Infants exposed to immunosuppressive therapy in utero or through breastmilk

• Infants exposed to immunosuppressive therapy in utero or through breastmilk can safely receive all non-live vaccines and other immunisation products (such as RSV monoclonal antibodies) as scheduled.
• Infants exposed in utero to immunosuppressive biological therapies (such as rituximab, infliximab, adalimumab and etanercept) should not receive live vaccines, including BCG vaccine, until at least 6 months of age.
• The exception is oral rotavirus vaccine, which is safe to administer to most infants exposed to biological therapies in utero, except those exposed to anti-CD20 antibodies (including rituximab).
• These recommendations are based on the current body of evidence. The decision to vaccinate should consider the type, timing and dose of drug exposure to immunosuppressive therapies in utero, with an individual risk–benefit assessment as needed. 

For more details about the immunosuppressive potential of various medications and medical conditions, see:

• Table. Types of medical conditions and immunosuppressive therapy and associated levels of immunocompromise
• Table. Immunosuppressive potential of cancer and organ rejection therapies
• Table. Immunosuppressive potential of conventional (non-biological) immunosuppressive therapies
• Table. Immunosuppressive potential of small molecule targeted therapies
• Table. Immunosuppressive potential of biological therapies
• Table. Immunosuppressive potential of corticosteroids
• Table. Immunosuppressive potential of certain medical conditions

Special considerations apply to vaccinating infants born to people taking biological therapies (such as adalimumab, etanercept, golimumab, infliximab and rituximab) while pregnant for treating autoimmune inflammatory or rheumatic disorders during pregnancy. These medications can be transferred to the fetus through the placenta. They may be detected in the infant’s blood for several months after they are born, potentially causing varying degrees of immunosuppression. In these infants, the immunosuppressive potential of biological medications is influenced by:

• the timing of administration of therapy — exposure closer to delivery is associated with a higher risk of immunosuppression.
• the number of immunosuppressive therapies used — neonates who were exposed to multiple immunosuppressive therapies in utero may have a higher rate of acute otitis media and respiratory infections during their infancy than those exposed to a single agent.¹

It is not clear whether serum drug levels collected from infants exposed to biological disease-modifying therapies in utero correlate to a clinically significant level of immune dysfunction and therefore it is not routinely recommended to measure serum drug levels before vaccinating these infants.

Infants may have ongoing exposure to biological therapies through breastmilk, but only very small quantities of these medications will be detected in breastmilk. Biological disease-modifying drugs undergo proteolysis in the stomach, resulting in an insignificant impact on the infant’s immune system.²

Infants exposed to biological therapies in utero or through breastmilk can safely receive non-live vaccines according to the routine schedule.

These infants should also receive an additional dose of PCV (pneumococcal conjugate vaccine) at 6 months of age. See Pneumococcal disease

Cellular and humoral immunity may be affected in infants exposed to biological therapies in utero. However, existing studies show adequate responses to routinely recommended non-live vaccines in these infants,^3-5 even if the infant had measurable drug levels, with no major adverse events reported.
 

Rotavirus vaccine

Most infants exposed to biological disease-modifying therapies in utero can safely receive rotavirus vaccine, except those exposed to anti-CD20 therapies such as rituximab.

Infants exposed to TNF-alpha inhibitors and other biological therapies (such as eculizumab, belimumab, vedolizumab, natalizumab) in utero have safely received oral rotavirus vaccine without significant adverse events.^6-14

Notably, infants exposed to anti-CD20 therapies (such as rituximab) should not receive oral rotavirus vaccine.^15-18 Rituximab can cross the placenta, and has been associated with low or absent B-cells in infants exposed in the 2nd or 3rd trimester in utero.^16,19 The potential immunosuppressive effects of rituximab exposure last beyond the upper age limit for administration of rotavirus vaccine (see Table. Upper age limits for dosing of oral rotavirus vaccines). Given the lack of published data on the safety of oral rotavirus vaccine in these infants, and the low incidence of rotavirus disease in Australia,²⁰ these infants should not receive rotavirus vaccine.

BCG vaccine

Infants exposed to biological therapies in utero should not receive BCG vaccine until they are at least 6 months of age. This is due to the risk of disseminated disease.

Some studies report that infants who were exposed to biological disease-modifying therapies in utero and received BCG vaccine at age <6 months did not experience serious adverse events.^21,22 However, there are case reports of deaths in infants exposed to TNF-alpha inhibitors in utero who received BCG vaccine at ≤3 months of age.^2,3,23

Other live vaccines

Although safety data is limited, live vaccines can be considered in certain circumstances for infants aged <12 months who were exposed to biological disease-modifying therapies in utero. Examples are measles-containing vaccines (see Measles) or the yellow fever vaccine from 9 months of age before overseas travel. Consult a specialist if unsure.

Infants exposed to biological therapies in utero can safely receive all scheduled live vaccines at ≥12 months of age, including MMR (measles-mumps-rubella) and MMRV (measles-mumps-rubella-varicella) vaccines. See Table. Administration of non-live and live vaccines to infants exposed to biological immunosuppressive therapies in utero.

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2. Russell MD, Dey M, Flint J, et al. British Society for Rheumatology guideline on prescribing drugs in pregnancy and breastfeeding: immunomodulatory anti-rheumatic drugs and corticosteroids. Rheumatology 2023;62:e48-88.
3. Gisbert JP, Chaparro M. Vaccines in children exposed to biological agents in utero and/or during breastfeeding: are they effective and safe? Journal of Crohn's and Colitis 2023;17:995-1009.
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5. Berkhout A, Clark JE, Wen SC. In utero exposure to biologic disease-modifying anti-rheumatic drugs and effects to the infant: infectious complications, vaccine response, and safety of live vaccine administration. Expert Review of Vaccines 2019;18:495-504.
6. Jurgens M, Brand S, Filik L, et al. Safety of adalimumab in Crohn's disease during pregnancy: case report and review of the literature. Inflammatory Bowel Diseases 2010;16:1634-6.
7. Nielsen OH, Loftus EV, Jr., Jess T. Safety of TNF-α inhibitors during IBD pregnancy: a systematic review. BMC Medicine 2013;11:174.
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9. Moens A, van Hoeve K, Humblet E, et al. Outcome of pregnancies in female patients with inflammatory bowel diseases treated with vedolizumab. Journal of Crohn's and Colitis 2019;13:12-8.
10. Hallstensen RF, Bergseth G, Foss S, et al. Eculizumab treatment during pregnancy does not affect the complement system activity of the newborn. Immunobiology 2015;220:452-9.
11. Haghikia A, Langer-Gould A, Rellensmann G, et al. Natalizumab use during the third trimester of pregnancy. JAMA Neurology 2014;71:891-5.
12. Schneider H, Weber CE, Hellwig K, Schroten H, Tenenbaum T. Natalizumab treatment during pregnancy – effects on the neonatal immune system. Acta Neurologica Scandinavica 2013;127:e1-4.
13. Julsgaard M, Christensen LA, Gibson PR, et al. Concentrations of adalimumab and infliximab in mothers and newborns, and effects on infection. Gastroenterology 2016;151:110-9.
14. Esteve-Solé A, Deyà-Martínez A, Teixidó I, et al. Immunological changes in blood of newborns exposed to anti-TNF-α during pregnancy. Frontiers in immunology 2017;8:1123.
15. Fitzpatrick T, Alsager K, Sadarangani M, et al. Immunological effects and safety of live rotavirus vaccination after antenatal exposure to immunomodulatory biologic agents: a prospective cohort study from the Canadian Immunization Research Network. The Lancet Child and Adolescent Health 2023;7:648-56.
16. Bass AR, Chakravarty E, Akl EA, et al. 2022 American College of Rheumatology guideline for vaccinations in patients with rheumatic and musculoskeletal diseases. Arthritis Care and Research 2023;75:449-64.
17. Zerbo O, Modaressi S, Goddard K, et al. Safety of live-attenuated vaccines in children exposed to biologic response modifiers in utero. Pediatrics 2022;150:e2021056021.
18. Dinelli MI, Dos Santos AM, Weckx LY, de Moraes-Pinto MI. Safe administration of rotavirus vaccine in a cohort of infants exposed to immunosuppressive drugs during gestation. Transpl Infect Dis 2018;20:e12951.
19. Ling J, Koren G. Challenges in vaccinating infants born to mothers taking immunoglobulin biologicals during pregnancy. Expert Review of Vaccines 2016;15:239-56.
20. Maguire JE, Glasgow K, Glass K, et al. Rotavirus epidemiology and monovalent rotavirus vaccine effectiveness in Australia: 2010–2017. Pediatrics 2019;144:e20191024.
21. Luu M, Benzenine E, Barkun A, et al. Safety of first year vaccination in children born to mothers with inflammatory bowel disease and exposed in utero to anti-TNFα agents: a French nationwide population-based cohort. Alimentary Pharmacology and Therapeutics 2019;50:1181-8.
22. Park SH, Kim HJ, Lee CK, et al. Safety and optimal timing of BCG vaccination in infants born to mothers receiving anti-TNF therapy for inflammatory bowel disease. Journal of Crohn's and Colitis 2020;14:1780-4.
23. Cheent K, Nolan J, Shariq S, et al. Case report: fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn's disease. Journal of Crohn's and Colitis 2010;4:603-5.