Efficacy and Adverse Side Effects of Two Forms of Iron in Pregnancy (EASE-Iron)

Efficacy and Adverse Side Effects of Two Forms of Iron in Prenatal Micronutrient Supplements (EASE-Iron): A Randomized Controlled Trial

This two-arm, double-blind randomized clinical trial will recruit 172 generally healthy, low-risk pregnant individuals aged 19-42 years living in Vancouver, Canada. Participants will be randomized to receive one of two forms of iron (ferrous fumarate or ferrous bisglycinate) in addition to a prenatal multivitamin (without iron) daily during their pregnancy until delivery, with optional continuation until ~4 weeks postpartum for breastmilk sample collection. Blood samples will be taken at baseline (13-25 weeks gestation) and follow-up (35-37 weeks gestation) to assess how different forms of iron impact body iron stores. Stool samples will be obtained within 1 week of both baseline and follow-up visits to assess changes in gut microbiome composition. This research will inform more specific guidelines for optimal iron supplementation practices for the prevention and treatment of iron deficiency for both mother and baby.

Study Overview

• Status: Recruiting
• Conditions: Pregnancy; Iron Deficiency
• Intervention / Treatment: Dietary supplement: Ferrous fumarate; Dietary supplement: Ferrous bisglycinate

Detailed Description

To address our primary aim of determining the optimal form of iron in prenatal supplements, we seek to answer the following research questions:

1. Does providing a more bioavailable form of iron (24 mg elemental iron as ferrous bisglycinate) effectively increase ferritin concentration in maternal venous blood and umbilical cord blood, as compared to the standard 24 mg elemental iron as ferrous fumarate?
2. Does 12 weeks of 24 mg daily oral iron as ferrous fumarate increase biomarkers of potential harm (adverse side effects, gut microbiome composition, gut inflammation) in pregnant individuals, as compared to 24 mg daily oral iron as ferrous bisglycinate?

Pregnant individuals 13-25 weeks gestation will be randomized to one of two trial arms to receive either 24 mg elemental iron as ferrous fumarate or 24 mg elemental iron as ferrous bisglycinate for a minimum of 12 weeks during pregnancy until delivery, with optional continuation until 4-weeks postpartum for breastmilk collection. All participants will also receive the standard form and dose of other critical micronutrients during pregnancy (e.g., folic acid, calcium) through the provision of a prenatal multivitamin (not containing iron).

Interested individuals may undergo the informed consent process anytime prior to 25 weeks gestation. Once an individual indicates that they are interested in participating in the trial, the individual will be assigned a unique study ID and a baseline visit will be scheduled.

The baseline visit will occur between 13-25 weeks gestation and will involve discontinuation of current iron/prenatal vitamin supplementation, review and signing the informed consent form (a scanned copy will be shared with the participant), randomization to an iron group, provision of study supplements, completion of a baseline questionnaire, measurement of weight and height, a small blood draw, and provision of a stool collection kit for at-home stool collection.

The intervention period is a minimum of 12 weeks (from baseline at 13-25 weeks to delivery). Participants will supplement daily with the iron and prenatal multivitamin supplements. Monthly follow-up surveys will be sent to participants via email to check-in and receive updates regarding any changes to medical history or medication use.

The follow-up visit will occur between 35-37 weeks gestation and will involve collecting any remaining supplements (for capsule counts and assessment of adherence), a weight measurement, a small blood draw, provision of at-home stool collection kit, and completion of a short follow-up questionnaire.

Optional continuation of study: After the follow-up visit, participants who are planning to breastfeed will have the option to continue supplementing with the study supplements and provide a prenatal colostrum sample and/or 4-week postpartum breastmilk sample.

• Study Type: Interventional
• Enrollment (Estimated): 172
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Crystal Karakochuk, PhD; Phone Number: 604-822-0421; Email: crystal.karakochuk@ubc.ca
• Study Contact Backup: Name: Lulu Pei, MSc; Phone Number: 604-822-0421; Email: lulu.pei@ubc.ca

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3N1
      • Recruiting
      • BC Women's Hospital
      • Contact: Lulu Pei, MSc; Phone Number: 604-822-0421; Email: lulu.pei@ubc.ca
    • Vancouver, British Columbia, Canada, V6T 1Z4
      • Recruiting
      • University of British Columbia, Food, Nutrition and Health Building
      • Contact: Lulu Pei, MSc; Phone Number: 604-822-0421; Email: lulu.pei@ubc.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Pregnant individual (singleton pregnancy)
• 19-42 years of age
• Living in the greater Vancouver area and willing to travel to the University of British Columbia or BC Women's Hospital for study visits
• 13-25 weeks gestation
• Willing to participate and able to provide informed consent

Exclusion Criteria:

• Having a pre-existing medical condition known to impact iron status (e.g., inherited hemoglobin disorder (i.e., sickle cell, hemochromatosis, thalassemia or other structural hemoglobin variant), malabsorptive disorders (i.e., chronic pancreatitis, cystic fibrosis, celiac disease) and inflammatory bowel disease (i.e., Crohn's disease, ulcerative colitis), gastric bypass surgery, atrophic gastritis, advanced liver disease, kidney dialysis)
• Using medications known to interfere with iron metabolism or the gut pathogen equilibrium (e.g., chronic use of proton pump inhibitors, anti-inflammatory agents, non-steroidal anti-inflammatory drugs, antibiotics)
• Having a personal neural tube defect (NTD) history or a previous NTD pregnancy
• Receiving ongoing blood transfusions
• Currently smoking or having smoked in the past 3 months
• Pre-pregnancy body mass index (BMI) ≥30 kg/m^2
• Allergy to any study supplement ingredients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ferrous fumarate; 24 mg elemental iron/day	Dietary supplement: Ferrous fumarate; Participants will supplement with 24 mg elemental iron in the form of ferrous fumarate daily for a minimum of 12 weeks.
Experimental: Ferrous bisglycinate; 24 mg elemental iron/day	Dietary supplement: Ferrous bisglycinate; Participants will supplement with 24 mg elemental iron in the form of ferrous bisglycinate daily for a minimum of 12 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal ferritin concentration	µg/L; reflects body iron stores	Blood sample collected at baseline (13-25 weeks gestation) and at follow-up (35-37 weeks gestation)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Umbilical cord ferritin concentration	µg/L; proxy measure for newborn iron stores	Umbilical cord blood collected at time of delivery
Umbilical cord hemoglobin concentration	g/L; measured using a HemoCue device	Umbilical cord blood collected at time of delivery
Placental iron concentration	µg/g; reflects iron transfer to fetus	Placenta collected at time of delivery
Breastmilk iron stores	Includes measurement of breastmilk iron content (mg/mL) and lactoferrin (mg/mL)	Breastmilk sample collected at 4-weeks postpartum
Maternal hemoglobin concentration	g/L; obtained through a complete blood count	Maternal blood sample collected at baseline (13-25 weeks gestation) and at follow-up (35-37 weeks gestation)
Gut microbial analysis	16S rRNA gene sequencing and targeted real-time PCR (qPCR); gut microbiome composition	Stool sample collected at baseline (13-25 weeks gestation) and at follow-up (35-37 weeks gestation)
Adverse side effects	Includes reported gastrointestinal side effects (e.g., constipation, diarrhea, nausea) and any other side effects experienced	Follow-up (35-37 weeks gestation)
Markers of inflammation	Includes alpha-1 acid glycoprotein (AGP; g/L) and C-reactive protein (CRP; mg/L), used in combination to adjust ferritin concentration	Maternal blood sample collected at baseline (13-25 weeks gestation) and at follow-up (35-37 weeks gestation); umbilical cord blood sample collected at time of delivery
Hepcidin concentration	nmol/L; hormone that influences iron regulation	Maternal blood sample collected at baseline (13-25 weeks gestation) and at follow-up (35-37 weeks gestation); umbilical cord blood sample collected at time of delivery

Collaborators and Investigators

• Sponsor: University of British Columbia
• Investigators: Principal Investigator: Crystal Karakochuk, PhD, University of British Columbia

Study record dates

Study Major Dates

• Study Start (Actual): April 12, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: August 22, 2023
• First Submitted That Met QC Criteria: August 25, 2023
• First Posted (Actual): August 28, 2023

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 23, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Pregnancy; Iron; Nutrition
• Additional Relevant MeSH Terms: Metabolic Diseases; Iron Metabolism Disorders; Nutritional and Metabolic Diseases; Iron Deficiencies; Physiological Effects of Drugs; Trace Elements; Micronutrients; ferrous fumarate; ferrous bisglycinate
• Other Study ID Numbers: H23-00016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Upon reasonable request, the Principal Investigator will share de-identified individual participant data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No