaccountably sleepy or difficult to rouse or have trouble coordinating complex motor activities, such as suckling. These observations reflect the degree to which medications given to the laboring woman have been transmitted to the fetus; sometimes the effects of such drugs are noticeable for many hours or days after birth. These effects include diminished alertness, poorer muscle tone, and poor or ineffective feeding behaviors (Crowell, Hill, & Humenick, 1994; Loftus et al., 1995; Matthews, 1989; Murray, Dolby, Nation, & Thomas, 1981; Sepkoski, Lester, Ostheimer, & Brazelton, 1992; Thorp & Breedlove, 1996; Youngstrom, Baker, & Miller, 1996). Even in cases in which the mother controls her own medication after delivery, such as when a patient-controlled analgesic pump is used for pain relief after cesarean section, similar outcomes have been observed, particularly with meperidine (Wittels et al., 1997).
A second myth says that an infant is exposed to as much medication through breastfeeding as a fetus would be through the placenta. Most health providers caution women against using medications unnecessarily or self-medicating during pregnancy on the grounds that the teratogenicity of the particular compound may contribute to fetal anomalies or other adverse outcomes. Such advice is appropriate, for the placenta is a far more effective route of transmission of drugs and their metabolites than is the breast and its productbreastmilk. However, drugs that should be avoided during pregnancy may pose little or no risk to the breastfeeding neonate or older infant. Operating under the same cautions appropriate when a woman is pregnant unnecessarily restricts the options available should a mother need drug therapy after the infant’s birth. In addition, the inappropriate cross-referencing of drug information in pregnancy to lactation may result in unnecessarily recommending interruption or cessation of breastfeeding.
D r u g s that should be avoided during pregnancy may pose little or no risk to the breastfeeding neonate or older infant.
Knowing the medications most likely to result in a delay in appropriate infant behaviors is essential to providing information about intrapartal analgesia to the pregnant woman and her family. Ideally, the information should be provided antenatally so the parturient couple can make a fully informed decision (Dillon et al., 1997). After the delivery, health care providers in the maternal-neonatal unit should observe infant behavior, provide additional support if the infant is experiencing
TABLE 1
-
Half-life of Selected Opioid Aiialgesics Often Given lliiriiig Labor
Agent
Morphine Meperidine (Demerol) Normeperidine Fentanyl Sufentanil Alfentanil
Adult Half-life (hrs)
Pediattic Half-life (hrs)
1.5-2 3.2 14-21 24 2-3 1-2
13.9 6-32 20-63 3-13 13-19
5-4
From: Hale, T. (1998, June). Anesthetic medications and breastfeeding mothers. Paper presented at Breastfeeding Support Consultants 2nd Annual North American Conference, Scottsdale, AZ.
SeptembedOctober 1999
JOG”
555
adverse effects of the maternally administered medication, and offer an explanation and reassurance to the mother that these effects are transitory.
Properties of the Drug Knowing certain characteristics about drugs and their diffusion in the body can be helpful in identifying the relative risk of giving a breastfeeding mother a drug. For example, all drugs enter breastmilk unless their molecular weight is so high (>800) that they cannot penetrate the cellular barrier. An example is heparin, which if given to the mother is not found in the breastmilk or in the breastfeeding infant. In the 1st few days of breastfeeding, the cells in the milk compartment are somewhat more permeable than they are 14 days later. In addition, some elements (such as bovine milk proteins) can enter the milk between the cellular junctions that otherwise would form a barrier. This early permeability explains why some infants may exhibit signs of milk sensitivity later in life, after a single exposure to such proteins in the 1st days of life (Lifschitz, Hawkins, Guerra, & Byrd, 1988). The milk compartment also is bidirectional: what gets in can get out. Thus, a drug that peaks in milk after several minutes also may leave the milk compartment and be undetectable sometime later. Pumping and dumping in an effort to more rapidly reduce the amount of drug in the breastmilk is neither necessary nor effective (Dillon et al., 1997). Breastfeeding when the drug is in a trough in the mother’s plasma results in markedly reduced infant exposure to the drug. Is the drug lipid or protein bound? Transcellular diffusion is the means by which drugs, particularly if lipid soluble and of low molecular weight, can enter the milk compartment. However, if a drug is highly protein bound, the amount of drug present in the breastmilk is low because it is trapped in the mother’s plasma compartment. Warfarin is an example of a drug that is highly protein bound. Thus, the amount that is found in the breastmilk is low. If the drug binds to lipids, the potential load in the breastmilk is higher, particularly after the 1st postpartum week, when mature milk production is well-established. Lipid soluble drugs also easily move through the lipid membranes. Mature human milk, in contrast to colostrum, has a high lipid load. Fluoxetine is an example of a drug that is highly lipid bound; thus, levels in the milk tend to be high. The mi1k:plasma (M:P) ratio can indicate whether the drug concentrates in human milk. Many care providers use the M:P ratio as a guide when determining whether to recommend the use of one drug, rather than another drug. Although the M:P ratio is helpful information, it does not provide a complete picture. In some cases, the M:P ratio of a given drug may be high, but if the absolute quantity of the drug is low, the in-
556 JOGNN
fant’s exposure will be low. Morphine is a good example. Although the M:P ratio ranges from 1.1 to 3.6, its absolute quantity in the infant is low. For example, if the total amount of morphine in the breastmilk is 0.5 mg/L, and it concentrates to even three times that level in the infant, the amount available to the infant is 4 0 g/L, an amount so low as to be of little clinical consequence (Hale, 1998). The means by which the infant is exposed to a given drug taken by the mother has many steps: the drug must first get into the mother’s plasma and then into the breastmilk. The infant must ingest the milk, which delivers the drug into the infant’s gastrointestinal tract, where it may be destroyed. If so, the drug will not be found in the infant’s plasma. (One example of such a drug is insulin.) If the drug is destroyed in the infant’s gastrointestinal tract, it is not bioavailable to the infant. The route of drug administration to the mother also is important. In general, a topical application is less likely to expose the infant to the same amount of drug administered orally. Intravenous or intramuscular administration of a drug increases the amount of the drug in human milk compared with oral administration of the drug. If the medication is to be given for an acute condition, the duration and dosing of the medication is likely to be such that the drug can be taken between breastfeedings or at times when the infant is unlikely to be feeding. In addition, the total potential time an infant is exposed to the drug through breastmilk is short. However, if the drug is being given to assist in the management of a chronic condition, the potential exposure may be higher and for a longer period. In addition, if more than one pharmaceutical preparation is prescribed, the interaction of the drugs must be considered. Unfortunately, the interaction effect of multidrug therapy in the breastfeeding infant is unknown in most cases.
Milk Composition and Volume The pH of colostrum (7.45) is somewhat higher than that of transitional milk and mature milk (7.0-7.1) (Bailey & Ito, 1997). As a result, basic drugs, as opposed to weak acids, concentrate more in colostrum than in mature milk. In contrast, lipophilic drugs are present in higher amounts in mature milk because it is higher in fat than is colostrum. Thus, fat-binding drugs given during the early postpartal period are present in breastmilk at lower levels during that period than when given 2 weeks later, when the breastmilk has a higher cream content. Fat content is somewhat lower in foremilk than in hindmilk. Because this concentration of cream in human milk varies by the timing in a given feeding and
Volume 28, Number 5
by the timing of a feeding throughout the day, breastfeeding at different times during the day or evening when the drug is at its peak represents a varying level of potential exposure to the infant. The milk production or milk volume also must be considered. A drug found in the milk compartment may be present in larger amounts if the mother is making a lot of milk and in smaller amounts if the mother is actively weaning and breastfeeding less frequently.
Infant Considerations In addition to the properties of the drug and considerations pertaining to breastmilk, one must consider the following about the infant. How old is the infant? The potential effect in a neonate is higher than in an older infant, when kidney function is more effective. A premature infant is more likely to have immature liver and renal systems that metabolize the drug more slowly than is a healthy 2month-old infant born at term. How often is the infant breastfeeding and how long are these breastfeeding? The infant who is suckling frequently and for long periods (which is typical during the early neonatal phase) is more likely to be exposed to maternal drugs taken frequently than is the infant who breastfeeds infrequently or for short periods, a pattern typical of the toddler or older infant or one who is receiving solid foods in addition to breastmilk. The gastric emptying time of breastfed infants is considerably shorter than that for bottle-fed infants (Cavell, 1981; Widstrom et al., 1987). This potentially reduces the exposure time of a drug that is not destroyed in the infant’s gastrointestinal tract. In addition, gastric acid secretion likely destroys many drugs, thus rendering moot their presence in the breastmilk. Drugs destroyed in the infant’s gastrointestinal tract will not be found in the infant’s plasma. Thus, knowing the amount of drug found in milk is only part of the story and may suggest a higher likelihood of infant exposure than would be the case if the infant’s serum is checked for the presence of the drug in question.
Other Considerations What is the recommended dosage and how often is the mother asked to take the medication? In most cases, dosing can be scheduled around breastfeeding episodes so the infant can be fed when the drug is at a trough, rather than a peak, level. For example, feeding the infant immediately before taking the drug would not expose the infant. Feeding the infant within the first 60 minutes after ingestion of the drug likely would expose the infant when the drug is at its peak in the mother’s system (including her milk compartment). Is the drug a SeptemberlOctober 1999
short- or long-acting preparation? In most cases, drugs are short-acting; that is, they peak soon after ingestion and trough quickly. These drugs pose a lesser risk for the breastfeeding infant than do long-acting drugs that are taken using a dosing pattern designed to increase
I n most cases, dosing can be scheduled around breastfeeding episodes so the infant can be fed when the drug i s at a trough, rather than a peak, level.
drug concentrations. However, if the drug in question is long-acting and protein bound, the amount the infant receives is lower than if the mother is given a short-acting lipid bound drug, particularly if she must take it several times a day. Can the drug in question be given to infants? If so, it is highly unlikely the amount available to the infant through the breastmilk exceeds the appropriate routinely prescribed therapeutic pediatric dose. Such drugs can be considered safe for use by the lactating mother for her breastfeeding infant or young child. Examples include the many antibiotics that are given to lactating women for mastitis and other acute conditions (see Tables 2 and 3).
Drugs Considered Safe During Breastfeeding Antibiotics Mothers continue to report being told to stop breastfeeding when they are prescribed an antibiotic. This advice is inappropriate. In most all cases, very low levels of antibiotics can be found in human milk. The antibiotics in the penicillin/cephalosporin and erythromycin classes are considered safe. If side effects are observed in the infant, they tend to be limited to the time when the drug is being taken and usually include minor gastrointestinal flora changes, resulting in a more odorous stool or in a diarrhea-like stool (Ito, Blajchman, Stephenson, Eliopoulos, & Koren, 1993). Particularly if the mother is being treated for mastitis, the antibiotic drug of choice should be one that has an antistaphylococcal action, such as cephalexin, dicloxacillin, or Augmentin. These drugs reduce the risk of abscess secondary to mastitis. An exception is the fluoroquinolones, which should be used with caution because it has been found to adversely affect the joints in young laboratory animals (Stoukides, 1991). See examples of drugs in Table 4.
JOG”
557
-
TABLE 2
Qirustioirs to Ash i k / i > wik,qiiiiiirig Drirg Tlwrsrpy ii r L Z Hrurrstfc.c.tiirrK Mother 1. What is the status of the infant (for example, is
the neonate preterm, ill, on an apnea monitor, a healthy toddler?): The age and status of the infant is a key element when considering maternal drug therapy. 2. Is the drug necessary to maintain the mother's health? 3. How long will the mother need the drug? At what doses? 4. What is known about the pharmacokinetics of the drug in breastfeeding women? 5. What is known about the drug concentration in human milk? 6. Can the drug have an adverse effect on the mother's milk supply? 7. Is this drug commonly used for treating pediatric patients? If so, the amount available from human milk is likely to be well below therapeutic levels and thus not a concern. 8. Is the drug bioavailable in the breastfeedmg infant, or is it destroyed in the infant's gastrointestinal tract? If bioavailable, what pharmacokinetic information is known about the drug in infants? 9. Have any known toxicities been reported from the drug in nursing infants? 10. Have any long-term effects been reported to occur in nursing infants or children? 11. What alternative drugs are available that a. do not appear in breastmilk? b. are found in breastmilk in lower concentraions? c. produce fewer (potentiallactual)adverse effects in breastfeeding infants?
Derived in part frm:!%graves, R. (1997). Drugs in breast milk: a scientific explanation. J o d of Pediam.c Hcaltb Core, 1 1 ; 230-237.
Vaccines Vaccines have heen clearcd h y the Centers for Disease Control and the American Academy of Pediatrics (AAI') for use i n breastfeeding women with few restrictions. Such clearcd vaccines include rabies, influenza, and other killed virus vLiccines. Breastfeeding is not a reason f o r delaying vaccinations of the infant. Breastfeeding Infants havc been found to develop and maintain highcr titers after vnccination than d o bottle-fcd infants (Hahn-Zoric et al., 1990; lirogh et al., 1989; I"1hst & Spady, 1930).
Antibacterial Agents I t the mother necds treatment, this is not the time t o stop breastfeeding. For example, the most effective dose for Tricliomonas is metronidazole in a 7-8 dose or
558 JOG"
7.50 nig three times a day for 10 days. However, the AAP Committee on Drugs ( 1994) recommends the breastfeeding woman piimp and discard for 24 hours after the last dose of nietronidazole. This recommendation has received criticism because it is difficult t o substantiate the reasoning. N o significant increases in adverse effects have been noted i n infants whose mothers received 400 mg of nictronidazole three times a day.
-
TABLE 3
issues L i HseListfec>dirrgA lotlwr- Slmirltl 13e Eircorriqqeti to Disc-irss W i t h Her- P r - i i i r t r q ~ C r 7 re Pro iiiticu 1. Select a route that will minimize potential drug ex-
2.
3.
4. 5.
6.
7.
8.
9.
posure to the infant. (Topical medications are less likely than drugs given orally to be found at high levels in the mother's milk; intravenously administered drugs likely will be higher than those given orally.) Select a drug that does not easily distribute into breastmilk. How new is the drug? Was the suggested drug one recently brought to the care provider's attention by a sales representative? If so, information about its effects during lactation on the mother or her neonate may be limited. Consider an appropriate alternative that has been available for a longer period and for whose during lactation are known. Consider a short-acting drug, rather than a longacting drug. Can the dosing schedule be adjusted so that feedings occur at troughs, rather than at peak drug concentration times? In many cases, a potential adverse reaction in the infant if exposed to the drug at peak levels can be avoided if breastfeedings occur at penods when the drug level is at a trough. Monitor the infant for signdsymptomsof drug toxicity. Obtain infant serum or urine drug concentrations if there is concern about infant toxicity. (This information cannot be determined from information about how much drug potentially may be in the mother's milk.) If a contraindicated drug must be used, what is the potential adverse effect on the breastfeeding infant and the lactating mother of interrupting breastfeeding for as long as four to five halflife periods before resuming breastfeeding?The mother will need instruction and access to appropriate equipment to express her breastmilk during this period. The neonate can be given previously expressed milk. Delay drug therapy until the infant is weaned if this is anticipated within an appropriate time period.
Detived in part from: Sagraves, R. (1997).Drugs in breast milk: A scientific explanation. ]onma1 of Pediatric Health Cure, 11;230-237.
The mean milk-to-plasma (M/P) ratio was 0.9 (less than 1) in this same study. In addition, the dose available through the milk is approximately 3 to 5 mg/kg, which is far less than the usual recommended pediatric therapeutic dose of 10 to 20 mg/kg for term infants. This is the drug of choice for pediatric Giardia; if the drug can be given to the infant in therapeutic doses, it is highly unlikely exposure through breastmilk will affect the infant (Passmore, McElnay, Rainey, & D'Arcy, 1988).
Analgesics
Drugs That Are Contraindicated During Breastfeeding The continuation of breastfeeding is a highly valued preventive health choice. Although some drugs are contraindicated during the lactation course, in nearly all
T h e continuation of breastfeeding is a
highly valued preventive health choice.
Analgesics include codeine, morphine, ibuprofen, and acetaminophen. These drugs tend to short-acting and likely appear in low levels in milk in most cases (Hale, 1999).
cases, appropriate alternatives are available that pose less risk to the mother or infant.
Serotonin Reuptake Inhibitors
Estrogen-Containing Birth Control Products
Serotonin reuptake inhibitors, such as fluoxetine, sertraline, paroxetine, to control symptoms of depression are increasingly used because postpartum depression can interfere with optimal parenting. Infants cared for by depressed mothers often show signs of depression (Cohen & Tronick, 1983). Although fluoxetine appears to work well during pregnancy, its metabolite has a long half-life, so another drug should be used after the infant's birth. Sertraline is becoming the drug of choice after delivery, in large part because concentrations of the drug in breastmilk are quite low. In many infants, plasma levels of sertraline were below the limit of detection (<2 ng/mL) (Kristensen et al., 1998; Stowe et al., 1997).
Radiocontrast Agents Radiocontrast agents (such as those used for magnetic resonance imaging and computed tomography scanning) are considered safe. The average half-life of these agents is 50 minutes or less. Mothers concerned about their infants being exposed through breastmilk could wait 5 half-lives (about 3 hours) and be assured that virtually none of the agents remain in the milk (Hale, 1998). If the mother becomes uncomfortably full while waiting to breastfeed, she can express her milk during the interim.
All estrogen-containing birth control products suppress milk production and are most likely to do so during the 1st month of lactation, when production is being established. Low-dose combination oral contraceptives can be given after 6 weeks, after milk production is well established (Kennedy, 1999). Encouraging their use during the first 6 weeks of lactation places some infants at risk of inadequate milk transfer and subsequent poor growth. If a minipill is prescribed, it should be a progestin-only preparation. If milk production is adversely affected, this medication can be stopped immediately to recover adequate milk production. Medroxyprogesterone has been observed to adversely affect some women when it is injected earlier than 6 weeks after delivery. In addition, its removal is more problematic than discontinuing an oral contraceptive (Kennedy, 1999, pp. 697-698).
Nonsteroidal Anti-inflammatoy Agents Nonsteroidal anti-inflammatory agents generally are considered safe for breastfeeding women. However, preparations such as naproxen that have long half-lives are considered somewhat less appropriate than other preparations. However, the AAP (1994) considers Advil, Motrin, and Nuprin safe for use by breastfeeding women.
Antianxiety Drugs and Sedatives Methadone Therapy Methadone therapy should be continued in the mother who is receiving it as an alternative to heroin addiction. The infant appears to be unharmed by receiving methadone through breastmilk (Hansen & Moore, 1989). The methadone received through breastmilk theoretically prevents the infant from experiencing painful withdrawal symptoms as a result of withdrawal of the drug after birth (Geraghty, Graham, Logan, & Weiss, 1997). SeptemberlOctober 1999
Long-term use of diazepam and possibly lorazepam can increase the risk of drug concentration in the infant. Products with a shorter half-life, such as alprazolam or midazolam are considered safer alternatives.
Radioactive Compounds Radioactive compounds, such as 1-125 (which has a half-life of 60.1 days) and 1-131 (which has a half-life of 8.2 days) should be avoided. Expressing milk and not using it for the equivalent decay time of 5 half-lives
JOG"
559
Dn4g class Analgesics Codeine Meperidine (Demerol) Oxycodone (Percodan) Propoxyphene (Darvon) Antibiotics Amoxicillin (Amoxil) Dicloxicillin (Dynapen) Cephalexin (Keflex) Ciprofloxacin (Cipro) Metronidazole (Flagyl)
saf;?
Con&a-
Caution
indicated
X X X
X
X X
X X
Ofloxacin (Floxin) Antidepressants and Antianxiety drugs Alpramlam (Xanax) Diazepam (Valium)
X
Fluoxetine (Prozac) Lorazepam (Ativan) Midazolam (Versed)
X X
X Paroxetine (Paxil) X Sertraline ( a l o f t ) Antifungals X Fluconazole (Diflucan) X Miconazole (Monistat) X Nystatin (Mycostatin) Antihistamines Bromphenaramine (Dimetane) Diphenhydramine (Benadryl) Hexofenadine (Allegra) X Loratidine (Claritin) X Terfenadine (Seldane) X Antihypertensives Atenolol (Tenormin) X Nifedipine (Adalat)
Sumatriptan (Imitrex) Verapamil (Isoptin)
Use with
X X
Additional Notes Use short-term in single doses Neurobehavioral depression in newborns Use short-term in single doses Use short-term in single doses Preferred for treatment of otitis media and Lyme disease in mothers and infants Preferred if mother has mastitis Minimal amounts found in milk Modest dose is preferred for no longer than 1 week Single dose preferred to reduce time of interrupted breastfeeding Modest dose is preferred for no longer than 1 week
Irritability after withdrawal has been noted in some infants The metabolite is longer lasting than the drug; infant should be monitored if drug is used long-term Colic, restlessness in infant Very low levels in milk Minimal amounts in milk, particularly after 4 h after administration Maximum dose to infant 1/3 that of mother Very low concentrations in infant Approved for use in neonates Poorly absorbed in topical form Not found in milk May cause drowsiness May cause drowsiness Nonsedating; no adverse effects on infants reported Nonsedating; no adverse effects on infants reported Undetectable in milk Avoid in a neonate when high doses are required Very low levels in milk; preferred for treatment of nipple vasospasm Milk concentration levels are low Not detected in infant serum (Continues)
560 JOGNN
Volume 28, Number 5
TABLE 4
-
Drug Classes a i d Kecoiiiii2eiinntioiis Pei+tniiiiiig to TIwir Use by n Lnctntiiig Mother (Coritinirecl)
Drug class
Use with Safe
Caution
Contraindicated
Additiml Notes
Bronchodilators X Cromolyn (Intal) Epinephrine (Primatene) x Theophylline (Aminophylline)x Nonsteroidal Antiinflammatories (NSAIJIs) Acetaminophen (Tylenol) X X Ibuprofen (Advil, Motrin) Naproxen (Aleve) X Steroids Prednisone (Meticorten) X Vaccines X Influenza Measles X MMR (measlesX mumps-rubella) Oral polio X Rabies (Imovax) Varicella (chicken pox) Radiocontrast agents Ga-67 1-123 1-125 1-131
Tc-99m Drugs of abuse Cocaine Heroin Marijuana Nicotine Phencyclidine (PCP)
Destroyed in infant gut Destroyed in infant gut Less than 1% in infant
Very low levels in milk Is used for infants Very low levels in milk Minimal amwnts in milk
No problems reported No problems reported Not to be given to a pregnant woman Do not give to mother if her infant is younger than 6 weeks Considered unlikely to produce untoward effects Avoid if infandyoung child is immunocompromised
X X
Half-life is 3.26 days Half-life is 13.2 h Half-life is 12 days Half-life up to 14 days Half-life 6.02 h
X X X X X
Intoxication in infant Tremors, poor feeding, restlessness, vomiting None reported Vomiting, diarrhea, decreased milk production Maternal hallucinations
X X X
X X
Infomution compiled fiom: AAP, 1994; Hale, 1999; Riordan & Auerbach, 1997.
is preferred to avoid exposing the infant to the compounds in question. In some cases, the period of interrupted breastfeeding may result in weaning the infant. Alternatives, such as technetium (with a half-life of 6.02 hours) and 1-123 (with a half-life of 13.2 hours) pose a lesser risk to the breastfeeding course because the interruption of breastfeeding is substantially shorter (Hale, 1998, p. 714).
Drugs of Abuse These drugs adversely affect the maternal ability to nurture in addition to their potential effects on the infant
SeptembedOctober 1999
exposed through breastmilk. Women whose toxicology screening tests are positive for heroin, cocaine, or similar drugs should be counseled regarding the adverse effects of these drugs on their infants and themselves.
Where to Seek Appropriate Information The Physicians Desk Reference is a fine reference if one is seeking information about the properties of a given pharmaceutical preparation. However, it is considered a poor source for information about the potential effects on the lactating mother or her breastfeeding infant. The
lOGNN 561
information contained within its pages is designed to prevent a lawsuit against the pharmaceutical firm. The standard recommendation for virtually all drugs includes proscriptions against their use by pregnant or lactating women. This caution is not necessarily based on the known effects of the drug on the woman or fetushnfant during pregnancy or lactation. Other sources are more helpful if one is seeking specific information and recommendations based on clinical studies and observations. For example, the American Academy of Pediatrics (AAP, 1994) document is easily obtained. Briggs, Freeman, and Yaffe (1998) and the related quarterly updates are an excellent resource on newer drugs. Hale’s Medications und Mothers’ Milk (1999) is considered an essential resource for identifying key properties of given drugs to make case-by-case decisions about drug therapy. This book is updated annually. No single document should be considered complete when contemplating drug therapy. It is always wise to check more than one source before providing information about a drug. In this manner, the information provided is more likely to be accurate.
Summary Few drugs represent a problem of such magnitude that the infant will experience sequelae as a result of exposure through breastfeeding. Health providers need to confirm for their patients that preservation of the breastfeeding experience is important, primary preventive health care. Within that frame of reference, any necessary drug therapy selected ideally would not interfere with continued breastfeeding. The plethora of drug preparations available nearly always offers numerous alternatives from which to choose. Selection of drugs for which the potential and observed effects on the breastfeeding infant are known is nearly always a more appropriate choice than a sample preparation that has appeared on the market and about which little clinical information is available. In situations in which safe, alternative drug therapy is unavailable, the mother has the right to choose whether to accept use of a contraindicated drug, one for which adverse effects on her infant are unknown, or to temporarily or permanently discontinue breastfeeding.
REFERENCES American Academy of Pediatrics, Committee on Drugs. (1994). The transfer of drugs and other chemicals into human milk. Pediatrics, 93, 137-150. Bailey, B., & Ito, S. (1997). Breast-feeding and maternal drug use. Pediatric Clinics of North America, 44, 41-54. Briggs, G. G., Freeman, R. K., & Yaffe, S. J. (Eds.). (1998). Drugs in pregnancy and lactation (5th ed.). Baltimore: Williams & Wilkins.
562 JOG”
Carrie, L. E. S., 0 Sullivan, G. M., & Seegobin, R. (1981). Epidural fentanyl in labour. Anaesthesia, 36, 965-969. Cavell, B. (1981).Gastric emptying in infants fed human milk or infant formula. Acta Paediatrica Scandinavica, 70, 639-64 1. Cohen, J. F., & Tronick, E. Z. (1983). Three-month-old infants’ reaction to simulated maternal depression. Child Development, 54, 185-193. Crowell, M. K., Hill, P. D., & Humenick, S. S. (1994). Relationship between obstetric analgesia and time of effective breastfeeding. Journal of Nurse-Midwifery, 39, 150-156. Dillon, A. E., Wagner, C. L., Wiest, D., & Newman, R. B. (1997). Drug therapy in the nursing mother. Obstetric and Gynecological Clinics of North America, 24, 675-696. Geraghty, B., Graham, E. A., Logan, B., & Weiss, E. L. (1997). Methadone levels in breast milk. Journal of Human Lactation, 13,227-230. Hahn-Zoric, M., Fulcoris, F., Minoli, I., Moro, G., Carlsson, B., Bottiger, M., Raiha, N., & Hanson, L. A. (1990). Antibody responses to parenteral and oral vaccines are impaired by conventional and low protein formulas as compared to breast-feeding. Acta Paediatrica Scandinavica, 79, 1137-1142. Hale, T. (1999). Medications and mothers’ milk (8th ed.). Amarillo, TX: Pharmasoft Medical Publishing. Hansen, B., & Moore, L. (1989).Recreational drug use by the breastfeeding woman. Part 1: Illicit drugs. Journal of Human Lactation, 5, 178-180. Ito, S., Blajchman, A., Stephenson, M., Eliopoulos, C., & Koren, G. (1993). Prospective follow-up of adverse reactions in breast-fed infants exposed to maternal medication. American Journal of Obstetrics and Gynecology, 168, 1393-1399. Kennedy, K. I. (1999). Fertility, sexuality, and contraception during lactation. In Riordan, J., & Auerbach, K. G. (Eds.), Breastfeeding and human milk (2nd ed.) (pp. 675-705). Boston: Jones and Bartlett Publishers, Inc. Kristensen, J. H., Ilett, K. F., Dusci, L. J., Hackett, L. P., Yapp, P., & Wojnar-Horton, R. E. (1998). Distribution and excretion of sertraline and N-desmethylsertraline in human milk. British Journal of Clinical Pharmacology, 45,453-457. Krogh, V., Duffy, L. C., Wong, D., Rosenband, M., Riddlesberger, K. R., & Ogra, P. L. (1989).Postpartum immunization with rubella virus vaccine and antibody response in breast-feeding infants. Journal of Laboratory and Clinical Medicine, 113, 695-699. Lifschitz, C. H., Hawkins, H. K., Guerra, C., & Byrd, N. (1988). Anaphylactic shock due to cow’s milk protein hypersensitivity in a breast-fed infant. Journal of Pediatric Gastroenterology and Nutrition, 7, 141-144. Loftus, J. R., Hill, H., & Cohen, S. E. (1995).Placental transfer and neonatal effects of epidural sufentanil and fentanyl administered with bupivacaine during labor. Anesthesiology, 83, 300-308. Matthews, M. K. (1989). The relationship between maternal labour analgesia and delay in the initiation of breastfeeding in healthy neonates in the early neonatal period. Midwifery, 5, 3-10.
Volume 28, Number 5
Murray, A. D., Dolby, R. M., Nation, R. C., & Thomas, D. B. (1981). Effects of epidural anesthesia on newborns and their mothers. Child Development, 52, 71-82. Pabst, H. F., & Spady, D. W. (1990). Effect of breast-feeding on antibody response to conjugate vaccine. Lancet, 336, 269-270. Passmore, C. M., McElnay, J., Rainey, E. A., & D’Arcy, P. F. (1988).Metronidazole excretion in human milk and its effect on the suckling neonate. British Journal of Clinical Pharmacology, 26, 45-51. Riordan, J., & Auerbach, K. G. (1997). Pocket guide to breastfeeding and human lactation. Boston: Jones and Bartlett Publishers, Inc. Sagraves, R. (1997). Drugs in breast milk: A scientific explanation. Journal of Pediatric Health Care, 1 1 , 230-237. Sepkoski, C. M., Lester, B. M., Ostheimer, G. W., & Brazelton, T. B. (1992). The effects of maternal epidural anesthesia on neonatal behavior during the first month. Developmental Medicine and Child Neurology, 34, 1072-1 080. Spigset, 0. (1994). Anaesthetic agents and excretion in breast milk. Acta Anaesthesiologica Scandinavica, 38, 94-103. Stoukides, C. A. (1991). Quinolone antibiotics and breastfeeding. Journal of Human Lactation, 7, 143-144. Stowe, Z . N., Owens, M. J., Landry, J. C., Kilts, C. D., Ely, T., Llewellyn, A., & Nemeroff, C. B. (1997).Sertraline and desmethylsertraline in human breast milk and nursing infants. American /ournal of Psychiatry, 154, 1255-1260.
SeptemberlOctober 1999
Thorp, J. A., & Breedlove, G. (1996). Epidural analgesia in labor: An evaluation of risks and benefits. Birth, 23, 63-83. Widstrom, A-M, Ransjo-Arvidson, A. B., Christensson, K., Matthiesen, A-S., Winberg, J., & Uvnas-Moberg, K. (1987). Gastric suction in healthy newborn infants. Acta Paediatrica Scandinavica, 76, 566-572. Wittels, B., Glosten, B., Foure, E. A. M., Moawad, A. H., Ismail, M., Hibbard, J., Senal, J. A., Cox, S. M., Blackman, s. C., Karl, L., & Thistad, R. A. (1997). Postcesarean analgesia with both epidural morphine and intravenous patient-controlled analgesia: Neurobehavioral outcomes among nursing neonates. Anesthesia and Analgesia, 85, 600-606. Youngstrom, P. C., Baker, S. W., & Miller, J. L. (1996). Epidurals redefined in analgesia and anesthesia: A distinction with a difference. J O G N N , 25, 350-354.
Kathleen G. Auerbach maintains a private lactation consulting practice at The Parent Center in Ferndale, WA, and is a frequent presenter at conferences and workshops. She is an Adjunct Professor in the School of Nursing at the University of British Columbia in Vancouvev, British Columbia, Canada. Address for correspondence: Kathleen G. Auerbach, PhD, IBCLC, The Parent Centev, 6145 North Beulah Avenue, Ferndale, WA 98248.
JOGNN 563