Intravenous versus oral iron for anaemia among pregnant women in Nigeria (IVON): an open-label, randomised controlled trial.

BACKGROUND: Oral iron for anaemia in pregnancy is often not well tolerated, with poor adherence. Iron administered intravenously might address these tolerance and adherence issues. We investigated the effectiveness and safety of intravenous ferric carboxymaltose versus oral ferrous sulphate on anaemia and iron deficiency among pregnant women in Nigeria. METHODS: We did a multicentre, open-label, parallel, randomised controlled trial of pregnant women (aged 15-49 years) with haemoglobin (Hb) concentrations of less than 10 g/dL at 20-32 weeks' gestation from 11 primary, secondary, or tertiary health facilities in Nigeria (five in Lagos and six in Kano). Exclusion criteria included vaginal bleeding, blood transfusion or major surgery within the past 3 months, symptomatic anaemia, anaemia known to be unrelated to iron deficiency, clinically confirmed malabsorption syndrome, previous hypersensitivity to any form of iron, pre-existing maternal depression or other major psychiatric illness, immune-related diseases, such as systemic lupus erythematosus or rheumatoid arthritis, or severe allergic reactions. Participants were randomly assigned (1:1) by nurses and doctors using a web-based randomisation service to either receive a single dose of intravenous ferric carboxymaltose (20 mg/kg to a maximum of 1000 mg) or oral ferrous sulphate (200 mg; 65 mg elemental iron) three times daily until 6 weeks postpartum. The study was primarily unmasked. Primary outcomes were maternal anaemia (Hb <11 g/dL) at 36 weeks' gestation and preterm birth at before 37 weeks' gestation, with analysis by intention to treat in participants with available data. This study was registered at the ISRCTN registry on Dec 10, 2020 (ISRCTN63484804) and on ClinicalTrials.gov (NCT04976179) on April 7, 2021. FINDINGS: Between Aug 10, 2021, and Dec 15, 2022, 13 724 pregnant women were screened for eligibility. 12 668 were excluded due to ineligibility for inclusion, and 1056 provided consent to participate and were randomly assigned to either the intravenous or oral administration groups. 527 were assigned to the intravenous ferric carboxymaltose group and 529 were assigned to the oral ferrous sulphate group. 518 in the intravenous group were assessed at 36 weeks' gestational age and after 518 deliveries, and 511 completed the 6 weeks postpartum visit. 513 in the oral ferrous sulphate group were assessed at 36 weeks' gestational age and after 512 deliveries, and 501 completed the 6 weeks postpartum visit. No significant difference was found in anaemia at 36 weeks (299 [58%] of 517 in the intravenous group vs 305 [61%] of 503 in the oral group; risk ratio 0·95, 95% CI 0·85-1·06; p=0·36), nor in preterm birth (73 [14%] of 518 vs 77 [15%] of 513; 0·94, 0·70-1·26; p=0·66). There were no significant differences in adverse events. The most common adverse events were diarrhoea (in six participants) and vomiting (in three participants) in the oral group and fatigue (in two participants) and headache (in two participants) in the intravenous group. INTERPRETATION: Although the effect on overall anaemia did not differ, intravenous iron reduced the prevalence of iron deficiency to a greater extent than oral iron and was considered to be safe. We recommend that intravenous iron be considered for anaemic pregnant women in Nigeria and similar settings. FUNDING: Bill & Melinda Gates Foundation.

Intravenous ferric carboxymaltose versus oral ferrous sulphate for the treatment of moderate to severe postpartum anaemia in Nigerian women (IVON-PP): protocol for an open-label randomised controlled type 1 hybrid effectiveness-implementation trial.

INTRODUCTION: Postpartum anaemia is often caused by iron deficiency with onset during the antepartum period and can be exacerbated by excessive blood loss at birth. Its prevalence is estimated as 50-80% in low-income and middle-income countries. It poses adverse consequences on the mother and negatively impacts her ability to care for her newborn. Prompt treatment of postpartum anaemia is thus important. Adherence to oral iron is reportedly low in Nigeria due to its side effects and forgetfulness by the mothers. Intravenous iron such as ferric carboxymaltose, given as a single dose, might help overcome adherence issues, but investigation in a high-quality randomised control trial in Nigeria is first required while evaluation of challenges around its implementation is also warranted. OBJECTIVE: To determine the clinical effectiveness, tolerability and safety, of using intravenous ferric carboxymaltose (intervention) vs oral ferrous sulphate (control) for treating moderate to severe iron deficiency anaemia in postpartum women and to evaluate implementation of ferric carboxymaltose in treating postpartum anaemia in Nigeria. METHODS AND ANALYSIS: This study is an open-label randomised controlled trial with a concurrent implementation study. It is a hybrid type 1 effectiveness-implementation design conducted in four states across Northern and Southern Nigeria. A total of 1400 eligible and consenting women with postpartum moderate to severe anaemia (haemoglobin concentration <100 g/L) will be randomised to intravenous ferric carboxymaltose; a single dose at 20 mg/kg to a maximum of 1000 mg infusion administered at enrolment (intervention) or oral ferrous sulphate; 200 mg (65 mg elemental iron) two times per day from enrolment until 6 weeks postpartum (control). The primary outcome, proportion of participants who are anaemic (Hb <110 g/L) at 6 weeks postpartum will be analysed by intention-to-treat. Haemoglobin concentration, full blood count, serum iron, serum ferritin, transferrin saturation and total iron binding capacity will be measured at specific intervals. Implementation outcomes such as acceptability and feasibility of using ferric carboxymaltose for postpartum anaemia treatment in Nigeria will be assessed. ETHICS AND DISSEMINATION: This study is approved by the ethics committee of the teaching hospitals, Ministry of Health of the four states as required, National Health Research Ethics Committee and the drug regulatory agency, National Agency for Food and Drug Administration and Control (NAFDAC). Findings of this research will be presented at conferences and will be published in international peer-reviewed journals and shared with stakeholders within and outside Nigeria. TRIAL REGISTRATION NUMBER: International standard randomised controlled trial number: ISRCTN51426226.

Acceptability of IV iron treatment for iron deficiency anaemia in pregnancy in Nigeria: a qualitative study with pregnant women, domestic decision-makers, and health care providers.

BACKGROUND: Anaemia in pregnancy causes a significant burden of maternal morbidity and mortality in sub-Saharan Africa, with prevalence ranging from 25 to 45% in Nigeria. The main treatment, daily oral iron, is associated with suboptimal adherence and effectiveness. Among pregnant women with iron deficiency, which is a leading cause of anaemia (IDA), intravenous (IV) iron is an alternative treatment in moderate or severe cases. This qualitative study explored the acceptability of IV iron in the states of Kano and Lagos in Nigeria. METHODS: We purposively sampled various stakeholders, including pregnant women, domestic decision-makers, and healthcare providers (HCPs) during the pre-intervention phase of a hybrid clinical trial (IVON trial) in 10 healthcare facilities across three levels of the health system. Semi-structured topic guides guided 12 focus group discussions (140 participants) and 29 key informant interviews. We used the theoretical framework of acceptability to conduct qualitative content analysis. RESULTS: We identified three main themes and eight sub-themes that reflected the prospective acceptability of IV iron therapy. Generally, all stakeholders had a positive affective attitude towards IV iron based on its comparative advantages to oral iron. The HCPs noted the effectiveness of IV iron in its ability to evoke an immediate response and capacity to reduce anaemia-related complications. It was perceived as a suitable alternative to blood transfusion for specific individuals based on ethicality. However, to pregnant women and the HCPs, IV iron could present a higher opportunity cost than oral iron for the users and providers as it necessitates additional time to receive and administer it. To all stakeholder groups, leveraging the existing infrastructure to facilitate IV iron treatment will stimulate coherence and self-efficacy while strengthening the existing trust between pregnant women and HCPs can avert misconceptions. Finally, even though high out-of-pocket costs might make IV iron out of reach for poor women, the HCPs felt it can potentially prevent higher treatment fees from complications of IDA. CONCLUSIONS: IV iron has a potential to become the preferred treatment for iron-deficiency anaemia in pregnancy in Nigeria if proven effective. HCP training, optimisation of information and clinical care delivery during antenatal visits, uninterrupted supply of IV iron, and subsidies to offset higher costs need to be considered to improve its acceptability. Trial registration ISRCTN registry ISRCT N6348 4804. Registered on 10 December 2020 Clinicaltrials.gov NCT04976179. Registered on 26 July 2021.

Low blood level in pregnancy is of public health importance and with common occurrence worldwide, but with a higher rate in low resource settings where its burden greatly affects both the mother and her baby. This low blood level is usually caused by poor intake of an iron-rich diet. It could lead to fatigue, decreased work capacity, and dizziness if not detected. Without treatment, this condition could affect the baby, possibly leading to its sudden demise in the womb, immediately after birth, or even the woman's death.The use of oral iron has been the primary treatment; however, it is associated with significant side effects, which have led to poor compliance. Fortunately, an alternative therapy in the form of a drip has been shown to overcome these challenges. However, it is not routinely used in countries like Nigeria. Moreover, being effective is different from being utilised. Therefore, this study was conducted to understand the factors that will make this treatment widely accepted.We interviewed pregnant women, family support and health care providers in 10 health facilities in Lagos and Kano States, Nigeria. Our findings revealed good attitudes to iron drip. However, its inclusion into routine antenatal health talk, training of health care providers, availability of space, drugs and health workers who will provide this care, and ensuring this drug is of low cost are some of the efforts needed for this treatment to be accepted.

Intravenous versus oral iron for iron deficiency anaemia in pregnant Nigerian women (IVON): study protocol for a randomised hybrid effectiveness-implementation trial.

BACKGROUND: Anaemia in pregnancy is highly prevalent in African countries. High-dose oral iron is the current recommended treatment for pregnancy-related iron deficiency anaemia (IDA) in Nigeria and other African countries. This oral regimen is often poorly tolerated and has several side effects. Parenteral iron preparations are now available for the treatment of IDA in pregnancy but not widely used in Africa. The IVON trial is investigating the comparative effectiveness and safety of intravenous ferric carboxymaltose versus oral ferrous sulphate standard-of-care for pregnancy-related IDA in Nigeria. We will also measure the implementation outcomes of acceptability, feasibility, fidelity, and cost-effectiveness for intravenous ferric carboxymaltose. METHODS: This is an open-label randomised controlled trial with a hybrid type 1 effectiveness-implementation design, conducted at 10 health facilities in Kano (Northern) and Lagos (Southern) states in Nigeria. A total of 1056 pregnant women at 20-32 weeks' gestational age with moderate or severe anaemia (Hb < 10g/dl) will be randomised 1:1 into two groups. The interventional treatment is one 1000-mg dose of intravenous ferric carboxymaltose at enrolment; the control treatment is thrice daily oral ferrous sulphate (195 mg elemental iron daily), from enrolment till 6 weeks postpartum. Primary outcome measures are (1) the prevalence of maternal anaemia at 36 weeks and (2) infant preterm birth (<37 weeks' gestation) and will be analysed by intention-to-treat. Maternal full blood count and iron panel will be assayed at 4 weeks post-enrolment, 36 weeks' gestation, delivery, and 6 weeks postpartum. Implementation outcomes of acceptability, feasibility, fidelity, and cost will be assessed with structured questionnaires, key informant interviews, and focus group discussions. DISCUSSION: The IVON trial could provide both effectiveness and implementation evidence to guide policy for integration and uptake of intravenous iron for treating anaemia in pregnancy in Nigeria and similar resource-limited, high-burden settings. If found effective, further studies exploring different intravenous iron doses are planned. TRIAL REGISTRATION: ISRCTN registry ISRCTN63484804 . Registered on 10 December 2020 Clinicaltrials.gov NCT04976179 . Registered on 26 July 2021 The current protocol version is version 2.1 (080/080/2021).