Iron deficiency anemia (IDA) is the most common form of anemia, afflicting over two billion people worldwide. It affects mainly infants, children, adolescents, and women of childbearing potential, whether pregnant or not [1-3].

Women who are pregnant or lactating and young children are the most affected, especially in the developing world, but IDA frequently occurs in developed countries as well [1-3]. World Health Organization (WHO) data showed that IDA in pregnant women has a prevalence of 17.4% in industrialized countries, whereas the underdeveloped countries have a 4x higher prevalence [2, 3].

Iron deficiency anemia leads to poor pregnancy outcomes and increases the risk for preterm labor, low-birth-weight babies, and infant mortality [4, 5]. Both iron deficiency (ID) and IDA in pregnant women are associated with increased risks of developing preeclampsia, low birth weight, prematurity, perinatal mortality, delayed fetal maturation, and irreversible compromise to infants’ neurocognitive development and motor capacity [6, 7]. The incidence of IDand IDA in infants born to mothers who are anemic is higher [6, 7]. Animal model studies consistently show that inadequate iron intake during pregnancy would lead to permanent changes in the offspring’s brains (structure and function) [7].

The prevention of ID and IDA in pregnancy in many countries is commonly done with routine iron supplementation (IS), once the iron obtained from diet fails to reach the recommended daily intake levels [8, 9].

The Centers for Disease Control and Prevention (CDC) recommends that all pregnant women should begin with a 30 mg/d iron supplement at the first prenatal visit, whereas the WHO suggests a dosage of 60 mg/d for all pregnant women [10-13].

The equivalent of 60 mg of elemental iron is 300 mg ferrous sulfate heptahydrate, 180 mg ferrous fumarate or 500 mg of ferrous gluconate. In the first and third trimesters, the hemoglobin (Hb) threshold for diagnosing anemia is 110 g/L; in the second trimester, the threshold is 105 g/L. If a woman is diagnosed with anemia during pregnancy, her daily elemental iron should be increased to 120 mg until her Hb concentration rises to normal. Later, she can resume the standard daily antenatal iron uptake in order to prevent recurrence of anemia (WHO, iron and folate supplementation) [2, 10, 14].

Iron protein acetyl aspartilate, a ferroprotein complex containing 5% trivalent iron bound to sucrose casein, is a product of long-term research and of multiple clinical studies. It is more efficient versus iron protein succinylate in relatively short periods of time, for example 30 days. [15] Also, it achieves a higher increase in hemoglobin and iron levels into the serum, compared to iron protein succinylate [15].

The aim of this clinical study was to investigate the efficacy of acetyl aspartate iron protein supplement in the treatment of anemia in pregnant women after the first trimester. This is the first real-time clinical study testing the usage of an iron protein supplement in a specific population, as there are not sufficient data for such studies in the literature. Eligible women attending antenatal clinics as outpatients of the Second Obstetrics Clinic of Hippokrateio Hospital in Thessaloniki, were enrolled according to the protocol approved by the Research Ethics Committee.

Sixty-three pregnant women aged 21 to 39 years (mean 30.56 ± 4.78 years) consecutively presenting in outpatient clinic were enrolled in the study, with hemoglobin <10.5 gr/dL at the completion of 12 weeks of pregnancy. They began a 3-6 month treatment with different iron supplements in a daily dose yielding 80 mg of elemental iron in two daily shots. According to the minimum sample size calculation method, the annual population of pregnant women is estimated to be about 88,533, while the pregnant women presenting with anemia are approximately 18,000 (18% of pregnant women); so the authors used a confidence interval of 12 and a confidence level of 95% in this study. Inclusion criteria were: age ≥ 18 years, gestational week ≥ 12, Hb ≤ 1 0.5 gr/dL, and Ht ≤ 32%. Exclusion criteria were: age < 18 years, absence of registration consent, step of pregnancy less than 12 weeks, coadministration formulations iron oral or parenterally, background of liver cirrhosis, background of aimosidirosis, background acquired or chronic aimatochromatosis, aplastic, hemolytic anemia and chronic diseases, chronic pancreatitis, subjective renal and/or liver disease, hypothyroidism or hyperthyroidism. The study took place from January 2015 to December 2017 and was approved by the medical ethics committee of Hippokratio General Hospital, University of Thessaloniki; the study code was NCT02957643.

Twenty-eight pregnant women, were treated with acetyl aspartate protein iron supplement (Omalin trademark) at a twice daily dose yielding 80 mg of elemental iron (study group), while 35 women received different iron supplements (as ferrus sulfate, ferrous fumarate, and ferrus gluconate) at the same daily dose (control group). Upon giving consent to participate in this study, patients were allocated into the two groups randomly and were very strictly enrolled according to all inclusion and exclusion criteria.

According to the study protocol, the treatment duration was four weeks, and Hb values were remeasured with a hematologic analyzer. The treatment effects were tested by comparing between the two groups: a) the Hb levels after treatment b) the increase in Hb level, and finally c) the percentage of Hb increment in relation to the initial measurement.

Consent forms were used, and the study was approved by the hospital’s scientific council. Randomization was based on a single or even number, as derived from the sum of the first five digits of patient’s social security number.

Statistical analysis was performed by the Kruskal-Wallis test using the SAS for 9.4 software platform. The significance level (p-value) was set at 0.05. For completeness, the descriptive statistics are reported as mean ± SD (standard deviation and median value).

The descriptive statistics between the treatment and control group are presented in Table 1. There was no statistically significant difference in terms of age, parity, week of gestation, and Hb levels between the two groups (p > 0.05 in all cases).

Treatment with acetyl aspartylated iron led to higher levels of Hb after four weeks of treatment. Following successive measurements of Hb levels in the 28 women of the study group, the levels increased from an initial mean value of 10.04 gr/dL to 10.69 gr/dL. In the control group of 35 pregnant women, an increase in the mean Hb was observed from 9.99 gr/dL to 10.46 gr/dL. The difference was statistically significant with p < 0.0001. The increment in the treatment group was 0.65 ± 0.17, while for the control group it was 0.47 ± 0.06 (p < 0.0001). While comparing the increment as a percentage in relation to initial Hb levels, it was found that for the treatment group, the increment percentage was 6.47% ± 1.84% while in the control group it was 4.71% ± 0.64% (p < 0.0001). Results are presented in Table 2 and Figure 1.

Figure 1.

— Box and whisker plots for the treatment and control groups.

Considering that the increment in Hb level was on a fourweek basis, it was calculated that on average, the treatment group had increased by 0.65/4 = 0.1625 units per week, while the control group had an increment of 0.47/4 = 0.1175 units/week. At this rate, the control group would require 5.5 weeks (1.5 additional weeks) to reach similar Hb levels. This additional time, especially if iron supplements should be provided for longer time periods, may be eventually, important for fetal development and women’s health. In both groups, no specific side effects were recorded and treatment was well tolerated.

Iron deficiency accounts for 75% of cases of anemia in pregnancy. The most common clinical manifestations of iron deficiency include epigastric pain, fatigue, tachycardia, constipation, diarrhea, dyspepsia, suboptimal work performance, postpartum depression, impaired lactation, low birth weight, premature delivery, intrauterine growth retardation, and increased fetal and neonatal mortality [16-19]. During pregnancy, the total maternal need for extra iron averages close to 1,190 mg, with a net iron balance during pregnancy of 580 mg, equating to a requirement of 2 mg daily. The fetus acquires about 280 mg of iron and a further 400-500 mg is required for the temporary expansion of maternal red cell mass. Another 200 mg of iron is lost with the placenta and with bleeding at delivery. The placental and fetal requirement is obligatory, though even with an iron-rich diet, this is difficult for the mother to maintain [20-22].

Current recommendations suggest that pregnant women should receive 15-30 mg daily of supplemental elemental iron. Nevertheless, it is not certain that the use of iron supplementation during pregnancy has a clear benefit in pregnancy outcomes. Much of the reportedly poor compliance with oral iron therapy is due to the associated side effects. Moreover, the increase in the number of tablets that are required daily is also prone to invite noncompliance. Therefore, a single daily dose of iron supplementation may be preferred. Ferrous gluconate is better tolerated due to fewer gastrointestinal effects than ferrous sulfate. For women who do not tolerate oral iron, parenteral iron may be used [21-23].

The main characteristic of the new iron protein compared complex with iron protein acetyl-aspartilate is that it is well absorbed by the gastric mucosa and does not irritate the gastric mucosa. This makes it a better choice for oral iron supplementation compared to ferrous sulfate, considering that it has an improved compliance in treatment and it well-tolerated by patients, avoiding most of the adverse effects of oral iron supplementations. The efficacy of iron protein acetyl-aspartilate compared to iron gluconate is similar. Both treatments have shown improvements in clinical and hematological parameters including significant increases in Hb and serum iron levels [24].

Dose-response studies demonstrated that 80 mg of iron protein acetyl-aspartilate is able to elicit an extremely rapid increase in serum iron levels. Iron protein acetyl-aspartilate is more effective than iron protein succinylate during short time periods. Also, iron protein acetyl-aspartilate achieves a larger increase in Hb and serum iron levels, compared to iron protein succinylate [24].

The present study showed that there was a statistically significant difference between the 28 women receiving acetyl aspartate protein iron and the 35 pregnant women receiving different iron preparations, in the one-month increase in Hb values compared to the initial mean Hb value (p < 0.0001). These findings are in line with other clinical studies, where acetyl aspartate protein iron was good or satisfactory in 97.9% of cases compared with 84.6% of reference drug cases, in pregnant population, and other populations with iron deficiency like pediatric, geriatric, and post-hemorrhagic patients [15, 24-31].

In conclusion, the proposed twice-daily dosage of 40 mg iron protein acetyl-aspartilate seems to significantly improve the hematologic parameters of anemia in a short period of time. This dosing regimen has a favorable risk-benefit relationship and is both statistically and clinically effective. These findings are in accordance with other clinical studies [24]. Nevertheless, larger clinical studies are required to prove that acetyl aspartate protein iron is more tolerable and efficient compared with IPS.

This is the first real-time clinical study testing the use of an iron protein supplement in a specific population, demonstrating that the use of acetyl aspartate iron protein is a very suitable option, as there has been a significant increase in Hb levels.

Clinical Trials.gov, ID: NCT02957643. Registered on 10 December 2016.

The authors appreciate the participation of all the study participants from Greece.

The authors declare no competing interests.