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| Name | Class |
|---|---|
| MOUNT SINAI HOSPITAL | OTHER |
| Crohn's and Colitis Foundation | OTHER |
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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:
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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
| |
| Healthy breastfeeding women | This group is composed of healthy breastfeeding women aged over 18 years and in their first 4-month postpartum period. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| The IBD group was divided into 2 subgroups: with or without anti-TNF antibody use | Other | 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. |
| 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) |
| 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. |
| 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 |
Inclusion Criteria:
Exclusion Criteria:
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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.
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| Name | Affiliation | Role |
|---|---|---|
| Shinya Ito, MD | The Hospital for Sick Children | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mount Sinai Hospital | Toronto | Ontario | M5G 1X5 | Canada | ||
| The Hospital for Sick Children |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39672826 | Background | Maron JL. The importance of investigating the effects of drug therapy on maternal breast milk composition. Pediatr Res. 2025 May;97(6):1765-1766. doi: 10.1038/s41390-024-03785-1. Epub 2024 Dec 13. No abstract available. | |
| 39487320 | Result | 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. 2025 May;97(6):1935-1942. doi: 10.1038/s41390-024-03672-9. Epub 2024 Nov 1. |
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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.
Data will be available from February 2025 to January 2028
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Participants enrolled between August 2017 to November 2022
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | Healthy Breastfeeding Women | This group is composed of healthy breastfeeding women aged over 18 years and in their first 4-month postpartum period. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Healthy Breastfeeding Women |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Control is non-IBD breastfeeding women. IBD group was divided into 2 subgroups based on the status of their treatment with anti-TNF antibody (TNFmAb). Participants were tested twice: first, during early lactation period and second, later during mid-lactation period. Six women in IBD group could not provide milk samples during the mid-lactation period. MCP-3 (CCL7) detection rate was 33% of all samples and therefore excluded from the analyses. | Posted | Median | Inter-Quartile Range | pg/ml | Two points at early-lactation (median 5-6 postpartum weeks) and mid-lactation (median 13-14 postpartum weeks) |
18 months from the delivery for both the mothers and infants.
This is an observational study of breastfeeding women with or without IBD. Some of women with IBD are receiving treatment using monoclonal antibody against TNF (TNFmAb), which is widely known as little to no excretion into milk and is considered no risk to breastfed infants. In addition, there was no study intervention for the purpose of treatment.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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This observational cohort study continued throughout the pandemic restrictions in person-to-person contact. This posed significant challenges to us. Despite this, the participating mother-infant pairs volunteered for the study. This may be the reason why many women in our IBD cohort were in remission, and those women on a severe end of IBD spectrum were not represented by our cohort, limiting the generalizability of our findings.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Shinya Ito | The Hospital for Sick Children | 4168135776 | shinya.ito@sickkids.ca |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP_ICF | Yes | Yes | Yes | Study Protocol, Statistical Analysis Plan, and Informed Consent Form | Nov 12, 2020 | Jan 9, 2025 | Prot_SAP_ICF_000.pdf |
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| ID | Term |
|---|---|
| D003424 | Crohn Disease |
| D003093 | Colitis, Ulcerative |
| D015212 | Inflammatory Bowel Diseases |
| D003092 | Colitis |
| ID | Term |
|---|---|
| D005759 | Gastroenteritis |
| D005767 | Gastrointestinal Diseases |
| D004066 | Digestive System Diseases |
| D007410 | Intestinal Diseases |
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Human milk samples will be collected and analyzed for TNF alpha, TNF alpha-dependent chemokines, and infliximab/adalimumab levels.
|
| At the infant age of 12 months and 18 months |
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. |
| Toronto |
| Ontario |
| M5G 1X8 |
| Canada |
| Withdrawal by Subject |
|
This group is composed of healthy breastfeeding women aged over 18 years and in their first 4-month postpartum period.
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex/Gender, Customized | Number | participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Maternal Weight | Median | Full Range | kg |
|
| Maternal BMI | Median | Full Range | kg/m^2 |
|
| Pregnancy period | Median | Full Range | week |
|
| Mode of Delivery | Number | participants |
|
| Infant Sex: Female | Number | participants |
|
| Infant birth weight | Median | Full Range | grams |
|
| Smoking during pregnancy | Number | participants |
|
| Breastfeeding status | Number | participants |
|
|
|
|
|
| Secondary | 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. | Language test was introduced to the project for completeness after the study had started. This created lower sample numbers at the 12 month point. | Posted | Mean | Standard Deviation | score on a scale | At the infant age of 12 months and 18 months |
|
|
|
|
| Other Pre-specified | 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. | Not Posted | 1-2 months | Participants |
| Other Pre-specified | 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. | Posted | Median | Inter-Quartile Range | postpartum weeks | postpartum weeks until 10 weeks. |
|
|
|
|
| Other Pre-specified | Milk Sampling Time Point in the Mid Lactation Period | This is the second milk sampling point corresponding to the mid-lactation period. | Posted | Median | Inter-Quartile Range | postpartum weeks | postpartum weeks of 10-20 weeks. |
|
|
|
|
| 0 |
| 46 |
| 0 |
| 46 |
| 0 |
| 46 |
| EG001 | Healthy Breastfeeding Women | This group is composed of healthy breastfeeding women aged over 18 years and in their first 4-month postpartum period. | 0 | 33 | 0 | 33 | 0 | 33 |
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| D003108 | Colonic Diseases |
| Title | Measurements |
|---|---|
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| Title | Measurements |
|---|---|
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| Title | Measurements |
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| Title | Measurements |
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| Title | Measurements |
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| Title | Measurements |
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| Title | Measurements |
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| Title | Measurements |
|---|---|
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| Title | Measurements |
|---|---|
|
| Language at 12 month |
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| Cognitive at 18 month |
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| Language at 18 month |
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|
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Language development at 12 months of age. |
| t-test, 2 sided |
| 0.56 |
| Superiority |
| Cognitive development at 18 months of age. | t-test, 2 sided | 0.16 | Superiority |
| Language development at 18 months of age | t-test, 2 sided | 0.75 | Superiority |
| Using pooled data of all participants at the early-lactation sample point, correlation between milk TNF levels and 12 month cognitive development was examined to investigate if they were inversely correlated. | Spearman rank correlation | 0.0853 | Spearman rank correlation | 0.2655 | 2-Sided | 95 | -0.047 | 0.5307 | Other | Correlation analysis |
| Using the pooled data of all participants, correlation analysis between milk TNF at early lactation and 12 month language score was done to see if they were inversely correlated. | Spearman rank correlation | 0.090 | Spearman rank correlation | 0.3705 | 2-Sided | 95 | -0.07385 | 0.6921 | Other | Correlation analysis |
| Kruskal-Wallis |
| 0.96 |
| Superiority |
| Kruskal-Wallis |
| 0.51 |
| Superiority |