Adverse Drug Reactions

Infant Age

An important finding relating to adverse reactions is the age distribution of the infants. Of the 151 published case reports in which infant age was reported, 58% of cases occurred in the first month of life, including five of the seven deaths. An additional 15% of adverse reactions occurred in the second month of life, for a total of 73% occurring in the first 2 months postpartum. These values are similar to those found in a French pharmacovigilance study of 174 cases of adverse reactions in breastfed infants reported over a 25.5-year period. ³ The authors found that 67% of cases occurred in the first month and 11% in the second month, for a total of 78% of the adverse reactions in the first 2 months of life.

Dose-Related Reactions

The most obvious adverse reactions are those caused by the direct pharmacologic actions of the maternal drug on the breastfed infant. These are dose-related or type A (“augmented”) reactions. There is a common-sense basis for this view: the higher the dosage that an infant receives, the more likely the infant is to have a side effect from the medication. A previous review by the editors of the World Health Organization's book, Drugs and Human Lactation, found that the greater the excretion of a drug into breast milk, the more likely there was to be a report of an ADR in a nursing infant. ⁴ Of the 205 drugs studied, 96 drugs with a relative infant dose (RID) less than 1% had no ADRs reported. All six of the drugs with an RID of 25% or greater had at least one ADR reported. Intermediate RID values produced intermediate ADR rates. These percentages refer to drugs that had at least one report of an adverse reaction, not that all infants exposed to that drug had an ADR.

Of the 160 published ADR case reports, 127 (79%) were most likely dose-related reactions and 88 (69%) of these drugs were central nervous system (CNS) depressants. All seven infant deaths involved one or more CNS depressants, and five of these involved an opiate. Because these effects are dose related, either maternal doses that are excessive or the use of more than one drug with similar side effects can cause an unwanted effect in the breastfed infant. Twenty-two of the case reports of dose-related adverse reactions occurred in infants exposed to more than one CNS depressant. A separate study on benzodiazepine use in nursing mothers found that the use of multiple CNS depressants, but not benzodiazepines alone, was a risk factor for infant ADRs. Furthermore, the greater the number of CNS depressants the mother took, the greater was the likelihood of an adverse effect. ⁵ Nevertheless, five ADRs from a benzodiazepine alone have been reported, including one death.

Another common finding is that various forms of excessive iodine exposure can cause thyroid dysfunction in breastfed infants. This has occurred through topical, vaginal, and oral exposure, for both medical and culinary iodine uses. Several cases have been reported in the newborns of mothers who ingested large amounts of iodine from seaweed soup. Great caution should be taken to avoid exposure of nursing mothers to high amounts of free or loosely bound iodine (e.g., povidone iodine), even topically.

One case of infant hypothyroidism after maternal use of amiodarone, which is a highly iodinated organoiodine compound, has been reported. This raises concern of whether iodinated X-ray contrast media are potentially problematic in nursing mothers. Current thinking is that the iodine in these products is so tightly bound to the carrier molecule and the drugs' half-lives are so short (unlike amiodarone) that iodine is not available to enter the breast milk. All expert radiologic opinion holds that no cessation of breastfeeding is necessary after administration of contrast media to nursing mothers. Measurements of breast milk iodine after administration of iodinated contrast media have not been reported in the literature. However, a recent article reported that patients who received an iodinated contrast medium for a computed tomography scan developed markedly elevated urinary iodine levels after the procedures. ⁶ None of the patients was breastfeeding, but it raises the question of whether there might also be elevated breast milk iodine after the use of these products. This is an interesting study waiting to be performed. Meanwhile, the absence of case reports of thyroid dysfunction in breastfed infants after administration of maternal iodinated contrast media provides a level of comfort.

Idiosyncratic Reactions

Idiosyncratic or type B (“bizarre”) reactions are those that are generally not related to drug dosage and are usually not predictable and not based strictly on the pharmacology of the drug. Twenty-eight of the 160 (18%) adverse reaction reports in breastfed infants can be considered idiosyncratic. Allergic reactions, such as rash with a penicillin, are the most common examples of idiosyncratic reactions. Given the frequency of penicillin use, it is surprising that only one published case report exists. Perhaps rash after exposure to a penicillin is considered too obvious to report. I once spoke to a mother whose nursing infant developed a rash when the mother began taking amoxicillin. The infant had previously developed a rash while being treated directly with amoxicillin. (I didn't report it either.) In the published case, urticaria occurred in a breastfed infant whose mother was treated with amoxicillin–clavulanate and gentamicin. Urticaria appeared after the first exposure to breast milk, after the mother began receiving the drugs, and recurred after the second nursing. It was not clear how or when the infant became sensitized (probably to penicillin), although the infant was also receiving formula and sensitization has occurred through cow's milk from cows treated with penicillin. Drug exposure in utero is perhaps another route of sensitization, although no documentation exists.

Other maternal drugs that caused allergic reactions in breastfed infants include single cases of rashes caused by acetaminophen, bromide, and sulfathiazole; urticaria caused by diclofenac; three cases of hepatitis caused by carbamazepine; agranulocytosis with clozapine; and one case each of thrombocytopenic purpura with valproic acid and aspirin.

Pharmacogenetic alterations can blur the line between types A and B reactions. What would initially seem to be unexpected and unpredictable reactions may actually be dose related, but at a lower dose. For example, some hemolytic reactions have occurred in infants with G-6-PD deficiency, including single cases of hemolytic anemia caused by concomitant nalidixic acid and amobarbital; concomitant propyphenazone and allobarbital; and the long-acting sulfa drug, sulfamethoxypyridazine. Fortunately, many of these drugs are no longer marketed or used extensively. Adverse reactions to codeine in CYP2D6 supermetabolizers are a more recent and salient example. As awareness of pharmacogenetic alterations becomes more common, we might be able to avoid drugs that cause these types of reactions in susceptible individuals.

One unusual case from the Netherlands was that of a 17-day-old breastfed infant who was nearly asphyxiated by miconazole gel applied to her mother's nipples. ⁷ The infant recovered after her mother removed the gel from the infant's mouth. The authors also reported nine previous cases in which miconazole gel applied directly to infants' mouths caused airway obstruction. Although miconazole gel is not available in the United States, this case does point out a possible hazard with over-application of creams and ointments to the nipples during breastfeeding without wiping off the excess before nursing. Another possible problem involves the application of ointments instead of creams to the nipple. A study found that ointments with a petroleum jelly-type base could result in a dose of long-chain hydrocarbons of up to 40 mg/kg in breastfed infants. ⁸ LactMed records on topical products note that only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins through licking.

Effects on the Microbiome

A current hot topic is the microbiome, in both breast milk and the infant. Several case reports have described major disruptions to the normal gastrointestinal flora of breastfed infants caused by antimicrobial agents. Reactions include several cases of severe diarrhea, occasionally with blood in the stools, caused by ciprofloxacin, cephalexin, metronidazole, sulfasalazine, and concurrent clindamycin and gentamicin. Five of 160 reactions reported were these major disruptions of the infant's gastrointestinal microbiome. The case associated with ciprofloxacin led to pseudomembraneous colitis, eventually requiring bowel resection in the infant. In one retrospective cohort study, 14 of 119 mothers who were taking an antibiotic reported diarrhea in their breastfed infants. ⁹ Effects on the breast milk microbiome have also been reported with cancer chemotherapy agents having antimicrobial properties such as bleomycin and doxorubicin.

The current focus has been on more subtle shifts in the bacterial makeup of the breast milk and infants' gastrointestinal tracts. Recent articles have reviewed much of the rapidly expanding knowledge on the topic.^10–12 Although we are just beginning to understand the implications of maternal antimicrobial therapy on the infant (breastfed or not), effects that have been identified include gastrointestinal health (e.g., necrotizing enterocolitis), childhood obesity, immune-related diseases, and possibly the response to childhood vaccines. As more information is published on the relationships between maternal antimicrobials, the microbiome, and infant health, it will be added to LactMed in the “Effects on Lactation and Breastmilk” section of the records.

Conclusions

Adverse reactions in breastfed infants from maternal drugs are uncommon. Age under 2 months and the use of maternal CNS depressants appear to be the most important risk factors. Among these groups, infants under 1 month, maternal opioids, and multiple concurrent CNS depressants seem to be the greatest risk factors. Excessive maternal exposure to iodine can also adversely affect the infant's thyroid. The effects of maternal drug therapy on the microbiomes of breast milk and the infant are emerging areas of interest.