The surprising lack of evidence for routine iron supplementation during pregnancy
For almost two years, I’ve had a paper sitting in my folder of ‘things I want to write about’, and my current miniseries on iron has finally set the stage for me to discuss it!
The paper in question, titled ‘Screening and Supplementation for Iron Deficiency and Iron Deficiency Anemia During Pregnancy’ appeared in JAMA Network, one of the stable of journals under the banner of the Journal of the American Medical Association, in August 2024. It was authored by the US Preventive Services Task Force (USPSTF), an independent, voluntary body whose operations are supported by the Agency for Healthcare Research and Quality. The USPSTF’s role is to scour, assess and synthesise the published literature to produce evidence-based recommendations about clinical preventive services – that is, screening questionnaires, blood tests, imaging and so forth that doctors, nurse practitioners and other healthcare workers might use to identify previously undetected conditions in their patients.
By definition, screening means searching for signs of an illness that the patient has not complained of suffering, rather than diagnosing the presenting complaint. If you go to the doctor complaining of knee pain, and he or she tells you that you’re overdue for a mammogram or colonoscopy, that’s opportunistic screening.
At first glance, screening for undetected conditions might seem like an unreservedly Good Thing. Who wouldn’t want a heads-up that they had some health problem that, if caught early, could be effectively treated, thus saving them from a much more serious (and possibly even fatal) illness down the line? And in the case of pregnancy, when (we are told) iron deficiency is so common, and its consequences so potentially damaging for both mother and infant, surely screening for and treating iron deficiency would be a slam dunk?
But regular readers will know that screening can create more problems than it solves. As I have written in previous posts, including Should you get an annual checkup? The experts say ‘no’, Skin cancer checks: life-saver or scam?, Major trial finds screening colonoscopy fails to ‘save lives’, New study on screening mammography shows more harms than benefits, PSA screening leads to unnecessary treatment… and suffering and Who says you’re depressed or anxious? Pfizer does, the vast majority of screening tests do not result in better outcomes for the patient, either for the condition that was diagnosed (or perhaps, overdiagnosed), or for overall quality of life and all-cause mortality. Screening does, however, generate extra business for the medical-pharmaceutical-industrial complex.
Enough of the preamble. By now, I’m sure you’re itching to know just what conclusions the USPSTF reached, about the value of screening pregnant women for iron deficiency, and routinely administering iron supplements to this population. They didn’t mince words:
“The USPSTF concludes that the current evidence is insufficient, and the balance of benefits and harms of screening for iron deficiency and iron deficiency anemia in asymptomatic pregnant persons on maternal and infant health outcomes cannot be determined. The USPSTF also concludes that the current evidence is insufficient, and the balance of benefits and harms of iron supplementation in asymptomatic pregnant persons on maternal and infant health outcomes cannot be determined.”
Screening and Supplementation for Iron Deficiency and Iron Deficiency Anemia During Pregnancy
(I know, I know – “pregnant persons” is vomit-inducing. Of course they mean “pregnant women“, since by definition, only women – physiologically adult females – can become pregnant. In their defence, they were assessing research on both pregnant adolescents and adults, so perhaps they chose the term “persons” to sidestep repetitive use of the more cumbersome phrase “adolescents and adults”. Or maybe they’re just irredeemably woke. I’ll leave it to you to decide.)
Let’s break this down, starting with some definitions.
“Screening for iron deficiency” means running blood tests to measure haematologic indices such as haemoglobin level and haematocrit, and iron biomarkers such as ferritin, transferrin and transferrin saturation, in women who are not manifesting signs of iron deficiency anaemia or iron deficiency without anaemia, such as tiredness (beyond what’s normal in pregnancy, particularly in the first and later third trimesters!), weakness, shortness of breath, heart palpitations, pallor, pica (strange cravings for non-food substances such as ice, clay, dirt, chalk, or paper), cold hands and feet, and proneness to infection.
Note that
“This recommendation applies to asymptomatic pregnant adolescents and adults. This recommendation does not apply to pregnant persons who are severely malnourished, have symptoms of iron deficiency or iron deficiency anemia, or have specific hematologic conditions (eg, sickle cell anemia) or nutritional deficiencies that may increase their need for iron.”
Screening and Supplementation for Iron Deficiency and Iron Deficiency Anemia During Pregnancy
“Iron supplementation” means routine provision of low-dose supplemental iron (including iron in prenatal vitamins) or intake of iron-fortified foods, without first establishing iron deficiency by measuring haematologic indices.
So, in this specific population of pregnant women who were not manifesting signs or symptoms of iron deficiency, what did they find?
Effects of screening for iron deficiency, and routine use of iron supplements, on health outcomes
As the USPSTF task force points out,
“The aim of routine screening or iron supplementation for treatment of iron deficiency and iron deficiency anemia during pregnancy is to improve maternal and infant health outcomes.”
Well, that seems self-evident. So it’s rather shocking to discover that there’s actually sod-all evidence that either maternal or infant health outcomes are actually improved, either by screening for iron deficiency, or by giving supplements to asymptomatic pregnant women who are considered to be “at risk of” iron deficiency but haven’t been formally diagnosed with it.
First, let’s look at the evidence for screening, and treatment of screen-detected iron deficiency. The USPSTF identified several issues:
- Lack of agreement on the haematologic cutoffs that define iron deficiency anaemia during pregnancy – that is, at what haemoglobin concentration and/or haematocrit a pregnant woman should be diagnosed with iron deficiency anaemia.
- Using haematologic indices rather than iron biomarkers to diagnose iron deficiency anaemia (note that anaemia simply means ‘low haemoglobin’, and there are many causes of anaemia besides iron deficiency).
- Limited evidence that any of the existing screening methods, including questionnaires and screening tools, reliably identify women at risk for iron deficiency, who might then be referred for testing.
- Factors that affect haematologic indices, such as cigarette smoking and living at high altitudes, both of which increase haematocrit and haemoglobin levels.
- Lack of evidence on any harms that might come from screening for iron deficiency – chiefly, harms that might come from taking iron supplements because of screening-detected iron deficiency – given that the papers they reviewed did not assess harms.
Given the high prevalence of screening for iron deficiency during pregnancy, and treatment of screen-detected deficiency with iron supplements, the USPSTF’s conclusion was startling:
“The review found no evidence on the benefits of screening and treatment for screen-detected iron deficiency and iron deficiency anemia during pregnancy on maternal and infant health outcomes.”
Screening and Supplementation for Iron Deficiency and Iron Deficiency Anemia During Pregnancy
They go on to explain that “a single observational study [i.e. not a randomised controlled trial] addressed the association between change in maternal iron status in pregnant persons with iron deficiency with or without anemia and clinical outcomes” and that this study did not adequately report how anaemia was defined in the patients or what dosages of iron supplementation were used, and also did not include a comparison group of pregnant women who were not taking iron supplements. In other words, it was pretty bloody useless for ascertaining the benefits of iron supplementation in women with screen-detected iron deficiency anaemia.
Now let’s turn to USPSTF’s assessment of the evidence for routine iron supplementation – that is, supplementation in women not diagnosed with iron deficiency with or without anaemia). 16 studies comparing maternal health outcomes in women who received routine supplementation vs no supplementation were identified.
“Across the 16 studies, evidence on the effects of iron supplementation during pregnancy on maternal or infant health outcomes was limited, inconsistent, or without clear benefit.1,17 One trial (n = 430) reported no differences in maternal quality of life (across 8 health concepts) with iron supplementation compared with placebo.1,17,20 Five trials21–25 (n = 13 610) found no statistically significant differences on rates of hypertensive disorders of pregnancy with iron supplementation compared with placebo or no iron (4.7% vs 3.1% [pooled, weighted rates]; relative risk [RR], 1.24 [95% CI, 0.75-2.06]; I2 = 48.0%).1,17 Based on a pooled analysis, 8 trials20,21,24–29 (n = 4919) found no statistically significant differences in rates of cesarean delivery (42.8% vs 41.5%; RR, 1.01 [95% CI, 0.90-1.14]; I2 = 42.7%).1,17 Generally, studies of cesarean delivery did not report procedure indications, which could reflect practice variability, limiting interpretation of this evidence.1,17 In 4 trials reporting maternal gestational diabetes and maternal hemorrhage, results were imprecise and uncertain.1,17 Two trials24,26 (n = 2214) found no differences in rates of maternal gestational diabetes in pregnant persons receiving iron supplementation vs placebo, and 2 trials21,29 (n = 341) found no statistically significant differences in rates of maternal hemorrhage.1,17“
Screening and Supplementation for Iron Deficiency and Iron Deficiency Anemia During Pregnancy
Studies that assessed haematological indices and iron status markers generally did show that women who took iron supplements had higher haemoglobin and ferritin, and lower risks of iron deficiency anaemia during the third trimester and at term. So they had prettier bloodwork, but no better pregnancy outcomes.
OK, how about infant health outcomes? Given the high prevalence of iron deficiency during pregnancy – “near 18% and increases across the 3 trimesters of pregnancy (from 6.9% to 14.3% to 28.4%)”, according to the USPSTF team – and the crucial role that iron plays in neurological development, surely babies of mothers who took iron supplements during pregnancy would benefit? Or maybe not:
“Across 6 supplementation trials (n = 17 863)20,21,23,25,27,30 reporting infant health outcomes, evidence was limited or demonstrated no benefit.1,17 Five trials reported no association between supplementation and infant mortality.1,17 In post hoc analysis, 1 trial (n = 3929) reported a statistically significant difference in rates of neonatal deaths in the supplementation group compared with the control group (1.1% vs 2.0%; RR, 0.53 [95% CI, 0.29-0.97]).1,17 Five trials22,24,26,30,31 (n = 16 827) of maternal iron supplementation reported no statistically significant differences in risk of preterm birth (5.5% vs 6.0%; RR, 0.92 [95% CI, 0.81-1.04]; I2 = 0.0%).1,17 Pooled analysis of 6 trials20–22,27,30,31 (n = 15 591) of maternal iron supplementation reported no statistically significant differences in infants with low birth weight (2.7% vs 2.9%; RR, 0.95 [95% CI, 0.79-1.14]; I2 = 0.0%).1,17 Across 4 trials24–26,30 (n = 5386) reporting infants small for gestational age, evidence was inconsistent and imprecise, with most studies reporting no differences (15.3% vs 15.2%; RR, 0.94 [95% CI, 0.67-1.31]; I2 = 75.5%).1,17 A pooled analysis reported few differences between supplementation compared with placebo.1,17“
Screening and Supplementation for Iron Deficiency and Iron Deficiency Anemia During Pregnancy
There were only two trials that assessed infant haematologic outcomes, and neither of these found any difference in haematologic indices at six months or one year, between infants of iron-supplemented vs unsupplemented mothers.
Reported harms of routine iron supplementation were confined to transient gastrointestinal effects such as nausea, constipation, and diarrhoea, and no infant harms were recorded. The USPSTF did not comment on whether or not trials were set up to assess harms beyond these, but it’s safe to assume that they were not.
The USPSTF was at pains to stress that its recommendation statement should not be construed as recommending against screening and supplementation, but instead, it “is a call for more research on the benefits and harms of screening and supplementation”.
Fair enough. More research is definitely needed. But in the mean time, professional organisations including the American College of Obstetricians and Gynecologists and the Academy of Nutrition and Dietetics, as well as the Food and Nutrition Board of the Institute of Medicine and the World Health Organisation, all recommend universal iron supplementation for pregnant women. In fact, the Academy of Nutrition and Dietetics goes so far as to insist that
“Maternal and fetal demand for iron increases during pregnancy; this increase cannot be met without iron supplementation.”
Position of the Academy of Nutrition and Dietetics: Nutrition and Lifestyle for a Healthy Pregnancy Outcome
So how likely is it that practitioners and researchers who are already convinced that iron supplementation is necessary during pregnancy, will be open to conducting studies in which pregnant women are randomised to take either iron supplements or placebos? And would such studies be adequately powered, and have sufficient follow-up periods, to detect adverse effects of iron supplementation for pregnant women and their babies?
Furthermore, all mass-market prenatal vitamins contain iron. Elevit, the most popular prenatal in Australia, contains a whopping 60 mg of iron (well above the threshold shown to inhibit zinc absorption), while Blackmores Conceive Well™ Gold contains 24 mg and Swisse Ultinatal Pre-Conception & Pregnancy Multivitamin contains 5 mg. Most pregnancy care providers recommend routine use of prenatal supplements to women intending pregnancy, and those already pregnant… which means that a mass uncontrolled experiment is being carried out on the routine use of iron supplements during pregnancy, and no one is collecting and analysing the data, because they assume that iron supplementation is at best, beneficial and at worst, benign.
Finally, let’s consider the USPSTF’s intriguing finding that iron supplementation improved haematologic indices and iron status markers in pregnant women, without improving pregnancy outcomes. What does this mean? Are we looking at looking at “iron deficiency” through the wrong lens? Is it possible that factors other than an inadequate intake of iron, could cause changes in biomarkers that are traditionally interpreted as indicating iron deficiency? We’ll explore these questions in Part 5 of The Iron Files.
