Assessing the Drug Exposure Risk of Infants Breastfed by Women With Inflammatory Bowel Disease

Breastfeeding is beneficial to both mother and baby. However, many breastfeeding women are affected by long-term health conditions and need to take medications. Sometimes, concerns about transfer of drugs to infants via breast milk lead the mothers to either avoid breastfeeding or stop their medication.

Inflammatory Bowel Disease (IBD) is a chronic condition that is marked by an abnormal response of the body's immune system, and high levels of certain proteins that cause inflammation (Cytokines like Tumor Necrosis Factor-alpha or TNFα). A group of drugs called "biologics" target and stop these proteins from causing inflammation, and have been successfully used to treat this condition. Inflammatory proteins may be present in breast milk of healthy women in variable levels, and may play a role in development of infant's brain and immune system.

This study is being conducted to investigate:

• Concentration of some of the inflammatory proteins in breast milk of mothers with IBD and healthy controls
• Interaction between these proteins and biologics in breast milk of women with IBD
• Potential role of these proteins (and their interaction with biologics) on development of infant learning and memory function It has been presumed that concentrations of TNFα and some other cytokines are higher in breast milk of women with IBD, and the biologics can normalize these high levels.

Due to precautions for COVID-19, the study now consists of only two mandatory study visits and two optional study visits. The mandatory visits include two home visits in the first 4 months postpartum to complete a participant questionnaire and collect a small sample of breast milk at each visit. The optional study visits consist of two visits at the Hospital for Sick Children for evaluation of learning and memory function of the infant at the ages of 12 and 18 months. Additionally, mothers will be required to complete for their infant subscales of The Ages and Stages Questionnaires®, Third Edition (ASQ®-3) either in person or over the telephone at the ages of 12 months and 18 months.

Study Overview

• Status: Active, not recruiting
• Conditions: Crohn's Disease; Ulcerative Colitis; Healthy Controls

Detailed Description

The inflammatory bowel disease (IBD) shows the highest incidence among people of childbearing age. Indeed, it is not uncommon that pregnant or lactating women with IBD require drug therapy, including monoclonal antibodies against Tumor Necrosis Factor-alpha (TNFα). However, these patients face challenges, because information on pregnancy and breastfeeding safety of these new medications is lacking due to exclusion of pregnant and breastfeeding women from drug development processes. Whereas the data necessary for fetal safety assessment is accumulating gradually, significant gaps in the research efforts and the understanding on excretion of TNFα inhibitors into milk remain. Experts generally consider it acceptable to use the TNFα inhibitors during breastfeeding, because the previous studies found relatively low levels of these drugs in milk. However, the existing data on milk levels of these drugs are highly inconsistent, probably because previous reports gave no consideration to potential interference from high levels of endogenous TNFα in milk. As a result, a comprehensive picture of TNFα inhibitors in breast milk remains obscure. Moreover, in a recent mouse study, transfer of TNFα-dependent chemokines through milk has been shown to play a role in shaping the postnatal programming of brain development, implying that altered disposition of endogenous TNFα and other chemokines in milk during anti-TNFα therapy has an impact on brain development of the offspring.

This is an observational cohort study with comparison group, which describes the first step to address the issue by uncovering the TNFα-dependent 'lactocrine' pathway and disposition of TNFα inhibitors in milk. The study will also investigate the pharmacokinetics of TNFα inhibitors in breast milk (as a sub-study), using the population pharmacokinetic (popPK) approach.

• Study Type: Observational
• Enrollment (Estimated): 160

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The study participants are required to live in the Greater Toronto Area. The IBD group will be selected from IBD clinics, while the healthy controls will be selected from the community samples who volunteer to participate.

Description

Inclusion Criteria:

• Breastfeeding women with IBD or healthy breastfeeding women in the first 4-month postpartum period

Exclusion Criteria:

• unable to communicate in English
• Present illness of chronic inflammatory conditions (except IBD)
• Mastitis
• Present acute or chronic infection
• use of a different anti-TNFα drug within the last 2 months

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Women with IBD; This group is composed of breastfeeding women aged over 18 years and in their first 4-month postpartum period, who are diagnosed with Crohn's disease or Ulcerative Colitis.
Healthy breastfeeding women; This group is composed of healthy breastfeeding women aged over 18 years and in their first 4-month postpartum period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of TNFα and its downstream chemokines (CCL2, CCL4, CCL7, and CXCL10) in breast milk of women with IBD and healthy controls by Multiplex assay	Multiplex assay will be used to measure TNFα and downstream chemokines including CCL2, CCL4, CCL7, CXCL10 in breast milk of two groups of participants (women with IBD and healthy controls). (The unit of measurement is the same for all these cytokines)	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Milk concentration of TNFα inhibitors (infliximab, adalimumab) at different time-points between two doses of medication, in lactating women with IBD by ELISA assay	ELISA assay will be used to measure total and free drug levels (bound and unbound to TNFα) in breast milk of lactating women with IBD. (The unit of measurement is the same for infliximab and adalimumab).	4 years
Scores on cognitive subset of Bayley Scales of Infant and Toddler development- Third Version (Bayley-III) in infants of healthy controls and women with IBD	The infants of women with IBD and healthy controls will be examined for cognitive development using Bayley-III	4 years
Scores on the "Problem-solving" and "Communication" subscales of The Ages and Stages Questionnaire (ASQ®-3) in infants of healthy controls and women with IBD	Infants of healthy controls and women with IBD will be examined for communication and problem-solving development using the ASQ®-3. This supplementary measure is intended to provide additional data as an alternative to Bayley test under unprecedented circumstances which preclude participants to complete Bayley test at the Hospital for Sick Children	4 years
Simulated/predicted profiles of TNFα inhibitors (infliximab, adalimumab) in breast milk in a large population of lactating women with IBD by population pharmacokinetic modelling	An estimation of the population distribution of anti-TNFα antibodies (infliximab and adalimumab) in breast milk of women with IBD will be made, using population pharmacokinetic modelling	4 years

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Collaborators: MOUNT SINAI HOSPITAL; Crohn's and Colitis Foundation
• Investigators: Principal Investigator: Shinya Ito, MD, The Hospital for Sick Children

Study record dates

Study Major Dates

• Study Start (Actual): July 4, 2017
• Primary Completion (Actual): November 30, 2022
• Study Completion (Estimated): November 30, 2024

Study Registration Dates

• First Submitted: December 19, 2017
• First Submitted That Met QC Criteria: January 5, 2018
• First Posted (Actual): January 11, 2018

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: April 9, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: monoclonal antibody; Inflammatory Bowel Disease; Crohn disease; TNF; Colitis; Breast milk
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Inflammatory Bowel Diseases; Crohn Disease; Intestinal Diseases; Colitis
• Other Study ID Numbers: 1000056982

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No