We found that the fetuses of pregnant women with iron intake in the 3rd tertile (>17.04 mg) had a significantly lower a biparietal diameter, abdominal circumference, and femur length than the fetuses of mothers in the second tertile of iron intake (11.49 ~ 17.04 mg). About 90% of the highest tertile were iron supplemental users and all the mothers who consumed iron above the UL (45 mg) took supplements containing iron. The average iron intake of supplement users was 76.9 ± 48.5 mg, which was three times higher than the RNI (24 mg) and the source was mainly from the supplements; while the iron intake from food sources was only 13.0 ± 3.9 mg which was lower than the EAR (18.5 mg). Fetal biometry and growth were not different according to the dietary iron intake adjusting for iron supplementation use, but were greater in the babies of mothers with iron supplementation than the babies of mothers without iron supplementation adjusting for dietary iron intake. These results indicate that supplemental iron in pregnancy is needed for fetal growth but also indicate that excessive consumption of iron, mainly from the supplements at mid-pregnancy may have adverse effects on fetal growth at mid-pregnancy.
Several studies have reported adverse effects of iron supplements on pregnancy outcomes. Ziaei et al.
 reported that SGA birth rate and the number of pregnant women with hypertension were significantly higher in the iron-supplemented group (50 mg/d) when compared with the non-iron-supplemented group (with Hb level of 132 g/L and above). In their study, no other differences were observed in the pregnancy outcomes between both the groups. A randomized trial has revealed that a higher frequency of infant hospitalization due to convulsions was observed in the routine iron supplemented group (100 mg/d) when compared with the selective iron supplemented group
. The selective iron supplemented group was given iron supplementation if the hematocrit was < 30% and the mother was diagnosed to be anemic. These results indicate that a high dose of general iron prophylaxis without due consideration about the maternal iron status might have a negative influence on fetus and infant health.
The mechanisms that explain these adverse effects due to excessive iron intake have not yet been clearly established; however, several potential mechanisms have been suggested. Primarily, excessive iron intake could cause free-radical damage during pregnancy
[30–32]. Pregnancy itself is vulnerable to oxidative stress
. Free iron catalyzes the transformation of hydrogen peroxide to a hydroxyl radical via the Fenton Reaction. Studies have shown that the levels of free radicals were higher in pregnant women who consumed iron supplements in Estonia (36 mg/d)
 and in the US (19 mg/d)
 than those without any consumption of supplements. The free radicals have been reported to damage cellular DNA, proteins and lipids
. According to Takagi et al., the level of oxidative stress and redox-related molecules was higher in the placenta in preeclampsia and IUGR than in normal pregnancy
. Secondly, previous studies have reported that iron supplements could interrupt the absorption of zinc and copper in pregnant women with Hb ≥132 g/L
[37, 38] or with normal Hb levels
[39, 40]; the reason being competitive absorption of iron, zinc, and copper from the small intestine via divalent metal transporter. Moreover, a high dose of iron supplements (>30 mg/day) can frequently lead to gastrointestinal problems such as constipation, diarrhea, nausea and vomiting
Our results indicate that iron intake from food in pregnant women was inadequate but supplement users consumed an excessively high amount of iron from the supplements. It is evident from the previous reports that iron requirements during pregnancy cannot be satisfied by iron from foods alone and iron supplementation is necessary during pregnancy
 and is helpful for adequate fetal growth. In our study, total iron intake was lower than the recommended level in women who did not consume iron supplements and amongst the women with iron intake below the RNI (24 mg), only 7% of them took iron supplements. In contrast, supplement users had iron intake of 76.9 ± 48.5 mg, which was three times higher than the RNI (24 mg) and the iron intake exceeded the UL in 65% of the supplement users. Some supplement users also took prescribed iron supplements in addition to over-the-counter multi-vitamin supplements, while others took higher dose of iron supplements than the prescribed dosage. This raises a potential problem that some pregnant women, non-anemic, non-iron deficient, might consume unnecessarily high amounts of general iron prophylaxis during pregnancy.
In the case of non-anemic pregnant women in Mexico, high dose of iron-supplementation (60 mg/day) was related to high rates of hemoconcentration (Hb > 145 g/L), which was further associated with a relatively high risk of low birth weight and premature delivery
. However, a low dose of iron supplement (30 mg/d) was significantly associated with a higher mean birth weight, a lower incidence of low-birth-weight infants and lower incidence of preterm low-birth-weight infants in 513 iron-replete non-anemic pregnant women in the U.S. Daily supplementation
. Therefore, a low dose of iron supplements (30 mg/d or 120 mg/wk) may be more beneficial for fetal growth than a high dose of iron and proper advice about iron supplementation should be provided by a nutritionist or health professionals to prevent excessive iron intake by pregnant women.
Iron is necessary for normal fetal growth and development and the physiologic iron requirements during the second half of pregnancy cannot be achieved by dietary iron only. Iron supplementation during pregnancy consistently increase serum ferritin and hemoglobin and decrease the prevalence of iron deficiency anemia. With consideration of negative influences of iron such as increased oxidative stress and competitive absorption with other divalent metals during pregnancy, the lowest effective dose of iron supplementation based on women’s iron status should be recommended. Milman
 suggested that individual iron prophylaxis according to serum ferritin status, indicative of risk for iron deficiency, should be preferred to general prophylaxis. In addition, bioavailability of iron from animal foods is higher than iron from plant foods due to high composition of hem iron and meat factors. Components in food such as phytate and polyphenols reduce the absorption of both dietary and supplementary iron. Maximum absorption of ferrous iron from supplementation can obtained when the tablets is taken between the meals rather than at or after a meal
Our present study was associated with several limitations. Firstly, maternal iron status in blood was not assessed in the present study although maternal hematological parameters such as, Hb and hematocrit levels are important ones to be considered when we study the effect of maternal iron intake on fetal growth
. Secondly, the employed dietary intake and supplements were investigated for only a single time. A 24-hour recall may be insufficient to postulate that the values are from a usual daily intake due to large intra-individual variability. Although measurements of dietary intake based on a single 24–hour recall per individual of the large sample size can provide a good probable estimate of the mean for a study population, the standard deviation will be greatly overestimated. Furthermore, the random within-person variation may reduce the strength of associations under the study, possibly to the point of being undetectable. However, trained dietitians employed standard protocols in helping the subjects in reporting their daily diet to minimize plausible errors. Third, recruitment from voluntary participation as well as non-participation or non-responses might have introduced a selection bias. But, general characteristics did not differ significantly between included and excluded subjects and high recruitment rate in main centers of the study minimizes the chance that results were distorted by selection bias. To the best of our knowledge, this is the first study to investigate the association between maternal total iron intake and fetal growth in a relatively large sample, as assessed by ultrasonography. In addition, this work had certain advantages over previous studies because it was a multi-center prospective cohort study that utilized a strict protocol. Moreover, possible confounders such as gestational age at the time of ultrasound measurement, maternal age, maternal height, urinary cotinine level, pre-pregnancy BMI, parity, family monthly income, sex of babies and energy intake were all accounted for the analyses.