Iron and Immune Response to Vaccine (IRONMUM)

Lead Sponsor: University of Oxford

Iron deficiency causes anaemia and is common in pregnant women especially for those living in tropical regions where a high burden of infection and poor nutrition can compromise health. Low iron has been recognized as a cause of poor immune response because the group of cells that need to increase to make the immune response need iron to function. Vaccination is an important part of care during pregnancy because components of the immune response can cross the placenta and protect the young infant. More recently COVID-19 vaccination has also been recommended for pregnant women due to their higher risk of dying from this infection. Deeper investigation of whether low iron results in poor immune response is needed because the vaccines may not be providing as much protection as needed. The World Health Organization also recommends nutritional iron supplements in pregnancy and whether these improve immune response to vaccines is also not known. This study aims to test the body's immune response to recommended vaccines in pregnant women (tetanus and diphtheria (combination) and COVID-19 vaccine (if indicated)) who are anaemic and receiving iron supplements and compare their response to women who are not anaemic, who only receive a preventive, lower dose of supplement.

This is a prospective interventional open label cohort study with an exploratory framework. After assessment of gestation by routine ultrasound, women will be invited to participate if they have a viable, singleton pregnancy with a gestation < 28 weeks. Consenting pregnant women will be enrolled at first antenatal clinic [7] visit and receive tetanus and diphtheria immunisation after confirmation of vaccination history, and SARS-CoV-2 immunisation (first dose if indicated). All women will be classified as non-anaemic or anaemic based on haematocrit (Haematocrit<33% in first trimester (defined <14 weeks) and Haematocrit <30% in 2nd trimester (defined 14 to <28 weeks)). Women will be assigned to groups and receive prophylactic (non-anaemic) or treatment (anaemic) doses of nutritional supplements, respectively, as per routine practice. These supplements will be provided daily for 3 months (12 weeks) and women will be followed up at day 7, 1 month (day 28), 2 and 3 months. There after they will follow routine antenatal care until birth when a cord blood sample will be taken. Mother and infant blood samples will be taken at the 2 months post-partum visit when the newborn attends for routine vaccinations of the expanded program of immunisation. Immunological and haematological responses will be measured by venous blood sampling and finger-prick sampling (routine at the clinics) at study visits; as will adverse events in relation to nutritional supplements by monthly questions using a checklist of common reactions to oral iron. The Adherence Starts with Knowledge (ASK-12) instrument has been modified and used in this population and will be compared to the Haematocrit levels, the pill count and adverse events, as a measure of adherence. IRONMUM study is funded by Procter and Gamble. The grant reference number is Thailand-UK-IRONMUM-2021-01.

• Pregnancy Related

Intervention Type: Dietary Supplement

Intervention Name: Sangobion and Thiamine Hydrochloride

Description: Prophylactic dietary supplements: 1 capsule of Sangobion + separate Thiamine Hydrochloride tablet 100mg per day for 12 weeks. Then non-anaemic pregnant women will continue with prophylactic nutritional supplements until delivery.

Arm Group Label: Non-anaemic pregnant women

Intervention Type: Dietary Supplement

Intervention Name: Sangobion, Thiamine hydrochloride and Vitamin B12

Description: Treatment dietary supplements: 3 capsules of Sangobion + separate Thiamine Hydrochloride tablet 100mg, Vit B12 100mcg per day for 12 weeks. If experience a therapeutic increase of 3% Haematocrit within 28 days (responders), they will continue with prophylactic nutritional supplements until delivery. If no affect in Haematocrit level within 28 days (non-responders; defined by trimester of diagnosis), they will be investigated for their serum ferritin and if this is low (<15ng/mL) intravenous (iv) iron supplement (Venofer®) will be provided. The dose will be calculated for the individual concerned (required iron dose (mg) = (2.4 x (target Hb of 11g/dL (Ht 33%) x pre-pregnancy weight (kg) +1000mg for replenishment of stores). Doses will be administered by slow iv infusion 200 mg per dose (maximum of 3 doses per week). Following treatment they will continue with prophylactic nutritional supplements.

Arm Group Label: Anaemic pregnant women

Criteria:

Inclusion Criteria: 1. Viable singleton pregnancy<28 weeks confirmed by ultrasound 2. 18 years and older 3. Willingness and ability to comply with the study protocol for the duration of the study 4. Can understand information about the study and provide consent Exclusion Criteria: 1. Any diphtheria-tetanus vaccine within the previous 2 years 2. History of allergic reaction to diphtheria-tetanus or COVID-19 vaccine 3. Haematocrit <21% or Haematocrit >50% 4. Known severe haemoglobinopathy (HbE/beta-thalassaemia syndrome, beta-thalassaemia major or HbH syndrome)* or G6PD deficiency * Iron supplementation is safe in pregnant women with haemoglobin E, alpha-thalassemia 1, or beta-thalassemia carriers. 5. HIV-positive 6. Slide confirmed presence of malaria 7. Fever (defined at >37.5°C) 8. Symptoms of COVID (these women will be PCR tested as routine in clinic) 9. Known severe medical or obstetric complication e.g. valvular heart disease, placenta praevia 10. Known or clinical vitB12 deficiency as indicated by megaloblastic anaemia (pernicious anaemia or clinical symptoms)

Gender:

Female

Gender Based:

Yes

Gender Description:

Pregnant women

Minimum Age:

18 Years

Maximum Age:

N/A

Healthy Volunteers:

Accepts Healthy Volunteers

2022-03-01

Type: Sponsor

• Iron supplementation
• Immune responses
• Maternal vaccination

Label: Non-anaemic pregnant women

Type: Other

Description: 50 pregnant women who have normal haematocrit (not anaemic) at 12 weeks.

Label: Anaemic pregnant women

Type: Other

Description: 100 pregnant women who have haematocrit below 33% (equates to Hb 11g/dL) in first trimester (<14 weeks gestation) and below 30% (equates to Hb 10g/dL).

Allocation: Non-Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Basic Science

Masking: None (Open Label)

Masking Description: This is a prospective open-label study in which both participants and investigators know the identity of the treatment and its dosage.