Breastfeeding with Inflammatory Bowel Disease

Aminosalicylates

Aminosalicylates are all mesalamine derivatives. The original drug in this category, sulfasalazine, is the least preferred, because it carries the sulfa drug, sulafpyridine attached to mesalamine. Mesalamine itself is fairly short acting and releases high in the intestine, so various formulations have been made to improve its release characteristics. For example, balsalazide is inactive until it is metabolized by gut bacteria into mesalamine and a carrier compound. Olsalazine is also a mesalamine prodrug. The prodrugs are poorly absorbed. Mesalamine is metabolized to 5-acetyl-aminosalicylate (acetyl-5-ASA), which can be detected in breast milk in small amounts as can mesalamine. In general, breastfed infants tolerate mesalamine and acetyl-5-ASA well in breast milk. Although the overall rate of side effects has not been greater in infants whose mothers were taking mesalamine products, several credible cases of infant diarrhea have been reported, including after mesalamine rectal suppositories in the mother. Virtually all experts and guidelines consider mesalamine derivatives to be safe during breastfeeding but recommend observing breastfed infants for diarrhea.

Immunomodulators

Cyclosporine was originally used as an immunosuppressant in transplant patients, but is now also used in inflammatory bowel disease. Most of the information on its use in nursing mothers comes from the transplant population. The cyclosporine concentration in milk is variable. With typical maternal cyclosporine blood levels, a completely breastfed infant would usually receive no more than about 2% of the mother's weight-adjusted dosage and often <1%. These doses also correspond to <2% of the infant maintenance dosage. Most infants studied have not had detectable cyclosporine blood levels, but two infants have had measurable levels, one with blood levels in the therapeutic range despite relatively low maternal milk levels. Numerous infants have been breastfed during maternal cyclosporine use, usually with a concurrent corticosteroid. No reports of adverse effects on infants' growth, development or kidney function have been reported, although thorough follow-up examinations have not always been performed or reported. The view on the use of cyclosporine during breastfeeding has evolved as more experience has been recorded, such that most sources now deem cyclosporine acceptable to use in nursing mothers.^3,4 Breastfed infants should be monitored if this drug is used during lactation, possibly including measurement of serum levels if there are signs of possible toxicity.

The thiopurines, azathioprine, and mercaptopurine have a relatively large amount of published experience in nursing mothers. Although most patients take azathioprine, mercaptopurine is one of its active metabolites, so the two drugs are usually considered together. Studies in women with inflammatory bowel disease, systemic lupus erythematosus or transplantation taking doses of azathioprine up to 200 mg daily for immunosuppression have found either low or unmeasurable levels of the active metabolites in milk and infant serum. Some evidence indicates a lack of adverse effects on the health and development of infants exposed to azathioprine during breastfeeding up to 3.5 years of age, but long-term follow-up for effects such as carcinogenesis have not been performed. Mothers with decreased activity of the enzyme that detoxifies azathioprine metabolites may transmit higher levels of drug to their infants in breast milk. Cases of mild asymptomatic neutropenia have been reported in breasted infants. It might be desirable to monitor exclusively breastfed infants with a complete blood count with differential, and liver function tests if azathioprine is used during lactation, although some authors feel that monitoring is unnecessary. Avoiding breastfeeding for 4 hours after a dose should markedly decrease the dose in breast milk.

Methotrexate is usually used in low, weekly doses as an immunosuppressant. Published data indicate that single maternal doses of methotrexate up to 92 mg (1.12 mg/kg) produce low levels in milk, leading some authors to state that low single or weekly doses are of low risk to the breastfed infant. However, much expert opinion warns against use of methotrexate in inflammatory bowel disease because of the small amount of published evidence. ³ Withholding breastfeeding for 24 hours after a weekly low dose of methotrexate may decrease the infant's dose by 40%. If breastfeeding during long-term low-dose methotrexate use is undertaken, monitoring of the infant's complete blood count and differential should be considered.

Tofacitinib is a small molecule immune modulator, although its mechanism is more specific than older immunosuppressants. It is a Janus kinase (JAK) inhibitor that modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of signal transducers and activators of transcription in the cell. No information is available on tofacitinib during breastfeeding. Because of its potential serious toxicity and likely passage into milk, breastfeeding should be discontinued during tofacitinib therapy and for 18 hours after the last dose of the immediate-release form or for 36 hours after the last dose of the sustained-release formulation. Tofacitinib is given once or twice daily and a course of therapy is 8 weeks or more. So, in practice, breastfeeding will likely need to be discontinued permanently if tofacitinib is used.

Biologicals

Biological therapies for inflammatory bowel disease are monoclonal antibodies directed against various inflammatory mediators, such as tumor necrosis factor (adalimumab, certolizumab, golimumab, and infliximab); integrins (natalizumab and vedolizumab); or interleukins 12 and 23 (ustekinumab). In theory, these drugs should not enter milk because of their high molecular weight of >140,000 Da. And, if they do enter the milk, they should be inhibited from absorption by the infant because they are proteins that can be digested in the gut. Although most of the individual agents have not been studied sufficiently to verify the theory, the cumulative information on monoclonal antibodies from case reports and the PIANO registry appears to confirm the theory. Levels of all of the monoclonal antibodies in milk range from undetectable to extremely low and blood levels in infants are usually undetectable. No adverse effects have been reported in any infants exposed to monoclonal antibodies in breast milk.

Even though certolizumab is a somewhat smaller molecule than the others (91,000 Da), levels in milk are minuscule. Certolizumab pegol is unusual because the manufacturer studied the drug's excretion into breast milk in a multicenter postmarketing study. Based on this study, the European Medicines Agency has deemed certolizumab pegol acceptable to use during breastfeeding.

Drugs Used for Disease Flares

Oral and rectal corticosteroids are used for disease flares. These drugs do not enter milk well. Older advice to withhold breastfeeding for a period of time after a dose is no longer thought to be necessary and no special precautions need to be taken. ³

Antibiotics are reserved for perianal disease and pouchitis. The most commonly used drugs for these conditions are amoxicillin-clavulanic acid, ciprofloxacin, and metronidazole. When one of the latter two are indicated, ciprofloxacin is generally preferred. ³ Case reports of infant candidal infections and diarrhea have been reported with maternal metronidazole use, and a comparative trial suggested that oral and rectal colonization with Candida might be more common in infants exposed to metronidazole. Because of the well-demonstrated genotoxicity and mutagenicity in bacteria, carcinogenicity in animals, and possible mutagenicity in humans, concern has been raised about exposure of healthy infants to metronidazole through breast milk. The relevance of these findings has been questioned and no definitive study has been performed in humans to clarify the risk.

Summary

Most drugs used in the treatment of inflammatory bowel disease are compatible with breastfeeding. One exception is tofacitinib that requires cessation of breastfeeding if it is used. The use of weekly methotrexate is controversial. Although no adverse effects have been reported and milk methotrexate levels are low, very few infants have been studied.