Since many patients with inflammatory bowel disease (IBD) are diagnosed in late adolescence or early adulthood, treatment decisions must often consider reproductive issues and family planning needs.1 For those taking infliximab, evidence supports the favorable safety profile of the drug during pregnancy and breastfeeding. However, some experts have debated the safety of administering live vaccines to infants exposed to tumor necrosis factor-alpha (TNF-α) inhibitors (TNFi) in utero, and the European Crohn’s and Colitis Organization and the Canadian Association of Gastroenterology have recommended delaying these vaccinations for 6 months in such cases.2

More recently, the European Medicines Agency recommended a 12-month delay in live vaccines for infants exposed to infliximab in utero or via breastfeeding.3 In response, the staff of the Lancet Gastroenterology and Hepatology published an editorial questioning the basis for this guidance and stated that the advice pertaining to exposure via breastmilk in particular does not appear to be evidence-based.4

We checked in with the following experts to gauge clinician perspectives regarding this topic: Cosby Stone, Jr., MD, MPH, assistant professor in the division of allergy, pulmonology, and critical care medicine at Vanderbilt University Medical Center; and Brigid S. Boland, MD, gastroenterologist and associate professor of medicine at the University of California, San Diego.


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What are your thoughts about the recent guidance by the European Medicines Agency?

Dr Stone: These recommendations have been made by European regulators in response to the theoretical concern that exposure to the immune-suppressing drug infliximab could transfer a temporary immune suppression to an infant in utero or while breastfeeding, which would impair the child’s ability to respond to live vaccines. While I can understand that conceptually this would be a cause for alarm, I would encourage us to slow down when considering these recommendations in the United States, in light of the very limited studies that have been done, as well as some key differences in our practice patterns in the US. 

Brigid S. Boland, MD

Dr Boland: I have reservations about some of the potential consequences of this recommendation and the lack of data to support these recommendations, particularly the risk for TNFi exposure through breastfeeding.   

I would break the recommendation into 2 parts:

The recommendation in the context of exposure to TNFi during pregnancy. Current IBD pregnancy guidelines recommend continuing therapies like TNFi during pregnancy to reduce the risk for maternal IBD flares, which is associated with better outcomes.5 During the second and third trimesters, TNFi other than certolizumab are known to cross the placenta and will be transferred to the baby. Based on current studies, it can take babies months to completely clear these medications from their bodies, though the studies examining drug concentrations in babies have some variability. However, in most studies, TNFi are undetectable by 12 months.  

With that in mind, the concerns about live vaccines in infants primarily come from a case report of an infant with TNFi exposure dying after a BCG vaccination. Studies to date have not shown adverse reactions to BCG vaccination before 6 months, nor in vaccination after 6 months.4

These current recommendations are conservative, though there are theoretical risks of live vaccination, especially during the first 6 months of life, with in utero TNFi exposure. However, I mostly agree with this. The potential downside of avoiding vaccination is the potential risk for infectious diseases in these infants. The decision should probably be influenced by the relative risk for the infections and potential mortality in a given region.    

The recommendation about babies exposed to TNFi via breastfeeding. This recommendation is where I have significant reservations. Although small amounts of TNFi can be detected in breast milk from mothers receiving TNFi, these concentrations are typically quite small.  For example, the infliximab concentration in a mother’s breast milk is approximately 1% of the maternal serum concentration.5 Furthermore, the breast milk then enters the infant’s intestinal system and may be degraded, so it is quite unlikely that any significant quantity of biologic would be absorbed and go into systemic circulation in the infant.   

I think that the evidence for this recommendation is particularly poor, and there are significant benefits to breastfeeding. There are significant potential risks related to this recommendation: Mothers may stop therapy to allow breastfeeding, or they may stop breastfeeding early based on this concern. I think that both of these scenarios have significant public health implications.  

Based on the available evidence in this area, what would you recommend to physicians who treat patients with IBD who are taking infliximab?

Dr Stone: Infliximab is a biologic agent that binds to and suppresses the inflammatory effects of the molecule TNF-α in order to decrease inflammation in certain diseases, especially those that have granulomatous-type inflammation, like IBD. For patients who are on infliximab, they have to be monitored for the possibility of infection while on treatment because TNF-α is also important in our immune responses to infections, particularly to bacteria that require the formation of granulomas to control them, like tuberculosis.   

The available evidence suggests that infliximab does cross the placenta in very small quantities, with persistence in the infant’s bloodstream for several months after birth, and that infliximab does cross into the breast milk in even smaller quantities. The available evidence does not clearly suggest whether this affects the infant’s immune system. There is 1 case report of a French infant who received the BCG vaccine after exposure to maternal infliximab during the pregnancy, in which the live bacterial strain caused a severe and ultimately fatal infection.6

However, this case report must be balanced by the fact that there are more than 150 infants in French and South Korean registries who are reported to have had the same exposures to both maternal infliximab and the BCG vaccine and did not have that outcome. The report also has to be balanced by the fact that TNF-α is not as crucially important in order to be able to respond to every type of infection or vaccine that a patient might get. 

Dr Boland: Based on the current evidence, I recommend continuing infliximab during pregnancy to optimize maternal health. There is evidence that stopping therapy will increase the risk for flare and potential preterm birth.5 The safety of infliximab during pregnancy has been studied extensively, and they have not seen increased risks for infection or negative outcomes. I recommend that mothers on infliximab breastfeed if they are able and willing, and I counsel that very little (1%) of the maternal infliximab is detectable in breast milk, so there is unlikely significant exposure to it from breastfeeding.   

I typically avoid live vaccinations during the first 6 months based on poor and limited data, and this is probably excessively conservative. In the US, the only vaccination that this affects is rotavirus, which usually does not cause mortality.    

What are additional considerations for US clinicians regarding this issue?

Dr Stone: There are 4 key pieces of information here that need to be addressed for our patients in the US:

  1. Importantly, this concern of possible infant immune suppression appears to be limited primarily to the first year of life because the exposure to infliximab or other immune-suppressing biologics in the womb appears to be out of the infant’s bloodstream typically by 6 to 7 months.  
  2. Additionally, ongoing exposure to infliximab via breastmilk appears to be exceedingly small ⁠— infant blood levels are less than 1% of maternal blood levels when the mothers are on treatment.5
  3. The BCG vaccine is not given routinely to infants in the US.  
  4. There is really only 1 live vaccine given routinely in the first year of life in the US, and it is the oral rotavirus vaccine, which contains a weakened virus, not a bacteria like BCG. A previous study in women in this particular scenario shows that at least 40 infants exposed to maternal infliximab have tolerated rotavirus vaccine safely so far. This study, called the PIANO study, also showed that infants who have been exposed to infliximab do appear to make fairly normal responses to their nonlive vaccines and would be presumably protected by them, just like infants who were not exposed to infliximab.7

What are important remaining research or treatment needs in this area?

Dr Stone: The key things that I think need to be done, if possible, would be to understand any other key differences that might exist between the case who had a bad outcome from BCG and the more than 150 other infants who are reported not to have had a problem, in case the infliximab wasn’t entirely to blame; and to continue to follow additional samples of mothers who need infliximab during pregnancy and breastfeeding, to monitor their infants and look at their responses to vaccines and infections during the first year of life. This would require doing more studies like the PIANO study and the other registries that are active around the world. 

Until then, the most important things for women who are in the scenario of needing to take immune-suppressing medications during pregnancy to consider are the following points:

If they were to become sick from their inflammatory disease during pregnancy because of stopping a drug like infliximab, getting sick may have a much greater effect on their pregnancy or their infant’s health than the effect of the infliximab itself would.

Therefore, they should have a careful discussion with their team of doctors⁠ — whoever is prescribing the infliximab, their obstetrician-gynecologist, their child’s pediatrician, and possibly an immunologist ⁠— about the use of infliximab and the timing of live vaccines. 

Dr Boland:  Additional research on this topic is definitely needed. There are so many restrictions on research in the setting of pregnancy that limits our ability to have good evidence to support recommendations.

References

  1. Brennan GT, Duong A, Nguyen ET, Nguyen DL. Are anti-TNF drugs safe for pregnant women with inflammatory bowel disease? Cleve Clin J Med. 2018;85(12):923-924. doi:10.3949/ccjm.85a.18037
  2. Bouri S, Hart AL. Editorial: how safe is it to administer the BCG vaccination to babies exposed to anti-TNFα medications antenatally? Aliment Pharmacol Ther. 2019;50:1239. doi:10.111/apt.15535
  3. European Medicines Agency. Infliximab (Remicade, Flixabi, Inflectra, Remsima and Zessly): Use of live vaccines in infants exposed in utero or during breastfeeding. Accessed online April 29, 2022. https://www.ema.europa.eu/en/medicines/dhpc/infliximab-remicade-flixabi-inflectra-remsima-zessly-use-live-vaccines-infants-exposed-utero-during
  4. The Lancet Gastroenterology Hepatology. Opacity over live vaccines in infants exposed to infliximab. Lancet Gastroenterol Hepatol. 2022;7(5):379. doi:10.1016/S2468-1253(22)00095-4
  5. Mahadevan U, Robinson C, Bernasko N, et al. Inflammatory bowel disease in pregnancy clinical care pathway: A report from the American Gastroenterological Association IBD Parenthood Project Working Group. Gastroenterology. 2019;156(5):1508-1524. doi:10.1053/j.gastro.2018.12.022
  6. Cheent K, Nolan J, Shariq S, Kiho L, Pal A, Arnold J. Case Report: Fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn’s disease. J Crohns Colitis. 2010;4(5):603-605. doi:10.1016/j.crohns.2010.05.001
  7. Beaulieu DB, Ananthakrishnan AN, Martin C, Cohen RD, Kane SV, Mahadevan U. Use of biologic therapy by pregnant women with inflammatory bowel disease does not affect infant response to vaccines. Clin Gastroenterol Hepatol. 2018;16(1):99-105. doi:10.1016/j.cgh.2017.08.041