Iron supplements: how to take them, if a blood test says you need one

Less often, and in the morning. Women who took 60 mg of iron every other day absorbed more of it than women taking the same tablet daily: 21.8% of what they swallowed against 16.3%, and more iron in total.¹ Splitting the dose across the day gained nothing at all.¹

Why less often works better

A dose of iron does not simply soak in. The body controls how much gets through, using a hormone called hepcidin that governs the crossing from gut into blood.⁶ A dose of iron pushes hepcidin up, and while it stays up, less of the next dose can follow. Much of what is odd about iron dosing follows from that one fact.

The timing has been measured. In iron-deficient women, doses of 60 mg or more set off that rise; in women who are already anemic it takes 100 mg or more.³ The rise is still present 24 hours later and has faded by 48.³ So a tablet taken the next morning arrives while hepcidin is still high. A tablet taken the morning after that does not.

A dose-finding study put a number on the penalty. Twenty-four hours after a dose of 60 mg or more, hepcidin was up and the fraction of iron absorbed was down by 35% to 45%.²

That gap between 24 and 48 hours is the basis of alternate-day dosing. It also explains why the older instruction some guidelines still carry, 150 to 200 mg of iron a day split into several doses, works against itself.³

How long one 60 mg iron dose keeps the gut gate shut48 h24 hNext tablet

1. 48 h before a dose: hepcidin has faded
2. 24 h before a dose: hepcidin is still up

One clarification about the numbers. These are doses of elemental iron, meaning the iron in the tablet rather than the weight of the tablet. The pregnancy trial further down prescribes 200 mg of ferrous sulfate, which is the whole salt, while the 60 mg in the absorption trials is the iron itself.^1,7

What the schedule trials found

Two unblinded trials tested the schedules directly, in iron-depleted women aged 18 to 40.¹

The first gave 60 mg of iron at 8 a.m., either on consecutive days for 14 days or on alternate days for 28.¹ Across the course of treatment, the alternate-day group absorbed 21.8% of the iron they swallowed against 16.3% for the consecutive-day group.¹ In absolute terms that is 175.3 mg of iron absorbed against 131.0 mg, a third more, from the same number of tablets spread over twice as many days.¹ Hepcidin ran higher in the consecutive-day group during the first 14 days.¹

Cumulative fractional iron absorption, 60 mg doses% of iron swallowed absorbed

Consecutive days (14 days)16.3%

Alternate days (28 days)21.8%

The second trial asked whether splitting a daily dose helps: 120 mg once in the morning against 60 mg twice, morning and late afternoon.¹ Absorption did not differ, 11.8% against 13.1%, and the split doses left hepcidin higher.¹ Splitting gains nothing and raises the hormone that will obstruct the next dose.

Why the morning? Hepcidin has a daily rhythm of its own, and a morning iron dose adds to it.³ A second dose that afternoon or evening, after a morning dose, therefore meets raised hepcidin.³ The regimen the review settles on is 60 to 120 mg of iron as a ferrous salt, with vitamin C, in the morning, on alternate days, for women with iron deficiency and mild anemia.³ That is a regimen for a deficiency a blood test has already found. It is not a dose for anyone to start on a guess.

A bigger dose is not a bigger absorbed dose

The returns flatten quickly. Raising the dose sixfold, from 40 mg to 240 mg, raised the iron actually absorbed only threefold, from 6.7 mg to 18.1 mg.² The fraction absorbed fell as the dose climbed, fast enough to cancel most of the increase. The authors concluded that lower doses, 40 to 80 mg, and avoiding twice-daily dosing, get the most out of what is swallowed.²

Iron that is not absorbed stays in the gut. The same control system throttles absorption during inflammation too, when hepcidin holds iron back from the blood whatever is swallowed.⁶

What the side effects track, and what they do not

Tolerability is a genuine problem, and it has been measured. Ferrous sulfate raised the odds of stomach and bowel side effects 2.32-fold against placebo, and 3.05-fold against iron given by drip.⁴ Among menstruating women taking iron daily, loose stools were about twice as common as in controls, a risk ratio of 2.13, and constipation much the same at 2.07.⁵

Then the finding that complicates the case for smaller doses. Across those same trials, there was no significant link between the size of the iron dose and the odds of side effects.⁴ The argument for taking less rests on absorption efficiency, not on any demonstrated reduction in symptoms.

What iron does when it is genuinely needed is not in dispute. Women given iron ended their trials far less likely to be anemic, a risk ratio of 0.39.⁵ That is under half the risk carried by the control groups. They were also less likely to be iron deficient, at 0.62.⁵ Hemoglobin rose, exercise capacity improved, and symptomatic fatigue appeared to fall.⁵

Where the schedule stops working, and why a test comes first

The absorption trials tracked labeled iron over days and weeks in iron-depleted young women.^1,2 Whether better absorption becomes better blood over months is a separate question. One recent trial suggests it may not, at least in pregnancy.

That trial gave pregnant women who were not anemic 200 mg of ferrous sulfate daily, on alternate days, or three times a week, and measured them early and again at 26 to 30 weeks.⁷ Iron status fell through pregnancy in every group. Despite supplementation, 69% to 72% of the women were iron deficient by 26 to 30 weeks.⁷ A marker that rises when demand is going unmet climbed in the alternate-day and three-times-weekly groups, but not in the daily group.⁷ The authors read that as daily dosing coming closest to meeting the iron demand of pregnancy.⁷

The trade-off is between how much of each dose gets through and how many doses there are. When demand is rising steeply, the second consideration may win.

The reason to test before supplementing is separate from all of this. Iron deficiency is a consequence of something. A Lancet review says an underlying cause should be sought in every patient who presents with it, and that screening for coeliac disease should be considered routinely.⁶ It adds that men and postmenopausal women with iron deficiency anemia warrant an endoscopy, to rule out bleeding in the gut.⁶ Iron taken on a hunch can lift a number while leaving the reason it fell unexamined.

What remains unknown

What blocks absorption is not in this evidence. No trial here compared iron taken with tea, coffee, calcium or a phytate-heavy meal against iron taken alone, so the familiar list of things to avoid cannot be sized from it. Nor did any trial give iron with and without vitamin C, even though vitamin C sits in the recommended regimen.³

The alternate-day trials were small and unblinded, and they enrolled women who were iron-depleted rather than anemic. Their own authors want the findings confirmed in anemic patients.¹ The dose-finding study says the longer-term effects of these schedules still need investigating.² The pregnancy trial asks for larger studies before its reading is accepted.⁷

And in the tolerability data, the overall estimate for gut side effects was rated low-quality evidence, even though the specific findings on loose stools and constipation were rated high.⁵