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When is the appropriate time to administer vaccines to an infant whose mother received anti-tumour necrosis factor (anti-TNF) alpha immunosuppressants during pregnancy?
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  1. Bryan Padraig Finn1,
  2. John Fitzsimons1,2
  1. 1 General Paediatrics, CHI at Temple Street, Dublin, Dublin, Ireland
  2. 2 Emergency Department, Temple Street Children's University Hospital, Dublin, Ireland
  1. Correspondence to Dr Bryan Padraig Finn, Paediatrics, University Hopsital Limerick, Limerick D01YC67, Ireland; 112305976{at}umail.ucc.ie

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Scenario

A mother being treated for rheumatoid arthritis has been advised by her rheumatologist not to give any vaccines to her child until he is over 6 months of age but now seeks a second opinion. She reports that this advice was given because she was receiving etanercept before conception but was switched to certolizumab prior to the second trimester which was continued until delivery. She breast fed for a few days following delivery.

Structured clinical question

In infants born to mothers receiving anti-tumour necrosis factor (anti-TNF) alpha, immunosuppressants during pregnancy (population), is the administration of live and non-live vaccines prior to 6 months of age (intervention) associated with an increased risk of vaccine-related adverse events and/or reduced efficacy (outcome) when compared with infants whose mothers did not receive anti-TNF therapy (control)?

Search

Primary sources: PubMed from inception to 04 January 2020 using (vaccin* OR immunization) AND (immunosuppress* OR TNF alpha blockers OR TNF OR etanerecept OR certolizumab OR infliximab) AND (infant OR neonat* OR mother OR parent). A total of 5377 results returned. Of these studies, only 43 papers were initially returned which were relevant including further studies obtained from the references of papers found in the original search. Seven papers were analysed in detail as per the attached table.

Secondary sources: Cochrane from inception to 30 March 2020 using vaccin*—141 results returned, no studies relevant. (vaccin* OR immunization) AND (immunosuppress* OR TNF alpha blockers OR TNF OR etanerecept OR certolizumab OR infliximab OR biologics) AND (infant OR neonat* OR mother OR parent)—10 Cochrane reviews returned—no results relevant. Seven hundred twenty-one trials returned—two trials relevant—of these, only one had been carried out which the PubMed search had found, the second remained an uncompleted methodology but no results or paper available.

Commentary

An increasing number of infants are born to mothers receiving anti-TNF agents as part of their treatment for inflammatory conditions, for example, inflammatory bowel disease.1 The rheumatologist’s advice not to administer any vaccinations until after 6 months is at odds with UK and Irish national immunisation guidelines, which advise avoiding live vaccines before 6 months but recommend non-live vaccines as normal.2 3 The avoidance of live vaccines is in keeping with two international consensus statements advising against live vaccinations until after 6 months of age following antenatal anti-TNF exposure.4 5

In Ireland and the UK, the only live vaccine routinely given in the first 6 months of life is the rotavirus vaccine, with the recommendation that all doses are given before 24 weeks in the UK and 8 months in Ireland.6 7 Public Health England states that the ‘rotavirus vaccine should not be administered to infants whose mothers have used biological medicines, such as Infliximab, during pregnancy and/or breastfeeding’.7 In the UK, BCG vaccination is not routine but is given to babies considered at risk of developing tuberculosis (TB) while unavailable in Ireland. It is recommended for maximum immune response that the BCG is given at birth but UK immunisation guidance recommends BCG should be delayed for 6 months in children exposed to antenatal biological therapy.8

The conclusions of the two international statements were based, in part, on a case report of fatal, disseminated TB in an infant who received the BCG vaccine at 3 months of age whose mother had received infliximab antenatally.9

Since then, there have been a small number of cohort studies assessing the BCG vaccine which have shown little evidence of significant harm. In the tuberculous endemic area of Korea, only 2 of 55 children with third trimester anti-TNF exposure who received the vaccine at a median age of 6 months (10 of 55 within the first 3 months) experienced an adverse reaction (swelling at injection site n=2, axillary lymphadenopathy n=1).10 Sixty-four children in non-endemic France exposed to anti-TNF (n=29 third trimester exposure) who received the BCG before 6 months did not experience a severe adverse event during the first year of life.11 Of 13 infants exposed to antenatal infliximab who received the BCG within the first week of life, 3 children developed a large local skin reaction, 1 of whom was further complicated with axillary lymphadenopathy.12 Of note, in all three studies, all adverse events were either local skin reactions or adenopathy.10–12

Regarding the rotavirus vaccine safety profile in the context of intrauterine maternal immunosuppression, one study found that there was no statistically significant difference in the incidence of diarrhoea post-vaccination and no patients experienced any vaccination-related hospitalisations.13 In a similar study, 17.5% of infants experienced a reaction, all of which were mild (fever or diarrhoea) following antenatal exposure to anti-TNF, no different than the rates reported for the general population (fever 42%, diarrhoea 19%).14 15

Decisions regarding rotavirus vaccination must be weighed against the increased risk of intussusception in infants whose first dose of rotavirus vaccine is given after 3 months.16 The necessity of the rotavirus vaccine for every child also needs to be considered as evidence of herd immunity has been demonstrated, with unimmunised children experiencing reduced hospital admissions and death.17

The specific anti-TNF agent used does not currently influence the decision on when to administer live vaccines, although it might. There are several anti-TNF agents including infliximab and adalimumab which are IgG1 antibodies. Transfer of these antibodies is low until the third trimester when they may exceed maternal levels.18 19

In contrast, certolizumab is a PEGylated Fab fragment of the anti-TNF antibody, crossing the placenta much more slowly through passive diffusion rather than by FcRn-mediated active transport as occurs with whole antibodies like infliximab.20–22 Cord blood levels for infliximab and adalimumab can be 150%–160% that of the mothers, but certolizumab is much less (3.9%) due to this minimal placental transfer.23 It takes 2–7 months for infliximab to become undetectable in infants, 11 weeks for adalimumab on average but levels were undetectable for certolizumab at birth.23 Some authors have questioned the need to avoid rotavirus vaccination in infants exposed to certolizumab pegol on this basis.24

Concerns regarding potentially reduced vaccine efficacy following antenatal anti-TNF exposure have been extensively examined. Prospective observational studies suggest no statistically significant difference in quantitative antibody responses at 6–7 months of age in infants post-tetanus and Haemophilus influenzae type B (HiB) vaccination(table 1).14 25 Equally, there was no difference in the rates of protective antibody formation in infants with very high biological concentrations (>20 µg/mL) at delivery.25 Duricova et al’s large, prospective case–controlled study did reveal suboptimal serological responses for Haemophilus and mumps vaccinations but the remainder of the Czech vaccination regimen resulted in normal humoural responses.26 De Lima et al found no difference in achieving satisfactory hepatitis B vaccine levels by 1 year of age irrespective of third trimester exposure.27 Many of these studies used post-immunisation antibody titres which act as a surrogate marker of vaccine efficacy which will have obvious deficits, yet still remain the best objective measure available to assess vaccine responses.28

Table 1

When is the appropriate time to administer vaccines to an infant whose mother received anti-tumour necrosis factor (TNF) alpha immunosuppressants during pregnancy?

Bortlik et al found no long-term negative impact on the developing immune system with detectable antibody levels against tetanus, Streptococcus pneumoniae, diphtheria and rubella.12

Regarding HiB, all children had measurable antibody levels, but 6 of 15 had levels below 1 mg/L, the threshold for reliable protection.12 There was no increase in infection rates or antibiotic use in these children.12

Current advice recommends the routine administration of all non-live vaccines to infants born to mothers receiving anti-TNF agents as there is no evidence of reduced efficacy or safety concerns.26 Regarding live vaccination after maternal infliximab, the rotavirus schedule could still be accomplished in the UK by delaying rotavirus administration to 4 and 6 months (two doses before 8 months) of age as per Irish guidelines. In the case of an infant born to a mother on certolizumab, it is likely safe to proceed with rotavirus vaccination as per both the UK and Irish schedules. MMR (Measles, Mumps and Rubella) is safe to administer at 1 year of age as there have been no residual levels of anti-TNF found in infant blood.28 BCG appears safe from 6 months of age onwards and is likely of low risk before 6 months of age so can be given earlier as per local guidelines if needed in endemic areas.29–31 We would recommend including parents in the risk–benefit discussion of BCG vaccination—in a low endemic setting such as Ireland and much of the UK, vaccination benefit is of questionable value. Most TB is transmitted within the household and screening of adults, including the mother who is on anti-TNF treatment, is likely to offer more health benefit for both the mother and infant. Equally, we should encourage all treated mothers to continue to breast feed as there is minimal delivery of anti-TNF via breastmilk.28

Paediatricians need to have greater awareness of medications used to treat mothers during pregnancy, especially those whose effect extends beyond the neonatal period. Likewise, adult physicians need an understanding of the implications of medications on infants of mothers treated, in particular which immunisations may be impacted so as they can give accurate advice and facilitate informed decision-making.

Clinical bottom line

  • Current advice recommends the routine administration of all non-live vaccines to infants born to mothers receiving anti-tumour necrosis factor (anti-TNF) agents as there is no evidence of reduced efficacy or safety concerns (Grade B recommendation).

  • For infants exposed to antenatal anti-TNF agents, rotavirus vaccination can still be accomplished by delaying vaccination to 4 and 6 months of age, except for certolizumab where infants may follow the routine schedule (Grade B recommendation).

  • The BCG appears safe from 6 months of age onwards and is likely of low risk before 6 months of age so can be given earlier as per local guidelines if needed in highly endemic areas (Grade C recommendation).

Ethics statements

Patient consent for publication

Acknowledgments

We would like to especially thank Professor Jonathan Hourihane, Consultant Paediatrician; Dr Clodagh Lowry, Consultant Paediatric Rheumatologist; and Dr Rob Cunney, Consultant Paediatric Microbiologist at CHI at Temple Street, Dublin, Ireland for taking the time to read our manuscript and provide excellent constructive feedback.

References

Footnotes

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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