Effect of ibuprofen and iron-containing micronutrients on menstrual blood loss and iron status in menstruating Malawian adolescent girls: a 2x2 factorial, randomized controlled trial

Background: Reducing menstrual blood loss in adolescent girls living in low- and middle-income countries (LMIC) may be key to meet their iron requirements for first pregnancy and to prevent severe, life-threatening anemia during pregnancy or after childbirth; it can also improve their psychosocial health, education, equity, empowerment, and rights. Iron supplementation has several limitations including limited efficacy, low adherence, and potential risk of infectious diseases. Few studies have been undertaken to assess the epidemiology of heavy menstrual bleeding in LMIC. While heavy menstrual bleeding (>80 mL/cycle) is associated with iron deficiency anemia, self-perceived heavy menstrual bleeding is also an important determinant of a woman’s physical, emotional, and social quality of life. Trial evidence suggests that non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen, a low-cost medicine that is efficacious against dysmenorrhea and that is widely available, can substantially reduce blood loss by 25-35% or more in women with heavy menstrual bleeding. Objectives: We will assess the effect of supplementation with iron-containing micronutrients and ibuprofen on menstrual blood volume loss, menstrual iron loss, iron status, menstrual duration, menstrual cycle length, and self-reported indicators of menstrual blood loss and quality of life in menstruating Malawian girls aged 15-20 years. We also aim to assess the changes in iron absorption, iron status, hematological parameters and hepcidin across the menstrual cycle among girls with iron deficiency anemia, and to validate the alkaline hematin method for menstrual blood loss measurement using isotope dilution methods. Design and methods: The main study concerns a 2x2 factorial, double-blind, placebo-controlled trial. Participating schoolgirls (n=450) will be randomly allocated to daily oral supplementation with iron-containing micronutrients or its placebo, and daily oral ibuprofen (1,200 mg/day in 4 doses for 4 days, starting on the first day of menstruation during each menstrual cycle) or its placebo, for a duration of 6 menstrual cycles or 8 months, whichever comes last. Menstrual blood loss will be assessed by alkaline hematin method during a run-in period for two menstrual cycles before randomization and throughout the intervention period, along with other outcome variables. In preparation for this, an exploratory study will be carried out to better understand the kinetics of those parameters throughout one menstrual cycle and to determine the ideal timepoints of measurement. Expected results and impact: a) compared to placebo, we expect the use of iron-containing micronutrients during menstruation to increase menstrual loss of blood and iron, and improve iron status b) compared to placebo, we expect the use of ibuprofen during menstruation to decrease menstrual loss of blood and iron and improve iron status; c) we expect to have validated the alkaline hematin method for menstrual blood loss measurement using isotope dilution methods; d) our results will inform policy-makers to design policies to reduce menstrual blood loss and to improve body iron stores of young women before pregnancy; e) our results will inform future studies to look into the optimal timing of iron supplementation during the menstrual cycle.