Efficacy and Adverse Side Effects of Two Forms of Iron in Pregnancy

Study Overview
=================
Brief Summary
-----------------
This two-arm, double-blind randomized clinical trial will recruit 208 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 and again at 37 weeks gestation to assess how different forms of iron impact body iron stores. Rectal swabs will also be taken at baseline and 37 weeks gestation to detect presence of harmful bacteria in the gut and quantify their abundance. 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.

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: 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? Does 12 weeks of 24 mg daily oral iron as ferrous fumarate increase biomarkers of potential harm (gut inflammation, gut pathogen abundance, adverse side effects) 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., folate, 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 collection of a rectal swab sample. 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 endline visit will occur at approximately 37 weeks gestation and will involve collecting any remaining supplements (for capsule counts and assessment of adherence), a weight measurement, a small blood draw, collection of a rectal swab sample, and completion of a short endline questionnaire. Optional continuation of study: After the endline visit, participants who are planning to breastfeed will have the option to continue supplementing with the study supplements until approximately 4 weeks postpartum, at which time they will provide a small breastmilk sample.

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

Conditions
-----------------
Pregnancy, Iron Deficiency

Intervention / Treatment
-----------------
* Dietary Supplement: Ferrous fumarate
* Dietary Supplement: Ferrous bisglycinate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pregnant individual (singleton pregnancy) 19-42 years of age Planning to deliver at BC Women's Hospital Living in the greater Vancouver area and willing to travel to the University of British Columbia 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

Ages Eligible for Study
-----------------
Minimum Age: 19 Years
Maximum Age: 42 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

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 endline (37 weeks gestation) | 
| Umbilical cord ferritin concentration | µg/L; proxy measure for newborn iron stores | Umbilical cord blood collected at time of delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maternal hemoglobin concentration | g/L; obtained through a complete blood count | Maternal blood sample collected at baseline (13-25 weeks gestation) and at endline (37 weeks gestation) | 
| 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 | 
| Gut pathogen abundance | Ct values; quantifies abundance of harmful bacteria in the gut | Flocked rectal swab collected at baseline (13-25 weeks gestation) and at endline (37 weeks gestation) | 
| Fecal calprotectin | µg/g; reflects gut inflammation | Flocked rectal swab collected at baseline (13-25 weeks gestation) and at endline (37 weeks gestation) | 
| Adverse side effects | Includes reported gastrointestinal side effects (e.g., constipation, diarrhea, nausea) and any other side effects experienced | Endline (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 endline (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 endline (37 weeks gestation); umbilical cord blood sample 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Iron, Pregnancy, Nutrition