Medication Information Sources for Breastfeeding Mothers

Abstract

“The answers you get depend on the questions you ask.” Thomas S. Kuhn, Physicist and Philosopher of Science

For information on the use and safety of drugs in nursing mothers, the answers you get also depend on where you look for the answers. Several studies have compared the information provided in different sources. A 2007 article found wide variation among sources queried about the advisability of using 14 commonly used drugs during lactation.¹ The most restrictive information came from official drug labeling (e.g., package insert, PDR, DailyMed [https://dailymed.nlm.nih.gov]) and data sources that used labeling as the basis of their information. These sources, which included widely used references, such as Micromedex, ePocrates, and electronic medical record drug databases, listed most or all of the 14 drugs as not safe during lactation. Evidence-based sources including LactMed and Medications and Mother's Milk listed 12 of the 14 drugs as acceptable during breastfeeding (2 of the drugs had not been studied at the time). A 2008 article comparing information on 17 beta-blocking drugs found similar discrepancies.² A 2015 article in this journal reviewed recommendations on 11 antihypertensive medications and found that the two evidence-based sources they compared, LactMed and Medications and Mother's Milk, were much more permissive toward breastfeeding during the use of antihypertensives than official labeling. European labeling was even more restrictive than U.S. labeling and it was sometimes internally inconsistent and self-contradictory.³

U.S. Labeling

The problem with lactation labeling in the United States originated in regulations promulgated by the U.S. Food and Drug Administration (FDA) in 1979, which allowed essentially only two options. In brief, the options were “do not breastfeed with this drug” or “use this drug with caution while breastfeeding,” neither of which was very informative. No mention was made of the benefits of breastfeeding. Fortunately, the FDA has recognized the shortcomings of these options and the benefits of breastfeeding in its new labeling standards called the Pregnancy and Lactation Labeling Rule (PLLR), which went into effect on June 30, 2015.⁴

The new labeling regulations require a “Lactation” section in the package insert consisting of three parts: Risk Summary, Clinical Considerations, and Data. Under the subheading, Risk Summary, “if the data demonstrate that the drug does not affect the quantity and/or quality of human milk and there is reasonable certainty either that the drug is not detectable in human milk or that the amount of drug consumed through breast milk will not adversely affect the breastfed child, the labeling must state: The use of (drug x) is compatible with breastfeeding.” When there are insufficient data the Risk Summary must state so. A statement regarding the benefits of breastfeeding is usually included.

After this statement, the Data section must summarize the drug's effect on milk production, what is known about the presence of the drug in human milk, and the effects on the breastfed child as well as the source(s) of the data (e.g., human, animal, in vitro). If human data are available, animal data are generally not included. Finally, the Clinical Considerations section provides information on ways to minimize the exposure of the breastfed infant to the drug and potential drug effects in the breastfed infant, including recommendations for monitoring or responding to these effects.

Although these labeling changes are to be applauded, there are some possible shortcomings. First, over-the-counter drugs and drugs that were approved before June 30, 2001, are exempted from labeling. Ironically, these drugs are much more likely to have breastfeeding safety data available than newer drugs. Second, these labeling changes will not be fully implemented until June 30, 2020. FDA expects that most requests for labeling changes will be submitted during 2019. Thus far, only a few hundred of the thousands of existing drug labels have been updated to meet PLLR requirements. Many of these revisions have been only changes in formatting to the Risk Summary subsection with no actual new information. However, the wording, “The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for (drug x),” is usually added, which is an improvement. Third, there is no requirement that manufacturers perform studies on their drug during breastfeeding. But on the positive side, if manufacturers do submit unpublished data to the FDA, it will be available in the package insert. Finally, it is unclear whether labeling will be updated in a timely manner after 2020 as new data become available.

To help address the lack of lactation data, the FDA issued a guidance document in 2005 for the drug industry on how to perform lactation studies. Two follow-up meetings have been held: one for the FDA Pediatric Advisory Committee in 2007 and a meeting entitled “Evaluation of the Safety of Drugs and Biological Products Used During Lactation” in April 2016. LactMed authors and consultants as well as the National Library of Medicine and the Academy of Breastfeeding Medicine were represented at this second meeting. A summary of this meeting has recently been published and selected portions of it are highlighted in the following section.⁵

Research Opportunities and Pitfalls

One problem with research into drug transfer into breast milk is that animal models poorly reflect drug transfer in humans because of interspecies differences in milk protein and lipid composition, milk pH, drug transporter systems, and some anatomical differences. Therefore, amounts of drugs excreted into animal milk can markedly differ from human milk. Even though many package inserts have statement about the drug appearing in the milk of rodents or primates, this information is generally not directly applicable to nursing mothers.

If only human data are useful, the issue of study design becomes important. In general, for new drugs with no experience in nursing mothers and infants, ethical considerations require discontinuation of breastfeeding after drug administration. This may not be acceptable for many mothers and presents some risk to the infant who will not benefit from breastfeeding. Mothers who require the drug for their own clinical care may be more suitable subjects for research than mothers with no need for the drug. One manufacturer described a rather complex and expensive postmarketing breast milk study in women with inflammatory conditions being treated at home with certolizumab pegol.^5,6 Methods of identifying nursing mothers who are taking medications are through pregnancy exposure registries, breast milk repositories (https://mommysmilkresearch.org/), and infants in neonatal intensive care units who are being supplied breast milk by their mothers. The latter method has the advantage of close monitoring of infants for any adverse effects of the drug in breast milk. Drug classes seen as research priorities include antimicrobial, anti-inflammatory, immunotherapeutic, cardiovascular, hormonal, psychotherapeutic, and neurological drugs.

Another important and unresolved issue from a regulatory perspective is the level of evidence needed before inclusion in the official labeling. Potential sources include pharmacokinetic studies, observational studies, mining of patient care databases, case reports, and computational models. Much current information on breastfeeding has been published in the form of case reports rather than well-controlled studies. Whether to include case report data in the official drug labeling is an ongoing discussion at the FDA.

Future Role of Independent Information Sources

Specialized information sources, such as LactMed and Medications and Mother's Milk, will have a continuing role to play, even after the PLLR is fully implemented. Not only will they provide information on drugs that are not covered by the PLLR but they will also probably be updated more rapidly and frequently than the product labeling, and they will probably present information that is not included in the labeling. For example, LactMed is updated monthly and attempts to provide all known published information on drugs and breastfeeding, including single case reports and possibly flawed studies, recognizing the limitations of these sources. LactMed also provides possibly safer alternative medications to use in nursing mothers, as discussed in a previous column.⁷ This level of reporting provides the prescriber both a complete picture of available data and a responsibility to judge the quality of the data and how the data apply to their patients.

Footnotes

Disclosure Statement

No competing financial interests exist.

References

Akus

, Bartick

. Lactation safety recommendations and reliability compared in 10 medication resources. Ann Pharmacother, 2007; 41:1352–1360.

Davanzo

, Rubert

, Oretti

. Meta-variability of advice on drugs in the breastfeeding mother: The example of beta-blockers. Arch Dis Child Fetal Neonatal Ed, 2008; 93:F249–F250.

Colaceci

, Giusti

, Chapin

, et al. The difficulties in antihypertensive drug prescription during lactation: Is the information consistent?. Breastfeed Med, 2015; 10:468–473.

Food and Drug Administration. Pregnancy and Lactation Labeling (Drugs) Final Rule. 2014. Available at www.fda.gov/drugs/developmentapprovalprocess/developmentresources/labeling/ucm093307.htm (accessed June 28, 2017).

Wang

, Johnson

, Sahin

, et al. Evaluation of the safety of drugs and biological products used during lactation: Workshop summary. Clin Pharmacol Ther, 2017; 101:736–744.

Thorp

, Clowse

, Forger

, et al. Evaluating transfer of certolizumab pegol into breast milk: Results from a prospective, postmarketing, multicenter pharmacokinetic study. Am J Obstet Gynecol, 2017; 216:S405–S406.

Anderson

. Choosing medication alternatives during breastfeeding, avoiding alternative facts. Breastfeed Med, 2017. PMID: 28650212.