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.

Inflammatory Bowel Disease (IBD) 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 TNF). 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 observational study is 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 TNF and some other cytokines are higher in breast milk of women with IBD, and the biologics can normalize these high levels.

Note: Due to the pandemic, the study now consists of reduced number of 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: Completed
• Conditions: Crohn's Disease; Ulcerative Colitis; Healthy Controls
• Intervention / Treatment: Other: The IBD group was divided into 2 subgroups: with or without anti-TNF antibody use

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 (TNF).

TNF and TNF-dependent chemokines are normally expressed in milk. Importantly, experimental data indicate enhanced brain growth and cognitive development in the mouse offspring given milk deficient in TNF and TNF-dependent chemokines. Patients with IBD are often treated with monoclonal antibodies against TNF (TNFmAb). Although TNFmAb is used during breastfeeding due to their minimal milk excretion, whether it affects endogenous TNF/chemokines in human milk is not known.

Our hypotheses are: 1) Women with IBD have higher TNF (and TNF-dependent chemokines) in milk than non-IBD control women, because of the inflammatory condition; and 2) Women with IBD receiving TNFmAb have lower TNF (and TNF-dependent chemokines) in milk than those with IBD who are not treated with TNFmAb.

We conduct an observational study of breastfeeding women with or without IBD. Some of these women with IBD are likely to be receiving TNFmAb. We measure milk concentrations of TNF and TNF-dependent chemokines in early (5-6 weeks postpartum) and mid-lactation period (13-14 weeks postpartum). Also, as an exploratory analysis, we assess their infant's cognitive and language development at 12 month and 18 months using Bayley-III tool.

Note:

Because there was no information at the outset of the study on cytokine profiles in milk of women with inflammatory conditions including IBD, a formal sample size could not be estimated. Although a provisional target was set, the study was designed to continue for the planned study duration as no stopping rule had been defined. Also, our original protocol included a population pharmacokinetic study of TNFmAb in milk. However, due to the pandemic and difficulty in developing the assay method, we were not able to start this part of the project.

• Study Type: Observational
• Enrollment (Actual): 79

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-Tumor Necrosis Factor (TNF) 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	Intervention / Treatment
Healthy breastfeeding women; This group is composed of healthy breastfeeding women aged over 18 years and in their first 4-month postpartum period.
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. Some of them were receiving anti-TNF monoclonal antibody prescribed by their prescribers (outside this observational study) at a standard dose and interval.	Other: The IBD group was divided into 2 subgroups: with or without anti-TNF antibody use; This observational study enrolled women with IBD, and some of them were receiving a treatment with anti-TNF monoclonal antibody, which was prescribed by their responsible prescribers at a standard dose and dosing interval.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of TNF (Tumor Necrosis Factor Alpha) and TNF-dependent Chemokines (MCP1, MIP-1beta and IP10) in Breast Milk of Women With IBD and Healthy Controls by Multiplex Assay	This observational study collected milk samples during the defined study periods: early-lactation and mid-lactation. To capture a temporal profiles of Tumour Necrosis Factor (TNF) and TNF-dependent chemokine levels, we analyzed these 2 sampling periods separately, instead of pooling them per sampling period. Multiplex assay was used to measure TNF and TNF-dependent downstream chemokines including MCP-1 (CCL2), MIP-1beta (CCL4) and IP10 (CXCL10) in breast milk of two groups of participants (women with IBD and healthy controls) at two sampling periods (early- and mid-lactation). Our original plan included MCP-3 (CCL7) as well, but an average quantification rate for this chemokine was only 33%, and therefore we excluded MCP-3 from our analyses.	Two points at early-lactation (median 5-6 postpartum weeks) and mid-lactation (median 13-14 postpartum weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	We used Bayley Scales of Infant and Toddler development- Third Version (Bayley-III): which is used widely to measure child's cognitive and language development. In this scale, for both cognitive and language scores, minimum standard score is 45 and maximum standard score is 155: Higher standard scores indicates stronger/better performance. Children of the participating mothers were tested at the age of 12 months and 18 months. The language assessment is also used for comprehensiveness, but this has been added after the study was started. The test is performed as a single-blinded assessment in a controlled environment at the Hospital for Sick Children by a trained psychometrist supervised by a psychologist.	At the infant age of 12 months and 18 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Population Pharmacokinetic Study of Anti-TNF Monoclonal Antibody in Milk	Concentrations of anti-TNF monoclonal antibody in milk will be measured once the method is validated. The data will be analyzed using population pharmacokinetic modeling.	1-2 months
Milk Sampling Time Point in the Early Lactation Period	This is the early lactation sampling points: one of the two milk sampling time points (post-partum weeks). The milk samples were analyzed for their TNF and chemokine levels.	postpartum weeks until 10 weeks.
Milk Sampling Time Point in the Mid Lactation Period	This is the second milk sampling point corresponding to the mid-lactation period.	postpartum weeks of 10-20 weeks.

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

Publications and helpful links

General Publications

• Maron JL. The importance of investigating the effects of drug therapy on maternal breast milk composition. Pediatr Res. 2024 Dec 13. doi: 10.1038/s41390-024-03785-1. Online ahead of print. No abstract available.
• Sepiashvili L, Brydon A, Koroshegyi C, Gold A, Dalvi P, Ghayoori S, Rahman M, Huang V, Maxwell C, Nguyen GC, Ito S. Reduction of tumor necrosis factor (TNF) in milk of women receiving anti-TNF antibody. Pediatr Res. 2024 Nov 1. doi: 10.1038/s41390-024-03672-9. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2017
• Primary Completion (Actual): November 30, 2022
• Study Completion (Actual): November 5, 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): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 25, 2025
• Last Verified: February 1, 2025

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; Colonic Diseases; Gastroenteritis; Colitis; Crohn Disease; Intestinal Diseases; Inflammatory Bowel Diseases; Immunologic Factors; Physiological Effects of Drugs; Antibodies
• Other Study ID Numbers: 1000056982

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Participant-level data collected during the study will be available for research purposes in a form of de-identified individual data upon reasonable request. Other research documents such as study protocol may be also available. This data sharing activity is contingent upon approval from the institutional research ethics board of the Hospital for Sick Children. An interested party may submit a proposal to the study team up to 36 months following article publication, describing the purpose and methods of data use. Data requestors may need to sign a data transfer agreement.
• IPD Sharing Time Frame: Data will be available from February 2025 to January 2028
• IPD Sharing Access Criteria: Request deemed reasonable by the study team; No objection from the research ethics board of the Hospital for Sick Children; No objection from the legal department of the Hospital for Sick Children
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

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