|Year : 2020 | Volume
| Issue : 1 | Page : 11-16
Intravenous Iron sucrose and change in hemoglobin, ferritin, and oxidative stress markers among moderately anemic pregnant women attending a secondary care level Hospital in Northern India
Olivia Marie Jacob1, Shashi Kant2, Partha Haldar3, Ravneet Kaur3, Vatsla Dadhwal4, Shyam Prakash5
1 Junior Resident, Centre for Community Medicine, All India Institute of Medical Sciences, New Delhi, India
2 Professor and Head, Centre for Community Medicine, All India Institute of Medical Sciences, New Delhi, India
3 Associate Professor, Centre for Community Medicine, All India Institute of Medical Sciences, New Delhi, India
4 Professor, Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India
5 Associate Professor, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||25-Jan-2019|
|Date of Decision||11-May-2019|
|Date of Acceptance||27-Jan-2020|
|Date of Web Publication||16-Mar-2020|
Centre for Community Medicine, Old OT Block, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Intravenous iron is associated with oxidative stress, and very few studies have assessed change in oxidative stress markers post infusion. Objectives: The study aimed to measure the change in levels of hemoglobin (Hb), serum ferritin, and select oxidative stress markers (malondialdehyde [MDA], superoxide dismutase [SOD], and ferric reducing ability of plasma [FRAP]) 4 weeks following the administration of intravenous iron sucrose (IVIS) among moderately anemic pregnant women who were attending a secondary-level health-care facility, Haryana, North India. Methods: An observational study was conducted (May 2016 to Jan 2018) among pregnant women receiving intravenous iron sucrose i.e., IVIS (300 mg per dose) diluted in 300 mL of normal saline over 20–45 min and were followed up for a period of 4 weeks after the last dose of IVIS (end line). The study outcomes were measured in the levels of Hb, serum ferritin, MDA, SOD, and FRAP from the baseline to the end line. Results: The mean (95% confidence interval) change in the Hb and serum ferritin level 4 weeks after the last dose of IVIS was an increase of 2.5 (2.1–3.0) g/dL (P < 0.001) and 63.0 (44.7–81.3) ng/mL (P < 0.001), respectively. There were no significant changes (baseline to end line) in mean (standard deviation [SD]) MDA level and mean (SD) FRAP level. The mean (SD) SOD level declined significantly (2.2 [0.4] U/mL to 1.6 [0.5] U/mL [P < 0.001]). No life-threatening adverse events were encountered during the study. Conclusion: IVIS was well tolerated and effective in treating moderate anemia in pregnancy. Body iron store was replenished following IVIS administration. There was no increase in oxidative stress following IVIS therapy.
Keywords: Anemia, intravenous iron sucrose, iron sucrose, oxidative stress, pregnancy
|How to cite this article:|
Jacob OM, Kant S, Haldar P, Kaur R, Dadhwal V, Prakash S. Intravenous Iron sucrose and change in hemoglobin, ferritin, and oxidative stress markers among moderately anemic pregnant women attending a secondary care level Hospital in Northern India. Indian J Public Health 2020;64:11-6
|How to cite this URL:|
Jacob OM, Kant S, Haldar P, Kaur R, Dadhwal V, Prakash S. Intravenous Iron sucrose and change in hemoglobin, ferritin, and oxidative stress markers among moderately anemic pregnant women attending a secondary care level Hospital in Northern India. Indian J Public Health [serial online] 2020 [cited 2021 Oct 17];64:11-6. Available from: https://www.ijph.in/text.asp?2020/64/1/11/280772
| Introduction|| |
Anemia in pregnancy is associated with poor maternal and fetal outcomes. Almost one-fifth of the maternal deaths worldwide can be attributed to anemia directly, whereas another 50% of the deaths are associated with anemia., Almost half of the pregnant women in India are anemic. This situation persists despite the existence of a national anemia control program for the past many decades. Since almost half of the anemic pregnant women in India have moderate anemia, they deserve priority attention.
Oral iron, the standard drug for the treatment of iron-deficiency anemia, is poorly tolerated during pregnancy due to its side effects. It takes 6–8 weeks to normalize hemoglobin (Hb) level. However, quick restoration of Hb level is possible by parenteral administration of iron. Studies report that intravenous iron sucrose (IVIS) is safe and an effective alternative for the treatment of anemia among pregnant women who did not tolerate oral iron.,,,,
Physiological and metabolic needs are altered in normal pregnancy leading to oxidative stress.,, Oxidative stress produces free radicals that cause cellular damage thus could potentially endanger both mother and fetus. Iron supplementation (oral and injectable forms) has been reported to cause oxidative stress.,, Very few human studies have assessed the likelihood of oxidative stress post-IVIS infusion. Therefore, we undertook this study.
The objective of this study was to measure the change in levels of Hb, serum ferritin, and select oxidative stress markers, following administration of IVIS among moderately anemic pregnant women who attended a secondary-level health-care facility for their antenatal care.
| Materials and Methods|| |
This was a prospective, observational follow-up study involving pregnant women with moderate anemia (Hb level between 7.0 and 9.9 g/dL). The study was conducted from May 2016 to January 2017at a secondary-level health-care facility at Ballabgarh block of Faridabad district of Haryana, India, where a total of 10,775 women registered in the antenatal clinic in the years 2018–2019 at the hospital.
Pregnant women aged 18 years or above, in their second or third trimester, with Hb level between 7.0 and 9.9 g/dL were eligible to be included in the study. We excluded those women who were known to be allergic to iron formulations, had received a blood transfusion in the preceding 3 months, or were suffering from any chronic/systemic illness or blood disorders. All consecutive eligible and consenting pregnant women who reported during the study period were included in the study.
Assuming a standard deviation of mean change of Hb of 1.7 g/dL, power of 95%, level of significance of 5%, nonresponse rate of 20%, and to detect 1.0 g/dL difference in the outcome (Hb) variable, the minimum required sample was 47 participants (n = [(zα/2+ zβ)2/d2]*variance). The minimum required sample size was inflated to account for loss to follow-up at 4 weeks post-IVIS infusion.
Hence, 66 women received IVIS during the study period, but only 45 (follow-up participants with baseline and end line samples) were finally included in the comparison. The staff nurse measured the Hb level using HemoCue201 (HemoCue AB-Hb photometer; čngelholm, Sweden) following the standard method as prescribed by the manufacturer. A schematic description of the study procedure is given in [Figure 1]. In addition, 5 ml of venous blood from the cubital fossa under strict aseptic precautions was collected for the estimation of serum ferritin and oxidative stress markers. We collected blood samples at the baseline, i.e., at the time of recruitment, and again at the end line, i.e., 4 weeks after the last dose of IVIS administration.
The total dose of iron requirement was calculated using the Ganzoni's formula, i.e., total iron requirement (in mg) = prepregnancy weight (in kg.) × (target Hb − actual Hb in g/dL) × 2.4 + iron stores. The target Hb was set at 12 g/dL and allowance for iron stores as 1000 mg.,
We used iron sucrose solution (Vivek Pharmachem (India) Ltd., Jaipur, Rajasthan, India). IVIS was administered in the doses of 300 mg (per dose per sitting) in 300 mL of normal saline over 30–45 min. Subsequent doses were administered over 20 min on an alternate day basis. Participants were advised not to consume any oral iron supplements. Adverse events during and after the IVIS administration were noted and addressed. Participants were followed up 4 weeks after the last dose of IVIS for estimating the change in Hb and serum ferritin levels.
The serum ferritin level was measured by chemiluminescence assay (Access 2 Beckman Coulter machine). Oxidative stress markers measured were superoxide dismutase (SOD), malondialdehyde (MDA) from serum, and ferric reducing ability of plasma (FRAP) from the plasma. Standard methods (described in Appendix) were used to estimate SOD, MDA, and FRAP levels.,, A periodic calibration of the study tools was done. Ethical approval was obtained from the Institutional Ethics Committee, AIIMS, New Delhi (vide Letter Reference No. IECPG-29/27.11.2015, RT-9/30.12.2015, RT-36/27.01.2016, RT-26/24.02.2016, OT-3/27.07.2016).
Data were entered in Microsoft Excel, and analysis was done using STATA 11, StataCorp 2009, College Station, TX, USA. Continuous data were expressed in mean (standard deviation [SD]) and categorical data were expressed in frequencies and percentages. Shapiro–Wilk test was applied to test for the normality of data. Nonnormal data were logarithmically transformed. Wilcoxon signed-rank test was applied to test for significance for nonnormal data. A paired t-test was applied for Hb and log-transformed data. P < 0.05 was considered statistically significant.
| Results|| |
Paired (baseline and end line) measurements were available for 45 participants for Hb, 28 participants for serum ferritin, 34 for MDA, and 36 participants for SOD and FRAP [Figure 1]. Serum samples were insufficient to test for ferritin and oxidative stress markers for the remaining participants.
The mean (SD) age of the study participants was 23.4 (3.2) years. The mean (SD) period of gestation was 21.0 (6.4) weeks. Most participants were in the second trimester of gestation (86.7%) and required four doses (56%) of IVIS. Twenty participants (44%) received five doses of IVIS. The mean (SD) iron requirement was 1347 (151.7) mg. The mean (SD) duration to complete total therapy was 1.2 (0.2) weeks.
Changes in levels of hemoglobin and serum ferritin
The mean Hb (SD) at the baseline and 4 weeks after IVIS was 8.7 (0.8) g/dL and 11.2 (1.2) g/dL respectively (P < 0.001) [Table 1]. The mean (95% confidence interval [CI]) increase in the Hb level 4 weeks after the last dose of IVIS was 2.5 (2.1–3.0) g/dL. The mean (95% CI) increase in the serum ferritin level 4 weeks after the last dose of IVIS was 63.0 (44.7–81.3) ng/mL [Table 1]. Four weeks after the IVIS administration, about two-third (67%) of the moderately anemic pregnant women became nonanemic. An additional four participants (9%) improved from moderate-to-mild category of anemia [Table 2].
|Table 1: Hemoglobin, serum ferritin, and oxidative stress marker level at the baseline and end line and mean (95% confidence interval) change in hemoglobin and serum ferritin levels|
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|Table 2: Distribution of anemia category 4 weeks after intravenous iron sucrose administration|
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Changes in the level of oxidative stress markers
The mean (SD) MDA level at the baseline was 8.3 (2.3) nmol/L, which declined to 8.0 (2.3 nmol/L). This decrease was not statistically significant. The mean (SD) SOD level declined from 2.2 (0.4) U/mL at the baseline to 1.6 (0.5) U/mL at the end line. The decline was statistically significant (P < 0.001). The mean (SD) FRAP level at the baseline was 681.8 (190.5) μM/L, which increased to 743.5 (172.2) μM/L at the end line. This increase was statistically not significant [Table 1].
Loss to follow-up
The study participants who were lost to follow-up (n = 21) were similar to those who were followed up for mean age, occupation, and educational status. There were more women in the third trimester in the lost-to-follow-up group (42.9% vs. 13.3% in the follow-up group). This difference is explained by the fact that pregnant women in our study area often go to their maternal/native homes for their delivery.
Compliance with medication was 100% as none of the study participants missed any of the prescribed doses of IVIS.
Adverse effects of intravenous iron sucrose
Three participants experienced adverse events (shivering, swelling of hands, and change in voice and heaviness in the chest). IVIS was discontinued for these study participants and they were treated with antihistaminic and hydrocortisone. These three participants were excluded from the study. The study participants were also informed regarding the reaction and advised to avoid injectable iron in the future due to possible allergy/hypersensitivity.
| Discussion|| |
To summarize, the mean (95% CI) increase in Hb level was 2.5 (2.1–3.0) g/dL 4 weeks following IVIS therapy among pregnant women who had moderate anemia. During the same period, the mean (95% CI) increase in the serum ferritin levels was 63.0 (44.7–81.3) ng/mL. There was a statistically significant decrease in the mean (SD) SOD level from 2.2 (0.4) to 1.6 (0.5) U/mL. There were no significant changes in the MDA and FRAP levels 4 weeks after IVIS therapy.
In our study, the Hb level increased by 2.5 (2.1–3.0) g/dL and this finding was consistent with other studies. Other observational studies report a mean increase in the Hb ranging between 2.0 g/dL and 3.3 g/dL, 3 and 4 weeks after IVIS therapy.,,,, The highest reported rise in Hb following IVIS therapy was 3.33 g/dL in a study by Patel et al. Inclusion of severely anemic pregnant women by Patel at el. probably resulted in a higher mean increase in Hb level.
Kumar et al. in a review concluded that oxidative stress worsens with anemia in most of the animal and human studies. Furthermore, in majority of the animal studies and studies in pregnant women, the oxidative stress increased when iron was supplemented. We measured MDA, SOD, and FRAP as oxidative stress markers following IVIS therapy.
The elevated MDA level is considered a marker of oxidative stress. MDA level is a highly sensitive but less specific test. Using a sensitive test, we aimed to detect the change in oxidative stress marker level though there was more likelihood of false-positive results. The important finding of our study was that the MDA level was not elevated at 4 weeks following IVIS administration. Thus, there was no evidence of increased oxidative stress following IVIS administration.
The mean (SD) SOD level before the IVIS administration was 2.2 (0.4) U/mL, which declined to 1.6 (0.5) U/mL at 4 weeks after IVIS administration. This decline in the SOD level was statistically significant. The normal SOD levels among healthy nonpregnant and second trimester pregnant Indian women have been reported as 2.84 (0.56) U/mL and 2.99 (0.57) U/mL, respectively. The relationship between iron-deficiency anemia and SOD level is not settled yet. There are conflicting reports about SOD level in iron-deficiency anemia. Some authors found elevated SOD level in iron-deficiency anemia.,, Others have reported depressed SOD levels in iron-deficiency anemia which increased after anemia was treated.,,,
We believe that IVIS Administration had led to nonsignificant decline in the MDA level at the end line, suggesting an easing of oxidative stress. A decline in oxidative stress resulted in a lowering of compensatory effort, and hence, a decline in the SOD level. Our findings do not support the suggestion that there is increased oxidative stress when anemia is treated with iron supplementation.
The plasma level of FRAP declines in the presence of oxidative stress. Indian studies among healthy adult population report FRAP level to approximately range between 700 and 1050 μmol/L.,, We found that the FRAP level at the baseline was 681.8 (190.5) μM/L. In fact, the FRAP level increased to 743.5 (172.2) μM/L after IVIS administration though this increase was statistically nonsignificant. The total antioxidant capacity of the plasma did not decline following the IVIS administration. A stable level of FRAP provided further evidence that the administration of IVIS did not result in oxidative stress.
The main aim of parenteral iron administration ought to be replenishment of iron stores in the iron-deficient moderately anemic pregnant women. Studies have reported that optimum iron repletion often results in the patient not having to return for more iron for 9 months or longer. Serum ferritin level is a good marker of body iron store. In our study, the mean (95% CI) rise in serum ferritin level was 63.0 (44.7–81.3) ng/dL. An erroneous rise in serum ferritin level can be seen during acute infection, for which C-reactive protein (CRP) is a proxy marker. We had not measured the CRP level in blood. It is possible that some women may have had a concurrent infection resulting in a falsely higher serum ferritin level. If there was no differential rate of infection among pregnant women during the two measurements, then the quantum of the mean rise in serum ferritin levels would remain unaffected. We could not find any reason that would support the assumption of differential rate of infection at two time points. Therefore, we feel that the increase in the level of serum ferritin observed valid and attributable to the administration of IVIS.
Iron sucrose in most studies was administered in doses of 200 mg per sitting. Up to 300 mg of iron can be administered safely in a single dose. There are a limited number of studies that had assessed the effect of 300 mg IVIS per dose. Our study provides evidence that IVIS in 300 mg per dose is safe and acceptable to participants. The higher dose would reduce the number of hospital visits required and improve treatment compliance. Good compliance seen in our study may partly be explained by participants requiring a lesser number of hospital visits. Compliance with prescribed IVIS therapy was 100% in the study, indicating that the therapy was acceptable to the participants. However, due to higher loss to follow-up as women wished to deliver at their maternal (20-37%), we think that there may be a need for cautious interpretation of certain parameters.
In most developing countries, pregnant women often report to health facilities when pregnancy is well advanced. Therefore, there is not sufficient time to correct the anemia through oral iron supplementation. In such a situation, for moderately anemic pregnant women, IVIS offers a faster, effective, and safe alternative to oral iron therapy.
| Conclusion|| |
IVIS administration was well tolerated, safe, and effective in treating moderate anemia among pregnant women attending a secondary-level hospital in Haryana, India. It also improved iron stores in the form of serum ferritin with good compliance to prescribed IVIS therapy in pregnancy. IVIS additionally did not contribute to significant oxidative stress and may, therefore, be considered for the treatment of moderate anemia in pregnancy. We also recommend further studies that assess the oxidative stress status in pregnancy following IVIS therapy and compare it with women who receive oral iron (with both prophylactic and therapeutic doses).
We gratefully acknowledge the laboratory support provided by Mrs. Priyatma and Mr. Manish (PhD scholars, Department of Laboratory Medicine, AIIMS, New Delhi). We also thank Dr. J B Sharma, Professor of Obstetrics & Gynecology, and Dr. Archana Singh, Assistant Professor of Biochemistry at AIIMS, New Delhi, for reviewing the draft manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]