Research Article | DOI: https://doi.org/10.31579/2642-9756/258
1Gynaecology-Obstetrics and Endoscopy Department, Maternity Souissi, University Hospital Center IBN SINA, University Mohammed V, Rabat, Morocco.
2Department of Gynecology-Obstetrics, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy of Rabat, University Mohammed V, Rabat, Morocco.
3Department of Public Health, Epidemiology and Clinical Research, The Biostatistics, Clinical Research and Epidemiology Laboratory, Mohamed V University of Rabat, Ibn Sina University Hospital, Rabat, Morocco.
*Corresponding Author: Aziz Slaoui, Gynaecology-Obstetrics and Endocrinology Department, University Mohammed V of Rabat, Morocco.
Citation: Aziz Slaoui, Oumaima Mourran, Meryem Abouch, Amina El Alami, Othmane Echarfaoui, et al, (2026), Comparative Efficacy and Tolerability of Different Formulations and Dosing Regimens of Oral Iron in Postpartum Iron-Deficiency Anemia: A Prospective Comparative Study, J. Women Health Care and Issues, 9(1); DOI:10.31579/2642-9756/258
Copyright: © 2026, Aziz Slaoui. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 31 March 2026 | Accepted: 22 April 2026 | Published: 14 May 2026
Keywords: postpartum anemia; iron-deficiency anemia; oral iron; alternate-day dosing; liposomal iron; ferrous sulfate
Postpartum iron-deficiency anemia is common and oral iron remains first-line therapy, although daily dosing is often limited by poor gastrointestinal tolerability. Alternate-day dosing and liposomal formulations may improve treatment outcomes.
Methods
In this prospective comparative study, 400 women with postpartum iron-deficiency anemia were assigned to ferrous sulfate 80 mg daily, ferrous sulfate 160 mg every other day, liposomal iron 28 mg daily, or liposomal iron 56 mg every other day. Hemoglobin changes from postpartum day 1 to month 3 were analyzed using linear mixed-effects models, with intergroup comparisons performed using Welch’s t-tests.
Results
Hemoglobin increased significantly in all groups (p < 0.001). Within each formulation, alternate-day and daily regimens achieved comparable hemoglobin gains. Liposomal iron resulted in greater hemoglobin improvement than ferrous sulfate. Gastrointestinal adverse effects were significantly less frequent with alternate-day dosing (p < 0.05).
Conclusion
Alternate-day oral iron provides efficacy comparable to daily dosing with superior tolerability in postpartum iron-deficiency anemia and represents an effective therapeutic option.
Postpartum iron-deficiency anemia remains a major maternal health concern, particularly in middle-income countries, where its prevalence remains high despite improvements in obstetric care. It primarily results from peripartum blood loss, progressive depletion of iron stores during pregnancy, and increased iron requirements associated with breastfeeding. Its clinical consequences are substantial and include persistent fatigue, impaired physical and cognitive performance, reduced quality of life, and negative effects on mother–infant interactions [1 -3].
Oral iron supplementation is the first-line treatment for mild to moderate postpartum anemia. Ferrous iron salts, particularly ferrous sulfate, are widely prescribed because of their well-established hematological efficacy. However, gastrointestinal intolerance is common and represents a major limitation, leading to poor adherence and reduced effectiveness in real-world clinical practice [4-5].
Recent physiological evidence suggests that intermittent oral iron administration may enhance intestinal iron absorption through more favorable hepcidin modulation while reducing gastrointestinal adverse effects. In parallel, innovative formulations such as liposomal iron have been developed to improve iron bioavailability and tolerability. Nevertheless, comparative data addressing both dosing frequency and formulation in the specific postpartum context remain limited [6 – 8].
The aim of this study was to compare the biological efficacy and clinical tolerability of different oral iron formulations and dosing regimens in women with postpartum iron-deficiency anemia.
Study design and setting
This prospective comparative interventional study was conducted in the Department of Gynecology-Obstetrics and Gynecological Endoscopy (M1) at Souissi Maternity Hospital, CHU Ibn Sina, Rabat, in accordance with the ethical principles of the Declaration of Helsinki.
Study population
Women in the immediate postpartum period presenting with iron-deficiency anemia, defined by a hemoglobin concentration between 7 and 10.5 g/dL on postpartum day 1, were eligible for inclusion. Exclusion criteria included severe maternal comorbidities, gastrointestinal disorders affecting iron absorption, and known intolerance to oral iron therapy.
Treatment groups
Participants were assigned to one of four treatment regimens:
• Group A: Ferrous sulfate 80 mg daily
• Group B: Ferrous sulfate 160 mg every other day
• Group C: Liposomal iron 28 mg daily
• Group D: Liposomal iron 56 mg every other day
Outcomes
The primary outcome was the change in hemoglobin concentration between postpartum day 1 and month 3. Secondary outcomes included changes in serum ferritin levels, gastrointestinal tolerability, treatment adherence, and evolution of anemia-related functional symptoms.
Data were analyzed using descriptive and comparative methods. Longitudinal hemoglobin changes were assessed using linear mixed-effects models accounting for repeated measurements. Between-group comparisons of hemoglobin change at month 3 were performed using Welch’s t-tests. Statistical significance was defined as p < 0>
Study population
Participants were distributed across the four treatment groups. Baseline characteristics, including age, hemoglobin concentration, and ferritin levels, were comparable between groups, with no statistically significant differences at inclusion (all p > 0.05).
| Group | Treatment regimen | N | Hemoglobin at day 1 (g/dL), mean ± SD | Ferritin at day 1 (ng/mL), mean ± SD |
| A | Ferrous sulfate 80 mg daily | 100 | ≈ 9.0 ± 0.7 | ≈ 18 ± 6 |
| B | Ferrous sulfate 160 mg every other day | 100 | ≈ 8.9 ± 0.8 | ≈ 19 ± 5 |
| C | Liposomal iron 28 mg daily | 100 | ≈ 9.1 ± 0.6 | ≈ 17 ± 6 |
| D | Liposomal iron 56 mg every other day | 100 | ≈ 9.0 ± 0.7 | ≈ 18 ± 6 |
Table 1: Baseline characteristics of the study population
No statistically significant differences were observed between groups at baseline (ANOVA, p > 0.05).
Hemoglobin evolution
Longitudinal analysis
Hemoglobin evolution from postpartum day 1 to month 1 and month 3 was analyzed using a linear mixed-effects model including time, treatment group, and their interaction as fixed effects, with patient as a random effect.
A significant overall increase in hemoglobin over time was observed across the study population (p < 0>Group Hb day 1 (g/dL) Hb month 1 (g/dL) Hb month 3 (g/dL) ΔHb day 1–month 3 (g/dL) A ≈ 9.0 ≈ 10.3 ≈ 10.7 +1.72 ± 0.6 B ≈ 8.9 ≈ 10.2 ≈ 10.6 +1.68 ± 0.6 C ≈ 9.1 ≈ 11.0 ≈ 11.6 +2.52 ± 0.7 D ≈ 9.0 ≈ 11.1 ≈ 11.7 +2.68 ± 0.7
Table 2: Hemoglobin evolution within each treatment group
Longitudinal analysis using a linear mixed-effects model:
Daily versus alternate-day regimens
In the ferrous sulfate groups, mean hemoglobin change between postpartum day 1 and month 3 was +1.72 g/dL in Group A and +1.68 g/dL in Group B. The mean difference was +0.04 g/dL (95% CI −0.18 to +0.26), with no statistically significant difference (Welch’s t-test, p = 0.706; Hedges’ g = 0.06). (Table 3)
Similarly, in the liposomal iron groups, mean hemoglobin change was +2.52 g/dL in Group C and +2.68 g/dL in Group D. The mean difference was −0.16 g/dL (95% CI −0.41 to +0.09), with no statistically significant difference (Welch’s t-test, p = 0.211; Hedges’ g = −0.18). (Table 3).
| Comparison | ΔHb group 1 (g/dL) | ΔHb group 2 (g/dL) | Mean difference | 95% CI | Test | p-value | Effect size |
| A vs B | +1.72 | +1.68 | +0.04 | [−0.18; +0.26] | Welch’s t-test | 0.706 | Hedges’ g = 0.06 |
| C vs D | +2.52 | +2.68 | −0.16 | [−0.41; +0.09] | Welch’s t-test | 0.211 | Hedges’ g = −0.18 |
| (A+B) vs (C+D) | +1.70 | +2.69 | −0.99 | [−1.12; −0.86] | Welch’s t-test | < 10> | Hedges’ g = −1.23 |
| (A+C) vs (B+D) | +2.12 | +2.20 | −0.08 | [−0.27; +0.11] | Welch’s t-test | 0.412 | Hedges’ g = 0.09 |
Table 3: Planned statistical comparisons of hemoglobin change (day 1–month 3)
These findings indicate that, within the same formulation, alternate-day administration provides hemoglobin increases comparable to daily dosing.
Ferrous sulfate versus liposomal iron
When ferrous sulfate (Groups A+B) was compared with liposomal iron (Groups C+D), mean hemoglobin change at month 3 was +1.70 g/dL and +2.69 g/dL, respectively. The mean difference of −0.99 g/dL favored liposomal iron (95% CI −1.12 to −0.86) and was highly significant (Welch’s t-test, p ≈ 8.7 × 10⁻²⁸; Hedges’ g = −1.23).
Ferritin evolution
Serum ferritin levels increased significantly from postpartum day 1 to month 3 in all treatment groups (effect of time, p < 0 xss=removed xss=removed xss=removed xss=removed>Group Ferritin Day 1 (ng/mL) mean ± SD Ferritin Month 3 (ng/mL) mean ± SD Δ Ferritin (Day 1–Month 3) p-value* A – Ferrous sulfate daily 18 ± 6 45 ± 12 +27 _ B – Ferrous sulfate alternate-day 19 ± 5 44 ± 11 +25 0.61 C – Liposomal iron daily 17 ± 6 58 ± 14 +41 _ D – Liposomal iron alternate-day 18 ± 6 60 ± 15 +42 0.54
Table 4 : Serum ferritin evolution according to treatment group
*p-value: comparison of daily vs alternate-day dosing within the same formulation (Welch’s t-test).
Overall, dosing frequency did not affect ferritin recovery, whereas liposomal iron was associated with greater ferritin repletion than ferrous sulfate (p < 0>
Gastrointestinal tolerability
Gastrointestinal adverse effects were assessed using a composite endpoint including constipation, nausea/vomiting, metallic taste, and appetite disturbances. Adverse effects were more frequent with daily dosing than with alternate-day regimens. Overall comparisons using the chi-square test showed a statistically significant reduction in gastrointestinal adverse effects with alternate-day dosing (p < 0>Table 5 : Gastrointestinal tolerability (composite endpoint)
| Group | Gastrointestinal adverse events, n (%) |
| A | High |
| B | Significantly lower |
| C | Moderate |
| D | Markedly lower |
Table 5 : Gastrointestinal tolerability (composite endpoint)
Global comparison using the chi-square test: p < 0>
Alternate-day regimens were associated with a significant reduction in gastrointestinal adverse events.
Main findings
This prospective comparative study highlights several key findings in the management of postpartum iron-deficiency anemia. First, alternate-day oral iron administration provides hemoglobin correction and iron store replenishment strictly comparable to daily administration, for both ferrous sulfate and liposomal iron. Second, this biological equivalence is accompanied by significantly better gastrointestinal tolerability in patients receiving alternate-day regimens. Finally, liposomal iron formulations were associated with greater hemoglobin improvement at three months compared with conventional ferrous sulfate. (Figure 1).
Figure 1: Mean hemoglobin evolution over time according to treatment group
X-axis: Time (Day 1, Month 1, Month 3)
Y-axis: Mean hemoglobin concentration (g/dL)
Legend:
Quantitatively, differences in hemoglobin change between daily and alternate-day regimens within the same formulation were minimal (≤ 0.2 g/dL), non-significant, and associated with negligible effect sizes, confirming the lack of clinical relevance of these differences and supporting the non-inferiority of alternate-day dosing.
Pathophysiological interpretation: the role of hepcidin
These findings align with current pathophysiological knowledge regarding intestinal iron absorption. Hepcidin, a key hepatic hormone regulating iron homeostasis, plays a central role in determining oral iron bioavailability. Daily iron administration has been shown to induce transient increases in hepcidin levels, thereby reducing iron absorption from subsequent closely spaced doses. [9 – 10] In contrast, alternate-day administration allows hepcidin levels to normalize more rapidly, promoting more efficient iron absorption with each dose. Although this mechanism has been demonstrated mainly in non-pregnant women and women of reproductive age, our study provides original clinical evidence that this theoretical benefit translates into sustained biological efficacy in postpartum women [9 – 10].
Comparison with recent studies on intermittent regimens
Our results are consistent with several recent studies demonstrating that intermittent oral iron regimens achieve hemoglobin increases comparable to daily dosing while significantly reducing gastrointestinal adverse effects. In the postpartum setting, available data remain limited, and current international guidelines still largely recommend daily supplementation due to a lack of specific evidence [9 – 10]. However, emerging observational data suggest improved adherence with less restrictive regimens, which may explain equivalent or even superior real-world effectiveness at medium term. Our study is distinguished by its direct comparison of daily and alternate-day regimens with equivalent cumulative doses and its simultaneous assessment of hemoglobin, ferritin, and tolerability, enabling a comprehensive evaluation of the efficacy–tolerability balance.
Pharmacological differences between ferrous sulfate and liposomal iron
The differences observed between ferrous sulfate and liposomal iron can be explained by distinct pharmacological and physiological mechanisms. Ferrous sulfate is a non-heme ionic iron formulation absorbed mainly via the DMT1 transporter in the duodenum and proximal jejunum. Its absorption is highly influenced by inflammatory status, intestinal pH, dietary inhibitors, and particularly by hepcidin-mediated negative regulation. Repeated daily dosing may therefore limit absorption and promote luminal iron accumulation, contributing to gastrointestinal adverse effects [11].
In contrast, liposomal iron consists of iron pyrophosphate encapsulated within a phospholipid membrane, allowing absorption through alternative mechanisms partially independent of classical iron transporters. This encapsulation protects iron from the acidic intestinal environment and limits direct mucosal contact, thereby reducing local irritation. Experimental studies suggest that liposomal iron may be absorbed via endocytosis or lymphatic pathways, partially escaping hepcidin-mediated regulation [11 – 12].
These mechanisms likely explain why liposomal iron achieved significantly greater hemoglobin increases at three months despite lower elemental iron doses, combined with improved gastrointestinal tolerability. Our findings are consistent with recent clinical studies reporting superior or comparable efficacy of liposomal or sucrosomial iron compared with ferrous salts, particularly in postpartum populations [12 – 13].
Comparison with intravenous iron and clinical positioning
Intravenous iron therapy has been increasingly proposed as an effective alternative for the management of postpartum iron-deficiency anemia, particularly in cases of moderate to severe anemia or poor tolerance to oral iron. A recent systematic review and meta-analysis by Sultan et al. [14] demonstrated that intravenous iron leads to a more rapid increase in hemoglobin levels compared with oral iron, especially within the first weeks postpartum. Similarly, the randomized controlled trial by Bombač Tavčar et al. [15] showed that ferric carboxymaltose resulted in faster hemoglobin recovery than oral ferrous sulfate in postpartum women, with a favorable short-term safety profile.
However, despite its superior speed of correction, intravenous iron requires hospital resources, trained personnel, and carries a risk of infusion-related reactions, limiting its widespread use as a first-line strategy. In contrast, the results of the present study show that optimized oral iron strategies—particularly alternate-day dosing and liposomal formulations—can achieve substantial and clinically meaningful hemoglobin improvements by three months postpartum, with excellent tolerability. While intravenous iron may remain the treatment of choice for severe anemia or when rapid correction is required, our findings support the role of well-tolerated oral iron regimens as an effective and pragmatic option for the majority of women with mild to moderate postpartum anemia. This positions alternate-day oral iron as a valuable intermediary strategy, bridging the gap between conventional daily oral iron and intravenous therapy in routine clinical practice.
Interpretation of ferritin recovery according to dosing frequency and formulation
The finding that dosing frequency did not significantly influence ferritin recovery, whereas liposomal iron resulted in greater iron store repletion than ferrous sulfate, has important physiological and clinical implications. Ferritin reflects cumulative iron storage rather than short-term erythropoietic response, and its recovery primarily depends on the amount of iron effectively absorbed over time rather than the frequency of administration [16 – 17].
Our results suggest that, when the cumulative iron dose is equivalent, alternate-day and daily oral iron regimens deliver a similar net amount of absorbed iron to storage compartments, explaining the comparable ferritin trajectories observed with both dosing strategies.
In contrast, the significantly greater ferritin increase observed with liposomal iron likely reflects its superior bioavailability and more efficient intestinal absorption. Unlike ferrous sulfate, which relies on divalent metal transporter 1 (DMT1) and is strongly regulated by hepcidin, liposomal iron is absorbed through alternative mechanisms that partially bypass classical transport pathways and are less susceptible to hepcidin-mediated inhibition. This allows a greater proportion of administered iron to be absorbed and stored, even at lower elemental doses. Moreover, reduced gastrointestinal irritation with liposomal formulations may further enhance adherence, indirectly contributing to improved iron store repletion [16 – 17].
Together, these findings indicate that while modifying dosing frequency optimizes tolerability without compromising iron storage, the choice of formulation plays a more decisive role in determining the magnitude of ferritin recovery. This distinction supports the use of alternate-day dosing as a tolerability strategy and highlights liposomal iron as a formulation with enhanced potential for restoring iron stores in postpartum iron-deficiency anemia.
Gastrointestinal tolerability and adherence
Gastrointestinal tolerability represents a critical determinant of successful postpartum anemia management. This period is characterized by significant physical, psychological, and social constraints that may limit adherence to treatment. In our study, alternate-day regimens were consistently associated with fewer gastrointestinal adverse effects, regardless of formulation [2-5].
Although adherence was not formally quantified using validated scales, reduced treatment discontinuation due to adverse effects suggests a clinically meaningful benefit of intermittent dosing.
Loss to follow-up and missing data management
As in most prospective real-world postpartum studies, a non-negligible proportion of participants was lost to follow-up, particularly at three months. This is common in the postpartum setting due to logistical, familial, and socio-economic constraints.
To mitigate the impact of missing data, hemoglobin evolution was analyzed using linear mixed-effects models, which incorporate all available observations without restricting analyses to complete cases. This approach is well suited for longitudinal data and strengthens the robustness of the findings. Nonetheless, selection bias cannot be entirely excluded if patients lost to follow-up differed in tolerability or adherence [18; 19].
Study limitations
Several limitations should be acknowledged. The non-randomized design introduces a potential selection bias, although baseline comparability across groups reduces this risk. The absence of hepcidin measurements precludes direct mechanistic confirmation of the observed effects. Adherence assessment relied mainly on indirect and self-reported data, which may introduce measurement bias. Finally, the three-month follow-up does not allow evaluation of long-term outcomes.
Strengths of the study
Despite these limitations, this study has several notable strengths. It employed a prospective design, included a substantial sample size, and compared clinically relevant regimens reflecting real-world practice. The combined evaluation of biological efficacy and tolerability provides a comprehensive assessment of the benefit–risk profile. The use of appropriate longitudinal statistical models further strengthens the methodological rigor.
In women with postpartum iron-deficiency anemia, alternate-day oral iron administration achieves hemoglobin correction and iron store replenishment equivalent to daily dosing while offering superior gastrointestinal tolerability. Liposomal iron formulations provide an additional benefit in terms of overall hematological efficacy while maintaining a favorable safety profile.
In a clinical context where treatment adherence is a key determinant of success, alternate-day oral iron regimens should be considered a preferred therapeutic option for postpartum iron-deficiency anemia. These findings support a re-evaluation of current recommendations and highlight the need for large randomized controlled trials to further define the role of intermittent dosing strategies in this setting.
Conflicts of interest
The authors declare that they have no competing interests.
Sources of funding
There are no funding sources to be declared.
Ethical approval
Ethics approval has been obtained to proceed with the current study.
Consent
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
AS: study concept and design, data collection, data analysis and interpretation, writing the paper. OM: study concept, data collection, data analysis, writing the paper. MA: study concept, data collection, data analysis, writing the paper. AEA: study design, data collection, data interpretation, writing the paper. OE: study design, data collection, data interpretation, writing the paper. ZZ: study design, data collection, data interpretation, writing the paper. SM: study concept, data collection, data analysis, writing the paper. JK: study design, data collection, data interpretation, writing the paper. AB: study design, data collection, data interpretation, writing the paper.
The corresponding author is the guarantor of submission.
Acknowledgements
None.
Availability of data and materials
Supporting material is available if further analysis is needed.
Provenance and peer review
Not commissioned, externally peer-reviewed.
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