Anemia is a worldwide problem with iron deficiency being the most common cause. When occurring in pregnancy, anemia increases the risk of adverse maternal, fetal and neonatal  outcomes, including maternal mortality, preterm and low birth weight (LBW) deliveries, perinatal and neonatal deaths, and long-term developmental sequelae in the surviving offspring.  Anemia rates are among the highest in south Asia, and India’s latest National Family Health Survey (NFHS-4) for 2015-16 indicates that anemia with hemoglobin (Hb) <11.0 g/dL affects over 50% of pregnant women.  For close to 40 years, India’s first-level treatment for anemia in pregnancy has been oral iron; however, side effects, poor adherence to tablet ingestion and low therapeutic impact are among reasons for consideration of a new paradigm for treatment of pregnant women with iron deficiency anemia. The Government of India has given high priority to reducing the prevalence of anemia in India, and several initiatives have been directed at this objective. The latest anemia strategy, built on prior strategies and  supported by the Ministry of Health and Family Welfare, was presented in a 2018 publication, Anemia Mukt Bharat-Intensified National Iron Plus Initiative.The same overall strategy remains in effect, but a few changes have been made to specific intervention guidelines. Notably, this research focuses on pregnant women, one of the population groups targeted by Anemia Mukt Bharat which has the goal of reducing prevalence of anemia among children, adolescents and women in the reproductive age group by 3% a year. The current anemia strategy, supported by the RAPIDIRON Trial, can help facilitate India’s efforts to achieve a 2025 Global World Health Assembly target of a 50% reduction of anemia among women of reproductive age.

This study, a 3-arm, randomized-controlled trial has two primary outcomes of interest.  The research is designed to assess if a single dose of an intravenous (IV) iron formulation (ferric carboxymaltose in intervention arm 1 or iron isomaltoside, also known by the international non-proprietary name of ferric derisomaltose, in intervention arm 2), administered early in the second trimester of pregnancy for treatment of moderate iron deficiency anemia (IDA), will result in a greater percentage of pregnant participants in the IV iron arms achieving a normal for pregnancy Hb concentration of >11 g/dL in the third trimester at either a 30-34 week antenatal visit or based on blood collected prior to delivery when compared to the percentage of participants randomized to an active, comparator arm (arm 3) provided oral iron.  Low birth weight (< 2500 grams), one of  several adverse pregnancy outcomes associated with IDA, is the other primary outcome. The hypothesis for this clinical outcome is that the LBW delivery rates for participants randomized to the IV iron arms will be significantly lower when compared to the LBW delivery rate of participants randomly assigned to the oral iron arm.

Comparison of differences between arms are proposed for the following secondary outcomes of interest: changes in hemoglobin concentration by moderate anemia subgroups (i.e., 7 - 7.9,   8  - 8.9, and 9 - 9.9 g/dL), other participant  iron indices (serum transferrin saturation and ferritin levels), Hb and other iron indices of cord blood, weight gain of participants by trimester of pregnancy, mode of delivery/C-section, antepartum and severe postpartum hemorrhage, hypertensive disorders (pre-eclampsia and eclampsia), maternal or neonatal infection including documented COVID-19 infection, maternal and neonatal mortality, preterm and small for gestational age births, pregnancy loss and stillbirths, birth weight and length of live born babies (measured within 72 hours post-delivery), the need for neonatal resuscitation, neonatal admissions to an intensive care unit, time from delivery to cord clamping, unanticipated or extended hospitalizations, breastfeeding practices including self-reported exclusive breastfeeding, and maternal well-being (quality of life). Due to consideration of current Anemia Mukt Bharat interventional guidelines for anemia treatment in pregnant women,³ two additional secondary outcomes will be assessed: participant need for “rescue therapy” when Hb concentration drops to <7 g/dL at any time after treatment; and referral to a higher level of care for evaluation because hemoglobin improvement is <1 g/dL based upon analysis of  blood collected at  26-30 weeks of pregnancy.

Transferrin saturation (TSAT) and ferritin level will be used in the study to establish that a pregnant woman has anemia and iron deficiency, and these indices will be monitored during the study.  At defined study visits when a complete blood count is performed, reticulocyte hemoglobin (Ret-He) and immature reticulocyte fraction (IRF) will also be calculated (to support exploratory analyses) since reticulocyte indices are markers for iron deficiency and potential tools for assessing response after iron therapy. Other tests to better understand the problem of anemia among pregnant women in India will also be performed.  Adverse reactions to oral or IV iron will be carefully monitored, documented and assessed by independent adjudicators with expertise in the use of IV iron. The research will additionally explore factors necessary for India-wide scale-up and identify obstacles to change as well as approaches for removing such obstacles.

The study will be carried out in India in primary and community health centers (PHCs, CHCs), hospitals and birthing facilities located in two research areas in the states of Karnataka and Rajasthan. Approximately 4,320 pregnant women who meet eligibility criteria and have hemoglobin (Hb) concentrations of 7 to 9.9 g/dL (the WHO definition of moderate anemia) and confirmed IDA will be randomized 1:1:1 to one of two IV iron intervention arms or to the arm that will be given oral iron. This study supports the overall goals of the Ministry of Health and Family Welfare (MOHFW) for pregnancy care; thus, all study participants will be followed according to the Ministry’s antenatal care guidelines, and data will be collected through 42 days post-delivery.