What is the issue?
Across the globe, approximately one out of three non-pregnant women of reproductive age are anaemic; i.e. have fewer red blood cells or less haemoglobin (a red substance that combines with oxygen and carries it around the body) in each red blood cell than normal. Although there are several causes of anaemia, it very often results from sustained iron deficiency. The standard practice to prevent or treat anaemia in women has been daily iron supplementation (sometimes combined with folic acid and other vitamins and minerals) for three months. However, it is frequently associated with side effects such as nausea or constipation. Intermittent supplementation (that is, the consumption of supplements one, two or three times a week on non-consecutive days) has been proposed as an effective and safer alternative to daily supplementation.
Why is this important?
Women with anaemia may have less energy for physical work and become more prone to infections. Most women throughout the world enter pregnancy with anaemia, putting them at greater risk of having low birth-weight babies and other complications during delivery.
Some scientists believe that taking iron a few times a week – instead of every day – can help women with anaemia to feel better and improve their haemoglobin without giving them as many side effects. If women have fewer side effects, they may be more likely to take iron supplements more regularly and for longer periods.
What evidence did we find?
We reviewed the evidence in February 2018. We included 25 randomised controlled trials (a type of experiment in which participants are randomly assigned to one or more treatment groups) involving 10,996 women. We included studies examining the administration of intermittent iron supplements versus no intervention, a placebo (dummy pill) or the same supplements given on a daily basis. Most studies were implemented in school settings and were mainly funded by international organisations, universities, and ministries of health within the countries. Approximately one-third of the included studies did not provide a funding source.
The findings show that women receiving intermittent supplementation with iron alone, or in combination with folic acid or other nutrients, were less likely to be anaemic or iron deficient than those women who received no iron supplements or a placebo. They also had higher concentrations of haemoglobin and ferritin (a protein that carries iron) but reported more side effects.
In addition, the findings indicate that intermittent supplementation was as effective as daily supplementation in reducing the prevalence of anaemia and increasing haemoglobin concentrations, with fewer side effects. It may have reduced the risk of having iron deficiency also, but it had no effect on raising ferritin concentrations more than the daily dose.
We found scarce evidence on the effect of intermittent supplementation compared to placebo or daily supplementation on iron deficiency anaemia, all-cause morbidity, disease outcomes, adherence, economic productivity, and work performance.
What does this mean?
Intermittent iron supplementation in menstruating women may be an effective intervention for reducing anaemia and improving haemoglobin concentrations compared to no treatment, placebo or daily supplementation. Intermittent supplementation may be associated with fewer side effects compared to daily supplementation. The findings were not affected by whether the supplements were given once or twice weekly, for less or more than three months, contained less or more than 60 mg of elemental iron per week, or given to populations with different degrees of anaemia at baseline (starting point for comparisons). The evidence base was of overall low quality.
Intermittent iron supplementation may reduce anaemia and may improve iron stores among menstruating women in populations with different anaemia and malaria backgrounds. In comparison with daily supplementation, the provision of iron supplements intermittently is probably as effective in preventing or controlling anaemia. More information is needed on morbidity (including malaria outcomes), side effects, work performance, economic productivity, depression, and adherence to the intervention. The quality of this evidence base ranged from very low to moderate quality, suggesting that we are uncertain about these effects.
Anaemia is a condition in which the number of red blood cells is insufficient to meet physiologic needs; it is caused by many conditions, particularly iron deficiency. Traditionally, daily iron supplementation has been a standard practice for preventing and treating anaemia. However, its long-term use has been limited, as it has been associated with adverse side effects such as nausea, constipation, and teeth staining. Intermittent iron supplementation has been suggested as an effective and safer alternative to daily iron supplementation for preventing and reducing anaemia at the population level, especially in areas where this condition is highly prevalent.
To assess the effects of intermittent oral iron supplementation, alone or in combination with other nutrients, on anaemia and its associated impairments among menstruating women, compared with no intervention, a placebo, or daily supplementation.
In February 2018, we searched CENTRAL, MEDLINE, Embase, nine other databases, and two trials registers. In March 2018, we also searched LILACS, IBECS and IMBIOMED. In addition, we examined reference lists, and contacted authors and known experts to identify additional studies.
Randomised controlled trials (RCTs) and quasi-RCTs with either individual or cluster randomisation. Participants were menstruating women; that is, women beyond menarche and prior to menopause who were not pregnant or lactating and did not have a known condition that impeded the presence of menstrual periods. The intervention was the use of iron supplements intermittently (one, two or three times a week on non-consecutive days) compared with placebo, no intervention, or the same supplements provided on a daily basis.
Both review authors independently assessed the eligibility of studies against the inclusion criteria, extracted data from included studies, checked data entry for accuracy, assessed the risk of bias of the included studies, and rated the quality of the evidence using GRADE.
We included 25 studies involving 10,996 women. Study methods were not well described in many of the included studies and thus assessing risk of bias was difficult. The main limitations of the studies were lack of blinding and high attrition. Studies were mainly funded by international organisations, universities, and ministries of health within the countries. Approximately one third of the included studies did not provide a funding source.
Although quality across studies was variable, the results consistently showed that intermittent iron supplementation (alone or with any other vitamins and minerals) compared with no intervention or a placebo, reduced the risk of having anaemia (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.49 to 0.87; 11 studies, 3135 participants; low-quality evidence), and improved the concentration of haemoglobin (mean difference (MD) 5.19 g/L, 95% CI 3.07 to 7.32; 15 studies, 2886 participants; moderate-quality evidence), and ferritin (MD 7.46 μg/L, 95% CI 5.02 to 9.90; 7 studies, 1067 participants; low-quality evidence). Intermittent regimens may also reduce the risk of having iron deficiency (RR 0.50, 95% CI 0.24 to 1.04; 3 studies, 624 participants; low-quality evidence), but evidence was inconclusive regarding iron deficiency anaemia (RR 0.07, 95% CI 0.00 to 1.16; 1 study, 97 participants; very low-quality evidence) and all-cause morbidity (RR 1.12, 95% CI 0.82 to 1.52; 1 study, 119 participants; very low-quality evidence). Women in the control group were less likely to have any adverse side effects than those receiving intermittent iron supplements (RR 1.98, 95% CI 0.31 to 12.72; 3 studies, 630 participants; moderate-quality evidence).
In comparison with daily supplementation, results showed that intermittent supplementation (alone or with any other vitamins and minerals) produced similar effects to daily supplementation (alone or with any other vitamins and minerals) on anaemia (RR 1.09, 95% CI 0.93 to 1.29; 8 studies, 1749 participants; moderate-quality evidence). Intermittent supplementation may produce similar haemoglobin concentrations (MD 0.43 g/L, 95% CI −1.44 to 2.31; 10 studies, 2127 participants; low-quality evidence) but lower ferritin concentrations on average (MD −6.07 μg/L, 95% CI −10.66 to −1.48; 4 studies, 988 participants; low-quality evidence) compared to daily supplementation. Compared to daily regimens, intermittent regimens may also reduce the risk of having iron deficiency (RR 4.30, 95% CI 0.56 to 33.20; 1 study, 198 participants; very low-quality evidence). Women receiving iron supplements intermittently were less likely to have any adverse side effects than those receiving iron supplements daily (RR 0.41, 95% CI 0.21 to 0.82; 6 studies, 1166 participants; moderate-quality evidence). No studies reported on the effect of intermittent regimens versus daily regimens on iron deficiency anaemia and all-cause morbidity.
Information on disease outcomes, adherence, economic productivity, and work performance was scarce, and evidence about the effects of intermittent supplementation on these outcomes unclear.
Overall, whether the supplements were given once or twice weekly, for less or more than three months, contained less or more than 60 mg of elemental iron per week, or given to populations with different degrees of anaemia at baseline did not seem to affect the findings. Furthermore, the response did not differ in areas where malaria was frequent, although very few trials were conducted in these settings.