Hypoferritinemia Without Anemia Among Reproductive Age Females

Hypoferritinemia Without Anemia Among Reproductive Age Females: Frequency, Determinants and Treatment Outcomes

The goal of this randomized controlled trial is to compare the treatment outcomes of oral iron supplementation (Group A) versus Intravenous (IV) iron supplementation (Group B) versus no treatment (Group C) on the serum ferritin level and to determine the outcomes in the severity of symptoms of HWA, among reproductive age females (age 18-45) with hypoferritinemia without Anemia (HWA), after four months of the start of the intervention.

Participants will:

• Randomly divided into 3 groups (A, B and C) to receive treatment.
• 100 patients will be allocated to each of the three study groups i.e., group A, B and C. The participants of Group A will get oral Iron III Hydroxide Polymaltose Complex eq. to Elemental Iron, 100 mg (Fersip) daily for three months, participants of group B will get IV Ferric Carboxymaltose (Ferinject) for 03 months (3 doses) and Group C will get no treatment.

Study Overview

• Status: Completed
• Conditions: Hypoferritenemia Without Anemia (HWA); Iron Deficiency Without Anemia)
• Intervention / Treatment: Drug: Iron III Hydroxide Polymaltose Complex eq. to Elemental Iron, 100 mg; Drug: Ferric Carboxymaltose

Detailed Description

At present the commonly identified presentation is Iron Deficiency Anemia which currently affects more than 1 billion people while Hypoferritenemia without Anemia (HWA) is at least twice as common. HWA is poorly recognized by clinicians despite its high prevalence, probably because of suboptimal screening recommendations.

HWA: Patients having normal Hemoglobin of ≥12 g/dl and having below normal range ferritin level < 30ng/ml and patients suffering from any of the following symptoms of

• Fatigue/ tiredness
• Poor work productivity
• Poor attention
• Poor memory
• Sore tongue
• Poor condition of skin, nails or hair, including hair loss.
• Delayed skin wound healing
• Palpitation
• Restless Leg Syndrome

As the symptoms and signs of the HWA are nonspecific which may happen in other systemic diseases or psychiatric disorders so patients with HWA are either recommended no tests or later on end up with expensive tests for heart failure and renal failure on the other end which can be the result of chronic iron deficiency. Clinicians usually advise iron studies when there is documented anemia which results in underdiagnoses of HWA.

To the best of researcher's knowledge, no study related to HWA has been conducted in Pakistan; therefore, the prevalence of Iron Deficiency Anemia (IDA) in Pakistan has been added in the present literature review. Results show that a total of 45% of population is suffering from IDA in Pakistan.

The rationale of this study is to highlight the struggling issue of HWA which is battling to be recognized as one of the factors contributing to the symptoms indicated above, as was previously stated. This study is important to be conducted as it will not only pave ways to recognize the category of HWA but will also help patients to receive targeted treatment and saving them from the risk of drug abuse and over-medication. As per the researcher's knowledge, there is a scarcity of data on Pakistan's population as no study exists on HWA in Pakistan.

Above literature review clearly reflects that there is a wide gap regarding some aspects of HWA. First, it is an underdiagnosed entity as it has nonspecific symptoms which can be found in other diseases. Although there are estimates of disease burden, but exact value is not known especially in developing countries. Secondly, there is a lot of data regarding causes of iron deficiency but paucity exists regarding determinants/causes of HWA. Thirdly, there is contrary data regarding management, few investigators believe that oral iron therapy shall be the first line therapy while other believes that intravenous (IV) therapy shall be given first to reduce symptoms.

OBJECTIVES

1. To determine the frequency of HWA among women of reproductive age
2. To compare the treatment outcomes of oral iron supplementation (Group 1) versus Intravenous (IV) iron supplementation (Group 2) versus normal diet (Group 3) on the serum ferritin level after four months of start of intervention
3. To determine the outcomes in the severity of symptoms of HWA after four months of start of intervention

Data Analysis Plan

The data analysis for this study is conducted using SPSS version 27 to evaluate the effects of oral iron supplementation, intravenous iron supplementation, and no treatment on serum ferritin levels and symptom severity after four months of intervention. To ensure the validity of statistical tests, the normality of the data is first assessed using the Shapiro-Wilk test, complemented by histograms and QQ plots for visual confirmation. The results from the Shapiro-Wilk test indicate that the data follows a normal distribution, validating the use of parametric tests for subsequent analyses.

For the primary outcome of serum ferritin levels, a paired sample t-test is applied to compare the pre- and post-treatment levels within each group. This test reveals the effectiveness of the interventions in increasing ferritin levels over time, highlighting significant changes, especially in the intravenous iron supplementation group. To assess the change in symptom severity, ANOVA is used to compare differences across the three groups, showing the relative impact of each treatment, for all tests, a significance level of p < 0.05 is considered. Missing data are handled using sensitivity analysis to ensure that any potential biases do not affect the results, allowing for a more robust and reliable interpretation of the treatment outcomes. The overall analysis provides strong evidence of the most effective intervention for improving serum ferritin levels and alleviating the symptoms of hypoferritinemia without anemia

• Study Type: Interventional
• Enrollment (Actual): 1331
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Pakistan
  • Punjab Province
    • Lahore, Punjab Province, Pakistan, 54782
      • Fatima Memorial Hospital
    • Lahore, Punjab Province, Pakistan, 54782
      • General hospital lahore
    • Lahore, Punjab Province, Pakistan, 54782
      • Gulab Devi Hospital
    • Lahore, Punjab Province, Pakistan, 54782
      • Sir Gangaram Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Reproductive age females: 18 to 45 years
• Clinical symptoms of iron deficiency which are fatigue/ tiredness, poor work productivity, poor attention and memory loss, sore tongue, poor condition of skin, nails or hair, including hair loss, delayed skin wound healing, palpitation and restless leg syndrome
• Normal CBC: hemoglobin level12mg/dl and above
• Serum ferritin levels: below 30 ng/ml
• Normal thyroid levels
• Normal blood sugar levels
• Willing and able to sign informed consent

Exclusion Criteria:

• Males
• Post-menopausal
• Premature menopause
• Anemic Females: hemoglobin levels i.e. less than 12 g/dl
• Serum ferritin level above 30 ng/ml.
• Disturbed thyroid levels
• Disturbed blood sugar levels
• Pregnant
• Lactating
• Blood donors
• Co-morbidities i.e., celiac disease, hemorrhoids, malignancies, hematuria, ulcers, heart failure, renal failure, chronic gastric symptoms/ gastric ulcers, chronic liver disease, disturbed thyroid levels and diabetes
• Any medication or supplement which may impact iron metabolism.
• History of iron or multivitamins supplementation in the last 3 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Oral iron supplement; 100 participants of Group A will get oral iron supplementation (Iron III Hydroxide Polymaltose Complex eq. to Elemental Iron), 100 mg for 03 months. Participants will consume 01 tablet per day for 03 months. After completion of the treatment period blood samples will be taken to evaluate the effect of iron supplementation on serum ferritin levels and severity of symptoms to assess the effectiveness of the intervention.	Drug: Iron III Hydroxide Polymaltose Complex eq. to Elemental Iron, 100 mg; 01 tablet daily for 03 months, This is assigned to Group A.; Other Names: Fersip
Active Comparator: Intravenous (IV) iron supplementation; 100 participants of Group B will get IV iron supplementation (Ferric Carboxymaltose) for 03 months (01 dose per month for 03 months). After completion of the treatment period blood samples will be taken to evaluate the effect of iron supplementation on serum ferritin levels and severity of symptoms to assess the effectiveness of the intervention.	Drug: Ferric Carboxymaltose; 03 doses (50 mg iron/mL) per month for 03 months. This is assigned to Group B.; Other Names: Ferinject
No Intervention: Normal diet; 100 participants will remain on their normal diet for 03 months. After 03 months blood samples will be taken to evaluate the effect of iron supplementation on serum ferritin levels and severity of symptoms to assess the effectiveness of the intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Socio demographic characteristics of participants	The characteristics that will be surveyed at level of education, region, religion, income, marital status, number of children, antenatal care and working status	Week 1 (Baseline)
Serum ferritin levels	Serum ferritin levels before and after intervention	Baseline, week 16
Changes in symptom severity	Symptom severity score before and after intervention: This questionnaire contains eight questions with multiple-choice responses, with a score ranging from 0 point (not at all), 1 point (mild symptoms/ rarely), 2 points (moderate/ sometimes) and 3 points (severe/ frequently). The total symptom severity score will be calculated as the mean of the scores for the eight individual items and will be recorded at week 2 and week 16	Week 2, Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Defined as participants self-reported adverse effects. Items that will be surveyed are nausea, vomiting, diarhhea, fever and others.	Week 6, 10, 16
Symptom severity scale	Change in symptoms severity score after intervention: This questionnaire contains eight questions with multiple-choice responses, with a score ranging from 0 point (not at all), 1 point (mild symptoms/ rarely), 2 points (moderate/ sometimes) and 3 points (severe/ frequently). The total symptom severity score will be calculated as the mean of the scores for the eight individual items and will be recorded at week 6, 10, 16	Week 6, 10, 16
Change in serum ferritin levels as result of oral intervention: Fersip	Change in serum ferritin levels as the result 90 tablets for 03 months (01 tablet everyday for 03 months)	Week 16
Change in serum ferritin levels as result of intravenous (IV) iron intervention: Ferinject	Change in serum ferritin levels as the result of 03 doses (500 mg) per month for 03 months. The change will be measured through serum ferritin blood test results.	Week 16
Comparison of treatment outcomes of groups (A, B and C)	Comparison of treatment outcomes of oral and IV iron supplementation and normal diet: The treatment outcomes will be measured through serum ferritin test as a comparison between 03 arms. Adverse events will also be compared. Items that will be surveyed for adverse events are are nausea, vomiting, diarrhea, fever and others	Week 16

Collaborators and Investigators

• Sponsor: Akram Medical Complex
• Collaborators: The Searle Company Limited Pakistan; Scotmann Pharmaceuticals
• Investigators: Study Chair: Dr. Abdul Majeed Akhtar, MBBS, PhD, The univeristy of Lahore; Study Director: Dr. Rubeena Zakir, MBBS, PhD, University of Punjab

Publications and helpful links

General Publications

• Abuaisha M, Itani H, El Masri R, Antoun J. Prevalence of Iron Deficiency (ID) without anemia in the general population presenting to primary care clinics: a cross-sectional study. Postgrad Med. 2020 Apr;132(3):282-287. doi: 10.1080/00325481.2020.1715701. Epub 2020 Jan 22.
• Adams J, White M. Characterisation of UK diets according to degree of food processing and associations with socio-demographics and obesity: cross-sectional analysis of UK National Diet and Nutrition Survey (2008-12). Int J Behav Nutr Phys Act. 2015 Dec 18;12:160. doi: 10.1186/s12966-015-0317-y.
• Al-Jafar HA. HWA: Hypoferritinemia without anemia a hidden hematology disorder. J Family Med Prim Care. 2017 Jan-Mar;6(1):69-72. doi: 10.4103/2249-4863.214986.

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2022
• Primary Completion (Actual): October 16, 2025
• Study Completion (Actual): October 16, 2025

Study Registration Dates

• First Submitted: May 21, 2024
• First Submitted That Met QC Criteria: May 25, 2024
• First Posted (Actual): May 31, 2024

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: May 15, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Intervention; Transferrin saturation (TSAT); Hypoferritenemia without Anemia (HWA); Reproductive age females; Symptoms of HWA; Determinants of HWA; Low serum ferritin levels, Iron deficiency; Cross-sectional study (Phase 1); Randomized controlled trial (Phase 2)
• Additional Relevant MeSH Terms: Metabolic Diseases; Iron Metabolism Disorders; Nutritional and Metabolic Diseases; Iron Deficiencies; ferric carboxymaltose
• Other Study ID Numbers: 70122031

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No