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Hepatitis B Vaccination Effective in Children Exposed to Anti-Tumour Necrosis Factor Alpha in Utero

Hepatitis B Vaccination Effective in Children Exposed to Anti-Tumour Necrosis Factor Alpha in Utero Abstract Introduction Neonates exposed to tumour necrosis factor [TNF] alpha inhibitors in utero are born with detectable drug levels which can still be detected throughout the first year of life. Since 2011, the hepatitis B virus [HBV] vaccine is routinely administered to all newborns in the Netherlands. Adults treated with anti-TNF have been reported to respond inadequately to the HBV vaccine. The aim of this study was to compare anti-HB levels in anti-TNF-exposed children with non-exposed children following routine Dutch HBV vaccination. Methods We performed a cross-sectional, controlled cohort study from 2014 to 2017 in a single, tertiary referral centre. Pregnant women treated with anti-TNF for inflammatory bowel disease [IBD] and their subsequent children were recruited from the IBD preconception outpatient clinic. Pregnant women not treated with anti-TNF for IBD and their subsequent children were eligible as controls. Adherence to the Dutch National Vaccination Programme was mandatory for participation in this study. A venous blood sample was obtained 1 month after final HBV vaccination. Anti-HB levels were measured by enzyme-linked immunosorbent assay. Results Anti-HB levels at 12 months did not differ between the anti-TNF-exposed [n = 15] and the control group [n = 12] [> 1000 IU/l vs > 1000 IU/l, p = 0.59]. All children were successfully immunized against HBV, defined as anti-HB > 10 IU/l. Median anti-TNF levels determined in cord blood at birth were 9.0 µg/ml [interquartile range: 3.0–15.0 µg/ml] for infliximab and 0.4. µg/ml [interquartile range: 0.3–0.6 µg/ml] for adalimumab. There were no differences in general birth and health outcomes. Conclusion Children born with detectable anti-TNF levels can be effectively vaccinated against HBV. Hepatitis B, anti-TNF alpha, vaccination 1. Introduction Anti-tumour necrosis factor [TNF] alpha agents such as adalimumab [ADA] and infliximab [IFX] are commonly prescribed treatments for inflammatory bowel disease [IBD] by successfully achieving and maintaining disease remission.1 IBD is a chronic, relapsing and remitting disease, which typically affects women in their childbearing years and men in the same age range.2 Active disease during pregnancy has been associated with adverse pregnancy outcomes,3–14 although more recent publications show acceptable pregnancy outcomes by means of adequate disease control in terms of stringent IBD treatment and follow-up throughout pregnancy.15–17 Anti-TNF alpha agents have been accepted as generally low-risk drugs during pregnancy as they are not associated with an increased risk of congenital abnormalities, preterm birth, low birth weight or miscarriages.18,19 Nonetheless, anti-TNF alpha actively crosses the placenta in the second and especially the third trimester of pregnancy, resulting in detectable anti-TNF alpha levels in the neonate which can still be detectable throughout the first year of life.20–25 The effects of anti-TNF alpha on the developing immune system of the child has been scarcely investigated. Hepatitis B virus [HBV] is a major global health issue associated with significant morbidity and mortality.26 Prevention is possible through vaccination and, since 2011, the HBV vaccine is routinely administered to all infants in the Netherlands. Interestingly, several reports suggest that the HBV vaccine in IBD patients treated with anti-TNF alpha agents fails to yield protective anti-HB levels after a primary vaccination regimen.27–32 Although the efficacy of several vaccines has been investigated in children exposed to anti-TNF alpha, such as haemophilus influenza B and tetanus,33,34 the efficacy of the HBV vaccine has not previously been investigated in infants born to mothers treated with anti-TNF alpha during pregnancy. The aim of this study is therefore to assess response to the HBV vaccine in children born to IBD mothers treated with anti-TNF alpha during pregnancy in terms of anti-HB levels after the administration of the final dose of the HBV vaccine. 2. Materials and Methods 2.1. Study design We performed a cross-sectional, controlled cohort study to determine HBV immunity in children who were exposed to anti-TNF in utero. Pregnant women with IBD were informed about the study from May 2014 to December 2016 at our IBD preconception outpatient clinic [POC] of the Erasmus University Medical Centre Rotterdam, a tertiary healthcare centre. At the IBD outpatient clinic, women with IBD were counselled before pregnancy and seen every second month during pregnancy by an experienced IBD physician. During visits, women were counselled on medication use, lifestyle habits [e.g. smoking, alcohol use], folic acid intake, and the importance of disease remission before and during pregnancy. Disease activity was assessed by the treating physician and treated according to current IBD pregnancy guidelines. At birth, an umbilical cord blood sample was drawn. In this sample anti-TNF levels were measured. In the Netherlands, the HBV vaccine [Engerix-B Junior, rDNA vaccine] is routinely administered to infants in the first year of life at 6 weeks, and 3, 4 and 11 months. To determine HBV immunity, a venous blood sample was obtained from the infant at the age of 12 months, 1 month after the final HBV vaccination, to assess anti-HB levels. Anti-HB levels were measured by a commercially available enzyme-linked immunosorbent assay [ELISA]. Written informed consent from both parents was obtained before the blood sample was collected. Children with an anti-HB level of ≥ 10 IU/l were considered immune. In case of insufficient anti-HB levels [< 10 IU/l] an HBV booster vaccine was given and anti-HB measurement was repeated after 3 months. If the anti-HB level exceeded 1000 IU/l, anti-HB level was displayed as > 1000 IU/l. In addition, birth outcomes such as birth weight, gestational age and the presence of congenital abnormalities were obtained from mothers during the first visit after delivery. One year after birth, health outcomes were obtained from the general practitioner [GP] with the informed consent of both parents. The following health outcomes were collected: growth, number of infections treated with antibiotics, hospital admissions because of infection, chronic diseases, allergies, adverse reactions to a vaccination and the presence of eczema. If data from the GP were unavailable, health outcomes as reported by the mother were used. 2.2. Exclusion criteria All women with IBD who visited our outpatient clinic during pregnancy were asked to participate in this study, but the following exclusion criteria were applied: mothers infected with HBV, hepatitis C virus [HCV] or human immunodeficiency virus [HIV], children with other immunocompromising conditions and children not vaccinated according to the Dutch National Vaccination Programme. 2.3. Anti-TNF alpha-exposed group The anti-TNF alpha-exposed group consisted of children born to mothers with IBD treated with anti-TNF during part of the pregnancy or the entire pregnancy. Women in the study group were treated with anti-TNF alpha during pregnancy, at least until the end of the second trimester. In cases of sustained disease remission from 6 months before conception until gestational week 22, the option of discontinuing anti-TNF treatment was discussed in a multidisciplinary team. In all other cases, anti-TNF treatment was continued throughout the entire pregnancy. The control group consisted of children born to mothers with IBD not treated with anti-TNF, but any other IBD medication was permitted. 2.4. Definitions Abnormal growth is defined as growth or height for age and gender deviating > 2 standard deviations [SD] from the mean Dutch growth chart. Preterm birth is defined as delivery before 37 weeks of gestation. Small for gestational age [SGA] is a weight below 2 SD for gestational age according to the Dutch reference chart.35 The presence of disease activity was assessed by the treating physician and based on the combination of clinical symptoms [Harvey–Bradshaw Index > 5 or Simple Clinical Colitis Activity Index > 2], C-reactive protein > 9.0 mg/l, fecal calprotectin (FCP) measurement > 200 µg/g, and when strongly indicated, an endoscopy was performed. 2.5. Sample size In healthy children and adults, HBV immunization rates after vaccination are high and considered to be around 95%.36,37 In adult IBD patients treated with anti-TNF, immunization rates after a primary vaccination regimen are reported to be approximately 50–60%.29,31,32 At a one-sided significance level of 0.05 and a power of 80%, this would require in an anti-TNF alpha-exposed group of 12 children and a control group of the same size. 2.6. Statistical considerations All analyses were performed using IBM SPSS statistics [version 21.0]. Descriptive statistics of continuous data are displayed as medians with interquartile ranges [IQR] and compared using Mann–Whitney U tests. Categorical data are shown as absolute numbers with percentages, and compared using Chi-square or Fisher’s exact tests. The tests were performed two tailed unless stated otherwise, and tested at a significance level of 0.05. 2.7. Ethical statement This study was approved by the local ethics committee of the Erasmus Medical Centre [Rotterdam, The Netherlands]. Legal guardians of the child signed informed consent before a venous blood sample was obtained from the child and again before data were collected from the GP. 3. Results In total 192 pregnant women [86 treated with anti-TNF alpha] were invited for participation in this study. Thirty mother–child pairs were included in the study [15.6%]. Measurement of anti-HB was not performed in three children; two samples were lost because of logistical problems and one sample could not be analysed because too little blood was drawn. Therefore, these children were excluded from further analyses. Overall, there were 15 children assigned to the anti-TNF alpha-exposed and 12 children to the control group. Baseline characteristics are shown in Table 1. Table 1. Baseline characteristics [n = 27]. Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Median maternal age at conception [years, IQR] 31 [29–33] 30 [27–35] 1.00 Diagnosis [n, %]  Crohn’s disease 12 [80] 8 [67] 0.66  Ulcerative colitis 3 [20] 2 [17] 1.00  IBD unclassified 0 [0] 2 [17] 0.20 Disease location CD [Montreal] [n, %]  L1 Ileal 3 [20] 1 [13] 0.61  L2 Colonic 1 [9] 1 [13] 1.00  L3 Ileocolonic 8 [73] 6 [74] 1.00 Disease behaviour CD [Montreal] [n, %]  B1 Non-structuring non-penetrating 7 [47] 7 [88] 0.34  B2 Stricturing 1 [8] 0 [0] 1.00  B3 Penetrating 3 [25] 1 [12] 0.61  B2+ B3 Stricturing and penetrating 1 [8] 0 [0] 1.00 P Perianal fistulizing disease [n, %] 4 [29] 1 [8] 0.33 Disease extent UC/IBDU [Montreal] [n, %]  E1 Proctitis 0 [0] 2 [50] 0.47  E2 Left-sided colitis 0 [0] 2 [50] 0.47  E3 Pancolitis 3 [100] 0 [0] 0.23 Disease duration [years, IQR] 10 [7–12] 7 [4–9] 0.38 Anti-TNF type [n, %]  IFX 8 [53] – –  ADA 7 [47] – – Co-medication [n, %]  Mesalazine 2 [13] 5 [42] 0.19  Steroids [systemic] 3 [20] 2 [17] 1.00  Thiopurine 4 [27] 4 [33] 1.00 IBD surgery [n, %]  Abdominal surgery 4 [27] 2 [17] 0.66  Perianal surgery 3 [20] 0 [0] 0.22 Nulliparous [n, %] 6 [40] 4 [33] 0.68 Disease relapse during [n, %] 2 [13] 2 [17] 1.00 Smoking during pregnancy [n, %] 1 [7] 1 [8] 1.00 Folic acid intake [n, %] 15 [100] 12 [100] 1.00 Mode of delivery [n, %]  Vaginal 9 [60] 8[67] 0.70  Caesarean section 6 [40] 4 [33] 0.70 Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Median maternal age at conception [years, IQR] 31 [29–33] 30 [27–35] 1.00 Diagnosis [n, %]  Crohn’s disease 12 [80] 8 [67] 0.66  Ulcerative colitis 3 [20] 2 [17] 1.00  IBD unclassified 0 [0] 2 [17] 0.20 Disease location CD [Montreal] [n, %]  L1 Ileal 3 [20] 1 [13] 0.61  L2 Colonic 1 [9] 1 [13] 1.00  L3 Ileocolonic 8 [73] 6 [74] 1.00 Disease behaviour CD [Montreal] [n, %]  B1 Non-structuring non-penetrating 7 [47] 7 [88] 0.34  B2 Stricturing 1 [8] 0 [0] 1.00  B3 Penetrating 3 [25] 1 [12] 0.61  B2+ B3 Stricturing and penetrating 1 [8] 0 [0] 1.00 P Perianal fistulizing disease [n, %] 4 [29] 1 [8] 0.33 Disease extent UC/IBDU [Montreal] [n, %]  E1 Proctitis 0 [0] 2 [50] 0.47  E2 Left-sided colitis 0 [0] 2 [50] 0.47  E3 Pancolitis 3 [100] 0 [0] 0.23 Disease duration [years, IQR] 10 [7–12] 7 [4–9] 0.38 Anti-TNF type [n, %]  IFX 8 [53] – –  ADA 7 [47] – – Co-medication [n, %]  Mesalazine 2 [13] 5 [42] 0.19  Steroids [systemic] 3 [20] 2 [17] 1.00  Thiopurine 4 [27] 4 [33] 1.00 IBD surgery [n, %]  Abdominal surgery 4 [27] 2 [17] 0.66  Perianal surgery 3 [20] 0 [0] 0.22 Nulliparous [n, %] 6 [40] 4 [33] 0.68 Disease relapse during [n, %] 2 [13] 2 [17] 1.00 Smoking during pregnancy [n, %] 1 [7] 1 [8] 1.00 Folic acid intake [n, %] 15 [100] 12 [100] 1.00 Mode of delivery [n, %]  Vaginal 9 [60] 8[67] 0.70  Caesarean section 6 [40] 4 [33] 0.70 View Large Table 1. Baseline characteristics [n = 27]. Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Median maternal age at conception [years, IQR] 31 [29–33] 30 [27–35] 1.00 Diagnosis [n, %]  Crohn’s disease 12 [80] 8 [67] 0.66  Ulcerative colitis 3 [20] 2 [17] 1.00  IBD unclassified 0 [0] 2 [17] 0.20 Disease location CD [Montreal] [n, %]  L1 Ileal 3 [20] 1 [13] 0.61  L2 Colonic 1 [9] 1 [13] 1.00  L3 Ileocolonic 8 [73] 6 [74] 1.00 Disease behaviour CD [Montreal] [n, %]  B1 Non-structuring non-penetrating 7 [47] 7 [88] 0.34  B2 Stricturing 1 [8] 0 [0] 1.00  B3 Penetrating 3 [25] 1 [12] 0.61  B2+ B3 Stricturing and penetrating 1 [8] 0 [0] 1.00 P Perianal fistulizing disease [n, %] 4 [29] 1 [8] 0.33 Disease extent UC/IBDU [Montreal] [n, %]  E1 Proctitis 0 [0] 2 [50] 0.47  E2 Left-sided colitis 0 [0] 2 [50] 0.47  E3 Pancolitis 3 [100] 0 [0] 0.23 Disease duration [years, IQR] 10 [7–12] 7 [4–9] 0.38 Anti-TNF type [n, %]  IFX 8 [53] – –  ADA 7 [47] – – Co-medication [n, %]  Mesalazine 2 [13] 5 [42] 0.19  Steroids [systemic] 3 [20] 2 [17] 1.00  Thiopurine 4 [27] 4 [33] 1.00 IBD surgery [n, %]  Abdominal surgery 4 [27] 2 [17] 0.66  Perianal surgery 3 [20] 0 [0] 0.22 Nulliparous [n, %] 6 [40] 4 [33] 0.68 Disease relapse during [n, %] 2 [13] 2 [17] 1.00 Smoking during pregnancy [n, %] 1 [7] 1 [8] 1.00 Folic acid intake [n, %] 15 [100] 12 [100] 1.00 Mode of delivery [n, %]  Vaginal 9 [60] 8[67] 0.70  Caesarean section 6 [40] 4 [33] 0.70 Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Median maternal age at conception [years, IQR] 31 [29–33] 30 [27–35] 1.00 Diagnosis [n, %]  Crohn’s disease 12 [80] 8 [67] 0.66  Ulcerative colitis 3 [20] 2 [17] 1.00  IBD unclassified 0 [0] 2 [17] 0.20 Disease location CD [Montreal] [n, %]  L1 Ileal 3 [20] 1 [13] 0.61  L2 Colonic 1 [9] 1 [13] 1.00  L3 Ileocolonic 8 [73] 6 [74] 1.00 Disease behaviour CD [Montreal] [n, %]  B1 Non-structuring non-penetrating 7 [47] 7 [88] 0.34  B2 Stricturing 1 [8] 0 [0] 1.00  B3 Penetrating 3 [25] 1 [12] 0.61  B2+ B3 Stricturing and penetrating 1 [8] 0 [0] 1.00 P Perianal fistulizing disease [n, %] 4 [29] 1 [8] 0.33 Disease extent UC/IBDU [Montreal] [n, %]  E1 Proctitis 0 [0] 2 [50] 0.47  E2 Left-sided colitis 0 [0] 2 [50] 0.47  E3 Pancolitis 3 [100] 0 [0] 0.23 Disease duration [years, IQR] 10 [7–12] 7 [4–9] 0.38 Anti-TNF type [n, %]  IFX 8 [53] – –  ADA 7 [47] – – Co-medication [n, %]  Mesalazine 2 [13] 5 [42] 0.19  Steroids [systemic] 3 [20] 2 [17] 1.00  Thiopurine 4 [27] 4 [33] 1.00 IBD surgery [n, %]  Abdominal surgery 4 [27] 2 [17] 0.66  Perianal surgery 3 [20] 0 [0] 0.22 Nulliparous [n, %] 6 [40] 4 [33] 0.68 Disease relapse during [n, %] 2 [13] 2 [17] 1.00 Smoking during pregnancy [n, %] 1 [7] 1 [8] 1.00 Folic acid intake [n, %] 15 [100] 12 [100] 1.00 Mode of delivery [n, %]  Vaginal 9 [60] 8[67] 0.70  Caesarean section 6 [40] 4 [33] 0.70 View Large 3.1. Anti-TNF alpha-exposed group In the anti-TNF alpha-exposed group, eight [53%] children were exposed to IFX and seven [47%] children were exposed to ADA. The median anti-TNF stop week was gestational week 25 [IQR 22–29] in the IFX group and gestational week 23 [IQR 22–24] in the ADA group [p = 0.34]. Anti-TNF cord blood measurements were obtained from ten children: six IFX-exposed children and four ADA-exposed children. Median anti-TNF concentration in cord blood was 9.0 µg/ml [IQR 3.0–15.0] in IFX-exposed children and 0.4 µg/ml [IQR 0.3–0.6] in ADA-exposed children which was a statistically significant difference [p = 0.01]. However, all children in the anti-TNF alpha-exposed group responded adequately to the vaccine and were considered immune for HBV (Figure 1). There was no difference between IFX-exposed children and ADA-exposed children in HBV immune status. Figure 1. View largeDownload slide Anti-hepatitis B levels in children exposed to anti-tumour necrosis factpr alpha and controls. Figure 1. View largeDownload slide Anti-hepatitis B levels in children exposed to anti-tumour necrosis factpr alpha and controls. In addition, we separately analysed the five mothers who received anti-TNF treatment in the third trimester of pregnancy, of whom four cord blood measurements were obtained at birth. All five mothers used IFX during pregnancy. The median anti-TNF stop week in this group was gestational week 29 [IQR 27–40] and the median anti-TNF concentration in cord blood was 12 µg/ml [IQR 8–16]. Overall, all children who were exposed to anti-TNF in the third trimester of pregnancy responded adequately to the vaccine and were considered immune for HBV. None of the anti-TNF alpha-exposed children required the HBV booster vaccine. 3.2. Control group The control group consisted of 12 children. Maternal IBD medication use is shown in Table 1, which was, other than anti-TNF, similar to the anti-TNF alpha-exposed group. All children in the control group responded adequately to the vaccine and were considered immune for HBV. None of these children required the HBV booster vaccine. 3.3. Birth outcomes Birth outcomes are shown in Table 2. There were no differences between the anti-TNF alpha-exposed group and control group regarding birth weight, low birth weight, gestational age, preterm birth, SGA or the presence of congenital abnormalities. Mothers in the control group more often breastfed than mothers in the anti-TNF alpha-exposed group. Table 2. Birth outcomes [n = 27]. Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Birth weight [g, IQR] 3495 [3285–3835] 3478 [3215–3866] 0.91 Low birth weight [n, %] 0 [0] 0 [0] 1.00 Gestational age [weeks, IQR] 39.4 [38.5–41.0] 38.5 [37.6–40.0] 0.08 Preterm birth [n, %] 0 [0] 1 [8] 0.44 Small for gestational age [n, %] 0 [0] 0 [0] 1.00 Major congenital abnormalities [n, %] 0 [0] 0 [0] 1.00 Breastfeeding more than 2 weeks [n, %] 2 [14] 8 [67] 0.01 Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Birth weight [g, IQR] 3495 [3285–3835] 3478 [3215–3866] 0.91 Low birth weight [n, %] 0 [0] 0 [0] 1.00 Gestational age [weeks, IQR] 39.4 [38.5–41.0] 38.5 [37.6–40.0] 0.08 Preterm birth [n, %] 0 [0] 1 [8] 0.44 Small for gestational age [n, %] 0 [0] 0 [0] 1.00 Major congenital abnormalities [n, %] 0 [0] 0 [0] 1.00 Breastfeeding more than 2 weeks [n, %] 2 [14] 8 [67] 0.01 View Large Table 2. Birth outcomes [n = 27]. Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Birth weight [g, IQR] 3495 [3285–3835] 3478 [3215–3866] 0.91 Low birth weight [n, %] 0 [0] 0 [0] 1.00 Gestational age [weeks, IQR] 39.4 [38.5–41.0] 38.5 [37.6–40.0] 0.08 Preterm birth [n, %] 0 [0] 1 [8] 0.44 Small for gestational age [n, %] 0 [0] 0 [0] 1.00 Major congenital abnormalities [n, %] 0 [0] 0 [0] 1.00 Breastfeeding more than 2 weeks [n, %] 2 [14] 8 [67] 0.01 Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Birth weight [g, IQR] 3495 [3285–3835] 3478 [3215–3866] 0.91 Low birth weight [n, %] 0 [0] 0 [0] 1.00 Gestational age [weeks, IQR] 39.4 [38.5–41.0] 38.5 [37.6–40.0] 0.08 Preterm birth [n, %] 0 [0] 1 [8] 0.44 Small for gestational age [n, %] 0 [0] 0 [0] 1.00 Major congenital abnormalities [n, %] 0 [0] 0 [0] 1.00 Breastfeeding more than 2 weeks [n, %] 2 [14] 8 [67] 0.01 View Large 3.4. One-year health outcomes We obtained 1-year health outcomes from 25 children [15 from the anti-TNF alpha-exposed group and ten from the control group] as shown in Table 3. Health outcomes were provided by the GP in 14 cases, while in other cases information from the parents was used. Overall, we found no differences in growth and health outcomes of children at 1 year of age between anti-TNF alpha-exposed children and controls. Table 3. One-year health outcomes [n = 27]. Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Growth deficiency [n, %] 0 [0] 0 [0] 1.00 Chronic disease [n, %] 0 [0] 0 [0] 1.00 Number of infections treated with systemic antibiotics [%] 0 11 [73] 9 [75] 0.61 1 3 [20] 1 [8] 0.63 2 or more 1 [7] 0 [0] 1.00 Hospitalization because of an infection [n, %] 0 [0] 0 [0] 1.00 Allergies [n, %] 0 [0] 0 [0] 1.00 Adverse reactions to vaccination [n, %] 0 [0] 0 [0] 1.00 Eczema [n, %] 4 [26] 1 [8] 0.30 Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Growth deficiency [n, %] 0 [0] 0 [0] 1.00 Chronic disease [n, %] 0 [0] 0 [0] 1.00 Number of infections treated with systemic antibiotics [%] 0 11 [73] 9 [75] 0.61 1 3 [20] 1 [8] 0.63 2 or more 1 [7] 0 [0] 1.00 Hospitalization because of an infection [n, %] 0 [0] 0 [0] 1.00 Allergies [n, %] 0 [0] 0 [0] 1.00 Adverse reactions to vaccination [n, %] 0 [0] 0 [0] 1.00 Eczema [n, %] 4 [26] 1 [8] 0.30 View Large Table 3. One-year health outcomes [n = 27]. Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Growth deficiency [n, %] 0 [0] 0 [0] 1.00 Chronic disease [n, %] 0 [0] 0 [0] 1.00 Number of infections treated with systemic antibiotics [%] 0 11 [73] 9 [75] 0.61 1 3 [20] 1 [8] 0.63 2 or more 1 [7] 0 [0] 1.00 Hospitalization because of an infection [n, %] 0 [0] 0 [0] 1.00 Allergies [n, %] 0 [0] 0 [0] 1.00 Adverse reactions to vaccination [n, %] 0 [0] 0 [0] 1.00 Eczema [n, %] 4 [26] 1 [8] 0.30 Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Growth deficiency [n, %] 0 [0] 0 [0] 1.00 Chronic disease [n, %] 0 [0] 0 [0] 1.00 Number of infections treated with systemic antibiotics [%] 0 11 [73] 9 [75] 0.61 1 3 [20] 1 [8] 0.63 2 or more 1 [7] 0 [0] 1.00 Hospitalization because of an infection [n, %] 0 [0] 0 [0] 1.00 Allergies [n, %] 0 [0] 0 [0] 1.00 Adverse reactions to vaccination [n, %] 0 [0] 0 [0] 1.00 Eczema [n, %] 4 [26] 1 [8] 0.30 View Large 4. Discussion This study assessed anti-HB levels after routine HBV vaccination in children exposed to anti-TNF alpha in utero. Given the high morbidity and mortality of the sequelae of HBV infection,26 we believe it is highly important to assess the efficacy of the vaccination regimen in children exposed to anti-TNF alpha in utero. This study suggests that HBV infection in these children can be effectively prevented, and that we do not observe the large difference in immunization rates as reported in the studies conducted in adult IBD patients. The data we present are reassuring, but caution is still warranted in its interpretation. First, the sample size was calculated based on an expected, large difference in immunization rate between anti-TNF alpha-exposed and unexposed children. The power calculation was based on data from the literature in an adult IBD population who were vaccinated against HBV while treated with anti-TNF alpha.29,31,32 The difference in HBV vaccination response between IBD patients treated with anti-TNF alpha and healthy individuals is quite impressive. Naturally, this study is unable to detect smaller differences in immunization rate between the two groups. The overall participation rate in this study was very low [15.6%]. Altthough this was not one of the parameters measured, a large proportion of parents enrolled in this study expressed the view that participation was associated with a high burden in terms of ethical concerns of invasive diagnostics in their healthy child. In particular, the parents of children who were not exposed to anti-TNF in utero expressed the fear of unnecessarily exposing their healthy child to a painful and possibly traumatizing venous puncture. In our view, these ethical concerns should weigh heavy in designing future similar studies. Importantly, these concerns led to the decision to limit this study to the investigation of the HBV vaccination response, as additional vaccination response measurements would require a larger blood sample and potentially burden the child and parents even more. Another limitation of this study is that we did not obtain anti-TNF cord blood levels from every study participant. A previous study suggested a dose-dependent response to the HBV vaccine in IBD patients, showing a double three-dose vaccine-series to be more effective than the single three-dose vaccine series.28 In the present study, all children were vaccinated with a four-dose vaccine series yielding protective anti-HB levels. The vaccination regimen, however, varies from country to country; for example, in the USA the three-dose regimen is used. Therefore, these study results might not be applicable to every country. This study was unable to investigate the efficacy of a three-dose vaccine series in anti-TNF alpha-exposed children. Anti-HB levels have been shown to decline over time.38,39 In an uncontrolled study performed in paediatric IBD patients treated with IFX, 50% of patients did not have protective antibodies against HBV.27 Insufficient anti-HB levels were associated with older age and the intensity of the IFX dose regimen. Anti-HB levels in the present study were measured 4 weeks after the final vaccination dose. Follow up of anti-HB levels in the children in the present study would be interesting, as the rate of decline of anti-HB levels in this specific population remains unknown. Furthermore, it is important to note that IBD mothers treated with anti-TNF alpha during pregnancy discontinued their anti-TNF alpha treatment at the end of the second trimester if the disease was in sustained remission.23 The goal of this policy is to limit anti-TNF alpha levels in the neonate. Therefore, this cohort of anti-TNF alpha-exposed children may have overall lower drug levels than children born to mothers who continued anti-TNF alpha throughout the entire pregnancy. It may be possible that children with higher anti-TNF levels at birth have a less adequate vaccine response, although we did not observe this effect in this small cohort. In a recent study reporting the efficacy of haemophilus B and tetanus vaccination immune response in anti-TNF alpha-exposed children, median anti-TNF levels [only IFX reported] were much higher than the median levels in this study [24.3–43.0 µg/ml vs 9.0 µg/ml] and this did not influence the immune response.33 In conclusion, the present study shows that children exposed to anti-TNF alpha in utero can be effectively vaccinated against HBV. Funding None. Conflict of Interest Neither the first author nor any of the co-authors have any conflict of interest with respect to the present study. Author Contributions ADL: study design, data collection and interpretation, writing of the manuscript. SLK: data collection and analysis, writing of the manuscript. JCE: data interpretation, critical review of the manuscript. CJW: initiator of the study, critical review of the manuscript. Conference: This work has been orally presented at the 25th United European Gastroenterology Week 2017 in Barcelona. References 1. Peyrin-Biroulet L , Deltenre P , de Suray N , Branche J , Sandborn WJ , Colombel JF . Efficacy and safety of tumor necrosis factor antagonists in Crohn’s disease: meta-analysis of placebo-controlled trials . Clin Gastroenterol Hepatol 2008 ; 6 : 644 – 53 . Google Scholar CrossRef Search ADS PubMed 2. Molodecky NA , Soon IS , Rabi DM , et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review . Gastroenterology 2012 ; 142 : 46 – 54.e42 ; quiz e30. Google Scholar CrossRef Search ADS PubMed 3. 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Dis Colon Rectum 1990 ; 33 : 869 – 73 . Google Scholar CrossRef Search ADS PubMed 9. Morales M , Berney T , Jenny A , Morel P , Extermann P . Crohn’s disease as a risk factor for the outcome of pregnancy . Hepatogastroenterology 2000 ; 47 : 1595 – 8 . Google Scholar PubMed 10. Bush MC , Patel S , Lapinski RH , Stone JL . Perinatal outcomes in inflammatory bowel disease . J Matern Fetal Neonatal Med 2004 ; 15 : 237 – 41 . Google Scholar CrossRef Search ADS PubMed 11. Nørgård B , Hundborg HH , Jacobsen BA , Nielsen GL , Fonager K . Disease activity in pregnant women with Crohn’s disease and birth outcomes: a regional Danish cohort study . Am J Gastroenterol 2007 ; 102 : 1947 – 54 . Google Scholar CrossRef Search ADS PubMed 12. Reddy D , Murphy SJ , Kane SV , Present DH , Kornbluth AA . Relapses of inflammatory bowel disease during pregnancy: in-hospital management and birth outcomes . Am J Gastroenterol 2008 ; 103 : 1203 – 9 . Google Scholar CrossRef Search ADS PubMed 13. Oron G , Yogev Y , Shcolnick S , et al. Inflammatory bowel disease: risk factors for adverse pregnancy outcome and the impact of maternal weight gain . J Matern Fetal Neonatal Med 2012 ; 25 : 2256 – 60 . Google Scholar CrossRef Search ADS PubMed 14. Bröms G , Granath F , Linder M , Stephansson O , Elmberg M , Kieler H . Birth outcomes in women with inflammatory bowel disease: effects of disease activity and drug exposure . Inflamm Bowel Dis 2014 ; 20 : 1091 – 8 . Google Scholar PubMed 15. Bortoli A , Pedersen N , Duricova D , et al. Pregnancy outcome in inflammatory bowel disease: prospective European case-control ECCO-EpiCom study, 2003–2006 . Aliment Pharmacol Ther 2011 ; 34 : 724 – 34 . Google Scholar CrossRef Search ADS PubMed 16. de Lima-Karagiannis A , Zelinkova-Detkova Z , van der Woude CJ . The effects of active IBD during pregnancy in the era of novel IBD therapies . Am J Gastroenterol 2016 ; 111 : 1305 – 12 . Google Scholar CrossRef Search ADS PubMed 17. Mahadevan U , Sandborn WJ , Li DK , Hakimian S , Kane S , Corley DA . Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California . Gastroenterology 2007 ; 133 : 1106 – 12 . Google Scholar CrossRef Search ADS PubMed 18. Casanova MJ , Chaparro M , Domènech E , et al. Safety of thiopurines and anti-TNF-α drugs during pregnancy in patients with inflammatory bowel disease . Am J Gastroenterol 2013 ; 108 : 433 – 40 . Google Scholar CrossRef Search ADS PubMed 19. Schnitzler F , Fidder H , Ferrante M , et al. Outcome of pregnancy in women with inflammatory bowel disease treated with antitumor necrosis factor therapy . Inflamm Bowel Dis 2011 ; 17 : 1846 – 54 . Google Scholar CrossRef Search ADS PubMed 20. Zelinkova Z , de Haar C , de Ridder L , et al. High intra-uterine exposure to infliximab following maternal anti-TNF treatment during pregnancy . Aliment Pharmacol Ther 2011 ; 33 : 1053 – 8 . Google Scholar CrossRef Search ADS PubMed 21. Zelinkova Z , van der Ent C , Bruin KF , et al. ; Dutch Delta IBD Group . Effects of discontinuing anti-tumor necrosis factor therapy during pregnancy on the course of inflammatory bowel disease and neonatal exposure . Clin Gastroenterol Hepatol 2013 ; 11 : 318 – 21 . Google Scholar CrossRef Search ADS PubMed 22. Mahadevan U , Wolf DC , Dubinsky M , et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease . Clin Gastroenterol Hepatol 2013 ; 11 : 286 – 92; quiz e24 . Google Scholar CrossRef Search ADS PubMed 23. de Lima A , Zelinkova Z , van der Ent C , Steegers EA , van der Woude CJ . Tailored anti-TNF therapy during pregnancy in patients with IBD: maternal and fetal safety . Gut 2016 ; 65 : 1261 – 8 . Google Scholar CrossRef Search ADS PubMed 24. 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 . Google Scholar CrossRef Search ADS PubMed 25. Seow CH , Leung Y , Vande Casteele N , et al. The effects of pregnancy on the pharmacokinetics of infliximab and adalimumab in inflammatory bowel disease . Aliment Pharmacol Ther 2017 ; 45 : 1329 – 38 . Google Scholar CrossRef Search ADS PubMed 26. Lozano R , Naghavi M , Foreman K , et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010 . Lancet 2012 ; 380 : 2095 – 128 . Google Scholar CrossRef Search ADS PubMed 27. Moses J , Alkhouri N , Shannon A , et al. Hepatitis B immunity and response to booster vaccination in children with inflammatory bowel disease treated with infliximab . Am J Gastroenterol 2012 ; 107 : 133 – 8 . Google Scholar CrossRef Search ADS PubMed 28. Gisbert JP , Menchén L , García-Sánchez V , Marín I , Villagrasa JR , Chaparro M . Comparison of the effectiveness of two protocols for vaccination (standard and double dosage) against hepatitis B virus in patients with inflammatory bowel disease . Aliment Pharmacol Ther 2012 ; 35 : 1379 – 85 . Google Scholar CrossRef Search ADS PubMed 29. Gisbert JP , Villagrasa JR , Rodríguez-Nogueiras A , Chaparro M . Efficacy of hepatitis B vaccination and revaccination and factors impacting on response in patients with inflammatory bowel disease . Am J Gastroenterol 2012 ; 107 : 1460 – 6 . Google Scholar CrossRef Search ADS PubMed 30. Salinas GF , De Rycke L , Barendregt B , et al. Anti-TNF treatment blocks the induction of T cell-dependent humoral responses . Ann Rheum Dis 2013 ; 72 : 1037 – 43 . Google Scholar CrossRef Search ADS PubMed 31. Andrade P , Santos-Antunes J , Rodrigues S , Lopes S , Macedo G . Treatment with infliximab or azathioprine negatively impact the efficacy of hepatitis B vaccine in inflammatory bowel disease patients . J Gastroenterol Hepatol 2015 ; 30 : 1591 – 5 . Google Scholar CrossRef Search ADS PubMed 32. Jiang HY , Wang SY , Deng M , et al. Immune response to hepatitis B vaccination among people with inflammatory bowel diseases: a systematic review and meta-analysis . Vaccine 2017 ; 35 : 2633 – 41 . Google Scholar CrossRef Search ADS PubMed 33. 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 : 99 – 105 . Google Scholar CrossRef Search ADS PubMed 34. Bortlik M , Duricova D , Machkova N , et al. Impact of anti-tumor necrosis factor alpha antibodies administered to pregnant women with inflammatory bowel disease on long-term outcome of exposed children . Inflamm Bowel Dis 2014 ; 20 : 495 – 501 . Google Scholar CrossRef Search ADS PubMed 35. Visser GH , Eilers PH , Elferink-Stinkens PM , Merkus HM , Wit JM . New Dutch reference curves for birthweight by gestational age . Early Hum Dev 2009 ; 85 : 737 – 44 . Google Scholar CrossRef Search ADS PubMed 36. Coates T , Wilson R , Patrick G , André F , Watson V . Hepatitis B vaccines: assessment of the seroprotective efficacy of two recombinant DNA vaccines . Clin Ther 2001 ; 23 : 392 – 403 . Google Scholar CrossRef Search ADS PubMed 37. Mast EE , Weinbaum CM , Fiore AE , et al. ; Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC) . A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults . MMWR Recomm Rep 2006 ; 55 : 1 – 33 ; quiz CE1–4. Google Scholar PubMed 38. European Consensus Group on Hepatitis B Immunity . Are booster immunisations needed for lifelong hepatitis B immunity? European consensus group on hepatitis B immunity . Lancet 2000 ; 355 : 561 – 5 . CrossRef Search ADS PubMed 39. Mast EE , Margolis HS , Fiore AE , et al. ; Advisory Committee on Immunization Practices (ACIP) . A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents . MMWR Recomm Rep 2005 ; 54 : 1 – 31 . Google Scholar PubMed Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Crohn's and Colitis Oxford University Press

Hepatitis B Vaccination Effective in Children Exposed to Anti-Tumour Necrosis Factor Alpha in Utero

Journal of Crohn's and Colitis , Volume 12 (8) – Aug 1, 2018
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Oxford University Press
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Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1873-9946
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1876-4479
DOI
10.1093/ecco-jcc/jjy053
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Abstract

Abstract Introduction Neonates exposed to tumour necrosis factor [TNF] alpha inhibitors in utero are born with detectable drug levels which can still be detected throughout the first year of life. Since 2011, the hepatitis B virus [HBV] vaccine is routinely administered to all newborns in the Netherlands. Adults treated with anti-TNF have been reported to respond inadequately to the HBV vaccine. The aim of this study was to compare anti-HB levels in anti-TNF-exposed children with non-exposed children following routine Dutch HBV vaccination. Methods We performed a cross-sectional, controlled cohort study from 2014 to 2017 in a single, tertiary referral centre. Pregnant women treated with anti-TNF for inflammatory bowel disease [IBD] and their subsequent children were recruited from the IBD preconception outpatient clinic. Pregnant women not treated with anti-TNF for IBD and their subsequent children were eligible as controls. Adherence to the Dutch National Vaccination Programme was mandatory for participation in this study. A venous blood sample was obtained 1 month after final HBV vaccination. Anti-HB levels were measured by enzyme-linked immunosorbent assay. Results Anti-HB levels at 12 months did not differ between the anti-TNF-exposed [n = 15] and the control group [n = 12] [> 1000 IU/l vs > 1000 IU/l, p = 0.59]. All children were successfully immunized against HBV, defined as anti-HB > 10 IU/l. Median anti-TNF levels determined in cord blood at birth were 9.0 µg/ml [interquartile range: 3.0–15.0 µg/ml] for infliximab and 0.4. µg/ml [interquartile range: 0.3–0.6 µg/ml] for adalimumab. There were no differences in general birth and health outcomes. Conclusion Children born with detectable anti-TNF levels can be effectively vaccinated against HBV. Hepatitis B, anti-TNF alpha, vaccination 1. Introduction Anti-tumour necrosis factor [TNF] alpha agents such as adalimumab [ADA] and infliximab [IFX] are commonly prescribed treatments for inflammatory bowel disease [IBD] by successfully achieving and maintaining disease remission.1 IBD is a chronic, relapsing and remitting disease, which typically affects women in their childbearing years and men in the same age range.2 Active disease during pregnancy has been associated with adverse pregnancy outcomes,3–14 although more recent publications show acceptable pregnancy outcomes by means of adequate disease control in terms of stringent IBD treatment and follow-up throughout pregnancy.15–17 Anti-TNF alpha agents have been accepted as generally low-risk drugs during pregnancy as they are not associated with an increased risk of congenital abnormalities, preterm birth, low birth weight or miscarriages.18,19 Nonetheless, anti-TNF alpha actively crosses the placenta in the second and especially the third trimester of pregnancy, resulting in detectable anti-TNF alpha levels in the neonate which can still be detectable throughout the first year of life.20–25 The effects of anti-TNF alpha on the developing immune system of the child has been scarcely investigated. Hepatitis B virus [HBV] is a major global health issue associated with significant morbidity and mortality.26 Prevention is possible through vaccination and, since 2011, the HBV vaccine is routinely administered to all infants in the Netherlands. Interestingly, several reports suggest that the HBV vaccine in IBD patients treated with anti-TNF alpha agents fails to yield protective anti-HB levels after a primary vaccination regimen.27–32 Although the efficacy of several vaccines has been investigated in children exposed to anti-TNF alpha, such as haemophilus influenza B and tetanus,33,34 the efficacy of the HBV vaccine has not previously been investigated in infants born to mothers treated with anti-TNF alpha during pregnancy. The aim of this study is therefore to assess response to the HBV vaccine in children born to IBD mothers treated with anti-TNF alpha during pregnancy in terms of anti-HB levels after the administration of the final dose of the HBV vaccine. 2. Materials and Methods 2.1. Study design We performed a cross-sectional, controlled cohort study to determine HBV immunity in children who were exposed to anti-TNF in utero. Pregnant women with IBD were informed about the study from May 2014 to December 2016 at our IBD preconception outpatient clinic [POC] of the Erasmus University Medical Centre Rotterdam, a tertiary healthcare centre. At the IBD outpatient clinic, women with IBD were counselled before pregnancy and seen every second month during pregnancy by an experienced IBD physician. During visits, women were counselled on medication use, lifestyle habits [e.g. smoking, alcohol use], folic acid intake, and the importance of disease remission before and during pregnancy. Disease activity was assessed by the treating physician and treated according to current IBD pregnancy guidelines. At birth, an umbilical cord blood sample was drawn. In this sample anti-TNF levels were measured. In the Netherlands, the HBV vaccine [Engerix-B Junior, rDNA vaccine] is routinely administered to infants in the first year of life at 6 weeks, and 3, 4 and 11 months. To determine HBV immunity, a venous blood sample was obtained from the infant at the age of 12 months, 1 month after the final HBV vaccination, to assess anti-HB levels. Anti-HB levels were measured by a commercially available enzyme-linked immunosorbent assay [ELISA]. Written informed consent from both parents was obtained before the blood sample was collected. Children with an anti-HB level of ≥ 10 IU/l were considered immune. In case of insufficient anti-HB levels [< 10 IU/l] an HBV booster vaccine was given and anti-HB measurement was repeated after 3 months. If the anti-HB level exceeded 1000 IU/l, anti-HB level was displayed as > 1000 IU/l. In addition, birth outcomes such as birth weight, gestational age and the presence of congenital abnormalities were obtained from mothers during the first visit after delivery. One year after birth, health outcomes were obtained from the general practitioner [GP] with the informed consent of both parents. The following health outcomes were collected: growth, number of infections treated with antibiotics, hospital admissions because of infection, chronic diseases, allergies, adverse reactions to a vaccination and the presence of eczema. If data from the GP were unavailable, health outcomes as reported by the mother were used. 2.2. Exclusion criteria All women with IBD who visited our outpatient clinic during pregnancy were asked to participate in this study, but the following exclusion criteria were applied: mothers infected with HBV, hepatitis C virus [HCV] or human immunodeficiency virus [HIV], children with other immunocompromising conditions and children not vaccinated according to the Dutch National Vaccination Programme. 2.3. Anti-TNF alpha-exposed group The anti-TNF alpha-exposed group consisted of children born to mothers with IBD treated with anti-TNF during part of the pregnancy or the entire pregnancy. Women in the study group were treated with anti-TNF alpha during pregnancy, at least until the end of the second trimester. In cases of sustained disease remission from 6 months before conception until gestational week 22, the option of discontinuing anti-TNF treatment was discussed in a multidisciplinary team. In all other cases, anti-TNF treatment was continued throughout the entire pregnancy. The control group consisted of children born to mothers with IBD not treated with anti-TNF, but any other IBD medication was permitted. 2.4. Definitions Abnormal growth is defined as growth or height for age and gender deviating > 2 standard deviations [SD] from the mean Dutch growth chart. Preterm birth is defined as delivery before 37 weeks of gestation. Small for gestational age [SGA] is a weight below 2 SD for gestational age according to the Dutch reference chart.35 The presence of disease activity was assessed by the treating physician and based on the combination of clinical symptoms [Harvey–Bradshaw Index > 5 or Simple Clinical Colitis Activity Index > 2], C-reactive protein > 9.0 mg/l, fecal calprotectin (FCP) measurement > 200 µg/g, and when strongly indicated, an endoscopy was performed. 2.5. Sample size In healthy children and adults, HBV immunization rates after vaccination are high and considered to be around 95%.36,37 In adult IBD patients treated with anti-TNF, immunization rates after a primary vaccination regimen are reported to be approximately 50–60%.29,31,32 At a one-sided significance level of 0.05 and a power of 80%, this would require in an anti-TNF alpha-exposed group of 12 children and a control group of the same size. 2.6. Statistical considerations All analyses were performed using IBM SPSS statistics [version 21.0]. Descriptive statistics of continuous data are displayed as medians with interquartile ranges [IQR] and compared using Mann–Whitney U tests. Categorical data are shown as absolute numbers with percentages, and compared using Chi-square or Fisher’s exact tests. The tests were performed two tailed unless stated otherwise, and tested at a significance level of 0.05. 2.7. Ethical statement This study was approved by the local ethics committee of the Erasmus Medical Centre [Rotterdam, The Netherlands]. Legal guardians of the child signed informed consent before a venous blood sample was obtained from the child and again before data were collected from the GP. 3. Results In total 192 pregnant women [86 treated with anti-TNF alpha] were invited for participation in this study. Thirty mother–child pairs were included in the study [15.6%]. Measurement of anti-HB was not performed in three children; two samples were lost because of logistical problems and one sample could not be analysed because too little blood was drawn. Therefore, these children were excluded from further analyses. Overall, there were 15 children assigned to the anti-TNF alpha-exposed and 12 children to the control group. Baseline characteristics are shown in Table 1. Table 1. Baseline characteristics [n = 27]. Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Median maternal age at conception [years, IQR] 31 [29–33] 30 [27–35] 1.00 Diagnosis [n, %]  Crohn’s disease 12 [80] 8 [67] 0.66  Ulcerative colitis 3 [20] 2 [17] 1.00  IBD unclassified 0 [0] 2 [17] 0.20 Disease location CD [Montreal] [n, %]  L1 Ileal 3 [20] 1 [13] 0.61  L2 Colonic 1 [9] 1 [13] 1.00  L3 Ileocolonic 8 [73] 6 [74] 1.00 Disease behaviour CD [Montreal] [n, %]  B1 Non-structuring non-penetrating 7 [47] 7 [88] 0.34  B2 Stricturing 1 [8] 0 [0] 1.00  B3 Penetrating 3 [25] 1 [12] 0.61  B2+ B3 Stricturing and penetrating 1 [8] 0 [0] 1.00 P Perianal fistulizing disease [n, %] 4 [29] 1 [8] 0.33 Disease extent UC/IBDU [Montreal] [n, %]  E1 Proctitis 0 [0] 2 [50] 0.47  E2 Left-sided colitis 0 [0] 2 [50] 0.47  E3 Pancolitis 3 [100] 0 [0] 0.23 Disease duration [years, IQR] 10 [7–12] 7 [4–9] 0.38 Anti-TNF type [n, %]  IFX 8 [53] – –  ADA 7 [47] – – Co-medication [n, %]  Mesalazine 2 [13] 5 [42] 0.19  Steroids [systemic] 3 [20] 2 [17] 1.00  Thiopurine 4 [27] 4 [33] 1.00 IBD surgery [n, %]  Abdominal surgery 4 [27] 2 [17] 0.66  Perianal surgery 3 [20] 0 [0] 0.22 Nulliparous [n, %] 6 [40] 4 [33] 0.68 Disease relapse during [n, %] 2 [13] 2 [17] 1.00 Smoking during pregnancy [n, %] 1 [7] 1 [8] 1.00 Folic acid intake [n, %] 15 [100] 12 [100] 1.00 Mode of delivery [n, %]  Vaginal 9 [60] 8[67] 0.70  Caesarean section 6 [40] 4 [33] 0.70 Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Median maternal age at conception [years, IQR] 31 [29–33] 30 [27–35] 1.00 Diagnosis [n, %]  Crohn’s disease 12 [80] 8 [67] 0.66  Ulcerative colitis 3 [20] 2 [17] 1.00  IBD unclassified 0 [0] 2 [17] 0.20 Disease location CD [Montreal] [n, %]  L1 Ileal 3 [20] 1 [13] 0.61  L2 Colonic 1 [9] 1 [13] 1.00  L3 Ileocolonic 8 [73] 6 [74] 1.00 Disease behaviour CD [Montreal] [n, %]  B1 Non-structuring non-penetrating 7 [47] 7 [88] 0.34  B2 Stricturing 1 [8] 0 [0] 1.00  B3 Penetrating 3 [25] 1 [12] 0.61  B2+ B3 Stricturing and penetrating 1 [8] 0 [0] 1.00 P Perianal fistulizing disease [n, %] 4 [29] 1 [8] 0.33 Disease extent UC/IBDU [Montreal] [n, %]  E1 Proctitis 0 [0] 2 [50] 0.47  E2 Left-sided colitis 0 [0] 2 [50] 0.47  E3 Pancolitis 3 [100] 0 [0] 0.23 Disease duration [years, IQR] 10 [7–12] 7 [4–9] 0.38 Anti-TNF type [n, %]  IFX 8 [53] – –  ADA 7 [47] – – Co-medication [n, %]  Mesalazine 2 [13] 5 [42] 0.19  Steroids [systemic] 3 [20] 2 [17] 1.00  Thiopurine 4 [27] 4 [33] 1.00 IBD surgery [n, %]  Abdominal surgery 4 [27] 2 [17] 0.66  Perianal surgery 3 [20] 0 [0] 0.22 Nulliparous [n, %] 6 [40] 4 [33] 0.68 Disease relapse during [n, %] 2 [13] 2 [17] 1.00 Smoking during pregnancy [n, %] 1 [7] 1 [8] 1.00 Folic acid intake [n, %] 15 [100] 12 [100] 1.00 Mode of delivery [n, %]  Vaginal 9 [60] 8[67] 0.70  Caesarean section 6 [40] 4 [33] 0.70 View Large Table 1. Baseline characteristics [n = 27]. Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Median maternal age at conception [years, IQR] 31 [29–33] 30 [27–35] 1.00 Diagnosis [n, %]  Crohn’s disease 12 [80] 8 [67] 0.66  Ulcerative colitis 3 [20] 2 [17] 1.00  IBD unclassified 0 [0] 2 [17] 0.20 Disease location CD [Montreal] [n, %]  L1 Ileal 3 [20] 1 [13] 0.61  L2 Colonic 1 [9] 1 [13] 1.00  L3 Ileocolonic 8 [73] 6 [74] 1.00 Disease behaviour CD [Montreal] [n, %]  B1 Non-structuring non-penetrating 7 [47] 7 [88] 0.34  B2 Stricturing 1 [8] 0 [0] 1.00  B3 Penetrating 3 [25] 1 [12] 0.61  B2+ B3 Stricturing and penetrating 1 [8] 0 [0] 1.00 P Perianal fistulizing disease [n, %] 4 [29] 1 [8] 0.33 Disease extent UC/IBDU [Montreal] [n, %]  E1 Proctitis 0 [0] 2 [50] 0.47  E2 Left-sided colitis 0 [0] 2 [50] 0.47  E3 Pancolitis 3 [100] 0 [0] 0.23 Disease duration [years, IQR] 10 [7–12] 7 [4–9] 0.38 Anti-TNF type [n, %]  IFX 8 [53] – –  ADA 7 [47] – – Co-medication [n, %]  Mesalazine 2 [13] 5 [42] 0.19  Steroids [systemic] 3 [20] 2 [17] 1.00  Thiopurine 4 [27] 4 [33] 1.00 IBD surgery [n, %]  Abdominal surgery 4 [27] 2 [17] 0.66  Perianal surgery 3 [20] 0 [0] 0.22 Nulliparous [n, %] 6 [40] 4 [33] 0.68 Disease relapse during [n, %] 2 [13] 2 [17] 1.00 Smoking during pregnancy [n, %] 1 [7] 1 [8] 1.00 Folic acid intake [n, %] 15 [100] 12 [100] 1.00 Mode of delivery [n, %]  Vaginal 9 [60] 8[67] 0.70  Caesarean section 6 [40] 4 [33] 0.70 Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Median maternal age at conception [years, IQR] 31 [29–33] 30 [27–35] 1.00 Diagnosis [n, %]  Crohn’s disease 12 [80] 8 [67] 0.66  Ulcerative colitis 3 [20] 2 [17] 1.00  IBD unclassified 0 [0] 2 [17] 0.20 Disease location CD [Montreal] [n, %]  L1 Ileal 3 [20] 1 [13] 0.61  L2 Colonic 1 [9] 1 [13] 1.00  L3 Ileocolonic 8 [73] 6 [74] 1.00 Disease behaviour CD [Montreal] [n, %]  B1 Non-structuring non-penetrating 7 [47] 7 [88] 0.34  B2 Stricturing 1 [8] 0 [0] 1.00  B3 Penetrating 3 [25] 1 [12] 0.61  B2+ B3 Stricturing and penetrating 1 [8] 0 [0] 1.00 P Perianal fistulizing disease [n, %] 4 [29] 1 [8] 0.33 Disease extent UC/IBDU [Montreal] [n, %]  E1 Proctitis 0 [0] 2 [50] 0.47  E2 Left-sided colitis 0 [0] 2 [50] 0.47  E3 Pancolitis 3 [100] 0 [0] 0.23 Disease duration [years, IQR] 10 [7–12] 7 [4–9] 0.38 Anti-TNF type [n, %]  IFX 8 [53] – –  ADA 7 [47] – – Co-medication [n, %]  Mesalazine 2 [13] 5 [42] 0.19  Steroids [systemic] 3 [20] 2 [17] 1.00  Thiopurine 4 [27] 4 [33] 1.00 IBD surgery [n, %]  Abdominal surgery 4 [27] 2 [17] 0.66  Perianal surgery 3 [20] 0 [0] 0.22 Nulliparous [n, %] 6 [40] 4 [33] 0.68 Disease relapse during [n, %] 2 [13] 2 [17] 1.00 Smoking during pregnancy [n, %] 1 [7] 1 [8] 1.00 Folic acid intake [n, %] 15 [100] 12 [100] 1.00 Mode of delivery [n, %]  Vaginal 9 [60] 8[67] 0.70  Caesarean section 6 [40] 4 [33] 0.70 View Large 3.1. Anti-TNF alpha-exposed group In the anti-TNF alpha-exposed group, eight [53%] children were exposed to IFX and seven [47%] children were exposed to ADA. The median anti-TNF stop week was gestational week 25 [IQR 22–29] in the IFX group and gestational week 23 [IQR 22–24] in the ADA group [p = 0.34]. Anti-TNF cord blood measurements were obtained from ten children: six IFX-exposed children and four ADA-exposed children. Median anti-TNF concentration in cord blood was 9.0 µg/ml [IQR 3.0–15.0] in IFX-exposed children and 0.4 µg/ml [IQR 0.3–0.6] in ADA-exposed children which was a statistically significant difference [p = 0.01]. However, all children in the anti-TNF alpha-exposed group responded adequately to the vaccine and were considered immune for HBV (Figure 1). There was no difference between IFX-exposed children and ADA-exposed children in HBV immune status. Figure 1. View largeDownload slide Anti-hepatitis B levels in children exposed to anti-tumour necrosis factpr alpha and controls. Figure 1. View largeDownload slide Anti-hepatitis B levels in children exposed to anti-tumour necrosis factpr alpha and controls. In addition, we separately analysed the five mothers who received anti-TNF treatment in the third trimester of pregnancy, of whom four cord blood measurements were obtained at birth. All five mothers used IFX during pregnancy. The median anti-TNF stop week in this group was gestational week 29 [IQR 27–40] and the median anti-TNF concentration in cord blood was 12 µg/ml [IQR 8–16]. Overall, all children who were exposed to anti-TNF in the third trimester of pregnancy responded adequately to the vaccine and were considered immune for HBV. None of the anti-TNF alpha-exposed children required the HBV booster vaccine. 3.2. Control group The control group consisted of 12 children. Maternal IBD medication use is shown in Table 1, which was, other than anti-TNF, similar to the anti-TNF alpha-exposed group. All children in the control group responded adequately to the vaccine and were considered immune for HBV. None of these children required the HBV booster vaccine. 3.3. Birth outcomes Birth outcomes are shown in Table 2. There were no differences between the anti-TNF alpha-exposed group and control group regarding birth weight, low birth weight, gestational age, preterm birth, SGA or the presence of congenital abnormalities. Mothers in the control group more often breastfed than mothers in the anti-TNF alpha-exposed group. Table 2. Birth outcomes [n = 27]. Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Birth weight [g, IQR] 3495 [3285–3835] 3478 [3215–3866] 0.91 Low birth weight [n, %] 0 [0] 0 [0] 1.00 Gestational age [weeks, IQR] 39.4 [38.5–41.0] 38.5 [37.6–40.0] 0.08 Preterm birth [n, %] 0 [0] 1 [8] 0.44 Small for gestational age [n, %] 0 [0] 0 [0] 1.00 Major congenital abnormalities [n, %] 0 [0] 0 [0] 1.00 Breastfeeding more than 2 weeks [n, %] 2 [14] 8 [67] 0.01 Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Birth weight [g, IQR] 3495 [3285–3835] 3478 [3215–3866] 0.91 Low birth weight [n, %] 0 [0] 0 [0] 1.00 Gestational age [weeks, IQR] 39.4 [38.5–41.0] 38.5 [37.6–40.0] 0.08 Preterm birth [n, %] 0 [0] 1 [8] 0.44 Small for gestational age [n, %] 0 [0] 0 [0] 1.00 Major congenital abnormalities [n, %] 0 [0] 0 [0] 1.00 Breastfeeding more than 2 weeks [n, %] 2 [14] 8 [67] 0.01 View Large Table 2. Birth outcomes [n = 27]. Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Birth weight [g, IQR] 3495 [3285–3835] 3478 [3215–3866] 0.91 Low birth weight [n, %] 0 [0] 0 [0] 1.00 Gestational age [weeks, IQR] 39.4 [38.5–41.0] 38.5 [37.6–40.0] 0.08 Preterm birth [n, %] 0 [0] 1 [8] 0.44 Small for gestational age [n, %] 0 [0] 0 [0] 1.00 Major congenital abnormalities [n, %] 0 [0] 0 [0] 1.00 Breastfeeding more than 2 weeks [n, %] 2 [14] 8 [67] 0.01 Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Birth weight [g, IQR] 3495 [3285–3835] 3478 [3215–3866] 0.91 Low birth weight [n, %] 0 [0] 0 [0] 1.00 Gestational age [weeks, IQR] 39.4 [38.5–41.0] 38.5 [37.6–40.0] 0.08 Preterm birth [n, %] 0 [0] 1 [8] 0.44 Small for gestational age [n, %] 0 [0] 0 [0] 1.00 Major congenital abnormalities [n, %] 0 [0] 0 [0] 1.00 Breastfeeding more than 2 weeks [n, %] 2 [14] 8 [67] 0.01 View Large 3.4. One-year health outcomes We obtained 1-year health outcomes from 25 children [15 from the anti-TNF alpha-exposed group and ten from the control group] as shown in Table 3. Health outcomes were provided by the GP in 14 cases, while in other cases information from the parents was used. Overall, we found no differences in growth and health outcomes of children at 1 year of age between anti-TNF alpha-exposed children and controls. Table 3. One-year health outcomes [n = 27]. Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Growth deficiency [n, %] 0 [0] 0 [0] 1.00 Chronic disease [n, %] 0 [0] 0 [0] 1.00 Number of infections treated with systemic antibiotics [%] 0 11 [73] 9 [75] 0.61 1 3 [20] 1 [8] 0.63 2 or more 1 [7] 0 [0] 1.00 Hospitalization because of an infection [n, %] 0 [0] 0 [0] 1.00 Allergies [n, %] 0 [0] 0 [0] 1.00 Adverse reactions to vaccination [n, %] 0 [0] 0 [0] 1.00 Eczema [n, %] 4 [26] 1 [8] 0.30 Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Growth deficiency [n, %] 0 [0] 0 [0] 1.00 Chronic disease [n, %] 0 [0] 0 [0] 1.00 Number of infections treated with systemic antibiotics [%] 0 11 [73] 9 [75] 0.61 1 3 [20] 1 [8] 0.63 2 or more 1 [7] 0 [0] 1.00 Hospitalization because of an infection [n, %] 0 [0] 0 [0] 1.00 Allergies [n, %] 0 [0] 0 [0] 1.00 Adverse reactions to vaccination [n, %] 0 [0] 0 [0] 1.00 Eczema [n, %] 4 [26] 1 [8] 0.30 View Large Table 3. One-year health outcomes [n = 27]. Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Growth deficiency [n, %] 0 [0] 0 [0] 1.00 Chronic disease [n, %] 0 [0] 0 [0] 1.00 Number of infections treated with systemic antibiotics [%] 0 11 [73] 9 [75] 0.61 1 3 [20] 1 [8] 0.63 2 or more 1 [7] 0 [0] 1.00 Hospitalization because of an infection [n, %] 0 [0] 0 [0] 1.00 Allergies [n, %] 0 [0] 0 [0] 1.00 Adverse reactions to vaccination [n, %] 0 [0] 0 [0] 1.00 Eczema [n, %] 4 [26] 1 [8] 0.30 Anti-TNF alpha-exposed group [n = 15] Control group [n = 12] p-value Growth deficiency [n, %] 0 [0] 0 [0] 1.00 Chronic disease [n, %] 0 [0] 0 [0] 1.00 Number of infections treated with systemic antibiotics [%] 0 11 [73] 9 [75] 0.61 1 3 [20] 1 [8] 0.63 2 or more 1 [7] 0 [0] 1.00 Hospitalization because of an infection [n, %] 0 [0] 0 [0] 1.00 Allergies [n, %] 0 [0] 0 [0] 1.00 Adverse reactions to vaccination [n, %] 0 [0] 0 [0] 1.00 Eczema [n, %] 4 [26] 1 [8] 0.30 View Large 4. Discussion This study assessed anti-HB levels after routine HBV vaccination in children exposed to anti-TNF alpha in utero. Given the high morbidity and mortality of the sequelae of HBV infection,26 we believe it is highly important to assess the efficacy of the vaccination regimen in children exposed to anti-TNF alpha in utero. This study suggests that HBV infection in these children can be effectively prevented, and that we do not observe the large difference in immunization rates as reported in the studies conducted in adult IBD patients. The data we present are reassuring, but caution is still warranted in its interpretation. First, the sample size was calculated based on an expected, large difference in immunization rate between anti-TNF alpha-exposed and unexposed children. The power calculation was based on data from the literature in an adult IBD population who were vaccinated against HBV while treated with anti-TNF alpha.29,31,32 The difference in HBV vaccination response between IBD patients treated with anti-TNF alpha and healthy individuals is quite impressive. Naturally, this study is unable to detect smaller differences in immunization rate between the two groups. The overall participation rate in this study was very low [15.6%]. Altthough this was not one of the parameters measured, a large proportion of parents enrolled in this study expressed the view that participation was associated with a high burden in terms of ethical concerns of invasive diagnostics in their healthy child. In particular, the parents of children who were not exposed to anti-TNF in utero expressed the fear of unnecessarily exposing their healthy child to a painful and possibly traumatizing venous puncture. In our view, these ethical concerns should weigh heavy in designing future similar studies. Importantly, these concerns led to the decision to limit this study to the investigation of the HBV vaccination response, as additional vaccination response measurements would require a larger blood sample and potentially burden the child and parents even more. Another limitation of this study is that we did not obtain anti-TNF cord blood levels from every study participant. A previous study suggested a dose-dependent response to the HBV vaccine in IBD patients, showing a double three-dose vaccine-series to be more effective than the single three-dose vaccine series.28 In the present study, all children were vaccinated with a four-dose vaccine series yielding protective anti-HB levels. The vaccination regimen, however, varies from country to country; for example, in the USA the three-dose regimen is used. Therefore, these study results might not be applicable to every country. This study was unable to investigate the efficacy of a three-dose vaccine series in anti-TNF alpha-exposed children. Anti-HB levels have been shown to decline over time.38,39 In an uncontrolled study performed in paediatric IBD patients treated with IFX, 50% of patients did not have protective antibodies against HBV.27 Insufficient anti-HB levels were associated with older age and the intensity of the IFX dose regimen. Anti-HB levels in the present study were measured 4 weeks after the final vaccination dose. Follow up of anti-HB levels in the children in the present study would be interesting, as the rate of decline of anti-HB levels in this specific population remains unknown. Furthermore, it is important to note that IBD mothers treated with anti-TNF alpha during pregnancy discontinued their anti-TNF alpha treatment at the end of the second trimester if the disease was in sustained remission.23 The goal of this policy is to limit anti-TNF alpha levels in the neonate. Therefore, this cohort of anti-TNF alpha-exposed children may have overall lower drug levels than children born to mothers who continued anti-TNF alpha throughout the entire pregnancy. It may be possible that children with higher anti-TNF levels at birth have a less adequate vaccine response, although we did not observe this effect in this small cohort. In a recent study reporting the efficacy of haemophilus B and tetanus vaccination immune response in anti-TNF alpha-exposed children, median anti-TNF levels [only IFX reported] were much higher than the median levels in this study [24.3–43.0 µg/ml vs 9.0 µg/ml] and this did not influence the immune response.33 In conclusion, the present study shows that children exposed to anti-TNF alpha in utero can be effectively vaccinated against HBV. Funding None. Conflict of Interest Neither the first author nor any of the co-authors have any conflict of interest with respect to the present study. 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Journal of Crohn's and Colitis – Oxford University Press

Published: Aug 1, 2018

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