Abstract
Anemia is the most frequent derailment of physiology in the world throughout the life of a woman. It is a serious condition in countries that are industrialized and in countries with poor resources. The main purpose of this manuscript is to give the right concern of anemia in pregnancy. The most common causes of anemia are poor nutrition, iron deficiencies, micronutrients deficiencies including folic acid, vitamin A and vitamin B12, diseases like malaria, hookworm infestation and schistosomiasis, HIV infection and genetically inherited hemoglobinopathies such as thalassemia. Depending on the severity and duration of anemia and the stage of gestation, there could be different adverse effects including low birth weight and preterm delivery. Treatment of mild anemia prevents more severe forms of anemia, strictly associated with increased risk of fetal–maternal mortality and morbidity.
Anemia is the most frequent derailment of physiology in the world throughout the life of a woman. It is a serious condition in industrialized and semi-industrialized countries and it becomes a very serious condition in poor resources countries. Anemia is a major public health problem, causing an unfavorable status in respect to upcoming pregnancy. Among fertile, nonpregnant women, approximately 40% have low iron reserves [1].
Anemia is one of the world's leading cause of disability and thus one of the most serious global public health issues. In fact, it involves issues of morbidity and mortality, but it can be mostly the basis of the inability of the woman to react to a postpartum blood loss thus leading to serious consequences [2].
The main purpose of this manuscript is to give the right concern for anemia in pregnancy. The authors reviewed literature about anemia during gestation, providing updated and clear guidelines for the prevention and treatment of this condition, which, if not adequately treated, could lead to severe maternal and perinatal complications.
The authors tried to select recent articles about anemia in pregnancy from the database PubMed, whereas other data have been selected from international guidelines, such as WHO or CDC, in order to give updated information about this disorder. Most of these articles and guidelines have been released in the last five years. However, we also included some older studies, which seemed to be essential for describing completely the disease.
Following a complete review of literature, the authors enclose in this work risks associated with this disorder, all available diagnostic tools, different treatments and reasons why iron deficiency anemia should be prevented and treated.
Definition
Anemia is defined as the reduction in absolute number of circulating red blood cells (RBC)s, indirectly measured by a reduction in hemoglobin (Hb) concentration, hematocrit (Hct) or RBC count. WHO has defined it as Hb of <11 g/dl but, during pregnancy [3], definition of anemia is different depending on trimester (<11 g/dl in the first trimester, <10.5 g/dl in the second trimester, <11 g/dl in the third trimester) [4].
Prevalence
Iron deficiency is the most widespread nutritional deficiency in the world and it accounts for 75% of all types of anemia in pregnancy [5,6].
In more than 80% of countries in the world, the prevalence of anemia in pregnancy is >20% [4]. The prevalence of anemia in pregnancy varies considerably because of the differences in social conditions, lifestyles and health seeking behaviors across different cultures. Anemia can affect pregnant women all over in the world (the global prevalence in pregnancy is estimated to be approximately 41.8%) with rates of prevalence that range from 35 to 60% for Africa, Asia and Latin America and it is reported to be <20% in industrialized countries [2–3,7–8]. The lowest estimated prevalence of anemia is of 5.7% in the USA and the highest is of 75% in Gambia and 65–75% in India [7,9].
Etiology
The most common causes of anemia are poor nutrition, deficiencies of iron, micronutrients deficiencies including folic acid, vitamin A and vitamin B12, diseases such as malaria, hookworm infestation and schistosomiasis, HIV infection and genetically inherited hemoglobinopathies, such as thalassemia [10]. There is also a possible association between
Iron deficiency is the most widespread nutritional deficiency in the world and it accounts for 75% of all types of anemia in pregnancy. It is due to the fact that diet in pregnancy is insufficient to supply iron requirement. It has high prevalence in developing countries, but it is also relevant in developed countries where other nutritional disorders have been almost eliminated [5,6]. Main manifestations of this disorder are pallor, glossitis and while patient may complain lassitude, weakness, anorexia, palpitation and dyspnea.
During pregnancy, there is a physiological hemodilution, with a peak during 20–24 weeks of gestation, and Hb varies through trimesters [7].
In fact, it is well established that there is a physiological drop in Hb in mid-trimester. This physiological drop is due to the higher increase in plasma volume, compared with RBC mass, which slightly increases during pregnancy. This physiological process produces relative hemodilution blood viscosity, helping the blood circulation in the placenta [12].
Moreover, during pregnancy, iron deficiency is relatively common because of the increased iron demand, with a mean iron requirement of 4.4 mg/day [13], and because many women start pregnancy with poor or deplete iron stores, so the amount of iron absorbed from diet, together with that mobilized from stores, is usually insufficient to meet the maternal demands imposed by pregnancy [13]. The serum ferritin level is a marker of depleted iron stores with a cut off value of <30 μg/l [2]. The iron availability is the rate limiting factor for RBC production by bone marrow. As iron deficiency occurs, iron stores in bone marrow decreases and serum ferritin level falls. As iron is essential in order to produce RBS in bone marrow, erythropoiesis starts to be impaired when serum iron is <50 μg/dl [8].
Beyond iron deficiency, a lack of other micro-nutrients can occur during pregnancy, influencing fetal–maternal outcome. For instance, folic acid depletion can increase risk of neural tube defects and calcium deficiency is associated with pre-eclampsia and growth restriction. Roughly 20–30% of women show a vitamin deficiency. Hence, iron supplementation is part of multiple micronutrients supplementation in pregnant women [14].
Maternal–fetal implications
Although one of the main target of WHO is prevention and treatment of anemia in pregnancy, it is still an underevaluated problem in developing countries with different adverse effects depending on the severity and duration of anemia and the stage of gestation. WHO classifies anemia mild when Hb is 10–10.9 mg/dl, moderate with Hb level of 7–7.9 mg/dl and severe when Hb level is <7 mg/dl [15]. Conclusions of several studies are controversial about the association of mild anemia and adverse maternal and fetal outcomes, resulting in the fact that a chronic mild anemia can lead to a normal course of the pregnancy and to a labor without any adverse consequences [9]. However, there is mounting evidence that iron deficiency may interfere with a defective myelination in infants, so that the resulting anemia produces long-lasting defects in mental development and performance that may further impair the child learning capacity [16]. Furthermore, treatment of mild anemia prevents moderate and severe forms of anemia, which are strictly associated with increased risk of fetal–maternal mortality and morbidity, requiring a treatment with higher doses of iron. Therefore, every case of anemia should be treated in pregnancy, in order to prevent adverse perinatal outcomes related to this disorder, considering a threshold <11 mg/dl, a good cut off to maintain optimal Hb (10–12 g/dl) throughout gestation with a better overall outcome.
International Nutritional Anemia Consultative Group, WHO and United Nations Childrens Fund reported that iron supplementation should be given in all pregnant women, as iron requirement during pregnancy is hard to meet only with diet, and in regions where iron deficiency anemia prevalence is >40%, supplementation should continue also in the postpartum period [5].
Even CDC suggests iron supplementation in pregnancy in order to prevent iron deficiency anemia (Box 1) [4].
Anemia in pregnant women has been considered as harmful for the fetal growth and fetal outcome. Low birth weight and preterm delivery have been persistently linked to anemia in pregnancy [21–23]. A significant increased risk of preterm birth in case of second trimester anemia has been demonstrated [21,22]. This could be explained to the state of chronic hypoxia consequent to anemia, which may induce a stress response, resulting in production of corticotropin-releasing hormone (CRH), elevated concentrations of which have been identified as a major risk factor of preterm birth. Additionally, the risk of preterm birth may increase owing to oxidative damage to erythrocytes and the fetoplacental unit.
Except for the first trimester, anemia in pregnant women has significantly increased the incidence of pre-term delivery. This association appears strongest in the third trimester. There are many studies showing similar association [24–27]. Kumar
Furthermore, an important issue is the increased risk for growth restrictions and impairment in mental and motor development in premature infants. Additionally, premature delivery is considered a frequent cause of death in newborns.
Rasmussen
Other complications are related with anemia in pregnancy (Box 2). A study of Colomer that showed an increased risk (5.7-fold) of anemia in infants delivered from mothers who were anemic during labor, compared with nonanemic mothers [31]; and several articles reported a correlation between maternal anemia and lower Apgar scores at birth. In fact, in a study with 102 Indian mothers, Rusia demonstrated that a higher Hb level during labor was associated with better Apgar scores and subsequently decreased risk of birth asphyxia and child's disabilities [24].
Supplementing iron earlier and maintaining optimal Hb (10–12 g/dl) throughout gestation have better overall outcome regarding premature deliveries and low birth weight babies [21,22,30].
Main reasons for iron deficiency.
Heavy or prolonged menstrual bleeding
Gastrointestinal bleeding
Pregnancy and lactation
Adolescence
Vegetarian or otherwise unbalanced diet
Eating disorder
Disease-related anorexia (cancer)
Malabsorption (chronic atrophic gastritis)
Chronic inflammatory or malignant diseases (HAMP)
Review of epidemiological studies shows that, women in low- or middle-income countries generally enter pregnancy with more limited iron stores and lower Hb concentrations compared with those who live in developed countries, consequently, an increased demand for iron in these women may thus enhance intestinal absorption, trying to compensate the iron deficiency, absorbing all iron available from diet.
Improved hematological status during pregnancy may also reduce the mortality risk in women with antepartum or postpartum hemorrhage and lead to improved iron status in the postpartum period [22,35–36]. Reducing iron deficiency anemia could be an important instrument, first, because among women, it should improve the iron stores of babies and, moreover, because there is evidence that iron status in young children predicts the risk of malaria and, possibly, the risk of invasive bacterial diseases [37].
Diagnosis
Detection of iron deficiency anemia early during pregnancy can reduce maternal and child mortality and morbidity.
Pallor of conjunctives, lips, oral mucosa, nail beds and palmar creases are possible findings in patients with anemia. Furthermore, a study of Strobach, showed a correlation between Hb concentration and the degree of pallor of lower eyelid conjunctiva, nail bed and palmar creases, demonstrating that an accurate physical examination can evaluate the severity of anemia [38], and for this reason, physical examination is an important step for the diagnose of this disorder, especially in developing countries where other tests are not available.
In case of iron deficiency anemia, a complete cell blood count shows reduced Hb concentration, reduced mean cell volume, reduced mean cell Hb, reduced mean cell Hb concentration and mild thrombocytosis.
Through the blood film, instead, in case of iron deficiency anemia, it can be possible to find microcytic hypochromic red cells with anisocytosis and poikilocytosis, but as hypochromic anemia can occur also in other cases (i.e., anemia of chronic disorders, thalassemias), other parameters should be included in the laboratory study in order to make diagnose of iron deficiency anemia. For this purpose, we can consider serum ferritin, the gold standard.
Although several authors suggest different ranges for normal and low serum ferritin, because of different methods and instruments each laboratory uses, our cut off for depleted iron stores is 30 μg/l, with a range of 30–100 μg/l at which ferritin concentrations are often inconclusive.
Nevertheless, serum ferritin is a parameter of acute-phase reaction, so its concentration increases in case of infections, systemic inflammations, malignancies, hepatopaties and chronic renal failure. This is why low levels of serum ferritin can be diagnostic of iron deficiency but normal values cannot exclude an iron shortage, and in such a situation, a decreased serum iron concentration has to be associated with a diminished transferrin saturation to diagnose iron depletion [8].
In fact, during iron deficiency states, liver produces more transferrin, but transferrin saturation decreases due to the low amount of iron storage, but also transferrin production is influenced from infections and inflammatory states, so that other parameters should be used in order to make an accurate evaluation of iron situation.
For this purpose, new tools are available today. For instance, soluble transferrin receptor protein is a peptide deriving from transmembrane transferrin receptor, which is expressed in iron requiring cells; therefore, soluble transferring receptor concentration is directly proportional with cellular receptor density, revealing total iron demand. Furthermore, this parameter seems to be unaffected from inflammatory states and chronic diseases [39].
Consequences of iron deficiency in pregnancy and during postpartum.
Chronic placental insufficiency
Impaired physical function
Increased cardiac failure and related death
Risk of severe maternal morbidity or mortality after postpartum hemorrhage
Chronic placental insufficiency
Reduced milk production, shorter lactation periods
Postpartum depression, emotional instability
Impaired physical function
Red cell distribution width is another parameter in fully automated hematology analyzer that can give the idea of early iron deficiency, earlier than other tests. It shows red cell size's variation, which is the earliest morphologic change occurring in iron deficiency anemia. Unlike mean cell volume, which appears normal in prelatent and latent stage of iron deficiency, red cell distribution width would be expected to increase as a result of a microcytic population of cells that appears in the blood [40]. Unfortunately, it is a test that often is not available in developing countries.
Anemia is an extremely serious and widespread problem. The goal of a proper management of anemia could be facilitated by an early diagnosis.
Reticulocyte hemoglobin content is a modern marker of cellular Hb content, which can be used to evaluate states of iron deficiency. The cut off of 27.2 pg can identify iron deficiency with a sensitivity of 93.3% [41].
Hadar
HAMP is a recently described amphipathic b-sheet hairpin peptide, which is expressed mainly in the liver, as a longer precursor known as pro-hepcidin [43–45], which through the binding to ferroportin, inhibits iron absorptionin the small intestine and regulates iron release into plasma. HAMP production is homeostatically regulated by anemia and hypoxia. When oxygen delivery is inadequate, HAMP levels decrease. Consequently, more iron is made available from the diet and from the storage pool in macrophages and hepatocytes. It is known that
Furthermore, HAMP could be a useful marker to evaluate iron availability during pregnancy, but there are few available studies in literature, and most of them involve a small number of pregnant patients. Hence, in the future, it will be necessary to conduct studies with bigger sample sizes of patients.
Still, different HAMP measurement methods give dissimilar values, limiting comparison between studies. So, a standard range for HAMP values is needed, in order to evaluate normal and abnormal HAMP values during all stages of pregnancy.
Moreover, future studies could examine correlation of maternal and fetal HAMP values with iron bioavailability during pregnancy and with possible pregnancy complications.
Another important issue is considering that further adjustments could be added to Hb cut offs. In fact, from a study of New and Wirth of 2015, it is reported that younger pregnant patients (<15 years old) manifest anemia more commonly, when compared with older pregnant populations, and have higher risk of postpartum hemorrhage [47]. Moreover, the same work, reported different mean Hb values between non-Caucasian women and Caucasian women, and between Chinese pregnant women and Nigerian pregnant women. This confirms the need in the future to give different Hb ranges for diagnosis of anemia in pregnancy for different populations.
As mean hemoglobin values are also influenced by several factors, for instance altitude, the same author suggests adjustment of Hb levels through an algorithm. Unfortunately, other unknown influencing factors could be present and also the severity of anemia cannot be assessed with this tool. Hence, more research studies are needed in the future [47].
Management
In 2011, Stevens reported that roughly 50% of anemia in pregnant women worldwide was due to iron deficiency [48]. The correction of iron deficiency involves an appropriate diet and iron supplementation. The use of iron during pregnancy may be a preventive tool to improve maternal hematological status and birth weight. The WHO has long recommended the prenatal use of iron supplements in low- and middle-income countries, as well as in many high-income countries [4–5,49].
Infectious and parasitic diseases cause about the remaining half of cases of anemia, and implementing measures to improve sanitation and disease control is expected to be a substantial contribution to anemia reduction [48].
Oral iron replacement therapy with gradual replenishment of iron stores and restoration of hemoglobin is the preferred treatment. Formulations may contain either the bivalent ferrous form or the trivalent ferric form, with the consideration that bivalent iron preparations are easily absorbed compared with the trivalent formulations.
The poorer bioavailability of trivalent ferric form is due to the lower solubility of the ion on alkaline environment and to the fact that it needs to be converted in the ferrous form, to be absorbed from the bowel. Furthermore, ferric iron formulations are more expensive and need a greater number of intakes in order to be effective.
The most common ferric formulation used for oral supplementation is ferric–polymaltose complex and several studies show that it is less effective and higher in cost compared with the ferrous sulfate formulations [50,51].
Unfortunately, ferrous iron preparations are associated with several adverse effects like gastric irritation, diarrhea, constipation, free radical generation, vomiting and abdominal pain, which can be reduced by administrating tablets after meal, but this would decrease iron absorption and the effectiveness of therapy.
However, it has been recently seen that a specific iron sulfate formulation in a polymeric complex is able to provide a gastric protection through a gradual intestinal release at levels of duodenum and jejunum. The best described is Tardyferon®, whose active ingredient is ferrous sulphate sesquihydrate present in an amount of 256.30 mg, and equivalent to 80 mg of elemental iron. Tardyferon contains mucoproteosis which contributes to a constant and slow release of iron ions Fe2+. The iron is gradually released with a peak of serum iron after 7 h, remaining elevated for 24 h [50]. In this way, an initial concentration rich in iron is avoided and this helps in reducing the percentage of undesirable secondary effects and facilitates compliance.
Parenteral iron therapy, given either by intramuscular or intravenous route, may be used if anemia is moderate or severe, if oral therapy has failed or in case of mild anemia, oral route is not tolerated or the patient tolerance is low.
Intravenous iron therapy is a safe alternative since it is able to reduce the need for blood transfusion. Furthermore, side effects related to supplementation of iron through this route, such as anaphylactic shock, febrile and hemolytic reactions, infections (hepatitis B, C, HIV, protozoan and bacterial) alloimmunization and graft versus host disease are very rare [52].
Shafi
Ferric carboxymaltose represents a new formulation for intravenous iron treatment, which, it has been demonstrated, can be used at high doses (up to 1000 mg) with better toleration and effectiveness, during second and third trimester of pregnancy, and with fewer side effects compared with iron sucrose formulation, also when the dose is double [53].
Another study shows effectiveness of ferric carboxymaltose for treatment of iron deficiency anemia, increasing levels of Hb and improving iron stores, and with good tolerability [54].
Although the Institute of Medicine reports that a dose of iron >45 mg/day can be associated to higher frequency of gastrointestinal side effects [43], the recommended dose of iron by WHO is 60 mg/day [55,56].
Haider
Contrarily, the recommended daily dose for treatment of manifest iron deficiency anemia is at least 120–200 mg/day up to 1000 mg/day, as demonstrated for ferric carboxymaltose [53].
In fact, a manifested anemia, especially when severe, put the patient at higher morbidity and mortality risk during and after labor, that requires a higher iron dose supplementation during pregnancy.
In a recent review, Haider
It has also be recently proposed an iron and folic acid supplementation program for the prevention of anemia in pregnancy with different characteristics according to the population to be treated [7].
Folic acid is a vitamin, belonging to group B, essential for DNA synthesis and for a physiological development of neural tube. During pregnancy, the folate requirement increases with the growth of the fetus, and a deficiency of this vitamin can cause megaloblastic anemia. For this reason, it has also be recently proposed an iron and folic acid supplementation program for the prevention of anemia in pregnancy with different characteristics according to the population to be treated.
A review by Yakoob
Another study reported that either iron supplementation alone or iron/folate, are effective in decreasing incidence of anemia at term in pregnancy [59], and in addition, a work of Juarez-Vazquez
However, the use of iron supplementation as part of multiple micronutrient supplementation for prevention of anemia and adverse pregnancy outcomes represents an important issue. There has been a lot of recent data on this and the recommendation from WHO may change in favor of multiple micronutrients compared with iron/folate.
Improved hematological status during pregnancy may also reduce the mortality risk in women with antepartum or postpartum hemorrhage and lead to improved iron status in the postpartum period [26,39–40].
In the end, in developing countries, although treatment of iron depletion can be an important tool in order to decrease fetal–maternal morbidity and mortality related to iron deficiency anemia, iron supplementation can lead to higher availability of the metal, increasing risk to host pathogens, which can cause severe perinatal infections. Hence, a proper antibiotic treatment or prophylaxis for some endemic infections during pregnancy, like malaria, can be a good approach [41].
Another important issue is the association between iron excess and tissue damage. As iron is able to catalyze formation of hydroxyl radicals, excessive accumulation of the metal can increase oxidative stress with possible tissue damage; indeed, several studies demonstrated a link between high-iron storage and gestational diabetes, diabetes Type II and other diseases [61–64], and for this reason, it has been supposed that iron intake could be associated with increased risk of diabetes.
However, several studies demonstrated that issue damage occurs only with chronic heme iron intake, leading to high-iron body stores [63]. Furthermore, nonheme iron, included supplemental iron, was not related to increased risk of Type II diabetes [65].
Conclusion
Due to the high implication of maternal and perinatal morbidity and mortality related to the iron deficiency anemia, it is necessary to act through:
Early detection in order to prevent fetal–maternal morbidity and mortality associated with this condition. Modern laboratory parameters could help in differential diagnosis of anemia, but as previously explained, this problem is more common in developing countries where laboratory studies are not available, and noninvasive diagnostic capabilities are often needed. For this purpose, accurate physical findings and evaluation of pallor of eyelid mucosa, palmar creases and nail bed should be performed;
Prevention of gastrointestinal infestations, which can cause half of anemia burden, is necessary. Early diagnose and treatment could decrease prevalence of such infestations. In the areas where infections from internal parasites are endemic, anthelmintic therapy should be given in cases of severe anemia;
Iron supplementation given through the best route of administration. More often, oral ferrous iron formulations are used, due to their effectiveness and low cost. Parenteral treatment should be isolated to treat moderate and severe cases of anemia, when a rapid iron supplementation is needed.
Several strategies should be adopted worldwide in order to prevent and treat anemia, so that the delivering woman would be able to face at least mild postpartum hemorrhage.
With this purpose, World Health Assembly has proposed a target of 50% reduction in anemia in women by 2025, and specific attention to maternal anemia as a problem of importance is now given by the US Global Health Initiative's Feed the Future program.
Future perspective
Due to severe implications and high rate of occurrence, iron deficiency anemia in pregnancy has been widely studied with its related complications, all available diagnostic tools and therapeutic strategies.
However, several points still need to be cleared. For instance, as previously showed in this manuscript, the knowledge about HAMP as a marker of iron status and its correlations with some fetal–maternal complications is still incomplete. Furthermore, the evaluation of different cut offs of Hb concentration for populations from different regions seem to be another important issue to be cleared for diagnosis of iron deficiency anemia.
Moreover, many diagnostic tools are not available in developing counties, because they are considered too expensive, with a consequently hard diagnosis of mild or moderate cases of anemia, increasing all risks related to more severe forms of this disease.
Research in the near future, and international organizations, should perform the task to improve management of anemia worldwide, lowering costs of diagnostic tools in developing countries, finding new markers for iron states and revealing other relations between iron deficiency states and fetal–maternal complications.
Executive summary
Anemia in pregnant women has high prevalence worldwide, with possible serious fetal-maternal sequelae. The main purpose of this manuscript is to give the right concern for anemia in pregnancy.
Most common causes of anemia are poor nutrition, deficiencies of iron, micronutrients deficiencies including folic acid, vitamin A and vitamin B12, diseases such as malaria hookworm infestations, schistosomiasis, HIV infection and genetically inherited hemoglobinopathies.
We consider anemia as mild, moderate and severe based on hemoglobin concentration.
Several adverse effects can be associated with iron deficiency anemia in pregnancy depending on severity and gestational age.
Iron deficiency anemia has been linked to low-birth weight and preterm delivery in several studies.
Prevention of anemia and treatment of mild forms prevent moderate and severe cases, which are related with increased risk of fetal-maternal mortality and morbidity.
Footnotes
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.