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Impact of Anti–Tumor Necrosis Factor Alpha Antibodies Administered to Pregnant Women With Inflammatory Bowel Disease on Long-term Outcome of Exposed Children

Impact of Anti–Tumor Necrosis Factor Alpha Antibodies Administered to Pregnant Women With... Background Prenatal exposure to anti–tumor necrosis factor α (TNF-α) antibodies seems to be safe for fetal development. Data on long-term outcome of exposed children are missing. Our aim was to assess long-term postnatal development of children exposed to anti–TNF-α during pregnancy. Methods Consecutive children aged ≥12 months exposed to anti-TNFs prenatally for maternal inflammatory bowel disease in 3 centers in the Czech Republic were enrolled. Data on psychomotor development, infections, antibiotics, vaccination, and allergy were retrospectively obtained from mothers, treating pediatricians, and children's vaccination cards. Furthermore, standardized laboratory tests on humoral and cellular immunity were performed. Results Twenty-five children exposed to biologicals were included (median age, 34 mo; range, 14–70 mo). All children had normal growth, and all but 1 had normal psychomotor development. Majority (80%) experienced at least 1 infection (mainly respiratory), and 60% of infants received antibiotics, 32% of those within the first year of life. Vaccination was undertaken according to vaccination protocol to 23 infants (92%). Fifteen children also had tuberculosis vaccination without serious complication. Immunological investigation was performed with 17 children (68%). Cellular immunity was normal in all infants, and 7 children had mild decrease in IgA and/or IgG immunoglobulins without clinical significance. All children had a detectable serologic response to vaccination. Conclusions Exposure to anti–TNF-α antibodies seems to be safe for growth and psychomotor development of children, although clinical significance of relatively high frequency of infections and antibiotic use among infants remains questionable because of the lack of a control group. Continuous follow-up of exposed children is absolutely warranted. anti–TNF-α therapy, children, inflammatory bowel disease, prenatal exposure, immune system Inflammatory bowel disease (IBD) frequently manifests in patients of childbearing age.1 Because disease activity, either at the time of conception or during pregnancy, increases the risk of unfavourable pregnancy outcomes, keeping pregnant IBD patients in remission is the primary goal of medical therapy.1 A growing body of evidence supports that anti-TNF alpha (anti–TNF-α) antibodies infliximab (IFX) and adalimumab (ADA) are safe if given to pregnant IBD patients.2,–4 A recent systematic review identified 375 pregnancy exposures to IFX or ADA in IBD patients.3 In general, the results confirmed favorable outcomes of pregnancies with anti–TNF-α exposure with rates of spontaneous abortions, stillbirths, and congenital abnormalities not exceeding those in the general population. Moreover, the live birth rate in the anti–TNF-α exposed group was even higher than that of the general population in the United States.3 In our own series of 41 pregnancies of IBD patients, we have not observed any harmful effect of IFX or ADA therapy in terms of pregnancy outcomes and newborn outcomes up to the first 30 days postpartum.2 Both IFX and ADA belong to the IgG1 class of antibodies and are capable of crossing the placental barrier particularly during the second half of pregnancy. They can be detected in the cord blood at delivery, usually in levels exceeding those in maternal serum.2,4,–7 Moreover, both agents can be present in infants for several months after the birth,6 which raises concerns about infections, safety of vaccination, and, in general, about the development of the immune system of the child. Hence, despite encouraging short-term data, there is insufficient evidence to prove the long-term safety of the use of anti–TNF-α antibodies during pregnancy. The results from an ongoing registry of pregnancy outcomes in IBD patients are yet to be published.8 Therefore, the aim of our study was to assess postnatal development of children exposed to IFX or ADA during pregnancy due to maternal IBD. Materials and Methods Study Population Three centers in the Czech Republic providing anti–TNF-α therapy for IBD participated in this project. The study population comprised consecutive children exposed to anti–TNF-α in utero for maternal IBD treated with biologics in the collaborating centres since 2007. Children aged at least 1 year were eligible for the study. Data Collection/Children Follow-up A structured questionnaire was created and sent to all mothers and treating pediatricians. Data on women's disease location and behavior, smoking habits during pregnancy, and medical therapy, including biologics, corticosteroids, and immunosuppressive agents given to mothers during pregnancy were taken from medical records of the patients. Information on perinatal period, vaccination, mental and physical development, atopy or allergy in children and in parents, infections, and antibiotic use in children were collected using the structured questionnaire completed by both the treating pediatrician (using children's chart) and the mother. In case of uncertainty, the gastroenterologist contacted both the pediatrician and the mother to clarify all ambiguities. Furthermore, the data were supplied from children's health and vaccination cards, which contain records of mandatory follow-up visits and of all vaccinations given to the child. In the Czech Republic, the children are regularly followed up by pediatricians starting at the first week of life with a subsequent regular visit at 6 weeks of age and then at 3, 6, 12, and 18 months. After that, the visits are scheduled every other year from the age of 3 until age of 18 or 19. At each visit, predefined parameters, such as nursing, growth, nutrition, and neuropsychological development, are examined, and any abnormalities are described. In November 2011, our collaboration was begun with the Department of Paediatrics, University Hospital Motol in Prague, where the children underwent specific laboratory immunological investigation. Laboratory Investigation Venous blood samples were taken and standard laboratory methods were used for analyses. Immunological laboratory investigation included (1) full blood count with differential count on the leucocytes; (2) lymphocyte subset analysis on the numbers of CD3+, CD4+, CD8+, CD16+/CD56+, and CD19+; (3) measurement of serum immunoglobulins (IgM, IgA, IgG); and (4) response to vaccination (tetanus, diphtheria, Haemophilus influenzae B (HiB), Streptococcus pneumoniae, rubella, morbilli, parotitis). Furthermore, total IgE and specific IgE (ALATop test, radioimmunoassay screening test for atopy) and eosinophil cationic protein were measured. Levels of IFX and ADA were measured at delivery in 4 mothers and in cord blood of 7 newborns. Drug levels were detected by the solid-phase enzyme-linked immunosorbent assay (Q-INFLIXI, Remicade and Q-ADA, Humira; MatriksBiotek [Ankara, Turkey], respectively). Optical densities were measured by MRXII photometer and analyzed by the Revelation software (both from Dynatech, Borehamwood, United Kingdom). Concentrations of IFX and ADA were expressed as microgram/milliliter with the lower limits for detection being 0.3 ng/mL for IFX and 0.01 ng/mL for ADA. Statistical Analysis Standard descriptive statistical analyses were performed, including frequency distributions for categorical data and calculation of mean or median and range for continuous variables. The impact of immunosuppressive therapy given to mothers during pregnancy on the occurrence of infections and on antibiotic use in infants was analyzed by Fisher's exact test. Ethical Considerations The local ethical committee approved the study, and a written informed consent was obtained from child participants' guardians. Results Twenty-five children were included with a median age at the last follow-up being 34 months (range, 14–70 mo). Two infants were twins, and 2 others were siblings. Twenty-two children were exposed to IFX and 3 to ADA with the mean gestational age of 26 weeks (range, 17–37 wk) at the last anti–TNF-α exposure. Twenty children (80%) were breastfed for a median of 6 months (range, 0.5–33 mo). Levels of IFX in cord blood were measured in 5 children with a mean value of 13.6 μg/mL (range, 1.8–25.0 μg/mL), whereas ADA levels were assessed in 2 infants (0.7 and 0.8 μg/mL). Clinical characteristics of the children at birth are summarized in Table 1. Table 1. Children Characteristics at Birth     View Large Table 1. Children Characteristics at Birth     View Large Twelve mothers (48%) were receiving concomitant azathioprine, and 6 (24%) were treated with corticosteroids (4 with systemic and 2 with topical) at any time during pregnancy. Five women (20%) smoked at conception; however, all discontinued smoking shortly after becoming aware of their pregnancies. IFX levels measured in 2 mothers at the time of delivery were 0.6 and 7.5 μg/mL, respectively, whereas ADA was not detectable in any of 2 women, in whom the blood sample was taken at delivery. We have not observed any case of disease flare between the last dose of anti-TNF and delivery, and no patient thus required rescue medication during that period. Clinical characteristics of mothers' IBD is summarized in Table 2. Table 2. Clinical Characteristics of IBD in Mothers     View Large Table 2. Clinical Characteristics of IBD in Mothers     View Large Growth and Neuropsychological Development All but 1 child had normal growth and neuropsychological development. In 1 boy, a dizygotic twin, there was a mild delay in his psychomotor development diagnosed by his pediatrician at the age of 6 months. He required special neurological care and physical exercise, and, although improved, was still present at the time of the last follow-up (33 mo). Otherwise, all remaining children had normal growth and neuropsychological development. Infections and Antibiotic Use The majority of children (n = 20, 80%) experienced at least 1 infection until the end of follow-up, most of which were respiratory (Table 3). Four infections were serious and required hospitalization or prolongation of hospitalization: there was 1 case of pyelonephritis reported in a girl at 11 months of age (prenatally exposed to ADA) and 1 case of pneumonia in a 29-month-old boy who had been exposed to IFX. This boy developed infection during hospitalization for an accidental skin burn (the boy with delayed psychomotor development mentioned above). There was also 1 case of laryngitis in a 10-month-old girl exposed to IFX, and a case of obstructive bronchitis in a 15-month-old boy who had been exposed to IFX during pregnancy. All infections resolved without any complication, and only the first 2 required antibiotic therapy. Table 3. Infections, Antibiotic Use, and Immunoglobulin Levels in Children Exposed to Anti–TNF-α In Utero     View Large Table 3. Infections, Antibiotic Use, and Immunoglobulin Levels in Children Exposed to Anti–TNF-α In Utero     View Large More than half of the children (n = 15, 60%) used an antibiotic with 8 infants (32%) treated within the first year of their life. Seven infants (47%) had 1 course of antibiotics, whereas 8 children obtained ≥2 antibiotic treatments (range, 2–7). The most commonly prescribed antibiotics were penicillins. No statistically significant difference in the occurrence of infections and use of antibiotics during the first year of life was observed among children exposed to anti-TNF monotherapy and combination therapy with thiopurines and/or corticosteroids (44% versus 50%, P = 1.00% and 22.2% versus 37.5%, P = 0.661, respectively). Vaccination Vaccination with inactivated vaccines was administered according to national vaccination protocol to 23 children (92%) (Table 4). Another 2 had their vaccines postponed upon pediatricians' decision because of IFX detected in cord blood. However, in both cases, gastroenterologists were not aware of this approach. Table 4. Mandatory Vaccination of Children in the Czech Republic     View Large Table 4. Mandatory Vaccination of Children in the Czech Republic     View Large Fifteen infants (60%) also received Bacillus Calmette–Guérin (BCG) vaccination within 1 week of birth, all of them being exposed to IFX. The mean gestational week of last exposure to IFX was week 23 (range, 17–37 wk), and none of these children had IFX level measured before vaccination. Three children had large local (skin) reaction, which was complicated by axillar lymphadenopathy in 1 child. However, all reactions resolved without the need for antituberculosis therapy, and no other complication after the BCG administration was observed. BCG was the only live vaccine among the mandatory vaccinations given to infants during the first year of their lives. In November 2011, it was eventually excluded from Czech national vaccination protocol. Serological response to vaccination was assessed in 15 children (60%). All children developed detectable antibodies against tetanus, S. pneumoniae, diphtheria, rubella, morbilli, and parotitis, and no case of such infection has been reported among the children. Regarding HiB, all children had measurable antibodies, although 6 of them had levels below 1.00 mg/L, which is considered a threshold for reliable protection against the infection. However, antibodies were not assessed within the constant interval from vaccination. One child had recurrent laryngitis with intermittent positivity of H. influenzae upon microbiological examination, but no specification of the type of bacteria was performed. Atopy and Allergy Clinical signs of atopy were observed in 7 children (28%). The majority of them (6 infants) have atopic dermatitis, with one of them also experiencing allergic bronchial asthma. One child developed an allergy to nuts. However, 4 children have positive family history of atopy in at least 1 parent. Laboratory tests for atopy were performed in 17 children and revealed 5 positive results (29%). All 5 infants had increased IgE antibodies overall and specific IgE to particular antigens, and 2 infants also had higher levels of eosinophil cationic protein. In 4 infants, the laboratory and clinical signs of atopy correlated well. Immunological Examination None of the children demonstrated any clinical sign of immunodeficiency as defined by Slatter and Gennery.9 Seventeen children (68%) were prospectively examined at a pediatric clinic and underwent laboratory immunological investigation. In all infants, the blood count including absolute counts on lymphocytes subpopulation did not reveal any significant abnormalities. Regarding immunoglobulins, 7 children (41%) had their levels mildly below the lower limits of normal range: 5 infants had low levels of IgA and 4 of them in combination with low IgG. One child had low level of IgG only, and the other had low level of IgM (Table 5). There was no increase in infection rate or antibiotic use among these children (Table 3). Table 5. Levels of Immunoglobulins in Children With Hypogammaglobulinemia     View Large Table 5. Levels of Immunoglobulins in Children With Hypogammaglobulinemia     View Large Other Diseases One child underwent surgery for an inguinal hernia at the age of 33 months. Another one had clinical symptoms suggesting a cow's milk allergy, but the diagnosis was not confirmed by means of the challenge test. Discussion Available evidence indicates that using anti–TNF-α blockers to treat pregnant IBD patients is probably safe for both mother and newborn.1 However, data regarding long-term safety of these medications for children exposed during pregnancy are sparse. In the present study, we aimed to assess the effect of biologics on children's growth, incidence of infections, allergies, or development of immunological system during a median follow-up period of almost 3 years after birth. All children in our group had normal growth with no case of growth retardation. There was only 1 case (4%) of mildly delayed psychomotor development in a boy born as a dizygotic twin. A special neurological care and exercise led to improvement, but the disorder was still apparent at the age of 33 months. Although most children experienced at least 1 infection during the follow-up, the majority were mild-to-moderate upper respiratory tract infections. This is quite common and usually not a serious infection in this age category. Nevertheless, 4 cases were considered serious and required hospitalization. All 4 resolved promptly, and most importantly, all occurred at the time when the biologic almost certainly had disappeared from the infants' circulation (between 10 and 29 mo). In addition, one of these cases was a direct consequence of hospitalization for relatively serious injury (a skin burn), which further minimizes the potential impact of prenatal exposure to biologic on this complication. No apparent negative impact of anti-TNFs on the development of the immune system has been observed in our cohort. None of the children had clinical signs of immunodeficiency as defined by Slatter and Gennery.9 Two thirds of children in our cohort underwent a detailed immunological laboratory workup, and no abnormality in cellular immunity was found. Although a substantial proportion of children had decreased levels of IgA and/or IgG immunoglobulins (41% of those examined), these cases were rather mild, and no severe decrease in immunoglobulins was found. Children with low immunoglobulins in our cohort most likely fulfill the criteria of so-called transient hypogammaglobulinemia of infancy.9 In the study by Dalal et al,10 the majority of such cases fully recovered in terms of immunoglobulins levels, and both the absence of invasive infections and the protective levels of tetanus antibodies at presentation were identified as predictors of immunoglobulin normalization. As there was no increase of severe infections among our children and all developed protective tetanus antibodies, it seems that clinical relevance of their hypogammaglobulinemia is not considerable. However, continued follow-up of all children is definitely warranted. Prospective observation of the large cohort of IBD patients confirmed an increased risk of serious infections in patients treated with IFX or systemic steroids,11 and the risk was even higher when 2 or more immunosuppressive agents were used.12 Also, preliminary results from a prospective registry of pregnancy outcomes in the United States (PIANO study) indicate that a combination of biologic and immunomodulator therapy in mothers during pregnancy slightly increases the risk of infections among exposed children.8 This increase in infections was apparent only among children between 9 and 12 months of age, suggesting the possibility of dysfunctional immune development. In our series, no relationship between combination therapy and occurrence of infections was observed. Nor did we find a relationship with the use of antibiotics or with unequivocal immunodeficiency. However, the sample size was too small to draw any firm conclusions. Another type of immune dysfunction—atopy and allergy—was diagnosed in more than 25% of children, which manifested in the majority as typical atopic dermatitis. As the prevalence of common types of allergy among children in the Czech Republic reaches more than 30%, the frequency of allergic disorders was not increased in our cohort.13 Moreover, 4 of 7 affected children had a positive family history of allergy for at least 1 parent that might also contribute to this result. The majority of children received vaccination according to vaccination protocol, including BCG vaccine given to two thirds of them. Vaccination with BCG was mandatory in the Czech Republic till November 2011, and all vaccinated children in our cohort received this vaccine between 2007 and 2010, when a report on the first case of lethally disseminated BCG infection was published.14 Upon publication of the Czech national guidelines for opportunistic infections and their prophylaxis in 2010,15 which included also recommendation on BCG vaccination in children exposed to anti-TNFs in utero, BCG vaccination was postponed in exposed children until the disappearance of the drug from the infants' circulation. Although the number of children in our cohort inappropriately vaccinated with BCG was high, there were only 3 larger skin reactions and 1 lymphadenopathy. Nevertheless, it has to be emphasized that BCG vaccination is contraindicated when anti-TNFs (IFX or ADA) are detected in the infant's circulation. Regarding other vaccines, all induced a detectable serological response, although the H. influenzae vaccine induced only a low titre of antibodies in 40% of children. Regardless of this fact, the case of repetitive H. influenzae infections in 1 child was most likely caused by a different type, as no case of infection with type B of Haemophilus has been identified in the Czech Republic since the time when mandatory vaccination started. Limitations of our study include, first of all, the absence of a control group of children born to IBD mothers and not exposed to anti-TNFs in utero. The number of children included in our cohort is relatively small, and data on drug levels in cord blood are also limited. Finally, the duration of the follow-up is still too short to be definitively convincing regarding the absolute long-term safety of biologics use during pregnancy. In summary, we believe that the present study brought another signal about both short- and long-term safety of biologics administered during pregnancy. We have not found any impact of IFX or ADA on children's growth or neuropsychological development, and most infections observed among our children were clinically not serious. Likewise, mild hypogammaglobulinemia in 40% of children does not seem to affect substantially their general health status. As neither control group of children unexposed to anti-TNFs nor relevant data on infections in the background pediatric population is available, the long-term clinical significance of relatively high frequency of respiratory infections is difficult to assess. Therefore, all children exposed to anti-TNFs during pregnancy deserve a close and long-term follow-up. References 1. van der Woude CJ, Kolacek S, Dotan I, et al.  . European evidenced-based consensus on reproduction in inflammatory bowel disease. J Crohns Colitis . 2010; 4: 493– 510. Google Scholar CrossRef Search ADS PubMed  2. Bortlik M, Machkova N, Duricova D, et al.  . Pregnancy and newborn outcome of mothers with inflammatory bowel diseases exposed to anti-TNF-alpha therapy during pregnancy: three-center study. Scand J Gastroenterol . 2013; 48: 951– 958. Google Scholar CrossRef Search ADS PubMed  3. Marchioni RM, Lichtenstein GR. Tumor necrosis factor-alpha inhibitor therapy and fetal risk: a systematic literature review. World J Gastroenterol . 2013; 19: 2591– 2602. Google Scholar CrossRef Search ADS PubMed  4. Zelinkova Z, van der Ent C, Bruin K, et al.  . 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– 321. Google Scholar CrossRef Search ADS PubMed  5. 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– 292. Google Scholar CrossRef Search ADS PubMed  6. Vasiliauskas EA, Church JA, Silverman N, et al.  . Case report: evidence for transplacental transfer of maternally administered infliximab to the newborn. Clin Gastroenterol Hepatol . 2006; 4: 1255– 1258. Google Scholar CrossRef Search ADS PubMed  7. 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– 1058. Google Scholar CrossRef Search ADS PubMed  8. Mahadevan U, Martin CF, Sandler RS, et al.  . PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy. Gastroenterology.  2012; 142: S149. Google Scholar CrossRef Search ADS   9. Slatter MA, Gennery AR. Clinical immunology review series: an approach to the patient with recurrent infections in childhood. Clin Exp Immunol . 2008; 152: 389– 396. Google Scholar CrossRef Search ADS PubMed  10. Dalal I, Reid B, Nisbet-Brown E, et al.  . The outcome of patients with hypogammaglobulinemia in infancy and early childhood. J Pediatr . 1998; 133: 144– 146. Google Scholar CrossRef Search ADS PubMed  11. Lichtenstein GR, Feagan BG, Cohen RD, et al.  . Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol . 2012; 107: 1409– 1422. Google Scholar CrossRef Search ADS PubMed  12. Toruner M, Loftus EV Jr, Harmsen WS, et al.  . Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology . 2008; 134: 929– 936. Google Scholar CrossRef Search ADS PubMed  13. Kratenova J, Zejglicova K, Maly M. Allergic disorders in children. Report from the National Institute of Public Health, July 2013, Prague, Czech Republic. Available at: http://www.szu.cz/uploads/documents/chzp/alergie/Subsystem_6_OZ_2013_2.pdf. Accessed December 7, 2013. 14. Cheent K, Nolan J, Shariq S, et al.  . Case report: fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn's disease. J Crohns Colitis . 2010; 4: 603– 605. Google Scholar CrossRef Search ADS PubMed  15. Stehlik J, Mares K, Lukas M, et al.  . Recommendation for vaccination in patients with Crohn's disease and ulcerative colitis on immunosuppressive and biological therapy. Ces a Slov Gastroent a Hepatol . 2010; 64: 40– 48. Copyright © 2014 Crohn's & Colitis Foundation of America, Inc. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Inflammatory Bowel Diseases Oxford University Press

Impact of Anti–Tumor Necrosis Factor Alpha Antibodies Administered to Pregnant Women With Inflammatory Bowel Disease on Long-term Outcome of Exposed Children

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Copyright © 2014 Crohn's & Colitis Foundation of America, Inc.
ISSN
1078-0998
eISSN
1536-4844
DOI
10.1097/01.MIB.0000440984.86659.4f
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24407486
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Abstract

Background Prenatal exposure to anti–tumor necrosis factor α (TNF-α) antibodies seems to be safe for fetal development. Data on long-term outcome of exposed children are missing. Our aim was to assess long-term postnatal development of children exposed to anti–TNF-α during pregnancy. Methods Consecutive children aged ≥12 months exposed to anti-TNFs prenatally for maternal inflammatory bowel disease in 3 centers in the Czech Republic were enrolled. Data on psychomotor development, infections, antibiotics, vaccination, and allergy were retrospectively obtained from mothers, treating pediatricians, and children's vaccination cards. Furthermore, standardized laboratory tests on humoral and cellular immunity were performed. Results Twenty-five children exposed to biologicals were included (median age, 34 mo; range, 14–70 mo). All children had normal growth, and all but 1 had normal psychomotor development. Majority (80%) experienced at least 1 infection (mainly respiratory), and 60% of infants received antibiotics, 32% of those within the first year of life. Vaccination was undertaken according to vaccination protocol to 23 infants (92%). Fifteen children also had tuberculosis vaccination without serious complication. Immunological investigation was performed with 17 children (68%). Cellular immunity was normal in all infants, and 7 children had mild decrease in IgA and/or IgG immunoglobulins without clinical significance. All children had a detectable serologic response to vaccination. Conclusions Exposure to anti–TNF-α antibodies seems to be safe for growth and psychomotor development of children, although clinical significance of relatively high frequency of infections and antibiotic use among infants remains questionable because of the lack of a control group. Continuous follow-up of exposed children is absolutely warranted. anti–TNF-α therapy, children, inflammatory bowel disease, prenatal exposure, immune system Inflammatory bowel disease (IBD) frequently manifests in patients of childbearing age.1 Because disease activity, either at the time of conception or during pregnancy, increases the risk of unfavourable pregnancy outcomes, keeping pregnant IBD patients in remission is the primary goal of medical therapy.1 A growing body of evidence supports that anti-TNF alpha (anti–TNF-α) antibodies infliximab (IFX) and adalimumab (ADA) are safe if given to pregnant IBD patients.2,–4 A recent systematic review identified 375 pregnancy exposures to IFX or ADA in IBD patients.3 In general, the results confirmed favorable outcomes of pregnancies with anti–TNF-α exposure with rates of spontaneous abortions, stillbirths, and congenital abnormalities not exceeding those in the general population. Moreover, the live birth rate in the anti–TNF-α exposed group was even higher than that of the general population in the United States.3 In our own series of 41 pregnancies of IBD patients, we have not observed any harmful effect of IFX or ADA therapy in terms of pregnancy outcomes and newborn outcomes up to the first 30 days postpartum.2 Both IFX and ADA belong to the IgG1 class of antibodies and are capable of crossing the placental barrier particularly during the second half of pregnancy. They can be detected in the cord blood at delivery, usually in levels exceeding those in maternal serum.2,4,–7 Moreover, both agents can be present in infants for several months after the birth,6 which raises concerns about infections, safety of vaccination, and, in general, about the development of the immune system of the child. Hence, despite encouraging short-term data, there is insufficient evidence to prove the long-term safety of the use of anti–TNF-α antibodies during pregnancy. The results from an ongoing registry of pregnancy outcomes in IBD patients are yet to be published.8 Therefore, the aim of our study was to assess postnatal development of children exposed to IFX or ADA during pregnancy due to maternal IBD. Materials and Methods Study Population Three centers in the Czech Republic providing anti–TNF-α therapy for IBD participated in this project. The study population comprised consecutive children exposed to anti–TNF-α in utero for maternal IBD treated with biologics in the collaborating centres since 2007. Children aged at least 1 year were eligible for the study. Data Collection/Children Follow-up A structured questionnaire was created and sent to all mothers and treating pediatricians. Data on women's disease location and behavior, smoking habits during pregnancy, and medical therapy, including biologics, corticosteroids, and immunosuppressive agents given to mothers during pregnancy were taken from medical records of the patients. Information on perinatal period, vaccination, mental and physical development, atopy or allergy in children and in parents, infections, and antibiotic use in children were collected using the structured questionnaire completed by both the treating pediatrician (using children's chart) and the mother. In case of uncertainty, the gastroenterologist contacted both the pediatrician and the mother to clarify all ambiguities. Furthermore, the data were supplied from children's health and vaccination cards, which contain records of mandatory follow-up visits and of all vaccinations given to the child. In the Czech Republic, the children are regularly followed up by pediatricians starting at the first week of life with a subsequent regular visit at 6 weeks of age and then at 3, 6, 12, and 18 months. After that, the visits are scheduled every other year from the age of 3 until age of 18 or 19. At each visit, predefined parameters, such as nursing, growth, nutrition, and neuropsychological development, are examined, and any abnormalities are described. In November 2011, our collaboration was begun with the Department of Paediatrics, University Hospital Motol in Prague, where the children underwent specific laboratory immunological investigation. Laboratory Investigation Venous blood samples were taken and standard laboratory methods were used for analyses. Immunological laboratory investigation included (1) full blood count with differential count on the leucocytes; (2) lymphocyte subset analysis on the numbers of CD3+, CD4+, CD8+, CD16+/CD56+, and CD19+; (3) measurement of serum immunoglobulins (IgM, IgA, IgG); and (4) response to vaccination (tetanus, diphtheria, Haemophilus influenzae B (HiB), Streptococcus pneumoniae, rubella, morbilli, parotitis). Furthermore, total IgE and specific IgE (ALATop test, radioimmunoassay screening test for atopy) and eosinophil cationic protein were measured. Levels of IFX and ADA were measured at delivery in 4 mothers and in cord blood of 7 newborns. Drug levels were detected by the solid-phase enzyme-linked immunosorbent assay (Q-INFLIXI, Remicade and Q-ADA, Humira; MatriksBiotek [Ankara, Turkey], respectively). Optical densities were measured by MRXII photometer and analyzed by the Revelation software (both from Dynatech, Borehamwood, United Kingdom). Concentrations of IFX and ADA were expressed as microgram/milliliter with the lower limits for detection being 0.3 ng/mL for IFX and 0.01 ng/mL for ADA. Statistical Analysis Standard descriptive statistical analyses were performed, including frequency distributions for categorical data and calculation of mean or median and range for continuous variables. The impact of immunosuppressive therapy given to mothers during pregnancy on the occurrence of infections and on antibiotic use in infants was analyzed by Fisher's exact test. Ethical Considerations The local ethical committee approved the study, and a written informed consent was obtained from child participants' guardians. Results Twenty-five children were included with a median age at the last follow-up being 34 months (range, 14–70 mo). Two infants were twins, and 2 others were siblings. Twenty-two children were exposed to IFX and 3 to ADA with the mean gestational age of 26 weeks (range, 17–37 wk) at the last anti–TNF-α exposure. Twenty children (80%) were breastfed for a median of 6 months (range, 0.5–33 mo). Levels of IFX in cord blood were measured in 5 children with a mean value of 13.6 μg/mL (range, 1.8–25.0 μg/mL), whereas ADA levels were assessed in 2 infants (0.7 and 0.8 μg/mL). Clinical characteristics of the children at birth are summarized in Table 1. Table 1. Children Characteristics at Birth     View Large Table 1. Children Characteristics at Birth     View Large Twelve mothers (48%) were receiving concomitant azathioprine, and 6 (24%) were treated with corticosteroids (4 with systemic and 2 with topical) at any time during pregnancy. Five women (20%) smoked at conception; however, all discontinued smoking shortly after becoming aware of their pregnancies. IFX levels measured in 2 mothers at the time of delivery were 0.6 and 7.5 μg/mL, respectively, whereas ADA was not detectable in any of 2 women, in whom the blood sample was taken at delivery. We have not observed any case of disease flare between the last dose of anti-TNF and delivery, and no patient thus required rescue medication during that period. Clinical characteristics of mothers' IBD is summarized in Table 2. Table 2. Clinical Characteristics of IBD in Mothers     View Large Table 2. Clinical Characteristics of IBD in Mothers     View Large Growth and Neuropsychological Development All but 1 child had normal growth and neuropsychological development. In 1 boy, a dizygotic twin, there was a mild delay in his psychomotor development diagnosed by his pediatrician at the age of 6 months. He required special neurological care and physical exercise, and, although improved, was still present at the time of the last follow-up (33 mo). Otherwise, all remaining children had normal growth and neuropsychological development. Infections and Antibiotic Use The majority of children (n = 20, 80%) experienced at least 1 infection until the end of follow-up, most of which were respiratory (Table 3). Four infections were serious and required hospitalization or prolongation of hospitalization: there was 1 case of pyelonephritis reported in a girl at 11 months of age (prenatally exposed to ADA) and 1 case of pneumonia in a 29-month-old boy who had been exposed to IFX. This boy developed infection during hospitalization for an accidental skin burn (the boy with delayed psychomotor development mentioned above). There was also 1 case of laryngitis in a 10-month-old girl exposed to IFX, and a case of obstructive bronchitis in a 15-month-old boy who had been exposed to IFX during pregnancy. All infections resolved without any complication, and only the first 2 required antibiotic therapy. Table 3. Infections, Antibiotic Use, and Immunoglobulin Levels in Children Exposed to Anti–TNF-α In Utero     View Large Table 3. Infections, Antibiotic Use, and Immunoglobulin Levels in Children Exposed to Anti–TNF-α In Utero     View Large More than half of the children (n = 15, 60%) used an antibiotic with 8 infants (32%) treated within the first year of their life. Seven infants (47%) had 1 course of antibiotics, whereas 8 children obtained ≥2 antibiotic treatments (range, 2–7). The most commonly prescribed antibiotics were penicillins. No statistically significant difference in the occurrence of infections and use of antibiotics during the first year of life was observed among children exposed to anti-TNF monotherapy and combination therapy with thiopurines and/or corticosteroids (44% versus 50%, P = 1.00% and 22.2% versus 37.5%, P = 0.661, respectively). Vaccination Vaccination with inactivated vaccines was administered according to national vaccination protocol to 23 children (92%) (Table 4). Another 2 had their vaccines postponed upon pediatricians' decision because of IFX detected in cord blood. However, in both cases, gastroenterologists were not aware of this approach. Table 4. Mandatory Vaccination of Children in the Czech Republic     View Large Table 4. Mandatory Vaccination of Children in the Czech Republic     View Large Fifteen infants (60%) also received Bacillus Calmette–Guérin (BCG) vaccination within 1 week of birth, all of them being exposed to IFX. The mean gestational week of last exposure to IFX was week 23 (range, 17–37 wk), and none of these children had IFX level measured before vaccination. Three children had large local (skin) reaction, which was complicated by axillar lymphadenopathy in 1 child. However, all reactions resolved without the need for antituberculosis therapy, and no other complication after the BCG administration was observed. BCG was the only live vaccine among the mandatory vaccinations given to infants during the first year of their lives. In November 2011, it was eventually excluded from Czech national vaccination protocol. Serological response to vaccination was assessed in 15 children (60%). All children developed detectable antibodies against tetanus, S. pneumoniae, diphtheria, rubella, morbilli, and parotitis, and no case of such infection has been reported among the children. Regarding HiB, all children had measurable antibodies, although 6 of them had levels below 1.00 mg/L, which is considered a threshold for reliable protection against the infection. However, antibodies were not assessed within the constant interval from vaccination. One child had recurrent laryngitis with intermittent positivity of H. influenzae upon microbiological examination, but no specification of the type of bacteria was performed. Atopy and Allergy Clinical signs of atopy were observed in 7 children (28%). The majority of them (6 infants) have atopic dermatitis, with one of them also experiencing allergic bronchial asthma. One child developed an allergy to nuts. However, 4 children have positive family history of atopy in at least 1 parent. Laboratory tests for atopy were performed in 17 children and revealed 5 positive results (29%). All 5 infants had increased IgE antibodies overall and specific IgE to particular antigens, and 2 infants also had higher levels of eosinophil cationic protein. In 4 infants, the laboratory and clinical signs of atopy correlated well. Immunological Examination None of the children demonstrated any clinical sign of immunodeficiency as defined by Slatter and Gennery.9 Seventeen children (68%) were prospectively examined at a pediatric clinic and underwent laboratory immunological investigation. In all infants, the blood count including absolute counts on lymphocytes subpopulation did not reveal any significant abnormalities. Regarding immunoglobulins, 7 children (41%) had their levels mildly below the lower limits of normal range: 5 infants had low levels of IgA and 4 of them in combination with low IgG. One child had low level of IgG only, and the other had low level of IgM (Table 5). There was no increase in infection rate or antibiotic use among these children (Table 3). Table 5. Levels of Immunoglobulins in Children With Hypogammaglobulinemia     View Large Table 5. Levels of Immunoglobulins in Children With Hypogammaglobulinemia     View Large Other Diseases One child underwent surgery for an inguinal hernia at the age of 33 months. Another one had clinical symptoms suggesting a cow's milk allergy, but the diagnosis was not confirmed by means of the challenge test. Discussion Available evidence indicates that using anti–TNF-α blockers to treat pregnant IBD patients is probably safe for both mother and newborn.1 However, data regarding long-term safety of these medications for children exposed during pregnancy are sparse. In the present study, we aimed to assess the effect of biologics on children's growth, incidence of infections, allergies, or development of immunological system during a median follow-up period of almost 3 years after birth. All children in our group had normal growth with no case of growth retardation. There was only 1 case (4%) of mildly delayed psychomotor development in a boy born as a dizygotic twin. A special neurological care and exercise led to improvement, but the disorder was still apparent at the age of 33 months. Although most children experienced at least 1 infection during the follow-up, the majority were mild-to-moderate upper respiratory tract infections. This is quite common and usually not a serious infection in this age category. Nevertheless, 4 cases were considered serious and required hospitalization. All 4 resolved promptly, and most importantly, all occurred at the time when the biologic almost certainly had disappeared from the infants' circulation (between 10 and 29 mo). In addition, one of these cases was a direct consequence of hospitalization for relatively serious injury (a skin burn), which further minimizes the potential impact of prenatal exposure to biologic on this complication. No apparent negative impact of anti-TNFs on the development of the immune system has been observed in our cohort. None of the children had clinical signs of immunodeficiency as defined by Slatter and Gennery.9 Two thirds of children in our cohort underwent a detailed immunological laboratory workup, and no abnormality in cellular immunity was found. Although a substantial proportion of children had decreased levels of IgA and/or IgG immunoglobulins (41% of those examined), these cases were rather mild, and no severe decrease in immunoglobulins was found. Children with low immunoglobulins in our cohort most likely fulfill the criteria of so-called transient hypogammaglobulinemia of infancy.9 In the study by Dalal et al,10 the majority of such cases fully recovered in terms of immunoglobulins levels, and both the absence of invasive infections and the protective levels of tetanus antibodies at presentation were identified as predictors of immunoglobulin normalization. As there was no increase of severe infections among our children and all developed protective tetanus antibodies, it seems that clinical relevance of their hypogammaglobulinemia is not considerable. However, continued follow-up of all children is definitely warranted. Prospective observation of the large cohort of IBD patients confirmed an increased risk of serious infections in patients treated with IFX or systemic steroids,11 and the risk was even higher when 2 or more immunosuppressive agents were used.12 Also, preliminary results from a prospective registry of pregnancy outcomes in the United States (PIANO study) indicate that a combination of biologic and immunomodulator therapy in mothers during pregnancy slightly increases the risk of infections among exposed children.8 This increase in infections was apparent only among children between 9 and 12 months of age, suggesting the possibility of dysfunctional immune development. In our series, no relationship between combination therapy and occurrence of infections was observed. Nor did we find a relationship with the use of antibiotics or with unequivocal immunodeficiency. However, the sample size was too small to draw any firm conclusions. Another type of immune dysfunction—atopy and allergy—was diagnosed in more than 25% of children, which manifested in the majority as typical atopic dermatitis. As the prevalence of common types of allergy among children in the Czech Republic reaches more than 30%, the frequency of allergic disorders was not increased in our cohort.13 Moreover, 4 of 7 affected children had a positive family history of allergy for at least 1 parent that might also contribute to this result. The majority of children received vaccination according to vaccination protocol, including BCG vaccine given to two thirds of them. Vaccination with BCG was mandatory in the Czech Republic till November 2011, and all vaccinated children in our cohort received this vaccine between 2007 and 2010, when a report on the first case of lethally disseminated BCG infection was published.14 Upon publication of the Czech national guidelines for opportunistic infections and their prophylaxis in 2010,15 which included also recommendation on BCG vaccination in children exposed to anti-TNFs in utero, BCG vaccination was postponed in exposed children until the disappearance of the drug from the infants' circulation. Although the number of children in our cohort inappropriately vaccinated with BCG was high, there were only 3 larger skin reactions and 1 lymphadenopathy. Nevertheless, it has to be emphasized that BCG vaccination is contraindicated when anti-TNFs (IFX or ADA) are detected in the infant's circulation. Regarding other vaccines, all induced a detectable serological response, although the H. influenzae vaccine induced only a low titre of antibodies in 40% of children. Regardless of this fact, the case of repetitive H. influenzae infections in 1 child was most likely caused by a different type, as no case of infection with type B of Haemophilus has been identified in the Czech Republic since the time when mandatory vaccination started. Limitations of our study include, first of all, the absence of a control group of children born to IBD mothers and not exposed to anti-TNFs in utero. The number of children included in our cohort is relatively small, and data on drug levels in cord blood are also limited. Finally, the duration of the follow-up is still too short to be definitively convincing regarding the absolute long-term safety of biologics use during pregnancy. In summary, we believe that the present study brought another signal about both short- and long-term safety of biologics administered during pregnancy. We have not found any impact of IFX or ADA on children's growth or neuropsychological development, and most infections observed among our children were clinically not serious. Likewise, mild hypogammaglobulinemia in 40% of children does not seem to affect substantially their general health status. As neither control group of children unexposed to anti-TNFs nor relevant data on infections in the background pediatric population is available, the long-term clinical significance of relatively high frequency of respiratory infections is difficult to assess. Therefore, all children exposed to anti-TNFs during pregnancy deserve a close and long-term follow-up. References 1. van der Woude CJ, Kolacek S, Dotan I, et al.  . European evidenced-based consensus on reproduction in inflammatory bowel disease. J Crohns Colitis . 2010; 4: 493– 510. Google Scholar CrossRef Search ADS PubMed  2. Bortlik M, Machkova N, Duricova D, et al.  . Pregnancy and newborn outcome of mothers with inflammatory bowel diseases exposed to anti-TNF-alpha therapy during pregnancy: three-center study. Scand J Gastroenterol . 2013; 48: 951– 958. Google Scholar CrossRef Search ADS PubMed  3. Marchioni RM, Lichtenstein GR. Tumor necrosis factor-alpha inhibitor therapy and fetal risk: a systematic literature review. World J Gastroenterol . 2013; 19: 2591– 2602. Google Scholar CrossRef Search ADS PubMed  4. Zelinkova Z, van der Ent C, Bruin K, et al.  . 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– 321. Google Scholar CrossRef Search ADS PubMed  5. 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– 292. Google Scholar CrossRef Search ADS PubMed  6. Vasiliauskas EA, Church JA, Silverman N, et al.  . Case report: evidence for transplacental transfer of maternally administered infliximab to the newborn. Clin Gastroenterol Hepatol . 2006; 4: 1255– 1258. Google Scholar CrossRef Search ADS PubMed  7. 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– 1058. Google Scholar CrossRef Search ADS PubMed  8. Mahadevan U, Martin CF, Sandler RS, et al.  . PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy. Gastroenterology.  2012; 142: S149. Google Scholar CrossRef Search ADS   9. Slatter MA, Gennery AR. Clinical immunology review series: an approach to the patient with recurrent infections in childhood. Clin Exp Immunol . 2008; 152: 389– 396. Google Scholar CrossRef Search ADS PubMed  10. Dalal I, Reid B, Nisbet-Brown E, et al.  . The outcome of patients with hypogammaglobulinemia in infancy and early childhood. J Pediatr . 1998; 133: 144– 146. Google Scholar CrossRef Search ADS PubMed  11. Lichtenstein GR, Feagan BG, Cohen RD, et al.  . Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol . 2012; 107: 1409– 1422. Google Scholar CrossRef Search ADS PubMed  12. Toruner M, Loftus EV Jr, Harmsen WS, et al.  . Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology . 2008; 134: 929– 936. Google Scholar CrossRef Search ADS PubMed  13. Kratenova J, Zejglicova K, Maly M. Allergic disorders in children. Report from the National Institute of Public Health, July 2013, Prague, Czech Republic. Available at: http://www.szu.cz/uploads/documents/chzp/alergie/Subsystem_6_OZ_2013_2.pdf. Accessed December 7, 2013. 14. Cheent K, Nolan J, Shariq S, et al.  . Case report: fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn's disease. J Crohns Colitis . 2010; 4: 603– 605. Google Scholar CrossRef Search ADS PubMed  15. Stehlik J, Mares K, Lukas M, et al.  . Recommendation for vaccination in patients with Crohn's disease and ulcerative colitis on immunosuppressive and biological therapy. Ces a Slov Gastroent a Hepatol . 2010; 64: 40– 48. Copyright © 2014 Crohn's & Colitis Foundation of America, Inc.

Journal

Inflammatory Bowel Diseases – Oxford University Press

Published: Mar 1, 2014

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