Risk of Anemia and Effects of Oral Iron Therapy in Non-Anemic Iron-Deficient Women (18-55 Years)

NCT ID: NCT07263529

Last Updated: 2025-12-04

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

NA

Total Enrollment

60 participants

Study Classification

INTERVENTIONAL

Study Start Date

2025-09-01

Study Completion Date

2026-02-28

Brief Summary

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This study investigates the risk of anemia development in women aged 18-55 years with non-anemic iron deficiency and evaluates the clinical effects of oral iron therapy. The study consists of a two-month nutritional intervention phase followed by a one-month oral iron treatment phase. Participants first receive dietary counseling aimed at increasing iron intake and absorption. After two months, changes in hematologic parameters and symptoms are evaluated. Women with persistent iron deficiency then receive daily oral ferrous sulfate (80 mg elemental iron) for one month. The study aims to identify early predictors of anemia progression and to assess the impact of dietary modification and oral iron therapy on symptoms and laboratory findings.

Detailed Description

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This study examines the risk of anemia development in women aged 18-55 years with non-anemic iron deficiency (NAID) and evaluates the clinical effects of oral iron therapy in those with persistent deficiency. The objective is to characterize individual and clinical factors associated with progression toward anemia and to assess the impact of nutritional modification and subsequent iron supplementation on hematologic and symptom-based outcomes.

Iron deficiency is one of the most common nutritional deficiencies globally. NAID often remains unrecognized despite its potential to cause fatigue, decreased physical performance, and progression to anemia if untreated. Iron plays a key role in oxygen transport, DNA synthesis, and muscle metabolism. Dietary intake includes both heme (animal-derived) and non-heme (plant-derived) forms with differing bioavailability. Ferritin is the primary biomarker used to diagnose iron deficiency, though inflammatory conditions may influence its accuracy. A careful differential evaluation is important to distinguish NAID from other causes of anemia such as chronic disease, B12 or folate deficiency, thalassemia syndromes, thyroid disorders, or gastrointestinal blood loss.

The study uses a two-phase, single-center prospective design at Kağıthane 5 No'lu Family Health Center (ASM), Istanbul, Turkey, conducted under ethics committee approval and institutional permission. In the initial two-month observational phase, participants receive standardized dietary counseling aimed at increasing iron intake and improving absorption. Health status and adherence are monitored biweekly. After this period, participants are categorized into four groups according to hematologic changes: isolated iron deficiency; microcytosis/hypochromia with minimal hemoglobin decline (\<1 g/dL) ; greater hemoglobin decline without meeting anemia thresholds; or overt iron deficiency anemia.

In the subsequent one-month experimental phase, participants with persistent deficiency receive oral ferrous sulfate providing 80 mg elemental iron daily. Clinical and laboratory evaluations are performed at designated time points to assess changes in complete blood count parameters, ferritin, serum iron indices, inflammatory markers, and patient-reported symptoms.

Primary outcomes include changes in symptom scores, while secondary outcomes evaluate hematologic and biochemical responses. Planned analyses explore associations between baseline characteristics, dietary habits, and anemia progression. Power analysis using repeated measures ANOVA indicated a required sample size of 60 participants.

This research highlights the importance of individualized management strategies for iron deficiency, aiming to support appropriate use of supplementation while reducing unnecessary treatment and potential adverse effects. Enhancing dietary iron intake may help prevent anemia progression, promote patient safety, and improve resource utilization in primary care settings.

Conditions

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Non-Anemic Iron Deficiency

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

All participants initially receive the same nutritional intervention; after post-intervention evaluation, subgroups are defined and those with persistent iron deficiency receive the drug intervention.
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

No parties are masked; this is an open-label study.

Study Groups

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ARM 1 - Nutritional Intervention with Post-Intervention Subgrouping

All participants (N=60) begin with isolated non-anemic iron deficiency and receive a 2-month standardized nutritional intervention to improve iron intake and absorption. Afterward, participants are stratified into five subgroups (ARM1-0 to ARM1-4) based on hematologic response. Subgroups ARM1-1 to ARM1-4 represent persistent deficiency (ferritin \<15 µg/L with normal CRP) and will receive oral elemental iron.

* ARM1-0: Normalized or maintained iron status (no deficiency) - no iron therapy administered.
* ARM1-1: Persistent isolated iron deficiency - receives oral elemental iron.
* ARM1-2: Minimal hemoglobin decline (\<1 g/dL) with microcytosis/hypochromia - receives oral elemental iron.
* ARM1-3: Hemoglobin decline \>1 g/dL but above anemia threshold, with microcytosis/hypochromia - receives oral elemental iron.
* ARM1-4: Overt iron deficiency anemia - receives oral elemental iron.

Group Type EXPERIMENTAL

Dietary Intervention (2 months)

Intervention Type OTHER

A two-month nutritional counseling program for all participants (N = 60) with isolated non-anemic iron deficiency. The program emphasized the inclusion of iron-rich foods (both heme and non-heme sources), the use of enhancers of iron absorption (such as vitamin C), and practical strategies to reduce absorption inhibitors (e.g., limiting tea and coffee consumption around meals, reviewing antacid use). Participants received biweekly phone follow-ups to monitor adherence and assess symptoms.

Oral Elemental Iron (Ferrous Sulfate) 80 mg/day

Intervention Type DRUG

One-month oral therapy with 80 mg elemental iron (ferrous sulfate) daily for participants with persistent iron deficiency after the nutritional phase (ferritin \< 15 µg/L). Biweekly phone follow-up for adherence and symptom checks. Adherence and side effects monitored at clinic visit or by phone.

Interventions

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Dietary Intervention (2 months)

A two-month nutritional counseling program for all participants (N = 60) with isolated non-anemic iron deficiency. The program emphasized the inclusion of iron-rich foods (both heme and non-heme sources), the use of enhancers of iron absorption (such as vitamin C), and practical strategies to reduce absorption inhibitors (e.g., limiting tea and coffee consumption around meals, reviewing antacid use). Participants received biweekly phone follow-ups to monitor adherence and assess symptoms.

Intervention Type OTHER

Oral Elemental Iron (Ferrous Sulfate) 80 mg/day

One-month oral therapy with 80 mg elemental iron (ferrous sulfate) daily for participants with persistent iron deficiency after the nutritional phase (ferritin \< 15 µg/L). Biweekly phone follow-up for adherence and symptom checks. Adherence and side effects monitored at clinic visit or by phone.

Intervention Type DRUG

Other Intervention Names

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Nutritional Intervention (2 months) Oral Iron Intervention (1 month)

Eligibility Criteria

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Inclusion Criteria

* Female participants aged 18-55 years (including premenopausal and menopausal women).
* Normal hemoglobin level (≥ 12 g/dL).
* Serum ferritin \< 15 μg/L (WHO criteria for iron deficiency).
* Mentzer index \> 13.
* Normal levels of vitamin B12, folic acid, thyroid hormones (TSH and sT4), and C-reactive protein (CRP \< 5 mg/L).
* Non-anemic iron deficiency confirmed by laboratory results.
* Good general health and cognitive capacity to provide informed consent.
* Willingness to participate, comply with study procedures, and provide written informed consent.

Exclusion Criteria

* Pregnancy or postpartum period.
* Acute or chronic infections.
* History or suspicion of malignancy.
* Chronic inflammatory or autoimmune diseases.
* Chronic fatigue syndrome or depressive disorders.
* Chronic kidney disease or renal failure (acute or chronic).
* Congestive heart failure, ischemic heart disease, or cerebrovascular disease.
* Coagulopathy or clinically significant bleeding tendency.
* Hematological disorders (e.g., thalassemia, hemoglobinopathies).
* Postoperative patients, transplant recipients, or dialysis patients.
* Currently using any form of iron supplementation or treatment.
* Any condition that, in the investigator's opinion, may interfere with the participant's safety or the interpretation of study results.
Minimum Eligible Age

18 Years

Maximum Eligible Age

55 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Sponsors

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Istanbul University - Cerrahpasa

OTHER

Sponsor Role lead

Responsible Party

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Osman Demir, MD

MD

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Osman Demir, MD

Role: PRINCIPAL_INVESTIGATOR

Kağıthane No.5 Family Health Center, Istanbul, Turkey

Ayşen Fenercioğlu, Assoc Prof

Role: STUDY_DIRECTOR

Istanbul University - Cerrahpaşa, Cerrahpaşa Faculty of Medicine

Locations

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Kagıthane No. 5 Family Health Center

Kâğıthane, Istanbul, Turkey (Türkiye)

Site Status RECRUITING

Countries

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Turkey (Türkiye)

Central Contacts

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Osman Demir, MD

Role: CONTACT

+90 532 291 4470

Ayşen Fenercioğlu, Assoc Prof

Role: CONTACT

+90 537 964 5751

Facility Contacts

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Osman Demir, MD

Role: primary

+90 532 291 4470

Ayşen Fenercioğlu, Assoc Prof

Role: backup

+90 537 964 5751

References

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Ortancil O, Sanli A, Eryuksel R, Basaran A, Ankarali H. Association between serum ferritin level and fibromyalgia syndrome. Eur J Clin Nutr. 2010 Mar;64(3):308-12. doi: 10.1038/ejcn.2009.149. Epub 2010 Jan 20.

Reference Type BACKGROUND
PMID: 20087382 (View on PubMed)

Skolmowska D, Glabska D, Kolota A, Guzek D. Effectiveness of Dietary Interventions to Treat Iron-Deficiency Anemia in Women: A Systematic Review of Randomized Controlled Trials. Nutrients. 2022 Jun 30;14(13):2724. doi: 10.3390/nu14132724.

Reference Type BACKGROUND
PMID: 35807904 (View on PubMed)

Silva Neto LGR, Santos Neto JED, Bueno NB, de Oliveira SL, Ataide TDR. Effects of iron supplementation versus dietary iron on the nutritional iron status: Systematic review with meta-analysis of randomized controlled trials. Crit Rev Food Sci Nutr. 2019;59(16):2553-2561. doi: 10.1080/10408398.2018.1459469. Epub 2018 Apr 30.

Reference Type RESULT
PMID: 29611716 (View on PubMed)

Moretti D, Goede JS, Zeder C, Jiskra M, Chatzinakou V, Tjalsma H, Melse-Boonstra A, Brittenham G, Swinkels DW, Zimmermann MB. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015 Oct 22;126(17):1981-9. doi: 10.1182/blood-2015-05-642223. Epub 2015 Aug 19.

Reference Type RESULT
PMID: 26289639 (View on PubMed)

Stefan MW, Gundermann DM, Sharp MH, Jennings BA, Gheith RH, Lowery RP, LowDog T, Ghatak SB, Barbosa J, Wilson JM. Assessment of the Efficacy of a Low-Dose Iron Supplement in Restoring Iron Levels to Normal Range among Healthy Premenopausal Women with Iron Deficiency without Anemia. Nutrients. 2023 Jun 3;15(11):2620. doi: 10.3390/nu15112620.

Reference Type RESULT
PMID: 37299583 (View on PubMed)

Nemeth E, Ganz T. Hepcidin and Iron in Health and Disease. Annu Rev Med. 2023 Jan 27;74:261-277. doi: 10.1146/annurev-med-043021-032816. Epub 2022 Jul 29.

Reference Type RESULT
PMID: 35905974 (View on PubMed)

Zhu XY, Wu TT, Wang HM, Li X, Ni LY, Chen TJ, Qiu MY, Shen J, Liu T, Ondo WG, Wu YC. Correlates of Nonanemic Iron Deficiency in Restless Legs Syndrome. Front Neurol. 2020 Apr 30;11:298. doi: 10.3389/fneur.2020.00298. eCollection 2020.

Reference Type RESULT
PMID: 32425874 (View on PubMed)

Sawada T, Konomi A, Yokoi K. Iron deficiency without anemia is associated with anger and fatigue in young Japanese women. Biol Trace Elem Res. 2014 Jun;159(1-3):22-31. doi: 10.1007/s12011-014-9963-1. Epub 2014 Apr 23.

Reference Type RESULT
PMID: 24756645 (View on PubMed)

da Silva Lopes K, Yamaji N, Rahman MO, Suto M, Takemoto Y, Garcia-Casal MN, Ota E. Nutrition-specific interventions for preventing and controlling anaemia throughout the life cycle: an overview of systematic reviews. Cochrane Database Syst Rev. 2021 Sep 26;9(9):CD013092. doi: 10.1002/14651858.CD013092.pub2.

Reference Type RESULT
PMID: 34564844 (View on PubMed)

Miles LF, Litton E, Imberger G, Story D. Intravenous iron therapy for non-anaemic, iron-deficient adults. Cochrane Database Syst Rev. 2019 Dec 20;12(12):CD013084. doi: 10.1002/14651858.CD013084.pub2.

Reference Type RESULT
PMID: 31860749 (View on PubMed)

Houston BL, Hurrie D, Graham J, Perija B, Rimmer E, Rabbani R, Bernstein CN, Turgeon AF, Fergusson DA, Houston DS, Abou-Setta AM, Zarychanski R. Efficacy of iron supplementation on fatigue and physical capacity in non-anaemic iron-deficient adults: a systematic review of randomised controlled trials. BMJ Open. 2018 Apr 5;8(4):e019240. doi: 10.1136/bmjopen-2017-019240.

Reference Type RESULT
PMID: 29626044 (View on PubMed)

Fletcher A, Forbes A, Svenson N, Wayne Thomas D; A British Society for Haematology Good Practice Paper. Guideline for the laboratory diagnosis of iron deficiency in adults (excluding pregnancy) and children. Br J Haematol. 2022 Feb;196(3):523-529. doi: 10.1111/bjh.17900. Epub 2021 Oct 24. No abstract available.

Reference Type RESULT
PMID: 34693519 (View on PubMed)

Clenin GE. The treatment of iron deficiency without anaemia (in otherwise healthy persons). Swiss Med Wkly. 2017 Jun 14;147:w14434. doi: 10.4414/smw.2017.14434. eCollection 2017.

Reference Type RESULT
PMID: 28634965 (View on PubMed)

WHO guideline on use of ferritin concentrations to assess iron status in individuals and populations [Internet]. Geneva: World Health Organization; 2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK569880/

Reference Type RESULT
PMID: 33909381 (View on PubMed)

Balendran S, Forsyth C. Non-anaemic iron deficiency. Aust Prescr. 2021 Dec;44(6):193-196. doi: 10.18773/austprescr.2021.052. Epub 2021 Dec 1.

Reference Type RESULT
PMID: 35002031 (View on PubMed)

Guideline on haemoglobin cutoffs to define anaemia in individuals and populations [Internet]. Geneva: World Health Organization; 2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK602198/

Reference Type RESULT
PMID: 38530913 (View on PubMed)

Soppi ET. Iron deficiency without anemia - a clinical challenge. Clin Case Rep. 2018 Apr 17;6(6):1082-1086. doi: 10.1002/ccr3.1529. eCollection 2018 Jun.

Reference Type RESULT
PMID: 29881569 (View on PubMed)

Provided Documents

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Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Related Links

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https://etikkurul.iuc.edu.tr/tr/iletisim

Ethical approval: Istanbul University-Cerrahpasa Clinical Research Ethics Committee.

https://www.kagithane5noluasm.com.tr/

Study site: Kagithane 5 No'lu Family Health Center (ASM), conducted by Dr. Osman Demir.

https://istanbulism.saglik.gov.tr/

Institutional authorization: Permission for study implementation obtained from Istanbul Provincial Health Directorate.

Other Identifiers

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E-14028348-302.14.02-985103

Identifier Type: OTHER

Identifier Source: secondary_id

E-15916306-604.01-281470566

Identifier Type: OTHER

Identifier Source: secondary_id

2024-KAEK-22

Identifier Type: -

Identifier Source: org_study_id

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