Breastfeeding and drugs.
(Food and nutrition)
Infants (Health aspects)
Breast feeding (Management)
|Publication:||Name: Kai Tiaki: Nursing New Zealand Publisher: New Zealand Nurses' Organisation Audience: Trade Format: Magazine/Journal Subject: Health; Health care industry Copyright: COPYRIGHT 2012 New Zealand Nurses' Organisation ISSN: 1173-2032|
|Issue:||Date: March, 2012 Source Volume: 18 Source Issue: 2|
|Topic:||Event Code: 200 Management dynamics Computer Subject: Company business management|
|Geographic:||Geographic Scope: New Zealand Geographic Code: 8NEWZ New Zealand|
The World Health Organisation (WHO) and the Ministry of Health
recommend babies be breastfed exclusively up to six months of age and
breastfeeding continue alongside appropriate supplementary foods until
two years or beyond. Barriers to breastfeeding initiation and duration
include the mother taking drugs (either ongoing or intermittently) and
concerns that this may affect her baby.
Knowledge of mechanisms by which drugs pass into breast milk and their effect on the baby can help nurses and other health professionals advise mothers about the risks and benefits of medication and other drugs during breastfeeding.
The Ministry of Health and WHO both recommend exclusive breastfeeding of infants to the age of six months. From then, suitable solids should be introduced in conjunction with continued breastfeeding to the age of two years and beyond. (1) In reality, breastfeeding rates decrease rapidly from 80 per cent of newborns being exclusively breastfed to 65 per cent at six weeks and 26 per cent at six months. (1) These data compare favourably with international rates: in the United Kingdom only 20 per cent of infants are exclusively breastfed at six months, (2) and only 14.8 per cent in the United States. (3)
Evidence suggests mothers taking long-term medication--eg those being treated for epilepsy, hypertension or psychiatric disorders--are less likely to start or continue breastfeeding their babies. (4,5) By contrast, a large number of women may take over-the-counter medications, herbal remedies, supplements and recreational drugs, including nicotine, while breastfeeding, being unaware of the risks posed by these drugs. (6,7) Concern about the effects of medication on their baby may contribute to cessation of breastfeeding for many women requiring short-term drug therapy, eg antibiotics, and, sadly, advice from health care professionals may reinforce this view. (8,9)
Nurses need to be able to counsel and support women in the breastfeeding process. Continuation of breastfeeding following discharge from maternity services depends, in part, on the knowledge and support of health professionals the woman encounters, (1) particularly advice about medications and other drugs. Breastfeeding mothers who are already unwell need particular encouragement to continue feeding. Nurses need to understand the processes involved in transfer of drugs from maternal to infant circulation and the possible risks involved. Adequate knowledge and support may increase breastfeeding duration for mothers on long-term medication and for those requiring short courses of drugs where the mother may stop feeding because of concern about her baby receiving unwanted doses of drugs.
There are ethical barriers to doing clinical drug trials on safety in breastfeeding. Drug companies largely rely on pharmacokinetic data and an understanding of developmental changes in infants and young children to determine drug safety. (10,11) Warnings provided by drug manufacturers tend to be cautious in the face of lack of hard evidence on safety. As with drugs given directly to children, clinicians must rely more on experience and case reporting than clinical trials to make therapeutic decisions.
The milk-to-plasma (M/P) ratio is often used to describe the degree of movement of drugs into breast milk. This figure compares the peak concentration of the drug in the maternal plasma with the peak concentration in the breast milk. A ratio of one indicates the drug is equally distributed. M/P ratio <1 indicates a drug that is less distributed to the breast milk, while >1 demonstrates accumulation of the drug in breast milk. (5,8,13)
Relative infant dose
An infant receiving a drug through breast milk may be at risk even though the dose is relatively small. The risk relates to the body weight of the infant, compared with that of adults. Drug doses are calculated on a per kilogram (kg) basis: a 500mg drug dose given to a 50kg woman results in a relative dose of 10mg per kilogram. An infant weighing 5kg given the same dose directly would be receiving 100mg per kilogram. For drugs received via breast milk, the dose needs to be assessed considering concentration of the drug in the milk, and the infant's body weight. A weight-adjusted dose of 10 per cent of the maternal dose is considered safe, although this is a theoretical figure and is obviously not applicable to drugs with high toxicity. (14)
Breast milk synthesis occurs in the alveoli of the mammary lobules. Milk travels from the alveoli, via ductules, into the lactiferous ducts that open on to the surface of the nipple. The alveoli are composed of layers of epithelial cells surrounded by smooth muscle and fat. During the initial stages of breastfeeding, the epithelial cells are arranged loosely, so large substances can cross into the breast milk, travelling between the cells. Once lactation becomes established, the cells are linked by tight junctions that prevent the passage of molecules between the cells. (15) Thus, by about eight days after birth, all substances entering the milk must pass through, rather than between, the alveolar cells.
Once feeding is established, there is a variation in milk components. Foremilk, produced earlier in the feed, has high water content and is rich in protein. Hind milk has a higher fat content. The volume of milk produced is usually greatest in the early morning, while fat content is normally highest in the late morning. The volume of milk an infant consumes in 24 hours varies with age and development: while being exclusively breastfed, the volume of milk ingested is assumed to be about 150ml/ kg/day, but as a baby matures and feeding becomes mixed, the volume ingested in 24 hours will be less per kilogram.
Knowledge of absorption, distribution, metabolism and elimination of drugs in both mothers and babies, allows predictions about the transfer of the drug and its possible effects in the child. Therefore nurses need some knowledge of the pharmacokinetic processes involved in drug movements within the body.
Pharmacokinetics describes what the body does to a drug. A drug must undergo absorption and distribution before it can exert a therapeutic effect. The body removes the active drug through alteration of its chemical structure (metabolism) and then excreting it, mainly through the kidneys or liver. All of these processes have an effect on the amount of the drug in the circulation at any given time and thus on the amount found in breast milk and passed on to the feeding baby.
Orally administered drugs must cross physiological barriers to be circulated and distributed about the body. These barriers are composed of cells, specifically the cell membrane--a lipid bilayer that is impermeable to some substances but allows others to move freely. Key barriers for the breastfeeding mother are the epithelial membrane that lines the gastrointestinal (GI) tract and the alveolar cells of the lactating breast.
Drug absorption and subsequent distribution to breast milk depend on how rapidly the drug can diffuse through a membrane barrier. The main determining factors in this movement are: lipid solubility of the drug molecule, its state of ionisation, and molecule size.
A lipid soluble (lipophilic) drug readily crosses membrane barriers. Small water-soluble drug molecules can also cross through water-filled channels in the cell membranes, although more slowly.
The speed at which a drug crosses membrane barriers is also affected by its state of ionisation. This refers to the charge on the drug molecules. A non-ionised molecule is more lipophilic and thus will cross barriers by simple diffusion through the lipid bilayer. An ionised molecule carries a charge that tends to make it less lipid-soluble.
Many drugs are weak acids or bases and their state of ionisation is affected by the pH of the body compartment they are exposed to. Acidic drugs (eg aspirin) remain largely un-ionised when in a low pH (acidic) environment such as the stomach. Aspirin is readily absorbed across the stomach wall. However, if exposed to a higher pH (more alkaline) environment, a proportion of the aspirin molecules become ionised and lose their lipid solubility.
Plasma pH is slightly alkaline (pH=7.4), so alkaline drugs in the plasma are largely non-ionised and can diffuse freely out of the plasma through cell membranes. Breast milk has a lower pH than plasma, so alkaline drugs moving into the breast milk may become ionised and "trapped" in the milk, unable to diffuse back out. Many psychotropic agents are alkaline, so are more likely to become trapped in the breast milk, giving an M/P ratio greater than 1. (17)
Given sufficient time, most drugs will cross membrane barriers and spread to other compartments of the body, including breast tissue. Drugs that readily cross the blood-brain barrier (eg psychoactive drugs and recreational drugs) will also enter breast milk.
Drugs such as heparin, insulin and interferon are exceptions to this. These drugs are composed of very large molecules (greater than 800 Daltons) that prevent them from crossing into the breast milk in any significant concentration. (16) This is also the reason these drugs must be administered via parenteral rather than oral routes.
In theory, a drug will diffuse from one compartment to another as long as there is a concentration difference between the two compartments. At steady state, the drug molecules will cross back and forth. Once the concentration of the drug in the plasma begins to fall (as the drug is excreted from the body), diffusion will occur in the opposite direction--from the body compartment back in to the plasma. If ion trapping occurs, the drug will diffuse back out very slowly but the concentration of the drug in the second compartment is much greater than would necessarily be expected, given the elimination rate from the plasma.
In infants and babies, absorption of drugs from the GI tract is highly variable. The stomach is less acid and GI motility reduced. The rate and amount of absorption of drugs following ingestion in breast milk cannot be generalised and must be considered separately for each drug.
Drugs that are poorly absorbed may cause GI adverse effects in the baby, eg babies may get diarrhoea or thrush after the mother takes antibioitics. Distribution
Once a drug has been absorbed from the GI tract, it is distributed to the rest of the body in the plasma. The way a drug gets distributed throughout the body depends on its ability to cross membrane barriers, as discussed above, and two further factors: plasma protein binding and accumulation into specific tissues.
Many drugs bind to plasma proteins when they enter the blood. An equilibrium is established between free and bound drug molecules. As unbound drugs are removed from the plasma (either by elimination or crossing into another body compartment), bound drug molecules will be released from the plasma proteins. This is important because only unbound drug molecules can exert a therapeutic effect in the body or undergo metabolism and excretion. Likewise, only unbound drug molecules can cross out of the plasma into other body compartments. The more highly protein-bound a drug is, the less rapidly it will cross out of the plasma into the breast milk.
Some drugs compete for binding sites on the proteins and can displace each other, leading to a higher than expected free plasma concentration of the second drug. This phenomenon is not a major clinical issue, as usually the displaced drug will also be eliminated more rapidly. However, in neonates with jaundice, some drugs displace bilirubin from plasma protein binding sites. Free bilirubin can then cross the blood-brain barrier and cause kernicterus.
Some drugs accumulate preferentially in body tissues, most commonly in fat, eg thiopentone and benzodiazepines. This leads to prolonged elimination of a drug so that it may be circulating in the plasma at low concentrations for some time after dosing. Tetracyclines have an affinity for calcium, so accumulate in bones and teeth--the reason they are not given to children and are contraindicated for long-term use while breastfeeding.
Although most drugs enter the breast milk by passive diffusion, there are some that are actively transported across the alveoli. Examples are ranitidine, cimetidine, nitrofurantoin and acyclovir. (16)
Drugs that are considered safe in pregnancy may not be safe in breastfeeding. During foetal life, drugs are metabolised and eliminated by the mother's liver and renal systems. After birth, the infant's immature liver and kidneys must metabolise and excrete all incoming drugs, so it is important to understand the metabolism of specific drugs in relation to a baby's developmental stage. The half-life of some drugs in the newborn or young infant's circulation may be much longer, leading to accumulation of the drug. Examples of drugs where this occurs are morphine, benzodiazepines and aspirin. Particular caution must be paid to premature infants where gestational age must be considered.
Generally, a drug that is available in an infant formulation will be safer to give to the breastfeeding mother.
Drugs taken orally are subjected to first-pass metabolism: a proportion of the active drug is removed from the plasma by the liver before it reaches general circulation. In adults, the oral dosage of a drug allows for this phenomenon. In an infant, the immature liver may be unable to extract the active drug in this way, so the plasma concentration may be higher than expected for a drug received via the breast milk.
Once in the general circulation, a drug is metabolised and made inactive over a period of time. The rate at which drugs are metabolised varies with both the drug and the person. Some drugs are metabolised rapidly and cleared from the plasma in a short space of time, while others may have prolonged half-lives due to slow metabolism and elimination, slow absorption (slow-release formulations), or accumulation in other body compartments apart from the plasma.
Some people metabolise some drugs more rapidly than the majority of the population, due to genetic variation in the liver enzymes responsible. In contrast, some people are slow metabolisers. This affects drug half-lives and exposure of an infant to the drug in the breast milk. This is particularly evident in the case of codeine.
In 2007, an infant in Toronto, Canada, died of morphine poisoning. The mother had been prescribed paracetamol with codeine for pain following the birth. This mother had a variant of the liver enzyme CYP2D6 and was an ultra-rapid metaboliser. CYP2D6 is the enzyme responsible for converting codeine to its active metabolite--morphine. This mother converted more of the codeine and more rapidly than the general population. Her baby was receiving a high concentration of morphine with every breastfeed and died from respiratory depression. (25)
Variation in CYP2D6 enzymes is genetic. Particular groups are more commonly ultra-rapid metabolisers: 20-30 per cent of North African and Arab populations, compared with one to four per cent of Caucasians.^ It is not possible to genotype all breastfeeding mothers, so all should be warned of the risk and made aware of the adverse effects to look for in their babies: lethargy, poor feeding, drowsiness, bradycardia and respiratory depression. Medsafe has issued a warning in the Prescriber Updates regarding the use of codeine while breastfeeding.
Most drugs are excreted in the urine or bile. Drugs excreted in the bile may be reabsorbed from the GI tract, prolonging the half-life. Drug excretion through the kidneys relies on the glomerular filtration rate (GFR), which is reduced in kidney failure and in very young babies. Babies' GFR equals and even exceeds adult rates by three months of age, leading to increased removal of some drugs. Active secretion of some drugs into the urine is also affected by developmental age--tubular secretion does not reach adult levels until about seven months, but can be greater than adult values throughout childhood. Drugs actively secreted into the renal tubules include digoxin and imipenem. (10)
It is generally assumed that, as the concentration of a drug in the mother's plasma falls, through metabolism and excretion, the concentration in the milk drops also. For many drugs this is true, so that at the time of the next dose, concentration of the drug in the milk is approaching its lowest--thus the advice to feed just before taking the scheduled dose of a drug. This is not always practical however, especially for younger infants feeding very frequently or unsettled babies. It is important to work with the mother to develop a feeding and dosing schedule that optimises the time between drug dosing and feeding. For longer-acting drugs, the advice is to take the medication just before the baby's longest sleep, which, hopefully, is overnight. Drugs with longer half-lives or those that accumulate are not subject to as much variation in plasma concentration, so for these, feeding just before the next dose is not as essential. (20)
NON-PRESCRIPTION AND RECREATIONAL DRUGS
Many mothers may be unaware that so-called natural therapies, such as herbal remedies, are as likely as conventional or prescribed medications to cross into breast milk. A key concern is lack of data about these drugs to determine their effects on the baby. Contents of herbal remedies, not being subject to the same strict regulatory controls, may vary significantly from the stated concentration of active ingredients and contain other compounds that may also cross to the baby via the breast milk. Because of lack of data and quality control around natural remedies, it should be emphasised to mothers that, if there is a need for medication, conventional medicines should be the treatment of choice. (16)
Recreational drugs are usually of the type that cross the blood-brain barrier, exerting psychoactive effects. This means these drugs also enter the breast milk. Because of the nature of their use, dosage and timing are uncontrolled. Current recommendations suggest breastfeeding be interrupted for up to 48 hours after using a single dose of these drugs. Once in the baby's system, these drugs and their metabolites can have very prolonged half-lives--up to weeks in some instances. (16)
This has been shown to enter the breast milk in only very low concentrations. Methadone is given to babies to assist with narcotic withdrawal and studies have demonstrated no serious health or developmental effects. Methadone is an example of a drug with a greatly shortened half-life in babies and children, compared to adults. Methamphetamine ('P')
Methamphetamine is metabolised into amphetamine, an alkaline drug with low molecular weight that accumulates in breast milk. The M/P ratio for this drug is around 3 to 7.5:1. Elimination of a single dose is within 48 hours. (21) Amphetamine-like drugs are known to suppress milk production, in a similar way to pseudoephedrine-type drugs. Adverse effects in the baby include irritability, crying, agitation and poor sleep. Long-term neurological changes have been seen in animal studies. (21)
The active metabolite of cannabis, tetrahydrocannabinol (THC), is rapidly distributed throughout the body, including the central nervous system, has a very long half-life (20-36 hours, and longer in chronic users), and accumulates and is excreted through the breast milk. In high users, the M/P ratio can be 8:1. (21) Adverse effects for the infant include sedation, lethargy, weakness and poor feeding. Long-term effects have not been well-studied but may include delayed motor development. (21)
Caffeine is transferred in the breast milk, but for older babies, the received dose is minimal unless the mother has a particularly heavy intake. (14) There is reduced metabolism of caffeine in young babies so the drug may accumulate. The effects of caffeine in the baby are variable and include irritability, poor sleep patterns, vomiting and withdrawal effects. (21)
Nicotine is known to reduce breast milk production and also milk fat content. Nicotine enters breast milk and, being slightly alkaline, undergoes ion trapping. The dose received by an infant via breast milk is proportional to the number of cigarettes smoked by the mother. Nicotine causes increased incidence of colic and respiratory tract infections and may have an effect on breathing and oxygen saturation. The baby may experience nicotine withdrawal between feeds if the mother is an exceptionally heavy smoker. There are no documented long-term adverse effects of nicotine exposure. (21)
The M/P ratio for alcohol is 1, meaning that alcohol passes freely in and out of breast milk. As the concentration of alcohol drops in the maternal plasma, it also decreases in the milk. Peak milk concentration is reached 30-60 minutes after a single drink and is largely eliminated within two to three hours. The more alcohol consumed by the mother, the higher the peak concentration and the longer to eliminate the drug from breast milk. Elimination rate cannot be increased by methods such as drinking water, drinking coffee, exercising or pumping and discarding breast milk. (21,22)
Alcohol may reduce the overall volume of milk in a feed. Alcohol dehydrogenase levels in the baby's liver do not reach adult levels until about one to two years of age. This can lead to an accumulation of alcohol in a younger baby's plasma. (11) Adverse effects include mild sedation, deep sleep, impaired motor development and reduced weight gain. (21)
Studies have demonstrated that health professionals, while keen to support breastfeeding, tend to base advice regarding medication on risk posed to the infant, without considering individual drug exposure. (9) Decision-making is often one-sided, with the mother advised to stop feeding. Conversely, many mothers do not regard a simple assurance that the drug is safe and will have no effect on the baby as sufficient. They are often left dissatisfied and may choose to refuse medication or to stop breastfeeding. (9, 23) It is important, therefore, that the mother make decisions about medications or other drug use following informed discussion about the risks and benefits of the proposed therapy for both her and her baby.
Discussion of the risks and benefits associated with the use of any drug--prescribed, over-the-counter, natural or recreational--while breastfeeding is an essential component of good practice. A baby receives no physical benefit from the ingestion of maternal drugs; however, the continuing good health of the mother is of definite benefit. There are significant physical, developmental, emotional and long-term health benefits to the baby from continued breastfeeding. Thus the starting point for any risk-benefit analysis should be continuation of breastfeeding.
The mother's decision about drug therapy should be discussed in terms of her absolute need for treatment. What are the consequences of not treating this condition? Can therapy be delayed? Can the condition be successfully treated by non-pharmacological means? Are there non-systemic versions of the therapy--eg nasal sprays, topical lotions or inhalers?
If treatment is necessary for the mother's health, then discussions about pharmacological therapies should include the availability of effective alternative drugs and data regarding their safety in breastfeeding, and the age, developmental stage and milk intake of the baby. (24)
The ideal drug for breastfeeding mothers has:
* Low oral bioavailability.
* An M/P ratio of less than 1.
* A short half-life, with no active metabolites. 9 High protein binding.
* High molecular weight (large molecules).
* Low pH to avoid ion trapping.
* Low toxicity.
* Documented experience of safe use in breastfeeding.
* Been used in an infant formulation.
See box (p23) for a list of websites on drugs and breastfeeding. Table 1 (p22) describes a decision process for drugs prescribed during lactation.
The majority of drugs are safe in breastfeeding, with minimal transfer between the milk and the baby's plasma. Some drugs are absolutely contraindicated, eg antineoplastic agents, radioisotopes and retinoids, while others, if used, require intensive monitoring of the baby, eg amiodorone and lithium. (20)
Practice recommendations (26)
Initially, consult with the mother about non-pharmacological remedies for her symptoms.
Work with the mother to establish a regular feeding regime, if one is not already established, that allows co-ordination with drug dosing.
Avoid recommending any medications that have more than one active ingredient, eg paracetamol and codeine (Panadeine), or cold remedies that contain anithistamines, decongestants and paracetamol. Pseudoephrine and phenylephrine both reduce milk production.
Discourage the use of medications that are "extra strength" or slow release. Recommend the lowest possible effective dose, in the shortest acting formulation.
Educate the mother and other caregivers about adverse effects in the baby. This should include signs and symptoms of the normal therapeutic action and withdrawal effects of the drug in adults. Remember that patterns of adverse effects in infants and babies might differ from those commonly seen for the same drug in adults. It can be difficult to attribute changes in the baby's patterns of behaviour to the effects of a drug. The only reasonably sure test is to withhold the drug for a suitable period and then reintroduce it and see if the behaviours return.
Common adverse effects that may be attributed to drug use include:
(1.) Changes in sleep patterns
The baby may become more drowsy, sleep more deeply and for longer, and be less easily roused. In contrast, sleep may be disturbed, restless and the baby may be harder to settle or sleep for shorter periods.
(2.) Changes in feeding patterns
The baby may feed for shorter times, or, if the drug affects milk taste, refuse the breast. If the drug reduces milk production, there may be increased hunger and feeding time. Colic, vomiting, diarrhoea or constipation might occur. The baby may fail to gain weight.
(3.) Motor effects
Weakness and floppiness or rigidity and tremor. Delayed motor development.
(4.) Behavioural changes
Agitation, restlessness, irritability, apathy.
Any detected changes should not be automatically attributed to maternal drug use, and further investigation to eliminate other causes should be done if warranted.
The transmission of drugs to babies via breast milk is common but the amount of drug entering the baby's plasma is normally sufficiently low to cause minimal or no adverse effects. Mothers need support from their health care providers to make informed decisions about drug use during lactation. Fear of delivering unwanted prescription medications to their babies might persuade mothers to either decline necessary treatment or stop breastfeeding. On the other hand, lack of awareness of the risks associated with herbal and other natural remedies, over-the-counter drugs or recreational drug use, may put breastfed babies at unnecessary risk.
After reading this article and completing the accompanying online learning activities, you should be able to:
* Explain factors that influence the movement of drugs into breast milk.
* Describe factors determining the amount of drug present in babies following ingestion in breast milk.
* Discuss risks associated with recreational drug use by breastfeeding mothers.
* Outline the elements of a risk-benefit analysis applied to maternal medications and breastfeeding.
* For this article's references, go to CPD4nurses.co.nz and click under the 'News' link.
WEBSITES ABOUT DRUG USE IN LACTATION
@ The Breastfeeding Network (UK). Consumer-friendly fact sheets about many different drugs: www.breastfeedingnetwork.org.uk/ drugs-in-breastmilk-information-and-factsheets.
@ Infant Risk Centre (USA) contains articles about medication use and breastfeeding: www.infantrisk.com/.
@ Infant Risk Centre is also linked from the NZ Ministry of Health information page: www.health.govt.nz/our-work/life-stages/ maternity-and-breastfeeding/breastfeeding/health-practitioners/ information-sheets-health-practitioners/medications-andbreastfeeding.
@ UK repository for journal articles about drugs in lactation: www.nelm.nhs.uk/en/Categories/Medicines-Information/445430/ ?category=4020.
@ UK drugs in lactation advisory service: www.ukmicentral.nhs.uk/ drugpreg/guide.htm.
@ NZ guidance about drugs in lactation: www.medsafe.govt.nz/profs/PUarticles/lactation.htm.
@ Specific information about drugs from the clinical pharmacology department at Christchurch Hospital: www.druginformation.co.nz/breastfeeding.htm.
@ National Library of Medicine (USA) Drugs and lactation database. Peer reviewed and fully referenced: toxnet.nlm.nih.gov/ cgi-bin/sis/htmlgen?LACT.
Georgina Casey, RN, BSc, PGDipSci, MPhil (nursing), is the director of CPD4nurses.co.nz. She has an extensive background in nursing education and clinical experience in a wide variety of practice settings.
By co-editor Teresa O'Connor
Table 120 IF THEN Drug does not enter milk. Continue breastfeeding as normal. Dose received by infant is low Continue breastfeeding with and drug unlikely to affect observation for adverse baby. effects. Dose received by infant is Continue breastfeeding with moderate and/or there may be close observation for adverse an effect on the infant. effects. If therapy is single dose or very short term, consider alternative feeding for duration, and expressing and discarding breast milk. Dose received by infant is Discontinue breastfeeding. high and/or the drug has high If therapy is single dose or toxicity. very short term, consider alternative feeding for duration, and expressing and discarding breast milk.
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