Sucrosomial® iron effectiveness in recovering from mild and moderate iron-deficiency anemia in the postpartum period

In the postpartum period, both iron deficiency (PPID) and iron deficiency anemia (PPIDA) are common and represent significant health problems in women of reproductive age [1]. In a series of 43,807 women who gave birth between 1993 and 2008 in Germany, the prevalence of PPA (hemoglobin [Hb] < 10 g/dL) 24–48 h after delivery was 22%. This prevalence increased up to 50% when PPA was defined as Hb < 11 g/dL [2]. In developing countries, the prevalence of PPA is in the range of 50–80% and, together with postpartum hemorrhage represents a major cause of maternal morbidity and mortality [1].

PPIDA leads to prolonged hospital stay, impaired quality of life, reduced cognitive abilities, emotional instability, and depression [3‐5]. In addition to anemia, ID has other manifestations, such as tiredness, hair loss, and restless legs [6]. However, the importance of PPIDA seems to be overlooked by both obstetricians and patients, even after severe postpartum hemorrhage [1, 7].

Therefore, the most frequent predisposing factors (placenta previa [OR 4.7], anemia during pregnancy [OR 2.7], multiple birth [OR 2.2], and blood loss > 1000 mL [OR 74.7]) [2] should be identified and modified when possible. Additionally, routine PPIDA screening should be considered, especially in women with antenatal ID/IDA and/or significant peripartum bleeding, in order to provide early and appropriate treatment [1].

As for women with mild-to-moderate anaemia postpartum who are haemodynamically stable, asymptomatic, or mildly symptomatic, daily administration of oral ferrous iron salts for three months has been recommend [1]. However, absorption and tolerance should be taken into account: 1) Up to 50–70% of patients on oral iron sulfate experience gastrointestinal side effects due to exposure to unabsorbed iron; 2) Co-administration of oral iron with food or drugs (e.g., antacids, proton pump inhibitors) may drastically reduce iron absorption; 3) In addition, hepcidin is up-regulated when a high iron dose is ingested, which may reduce the absorption of the next oral iron dose [8]. Thus, whenever possible, Hb concentration should be determined after 2–4 weeks of treatment initiation. For those with confirmed ID and lack of responsiveness or intolerance to oral iron, intravenous treatment was the recommended treatment alternative [1].

Sucrosomial® iron (SI, Pharmanutra, S.p.A., Italy) is a newer oral iron formulation consisting of a ferric pyrophosphate covered by phospholipids and sucrester matrix. The absorption of SI is mostly hepcidin-independent, as is taken up in the lymphatic circulation through transcellular and M cell-mediated endocytosis routes [9]. Oral SI has been shown to be safe and efficacious for treating ID and IDA in a variety of clinical scenarios [9].

As oral SI has been shown efficacious and well tolerated in the prophylaxis of pregnancy-associated ID and IDA [10], and preliminary data suggested its efficacy in PPIDA [11], this non-comparative pilot study aimed to investigate whether supplementation with SI was efficacious at correcting mild or moderate PPIDA (as measured by significant improvement in hemoglobin levels over time for each group when compared to baseline levels; primary outcome) and improving PPIDA-associated subjective symptoms (as measured by a 3-point Likert scale; secondary outcome).

Seventy-three consecutive women presenting with mild or moderate postpartum anemia were approached for recruitment. Thirteen were excluded because they had non-ID anemia. The remaining 60 women (30 with mild anemia, Group A; 30 with moderate anemia, Group B) were enrolled in the study (Fig. 1). As shown in Table 1, there were no differences in demographic and baseline clinical characteristics between the two groups of subjects.

Patients’ disposition and follow-up are depicted in Fig. 1. Three patients from group A discontinued iron supplementation or were lost during follow-up. The first one developed infectious mastitis (not related to iron treatment) and declined to continue treatment after T1, the second was advised externally to discontinue treatment before T1, and the third did not attend the follow-up visits. Finally, 57 patients (27 in Group A and 30 in Group B) completed the 60-days follow-up program and were included in the data analysis. No patient discontinued treatment due to gastrointestinal adverse events.

Iron replacement therapy with oral Sucrosomial® iron led to improvement in laboratory parameters in both study groups (Table 2). For the entire study sample (n = 57), Hb concentration increased from 9.2 ± 1.0 g/dL at T0 to 12.8 ± 1.0 at T60 (mean Hb increment: 3.6 ± 1.5 g/dL; p < 0.01) (Fig. 2A), and 81% of patients experienced correction of anemia (Hb ≥ 12 g/dL) (Fig. 2B). For women still anemic at day 60, the mean Hb was close to normal (11.3 ± 0.8 g/dL). CRP concentrations abruptly decreases from T0 to T10, remaining low thereafter (Table 2A). There was a progressive increase in the percentage of women attaining a ferritin concentration ≥ 30 ng/mL (p < 0.05) and/or a TSAT value ≥ 20% (p < 0.01) from T0 to T60 (Table 2A). However, as there were two different iron supplementation schedule according to anemia severity, these changes were analyzed separately for women presenting with mild (Group A) or moderate (Group B) PPIDA.

In Group A, mean Hb concentration at T0 was 10.1 ± 0.4 g/dL. The daily administration of 30 mg elemental iron for 60 days resulted in a mean Hb increment of 2.7 ± 0.9 g/dL from T0 to T60 (p < 0.01), leading to normalization of the mean Hb concentration at T60 (12.7 ± 0.8 g/dL; p < 0.01) (Fig. 2A). This led to anemia correction in 25 out of 27 women (93%) in this group (Fig. 2B). For the 2 women who were still anemic at T60, their Hb concentrations were close to normal (10.9 and 11.5 g/dL).

There were no significant changes in ferritin concentration throughout the study period or in the percentage of patients achieving a normal ferritin concentration (≥ 30 ng/mL) (Table 2B). However, the TSAT significantly increased throughout the study period from T10 onwards, as did the percentage of patients achieving a TSAT ≥ 20% (Table 2B).

In Group B, the mean Hb concentration at T0 was 8.4 ± 0.6 g/dL. The administration of 60 mg elemental iron/day from T0 to T10, followed by 30 mg/day from T10 to T60, resulted in a mean Hb increment of 4.4 ± 1.5 g/dL from T0 to T60 (p < 0.01), leading to normalization of the mean Hb concentration a T60 (12.8 ± 1.2 g/dL; p < 0.01) (Fig. 2A). This led to anemia correction in 21 out of 30 women (70%) in this group (Fig. 2B). For the 9 women who were still anemic at T60, the mean Hb concentration was close to normal (11.3 ± 0.8 g/dL).

Again, there were no significant changes in ferritin concentration throughout the study period or in the percentage of patients achieving a normal ferritin concentration (≥ 30 ng/mL) (Table 2C). However, the TSAT significantly increased throughout the study period from T10 onwards, as did the percentage of patients achieving a TSAT ≥ 20% (Table 2C).

Remarkably, the beneficial effects of replacement therapy with oral Sucrosomial® iron on both Hb increment (Fig. 2A) and anemia correction (Fig. 2B) were observed as early as 10 day after treatment initiation. This rapid effect of Sucrosomial® iron administration had an impact on clinical symptoms associated with mild and moderate PPIDA. As shown in Fig. 3, there is a clear trend towards improvement in the time-course of all clinical symptoms in both mild IDA (black bars) and moderate IDA (grey bars). From day 10 onwards, there were no clinically relevant symptoms in either group.

Iron supplementation has been proven to be effective in increasing hemoglobin levels in pregnant and postpartum women, and it has been suggested as a public health solution to improve maternal and child health outcomes across different age groups [14, 15].

In this pilot study, we demonstrated that replacement therapy with Sucrosomial® iron, an innovative oral formulation, was well tolerated (no woman discontinued treatment due to gastrointestinal adverse events) and potentially effective in treating mild and moderate PPIDA. Mean Hb increment was 3.6 ± 1.5 g/dL, and 81% of patients achieved Hb levels of ≥ 12 g/dL at the end of the treatment period. These results are comparable to those obtained 6–24 weeks after the administration of intravenous iron to women with moderate PPIDA (mean Hb increment, 3.8 g/dL; anemia correction, 88%; n = 658) [16‐19].

It has been argued that intravenous iron administration to women with moderate PPIDA results in a faster increase in Hb levels compared to oral iron (ferrous sulfate). However, in moderate IDA, the Hb increment (2.4 ± 0.9 g/dL) observed after 10 days of iron replacement therapy with Sucrosomial® iron (60 mg/day, Hb in) was similar to those observed 2 weeks after intravenous iron administration (2.2 g/dL – 3.2 g/dL) [17, 20‐23], which is reflected in the rapid improvement of clinical symptoms (Fig. 3). These effects of Sucrosomial® iron on quality of life have also been observed in heart failure patients with reduced ejection fraction and iron deficiency [24].

As mentioned erlier, Sucrosomial® iron absorption is mostly hepcidin-independent, as it is taken up to the lymphatic circulation through transcellular and M cell-mediated endocytosis routes [9]. This gives Sucrosomial® iron the ability to increase Hb levels, even in the presence of inflammation, as demonstrated in cardiac surgery [25, 26] and in patients with chronic kidney disease [27], cancer [28] or inflammatory bowel disease [29, 30]. Notably, the efficacy of Sucrosomial® iron is observed at much lower dose and with fewer gastrointestinal adverse events compared to oral iron sulfate.

Furthermore, the difference in Hb increment between the study groups at T10 also suggests a correlation between the dose used (60 mg/day vs. 30 mg/day) and the speed of Hb recovery. As endogenous erythropoietin production is higher at low Hb concentrations, a higher initial oral Sucrosomial® iron dose may result in a faster recovery from PPIDA. Subsequently, the dose could be reduced to ensure adequate iron supply to the bone marrow. In this regard, Giordano et al. (2021) [14] recently demonstrated the efficacy and tolerability of high-dose oral Sucrosomial® iron (120 mg elemental iron/day) for 4 weeks, compared to intravenous ferric gluconate, in severe IDA patients intolerant/refractory to iron sulfate.

With regards to iron biomarkers, the accurate assessment of the actual effect of Sucrosomial® iron on the improvement of ferritin and TSAT levels was hampered by the influence of inflammation on the levels of these biomarkers at T0 [31]. Therefore, instead of evaluating the differences between T0 and T60, we assessed the percentage of patients presenting with ferritin and TSAT levels above their thresholds for defining ID at T60, when no inflammation is present.

A serum ferritin level < 30 ng/mL is the most sensitive (92%) and specific (98%) cut-off level for the identification of true ID (with or with-out anaemia) and a TSAT < 20% is insufficient to meet the iron requirements for erythropoiesis [32]. In our study, 45% of the patients achieved a TSAT level within the normal range (≥ 20%), and 36% achieved a ferritin level within the normal range (≥ 30 ng/mL) at T60. We used these thresholds in accordance with current guidelines for the diagnosis of ID [1, 5, 33], although more conservative thresholds are generally used in women (12–18 ng/mL for ferritin, and 15% for TSAT).

Moreover, as mean ferritin levels remained largely unchanged at T60, it can be inferred that the absorbed iron was mainly utilized for erythropoiesis and other physiological functions, such as energy production, rather than for building up iron stores. Therefore, Sucrosomial® iron replacement should be extended, at least, up to the third month of the postpartum period to replenish iron stores, as recommended in guidelines [5].

This research has several limitations. Firstly, it is a study pilot, and there is no control group of untreated patients. The lack of a control group is acknowledged as a study limitation, and it represents a shortcoming. However, it is also noteworthy that leaving a proportion of PPIDA untreated is not appropriate as it poses a risk to both the mother's health and the newborn's care. Therefore, it was decided that all participants would receive treatment. Secondly, compared to previous studies, our study had a limited follow-up time and a relatively small sample size, which may result in diminished predictive capacity, limited value for demographic variables, and lower implication in conclusions. We acknowledge the value of undertaking broader and longer trials on various cohorts of postpartum anemia women to validate our results. However, the demonstrated effectiveness of Sucrosomial® iron and the absence of associated gastrointestinal side effect in a difficult-to-treat population may have significance in clinical practice [30, 33, 34]. In particular, commitment to therapy remains a core determinant of positive health outcomes for postpartum women in need of iron supplementation. We assume that Sucrosomial® iron has the potential to enhance adherence to iron supplementation in postpartum women.

This pilot study provides preliminary evidence supporting the potential effectiveness of Sucrosomial® iron in the treatment of mild and/or moderate postpartum IDA in women. The results indicate a significant increase in hemoglobin levels in both groups, observed as early as 10 days after treatment initiation. While the study has limitations due to the absence of a control group and a limited sample size, these findings warrant further investigation in larger and longer-term trials. Sucrosomial® iron may represent a promising alternative for the treatment of PPIDA, and future studies should aim to compare its efficacy and safety with standard iron supplementation protocols.