Ferric carboxymaltose versus standard-of-care oral iron to treat second-trimester anaemia in Malawian pregnant women: a randomised controlled trial

**Background:** Anaemia affects 46% of pregnancies in Africa and is associated with maternal and neonatal risks. WHO recommends daily oral iron, but adherence is often poor. Ferric carboxymaltose (FCM) is a modern intravenous iron formulation that can be given as a single dose. This trial tested whether FCM is superior to standard oral iron in reducing anaemia and improving birthweight in anaemic pregnant women in a malaria-endemic, resource-limited setting in Malawi.

**Methods:** This open-label, individually randomised controlled trial (REVAMP) enrolled women with a singleton pregnancy of 13–26 weeks' gestation, capillary haemoglobin <10.0 g/dL, and negative malaria rapid diagnostic test (RDT). Participants were recruited from primary care and outpatient settings in two regions of southern Malawi between Nov 12, 2018, and March 2, 2021. They were randomised 1:1 to receive either a single intravenous dose of FCM (up to 1000 mg) or standard-of-care oral iron (60 mg elemental iron twice daily for 90 days). All participants received intermittent preventive treatment for malaria (sulfadoxine-pyrimethamine). The primary maternal outcome was anaemia (venous haemoglobin <11.0 g/dL) at 36 weeks' gestation; the primary neonatal outcome was birthweight. Secondary outcomes included anaemia at other timepoints, iron deficiency, iron deficiency anaemia, and safety events. Analyses were intention-to-treat. The trial was registered with ANZCTR (ACTRN12618001268235).

**Key Results:** Of 21,258 women screened, 862 were randomised (430 to FCM, 432 to standard care). Baseline characteristics were balanced: mean venous haemoglobin 8.83 g/dL, 76% moderate anaemia, 7% severe anaemia, 43% iron deficient, 51% with inflammation, and 17% HIV positive. At 36 weeks' gestation, anaemia prevalence was 52% (179/341) in the FCM group vs 57% (189/333) in the standard care group (prevalence ratio [PR] 0.92, 95% CI 0.81–1.06; p=0.27). Anaemia was numerically lower with FCM at all timepoints but only reached significance at 4 weeks post-treatment (PR 0.91, 95% CI 0.85–0.97). Mean birthweight was similar: 2893.2 g (FCM) vs 2896.2 g (standard care); mean difference –3.1 g (95% CI –75.0 to 68.9; p=0.93). FCM significantly reduced iron deficiency at 36 weeks (18% vs 42%; PR 0.43, 95% CI 0.33–0.55) and iron deficiency anaemia (9% vs 29%; PR 0.30, 95% CI 0.20–0.44). Safety outcomes were similar between groups: at least one adverse event occurred in 43% (FCM) vs 39% (standard care) (risk ratio 1.08, 95% CI 0.92–1.27; p=0.34). There was a transient increase in hypophosphataemia at 4 weeks post-treatment with FCM (5% vs 2%; PR 2.67, 95% CI 1.20–5.93; p=0.016). No infusion-related serious adverse events occurred.

**Clinical Implications:** In this malaria-endemic sub-Saharan African setting, a single dose of intravenous ferric carboxymaltose was safe but did not reduce anaemia at 36 weeks' gestation or improve birthweight compared with standard oral iron. The lack of effect on anaemia may be due to the high burden of non-iron-deficiency anaemia, particularly inflammation. FCM effectively corrected iron deficiency and iron deficiency anaemia, which may have long-term benefits for maternal and child health, including neurodevelopment. The findings highlight the need for point-of-care diagnostics to identify the causes of anaemia and for integrated strategies that address both iron deficiency and inflammation in pregnancy.