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Results of a randomized and triple-blinded clinical trial were recently published in Nutrients, reporting the effects of varying doses of iron on fetal growth and development when given to pregnant women, stratified by their hemoglobin levels. Nearly 800 pregnant women living in Spain (the ECLIPSES study) were included. Beginning in the 12th week of pregnancy, they received a dosage of iron based on their baseline hemoglobin (measured prior to the 12th week). Women with frank anemia (hemoglobin <11 g/dL) were excluded from the study; i.e., the purpose of this study was to evaluate the effects of iron when given to non-anemic women along a spectrum of hemoglobin to determine if personalization of dosage could improve the health of their children.
Women with lower levels of hemoglobin (11-13 g/dL) received either 40 or 80mg of elemental iron per day (given as ferrimannitol ovalbumin), while women with “medium-high” levels (>13 g/dL) received either 20 or 40mg iron per day, all given from 12 weeks until partum. Fetal growth was monitored during pregnancy by ultrasound (1 per trimester), and birth weight, length, and head circumference were used to diagnose either small-for-gestational age (SGA) or large-for-gestational age (LGA).
Overall, the higher doses of iron were associated with less favorable outcomes on fetal and birth development in both groups of women, increasing the risk for both SGA and LGA. Specifically, women with lower hemoglobin levels receiving 80mg of iron had a significantly increased risk for delivering an LGA baby (OR [Odds Ratio] = 2.35) as well as a non-significant risk for delivering an SGA baby (OR 1.60) compared to women who received 40mg. The 80mg dose was also associated with signs of abnormal fetal growth, such as a head circumference above the 90th percentile in the second trimester (OR 2.49) and an estimated fetal weight below the 10th percentile (OR 2.36) in the 3rd trimester, risks significantly greater than compared to 40mg. Similarly, among women with higher hemoglobin levels, the 40mg dose was associated with a higher risk for an elevated head circumference in the 3rd trimester (OR 3.19) compared to the 20mg dose, though no significant differences at birth were observed between these two doses.
Though this study alone does not help provide good guidelines for iron dosing during pregnancy, it does support the general line of evidence that both excess and deficient levels of iron are associated with adverse birth outcomes; i.e., there is a U-shaped curve between maternal hemoglobin levels and adverse outcomes, particularly with hemoglobin levels measured earlier during pregnancy and especially in the 1st trimester. For example, an older but very large cohort analysis in the U.S. found that while anemia was associated with an increased risk for preterm birth, it was not linked to an increase in risk for SGA. However, higher hemoglobin levels in this study were associated with SGA, but not preterm birth. A hemoglobin of 14.9 g/dL at 12 weeks, for example, was linked to a 27% significant increase in the risk for SGA compared to lower hemoglobin levels.
Serum ferritin is also used as a proxy for iron status, with low levels sometimes linked to an increased risk for SGA, and high ferritin linked to preterm birth and low birth weight (in some but not all studies, reviewed here). Ferritin has the unfortunate complication of increasing in response to infection and inflammation, and thus the adverse associations with higher ferritin are not necessarily reflective of elevated iron levels.
Several clinical trials and observational studies suggest that iron supplementation among non-anemic pregnant women may have adverse consequences, depending on the dose. The dose typically used in these studies and associated with adverse effects ranges from 30-50mg per day. Several mechanisms could plausibly explain the adverse consequences of elevated iron levels. The absorption of iron is not subject to its usual regulation during pregnancy, and absorption is elevated even in iron-replete women, especially in the 3rd trimester. Elevations in hemoglobin may increase blood viscosity and potentially reduce blood flow in the placenta, and when present in high amounts, iron may oxidize lipids and DNA in placental tissue. Additionally, an experimental animal model of gestational diabetes has suggested that the oxidative effects of even moderate levels of iron may lead to insulin resistance and hyperglycemia, and that newborns are much more sensitive to this metabolic disturbance than their mothers. Hyperglycemia and hyperinsulinemia are established risk factors for excessive fetal growth. Excess iron may also increase the risk for zinc deficiency, which itself has been associated with both low birth weight and SGA.
While iron deficiency anemia is often screened for during pregnancy and appropriately treated, clinicians should also be aware of the consequences of excess iron given to iron-replete women during pregnancy. Results from the same study population (the ECLIPSES study) suggest that ferritin and hemoglobin could be considered in combination. For example, women with hemoglobin levels >13 g/dL and a ferritin ≥ 15 μg/L might benefit from 20mg per day, while those with a ferritin of < 15ug/L may be better off with 40mg per day. Similar ferritin cut-offs may also help to determine whether 40 vs. 80mg would be beneficial for women with hemoglobin between 11 and 13 g/dL, though elevated ferritin levels should be taken in context, using other markers of inflammation and/or genetic analysis of the risk for iron toxicity (e.g., mutations in the HFE gene).
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