Annals of the New York Academy of Sciences Copyright 2000 by the New York Academy of Sciences.

Volume 900, 2000, pp 125-136 Anemia in Pregnancy [The Young Woman at the Rise of the 21st Century Gynecological and Reproductive Issues in Health and Diseasea: Part III. Prenatal and Perinatal Care in Maternal and Fetal Well-being and Disease] SIFAKIS, S.a; PHARMAKIDES, G. Department of Obstetrics and Gynecology, University Hospital of Heraklion, University of Crete, Heraklion, Greece aAddress for correspondence: Stavros Sifakis, 22 Apolloniou Rodiou Str., 71305, Heraklion Crete, Greece. Phone: 0030 81 212915; fax: 0030 81 392759. ---------------------------------------------Outline Abstract INTRODUCTION PHYSIOLOGIC BACKGROUND CAUSES OF ANEMIA IN PREGNANCY MATERNAL EFFECTS OF ANEMIA EFFECTS ON THE FETUS NORMAL VALUES AND LOWER LIMITS FOR HEMOGLOBIN LEVELS IN PREGNANT WOMEN COMMON TYPES OF ANEMIA IN PREGNANCY Iron-Deficiency Anemia Therapy of Iron-Deficiency Anemia and Iron Supplementation Folic Acid Deficiency Anemia Other Deficiency Anemias in Pregnancy HIGH MATERNAL HEMOGLOBIN AND THE FETUS REFERENCES Section Description Graphics Equation 1 Abstract Anemia is one of the most frequent complications related to pregnancy. Normal physiologic changes in pregnancy affect the hemoglobin (Hb), and there is a relative or absolute reduction in Hb concentration. The most common true anemias during pregnancy are iron deficiency anemia (approximately 75%) and folate deficiency megaloblastic anemia, which are more common in women who have inadequate diets and who are not receiving prenatal iron and folate supplements. Severe anemia may have adverse effects on the mother and the fetus. Anemia with hemoglobin levels less than 6 gr/dl is associated with poor pregnancy outcome. Prematurity, spontaneous abortions, low birth weight, and fetal deaths are complications of severe maternal anemia. Nevertheless, a mild to moderate iron deficiency does not appear to cause a significant effect on fetal hemoglobin concentration. An Hb level of 11 gr/dl in the late first trimester and also of 10 gr/dl in the second and third trimesters are suggested as lower limits for Hb concentration. In an iron-deficient state, iron supplementation must be given and follow-up is indicated to diagnose iron-unresponsive anemias. ---------------------------------------------INTRODUCTION Anemia is one of the most frequent complications related to pregnancy. The word implies a decrease in the oxygen-carrying capacity of the blood and is best characterized by a reduction in hemoglobin concentration. This may be either relative or absolute. It is known that there is a larger increase in plasma volume relative to red cell mass in almost all pregnancies, and it accounts for "physiologic anemia." These alterations have been known for centuries, and the term "plethora gravidarum" from medieval ages indicates this condition. However, it is still an open question to what extent this "hydremia" is physiologic or pathologic. There are two contrasting medical philosophies covering this problem. According to the first, it is preferable to prevent pregnant women from developing too low hemoglobin concentrations. According to another point of view the "physiologic anemia" is of great importance for normal fetal growth and should be passively observed. Moreover, the relationship between a successful outcome of pregnancy and this normal expansion in maternal plasma volume has been noted. 1 This controversy is reflected in the recommendations from the World Health Organization on the optimal hemoglobin (Hb) concentrations or hematocrit (Hct) level. Thus, in 1965 a WHO expert committee suggested that 10 gm/dl should be accepted as the lower limit of the physiologic adjustments made during pregnancy. 2 However, three years later another WHO scientific group recommended that when Hb values All rights reserved.

are lower than 11 gr/dl anemia should be considered to exist in pregnant women, and diets must be supplemented with medical iron. 3 PHYSIOLOGIC BACKGROUND The plasma volume starts to increase at about 6 weeks of pregnancy in a healthy woman. 4 This increase, which is disproportionately greater than the corresponding changes on the red cell mass, accounts for the physiologic fall in the Hb concentration during pregnancy. As a consequence, there is a significant reduction in arteriovenous oxygen extraction at the heart and an important increase of the oxygen-carrying capacity of the pregnant woman, despite the fall in the Hb level. The increase in plasma volume is about 1,250 ml at term, a total increase of about 48% above the nonpregnant state. This is the result of an initial rapid rise, followed by a slower rise after the 30th week of pregnancy. Several studies demonstrate the positive correlation between the weight of the newborn and the increase in the plasma volume. 1,5-8 It seems that the increase in plasma volume is an indication of normal growth of the fetus and one of the hallmarks of a successful pregnancy. As regards the red cell mass, it also increases although, in contrast to the plasma volume, it does so more slowly. The total increase is about 18% or 250 ml at term. After stimulation with iron supplements, however, the red cell mass may reach 400 ml-a total increase of about 30% compared with the nonpregnant state. Similar to the plasma volume, the increased red cell mass is linked to fetal growth, although probably to a lesser degree. CAUSES OF ANEMIA IN PREGNANCY Because of the normal physiologic changes in pregnancy that affect the hematocrit and certain other parameters, such as hemoglobin, reticulocytes, plasma ferritin, and unsaturated iron-binding capacity, diagnosing true anemia, as well as determining the etiology of anemia, is challenging. The most common anemias are iron-deficiency anemia and folate deficiency megaloblastic anemia. These anemias are more common in women who have inadequate diets and who are not receiving prenatal iron and folate supplements. Other less common causes of acquired anemia in pregnancy are aplastic anemia and hemolytic anemia. In addition, anemias such as thalassemia and sickle cell disease can have an impact on the health of the mother and fetus. As was stated above, the most frequent causes of true or absolute anemia are nutritional deficiencies. Frequently, these deficiencies are multiple, and the clinical presentation may be complicated by attendant infections, generally poor nutrition, or hereditary disorders such as hemoglobinopathies. 9,10 However, the fundamental sources of nutritional anemia embody insufficient intake, inadequate absorption, increased losses, expanded requirements, and insufficient utilization of hemopoietic nutrients. Approximately 75% of all anemias diagnosed during pregnancy are due to iron deficiency. Significant deficiency of iron leads to characteristic hypochromic, microcytic erythrocytes on the peripheral blood smear. Other causes of hypochromic anemias, even rare, must be considered, including hemoglobinopathies, inflammatory processes, chemical toxicity, malignancy, and pyridoxine-responsive anemia. However the greater percentage of the remaining cases of anemia in pregnancy other than the iron-deficiency type consists of the megaloblastic anemia of pregnancy due to folic acid deficiency and, to a lesser extent, to vitamin B12 deficiency. Anemia caused by deficiencies of other vitamins or elements does not commonly occur in humans. Nutritional anemia is not a broad-based problem in the populations of developed countries. It is nevertheless a problem for many individuals in these countries, and it is certainly a major health problem in poor, underdeveloped countries. Pregnant women as well as menstruating women and children make up the segment of the population in third-world countries-and even in the United States and Europe-that is affected by nutritional deficiency, sometimes accompanied by frank anemia. 11 In conclusion, the investigation of acquired anemias during pregnancy is very important, considering that inadequate nutrition and nutritional deficiencies have an adverse impact on pregnancy outcome, without excluding a priori other, less common types of anemia. MATERNAL EFFECTS OF ANEMIA Obviously, severe anemia has adverse effects on the mother and the fetus. There is also evidence that less severe anemia is associated with poor pregnancy outcome. Major maternal complications directly related to anemia are not common in women with a hemoglobin level greater than 6 gr/dl. However, Hb levels even lower may lead to significant morbidity in pregnant women, such as infections, increased hospital stays, and other general health problems. 10 A lot of symptoms and signs may accompany this clinical state, to a variable degree. The commonest of these are headache, fatigue, lethargy, paresthesia, and the clinical signs of tachycardia, tachypnea, pallor, glossitis, and cheilitis. In more severe cases, especially in pregnant women with hemoglobin levels less than 6 gr/dl, significant life-threatening problems secondary to high-output congestive heart failure and decreased oxygenation of tissues, including heart muscle may be encountered. Such conditions are rare as a result of nutritional deficiency anemias, at least in developed countries or when the pregnant woman receive iron supplementations. However, severe iron deficiency anemia or methemorragic anemia may be presented by complications of pregnancy, such as placenta previa or abruptio placenta, operative delivery and post partum hemorrhage. 12 These conditions if untreated by iron supplementation or blood transfusion may lead to severe complications. EFFECTS ON THE FETUS There are a lot of indications that severe maternal anemia in pregnancy is associated with poor pregnancy outcome and that the cause of this association

has yet to be elucidated. 10 Moreover, what effects the maternal anemia has on the fetus are not well defined; however, several reports in the literature associate the reduction in hemoglobin level with prematurity, spontaneous abortions, low birth weight, and fetal deaths. Some authors believe that even a mild reduction in Hb level (8-11 gr/dl) may produce a predisposition to these conditions; in contrast, other authors support a direct relationship between anemia and fetal distress only when the maternal Hb levels re less than 6 gr/dl. 13 It is important to know what effect the iron status of the mother has on the iron status of the fetus for definitive and correct conclusions about management. There are controversial opinions about this: some investigators found that levels of maternal iron exert little effect on that of the neonate at birth. 14 On the other hand, studies of cord blood serum iron levels have shown a direct relationship between maternal and fetal iron levels. 15 Additionally, when serum ferritin is used as an indicator of iron status, it was found that babies born to mothers who did not take iron supplements during pregnancy had reduced iron stores at birth. 16,17 Most authors agree that only severe anemia may have direct adverse effects on the fetus and neonate and that a mild to moderate maternal iron deficiency does not appear to cause a significant effect on fetal hemoglobin concentration. 15 There are several reports that correlate the anemia during pregnancy with prematurity and low-birthweight infants, indicating a direct relationship between low birth weight and low maternal Hb level. 18-20 In a large epidemiologic study, it was shown that the risk of a preterm delivery was increased by 20% in pregnancies with Hb levels between 10 and 11 gr/dl and by 60% in pregnancies with Hb levels between 9 and 10 gr/dl. Below 9 gr/dl, the risk was more than doubled, tripled, and so on for each fall of 1 gr/dl. 21 In the same study, no correlation was found between maternal Hb levels and growth retardation. In another large epidemiologic study, perinatal mortality was found to be tripled when the maternal Hb levels fell below 8 gr/dl in comparison with Hb levels above 11 gr/dl. 22 In addition, Garn et al. 23 demonstrated an association between low maternal Hb levels and poor pregnancy outcomes such as prematurity, low birth weight, fetal death, and other medical abnormalities with increasing complication rates when there were lower maternal Hb concentrations. Nevertheless, all these reports are strong indications of an adverse effect of maternal anemia on fetal growth and pregnancy outcome. Nevertheless, it would be better, at least in cases of mild to moderate maternal anemia, to characterize these simply as possible risk factors rather than as an adequate evaluation indicating an obvious adverse impact on the fetus. Moreover, it is important to stress that low maternal Hb levels are often associated with other pathologic conditions, so it is difficult to be sure whether maternal anemia per se causes or even contributes directly to the increased mortality and morbidity rates. In other words, low Hb levels are often a secondary phenomenon caused by antecedent infections or chronic illnesses that in turn may lead to severe complications during pregnancy that do not fundamentally depend on the hematologic profile of the pregnant woman. NORMAL VALUES AND LOWER LIMITS FOR HEMOGLOBIN LEVELS IN PREGNANT WOMEN There are conflicting views on the optimal Hb concentrations during pregnancy. One of the reasons for this is that the prepregnant hematologic state of the woman is rarely known, and this, to a large extent, determines the hematologic reactions during pregnancy. Thus, one important parameter is the knowledge of normal nonpregnant Hb variation. Another point is the use of +/-2 SD as limits for the variation of Hb levels during pregnancy. Finally, it is best to consider what is known about the physiological changes in plasma volume and in red cell mass during pregnancy that lead to physiological anemia. In the nonpregnant state, Hb and Hct values are more indicative of the plasma volume than of the red cell mass in women. It is possible that individual factors influence the plasma volumes from consistently high to average or low. 4 There is also often a gradual transition from normal iron stores to slight or moderate iron deficiency anemia during which the symptoms are inconspicuous. Two-thirds or more of healthy women of reproductive age in several countries have been found to have scanty or absent iron stores. 24 This situation may have not consequences in a non-pregnant state but during pregnancy such women are at a variable risk of developing frank anemia. The normal variations of Hb and Hct values in a nonpregnant state are wide. In one study, however, which is in close agreement with the results of many others, 25 young, healthy, nonpregnant women have the following values: Hb: 12.3 +/- 0.9 gr/dl (range, 11.4-14.3 gr/dl); Hct: 38% +/- 3 (range: 34-45%). It is important to ask, however, what is the optimal (or normal) Hb level for pregnant women and what is the lower limit of normal variation? This is a very difficult problem for which there are lot of conflicting views and strong discrepancies. Nevertheless, there is fairly good agreement among several investigators that the lower limit of normal physiologic variation of Hb levels is about 10 gr/dl. 23,26,27 This lowest value occurs in weeks 25 and 26 with a mean Hb value of 11.4 gr/dl, making the lower (+/- 2 SD) limit 9.8 gr/dl, 26 a figure very close to the lower limits of 10 gr/dl and 10.4 gr/dl of two other reports. 23,27 In the other trimesters of pregnancy, an Hb level of 11 gr/dl in the late first trimester and of 10 gr/dl in the third trimester are suggested as lower limits for Hb concentration. Koller et al. investigated the optimal Hb levels in iron-supplemented pregnant women and created a diagram based on the results of uncomplicated pregnancies resulting in healthy, normal neonates. 26 This pregnant population routinely used iron supplementation of 100 to 200 mg Fe per day (both doses have about the same effect on Hb levels). 28 According to the results of this study, it is remarkable that supplements had very little influence on the Hb levels before 25 weeks of gestation, although from that time on, these levels increased gradually compared with those of nonsupplemented women. Other authors supported that the difference at term between Hb levels in pregnant women with or without iron supplementation will be about 1 gr/dl. 29,30

About of 3% pregnant women have Hb levels below the lower limit of 10 gr/dl in the second trimester, 26,31 whereas the corresponding number in the third trimester is 1%. 31 The decrease in Hb concentration is positively correlated with the prepregnancy Hb value. 24 The low values (10 to 11 gr/dl) often show no drop in value, however. 28 This may be explained by considering that these low values indeed represent iron deficiency anemia that reacts rapidly to iron supplementation with hemoglobin production, thus preventing a further drop in Hb concentration. It is remarkable that this "resistance" to further decrease in Hb levels also appears in pregnant women without iron supplementation. It may represent a physiologic "adaptation" to pregnancy in order to keep the Hb concentration at sufficient levels for placental perfusion. 24 Another explanation is that women with low prepregnancy Hb levels may have larger plasma volumes than the women with higher Hb levels, and as a consequence they do not experience the plasma expansion that appears at early stages of pregnancy. COMMON TYPES OF ANEMIA IN PREGNANCY Iron-Deficiency Anemia The majority of all anemias diagnosed during pregnancy are characterized as iron-deficiency anemias. It is estimated that about 80% of pregnant women at term who do not use iron supplementation have hemoglobin concentrations less than 11 gr/dl. 13 The increased fetal need for iron as well as a number of other factors constitute the iron-deficiency profile of the pregnant woman and the need for supplementation. The factors contributing to that state include poor iron absorption during pregnancy, multiple gestations or successive gestations less than two years apart, adolescent pregnancy, and any associated chronic blood loss, as well as decreased amounts of total body iron before the pregnancy. The most usual clinical symptoms of iron-deficiency anemia are lethargy and fatigue, although they are also seen in normal pregnancy. Other symptoms are headache, paresthesia, burning sensation of the tongue, and pica, which is the ingestion of substances with no dietary value and appears in severe cases of anemia after the twentieth week of gestation. Glossitis, pallor, and inflammation of the lips (cheilitis) are clinical signs of iron deficiency, whereas koilonychia and "spooning" nails are less common findings. In cases of severe anemia, retinal bleeding, conjunctivitis, tachypnea or tachycardia, and splenomegaly may be presented. Nevertheless, these signs are rarely seen in developed countries because of the rarity Hb levels of 5 or 6 gr/dl. Some authors support a correlation of iron-deficiency anemia with defects in cellular immunity and decreased defense to bacteria by white blood cells, 32 but it is not clear whether this immune depression associated with anemia, predisposes a person to infection. 33 The laboratory evaluation of iron-deficiency anemia is quite difficult because of the physiologic hydremia of pregnancy and the subsequent changes in the values of the main hematologic parameters. Moreover, a differential diagnosis must be done between the hypochromic microcytic anemia of iron deficiency and other hypochromic anemias such as hemoglobinopathies or anemias induced by chemicals or inflammatory processes or malignancies. In these conditions the mean corpuscular volume (MCV) is often decreased, although it is the rule in iron-deficiency anemia. 34 The expected increase in the red blood cell mass after week 20 of gestation will not observed if iron stores are depleted. The serum iron levels decline as pregnancy advances for the reasons presented above. Values 400 [mu]g/dl. 35 The earliest tissue indicator of an iron-deficient state is decreased iron stores in the bone marrow, but aspiration in pregnancy is usually not indicated. Therapy of Iron-Deficiency Anemia and Iron Supplementation Most clinicians advocate iron supplementation in pregnant women. Others believe that supplementation has no value when hemoglobin levels are equal to or greater than 10 gr/dl. They believe that there is no need for extra therapy, on the grounds that hemodilution during pregnancy is an important physiologic adaptation, important for adequate uteroplacental circulation. 36 In an iron-deficient state, however, iron supplementation must be given, and follow-up is indicated to diagnose iron-unresponsive anemias. Reticulocytosis is normally observed 10 days after the initiation of iron therapy. The increased demand for iron and the hemodilution during pregnancy may mask the response to iron supplementation. It is self-evident that other causes of anemia have been excluded. In these cases iron supplementation should continue throughout pregnancy, and it can be accomplished with a variety of agents. Oral preparations containing elemental salt are the most commonly employed, whereas ferous sulfate compounds are the least expensive and have been demonstrated to be efficacious for iron supplementation. It should be taken three or four times daily in a dosage of 30-60 mg for a conservative dosage to 200-300 mg per day in the iron-deficient state. Nausea, vomiting, diarrhea, and constipation are the most common side effects of the ingestion of oral iron. The sustained release capsules, iron compounds that are slowly absorbed, and syrups may reduce some of the intolerance and increase patient compliance. Patients with severe iron deficiency anemia who cannot tolerate oral administration or who demonstrate noncompliance with the oral administration of iron, can be treated with intramuscular (i.m.) or intravenous (i.v.) administration. Additionally, parenteral therapy is preferred when rapid replenishment of iron stores is necessary. However, the hematologic response to the i.m. or i.v. route of therapy is no more rapid than that of the response to oral iron, and adverse effects including fatal anaphylaxis can be observed due to immediate or delayed reactions to iron dextran. It is more likely to appear when oral iron and parenteral iron are given concomitantly; therefore, this combination is not indicated. A test dose is strongly recommended before the first parenteral administration. A formula for the dose of iron needed to restore hemoglobin is the following 37: Equation 1 The side effects of such a route of iron administration include discomfort at the injection site, skin staining, malaise, and metallic taste. Moderate reactions of hyperpyrexia, lymphadenopathy, and phlebitis occur in 1-2% of patients, whereas anaphylaxis may occur in about 0.5% of them. ----------------------------------------------

Equation 1

---------------------------------------------Folic Acid Deficiency Anemia Folic acid deficiency causes a megaloblastic type of anemia that is second in occurrence as a cause for nutritional deficiency anemia of pregnancy after iron deficiency anemia. Folates and especially their derivative formyl FH4 are necessary for appropriate DNA synthesis and amino acid production. Insufficient levels of folic acid may lead to the manifestations noted in megaloblastic anemia. 38 Folic acid must be provided in the diet: common sources are green vegetables, fruits (lemons, melons), and meats (liver, kidney). The absorption happens in the proximal jejunum. The etiology of folic acid deficiency is variable and decreased intake is associated with poor nutrition and impaired absorption as well as increased folic acid requirements seen in pregnancy because of the increased demands of fetal growth and maternal erythropoiesis. Additionally, the higher levels of estrogen and progesterone during pregnancy seem to have an inhibitory effect on folate absorption The symptoms of folic acid deficiency are those of general anemia plus roughness of the skin and glossitis. The erythrocyte precursors are morphologically larger ("macrocytic"), and an abnormal nuclear-cytoplasmic appearance as well as normochromic and macrocytic findings are diagnostic criteria for megaloblastic anemia. MCH and MCHC are usually normal, whereas the large MCV is helpful in differentiation of this anemia from physiologic changes of pregnancy or irondeficiency anemia. For MCV, the presence of increased serum iron and transferrin saturation are also helpful. Neutropenia and thrombocytopenia are the results of abnormal maturation in granulocytes and thrombocytes. A low serum level ( The daily requirement in a nonpregnant state is at least 0.4 mg. In pregnancy or increased growth states, such as during infancy and adolescence, however, the requirements are increased to 0.8-1.0 mg. 39,40 It is possible that multiple gestations or short intervals between pregnancies increase folate requirements further. It has been reported that folate deficiency affects about 60 to 95% of untreated women at term. 13 However, true megaloblastic anemia due to folic acid deficiency is uncommon, although megaloblastic changes produced by this state are not uncommon. Half of the pregnant women with this type of anemia present before delivery with the remaining cases being detected puerperally. The majority of folic acid deficiencies during pregnancy appear in the third trimester. 13 Severe folic acid deficiency in experimental animals has been linked to an increased appearance of pregnancy abnormalities such as prematurity, fetal death, hypertension, placental abruption, or fetal malformations. A direct relationship of these outcomes with iron deficiency in humans has not been proven. 38 The fetus seems to have the ability to sustain stable hemoglobin and folate levels even in cases of obvious or severe maternal folate deficiency anemia. It is possible that the fetus removes folic acid from maternal circulation even in her deficit state. Thus, the infants in such cases are not anemic and appear unaffected. However, it has been found that megaloblastic anemia in pregnancy may be accompanied by smaller blood volume 40 and may be related to fetal growth retardation in some cases. 41 On the other hand, when there are no signs of anemia, the effects of folic acid deficiency are controversial or unclear. Nevertheless, the majority of physicians consider folate supplementation useful, especially for those at risk for developing deficiency states. Intake of 0.5 mg to 1 mg two or three times daily orally is generally adequate. A response to therapy within 48-72 hours can be expected as reticulocytes and platelets increase. A neutrophilic response can be observed within 2 weeks. If there are low serum iron levels, the existence of concomitant iron deficiency anemia is possible. 42 In these cases serum iron levels may be elevated and erythropoiesis will not be efficient. Other Deficiency Anemias in Pregnancy Hemic nutrients, trace elements, vitamins, and proteins are necessary for growth and maintenance of various bodily functions, especially for the hematologic system functions of the mother, fetus, and newborn. They are vital in facilitating the metabolism of amino acids, carbohydrotes, and fat and are therefore involved in anemias. The increased nutritional requirements during pregnancy commonly result in inadequate dietary intake. Nutritional anemia is not a very common problem in developed countries, except for irondeficiency or folic acid deficiency anemia. However, anemia caused by deficiencies in a number of iron, folic acid, vitamins, and proteins may be an important problem in poor, underdeveloped countries. Except for iron deficiency, which is responsible for the great majority of anemias diagnosed during pregnancy, deficiencies in some other minerals may account for some cases of anemias in rare cases. Severe phosphorus deficiency can cause hemolytic anemia because of adenosine triphosphate depletion in the red cells with subsequent osmotic fracture. 13 Moreover, severe copper deficiency has been characterized to iron supplementation. 43 Zinc deficiency has been noted in patients with sickle cell anemia and thalassemia. However, there is no evidence that this deficiency causes worsening of anemia. 44 Of the watersoluble vitamins, folic acid deficiency accounts for a large pregnancy which is megaloblastic in type. Except for folic acid, vitamin B12 deficiency is clinically important because of its role in the metabolism of folate through the production of active FH4. When serum B12 levels are depressed during pregnancy, it may lead to a type of megaloblastic anemia which exists in common with folic acid-related anemia in 98% of megaloblastic anemias at pregnancy. 45 Other B complex vitamin-related anemias are almost never seen in pregnancy. Though rare, vitamin B6 (pyridoxine) deficiency is noted during pregnancy by a decrease to about 75% of normal levels. A relationship between

this deficiency and hypochromic microcytic anemia has been reported. 43 Another hypochromic-type anemia has been noted in 80% of pregnant women with ascorbic acid (vitamin C) deficiency (scurvy). The interaction of ascorbic acid and iron metabolism is regarded as the etiologic reason for this anemia. 13 Of the fat-soluble vitamins (A, D, E, K), vitamin A deficiency has been shown by some investigators to produce an anemia similar to iron-deficiency anemia. 43 A mixed pattern of anemias has been associated with protein deficiency in pregnancy. The increasing needs of the mother and the demands from the fetus increase protein requirements from about 45 g in the nonpregnant state. Protein deficiency is not uncommon in a great part of the world, and anemia associated with kwashiorkor is a characteristic normochromic and hormocytic anemia 43 that is associated with decreased erythropoiesis and reduced iron intake. 46 A variety of anemias are associated with chronic ingestion of alcohol. Alcohol decreases folate levels through a direct effect on folate metabolism, and poor dietary intake leading to nutritional deficiency is common in these pregnant women. Therefore alcohol-related anemia may present with microcytic red cells or normochromic and macrocytic cells, with an increased number of ring sideroblasts. 43 HIGH MATERNAL HEMOGLOBIN AND THE FETUS Significantly higher Hb levels have been found in pregnancies complicated by fetal growth retardation and perinatal distress. 47,48 A number of important reports have also demonstrated a correlation between high maternal Hb levels in the first and second trimester with pregnancy complications including low birth weight, preterm birth, pregnancy-induced hypertension, and intrauterine death of unknown cause. 27,49 Murphy et al. showed that the frequency of hypertension in primiparas ranged from 7% with Hb values under 10.5 gr/dl to 42% with Hb concentrations over 14.5 gr/dl. 27 Garn et al. found that fetal death was 2.6 times more frequent with maternal Hb levels around 14 gr/dl than when it was around 8 gr/dl. 23 It is probably that the explanation for the development of these complications is the failure of the pregnancy to induce sufficient hemodilution, a major adjustment of normal pregnancy. This failure may be caused by faulty implantation or by inadequate genetic endownment. Moreover, a number of studies have shown that abnormally high maternal Hb levels probably impair the uteroplacental circulation by raising the whole-blood viscosity. 50,51 It is known that the major component of whole-blood viscosity is the concentration of Hb/Ht. 52 Garn et al. found that Hb values of 11 gr/dl (Ht 34) for blacks and Hb 12 gr/dl (Ht 36) for whites are the optimum values for pregnant women, whereas Hb values of 13 gr/dl (Ht 41) are the upper border values for an optimal outcome. 23 A practical conclusion is that an Hb value of 13 gr/dl or higher in the second trimester should be a cause for concern. REFERENCES 1. Goodland, R.D. et al. 1983. Clinical science of normal plasma volume expansion during pregnancy. Am. J. Obstet. Gynecol. 145: 1001. 2. World Health Organization. 1965. Nutrition in pregnancy and lactation. WHO Tech. Rep. Ser. 302. 3. World Health Organization. 1968. Nutritional anemias. WHO Tech. Rep. Ser. 405. 4. Lund, C.J. et al. 1967. Blood volume during pregnancy. Significance of plasma red cell volumes. Am. J. Obstet. Gynecol. 98: 393. 5. Retief, F.P. et al. 1967. P study of pregnancy anemia, blood volume changes correlatated with other parameters of haemopoietic efficiency. J. Obstet. Gynaecol. Br. Commonw. 74: 683. Bibliographic Links 6. Duffus, G.M. et al. 1971. The relationship between baby weight and changes in maternal weight, total body water, plasma volume electrolytes and proteins, and urinary oestriol excretion. J. Obstet. Gynaecol. Br. Commonw. 78: 97. Bibliographic Links 7. Gibson, H.M. 1973. Plasma volume and glomerular filtration rate in pregnancy and their relation to differences in fetal growth. J. Obstet. Gynaecol. Br. Commonw. 80: 1067. Bibliographic Links 8. Pirani, B.B.K. et al. 1973. Plasma volume in normal first pregnancy. J. Obstet. Gynaecol. Br. Commonw. 80: 884. Bibliographic Links 9. Baker. S.J. 1983. Nutritional anemias. Part 2: Tropical Asia. Clin. Haematol. 10: 843. 10. Williams, M.D. et al. 1992. Anemia in pregnancy. Med. Clin. N. Am. 76(3): 631-647. Bibliographic Links 11. Cook, J.D. 1983. Nutritional anemia. Contemp. Nutr. 8: 366. 12. Flessa, H.C. 1974. Hemorrhagic disorders and pregnancy. Clin. Obstet. Gynecol. 17: 236. Bibliographic Links 13. Pryor, J. et al. 1990. In Hematologic Disorders in Maternal-Fetal Medicine. Wiley-Liss Inc. New York. pp. 93-111. 14. Sturgeon, P. 1959. Studies of iron requirements in infants III. Influence of supplemental iron during normal pregnancy on mother and infant. B. The infant. Br. J. Haematol. 5: 45. 15. Werner, E.J. et al. 1983. Red cell disturbances in the feto-maternal unit. Semin. Perinatol. 3: 139. Bibliographic Links

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