Title: The 'PANDA' research programme: Primary prevention of maternal ANaemia to avoid preterm Delivery and other Adverse outcomes
Funder: Department of Health and Social Care

Abstract: Research Question Does universal primary prevention of anaemia during pregnancy with oral-iron supplementation have an incremental benefit on reducing adverse maternal and infant outcomes? Background Around a third of UK-women develop anaemia during pregnancy, which is associated with adverse outcomes including maternal and neonatal mortality, haemorrhage, prematurity, and stillbirth. Preventing antenatal anaemia using oral-iron supplementation is a significant opportunity for improving maternal and infant outcomes. There is a need for a pragmatic randomised trial of preventative oral-iron supplementation powered on clinical outcomes. Aims and Objectives This programme aims to improve maternal and infant outcomes by evaluating prevention of anaemia during pregnancy with oral-iron supplementation. The specific objectives are to: 1) identify the barriers and facilitators to the initial decision to take, and ongoing adherence to oral-iron, as a basis for designing a behavioural intervention to improve recruitment and adherence during the definitive trial; 2) identify the optimal preventative oral-iron dose, pilot behavioural intervention, and finalise definitive trial protocol; 3) establish clinical and cost-effectiveness in a definitive trial of oral-iron supplementation with a behavioural intervention; 4) evaluate intervention fidelity and enactment; and 5) explore the impact of anaemia prevention on long-term neurodevelopment and maternal outcomes. Methods Five interlinked workstreams (WS) will be conducted. WS1 includes theory-based semi-structured interviews to understand factors influencing preventative oral-iron use during pregnancy. We will develop a behavioural intervention to target the barriers/enablers to initiating taking oral-iron supplements and ongoing adherence. WS2 will select an optimal dose schedule for oral-iron supplementation and pilot the behavioural intervention, to inform the main trial protocol. 240 women will be randomised to one of three oral-iron schedules: single-daily dose; alternate-daily; and three-times/week, taken up to 28-weeks gestation. Outcomes for WS2 will include intervention acceptability, feasibility, adherence, tolerability and changes in haemoglobin concentration. WS3 is a pragmatic, two-arm, multicentre trial of oral-iron supplementation versus placebo, using the preventative dosage regimen defined in WS2. The behavioural intervention will be delivered to all participating women in both trial arms, to optimise recruitment and oral-iron adherence. A sample of 11020 pregnant women will be enrolled across 20 maternity units. The primary outcome is a composite of pre-term birth, stillbirth, neonatal death and small-for-gestational age. Analysis will apply mixed logistic regression alongside an economic evaluation. A mixed-methods parallel process evaluation (WS4) using observations, interviews and surveys will assess fidelity of intervention delivery, adherence and acceptability. WS5 includes seeking consent from women (participating in WS3) to support future data collection from national databases to evaluate long-term maternal and infant neurodevelopment outcomes. Timelines for delivery The research is planned over 61 months. WS1 and WS2 will be completed by month 27 as the definitive trial starts. Anticipated Impact and Dissemination The findings will address the clinical/cost-effectiveness of a primary prevention strategy of anaemia. If effective, understanding barriers/enablers to adherence will inform subsequent wider-scale implementation, as well as having broader implications for other areas of prevention medicine. Dissemination of findings will target key stakeholders including media, online forums, patient and public involvement and health care professional events, and publications.

Lay abstract: Around a third of UK pregnant women develop anaemia (reduced numbers of red blood cells) caused by lack of iron. Anaemia may mean that women experience general health problems such as excessive tiredness. Severe anaemia during pregnancy might increase the risk of a baby being stillborn, born early, or born small (with a low birthweight). It may also increase the risk of blood loss during childbirth and affect a baby s development. We know that treating anaemia after it develops does not reduce all the risks. We therefore want to find out whether we can prevent anaemia in the first place by giving iron tablets. We also heard from women with experience of anaemia and maternity services and they highly supported the need for this research. Our proposed research consists of five parts that build on each other. The first part will tell us what women think about anaemia and why women do (or do not) take iron tablets during pregnancy. This will help us to support women to take iron supplements regularly. In the second part, we will do a small study amongst non-anaemic pregnant women to find the best dose of iron supplement with the fewest side effects, and to try a support-tool to check if it would help women to take the iron tablets. In the third part, we want to understand the real effects of giving low-dose iron supplements during pregnancy to prevent anaemia and its harmful complications, such as babies being born early. We will run a large study, in which 11,020 women will be allocated by chance (like tossing a coin) to receive either iron tablets or placebo (an inactive tablet that looks like an iron-tablet) during their pregnancy and up to 6 weeks after childbirth. We will use the tool developed in the second part to support women to take the tablets, which will give us the best possible chance of testing whether or not oral iron supplements work to prevent anaemia. We will find out if there is any difference between the two groups of women; such as whether their babies are born early, or with a low birthweight. The fourth part will tell us what women thought about taking iron and potential factors influencing this. This will help us to shape how a strategy for preventing anaemia in pregnancy is rolled out nationally. The final part is seeking women s permission for data to be collected from national databases in a future project to assess the development of babies born to mothers participating in the trial. Our programme of research will help us to understand all the benefits for women and babies if we give low-dose iron supplements during pregnancy to prevent anaemia.

Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;3.3 NUTRITION AND CHEMOPREVENTION;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;BLOOD