Current guidelines for treating inflammatory bowel disease (IBD) advise women to maintain immunomodulating therapy during pregnancy because relapse has been associated with unfavorable pregnancy outcome.1 Most IBD drugs, including biologics such as antitumor necrosis factor alpha (anti-TNFα) are considered of low-risk during pregnancy because no increase of congenital malformations has been reported so far. However, the effects on the developing immune system are largely unknown.
Anti-TNFα drugs are transferred across the placenta both passively and actively, leading to high concentrations of anti-TNFα in the neonate.2 Intrauterine exposure extends beyond the neonatal period because of the long half-life of this biologic, which is at least twice as long as in adults.2 Anti-TNFα can at times still be detected 12 months after birth.2 An infant who died of disseminated Bacillus Calmette-Guérin following Bacillus Calmette-Guérin vaccination associated with exposure to anti-TNFα in utero has been reported.3 Therefore, it is advised to avoid live attenuated vaccines until the levels of anti-TNFα are undetectable.1 Moreover, concerns are raised about the protective efficacy of routine vaccinations in these children. Several studies have suggested inadequate response to Haemophilus influenzae vaccine4 or response rates that were lower than historically reported.5 Others have observed hypogammaglobulinemia, neutropenia and changes in T and B cell phenotype.6 In this retrospective cohort study, we report on the response to vaccination in 27 children who were exposed to anti-TNFα in utero.
For this retrospective study, we collected the data of routine clinical follow-up of children who have been exposed to anti-TNFα in 3 Dutch General Hospitals (Amphia Hospital, Breda; Haga Teaching Hospital, Juliana Children’s Hospital, The Hague and Haaglanden Medical center, The Hague). These data included the measurement of immunoglobulin levels, leukocyte count, lymphocyte subsets and response to routine vaccinations, given the previous observations of possible effects on the immune system.3
The available data from routine clinical care and laboratory data of 40 children were retrospectively collected and anonymized for analysis; therefore, informed consent was waived. The study was approved by the medical ethical committee Leiden-Den Haag-Delft.
Children were vaccinated in the first year of life according to the Dutch National Immunisation Programme (RVP): diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus and H. influenzae type B vaccine (DTP-HBV-IPV-Hib) (Infanrix Hexa, Glaxo Smith Kline Biologicals, Belgium) was administered at 2, 3, 4 and 11 months of age; 10-valent conjugated pneumococcal vaccine (Synflorix, Glaxo Smith Kline Biologicals, Belgium) at 2, 4 and 11 months of age.
Children were clinically monitored, concentration of anti-TNFα drug and immunologic assays (immunoglobulin levels, leukocyte count and lymphocyte subsets) were performed at birth (cord blood), 3, 5 and 12 months of age according to the routine clinical follow-up schedule.
Vaccination response was measured 1 month after primary vaccination series (age 5 months) or 1 month after the booster vaccination (age 12 months).
IgG antibody concentrations against the capsular polysaccharide polyribosylribitol phosphate (PRP) of Hib, pertussis antigen PT and pneumococcal capsular polysaccharides were measured with a fluorescent multiplex immunoassay at the participating hospitals. IgG antibody concentrations against PRP of Hib were measured using VaccZyme Human Anti-Haemophilus influenzae type b Enzyme immunoassay Kit (Binding Site Group Ltd, Birmingham, UK, Lower limit of quantification [LLOQ] 0.11 µg/mL) or in-house Elisa (LLOQ 0.35 µg/mL). For measuring the IgG antibody concentrations against pneumococcal serotypes, in-house Luminex ELISAs were used in the participating hospitals. LLOQ differed between 0.01 and 0.04 µg/mL for the measured pneumococcal serotypes. For IgG antibody concentration against Pertussis toxin antigen Serion ELISA Classic Bordetella Pertussis IgG (Serion Diagnostics, Wurzburg, Germany, LLOQ 10 IU/mL) or CLIA Bordetella pertussis toxin IgG (Selinion, ‘s Hertogenbosch, The Netherlands, LLOQ 6 IU/mL) were used.
In 2 hospitals, a response to pneumococcal vaccine was evaluated by measuring specific pneumococcal antibody concentration against serotypes 6B, 9V, 14, 19F, 23F, and in the third hospital against serotypes, 1, 6B, 9V and 19F were measured. Serotypes that were measured in all hospitals (6B, 9V and 19F) were included in the analysis.
For Hib the protective threshold is 1.0 µg/mL or greater.7 For pneumococcal serotypes, an IgG level of 0.35 µg/mL was considered protective.8 In the absence of an established protective level of antibodies for PT, we used the arbitrary threshold of 20 IU/mL or greater.9
Anti-TNFα levels for all included infants were measured at the Sanquin laboratory using in-house developed ELISAs as previously described.10
Data on the response to vaccination were plotted in relation to anti-TNFα levels at birth for each individual patient.
Statistical analyses were performed using IBM SPPS (version 26.0; Chicago, IL). Descriptive statistics of continuous variables are depicted as geometrical mean concentrations or medians with minimum and maximum values. Categorical variables are displayed in absolute numbers and percentages. Spearman correlation was used for bivariate correlation analysis between non-normally distributed variables.
Between 2013 and 2018, follow-up of 40 infants exposed to anti-TNFα in utero was performed. The concentration of anti-TNFα at birth according to the number of gestational weeks between last maternal use of anti-TNFα and birth is shown in Figure 1A and B (Supplemental Digital Content 1, https://links.lww.com/INF/E484). There was a significant correlation between less exposure free weeks and a higher concentration of infliximab at birth. Correlation analysis of the number of exposure free weeks in 6 infants exposed to adalimumab, and the concentration of adalimumab at birth was not significant. Information on maternal medication, infants’ characteristics and basic immunologic assays are described in Tables 1 and 2 (Supplemental Digital Content 2, https://links.lww.com/INF/E485 and 3, https://links.lww.com/INF/E486). Some cases of transient lymphopenia (2 infants at age 3 months, 1 infant at 5 months), neutropenia (1 infant at 3 months of age, 1 infant at 12 months of age) or hypogammaglobulinemia (low IgA in 7, 3 and 1 infant at age 3, 5 and 12 months, respectively; low IgG in 2 infants at age 3 months and 2 infants at age 6 months) were detected. Vaccination response to at least one of the routine vaccinations was measured in 18 patients after the primary set of routine vaccinations (Figure 2A and Table 3A, Supplemental Digital Content 4, https://links.lww.com/INF/E487) and in 9 patients after booster vaccination (Figure 2B and Table 3B, Supplemental Digital Content 4, https://links.lww.com/INF/E487 and 5, https://links.lww.com/INF/E488). At 5 months of age response to Hib vaccine was <1.0 μg/mL in 3 of 17 infants (18%). In 3 of 16 patients (19%), the response to pertussis vaccine was inadequate. The percentage of infants with serotype-specific pneumococcal antibody concentration <0.35 μg/mL varied depending on the specific serotype and was highest for 6B (24%) (Table 3A, Supplemental Digital Content 3, https://links.lww.com/INF/E486). Correlation analysis only showed a significant correlation between concentration of anti-TNFα at birth and vaccination response to pneumococcal serotype 19F at 5 months of age. Response to vaccination below protective thresholds for other vaccinations were seen at variable anti-TNFα levels (Figure 2A and B, Supplemental Digital Content 2, https://links.lww.com/INF/E485).
One premature born infant born at 29 6/7 weeks suffered from a PCR proven Bordetella pertussis infection 8 weeks after birth with severe apnea’s requiring intubation and ventilation. This infant also had a transient mild neutropenia (0.99 × 10E9/L) and a low IgG at 3 months of age. Both blood cell count and IgG levels were normal at 5 months of age. One infant required antibiotic treatment at one month of age for a skin infection after the use of a scalp electrode during delivery. Two patients had recurrent upper airway infections, for which 1 patient received antibiotics on 4 occasions during the first year of life.
To our knowledge, this is the first study in infants exposed to anti-TNFα to describe response to vaccination after the primary set of routine vaccinations. Previous studies in children exposed to anti-TNFα reported on vaccination after booster vaccine and therefore at an older age.4,5
Concerns have been raised on the effects of intrauterine exposure to anti-TNFα on the developing immune system and response to vaccination. Especially since anti-TNFα levels are often within therapeutic range in the first months of life, as was also shown in our cohort. Studies in adults with IBD using anti-TNFα alone or in combination with immunomodulators have shown decreased response to pneumococcal vaccine11 and lower pertussis antibodies.12
In our study, the overall response to Hib and pneumococcal vaccine seems comparable with healthy infants, but response to vaccination at 5 months was below the protective threshold in 18% and 24% of exposed infants, respectively. Correlation analysis only showed a significant correlation between concentration of anti-TNFα at birth and vaccination response on pneumococcal serotype 19F at 5 months of age. The response to other pneumococcal serotypes and Hib was below protective threshold in some children at variable concentrations of anti-TNFα. Although a healthy control group is lacking, an effect of anti-TNFα on the response to vaccination cannot be excluded at 5 months of age.
In almost 20% of infants the response to pertussis vaccine was <20 IU/mL. Interpretation of response to pertussis vaccine, however, is complicated because seroprotective cutoff values are not well defined.
Response to vaccination with Hib and pneumococcal conjugate vaccine, after booster at 12 months of age, was measured in 9 different infants and was normal in most infants. This is reassuring and in accordance with the few other studies that have been published on vaccination response in exposed children,4,5,13 although overall response rates of some vaccines included in these studies were lower than historically reported.4,5 In a recent study, serologic response to Hib vaccine was found to be inadequate in 17 of 49 (34.7%) exposed children,4 and 9 of 37 children had inadequate response to mumps (24.3%). However, measurement of vaccination response should ideally be performed 1 month after vaccination, and in these children, responses were performed almost 2 years after vaccination.
Beaulieu et al5 compared vaccination response for Hib and tetanus between 42 children exposed to biologics and 8 children exposed to either other immunosuppressive drugs or no immunosuppressive drugs. No significant differences were found, but overall response rates were lower than historically reported.5 De Lima et al13 did not observe a difference between response to hepatitis B vaccination in 15 children exposed to anti TNFα compared with 12 children not exposed to anti-TNFα.
The risk of serious infections, requiring hospitalization or antibiotic treatment in children exposed to anti-TNFα in our study did not seem to be increased, as was shown by others.6
Our study has several limitations. Our cohort was small, data were collected retrospectively, and an age-matched control group is missing. As a result, data were heterogenous with respect to gestational age, medication used and exposure free weeks during gestation. As adalimumab and infliximab have a different half-life, the effect on the development of the immune system and response to vaccination might be different. The follow-up protocol which was used for exposed infants was adjusted on clinical grounds at the discretion of the pediatrician. As a result, vaccination response was only obtained in 27 of 40 patients and some laboratory data were missing during follow-up. Because data were included from 3 different hospitals measured serotypes were different between infants from these 3 hospitals and measurements were performed at different laboratory sites. Finally, mothers used other immunomodulating therapy besides anti-TNFα. These drugs, for example, azathioprine can also be transported across the placenta and might have an effect on the development of the immune system of the infants. Given the small size of our study, we were not able to correct for co-medication.
This is the first study to provide detailed information on the response to primary vaccination series in infants exposed to anti-TNFα in utero. Response to Hib and pneumococcal vaccine seems comparable with healthy infants at 12 months (after booster vaccination). But subtle effects on the developing immune system cannot be excluded. After primary vaccination series, an inadequate response to vaccination was present in some patients and might be related to exposure to anti-TNFα. This will need to be explored in a larger controlled study.
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