Annals of the New York Academy of Sciences

Copyright 2000 by the New York Academy of Sciences. All rights reserved.

Volume 900, 2000, pp 125-136

Anemia in Pregnancy[The Young Woman at the Rise of the 21st Century Gynecological and ReproductiveIssues in Health and Diseasea: Part III. Prenatal and Perinatal Care in Maternaland Fetal Well-being and Disease]

SIFAKIS, S.a; PHARMAKIDES, G.Department of Obstetrics and Gynecology, University Hospital of Heraklion,University of Crete, Heraklion, GreeceaAddress for correspondence: Stavros Sifakis, 22 Apolloniou Rodiou Str., 71305,Heraklion Crete, Greece. Phone: 0030 81 212915; fax: 0030 81 392759.

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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. Normalphysiologic changes in pregnancy affect the hemoglobin (Hb), and there is arelative or absolute reduction in Hb concentration. The most common true anemiasduring pregnancy are iron deficiency anemia (approximately 75%) and folatedeficiency megaloblastic anemia, which are more common in women who haveinadequate diets and who are not receiving prenatal iron and folate supplements.Severe anemia may have adverse effects on the mother and the fetus. Anemia withhemoglobin levels less than 6 gr/dl is associated with poor pregnancy outcome.Prematurity, spontaneous abortions, low birth weight, and fetal deaths arecomplications of severe maternal anemia. Nevertheless, a mild to moderate irondeficiency does not appear to cause a significant effect on fetal hemoglobinconcentration. An Hb level of 11 gr/dl in the late first trimester and also of10 gr/dl in the second and third trimesters are suggested as lower limits for Hbconcentration. In an iron-deficient state, iron supplementation must be givenand follow-up is indicated to diagnose iron-unresponsive anemias.

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INTRODUCTION

Anemia is one of the most frequent complications related to pregnancy. The wordimplies a decrease in the oxygen-carrying capacity of the blood and is bestcharacterized by a reduction in hemoglobin concentration. This may be eitherrelative or absolute. It is known that there is a larger increase in plasmavolume relative to red cell mass in almost all pregnancies, and it accounts for"physiologic anemia." These alterations have been known for centuries, and theterm "plethora gravidarum" from medieval ages indicates this condition. However,it is still an open question to what extent this "hydremia" is physiologic orpathologic.

There are two contrasting medical philosophies covering this problem. Accordingto the first, it is preferable to prevent pregnant women from developing too lowhemoglobin concentrations. According to another point of view the "physiologicanemia" is of great importance for normal fetal growth and should be passivelyobserved. Moreover, the relationship between a successful outcome of pregnancyand this normal expansion in maternal plasma volume has been noted. 1 Thiscontroversy is reflected in the recommendations from the World Health Organizationon 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 thelower limit of the physiologic adjustments made during pregnancy. 2 However,three years later another WHO scientific group recommended that when Hb values

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 healthywoman. 4 This increase, which is disproportionately greater than the correspondingchanges on the red cell mass, accounts for the physiologic fall in the Hbconcentration during pregnancy. As a consequence, there is a significantreduction in arteriovenous oxygen extraction at the heart and an importantincrease of the oxygen-carrying capacity of the pregnant woman, despite the fallin the Hb level.

The increase in plasma volume is about 1,250 ml at term, a total increase ofabout 48% above the nonpregnant state. This is the result of an initial rapidrise, followed by a slower rise after the 30th week of pregnancy. Severalstudies demonstrate the positive correlation between the weight of the newbornand the increase in the plasma volume. 1,5-8 It seems that the increase inplasma volume is an indication of normal growth of the fetus and one of thehallmarks of a successful pregnancy.

As regards the red cell mass, it also increases although, in contrast to theplasma volume, it does so more slowly. The total increase is about 18% or 250 mlat term. After stimulation with iron supplements, however, the red cell mass mayreach 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 fetalgrowth, although probably to a lesser degree.

CAUSES OF ANEMIA IN PREGNANCY

Because of the normal physiologic changes in pregnancy that affect thehematocrit 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 commonanemias are iron-deficiency anemia and folate deficiency megaloblastic anemia.These anemias are more common in women who have inadequate diets and who are notreceiving prenatal iron and folate supplements. Other less common causes ofacquired anemia in pregnancy are aplastic anemia and hemolytic anemia. Inaddition, anemias such as thalassemia and sickle cell disease can have an impacton the health of the mother and fetus.

As was stated above, the most frequent causes of true or absolute anemia arenutritional deficiencies. Frequently, these deficiencies are multiple, and theclinical presentation may be complicated by attendant infections, generally poornutrition, or hereditary disorders such as hemoglobinopathies. 9,10 However, thefundamental sources of nutritional anemia embody insufficient intake, inadequateabsorption, increased losses, expanded requirements, and insufficient utilizationof hemopoietic nutrients. Approximately 75% of all anemias diagnosed duringpregnancy are due to iron deficiency. Significant deficiency of iron leads tocharacteristic hypochromic, microcytic erythrocytes on the peripheral bloodsmear. 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 ofthe remaining cases of anemia in pregnancy other than the iron-deficiency typeconsists of the megaloblastic anemia of pregnancy due to folic acid deficiencyand, to a lesser extent, to vitamin B12 deficiency. Anemia caused by deficienciesof other vitamins or elements does not commonly occur in humans.

Nutritional anemia is not a broad-based problem in the populations of developedcountries. 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 ofthe population in third-world countries-and even in the United States andEurope-that is affected by nutritional deficiency, sometimes accompanied byfrank anemia. 11

In conclusion, the investigation of acquired anemias during pregnancy is veryimportant, considering that inadequate nutrition and nutritional deficiencieshave 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. Thereis also evidence that less severe anemia is associated with poor pregnancyoutcome. Major maternal complications directly related to anemia are not commonin women with a hemoglobin level greater than 6 gr/dl. However, Hb levels evenlower 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 variabledegree. The commonest of these are headache, fatigue, lethargy, paresthesia, andthe clinical signs of tachycardia, tachypnea, pallor, glossitis, and cheilitis.In more severe cases, especially in pregnant women with hemoglobin levels lessthan 6 gr/dl, significant life-threatening problems secondary to high-outputcongestive heart failure and decreased oxygenation of tissues, including heartmuscle may be encountered. Such conditions are rare as a result of nutritionaldeficiency anemias, at least in developed countries or when the pregnant womanreceive iron supplementations. However, severe iron deficiency anemia ormethemorragic anemia may be presented by complications of pregnancy, such asplacenta previa or abruptio placenta, operative delivery and post partumhemorrhage. 12 These conditions if untreated by iron supplementation or bloodtransfusion may lead to severe complications.

EFFECTS ON THE FETUS

There are a lot of indications that severe maternal anemia in pregnancy isassociated with poor pregnancy outcome and that the cause of this association

has yet to be elucidated. 10 Moreover, what effects the maternal anemia has onthe fetus are not well defined; however, several reports in the literatureassociate the reduction in hemoglobin level with prematurity, spontaneousabortions, low birth weight, and fetal deaths. Some authors believe that even amild reduction in Hb level (8-11 gr/dl) may produce a predisposition to theseconditions; in contrast, other authors support a direct relationship betweenanemia 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 theiron status of the fetus for definitive and correct conclusions about management.There are controversial opinions about this: some investigators found thatlevels of maternal iron exert little effect on that of the neonate at birth. 14On the other hand, studies of cord blood serum iron levels have shown a directrelationship between maternal and fetal iron levels. 15 Additionally, when serumferritin is used as an indicator of iron status, it was found that babies bornto mothers who did not take iron supplements during pregnancy had reduced ironstores at birth. 16,17 Most authors agree that only severe anemia may havedirect adverse effects on the fetus and neonate and that a mild to moderatematernal iron deficiency does not appear to cause a significant effect on fetalhemoglobin concentration. 15

There are several reports that correlate the anemia during pregnancy withprematurity and low-birthweight infants, indicating a direct relationshipbetween low birth weight and low maternal Hb level. 18-20 In a large epidemiologicstudy, it was shown that the risk of a preterm delivery was increased by 20% inpregnancies with Hb levels between 10 and 11 gr/dl and by 60% in pregnancieswith Hb levels between 9 and 10 gr/dl. Below 9 gr/dl, the risk was more thandoubled, tripled, and so on for each fall of 1 gr/dl. 21 In the same study, nocorrelation was found between maternal Hb levels and growth retardation. Inanother large epidemiologic study, perinatal mortality was found to be tripledwhen the maternal Hb levels fell below 8 gr/dl in comparison with Hb levelsabove 11 gr/dl. 22 In addition, Garn et al. 23 demonstrated an associationbetween low maternal Hb levels and poor pregnancy outcomes such as prematurity,low birth weight, fetal death, and other medical abnormalities with increasingcomplication rates when there were lower maternal Hb concentrations. Nevertheless,all these reports are strong indications of an adverse effect of maternal anemiaon fetal growth and pregnancy outcome. Nevertheless, it would be better, atleast in cases of mild to moderate maternal anemia, to characterize these simplyas possible risk factors rather than as an adequate evaluation indicating anobvious adverse impact on the fetus. Moreover, it is important to stress thatlow maternal Hb levels are often associated with other pathologic conditions, soit is difficult to be sure whether maternal anemia per se causes or evencontributes directly to the increased mortality and morbidity rates. In otherwords, low Hb levels are often a secondary phenomenon caused by antecedentinfections or chronic illnesses that in turn may lead to severe complicationsduring pregnancy that do not fundamentally depend on the hematologic profile ofthe 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 thewoman is rarely known, and this, to a large extent, determines the hematologicreactions during pregnancy. Thus, one important parameter is the knowledge ofnormal nonpregnant Hb variation. Another point is the use of +/-2 SD as limitsfor the variation of Hb levels during pregnancy. Finally, it is best to considerwhat is known about the physiological changes in plasma volume and in red cellmass during pregnancy that lead to physiological anemia.

In the nonpregnant state, Hb and Hct values are more indicative of the plasmavolume than of the red cell mass in women. It is possible that individualfactors influence the plasma volumes from consistently high to average or low. 4There is also often a gradual transition from normal iron stores to slight ormoderate iron deficiency anemia during which the symptoms are inconspicuous.Two-thirds or more of healthy women of reproductive age in several countrieshave been found to have scanty or absent iron stores. 24 This situation may havenot consequences in a non-pregnant state but during pregnancy such women are ata variable risk of developing frank anemia.

The normal variations of Hb and Hct values in a nonpregnant state are wide. Inone 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 +/- 0.9gr/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 forpregnant women and what is the lower limit of normal variation? This is a verydifficult problem for which there are lot of conflicting views and strongdiscrepancies. Nevertheless, there is fairly good agreement among severalinvestigators that the lower limit of normal physiologic variation of Hb levelsis about 10 gr/dl. 23,26,27 This lowest value occurs in weeks 25 and 26 with amean Hb value of 11.4 gr/dl, making the lower (+/- 2 SD) limit 9.8 gr/dl, 26 afigure very close to the lower limits of 10 gr/dl and 10.4 gr/dl of two otherreports. 23,27

In the other trimesters of pregnancy, an Hb level of 11 gr/dl in the late firsttrimester and of 10 gr/dl in the third trimester are suggested as lower limitsfor Hb concentration. Koller et al. investigated the optimal Hb levels iniron-supplemented pregnant women and created a diagram based on the results ofuncomplicated pregnancies resulting in healthy, normal neonates. 26 Thispregnant population routinely used iron supplementation of 100 to 200 mg Fe perday (both doses have about the same effect on Hb levels). 28 According to theresults of this study, it is remarkable that supplements had very littleinfluence on the Hb levels before 25 weeks of gestation, although from that timeon, these levels increased gradually compared with those of nonsupplementedwomen. Other authors supported that the difference at term between Hb levels inpregnant 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 inthe second trimester, 26,31 whereas the corresponding number in the thirdtrimester is 1%. 31 The decrease in Hb concentration is positively correlatedwith the prepregnancy Hb value. 24 The low values (10 to 11 gr/dl) often show nodrop in value, however. 28 This may be explained by considering that these lowvalues indeed represent iron deficiency anemia that reacts rapidly to ironsupplementation with hemoglobin production, thus preventing a further drop in Hbconcentration. It is remarkable that this "resistance" to further decrease in Hblevels also appears in pregnant women without iron supplementation. It mayrepresent a physiologic "adaptation" to pregnancy in order to keep the Hbconcentration at sufficient levels for placental perfusion. 24 Anotherexplanation is that women with low prepregnancy Hb levels may have larger plasmavolumes than the women with higher Hb levels, and as a consequence they do notexperience 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 asiron-deficiency anemias. It is estimated that about 80% of pregnant women atterm who do not use iron supplementation have hemoglobin concentrations lessthan 11 gr/dl. 13 The increased fetal need for iron as well as a number of otherfactors constitute the iron-deficiency profile of the pregnant woman and theneed for supplementation. The factors contributing to that state include pooriron absorption during pregnancy, multiple gestations or successive gestationsless than two years apart, adolescent pregnancy, and any associated chronicblood loss, as well as decreased amounts of total body iron before thepregnancy.

The most usual clinical symptoms of iron-deficiency anemia are lethargy andfatigue, although they are also seen in normal pregnancy. Other symptoms areheadache, paresthesia, burning sensation of the tongue, and pica, which is theingestion of substances with no dietary value and appears in severe cases ofanemia after the twentieth week of gestation. Glossitis, pallor, and inflammationof the lips (cheilitis) are clinical signs of iron deficiency, whereaskoilonychia and "spooning" nails are less common findings. In cases of severeanemia, retinal bleeding, conjunctivitis, tachypnea or tachycardia, andsplenomegaly may be presented. Nevertheless, these signs are rarely seen indeveloped countries because of the rarity Hb levels of 5 or 6 gr/dl. Someauthors support a correlation of iron-deficiency anemia with defects in cellularimmunity and decreased defense to bacteria by white blood cells, 32 but it isnot clear whether this immune depression associated with anemia, predisposes aperson to infection. 33

The laboratory evaluation of iron-deficiency anemia is quite difficult becauseof the physiologic hydremia of pregnancy and the subsequent changes in thevalues of the main hematologic parameters. Moreover, a differential diagnosismust be done between the hypochromic microcytic anemia of iron deficiency andother hypochromic anemias such as hemoglobinopathies or anemias induced bychemicals or inflammatory processes or malignancies. In these conditions themean corpuscular volume (MCV) is often decreased, although it is the rule iniron-deficiency anemia. 34 The expected increase in the red blood cell massafter week 20 of gestation will not observed if iron stores are depleted. Theserum iron levels decline as pregnancy advances for the reasons presented above.Values 400 [mu]g/dl. 35 The earliest tissue indicator of an iron-deficientstate is decreased iron stores in the bone marrow, but aspiration in pregnancyis usually not indicated.

Therapy of Iron-Deficiency Anemia and Iron Supplementation

Most clinicians advocate iron supplementation in pregnant women. Others believethat supplementation has no value when hemoglobin levels are equal to or greaterthan 10 gr/dl. They believe that there is no need for extra therapy, on thegrounds that hemodilution during pregnancy is an important physiologicadaptation, important for adequate uteroplacental circulation. 36 In aniron-deficient state, however, iron supplementation must be given, and follow-upis indicated to diagnose iron-unresponsive anemias. Reticulocytosis is normallyobserved 10 days after the initiation of iron therapy. The increased demand foriron and the hemodilution during pregnancy may mask the response to ironsupplementation. It is self-evident that other causes of anemia have beenexcluded. In these cases iron supplementation should continue throughoutpregnancy, and it can be accomplished with a variety of agents. Oral preparationscontaining elemental salt are the most commonly employed, whereas ferous sulfatecompounds are the least expensive and have been demonstrated to be efficaciousfor iron supplementation. It should be taken three or four times daily in adosage of 30-60 mg for a conservative dosage to 200-300 mg per day in theiron-deficient state. Nausea, vomiting, diarrhea, and constipation are the mostcommon side effects of the ingestion of oral iron. The sustained releasecapsules, iron compounds that are slowly absorbed, and syrups may reduce some ofthe intolerance and increase patient compliance. Patients with severe irondeficiency anemia who cannot tolerate oral administration or who demonstratenoncompliance with the oral administration of iron, can be treated withintramuscular (i.m.) or intravenous (i.v.) administration. Additionally,parenteral therapy is preferred when rapid replenishment of iron stores isnecessary. However, the hematologic response to the i.m. or i.v. route oftherapy is no more rapid than that of the response to oral iron, and adverseeffects including fatal anaphylaxis can be observed due to immediate or delayedreactions to iron dextran. It is more likely to appear when oral iron andparenteral iron are given concomitantly; therefore, this combination is notindicated. A test dose is strongly recommended before the first parenteraladministration. A formula for the dose of iron needed to restore hemoglobin isthe following 37: Equation 1 The side effects of such a route of iron administrationinclude discomfort at the injection site, skin staining, malaise, and metallictaste. Moderate reactions of hyperpyrexia, lymphadenopathy, and phlebitis occurin 1-2% of patients, whereas anaphylaxis may occur in about 0.5% of them.

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Equation 1

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Folic Acid Deficiency Anemia

Folic acid deficiency causes a megaloblastic type of anemia that is second inoccurrence as a cause for nutritional deficiency anemia of pregnancy after irondeficiency anemia. Folates and especially their derivative formyl FH4 arenecessary for appropriate DNA synthesis and amino acid production. Insufficientlevels of folic acid may lead to the manifestations noted in megaloblasticanemia. 38 Folic acid must be provided in the diet: common sources are greenvegetables, fruits (lemons, melons), and meats (liver, kidney). The absorptionhappens in the proximal jejunum.

The etiology of folic acid deficiency is variable and decreased intake isassociated with poor nutrition and impaired absorption as well as increasedfolic acid requirements seen in pregnancy because of the increased demands offetal growth and maternal erythropoiesis. Additionally, the higher levels ofestrogen and progesterone during pregnancy seem to have an inhibitory effect onfolate absorption The symptoms of folic acid deficiency are those of generalanemia plus roughness of the skin and glossitis. The erythrocyte precursors aremorphologically larger ("macrocytic"), and an abnormal nuclear-cytoplasmicappearance as well as normochromic and macrocytic findings are diagnosticcriteria for megaloblastic anemia. MCH and MCHC are usually normal, whereas thelarge MCV is helpful in differentiation of this anemia from physiologic changesof pregnancy or irondeficiency anemia. For MCV, the presence of increased serumiron and transferrin saturation are also helpful. Neutropenia and thrombocytopeniaare the results of abnormal maturation in granulocytes and thrombocytes. A lowserum level (

The daily requirement in a nonpregnant state is at least 0.4 mg. In pregnancy orincreased growth states, such as during infancy and adolescence, however, therequirements are increased to 0.8-1.0 mg. 39,40 It is possible that multiplegestations or short intervals between pregnancies increase folate requirementsfurther. It has been reported that folate deficiency affects about 60 to 95% ofuntreated women at term. 13 However, true megaloblastic anemia due to folic aciddeficiency is uncommon, although megaloblastic changes produced by this stateare not uncommon. Half of the pregnant women with this type of anemia presentbefore delivery with the remaining cases being detected puerperally. Themajority of folic acid deficiencies during pregnancy appear in the thirdtrimester. 13 Severe folic acid deficiency in experimental animals has beenlinked to an increased appearance of pregnancy abnormalities such as prematurity,fetal death, hypertension, placental abruption, or fetal malformations. A directrelationship of these outcomes with iron deficiency in humans has not beenproven. 38 The fetus seems to have the ability to sustain stable hemoglobin andfolate levels even in cases of obvious or severe maternal folate deficiencyanemia. It is possible that the fetus removes folic acid from maternalcirculation even in her deficit state. Thus, the infants in such cases are notanemic and appear unaffected. However, it has been found that megaloblasticanemia in pregnancy may be accompanied by smaller blood volume 40 and may berelated to fetal growth retardation in some cases. 41 On the other hand, whenthere are no signs of anemia, the effects of folic acid deficiency arecontroversial or unclear. Nevertheless, the majority of physicians considerfolate supplementation useful, especially for those at risk for developingdeficiency states. Intake of 0.5 mg to 1 mg two or three times daily orally isgenerally adequate. A response to therapy within 48-72 hours can be expected asreticulocytes and platelets increase. A neutrophilic response can be observedwithin 2 weeks. If there are low serum iron levels, the existence of concomitantiron deficiency anemia is possible. 42 In these cases serum iron levels may beelevated and erythropoiesis will not be efficient.

Other Deficiency Anemias in Pregnancy

Hemic nutrients, trace elements, vitamins, and proteins are necessary for growthand maintenance of various bodily functions, especially for the hematologicsystem functions of the mother, fetus, and newborn. They are vital in facilitatingthe metabolism of amino acids, carbohydrotes, and fat and are therefore involvedin anemias. The increased nutritional requirements during pregnancy commonlyresult in inadequate dietary intake. Nutritional anemia is not a very commonproblem in developed countries, except for irondeficiency or folic aciddeficiency 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 ofanemias diagnosed during pregnancy, deficiencies in some other minerals mayaccount for some cases of anemias in rare cases. Severe phosphorus deficiencycan cause hemolytic anemia because of adenosine triphosphate depletion in thered cells with subsequent osmotic fracture. 13 Moreover, severe copperdeficiency has been characterized to iron supplementation. 43 Zinc deficiencyhas 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 largepregnancy which is megaloblastic in type. Except for folic acid, vitamin B12deficiency is clinically important because of its role in the metabolism offolate through the production of active FH4. When serum B12 levels are depressedduring pregnancy, it may lead to a type of megaloblastic anemia which exists incommon with folic acid-related anemia in 98% of megaloblastic anemias atpregnancy. 45 Other B complex vitamin-related anemias are almost never seen inpregnancy. Though rare, vitamin B6 (pyridoxine) deficiency is noted duringpregnancy by a decrease to about 75% of normal levels. A relationship between

this deficiency and hypochromic microcytic anemia has been reported. 43 Anotherhypochromic-type anemia has been noted in 80% of pregnant women with ascorbicacid (vitamin C) deficiency (scurvy). The interaction of ascorbic acid and ironmetabolism is regarded as the etiologic reason for this anemia. 13 Of thefat-soluble vitamins (A, D, E, K), vitamin A deficiency has been shown by someinvestigators to produce an anemia similar to iron-deficiency anemia. 43

A mixed pattern of anemias has been associated with protein deficiency inpregnancy. The increasing needs of the mother and the demands from the fetusincrease protein requirements from about 45 g in the nonpregnant state. Proteindeficiency is not uncommon in a great part of the world, and anemia associatedwith kwashiorkor is a characteristic normochromic and hormocytic anemia 43 thatis associated with decreased erythropoiesis and reduced iron intake. 46

A variety of anemias are associated with chronic ingestion of alcohol. Alcoholdecreases folate levels through a direct effect on folate metabolism, and poordietary intake leading to nutritional deficiency is common in these pregnantwomen. Therefore alcohol-related anemia may present with microcytic red cells ornormochromic 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 byfetal growth retardation and perinatal distress. 47,48 A number of importantreports have also demonstrated a correlation between high maternal Hb levels inthe first and second trimester with pregnancy complications including low birthweight, preterm birth, pregnancy-induced hypertension, and intrauterine death ofunknown cause. 27,49 Murphy et al. showed that the frequency of hypertension inprimiparas ranged from 7% with Hb values under 10.5 gr/dl to 42% with Hbconcentrations over 14.5 gr/dl. 27 Garn et al. found that fetal death was 2.6times more frequent with maternal Hb levels around 14 gr/dl than when it wasaround 8 gr/dl. 23

It is probably that the explanation for the development of these complicationsis the failure of the pregnancy to induce sufficient hemodilution, a majoradjustment of normal pregnancy. This failure may be caused by faulty implantationor by inadequate genetic endownment. Moreover, a number of studies have shownthat abnormally high maternal Hb levels probably impair the uteroplacentalcirculation by raising the whole-blood viscosity. 50,51 It is known that themajor 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 valuesof 13 gr/dl (Ht 41) are the upper border values for an optimal outcome. 23 Apractical conclusion is that an Hb value of 13 gr/dl or higher in the secondtrimester should be a cause for concern.

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Section Description

aThis volume is the result of a conference entitled The Young Woman at the Riseof the 21st Century: Gynecological and Reproductive Issues in Health and Diseaseheld by the Second Department of Obstetrics and Gynecology of the University ofAthens, the Hellenic Society of Pediatric and Adolescent Gynecology, and theInternational Federation of Pediatric and Adolescent Gynecology on November 18through 21, 1998 in Athens, Greece.

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