1018097 research-article20212021 TAG0010.1177/17562848211018097Therapeutic Advances in GastroenterologyM Chaparro, MG Donday Therapeutic Advances in Gastroenterology Study Protocol The safety of drugs for inflammatory Ther Adv Gastroenterol 2021, Vol. 14: 1–9 bowel disease during pregnancy and DOI: 10.1177/ https://doi.org/10.1177/17562848211018097 https://doi.org/10.1177/17562848211018097 17562848211018097 breastfeeding: the DUMBO registry © The Author(s), 2021. Article reuse guidelines: sagepub.com/journals- study protocol of GETECCU permissions María Chaparro , María G. Donday, Francisco Abad-Santos, Francisco Javier Martín de Carpi, Miguel Ángel Maciá-Martínez, Dolores Montero, Diana Acosta, Yanire Brenes and Javier P. Gisbert Abstract Correspondence to: Background: Active disease during conception and pregnancy in women with inflammatory María Chaparro bowel disease (IBD) increases the risk of pregnancy complications and adverse neonatal Inflammatory Bowel Disease Unit, Department outcomes. The use of IBD treatments during pregnancy should be weighed against their of Gastroenterology, Hospital Universitario de adverse effects on the neonate, but longer-term safety data and data on serious infection La Princesa, Instituto de rates and malignancies postnatally are lacking, particularly for newer drugs, such as Investigación Sanitaria Princesa (IIS-IP), tofacitinib, vedolizumab and ustekinumab. Universidad Autónoma de Methods: This ongoing, prospective registry study being conducted at 70 centres in Spain is Madrid (UAM), Centro de Investigación Biomédica enrolling pregnant women who are ⩾18 years, are at any point in pregnancy up to the end of en Red de Enfermedades Hepáticas y Digestivas the second trimester and have a diagnosis of Crohn’s disease, ulcerative colitis or unclassified (CIBEREHD), Diego de IBD. Patients will receive treatment decided independently by their IBD specialist. Each León, 62, Madrid 28006, Spain incident gestation will be followed up through pregnancy and the first 4 years postnatally. mariachs2005@gmail.com Three cohorts will be compared: biologicals exposed, immunomodulatory exposed and non- María G. Donday Diana Acosta exposed. The primary endpoint is the risk of severe infection in newborns postnatally up to Yanire Brenes Javier P. Gisbert 4 years of age; other endpoints include serious adverse events (SAEs) such as pregnancy Inflammatory Bowel and delivery complications, neonatal SAEs, development [Ages and Stages Questionnaire-3 Disease Unit, Department of Gastroenterology, (ASQ3)], and malignancy incidence, up to 4 years of age. IBD specialists will collect maternal Hospital Universitario de data (baseline/end of each trimester/1 month post-delivery), neonatal birth data, and the SAE La Princesa, Instituto de Investigación Sanitaria and ASQ3 data in children exposed during pregnancy, reported every 3 months by the mother. Princesa (IIS-IP), Universidad Autónoma de Statistical analysis will include summary statistics for quantitative variables, comparisons of Madrid (UAM), Centro de qualitative variables with significance set at p < 0.025 and a binary logistic regression model to Investigación Biomédica en Red de Enfermedades determine the risk factors for severe infections. Hepáticas y Digestivas Results: Enrolment began in September 2019 and study completion is expected in September 2028. (CIBEREHD), Madrid, Spain Francisco Abad-Santos Conclusions: This prospective, controlled study will provide evidence on the long- Clinical Pharmacology term safety profile in children after intrauterine and lactation exposure to biological Department, Hospital Universitario de La and immunomodulatory IBD treatments, including data on postnatal severe infections, Princesa, Instituto Teófilo Hernando, Facultad development and malignancies. de Medicina, UAM, ClinicalTrials.gov identifier: NCT03894228 Instituto de Investigación Sanitaria La Princesa (IP), CIBEREHD, Madrid, Spain UICEC Hospital Keywords: anti-TNF, biological agents, breastfeeding, immunosuppressants, inflammatory Universitario de La bowel disease, pregnancy, tofacitinib, ustekinumab, vedolizumab Princesa, Plataforma SCReN (Spanish Clinical Research Network), IP, Received: 4 December 2020; revised manuscript accepted: 13 April 2021. Madrid, Spain journals.sagepub.com/home/tag 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Gastroenterology 14 Francisco Javier Introduction did include pregnant women had only a small Martín de Carpi Department of Paediatric Inflammatory bowel disease (IBD) affects many number of patients and a short follow-up period Gastroenterolgoy, female patients of childbearing age.1 Women with (usually only up to the time of childbirth).1 Hepatology and Nutrition; Hospital Sant IBD who would like to become pregnant are Joan de Deu, Barcelona, faced with several concerns, such as the influence Therefore, there is a need for a prospective register Catalunya, Spain Miguel Ángel of their disease on the foetus and whether their that will provide information on the safety of IBD Maciá-Martínez IBD treatment(s) will affect their chances of con- drugs, both well-established and newer agents, in Dolores Montero ception, the foetus during pregnancy, and their the mother and her exposed child, up to and Pharmacoepidemiology and Pharmacovigilance baby when breastfeeding.1,2 beyond the first year of age. The aim of the Safety Division, Medicines for of IBD drugs during pregnancy and breastfeeding: Human Use Department, Spanish Agency for IBD does not increase the risk of pregnancy com- Mothers’ and Babies’ Outcomes (DUMBO) regis- Medicines and Medical plications per se; disease activity is the main factor try is to assess the long-term safety of the intrauter- Devices (AEMPS), Madrid, Spain associated with increased risk of pregnancy com- ine exposure to biological and immunomodulatory plications.3 Numerous studies have shown that agents up to 4 years of age. active disease is associated with poor obstetric or neonatal outcomes, including spontaneous abor- tion,4,5 low birth weight,6,7 small for gestational Methods age6 and preterm birth.4,6 Study design and population Indeed, if a patient with IBD conceives when her DUMBO is a prospective, observational registry disease is in remission, the risk of flare-ups is sim- that will enrol pregnant women with IBD [either ilar to that of non-pregnant women,8 but if the Crohn’s disease (CD), ulcerative colitis (UC) or woman conceives during a period of active dis- unclassified IBD] over a 5-year period at 70 cen- ease, there is an eight-fold greater risk of disease tres across Spain [ClinicalTrials.gov identifier: flare-up during pregnancy,9 and a two-fold greater NCT03894228]. risk of the disease remaining active throughout the pregnancy compared with a patient in remis- Recruitment began in September 2019 and will sion at the time of conception.10 Effective disease end in September 2024, with an expected study control both prior to and during pregnancy is completion date of September 2028. Registration therefore critically important.11 Treatment should of the patient and obtaining patient permission is be optimised to reduce the risk of IBD flare-up, performed by the IBD specialists at each partici- but any risks associated with continuing IBD pating centre. Study investigators are responsible treatment before and during pregnancy should be for data collection. Each incident gestation will be taken into account.12–14 followed up through pregnancy and during the first 4 years of the child’s life. Treatment and any There is evidence that most drugs are safe for use other interventions are decided independently by during pregnancy and lactation, although metho- the treating physician and according to local clini- trexate and thalidomide are contraindicated.12–14 cal practice. However, few studies to date have provided long- term follow up of children exposed to IBD drugs.1 Study population Biological drugs have increasingly been used in Female patients aged ⩾18 years with an IBD the treatment of IBD. The majority of evidence diagnosis and confirmed pregnancy, with the on their use during pregnancy is available for the pregnancy known to the study researcher prior to anti-tumour necrosis factor (anti-TNF) agents gestation week 28, are being included in the infliximab and adalimumab, which appear to be study. Patients are excluded if they do not con- associated with a low risk of adverse outcomes.13,14 sent to participate in the study. There is a lack of evidence for the use of newer biological agents (such as vedolizumab and These female patients, as well as the children ustekinumab) and JAK inhibitors (such as tofaci- born to them will comprise the study population, tinib) for IBD during pregnancy and lactation, which will be classified into three cohorts as fol- and their long-term effect on children exposed to lows: (a) biological-exposed cohort: children born them in utero.1 Most clinical trials of these newer to mothers treated with biological agents (with or agents excluded pregnant women, and those that without immunomodulatory agents) at any time 2 journals.sagepub.com/home/tag M Chaparro, MG Donday et al. during pregnancy or the 3 months prior to con- include severe infections, congenital malforma- ception; (b) immunomodulator-exposed cohort: tions, admission to the intensive care unit, low children born to mothers treated with immu- birth weight, hypoxic–ischaemic encephalopathy, nomodulatory agents only, at any time during neonatal stroke or low Apgar score and tumours pregnancy or 3 months prior to conception; or (c) (among others). A complete list of study defini- non-exposed cohort: children born to mothers tions is provided in Table 1. with IBD treated with neither biological nor immunomodulatory agents at any time during pregnancy and in the 3 months prior to concep- Data collection and follow up tion. Children will be assigned to these cohorts Maternal demographic and clinical data (disease based on the treatment (or lack thereof) their characteristics, activity and treatment) will be col- mother was receiving at the time of conception lected at baseline (visit 0), defined as the time of (i.e. before study entry). Pregnancy outcome data study enrolment (after confirmation of pregnancy will also be collected. but before the end of the second trimester). At the end of each trimester and 1 month after deliv- ery (visits 1–4) the following data will be col- Study objectives lected: disease activity; treatment(s); and SAEs The primary study objective is to determine the risk during pregnancy and delivery. In addition, of severe infections in the child from birth to 4 years mothers will be asked to provide information of age. Other study objectives include establishing about whether or not they are breastfeeding, and the risk of serious adverse events (SAEs) during any concomitant medications they took while pregnancy and delivery associated with drugs used breastfeeding at each 3-month visit after birth. All to treat IBD, assessing developmental status of the data will be collected prospectively. child during the first 4 years of life, comparing the risk of SAEs in children exposed in utero to drugs Each live birth will be registered in the database used to treat IBD with the risk in children who were as a case at visit 4 (1 month after delivery), and not exposed, comparing the prevalence of congeni- the following clinical information will be recorded: tal abnormalities in children exposed in utero to date of birth; sex; birth weight; Apgar score at drugs used to treat IBD with the prevalence in chil- 5 min and 10 min; vaccinations; and SAEs. SAE dren who were not exposed, and evaluating the risk and developmental status data pertaining to the of developing neoplasm(s) in children exposed in neonate/child will be reported by the mothers utero to drugs used to treat IBD compared with every 3 months after birth; this information will children who were not exposed. be confirmed annually by medical record review. A study investigator from the coordinating group will contact the mother for completion of the Study definitions Ages and Stages Questionnaire (ASQ3) every IBD location and phenotype will be classified as 2 months (age 2–24 months), at 9 months, then per the Montreal classification15 and IBD activity every 3 months (age 27–36 months), at 42 months measured using the Harvey–Bradshaw Index for and 48 months of age, and answers will be regis- CD16 and the partial Mayo Score for UC.17 IBD tered with their IBD specialist by the coordinat- treatment is considered as treatment received by ing centre on a yearly basis. the mother in the 3 months prior to conception, during pregnancy and during lactation. SAEs are All study data will be collected by the IBD spe- defined as AEs leading to death, a life-threatening cialists using the electronic data capture software event, hospitalisation, disability or permanent tool REDCap (Research Electronic Data Capture; damage, congenital anomaly or birth defect, and Vanderbilt University, Nashville, TN, USA),20 other AEs that the investigator felt may require which is hosted by the Asociación Española de intervention to prevent one of the other outcomes. Gastroenterología (AEG, Madrid, Spain), a not- Specific maternal SAEs of interest include abor- for-profit medical society. tion, stillbirth, growth retardation, severe infec- tion, eclampsia, placenta praevia, chorioamnionitis or abruptio placentae, foetal malformations and Data verification any SAEs during delivery (e.g. instrumental deliv- Data entered in the registry will be verified by the ery). Neonatal and childhood SAEs of interest investigators (MGD, DA, YB) from the Hospital journals.sagepub.com/home/tag 3 Therapeutic Advances in Gastroenterology 14 Table 1. Study definitions. Term Definition IBD IBD location and phenotype classified per Montreal classification15 Date of conception The date of last menstruation before becoming pregnant Smoking Smoking status will be categorised at the time of conception as follows: ‘Smokers’: mother smoked >7 cigarettes per week for ⩾6 months prior to conception ‘Ex-smokers’: mother quit smoking before conception ‘Non-smokers’: mother never smoked Pregnancy Elevated hCG hormone in blood or urine (biochemical pregnancy) Miscarriage Natural death of an embryo or foetus before it was able to survive independently Elective abortion The removal of an embryo or foetus from the uterus to end a pregnancy Comorbidities Maternal comorbidities, including hypertension, diabetes mellitus, seizure disorders, thyroid disorders, allergic disorders, heart diseases, connective tissue diseases, autoimmune diseases and hepatitis Risk factors Known circumstances or determinants that increase the possibility for developing adverse pregnancy outcomes, including the following: type of IBD; maternal age at conception; consumption of toxic substances during pregnancy; IBD activity at the moment of conception; disease activity during pregnancy; low birth weight; prematurity; exposure to immunomodulatory agents; and exposure to biologic drugs Treatments Treatments, including any/all IBD treatments, received by the mother in the 3 months before conception, during pregnancy and during breastfeeding Maternal SAEs SAEs during pregnancy: any event that meets the criteria of an SAE will be registered in the database (see main text for definition of an SAE) SAEs of special interest (listed in the registry and asked of the patient at visits): abortion, stillbirth, growth retardation, severe infection, eclampsia, placenta praevia, chorioamnionitis or abruptio placentae Abnormalities found in the 20th-week ultrasound will be registered (although malformations should be confirmed after birth and included in the neonatal SAE section) Foetal malformations that lead to abortion or stillbirth will be included as cause of abortion or cause of stillbirth in their specific sections (SAEs of the mother) SAE during delivery Includes instrumental delivery or preterm delivery and registered as a maternal SAE The admission for delivery will not be considered an SAE, but any event causing prolongation of hospitalisation will be considered as an SAE SAEs during delivery are classified as a maternal SAE SAE in neonates and Includes congenital malformations, ICU admission, low birth weight, hypoxic–ischaemic encephalopathy, neonatal stroke or low children Apgar score, severe infections and tumours Preterm delivery Delivery before week 37 of gestation13,18 Low birth weight <2500 mg13,18 IBD activity Assessed per the Harvey–Bradshaw Index for CD16 and partial Mayo Score for UC17 Low versus normal At 10 min after birth, a low Apgar score is <7 and a normal Apgar score is ⩾719 Apgar score Severe infection Infections that lead to hospitalisation and/or death, life-threatening events, disability or permanent damage, congenital anomaly or birth defect Developmental status Assessed using the ASQ3 questionnaire Immune modulators Azathioprine, mercaptopurine, methotrexate, tacrolimus, cyclosporine and tofacitinib Biologics Monoclonal antibodies such as vedolizumab, ustekinumab, infliximab, adalimumab, natalizumab, certolizumab and golimumab that target different inflammatory pathways ASQ3, Ages and Stages Questionnaire, third edition; CD, Crohn’s disease; hCG, human chorionic gonadotropin; IBD, inflammatory bowel disease; ICU, intensive care unit; SAE, serious adverse event; UC, ulcerative colitis. 4 journals.sagepub.com/home/tag M Chaparro, MG Donday et al. Universitario de La Princesa (Madrid, Spain), de Medicamentos y Productos Sanitarios (AEMPS): who will conduct a review of all cases. EPA-AS code: GET-VED-2018-01]. As per current pharmacovigilance legislation, Statistical analysis investigators are asked to report any suspected Sample size. In order to ensure sufficient statisti- adverse reactions recorded in the study via the cal power, the study sample size was calculated web page of the national reporting system [Sistema based on an estimated severe infection rate of Español de Farmacovigilancia de Medicamentos 3.2% per person-year of follow up, which is two- de Uso Humano (www.notificaRAM.es)]. fold higher than the rate observed in our previous study with children not exposed to anti-TNF The study will be conducted in accordance with treatment born to mothers with IBD (1.6% per the 2013 version of Declaration of Helsinki, and person-year of follow up).21 Given an estimated according to current Spanish legislation. Patients loss to follow up of 5%, for 80% statistical power or their legal guardians will provide written at a significance level α of 5%, the required sam- informed consent to participate in the study in ple size was calculated to be 1500 person-years accordance with the International Conference on per cohort, which equates to a total of 375 chil- Harmonisation’s Guidelines for Good Clinical dren per cohort (exposed to biologics and non- Practice and local legal and administrative regula- exposed) and followed for 4 years. Therefore, data tions. Patient identity will remain unknown to the will need to be collected on a minimum of 750 study sponsor; the principal investigator is respon- children born to IBD mothers. sible for maintaining patient confidentiality. Descriptive statistics will be used for quantitative variables (mean, standard deviation, median and Discussion interquartile range) with comparisons made using The aim of the DUMBO registry study is to the Student’s t test. The chi-squared test and/or address the significant gaps in knowledge regard- Fisher’s exact test will be used to compare quali- ing longer-term outcomes of children born to tative variables to derive statistical significance for mothers receiving IBD treatment during preg- the overall three-way cohort comparison. If sig- nancy and lactation. The study population will be nificant, comparisons will be made between each grouped by type of IBD treatment into two exposed cohort with the non-exposed cohort with cohorts, the biologicals exposed and immu- significance set at p < 0.025 after adjustment by nomodulator exposed, and compared with each Bonferroni correction for multiple comparisons. other and with a reference cohort of children exposed to neither of these drugs. The novelty of A binary logistic regression model will be used to this registry study will be in obtaining long-term determine risk factors for severe infections. safety data on IBD treatment in pregnancy, par- Factors both statistically significant and of clinical ticularly with regard to newer biological and relevance in the univariate analysis will be incor- immunomodulatory agents. We asked the centres porated in the multivariate analysis, where the included in this study about their ability to recruit dependent variable will be the presence of severe eligible pregnant patients, and according to their infections. Independent variables will include: responses, we estimate that we will be able to type of IBD; maternal age at conception; con- include data from more than 1500 pregnancies. sumption of toxic substances during pregnancy; So far, we have already collected data from 420 IBD activity at the moment of conception; activ- pregnancies in the first 18 months of the study. ity disease during pregnancy; low birth weight; After completion, our registry with 1500 preg- prematurity; exposure to immunomodulatory nancies will compare favourably to all other regis- agents; and exposure to biological drugs. tries we are aware of. Previous studies have frequently examined the Ethics effect of IBD treatment exposure in utero on preg- This study protocol was approved by the Research nancy outcomes, including abortion, stillbirth, Ethics Committee of Hospital Universitario de La growth retardation and preterm birth, and on Princesa (Madrid, Spain) and by the Spanish neonatal outcomes, such as Apgar scores, con- Medicines Regulatory Authority [Agencia Española genital malformation and low birth weight. journals.sagepub.com/home/tag 5 Therapeutic Advances in Gastroenterology 14 However, data on severe infection rates, tumours without sequelae.28 In the TEDDY study, anti- and developmental milestones in infants beyond TNF exposure (with or without thiopurines) was 1 year of age are very limited, particularly for associated with a similar incident rate of infection newer agents like tofacitinib, vedolizumab and to that observed in non-exposed children over a ustekinumab. postnatal follow-up period of 47 months (~4 years; exposed group) or 68 months (5.7 years; non- Immunomodulatory agents, such as thiopurines, exposed group).21 carry a low risk of adverse pregnancy, neonatal or infant outcomes,22,23 and in utero thiopurine expo- With respect to the current evidence on the safety sure is not associated with changes in neurocogni- profile of vedolizumab in pregnant women with tive development or physical or social health.24 IBD and in their infants, the majority of studies were retrospective and lacked a control group, Anti-TNF biological agents are generally consid- and did not examine outcomes beyond early ered safe for use during pregnancy.1,25 A meta- infancy.1 The retrospective, pan-European analysis of pregnant women with UC or CD CONCEIVE study was one of the few to collect found no increase in the risk of adverse pregnancy data on infection rates and malignancies follow- outcomes with anti-TNF therapy versus disease- ing vedolizumab exposure in infants up to 1 year matched controls.26 Limited longer-term data of age.30 Among live-born infants, there were no suggest in utero exposure to anti-TNF therapy malignancies, and serious infection rates did not had no adverse effects on postnatal development significantly differ between the vedolizumab- or malignancy risk. In the Pregnancy in exposed cohort, the anti-TNF-exposed cohort or Inflammatory Bowel Disease and Neonatal the control cohort. Most pregnancy and neonatal Outcomes (PIANO) registry study (which col- outcomes showed no significant differences lected data in approximately 1000 children born between groups; the live infant birth rate was sig- to IBD mothers), developmental outcomes up to nificantly lower in the vedolizumab group than 1 year of age were unaffected by in utero anti-TNF the control group (78% versus 89%; p = 0.038), exposure.27 Bortlik et al.28 conducted a study with but this difference was no longer significant when longer follow up of 25 children exposed to inflixi- patients with active disease during any stage of mab or adalimumab in utero; these children were pregnancy were excluded.30 To date, one pro- followed for up to 70 months (5.8 years), and spective study has been conducted in pregnant their growth and psychomotor development was women with IBD who were treated with either normal in most cases. None of these studies vedolizumab, anti-TNF agents or conventional reported data on malignancies; in the long-term, therapy,31 and vedolizumab appeared to be asso- retrospective TEDDY study, there were no ciated with low risk during pregnancy, although malignancies reported in 388 children who were the authors concluded that studies with larger exposed to anti-TNF therapy in utero.21 populations and longer follow up were needed to confirm this.31 A clinical programme of six stud- The short-term risk of infection does not appear ies in pregnant women provided further evidence to be increased among children exposed to anti- on the safety profile of vedolizumab for infants TNF therapy in utero. In the retrospective born to women with IBD,32 but study population EVASION study of pregnant women with IBD, was small and follow up of short duration.32 the risk of infection in the first year of life was not increased in children exposed to anti-TNF ther- Published evidence on the use of ustekinumab apy in utero compared with those not exposed.29 during pregnancy and its effect on neonates is However, in the PIANO registry study, an even more limited than for vedolizumab. Most increased risk of infection was observed in chil- pregnancy/neonatal safety data are available for dren aged 9–12 months exposed to both anti- patients with psoriasis, where lower ustekinumab TNF therapy and thiopurines versus those not doses are used, and therefore, cannot be extrapo- exposed to either drug class,27 suggesting an lated to patients with IBD.1 To the best of our increased risk of neonatal infection with combina- knowledge, evidence is limited to five case reports tion therapy. Bortlik and colleagues reported a of women with CD treated with ustekinumab high incidence of infant infection following in during pregnancy.33–37 Pregnancy and neonatal utero infliximab or adalimumab exposure, but a outcomes were uneventful in three of them; how- low rate of severe infection; all infections resolved ever, for the remaining women, there was one 6 journals.sagepub.com/home/tag M Chaparro, MG Donday et al. case of a miscarriage at 8 weeks’ gestation33 and of the children born to mothers with IBD. The one of caesarean section due to spontaneous rup- DUMBO study includes a control cohort, and is ture of membranes at 37 weeks’ gestation.37 Infant prospective, which should yield better accuracy of follow-up duration was ⩾1 year in three cases, all data collection on treatment exposure, endpoints reporting normal development.34–36 and confounding variables.39 The primary end- point of the DUMBO study is the severe infection The majority of safety evidence for tofacitinib in rate during postnatal development up to 4 years pregnant women and their infants is from studies of age, which will provide valuable data regarding in patients with rheumatological diseases (e.g. the longer-term severe infection risk following in psoriatic arthritis and rheumatoid arthritis).1 One utero exposure to IBD treatment. Similarly, the analysis of tofacitinib interventional studies registry’s secondary endpoints on long-term risk reported positive pregnancy/neonatal outcomes of SAEs, effects on developmental status, and in women with UC receiving tofacitinib at con- malignancy rate, as well as monitoring the safety ception or during pregnancy.38 All women initi- of IBD treatment in children who are breastfed ated tofacitinib in the first trimester; no foetal or (Table 1), will provide further long-term safety neonatal deaths nor congenital abnormalities data in children up to 4 years of age regarding the were reported, being the most common outcome use of biological and immunomodulatory agents a healthy newborn. These results were generally during pregnancy in women with IBD. In addi- consistent with those observed in the entire tofac- tion, developmental status will be recorded for- itinib clinical programme (i.e. UC, psoriasis, pso- mally using a standardised, well-recognised riatic arthritis and rheumatoid arthritis); however, metric (ASQ3), which will help reduce recall bias the authors concluded that there was insufficient regarding the child’s development. Statistical evidence to confirm the safety profile of tofaci- analyses are planned to minimise selection bias tinib in pregnant women or their infants, particu- and the effect of confounding variables. larly given the small patient numbers, lack of controlled studies, and preclinical data indicating In summary, the DUMBO study will provide tofacitinib’s foeticidal and teratogenic effects.38 clinicians with important information on the short- and long-term risks associated with in Anti-TNF agents and the newer biological agents utero exposure to biological or immunomodula- vedolizumab and ustekinumab have been detected tory agents in women with IBD and their chil- in very small quantities in human breastmilk; dren. It is expected that the results of the consequently, breastfeeding while taking any of registry will address the need for information these agents is likely to be of low risk to the neo- on the safety of treatments for IBD during preg- nate.1,11 However, the currently available evi- nancy and lactation and will contribute on dence does not allow for an unequivocal establishing evidence-based recommendations recommendation to continue treatment with for the use of these agents in pregnant women these agents during breastfeeding.1,11 with IBD. Treatment guidelines recommend that adminis- Acknowledgements tration of live vaccinations to infants with intrau- We would like to thank Tracy Harrison of terine exposure to anti-TNF agents12–14,18 and Springer Healthcare Communications for her other biologicals12,14 be delayed to after 6 months assistance writing the outline and first draft of this of age. Non-live vaccinations may be adminis- manuscript. This editorial assistance was funded tered according to standard national immunisa- by a grant from Instituto de Salud Carlos III tion schedules. To improve evidence regarding (grant number ICI19/00083). the tolerability of vaccinations, all relevant data on vaccinations will be captured for infants Author contributions included in the DUMBO registry. María Chaparro1, Francisco Abad Santos2,3, Francisco Javier Martín de Carpi4, Miguel Ángel The DUMBO registry has been designed to Maciá-Martínez5, Dolores Montero5 and Javier address the dearth of evidence from prospective P. Gisbert1: study design. controlled studies on the longer-term effects of in utero exposure to IBD treatments, particularly María G Donday, Diana Acosta, Yanire Brenes: biological agents, on the health and development study management, case report form design. journals.sagepub.com/home/tag 7 Therapeutic Advances in Gastroenterology 14 Conflict of interest statement 5. Nielsen OH, Andreasson B, Bondesen S, MCh has served as a speaker, or has received et al. Pregnancy in ulcerative colitis. Scand J research or education funding from MSD, Gastroenterol 1983; 18: 735–742. Abbvie, Hospira, Pfizer, Takeda, Janssen, 6. Leung KK, Tandon P, Govardhanam V, Ferring, Shire Pharmaceuticals, Dr Falk, Pharma, et al. The risk of adverse neonatal outcomes Tillotts Pharma. with maternal inflammatory bowel disease: a systematic review and meta-analysis. Inflamm FAS has been consultant or investigator in clini- Bowel Dis 2021; 27: 550–562. cal trials sponsored by the following pharmaceuti- cal companies: Abbott, Alter, Chemo, Cinfa, 7. Bortoli A, Pedersen N, Duricova D, et al. FAES, Farmalíder, Ferrer, GlaxoSmithKline, Pregnancy outcome in inflammatory bowel disease: prospective European case-control Galenicum, Gilead, Italfarmaco, Janssen-Cilag, ECCO-EpiCom study, 2003–2006. Aliment Kern, Normon, Novartis, Servier, Silverpharma, Pharmacol Ther 2011; 34: 724–734. Teva and Zambon. 8. Miller JP. Inflammatory bowel disease in JPG has served as a speaker, a consultant and advi- pregnancy: a review. J R Soc Med 1986; 79: sory member for or has received research funding 221–225. from MSD, Abbvie, Hospira, Pfizer, Kern Pharma, 9. Oron G, Yogev Y, Shcolnick S, et al. Biogen, Takeda, Janssen, Roche, Ferring, Faes Inflammatory bowel disease: risk factors for Farma, Shire Pharmaceuticals, Dr. Falk Pharma, adverse pregnancy outcome and the impact of Tillotts Pharma, Chiesi, Casen Fleet, Gebro maternal weight gain. J Matern Fetal Neonatal Pharma, Otsuka Pharmaceutical, Vifor Pharma. Med 2012; 25: 2256–2260. 10. Abhyankar A, Ham M and Moss AC. 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