Abstract
Many new monoclonal antibody (mAb) products have been marked for a large number of conditions. Importantly, the understanding of their impact on infants receiving breast milk has also increased and several professional guidelines have published statements on their use in lactation. This column reviews the current state of affairs. More detailed information and references on the specific drugs, when available, can be found in the corresponding LactMed records.
The mAbs are biosynthetic immunoglobulin G (IgG) proteins, mostly IgG1, with molecular weights of 145,000–150,000 Da. They are given at long intervals and their absorption from the gastrointestinal (GI) tract is minimal. In addition, the peak serum concentration typically occurs 4–7 days after a dose, but the peak can occur >2 weeks after a dose. With long-term use, serum concentrations can continue to rise and interpatient variability in drug distribution and elimination is greater than with conventional drugs. 1 These characteristics are very different from those of the small molecules on which the standard measures of drug acceptability during breastfeeding are based.
In the 1980s, the World Health Organization (WHO) formed a Working Group of experts on drug use during breastfeeding. 2 The Working Group proposed measurements of passage of drugs into breast milk that are still widely used, such as the weight-adjusted percentage of maternal dosage or relative infant dose (RID). The RID is defined as the infant's mg/kg dose of the drug from milk divided by the maternal mg/kg dose times 100 to create a percentage. The RID was based on small-molecule drugs given one or more times a day that were relatively well absorbed by the infant. Only one drug reviewed by the Working Group had negligible absorption from the GI tract, but oral drug absorption by the infant was not considered in any calculations.
As an example of applying the RID to an mAb, natalizumab was given to a mother in a dosage of 5 mg/kg given every 8 weeks (56 days) and resulted in a peak milk concentration of 2.83 mg/L. This was the highest level reported for any mAb found in a recent review of 30 articles. 3 Natalizumab is an IgG4 mAb and this IgG subclass passes into mature milk to a greater extent than other IgG classes. 4
Applying the standard RID equation to this case leads to some strange results. Since mAbs are given very infrequently, the RID can be calculated in two different ways. Either the dose could be considered a one-time dose or the dose could be apportioned across the entire dosage interval to give an average daily dose. If careful attention is paid to the units of measurement, the first calculation method gives an RID of 2.2%/day, which is not how RID is usually expressed—it is just a percentage. The second method gives an RID of 124%, which is 2.2%/day times 56 days. In other words, the calculation predicts that the infant would receive a dosage 24% greater than the mother's dosage. This is an absurd outcome for a drug that has low penetration into milk and is barely absorbed by the infant. The RID is simply not meaningful in the context of monoclonal antibodies.
The WHO Working Group also proposed that the ratio of the infant and maternal serum concentrations could be used to estimate safety. This methodology is much more reasonable for assessing mAbs. Several steps are involved in the transit of an mAb from mother to infant through milk. The first is passage across the mammary epithelium from maternal blood into milk. Reported measurements of breast milk concentrations find that mAbs are not detectable in milk in many if not most mothers, probably because of their large size. However, in some cases they are detectable, such as in the natalizumab case noted previously. 3
Second, some digestion of the mAb occurs in the infant's GI tract. Studies on digestion of the IgG1 mAb palivizumab in neonatal intestinal fluid have found an average, but variable, destruction of about 50%. 5 Applied to the maximum natalizumab concentration of 2.83 mg/L, this leaves a maximum concentration of about 1.4 mg/L in the infant's GI tract available for absorption. With a daily intake of 750 mL of milk, 6 this amounts to about 1 mg available for absorption by the infant. No direct measurement has been made in infants, but in adults, native IgG is only 0.01% absorbed intact from the GI tract. 7 This would leave a maximum of 0.01 mg entering the infant's circulation, which then distributes in the infant's body. Using an estimated volume of distribution of 0.25 L, 8 the final concentration in the infant's serum would be about 0.04 mg/L. Natalizumab's package insert states that the average serum concentration after the standard 300 mg dose of natalizumab is about 110 mg/L. So, in the most extreme case published to date, the infant would have an estimated serum concentration of about 0.04% of the mother's serum concentration. This is a trivial amount considering the Working Group proposed that an infant to maternal serum level ratio of up to 10% is acceptable. 2
Special Considerations
Certain factors could increase the amount of an mAb in infant serum. Perhaps the greatest factor occurs during the first 4–7 days postpartum before lactogenesis II occurs. During this time, the spaces between both the mammary epithelial cells and the neonate's GI epithelial cells are greater and large molecules, including IgG, can pass into milk and be absorbed by the infant. However, the colostrum volume is lower during this time, which would reduce the amount of mAb transferred into colostrum. Digestion of the mAb in the infant's gut might also be diminished during this time. Furthermore, since most mAbs are of the IgG1 class and IgG1 concentrations are higher in colostrum than IgG4, 9 infant serum concentrations of most mAbs could be higher during the colostral phase, although the exact percentage is difficult to estimate with available data. Waiting until lactogenesis II takes place to administer the first postpartum mAb dose might be a good strategy.
Mastitis can result in higher concentrations of drugs in breast milk. One study found that IgG levels in the milk of women with mastitis increased 4-fold on average, but ranged from no increase to a 35-fold increase. Subclinical mastitis, which is fairly common, may also result in increased IgG, and presumably mAbs, in milk. 10 Mastitis might explain why studies occasionally report outliers with much higher milk mAb levels than in other subjects.
Another concern that has been raised is the possibility of adverse effects of mAbs on the infant's gut. No data are available, but it seems possible that only the most toxic mAbs, such as those used to treat cancer, might be of concern. In addition, some anticancer mAbs are attached to a toxin to deliver it directly to the tumor. With these drugs, the toxin probably would be of greater concern than the mAb.
Clinical Implications and Guidelines
When given during the third trimester of pregnancy, mAbs are actively transported across the placenta. Because of their long half-lives, neonates may be born with measurable serum levels of the drugs. Of all the reports of measurable serum concentrations of mAbs in infants, only one case was possibly related to breast milk passage, although it is unclear why measurable serum levels of infliximab were found in the infant. 11 Of particular importance is that of all the cases of newborns with measurable mAb serum levels from placental transfer, none had any discernible adverse reactions reported. In addition, 368 infants who were exposed to mAbs in breast milk have been followed for at least 6 months with no reports of adverse reactions or developmental delay. 3 These finding might be somewhat skewed because nursing has generally not been allowed in mothers receiving mAbs for cancer.
Overall, several generalizations can be made: (1) most mothers receiving mAbs have unmeasurable or extremely low levels of the mAb in their breast milk; (2) about half of the mAb will be digested in the infant's tract; (3) negligible amounts of mAbs are absorbed by infants from breast milk; (4) when infants do have low but detectable blood levels of mAbs from placental transfer, no adverse reactions have been reported, although there is the potential for increased risk of infections and complications from vaccines (i.e., infection with live vaccines or poor response to inactivated vaccines) with immunosuppressive mAbs.
Given these generalizations, several specialty organizations have developed increasingly permissive guidelines for breastfeeding by mothers receiving mAbs.12–15 These specialties primarily use mAbs for inflammatory bowel disease, psoriasis, rheumatoid arthritis, and related conditions. Of particular note are the guidelines from the American Gastroenterological Association, which state that biologics for treatment of inflammatory bowel disease may be resumed 24 hours after vaginal delivery and 48 hours after cesarean delivery. 13 Labeling (i.e., package inserts) of anti-inflammatory mAbs typically state something like, “The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for the drug and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition,” placing the ultimate decision on the clinician and mother.
No breastfeeding guidelines exist from oncology groups for mAbs used to treat neoplastic diseases. In general, labeling of mAbs directed against cancers state that breastfeeding should be withheld for varying periods of time, most often about 5–6 drug half-lives. This period can amount to months, making breastfeeding impossible. However, the labeling of one mAb, daratumumab (for multiple myeloma), acknowledges that, “Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts.”
Conclusion
There is growing recognition that most monoclonal antibodies given to nursing mothers pose little risk to their infants because of their poor excretion into milk and negligible absorption by their infants. Oncological drugs are currently the exception, with breastfeeding discouraged, partly because of concern for toxicity and partly because of a lack of information. Whether this extreme caution is warranted is an open question.
Footnotes
Disclosure Statement
No competing financial interests exist.
Funding Information
No funding was received for this article.