Iron deficiency is a public health problem, being one of the most common micronutrient deficiencies in the general population(1). Globally, disproportionately affecting women compared to men, one in four people is anemic, according to estimates(2). The prevalence of anemia follows an upward trend, according to the World Health Organization, reaching up to 30% among non-pregnant women, compared to 42% among pregnant women(1,2). This number is strongly influenced by economic factors, varying between 20% and 90%, depending on the population studied(3).
Among the causative factors of iron-deficiency anemia in the case of women of reproductive age, poor nutrition (vegetarian diets, low socioeconomic level), as well as a number of chronic diseases are found in most cases(4). Heavy bleeding during puberty or due to gynecological conditions also increases the risk of developing iron deficiency anemia(5). At the same time, recent studies describe obesity as a risk factor in the occurrence of iron deficiency, leading to a decrease in its absorption through a mechanism related to excess adipose tissue(6).
1. Importance of the issue
Iron deficiency anemia can affect daily life, leading to low energy levels, memory impairment and delays in cognitive development, while increasing maternal-fetal risk in the context of pregnancy(5,6). Thus, although it is recognized as one of the most important public health issues, the solution is slow to appear, as increased efforts are needed to counteract the predisposing factors, even more so in risk groups (children, women of reproductive age, pregnant women, as well as those who are breastfeeding)(4).
Considering the frequency with which iron deficiency anemia occurs among pregnant women, the need to correct the low hemoglobin levels derives from the adverse effects they have on the woman, the fetus and the pregnancy itself(7). In developing countries, the trend consists in the appearance of menarche in already anemic adolescent girls, an iron deficiency that is not corrected with nutrition due to low resources or lack of awareness of the problem, a sustained deficiency until the moment of pregnancy, leading to maternal-fetal complications(8). These can range from fatigue concerning the mother, to premature birth or low birth weight in the case of the fetus(4).
2. Investigation of anemia in pregnancy
2.2 Iron homeostasis and pathophysiology. Causes of iron deficiency
Iron is the most abundant trace element present in the human body. Thus, its most important role is to participate in the formation of hemoglobin, the latter being an essential protein in the transport of oxygen to tissues(9).
In food, it is found in two forms: heme and non-heme iron. Heme iron comes from the splitting of myoglobin and hemoglobin from animal protein, having a total absorption of approximately 40%, while non-heme iron has a reduced bioavailability, its absorption being inhibited by certain compounds, such as phytates or polyphenols(10).
In pregnancy, red cell mass increases by up to 25%, while plasma volume increases by 50%, thus physiologically there is a decrease in hemoglobin concentration. Moreover, there is an additional loss associated with pregnancy and lactation of about 1 g per day (at a weight of 55 kg)(11). The iron required for fetal and placental development, totaling an estimated 250 mg, is actively transported from the mother to the fetus, via the placenta(10,11). In the last trimester of pregnancy, about 5.6 mg of maternal iron passes transplacentally daily, six times more than its intestinal absorption capacity from food outside of pregnancy and up to 30% of the 20 mg of iron obtained through the catabolism of senescent red blood cells(12).
Iron requirements range from 0.8 mg iron per day in the first trimester to an estimated 7.5 mg per day toward the end of pregnancy, with an estimated total of 1240 mg throughout pregnancy. Postpartum, the erythrocyte mass is reduced to the pre-pregnancy level and the iron in the hemoglobin is reused to restore the maternal stores(13).
With a reduced frequency compared to iron deficiency, there are other causes of anemia that can be diagnosed through prenatal investigations or during pregnancy exacerbations. They can have a genetic component (thalassemia, sickle cell disease), they can can be caused by micronutrient deficiencies (folate deficiency, vitamin B12 deficiency) or in chronic pathologies (infectious, autoimmune or inflammatory)(4).
2.2 Clinical manifestations of iron deficiency
Anemia in pregnancy can manifest itself in different ways, having, in mild deficits, a nonspecific character. Thus, the symptomatology can have the character of fatigue, asthenia, dizziness, headache, palpitations or a feeling of general discomfort, manifestations that can easily be attributed to the state of pregnancy(4,11). In certain cases, iron deficiency can lead to specific impairment, such as reduced cognitive abilities, emotional instability or restless legs syndrome(4). Pagophagia, a specific variant of Pica syndrome, manifested by ice ingestion, has a specificity of 95% for iron deficiency anemia in women, which can occur in severe cases(11).
2.3 Screening for anemia in pregnancy
In current practice, there are a series of serum biomarkers used in the diagnosis of anemia and in the assessment of maternal iron stores throughout pregnancy, such as hemoglobin, hematocrit, but also serum ferritin or the soluble receptor for transferrin(12). Because of the physiological hemodilution present in pregnancy, these factors reduce their concentration independently of iron deficiency, except for iron binding capacity which increases its capacity by up to 50%. Consequently, there are an increase in the plasma transferrin concentration and a decrease in the transferrin saturation coefficient. Studies recommend the concentration of serum transferrin receptors as a method of differential diagnosis between the physiological changes of pregnancy and iron deficiency anemia(8).
In Romania, the guidelines recommend measuring hemoglobin on the occasion of taking into account the pregnant woman, at 28 weeks of pregnancy or whenever symptoms appear that suggest the onset of anemia. The dosage of serum ferritin, a reliable marker of iron stores, is recommended in selected cases, such as women at risk of iron deficiency (adolescents, multiparous, twin pregnancies, pregnancies less than one year apart) or women in whom the evaluation of iron deposits is necessary (patients with hemoglobinopathies or those at risk for plurifactorial anemia)(14).
The cut-off values of the serological markers of anemia vary depending on the trimester of pregnancy, but also on demographic factors such as race, environment or tobacco use(12). The World Health Organization has established a threshold value of 11 g/dL (110 g/L) hemoglobin in establishing the diagnosis of anemia. It also defines the values between 10 and 10.9 g/dL as a mild form, the range 7-9.9 g/dL as moderate anemia, and values below 7 g/dL are described as severe anemia(15).
2.4 Impact of anemia on the mother
Iron deficiency alone or associated with iron deficiency anemia is a factor known to be a major component in increasing morbidity and mortality in pregnant women(1). Among the maternal effects of iron deficiency in pregnancy, we can list placental apoplexy, endocrine gland imbalances such as thyroid function disorders, preeclampsia, eclampsia and an increase in the rate of caesarean delivery(11).
Studies have shown that a decrease in hemoglobin in the first trimester of pregnancy leads to an increase in the risk of placental abruption up to 3.6 times higher than in pregnancies in physiological parameters. Also, a relative risk of developing severe hemorrhage in the postpartum period between 1.45 and 15.65 has been demonstrated, depending on the severity of the anemia(1). Additionally, there is an increase in the relative risk of up to 7.66 times of performing a hemostatic hysterectomy in the context of postpartum hemorrhage, the occurrence of hemorrhagic shock and hospitalization in the intensive care unit(11).
Data from the literature suggest a significant increase in the development of postpartum depression in patients with iron deficiency anemia during pregnancy(11). Although the pathophysiology of the disorder is not fully elucidated, one factor appears to be represented by altered neurotransmitters amid decreased hemoglobin, changes that lead to altered cellular, oxidative and thyroid hormone metabolism. Also, the decrease in inflammatory cytokines such as interleukin 2 as a cause of anemia seems to influence the development of postnatal depression(16).
2.5 Impact of anemia on the fetus
In pregnancy, the need for iron increases exponentially to support the expansion of plasma volume, being essential in fetal and placental development. Thus, low iron stores in pregnancy increase the risk of fetal and neonatal iron deficiency anemia(17).
Regarding pregnancy prognosis, iron deficiency is associated with low birth weight, small-for-gestational-age babies and with preterm delivery. Studies have shown a twofold higher risk of preterm birth in women with moderate anemia and a threefold higher risk in those with severe anemia(13,18).
In utero, the greatest amount of iron is transferred to the fetus in the third trimester of pregnancy to support the rapid growth rate in the first 4-6 months postpartum(19). This process occurs through an increase in placental iron receptors to ensure optimal intake, even in the case of insufficient maternal iron stores(19). Despite these mechanisms, recent data in the literature demonstrate that newborns of anemic mothers will also have iron deficiencies from birth, this being associated in the long term with cognitive deficits and with behavioral disorders(12).
3. Anemia in the postpartum period
Anemia in the postpartum period occurs relatively frequently, the main cause being iron deficiency. It has been proven that 30% of patients have a hemoglobin value below 10 g/dL in the postpartum period, 10% of them having a value below 8 g/dL(20). This value is multifactorially influenced, being mainly given by the loss of deposits due to the increased need for iron during pregnancy, the blood loss from the moment of birth, but also by the rapid return to normal values of the mother’s plasma volume(2,20).
In the case of vaginal, peripartum and immediate postpartum births, an average loss of approximately 500 ml of blood is accepted. However, approximately 5% of vaginal births can result in a hemorrhage of up to 1000 ml of blood volume, with hemodynamic repercussions and consequences regarding iron stores(2). Thus, a blood loss between 500 and 1000 ml increases the risk of anemia up to 15 times, following that a loss of 1000 ml increases the risk of postpartum anemic syndrome by 75 times(21). High obstetric risk pregnancies complicated by placenta praevia have a five times higher risk of developing anemia during pregnancy and after birth(21).
4. Iron deficiency treatment
During pregnancy, the iron requirement of women increases up to three times compared to that of a woman who has physiological menstruation, reaching up to 6 mg of iron daily(19). Thus, recent studies encourage a diet rich in foods that are concentrated in iron, especially heme iron (mainly from animal sources) which has been shown to have superior absorption compared to non-heme iron (from plant sources)(12). However, approximately 95% of dietary iron is non-heme iron(19). Ideally, pregnant women should be informed and educated about the appropriate sources of dietary iron and the micronutrients that enhance or inhibit iron absorption and bioavailability, so as to support the increased requirement of pregnancy(19).
In addition to a balanced diet, in the context of the increased need for iron, data from specialized literature suggest the need for oral supplementation with iron preparations in case of pregnant women(12). An updated study published by Cochrane shows a reduced risk of developing anemia and improved serum hemoglobin levels in patients who have daily or intermittent oral supplementation with oral iron preparations(22).
In order to prevent iron-deficiency anemia, the recommendation of the World Health Organization is to supplement with 30-60 mg of elemental iron, along with 0.4 mg of folic acid administered daily, having an effective preventive effect on premature birth or low birth weight. In the case of pregnant women diagnosed with iron deficiency anemia, it is recommended to increase the dose to 120 mg of elemental iron daily(23).
The disadvantage of the administration of oral preparations is represented by the high frequency of adverse effects, such as gastrointestinal disorders, nausea or constipation that systematically decrease patients’ compliance(12). One solution would be the intermittent administration of an increased dose of iron, such as 120 mg of elemental iron once weekly, with the caveat that the applicability of this regimen is limited to populations with low anemia frequency(23).
In the case of complete intolerance to oral administration or in severe anemias, preoperatively or before the moment of birth, but also in the case of insufficient change in biological parameters after the administration of oral iron supplements, there is the possibility of intravenous iron administration(24). Studies have shown a net increase in ferritin and hemoglobin levels comparing parenteral to oral administration, demonstrating up to a 22-fold increase in ferritin(25). Despite the effectiveness of intravenous treatment with iron supplements, its administration is not considered to be the first choice, being limited by the increased risk of allergic reactions, sometimes even anaphylactic shock(26).
Iron deficiency continues to be a real public health problem, despite numerous attempts to combat this condition. Among the most affected categories are women, especially during pregnancy, due to the increased need of iron for fetoplacental support. Anemia in pregnancy can have consequences for both the mother and the newborn. Thus, the mother may suffer from nonspecific symptoms such as asthenia, memory or concentration disorders up to reduced cognitive abilities or emotional instability. Regarding pregnancy, studies have shown a significantly increased risk of placental apoplexy, as well as an increased probability of developing postpartum hemorrhage, which may lead to hemostatic hysterectomy with prolonged hospitalization in the intensive care unit. Maternal iron deficiency anemia has been shown to be a risk factor for anemia in the newborn, despite placental mechanisms designed to prevent this. Thus, newborns from anemic mothers have an increased risk of low birth weight, low weight for gestational age, but also a risk of premature birth, subsequently developing cognitive and behavioral difficulties, according to the specialized literature. For a better understanding of the long-term effects of anemia, there is a need for extensive prospective studies that provide a proper follow-up of newborns with iron deficiency anemia that also offer the option of correcting nutritional deficits. Thus, in the fight against anemia, extensive campaigns to combat subsistence and lack of nutrition education are needed, sustained over a sufficiently long period of time to succeed in maintaining the serum iron levels at an optimal level within the groups considered at risk (children, women of reproductive age, pregnant or lactating women).
Conflict of interests: The authors declare no conflict of interests.