Safety of IBD Drugs During Pregnancy and Breastfeeding: Mothers and Babies' Outcomes (DUMBO Registry)

OBJECTIVES Main objective - To assess the safety of drugs used for IBD treatment both for pregnancy and for the offspring mainly focused on the risk of serious infections (from birth and in the first 4 years of life).

Specific objectives

• To know the risk of serious adverse events (including abortions) during pregnancy and delivery associated with drugs used for the treatment of IBD.
• To asses the developmental status of children born from IBD mothers during the first 4 years.
• To compare the relative risk of serious adverse events in children born from mothers with IBD who have been exposed in utero to different drugs to treat IBD with the risk in children who were not exposed.
• To compare the prevalence of malformations in children exposed to drugs to treat IBD in utero with the prevalence in children who were not exposed.
• To evaluate the relative risk of developing neoplasm in children exposed to drugs to treat IBD.

Inclusion criteria

• Patients over 18 years of age diagnosed with IBD.
• Confirmed pregnancy.
• Awareness of the pregnancy (by the researcher) before week 28th of gestation (the end of the second trimester).

Exclusion criteria. - Patients who do not accept to participate in the study Study cohorts

• Biologics exposed cohort: Children born from mothers treated with biologic drugs (with or without immunomodulators) at any time during pregnancy or the three months before conception. Biologic drugs are IgG monoclonal antibodies able to cross the placenta.
• Immunomodulators exposed cohort: Children born from mothers treated with immunomodulators (without biologics) during pregnancy or the three months before conception.
• Non-exposed cohort: Children born from mothers treated neither with biologic drugs nor with immunomodulators at any time during pregnancy or the three months before conception.

Tasks and responsibilities:

IBD specialists from the participating centers will be responsible for identifying the patients, obtaining the informed consent and registering them in the database.

Each participating investigator will register all the demographic and clinical data of the mother at the time of entering in the study and will contact the pregnant woman at the end of first trimester, the end of second trimester, the end of third trimester and one month after delivery to prospectively include information about disease activity, treatments and serious adverse events (if any) during pregnancy and delivery. If the mother contacts the clinician (researcher) after the end of the first trimester but before the end of the second trimester of gestation, the case can be included and data up to the entry date registered retrospectively. In order to ensure data quality, patients who inform about the pregnancy after the end of the second trimester of gestation will be excluded.

After birth, the mother will be contacted every 3 months to include information about the child development and serious adverse events (mainly malformations, infections, hospital admissions or neoplasias such as developmental tumors). After consenting, contact information of the mother will be shared with the research team in Hospital Universitario de La Princesa in order to complete the information every 3 months. On a yearly basis, the mothers will provide the site investigator with the reports that support the information given in the remote contact. In addition, in the first visit after birth, mothers will be provided with the Ages and Stages Questionnaire (ASQ 3, annex 2) that should be completed during follow-up (2, 4, 6, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 42, 48 months of age). The mother should give the questionnaire she has completed once per year. External monitoring of cases included in the registry will also be performed by review of some cases selected at random by the research team of Hospital Universitario de La Princesa.

Definitions

1. Disease location and phenotype: IBD location and phenotype will be defined according to the Montreal classification.
2. Date of conception: It will be defined as the date of last menstruation before becoming pregnant.
3. Smoking: Smoking status will be categorized as "non-smoker", "smoker", or "ex-smoker", and will be considered at the time of conception. Patients will be considered "smokers" if they smoked more than 7 cigarettes per week for at least 6 months prior to conception. Patients will be considered "ex-smokers" if they quit smoking before conception. Patients will be considered "non-smokers" if they never smoked.
4. Diagnosis of pregnancy: Elevated human chorionic gonadotropin (hCG) hormone in blood or urine (biochemical pregnancy).
5. Miscarriage: Natural death of an embryo or fetus before it is able to survive independently.
6. Elective abortion: The removal of an embryo or fetus from the uterus in order to end a pregnancy.
7. Comorbidities: Mother's diseases, with special mention to hypertension, diabetes mellitus, seizure disorders, thyroid disorders, allergic disorders, heart diseases, connective tissue diseases, autoimmune diseases, hepatitis.
8. Known risk factors for adverse pregnancy outcomes, including environmental or occupational exposure, among others.
9. Treatments: Treatments received by the mother in the 3 months before conception, during pregnancy and breastfeeding will be recorded.
10. Serious adverse events: In order to harmonize the inclusion of adverse events and complications, only serious adverse events will be registered (see the definition of adverse events in the Annex 1 of the protocol). Nevertheless, the investigators have predefined the most frequent serious adverse events during pregnancy and in the offspring. In this respect, the main variable in our study will be the development of serious infection in the offspring (infection meeting criteria of serious adverse event).

9.1. Serious adverse events during pregnancy: Any event that meets the criteria of serious adverse event will be registered in the database. Some of the most frequent serious adverse events during pregnancy are specifically defined and inquired by the registry: abortion, stillbirth, growth retardation, serious infection, eclampsia, placenta previa, chorioamnionitis, or abruptio placenta. Abnormalities found in the 20th week ultrasound will be registered (although malformations should be confirmed after birth and included in the Serious Adverse Events section of the newborn). Fetal malformations that lead to abortion or stillbirth will be included as cause of abortion or cause of stillbirth in their specific sections (Serious adverse events of the mother).

9.2. Serious adverse events during delivery: Serious adverse events, such as instrumental delivery or preterm delivery will be registered in the Serious adverse events of the mother section. The admission for delivery will not be considered as a serious adverse event, but any event causing prolongation of the admission will be considered as a serious adverse event and registered in the specific section.

9.3. Serious adverse events in the newborns and children: Serious adverse events in the newborn and children, such as congenital malformations, admission to the intensive care unit, low birth weight, hypoxic-ischemic encephalopathy, neonatal stroke or low Apgar score, severe infections and tumors will be included.

1. Preterm delivery: Delivery before week 37 of gestation18, 19. 11. Low birth weight: <2,500 mg18, 19. 12. IBD activity: The IBD activity will be assessed at conception (when the physician is aware of the pregnancy) and in each trimester of gestation based on the Harvey-Bradshaw for CD and Partial Mayo Score for UC patients.
2. Low Apgar score: Apgar scores lower than 7 are considered low, and scores of 7 or higher are considered normal at ten minutes after birth20.
3. Serious infection: Only infections that meet the criteria of serious adverse event will be included. The inclusion of any infection, irrespective of its seriousness, would be very heterogeneous among investigators, leading to reporting bias which might affect the interpretation of the results. This variable will be the main outcome.
4. Developmental status: The developmental status will be assessed by the ASQ-3 questionnaire (annex 2). The mothers will complete the questionnaire at home and send the completed forms yearly to their treating clinicians.

Data collection and follow-up After the case is registered, four other visits will be recorded during pregnancy, coinciding with the routine visits of the patient for the follow-up of her disease. After delivery, the children will be followed-up until the age of 4 years. In case of multiple gestations, each child will be considered as a case with his/her own follow-up. Only live newborns will be considered cases. Abortions or stillbirths will be registered as mothers' adverse events. In multiple gestations, the number of fetuses affected by a certain serious adverse event will be indicated in the CRF. During the child's follow-up period, the mother (that is the patient, indeed) will be contacted remotely every-three months to complete information about child complications (if any). The visits over the study are described below. The variables included in the eCRF are listed in Annex 3.

• Visit 0 (baseline): inclusion of patient in the study (after confirmed pregnancy) and registration of clinical data (characteristics of the disease, disease activity and treatments).
• Visit 1 (end of first trimester of gestation): Updating of data related to treatment, disease activity and serious adverse events (if any).
• Visit 2 (end of second trimester of gestation): Updating of data related to treatment, disease activity and serious adverse events (if any).
• Visit 3 (end of third trimester of gestation): Updating of data related to treatment, disease activity and serious adverse events (if any).
• Visit 4 (1 month after delivery): Updating of data related to treatment, disease activity and serious adverse events (if any). In addition, in this visit, the child will be registered in the database as a case. Information of the newborn, such as date of birth, sex, birth weight, Apgar score (at 5 and 10 minutes), vaccines, breastfeeding, serious adverse events, etc., will be included.
• Visit 5 (3 months of age, 2 months after visit 4) to 20 (4 years of age): Updating of data related to children development, vaccines, breastfeeding, date of schooling, infections, hospitalizations, allergies or any other complications. The same data will be queried to the mother every-three months after the age of 4 years. Remote contacts will be allowed to complete the children information, as the investigators believe that this way of obtaining information will not have impact on the quality of data and will improve the adherence to the protocol. Nevertheless, once per year data should be confirmed with medical reports provided by the mothers.

Study data will be collected and managed using an electronic data capture tool (Research Electronic Data Capture [REDCap]1, 18, 19), which is hosted at Asociación Española de Gastroenterología21, a non-profit scientific and medical society focusing on gastroenterology. AEG provides this service free of charge, with the sole aim of promoting independent investigator-driven research. REDCap is a secure, web-based application designed to support data capture for research studies that provides the following: 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources.