|Year : 2016 | Volume
| Issue : 2 | Page : 31-41
Effects of oral iron (ferrous versus ferric) supplementation on oxidative stress and antioxidant status in pregnant women with iron deficiency: controlled trial
Sanaa S Aly1, Hanan M Fayed MD 1, Samar S Ahmed2, Ahmed H Abdella3, Abdel-Aziz E Tamam3, Nadia A Mohmmed4
1 Department of Clinical and Chemical Pathology, Faculty of Medicine, South Valley University, Qena, Egypt
2 Department of Community Medicine, Faculty of Medicine, South Valley University, Qena, Egypt
3 Department of Obstetrics and Gynecology, Faculty of Medicine, South Valley University, Qena, Egypt
4 Department of Nursing Obstetrics and Gynecology, Faculty of Nursing, South Valley University, Qena, Egypt
|Date of Submission||13-Jan-2016|
|Date of Acceptance||09-Feb-2016|
|Date of Web Publication||15-Jul-2016|
Hanan M Fayed
Qena University Hospital, Mabber El-shbab Street, Qena, 83523
Source of Support: None, Conflict of Interest: None
Background Pregnant women are more prone to oxidative stress. Iron deficiency anemia not only affects hematological parameters but also disturbs body oxidative balance, which impairs pregnancy outcome. Besides, iron therapy may generate harmful oxygen species.
Objectives The aim of this study was to investigate the effect of the nature of oral iron supplementation (ferrous vs. ferric) in pregnant women with iron deficiency on oxidative stress and its correlation with peripheral systemic inflammatory response markers.
Patients and methods A clinical trail study involves study included 30 healthy and 50 anemic pregnant women in their 20th-36th gestational weeks who fulfilled the inclusion criteria. They were randomly distributed to receive either ferrous sulfate or ferric polymaltose complex. Outcome was assessed after 8 weeks of iron supplementation and included hematological parameters, neutrophil : lymphocyte ratio, platelet : lymphocyte ratio, mean platelet volume, serum malondialdehyde (MDA), total antioxidant capacity (TAC), iron, and ferritin.
Results Anemic pregnant women have increased oxidative stress with high levels of MDA and TAC, both at baseline and following iron supplementation (P < 0.001). Following 8 weeks of iron supplementation, there were a significant increase (P < 0.001) in hemoglobin and serum ferritin, and a significant decrease (P < 0.001) in the peripheral inflammatory markers neutrophil: lymphocyte ratio, platelet: lymphocyte ratio, mean platelet volume, and absolute lymphocyte counts.
Conclusion Iron polymaltose complex was as effective as ferrous sulfate as both were able to correct hematologic parameters in parallel to a decrease in MDA and peripheral inflammatory markers together with an increase in TAC levels to maintain oxidative balance.
Keywords: anemia, inflammatory response markers, iron, malondialdehyde, oxidative stress, pregnancy
|How to cite this article:|
Aly SS, Fayed HM, Ahmed SS, Abdella AH, Tamam AAE, Mohmmed NA. Effects of oral iron (ferrous versus ferric) supplementation on oxidative stress and antioxidant status in pregnant women with iron deficiency: controlled trial. Egypt J Haematol 2016;41:31-41
|How to cite this URL:|
Aly SS, Fayed HM, Ahmed SS, Abdella AH, Tamam AAE, Mohmmed NA. Effects of oral iron (ferrous versus ferric) supplementation on oxidative stress and antioxidant status in pregnant women with iron deficiency: controlled trial. Egypt J Haematol [serial online] 2016 [cited 2020 May 30];41:31-41. Available from: http://www.ehj.eg.net/text.asp?2016/41/2/31/186392
| Introduction|| |
Pregnancy is a physiological occasion primarily causing oxidative stress, mostly because of the mitochondria-rich placenta . Pregnant women are more prone to oxidative stress as a result of an imbalance between the pro-oxidant-antioxidant levels . Under normal conditions, the cells develop a number of counteracting antioxidant defenses. Free radical scavenging mechanisms include both enzymatic and nonenzymatic antioxidants that limit the cellular concentration of free radical and prevent excessive oxidative stress .
Iron deficiency anemia (IDA) (low Hb and serum ferritin values) is the most prevalent deficiency anemia in pregnant women. IDA has been associated with increased risks for prematurity, low birth weight, and maternal morbidity . Iron is required by the enzymes involved in oxidative metabolism . In addition, iron requirements increase during pregnancy , and this may lead to anemia in pregnant women .
Maternal anemia before midpregnancy is associated with increased risk for preterm birth. Maternal anemia during the third trimester is usually not associated with an increased risk for adverse pregnancy outcomes and may be an indicator of an expanded maternal plasma volume. In contrast, high levels of hemoglobin, hematocrit, and ferritin are associated with an increased risk for pre-eclampsia, gestational diabetes mellitus, fetal growth restriction, and preterm delivery .
Ferrous iron used for oral iron therapy in pregnancy is a potent pro-oxidant, and many studies suggested that iron-deficient women were more susceptible to this iron therapy-induced oxidative stress . About 3-5% of the iron present in the alimentary canal in ferrous form is absorbed. Acidic milieu facilitates iron absorption by keeping iron in ferrous form. Ferrous iron is a central pro-oxidant that propagates free radical reactions through Fenton chemistry both locally and systemically . Consequently, although iron supplementation may improve pregnancy outcome when the mother is iron deficient, it is probable that prophylactic supplementation may increase risk when the mother does not have iron deficiency or IDA .
Oral iron is frequently used as a first-line therapy, but iron salts such as ferrous sulfate are associated with a high incidence of gastrointestinal side effects. However, a ferric (Fe 3+ ) iron polymaltose complex (IPC) contains iron in a nonionic form that provides similar iron bioavailability as ferrous sulfate but has a stable structure that has more controlled absorption of iron, thus making it less toxic . The available data comparing IPC versus ferrous sulfate in pregnant women suggest that efficacy is similar with the two preparations, but randomized trials are rarer than that in adults and long-term data are lacking .
Supplementation with iron obviously augments iron status and iron stores. There are few studies on whether supplementation during pregnancy increases oxidative stress and whether the nature of oral iron supplementation (ionized and nonionized) has the same effect on the index of systemic inflammation and oxidative stress defense mechanisms in maternal blood.
| Aim of the work|| |
Aim of the work was to investigate effect of nature of iron supplementation (ferrous/ferric) in pregnant women with iron deficiency on oxidative stress using malondialdehyde (MDA) as a marker of lipid peroxidation and total antioxidant capacity (TAC) as an anti-oxidative marker and its correlation to peripheral systemic inflammatory response markers [neutrophil to lymphocyte ratio and platelet lymphocyte ratio and mean platelet volume] and oxidative stress.
| Subjects and methods|| |
This was a open-label randomized clinical trail. Pregnant women were eligible for enrollment if they presented with at least one of the symptoms of fatigue, faintness, or getting tired quickly, without known underlying chronic disease. Diagnosis of IDA was based on lower Hb values below normal and mean corpuscular volume less than 80 fl, or serum ferritin less than 30 μg/l. The anemic patients were randomized 1 : 1 to iron treatment either with ferrous sulfate or with IPC.
Sample size was calculated at power 80% to be at least 36 pregnant women with IDA allocated randomly to two equal groups of oral iron therapy with ferrous versus ferric to detect whether both iron therapies are effective in the treatment of IDA with no preferences, and to detect the effect of both forms of oral iron treatment on MDA and TAC.
A total of 50 iron-deficient women and 30 healthy pregnant women in 20th-36th weeks of gestation recruited from the tertiary antenatal care clinic of Qena University Hospital were enrolled in the study and fulfilled the inclusion criteria. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol was approved by Qena Faculty of Medicine Ethics Committee and informed written consent was obtained from each participant. They were divided as follows:
- Group 1 included 50 anemic pregnant women before supplementation with iron. This group was divided into two groups after random allocation based on iron therapy into group 2a and group 2b.
- Group 2a included 25 anemic pregnant women prescribed with 100 mg of ferrous sulfate twice a day.
- Group 2b included 25 anemic pregnant women prescribed with 200 mg ferric hydroxide-IPC once a day.
- Group 3 included 30 age-matched healthy nonanemic pregnant women (Hb>11 g/dl) who were selected as controls.
Pregnant anemic women with normal blood pressure and having a gestational age greater than 12 weeks were included in the study; all were consumers of normal mixed food and none had taken any form of vitamin and iron supplementation 1 month before participation in the study.
All cases were free from any chronic prepregnancy conditions such as kidney, liver, heart, pulmonary, and endocrine diseases, diabetes mellitus, infectious diseases such as tuberculosis, hypertension, obstetric diseases such as pre-eclampsia, placental abruption, antepartum hemorrhage in the current or any previous pregnancy, and intolerance to oral iron in previous pregnancies, smoking, or alcoholism. Cases with severe anemia (Hb < 7 g/dl) were excluded. Women in the first trimester of pregnancy were excluded because of gastrointestinal symptoms such as nausea, vomiting, dyspepsia, and heartburn, which encourage them to change their food habits .
Anemia cutoff value was assessed according to the criteria of WHO , and anemia during pregnancy defined as Hb concentration of less than 11 g/dl, mild anemia as Hb 10.0-10.9 g/dl, moderate as Hb 7.0-9.9 g/dl, and severe as Hb less than 7.0 g/dl. In addition, IDA was defined as iron deficiency concurrent with anemia. Iron deficiency was defined as serum ferritin less than 30 ng/ml .
All cases and controls were subjected to the following
At first visit, for each pregnant woman, assessment of basic information and clinical evaluation was performed, including age, complete history of previous pregnancies, and medical and surgical history. Detailed general, physical, and clinical examination was carried out (including maternal age, body weight, height, estimation of fetal age both through examination and sonography and biochemical assay). Each woman with IDA had a follow-up visit after 4 and 8 weeks, when all physical and clinical examinations and biochemical measurements were repeated.
In each visit, 5 ml of venous blood was drawn from each participant after an overnight fast and divided into three aliquots. Two milliliters of blood was transferred to an evacuated tube containing EDTA used to determine CBC and total antioxidant. Remaining 3 ml of blood was also centrifuged at 3000 rpm for 15 min, and serum was separated for assessment of iron and ferritin. The rest of the serum was aliquot into two 1 ml cryo tubes kept at −70°C until analysis of MDA.
- CBC with differential count was carried out using cell dyne-1800 (Abbott Diagnostics, Santa Clara, California, USA); the neutrophil and lymphocyte absolute counts, platelets count, and MPV were retrieved separately, and NLR and PLR were calculated as they were representative indexes of systemic inflammation .
- NLR was calculated by dividing absolute neutrophil count by the absolute lymphocyte count. This calculated value was divided into two groups as 3or less and more than 3 .
- PLR was calculated by dividing absolute platelet count by lymphocyte count. The calculated value was divided into two groups as less than 160 and 160 or more .
- MPV values of our patients were divided as less than 8.9 and 8.9 or more .
- Lymphocyte counts were divided as less than 1.500/mm 3 and 1.500/mm 3 or more .
- Serum ferritin was evaluated using commercial automated chemiluminescent microparticle immune assay (Architect i2000; Abbott Diagnostics).
- Serum iron was measured spectrophotometrically using Cobas c311 automated chemistry analyzer (Roche Diagnostics, Mannheim, Germany).
- MDA was measured according to the manufacturer's instructions provided by biodiagnostic, pharmaceutical industries (Cat. No. 2528; Biodiagnostics, Giza, Egypt) using quantitative colorimetric endpoint assay. Briefly, thiobarbituric acid reacts with MDA in an acidic medium at a temperature of 95°C for 30 min to form thiobarbituric acid reactive product; the absorbance of the resultant pink product was measured at 534 nm .
- TAC level was measured using quantitative colorimetric endpoint assay according to the manufacturer's instructions provided by biodiagnostic, pharmaceutical industries (Cat. No. 2512; Biodiagnostics, Giza, Egypt). Briefly, TAC was determined with the reaction of antioxidants in the sample with a defined amount of exogenously provided hydrogen peroxide (H 2 O 2 ). The antioxidants in the sample eliminate a certain amount of the provided H 2 O 2 . The residual H 2 O 2 was determined colorimetrically using an enzymatic reaction, which involves the conversion of 3,5 dichloro-2-hydroxyl benzene sulphonate to a colored product measured at 500-510 nm. Serum normal reference value: 0.5-2 mmol/l .
Data were collected for 1 year from January 2014 to the end of December 2014, followed by data entry and analysis and writing the study results, which required 4 months.
SPSS version 20.0 for Windows 10 software package was used to analyze (IBM, Armonk, NY, USA) the data of various parameters. Quantitative variables were presented as mean, SD, and SE. The independent t-test was used to compare two different groups, the anemic group and the control group, and the ferrous sulfate group and the IPC group. The paired t-test was used to compare pregnant women before supplementation of iron and after iron supplementation. Qualitative variables were presented as median, range number, and percentage. The χ2 -test was used to compare qualitative variables in pregnant women with IDA before and after treatment: NLR less than 3 and greater than 3; PLR less than 160 and greater than 160; absolute lymphocyte less than 1500 and greater than 1500; and MPV less than 8.9 and greater than 8.9. Correlation was made between measurements of MDA oxidative stress parameters and TAC with all of the following: Hb, iron status, ferritin, and antioxidant (albumin and uric acid); peripheral systemic inflammatory response values of NLR, PLR, and MPV were computed using Pearson's correlation coefficients (r). A P value less than 0·05 was considered significant and P value less than 0.001 as highly significant.
| Results|| |
A total of 50 pregnant women with a mean age of 25.0 ± 3.25 years were enrolled in the study, and the overall mean gestational age was 25.04 ± 6.25 weeks.
The baseline hematologic parameters, including Hb concentration, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, serum ferritin, and iron were comparable in both studied groups, whereas the mean Hb, serum ferritin, and iron levels were significantly low when compared with healthy pregnant controls. The NLR values and the levels of MDA were significantly increased in anemic patients when compared with controls. After iron supplementation, absolute lymphocyte count was significantly decreased; otherwise, no statistically significant differences were determined between cases and controls with regard to other markers (MPV, NLR, and PLR) ([Table 1] and [Table 2]).
|Table 1 Comparison between pregnant anemic women before treatment and controls |
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|Table 2 Comparison between pregnant anemic women after treatment with both iron formula and controls |
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Compared with the basal levels, iron supplementation was associated with a significant increase in the mean Hb, serum iron, and ferritin together with the biomarkers of oxidative stress (MDA) and indexes of systemic inflammation (NLR) and absolute counts of neutrophil, monocyte, and lymphocyte ([Table 3]).
|Table 3 Comparison between anemic pregnant women before and after iron supplementation with ferrous sulfate |
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Compared with the baseline value, pregnant women treated with IPC showed a significant increase in Hb levels, red cell indexes, and ferritin level together with a significant decrease in MDA levels, red cell distribution width (RDW), platelet count, and PLR ([Table 4]).
|Table 4 Comparison between pregnant anemic women before and after treatment with iron polymaltose complex |
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As regards treatment with ferrous sulfate compared with treatment with IPC treatment, both groups showed a significant increase in Hb level in the ferrous sulfate group (11.66 ± 0.35 g/dl) and in the IPC group (11.45 ± 1.34 g/dl) compared with the baseline levels. However, there was no difference between the two treatment groups ([Table 5]).
|Table 5 Comparison between anemic pregnant women treated with ferrous sulfate and those treated with iron polymaltose complex |
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On comparing the peripheral inflammatory markers NLR, PLR, MPV, and absolute lymphocyte counts before and after treatment with either ferrous sulfate or IPC, both groups showed a significant decrease ([Table 6]).
|Table 6 NLR and PLR, MPV and absolute lymphocyte count before and after treatment with ferrous sulfate and IPC |
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- There was a significant positive correlation between MDA and serum iron in anemic women before treatment with iron.
- There was a significant positive correlation between MDA and uric acid in anemic women before treatment with ferrous.
- There was a significant positive correlation between MDA and ferritin after IPC treatment ([Table 7]).
- There was a significant positive correlation between TAC and Hb in anemic women before treatment with ferrous.
- There was a significant positive correlation between TAC and ferritin in anemic women after ferrous treatment.
- There was a significant positive correlation between TAC and NLR and MPV after both ferrous treatment and ferric treatment ([Table 8]).
|Table 7 Correlation between MDA and Hb, serum iron, ferritin, TAC, uric acid, albumin, NLR, PLR and MPV in control, anemic pregnant women before and after treatment with ferrous sulfate and iron polymaltose complex 'ferric |
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|Table 8 Correlation between TAC and Hb, serum iron, ferritin, uric acid, albumin, NLR, PLR, and MPV in control, anemic pregnant women before and after treatment with ferrous sulfate and iron polymaltose complex 'ferric' |
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| Discussion|| |
According to the WHO, half of all pregnant women develop anemia. The mean prevalence of anemia in pregnant women from developed and developing countries is 18 and 56%, respectively . Allen  proposed three potential mechanisms whereby maternal IDA might give rise to preterm delivery: hypoxia, oxidative stress, and infection.
In this study, with respect to the improvement in iron status during pregnancy with iron supplementation with either sulfate or IPC, the increment in Hb concentration was similar; this is in agreement with the study by Ortiz et al. .
In the current study, levels of MDA and TAC were significantly increased in anemic patients when compared with controls; this is in agreement with the findings of Sujata and colleagues ,.
Our results revealed a significant increase in MDA together with elevated antioxidative defense TAC in anemic pregnant women compared with controls and after 2 months supplementation with ferrous sulfate or IPC, which not only significantly improved hematologic indicators but also decreased oxidative stress marker (MDA), but failed to reach normal pregnant levels. This is in accordance with the findings of Isler and colleagues ,,,.
In contrast to our study, Kurtoglu and colleagues ,, found a substantial increase in the markers of lipid peroxidation that occurred during iron supplementation. Moreover, Tuomainen et al.  reported that nonionic IPC have no oxidative potency on lipoproteins in healthy individuals with low iron stores, and this was attributed to different mechanisms of absorption. Rapid iron release from ferrous sulfate within the gastric lumen can temporarily overload the active, controlled uptake mechanism in the enterocytes, leading to local gut reactions and symptoms, together with passive absorption through the intercellular route and absorption of iron from the gut directly into the bloodstream with a consequent increase in nontransferrin bound iron that was known to induce oxidative stress. However, Dresow et al.  found that IPC has a high complex stability as the release of iron from ferric hydroxide preparations occurs at low rate.
Our results revealed a significant increase in serum ferritin in response to iron supplementation; this may be as a response to oxidative stress, as ferritin sequesters nontransferrin bound iron to prevent oxidative damage to tissues . These findings were associated with a relative decrease in the peripheral inflammatory markers NLR, PLR, MPV, and absolute lymphocyte counts after iron supplementation. Thereby, systemic inflammation can be assessed using a number of prognostic indexes such as NLR, PLR, and MPV as are derived from inflammation-induced derangements in the full blood count that might provide valuable information in the follow-up setting to assess the oxidative stress in response to iron treatment.
Limitation and strength of the study
Study limitation mainly confined to a lack of dietary and nutritional history of the studied group and ungeneralization of the study beyond the setting in Qena governorate. Paucity of studies, specifically in Egypt, that compare the effect of ferrous versus ferric oral iron supplementation in pregnant women and its effect on oxidative stress and antioxidant status in pregnant women make this study a preliminary study for more in-depth studies. There are limited studies in the literature investigating the relationship between IDA and/or iron supplementation and MPV, NLR, and PLR. More comprehensive studies are needed for the routine use of MPV, NLR, and PLR values as useful and cost-effective markers for follow-up purpose in those patients.
| Conclusion|| |
Pregnant women with iron deficiency had higher levels of MDA as compared with normal pregnant women. Oral daily supplementation with IPC was as effective as ferrous sulfate when used as a replacement therapy in anemic pregnant women as both are able to correct hematologic parameters in parallel to a decrease in MDA together with peripheral inflammatory markers and an increase in TAC levels to maintain oxidative balance.
We recommend that strategies be implemented to improve iron status before pregnancy to reduce the prevalence of anemia and develop routine dietary and nutritional counseling during the prenatal period. Wide base studies are needed to investigate the effect of iron formula ferrous versus ferric on treatment of IDA in pregnancy. Moreover, we recommend that the effect of iron formula on oxidative stress and antioxidants status in pregnant women be investigated.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]