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.

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

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

Females of reproductive age