Occurrence of side effects
Most data on side effects in breast-fed infants are derived from published case reports. Such reports are important since they can help generate hypotheses, but it is often difficult to determine whether there is a causal correlation between the symptoms in the infant and the drug exposure via the milk. Systematic prospective studies are therefore required. In a cohort study of breastfeeding women who were using a variety of drugs, the mothers were interviewed about possible side effects in their infants. The women reported suspected side effects in 11 of these 838 infants
(5). The most frequently reported symptoms included pharmacologically plausible effects such as diarrhoea (antibiotics), drowsiness (opioids, hypnotics) and irritability (first-generation antihistamines). None of the cases required medical attention. These results indicate that the vast majority of cases of possible side effects are self-restricting and mild. There is also a prospective study of transfer of serotonin reuptake inhibitors to mother’s milk, which included 26 exposed infants and 68 controls (6). No increased risk of side effects was detected in these infants.
In a literature review published in 2003 in which side effects in 100 breast-fed infants were studied, two findings are especially relevant with regard to clinical practice. First, in nearly eight of ten cases, the infant was younger than two months and second, drugs that affect the central nervous system accounted for approximately half of all side effects
Psychotropic drugs are the drug group that have been at the centre of attention among clinicians as well as researchers, and also the group that have been subject to the highest degree of uncertainty. Fortinguerra and colleagues reviewed the literature from 1967 to 2008 and identified 183 original contributions describing the use of psychotropic drugs during breastfeeding
(8). They found that cases of side effects had been published for all groups of psychotropic drugs (except for psychostimulants, for which only one case report had been published) (8). Seen in relation to the number of mothers who are likely to have used such medications and breast-fed, the risk appears to be very low, however.
Breastfeeding is absolutely contraindicated for only a very few drugs (Table 1)
(1, 2, 4, 9) – (21). Examples of such drugs include cytostatics, radiopharmaceuticals, iodine-based x-ray contrast fluids and gold compounds. Some drugs, such as cabergoline, are contraindicated because they may interfere with milk production or the process of lactation. It is far more common to advise caution with the use of a drug during breastfeeding on the basis of the pharmacological effects of the drug or its ability to pass into the mother’s milk. Examples of such drugs include antipsychotics, opioids, benzodiazepines and certain antiepileptics (Table 1). The Journal of the Norwegian Medical Association has previously published articles on the use by breastfeeding women of analgesics (14), anaesthetics (15), antidepressants (16), antipsychotics (17, 18) and mood stabilisers (18).
Recommendations concerning breastfeeding and drugs – some examples (1, 2, 4, 9 – 21)
Can be used by breastfeeding mothers
Can be used by breastfeeding mothers
Can be used by breastfeeding mothers
To be used with caution in breastfeeding mothers.
Single doses/sporadic use is regarded as safe
Breastfeeding must be assessed on an individual basis, if necessary with close follow-up of the infant.
Breastfeeding is contraindicated.
Contraceptive pills containing gestagen/mini-pills
Iodine-based x-ray contrast fluids
No risk detected
Small risk, provided that the drugs are used in single doses/sporadically
The pharmacokinetics of these drugs indicate little or no systemic absorption from the infant’s digestive tract.
These drugs have been used over long periods by breastfeeding mothers without any side effects in breast-fed infants being reported.
Studies show that the risk of side effects is low, or that the theoretical risk is low.
Studies show a small risk of side effects after repeated intake, or there is a theoretical risk of side effects in breast-fed infants because of accumulation.
Side effects have been reported, or the mechanism of action of these drugs indicates a risk of side effects.
Documented high risk in breast-fed infants, or the mechanism of action of these drugs indicates high toxicity.
In Box 2 we present questions that health workers should ask themselves on an individual basis to assess whether breastfeeding can be recommended or not. In some situations the problem can be solved by choosing a therapeutically equivalent alternative that is transferred to mother’s milk to a lesser extent. In other situations this may not be possible. At the same time, it is essential to regard the exposure in a proper perspective: if the woman has used a drug during pregnancy she can most often continue using the drug while breastfeeding, since the infant’s exposure will be far smaller than during pregnancy. This applies even though breast-fed infants themselves must metabolise and excrete drugs ingested via the milk. At the same time, in this situation the mother can choose to abstain from breastfeeding, thereby ceasing infant exposure. Recommendations to breast-feed or not should be based on a thorough risk/benefit assessment, in which the benefits of receiving mother’s milk and the woman’s own viewpoints should also be taken into account.
Questions that can be used to clarify the risk/benefit relationship of drug use when the mother breastfeeds.
About the infant:
How old is the infant?
Was the infant born prematurely?
Is the infant healthy?
Is the infant fully breast-fed?
About the mother:
How necessary is this drug for the mother?
For how long will the mother use the drug?
How important is breastfeeding to her?
About the drug:
Are there any alternative drugs that would be safer for the infant?
How large is the drug dose that the infant will ingest via mother’s milk (if possible compared to a therapeutic dose for infants)?
Have any side effects in breast-fed infants been previously reported?
Factors affecting the risk of side effects
Factors affecting the risk of side effects
Several factors may increase the risk of side effects in breast-fed infants: high levels of the drug in the mother’s milk, high toxicity, long-term drug therapy, infant health and not least the age of the infant.
Newborns, and premature infants in particular, eliminate many drugs at a considerably slower rate than older children and adults, because their liver and kidney functions are not yet fully developed
(22). This applies both to drugs that are metabolised by the cytochrome P-450 system and drugs that undergo glucuronidation, and is reflected in elimination half-lives that vary with age. For example, the half-life of diazepam is approximately 80 hours in premature infants, approximately 30 hours in full-term newborns and 10 – 20 hours in infants after the newborn period (23). The renal function is not fully developed until the infant is 6 – 9 months old. Therefore, drugs with a high degree of renal elimination, such as lithium, have a considerably longer half-life in infants and in newborns in particular. In addition, seriously ill as well as premature infants will have a lower tolerance and will often be more sensitive than healthy children to the effects of drugs.
When using drugs with a long half-life, there will be a risk of accumulation in the infant if the ingested volume is larger than the infant’s capacity for metabolising and excreting the drug. This could happen, for example, after continuous use of benzodiazepines, and drugs belonging to this group should therefore only be used sporadically in single doses in breastfeeding mothers.
On rare occasions, genetic factors will have an impact on the risk of side effects. Codeine is a clinically relevant example, e.g. when used after Caesarean sections or for painful vaginal tearing. A case of lethal morphine poisoning has been described in a 13 day-old breast-fed infant
(24). The mother, who was an ultra-rapid metaboliser of the drug via the liver enzyme CYP2D6, had used codeine in amounts corresponding to two tablets of Paralgin Forte/Pinex Forte daily for somewhat less than two weeks. Blood samples from the infant showed a morphine concentration of 70 ng/ml, approximately 35 times the expected level. In comparison, the concentration in breast-fed infants is usually lower than 2 ng/ml. The mother’s genotype resulted in increased production of morphine from codeine, and thereby in an abnormally high concentration in the mother’s milk (measured to 87 ng/ml). Several cases of apnoea, drowsiness and bradycardia have been reported in infants exposed to codeine via mother’s milk (21, 25). The use of codeine among breastfeeding mothers should therefore be restricted to a maximum of 2 – 3 days.
When side effects are suspected, analysis of the serum concentration of the drug in the mother as well as the infant, and possibly also in the milk, may be useful when assessing causality. A period without breastfeeding (when the mother pumps out and discards her milk) could be scheduled to observe whether the infant’s symptoms disappear. If the symptoms return when breastfeeding is resumed this would give even stronger indications of causality. Suspected side effects should be reported to the nearest drug information centre
How to reduce exposure
How to reduce exposure
Occasionally it may be uncertain whether breastfeeding can be safely recommended when the mother uses drugs, for example during long-term treatment with some antiepileptics, antipsychotics and immunosuppressants
(8, 11, 17) – (19). A possible solution in this situation could be to administer mixed nutrition, i.e. some mother’s milk and some breast-milk substitute. With this compromise, the infant will be less exposed to the drug, and at the same time to some extent benefit from the valuable mother’s milk.
For drugs with a short half-life, such as zolpidem, the risk of side effects can be reduced by breastfeeding at times when the drug concentration in the mother’s milk is at its lowest level. This can be achieved by taking the drug immediately after breastfeeding, or immediately before the infant’s longest sleep period.
If the woman is recommended to avoid breastfeeding while exposed to a drug, an estimation can be made of the time interval required before the drug is cleared from the milk or is present only in insignificant concentrations, so that breastfeeding can be resumed as quickly as possible. Information on the elimination half-lives of drugs can be found in the
Felleskatalogen (27) and the Norsk legemiddelhåndbok (28). After a period equal to five times the half-life, for practical purposes all of the drug will have been eliminated from mother’s plasma, and thereby also from her milk. For example, a woman who uses sumatriptan (with a half-life of approximately 1 – 1.5 hours) against migraine will be able to breastfeed after 5 – 8 hours.
When breastfeeding needs to be individually adapted to reduce the infant’s exposure to drugs, this will often require an extra effort from the responsible doctor in terms of providing information to the mother and performing follow-ups of the mother and infant. One example is when the mother uses lithium and has a strong desire to breastfeed; in some cases this may be possible, even though it is generally discouraged. This solution presupposes that the mother receives thorough information and that the infant is monitored closely both clinically and by laboratory testing
Norsk legemiddelhåndbok contains a separate chapter on drugs and breastfeeding. Here, each individual compound is assessed in terms of its safety of use during periods of breastfeeding (2). Each drug is classified in one of six risk categories, which may be of help for an individual risk/benefit assessment. Side effects that may occur in breast-fed infants and of which breastfeeding mothers should be aware are also described. Information pertaining to infant safety in breastfeeding is also found in national therapy guidelines with regard to several groups of drugs, such as antiepileptics (19), antibiotics (20) and analgesics (21).
The descriptions in the product monograph
Felleskatalogen will rarely be a good source of information to breastfeeding mothers, because of the legal provisos that the manufacturers tend to include in their texts. As far as international literature is concerned, we can especially recommend Hale’s Medications and mother’s milk (1). Most questions pertaining to the safety of breastfeeding and the use of drugs can be answered with the aid of this manual. Several good online resources are also available (Table 2) (28) – (32).
Online resources for drug use and breastfeeding
Norwegian pharmaceuticals handbook. The chapter Breastfeeding and drugs (G8) provides a general description of drug therapy with respect to breastfeeding women, and shows tables for drugs and groups of drugs sorted alphabetically and by active ingredient/group name (28)
Regional drug information centres (RELIS). Contains a searchable database with responses to previous questions regarding drugs and breastfeeding (29).
Janusinfo is a publicly funded Swedish website that provides information on drugs and breastfeeding, sorted alphabetically and by active ingredient and (Swedish) trade names (30)
UK Midland Information Service contains lists of drug groups and their associated risk for breastfeeding women provided by British drug information centres (31)
Drugs and Lactation Database (LactMed) contains a searchable database of drugs/chemicals and breastfeeding from the US National Institute of Health (32)