Safety and Optimal Timing of BCG Vaccination in Infants Born to Mothers Receiving Anti-TNF Therapy for Inflammatory Bowel Disease

Abstract

1. Introduction

Among vaccine-preventable infectious diseases, tuberculosis is an important health issue worldwide and most countries require that all infants receive Bacille Calmette–Guérin [BCG] vaccination, usually at birth or within 4 weeks after birth.¹ For pregnant mothers with inflammatory bowel disease [IBD], recent guidelines recommend continuing anti-tumour necrosis factor [anti-TNF] therapy even through the third trimester based on the safety of these medications in both mothers and infants.^2–4 However, the safety and optimal timing of administering live vaccines including BCG in anti-TNF-exposed infants have yet to be determined. Current guidelines recommend that infants exposed to anti-TNF agents during the third trimester should not be given live vaccines during the first 6 months of life.^2–4 Moreover, an international multicentre study found that a small portion of infants exposed to anti-TNF agents in utero had detectable serum levels of anti-TNF agents until 12 months after birth, and thus suggested that live vaccines should be avoided during the first year of life unless drug clearance is confirmed.⁵ In addition, the American Academy of Pediatrics suggested that the appropriate timing of administering live vaccines may vary among countries depending on the respective risks of wild infection.⁶

Thus far, the data on the adverse events of BCG vaccination in infants exposed to anti-TNF agents in utero are sparse and controversial. One fatal case of BCG infection was reported in an infant who was exposed to infliximab 10 mg/kg every 8 weeks in utero, was born at gestational week 36 and received BCG vaccination at 3 months of age; however, the timing of the last infliximab infusion was not specified in the report.⁷ In a study from the Czech Republic, 15 infants who were last exposed to anti-TNF agents at a mean of gestational week 26 received BCG vaccination within 1 week of birth and did not show serious complications; however, the number of infants who were exposed to anti-TNF agents in the third trimester was not specified.⁸ In a recent French study using a health insurance database, 29 children who were exposed to anti-TNF agents within 12 weeks before delivery received BCG vaccination before 6 months of age without severe adverse events.⁹ These results suggest that there is a gap in our knowledge regarding the safety and optimal timing of BCG vaccination in infants exposed to anti-TNF agents in utero, especially in a tuberculosis-endemic area.

Therefore, we evaluated the safety and optimal timing of BCG vaccination in infants born to mothers who were receiving anti-TNF therapy due to IBD in a tuberculosis-endemic area.

2. Materials and methods

Ten hospitals in Korea participated in this retrospective study. We included infants exposed to anti-TNF agents in utero due to their mothers receiving anti-TNF therapy for IBD between 2010 and 2019; 18 of the mothers were described in our previous study.¹⁰ Through medical record review and patient interview, we collected data on maternal IBD including age at diagnosis, date of diagnosis, smoking status, disease location and behaviour for Crohn’s disease [CD] and disease extent for ulcerative colitis [UC] by the Montreal classification,¹¹ and medical therapy given to mothers during pregnancy. We also collected data on birth outcomes including the last date of receiving anti-TNF agents during pregnancy, date of delivery, birth weight and congenital malformations. Information on the timing of BCG vaccination and any adverse events associated with the vaccination were also collected. Continuous variables are presented as medians with ranges, and categorical variables are presented as numbers with percentages. Fisher’s exact test was used to compare the categorical variables. All p-values < 0.05 were considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics for Windows, version 21.0 [IBM Corp.]. The institutional review boards of all participating hospitals approved this study.

3. Results

Clinical characteristics of the 74 mothers are shown in Table 1. A total of 90 infants, including four sets of twins, from the 74 mothers were included in the analysis, and their clinical characteristics are shown in Table 2. Sixty-six infants [73.3%] were exposed to infliximab [5 mg/kg every 8 weeks in 57 and 10 mg/kg every 8 weeks in nine] and 24 [26.7%] were exposed to adalimumab [40 mg every 2 weeks in 23 and 40 mg every week in one]. The median gestational week at last exposure to anti-TNF agents was 30 [range, 12–37]: 29 weeks [range, 12–36] for infliximab and 31 weeks [range, 13–37] for adalimumab.

All infants received BCG vaccination at a median of 6 months [range, 0.25–11] after birth. The infant who received BCG vaccination at the earliest age [1 week after birth] had been last exposed to infliximab at gestational week 24. Details of the BCG vaccination are shown in Figure 1. Thirty-five infants [38.9%] were exposed to the last dose of anti-TNF agents [28 infliximab and seven adalimumab] before the third trimester [median gestational week: 24] and one infant [2.9%] showed swelling of the injection site and axillar lymphadenopathy. The other 55 infants [61.1%] were exposed to the last dose of anti-TNF agents [38 infliximab and 17 adalimumab] during the third trimester [median gestational week: 32], ten [six infliximab and four adalimumab] of whom received BCG vaccination within 3 months of age. Of these 55 infants, two [3.6%] experienced adverse events [swelling of injection site, n = 2; axillar lymphadenopathy, n = 1]. The details of infants who experienced adverse events after BCG vaccination are provided in Table 3. The rates of adverse events did not differ significantly between infants who were last exposed to anti-TNF agents before the third trimester and those who were last exposed in the third trimester [2.9% vs 3.6%; p = 1.0]. Adverse events occurred in three of the 66 [4.5%] infants who were exposed to infliximab and in none of the 24 infants who were exposed to adalimumab [p = 0.562]. All adverse events resolved spontaneously and there were no serious adverse events such as the development of active tuberculosis infection or death.

Figure 1.

Flowchart of the study population according to the timing of last exposure to anti-tumour necrosis factor therapy and Bacille Calmette–Guérin vaccination.

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4. Discussion

This is the largest study to date that has evaluated the safety of BCG vaccination in infants born to mothers who received anti-TNF therapy due to IBD. We did not observe any adverse event in infants who received the BCG vaccine later than 6 months after birth, which supports the recommendations from current guidelines. This result also suggests that if early vaccination is necessary, BCG vaccination does not have to be delayed until 12 months even if drug level testing is not available. Moreover, even in infants who received the BCG vaccine within 6 months after birth, the risk of adverse events was low and no serious adverse events were observed. This result suggests the possibility of administrating BCG vaccination earlier than the current recommendation, especially in tuberculosis-endemic areas.

In this study, we could not present the data on the serum level of anti-TNF agents at the time of BCG vaccination. A previous study on infants exposed to anti-TNF therapy in utero showed that anti-TNF agents were detected in the serum until 12 months of age.⁵ Nevertheless, low serum levels of anti-TNF agents seem to have negligible clinical significance in terms of the safety of the BCG vaccine, considering that we did not observe any serious adverse events in our infants. A study evaluating the cut-off serum level of anti-TNF agents for safe BCG vaccination would be helpful in providing a more definite answer to this issue.

During the study period, data on the safety of first-year vaccination in children born to mothers with IBD who were receiving anti-TNF agents were published using a French Health Insurance Database.⁹ In their nationwide study, 88 [13.1%] out of 670 children who were antenatally exposed to anti-TNF agents received BCG vaccination after birth; of them, 64 children [72.7%] received BCG vaccination before 6 months of age, of whom 29 [45.3%] were exposed to anti-TNF therapy within 12 weeks prior to delivery. None of these children showed BCG-related severe adverse events during their first year of life.⁹ Although this finding seems comparable with the results of the current study, there are some notable differences between the two studies. First, our study was performed in a tuberculosis-endemic area where the BCG vaccination is recommended for all children; in contrast, the French study was performed in a non-endemic area, in which only 13% of the total children who were antenatally exposed to anti-TNF therapy received the BCG vaccine, which may act as a potential selection bias. Second, data from health insurance databases lack detailed clinical information and may be prone to misclassification bias due to inaccuracy in coding.¹² In contrast, we gathered detailed information on the mothers and their children by reviewing the medical records and directly interviewing the patients. This enabled us to collect detailed data on maternal IBD, birth outcomes and any mild adverse events after BCG vaccination. Taken together, the findings of the current study may have a stronger clinical value, especially for tuberculosis-endemic areas. However, the findings of the current study should be interpreted with caution considering its retrospective design that the data were obtained from tertiary referral centres.

In conclusion, BCG vaccination after 6 months of age is of low risk in infants born to IBD mothers on anti-TNF therapy. Also, our results suggest that the optimal timing of BCG vaccination in infants exposed to anti-TNF agents in utero may be determined based on the risk–benefit assessment of BCG vaccination according to the prevalence of tuberculosis in each country.

Funding

None.

Conflict of interest

SKY received a research grant from Janssen Korea, but this grant is not related to the topic of the current study. The remaining authors disclose no conflicts.

Author Contributions

Study concept and design: SHP, SJ, SKY. Acquisition of data: SHP, HJK, CKL, SJ, EMS, SK, BIJ, ESK, KOK, YJL, EYK, YJJ, SP, DIP, BDY, SKY. Statistical analysis and interpretation of data: SHP, SKY. Drafting of the manuscript: SHP, SKY. Critical revision of the manuscript for important intellectual content: SJ, SKY.

Acknowledgments

None.

References