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Iron endowment at birth: maternal iron status and other inuences

nure_449 3..16

Fernando E Viteri
The iron endowment at birth depends, in large part, on the newborn's birth weight and gestational age. These are determined by many factors, some of which are maternal characteristics, including the following: maternal iron stores at her own birth and during her own early life, maternal growth and development, maternal age at conception, intergenesic intervals, maternal body characteristics and iron status at conception and during early pregnancy, gestational body weight gain, and iron status throughout gestation, particularly at conception and early pregnancy, and gestational body weight gain. Although less studied, paternal inuences on the initiation and progression of pregnancy and on maternal environmental exposures are also important. Even though tools for the quantitative evaluation of women's iron status are very well developed, the quantitative estimation of body iron in the newborn and young infant remains a challenge. This article describes the crucial role played by the placenta in protecting the embryo and the fetus. In addition, neonatal health, particularly early in pregnancy, is briey addressed, as are some important aspects of antenatal nutritional interventions that include iron.
2011 International Life Sciences Institute

INTRODUCTION The old concept of the fetus as a parasite of the pregnant woman has evolved dramatically in recent decades, largely as a consequence of fundamental, clinical, and epidemiological research exploring how the conditions of the mother prior to and during gestation aect her newborn. While the embryo and the fetus are protected during pregnancy, the fetus interacts with the mother and partially determines their common fate. The prepregnancy and pregnancy iron status of the mother constitute an important component of her overall health, conditioning her reproductive performance, which, in turn, determines, in part, the infants iron endowment at birth. However, as this article aims to reinforce, neither iron nor pregnancy should be isolated from the rest of the nutrients and from the overall life-cycle characteristics, respectively, of both the future mother and father. Conditioning of the future mother that inuences her reproductive performance and the health of her

ospring begins with her own characteristics at birth and continues with the eects of environmental factors (her nutrition and health) that modify her growth and development, which determine, in turn, her adult height and her functions in the physical and mental spheres.1 A height below 145 cm has been identied as a gestational risk factor for a mother and her baby.2 Other important modiers that inuence her reproductive performance are her age at conception, her overall health and habits, her previous number of pregnancies and the intergenesic time span, her weight and body mass index prior to conception, her gestational weight gain, and her specic nutritional status prior to and during pregnancy. The paternal genetics, health, nutrition, and habits, which are often ignored, also contribute to the quality of the reproductive process and of the newborns health3; these are expanded upon towards the end of this article. It is clear that maternal health and nutrition during gestation modify fetal growth and pregnancy duration; to this, the following characteristics must be added: the

Aliation: FE Viteri is with the Department of Nutritional Sciences and Toxicology, University of California, Berkeley and Childrens Hospital Oakland Research Institute, Oakland, California, USA. Correspondence: FE Viteri, Childrens Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, 2909, Oakland, CA 94609, USA. E-mail: viteri@berkeley.edu, Phone: +1-510-450-7938, Fax: +1-510-450-7910. Key words: iron endowment, iron deciency, maternal iron status, newborns
doi:10.1111/j.1753-4887.2011.00449.x Nutrition Reviews Vol. 69(Suppl. 1):S3S16 S3

Table 1 Iron requirements, costs, and savings during pregnancy and at delivery. Requirements, costs, and savings Amount of iron (mg) Requirements and costs Fetus 270* Placenta 90 Expansion of red cell mass 450 Obligatory basal stores 230 Total cost of pregnancy 1,040 Maternal blood loss at delivery 150 Cost including delivery loss 1,190 Savings Contraction of maternal red 450 cell mass after birth No menstrual losses during 160 pregnancy Total 610* Net cost 580
* Normal fetal iron content at term has been estimated to be as high as 377 mg of iron, which would increase the total iron cost, without including blood loss at delivery, to 1,297 mg, and the net cost of iron, after reutilization of iron from maternal expanded hemoglobin mass, to 717 mg. The value of 450 mL applies to iron-supplemented women. In non-iron-supplemented women Hytten (6) measures maternal expansion of red cell mass to be 200250 mL, in which case total iron cost, without including blood loss at delivery, would be approximately 990 mg. The net cost would be the same: 580 mg. The whole issue of iron utilization in pregnancy is complex given that fetal demands for iron increase signicantly in the third trimester (approximately 370 mg at term for a normal baby), and that placental iron content varies (75 to 90 or up to 130 mg of iron). Data from Bothwell.5

environment, exposure of the mother to toxic elements, the quality of antenatal health care, and management of the birth process. These complex interactions determine the neonates health and development and the newborns iron endowment at birth. Moreover, these factors partially determine the long-term health of the new human being.4 A brief review of iron requirements during an average pregnancy provides a useful basis for interpreting the information that follows in this article. The values in Table 1 are taken from the estimates calculated by Bothwell5 for iron-sucient women with an average delivery blood loss of 300 mL. It is evident that increased red blood cell and hemoglobin production contribute to the maternal iron requirements.6 A strong association exists between fetal growth (size), duration of pregnancy, and the newborns iron endowment. The original and groundbreaking studies by Widdowson7 on the trace elements of the fetus demonstrated, indirectly, that anything aecting fetal growth and time of delivery would aect the iron endowment of the newborn (Table 2). Fetal ferritin concentrations also follow the gestational age-related iron content of the fetus, and formulas have been derived to estimate the iron stores of the newborn.810 In summary, the many factors aecting the pregnant woman, as well as fetal size and duration of gestation, are important determinants of the iron endowment of the newborn. Therefore, any circumstances that modify these conditions also modify the newborns iron endowment. The mothers iron status prior to and during pregnancy, as well as interventions aimed at maintaining and improving maternal health and iron nutrition, can also

Table 2 Fetal total body mineral contents at dierent gestational ages. Gestational age Zinc (mg) Copper (mg) Iron (mg) Body content Week 16 4.5 0.8 10 Week 24 15 1.7 38 Week 32 28 5.8 122 Week 40 60 18.4 377 Content (mg/g body weight) Week 16 (wt 100 g)* 0.05 0.001 0.12 Week 24 (wt 600 g)* 0.02 0.003 0.08 Week 32 (wt 1,918 g) 0.02 0.002 0.07 Week 36 (wt 2,383 g) 0.02 0.002 0.08 Week 40 (wt 3,462 g) 0.02 0.002 0.11 Ratio (mg liver/total) Week 16* 0.38 0.64 0.12 Week 24* 0.44 0.61 0.12 Week 32 0.27 0.66 0.12 Week 36 0.25 0.43 0.12 Week 40 0.25 0.47 0.11
* Values estimated from graphs. Data from Widdowson.7
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change the osprings iron endowment. But interventions to ensure that the iron needs of the infant continue to be met post partum are also important, e.g., management of the delivery process, feeding practices of the newborn, including breast or formula feeding, and, later, complementary food practices. Several of these important aspects and their consequences are expanded upon in other articles in the present supplement. This article focuses on how many maternal characteristics especially during gestation, not only her iron nutritional status, and the managing of delivery aect iron endowment at birth. The often neglected paternal inuences on the course of pregnancy and thus the endowment at birth are briey described. MATERNAL IRON STATUS AND HEALTH PRIOR TO AND DURING GESTATION How well can iron status and health be measured and when should they be evaluated? A variety of tools have been developed for evaluating the iron nutritional status and metabolism of women of reproductive age (WRA) prior to and during pregnancy, and for evaluating the likelihood of a pregnant woman producing a baby with desirable iron conditions. Specically, the biochemical indicators of the iron status of nonpregnant WRA are unique in that they can measure with accuracy the dierent metabolic stages of this metal, from its absorption, transport once absorbed, utilization in heme formation, storage, reutilization, and its decit or excess at the cellular level.1113 Important and simple surrogates indicating a prolonged decit of iron are the measurement of hemoglobin (Hb) concentration and the characteristics of red blood cells. Unfortunately, they lack the desired specicity. Specialized biochemical techniques have been developed to measure iron stores and factors that control iron absorption and the regulation of iron metabolism.14 Also, body iron reserves can be measured by the superconducting quantum interference device (Ferritometer), of which there are only four worldwide (one is at Childrens Hospital Oakland Research Institute). This non-invasive device eectively measures liver iron content, particularly when it is elevated. Unfortunately, its use is expensive, body characteristics may interfere with its performance, and its precision decreases in the lower ranges of liver iron stores when compared to liver biopsy iron measurements.15 In any case, there are no studies on measurements of iron stores in pregnant women using this non-invasive method. How well do the commonly available biochemical techniques function in dening mild-to-moderate iron deciency (ID) in pregnancy? Unfortunately, not that well. There is overwhelming evidence indicating that the
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great majority of cases of gestational anemia from the second trimester onwards are due to ID because of the overall higher demands for iron during the second and third trimesters. However, the denition of gestational anemia and of hemoconcentration, as well as that of ID and excess, are not that well dened, particularly considering that ID of nutritional origin and anemia associated with it are generally mild to moderate.16,17 Severe anemia is generally the result of complicating factors. An important example of the relationship between a womans iron status at or near the time of conception and the occurrence of gestational anemia later in pregnancy is a publication from Mexico by Kaufer and Casanueva.18 Their report showed very clearly that women with absent or with low iron reserves (serum ferritin < 20 mg/L) at the beginning of pregnancy developed gestational anemia later in pregnancy more than ve times more frequently than women with larger iron reserves at gestational week 10. Similarly, other studies19 have reinforced the importance of pre-pregnancy iron nutrition for the prevention of gestational ID and anemia during the course of pregnancy and for the welfare of ospring. In anemic pregnant women, ID is generally the primary cause but this may not be the case in women with concomitant malaria, HIV, and other infections and in the presence of hemoglobinopathies. Importantly, about one-third of non-pregnant WRA worldwide are iron decient, and even in industrial societies close to half have unsatisfactory iron reserves.20,21 The specicity with which iron status is measured during pregnancy is limited because of several changes that aect the indicators of iron nutrition. For example, Table 3 presents the evolution of the mean values of indicators commonly used during pregnancy, based on the classic longitudinal studies by Milman et al.,22 Romslo et al.,23 Svanberg,24 Sjostedt et al.,25 Puolakka,26 and Scanlon et al.,27 with female participants who were healthy, non-anemic, and iron-sucient. In these studies, women received the following daily doses of iron supplements from early pregnancy: 2080 mg,22 100 mg,23 and 200 mg24, 50200 mg,26 or placebo23,24. Despite the various levels of iron supplementation, in the Milman sample,22 there were no dierences in the parameters measured except for serum ferritin levels, that decreased continuously up to gestational week 32 among women receiving 20 mg of iron daily, while serum ferritin levels showed an increasing trend at that gestational week among women receiving more supplementary iron. Therefore, all the values in that publication are pooled as a single supplemented group. The geometric mean values for Hb do not dier from those reported by Scanlon27 in a crosssectional study of iron-supplemented women in the United States and from the median values considered normal by the Centers for Disease Control (CDC),28 as based on four studies with a small number of healthy
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Table 3 Evolution of the mean blood values of selected iron nutrition indicators during pregnancy in normal women receiving antenatal iron supplements.a Parameter Normal values for females Males Non-pregnant Pregnant 1st T.* 2nd T* 3rdT* 3.94.9 3.9 3.9 4.0 4.35.5 Erythrocytes (1012/L)1 120147 120 118 124 131165 Hemoglobin (g/L)1 3644 35 35 37 3849 Hematocrit (%)1 8294 89 91 91 8294 MCV (fL)1 Serum iron (mg/dL) 40150 106 90 80 50175 TIBC (mg/dL) 240450 347 430 506 240450 Saturation of TIBC (%) 2050 30.5 20.9 15.9 2050 FEPmg/100 mL RBC 15.71 7.26 15.7 18.2 23.2 15.71 7.26 FEP/Hb ratio 0.44 0.21 0.52 0.61 0.78 0.44 0.21 Serum ferritin mg/L 12150 32 18 21 12300 Soluble Transferrin Receptors (mg/L) 5.36 0.82 5.4 8.0 8.6 5.36 0.82 (STfR) <8.0 2833 32 33 32 2833 MCH1 (pg/cell) 3236 33.8 33.8 33.8 3235 MCHC1 (g/dL) Red cell diameter width coecient of 1115 1115 1115 variation Reticulocyte Hemoglobin contents (pg) 2632 >26 pg/L 2632 Bone marrow iron** Gestational week 12 1 35 1 % in Placebo group respectively** 0, +, ++, +++ or ++++ 2, 10, 31,53, 4** 79, 21, 0, 0, 0** % in Supplemented group 0, +, ++, +++ ++++ 2, 2, 38, 44, 14** 41, 24, 35, 0, 0** respectively**
Blood and serum values were taken from references 2227 cited in this paper. At higher altitudes, due to lower oxygen tensions, the Hb levels, erythrocyte numbers and hematocrit increase and derived parameters are aected. * 1st T. = About First Trimester (12 weeks); 2nd T = About Second Trimester (24 weeks); 3rdT = About Third Trimester (36 weeks). 1 MCV, MeanCorpuscular Volume; MCH, Mean corpuscular Hemoglobin; MCHC, Mean corpuscular Hemoglobin Concentration. ** Distribution of women with dierent amounts of bone marrow iron are taken from the studies by Svanberg24 where normal Scandinavian women received antenatally either iron supplements or placebo. Percent of women at 12 1 gestational week, and at 35 1 gestational week with dierent amounts of bone marrow iron (** 0, TRACE, +, ++. +++ respectively). NOTE: 9 weeks post-partum the % distribution of women with the dierent amounts of bone marrow iron were: for the placebo group 9, 17, 32, 42, and 0. The % distribution of women in the dierent categories for the supplemented group was 0, 0, 8, 71 and 21, indicating a signicant increase in iron stores in the supplemented group compared to women in the 12th gestational week, even though bone-marrow iron at week 35 showed many women (41%) with iron depletion among the supplemented group.
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supplemented women in northern Europe. The CDC values for Hb concentration at week 24 are 115 g/L. These values are lower than 118 and 117 g/L reported by Scanlon27 and Milman22 respectively. The indicators of iron status in the women receiving supplements and in those receiving placebos were all modied in the direction of having lower iron status up to gestational weeks 3032; serum ferritin and serum iron both declined (serum iron less dramatically in the iron-supplemented groups), while total iron-binding capacity rose more in the placebo group, making the percent saturation of total ironbinding capacity lower. Free erythrocyte protoporphyrins rose moderately at the same gestational weeks. Hb concentrations also dropped moderately in both groups until about gestational weeks 3032, when those in the supplemented groups rose while those in the placebo groups continued to fall. Most other indicators tended to improve after weeks 3234 in the supplemented group only.
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What is important is that, even when normal European women were receiving as much as 200 mg of iron daily, the biochemical indicators pointed in the direction of poorer iron status. Similarly, the marked decline in bone-marrow iron (Table 3) even in women receiving 200 mg of iron daily24 by gestational week 35, strongly suggests there are modications in iron metabolism and in several of the indicators of iron nutritional status during pregnancy that need clarication. Notably, even though these indicators suggest an iron-decient state, particularly late in gestation (week 36), the incorporation of absorbed iron into Hb was lower than in the iron-decient, non-pregnant women,24 which suggests eective competition for iron utilization from the feto-placental unit. The cuto points for Hb levels in the diagnosis of gestational anemia, as proposed by the CDC and the World Health Organization (WHO),28,29 do not coincide
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Figure 1 Bone marrow iron during and after pregnancy. * Arbitrary scale by the total sum of points, assigning values of 0, 1, 2, 3, and 4 points to percent cases with 0, +, ++, +++, and ++++ iron staining in bone marrow at each occasion. Prepared from Svanbergs data.24 with the Hb levels reported as predictors of pregnancy outcome. Specically, several studies indicate that the outcome of pregnancy is best when maternal Hb levels during the second and third trimesters are higher than 90100 g/L and lower than 125 g/L.3036 The lower concentrations are below the CDC/WHO cuto levels for anemia (110 g/L in the rst and third trimesters and 105 g/L during the second trimester). Whether or not anemia is a cause of low birth weight or premature delivery and of perinatal risk is controversial, depending on if it is due to ID in the rst trimester of pregnancy, as described in the Camden study,37 or later, or if it is mild, moderate, or severe. Mild-to-moderate maternal anemia (Hb > 90 100 g/L) has little, if any, eect on raising the incidence of premature delivery or low birth weight, including small-for-gestational-age (SGA) deliveries.3840 However, the more severe the anemia, the higher the obstetric and perinatal risks.38 On the other hand, the risk for low birth weight and premature delivery begins to increase steeply when Hb levels rise above 125 g/L in the second and third trimesters.36 It is important to keep in mind that in the case of black women, more cases of anemia are observed if the distributions and cuto points derived from the northern European and CDC population studies are used because Hb levels in healthy black women are 0.8 g/L lower.29 This means ethnicity must be taken into account when Hb level is a variable being considered. The indications suggestive of iron depletion during gestation, even when supplementation with high iron doses is administered, was corroborated by the studies of Svanberg et al.,24 who demonstrated a marked decline in bone-marrow iron among women supplemented with 200 mg of iron daily, as indicated above. Moreover, his studies clearly show increased iron absorption in the third trimester of pregnancy. In contrast, in bone marrow
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samples taken 9 weeks post partum, the supplemented women had higher levels of iron in bone marrow than was present early in pregnancy, indicating that the high levels of supplemented iron were partially accumulated despite the blood biochemical indicators reductions in bone marrow iron, suggesting progressive depletion of the metal during pregnancy (Figure 1). The well-known changes in plasma and red-cell volumes do not fully explain the changes in Hb concentration and in the biochemical indicators of iron status compared to their behavior in non-pregnant women, except that according to Hytten6 iron-supplemented pregnant women increase their total red cell volume by 400450 mL compared to non-supplemented women, who increase their total red cell volume by about 250 mL. The post-partum resorption of the larger Hb mass may explain the post-partum increase in bone marrow iron among the supplemented women. The parallel changes in bone marrow iron observed in the groups in Figure 1 are quite striking. However, the components of total points in each are dierent in that 79% of the non-supplemented group at week 35 had no bone marrow iron while 41% of the supplemented group had no bone marrow iron; in the non-supplemented group in the post-partum period, only 9% lacked bone marrow iron and 47% had 3 plus 4 plus iron estimates (3 and 4 being +++ and ++++ iron, respectively), while in the supplemented group, the same bone marrow iron categories were 0% and 92% respectively. A new form of estimating body iron, rst proposed by Skikne et al.41 and Cook et al.,42 consists of the logarithm of the ratio of soluble transferrin receptors to serum ferritin. This has facilitated the estimation of iron stores as compared to previous methods. The two groups of researchers demonstrated that the logarithm of this ratio was linearly correlated with body iron stores and
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their decit in mg/kg. This method is extremely useful and suciently accurate and precise, except at the extremes of iron excess and deciency. Moreover, the plotting of body iron (mg/kg body weight) scores estimated using this method, versus the percent cumulative frequency distribution of populations, reveals deviation of the linear regression to indicate a higher prevalence of ID at the high values of this ratio in a population of US women between the ages of 20 and 45 years; this indicates the presence of ID in this female population while the straightness of the regression line is conserved in the case of a US male population, as is to be expected due to the absence of ID in this group. Similar results were obtained using a previous algorithm to estimate iron status.43,44 When this method is applied to pregnant women, it appears that 50% of pregnant Jamaican women are iron decient, yet the cumulative frequency line is completely straight without showing any deviation in the decient status compared to the sucient status. This suggests that iron depletion does not exist beyond a normal depletion determined by this method, which displays a normally distributed continuum rather than a tail that deviates from the straight line indicating a true state of iron deciency. This may be due to the changes in indicators that take place during pregnancy, whereby serum ferritin levels decline even when women are ingesting large doses of iron supplements, and transferrin receptor levels increase as a consequence of increased erythropoiesis45,46; this aects the ratio independently of true iron status. New technologies also allow study of the regulation of iron metabolism, beginning with iron absorption, by measuring regulatory proteins like hepcidin47,48 and iron availability for erythropoiesis by the characteristics of red cells and of reticulocytes46,49 as well as by estimating the hypoxic state and the response to that stimulus by measuring erythropoietin.50 Hypoxic inducible factor (HIFa2) and gestational-associated hormonal changes also modify erythropoietic activity.5153 Maternal iron status after delivery and during lactation depends on the iron status during gestation, with the additional consequences of blood loss during delivery and of the reutilization after childbirth of the iron incorporated into the mothers increased red cell mass. The indicators of iron status readjust a few weeks after delivery, returning to their original pre-pregnancy meaning and the estimate of body iron can again be measured with condence. In essence, researchers are now uniquely able to quantify the iron content of most non-pregnant persons thanks to the development of technology that, when properly used, can determine not only a decient or an excessive level of this metal but also how the level evolves over the course of life events and diverse interventions. Unfortunately, in the case of the pregnant woman, techS8

nological capabilities are still limited, with obstacles to determining the relationship between maternal iron status and fetal-newborn iron status remaining, as explained below. If possible, studies using the superconducting quantum interference device in pregnant women could be very revealing if dierent obstacles posed by maternal and fetal anatomical/structural changes can be overcome. The estimation of iron reserves of the newborn is not that simple either. It is based on total Hb-iron, serum ferritin concentration, body weight, and functional body iron content estimated by a constant per kg body weight.9,10 How do maternal iron status and health inuence pregnancy outcome? There is evidence that supports a negative eect of ID anemia early in pregnancy on increasing the risk of premature delivery and low birth weight37 and of non-ID anemia during pregnancy aecting its outcome.29 In contrast, many results from interventions aimed at improving the iron status of mothers show that there are, under most circumstances, positive eects from iron and micronutrient supplementation prior to and during pregnancy on infant birth weight and on gestation in general.2,19,5457 However, many studies fail to show clearly benecial eects on the outcome of pregnancy. This may be due to the multiple causalities of birth weight and gestation duration, as indicated above. Also, there is mounting evidence that suggests more iron intake is not always better.58 The same applies to other nutrients, like vitamin A.59,60 Indeed, high iron intake can have undesirable eects through diverse mechanisms including oxidative stress due to reactive oxygen species and, probably, by inducing hemoconcentration leading to elevated blood viscosity, poor placental perfusion, and risk of preeclampsia.6164 Risk of low birth weight, premature delivery, and of small-for-gestationalage deliveries have been documented among pregnant women with hemoconcentration, especially during the second and early third trimesters.33,36,58,6569 ROLE OF THE PLACENTA IN TRANSFERRING IRON TO THE FETUS The rapid speed at which events happen from the moment of conception is amazing, and it reinforces the importance of pre-pregnancy nutrition in general and of iron in particular, given the high prevalence of ID in women of fertile age.In another article in this supplement,Dr.H.McArdle70 expands upon the brief account of the placentas role in iron regulation provided here.However,it should be noted that the health and habits of the male parent, especially
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smoking and some specic nutrient deciencies (i.e.,folate and zinc) must not be ignored, since there is a risk of defective DNA in sperm that can aect early gestational processes and birth defects. Trophoblasts, the precursor cells leading to development of the placenta, begin to appear only 4 days after conception, as the fertilized ovum traverses the fallopian tubes. These cells are critical for all placental functions, including implantation, immune protection of the fetus, placental hormone production, and placental perfusion. Defective production of trophoblasts because of prepregnancy and periconceptional deciencies can impair implantation and if implantation occurs, can aect all placental functions. By day 6 of fertilization, uterine implantation takes place, and by days 56 human chorionic gonadotrophin is produced by the embryo, leading to preparation of the decidual endometrium for these events. The embryo is in the form of a blastocyst with a cellular mass on the implantation site that will develop into the placenta and the fetus, and with a cyst that will become the amniotic sac, contained within the amnionchorion membrane.71 Decidual circulation is reduced and oxidative stress, together with a hypoxic state, activates the production of growth transforming factor-beta-3, which is essential for normal placentation.7274 Trophoblast invasion of the endometrium is further modulated by uterine cytokines and proteases and by a highly regulated oxidative process essential for healthy placental development.75,76 Excessive oxidation can impair the delicate steps in the formation of cytotrophoblasts and scyncytiotrophoblasts, that start by day 9. These cells in the placental membranes are involved in nutrient transfer to the fetus. As invasion continues, villi form that are bathed by maternal blood originating from spiral arteries in the endometrium. Blood dilution favors circulation in these convoluted arteries. By week 3 of gestation, fetal circulation becomes evident, and by week 4 the neural tube has closed. These very early events that include organogenesis (beginning by week 3 and almost complete by weeks 78 of fertilization) reinforce the importance of optimizing pre- and periconceptional nutritional status and health. By week 20, the amnion-chorion membrane reaches the distant endometrium from the implantation site and forms the amniotic membrane; this consists of amnionchorionic and decidual layers that degenerate, forming the complete external membrane. Healthy collagen in these membranes protects the fetus, and vitamin C plays an important role in this process, preventing premature rupture of the membranes and premature delivery.77,78 In summary, by mid-pregnancy, most essential events have occurred. During the rst trimester of gestation, the major organ systems develop; during the second trimester (weeks 1324) rapid growth and matuNutrition Reviews Vol. 69(Suppl. 1):S3S16

ration take place; this continues through the third trimester, when fetal weight and length become accelerated. Deposition of minerals in general is particularly important with each day of pregnancy duration, given the accelerated fetal growth during the 3rd trimester (Table 2).7 Fetuses accumulate iron throughout gestation, with accumulation accelerating from week 24 onwards, reaching the fastest increments in iron accumulation (mg per gram body weight) near term. Body contents of copper and zinc also increase with gestational age, but their concentrations per gram of body weight remain constant. Consequently, prematurity and low birth weight place newborns and infants at greater risk of ID. Importantly, fetal liver iron concentration and total body iron maintain a constant ratio throughout pregnancy while erythropoietic acceleration and growth occur. Between gestational weeks 8 and 30, the liver is the main erythropoietic organ79 it produces erythropoietin and is also the main producer of hepcidin in direct relation to liver iron reserves. It would appear logical that liver iron would be reduced because of high demands for Hb synthesis and this would result in lower hepcidin production, favoring iron transport. Fetal hepcidin would then regulate ferroportin and Divalent Metal Transporter 1 (DMT1) levels in the placenta, thus establishing the communication between mother and fetus as determinants of their iron status. Fetal bone marrow erythropoiesis starts early but accelerates from week 24 to birth, surpassing liver red cell production at about week 30, a time when 50% of red cells are produced by each of these two organs. Liver erythropoiesis declines from about week 24 to birth, while both fetalplacental and maternal demands for iron increase. Fetal ferritin levels increase faster after week 30,8 indicating a drastic change in the fetuss dominant utilization of iron from liver Hb production to bone-marrow blood production and ferritin iron storage (iron reserves). The fetal-placental environment is hypoxic, particularly in early pregnancy when the family of hypoxiainducible factors, in coordination with iron-based increased reactive oxygen species, possibly modulate trophoblastic invasion of the decidua, leading to adequate placentation.8082 Hypoxia augments the production of hypoxiainducible factor 1, which results in the transcriptional activation of several genes that increase iron capture and utilization in the following ways: elevating divalent metal transporter 1 and transferrin receptor levels, modifying iron regulatory proteins, increasing ferroportin, and elevating copper uptake and ceruloplasmin production at the fetal side, as needed to oxidize iron for transferrinbinding and fetal transport.8388 However, the oxidative environment, including the iron contents, must be
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controlled to avoid excessive stress that can induce placental pathology.8893 On the maternal side, erythropoietic acceleration starts slowly at about gestational week 14 and accelerates until it stabilizes at about week 2830. This coincides with the decline in maternal hepcidin production, with the changes in maternal biomarkers mimicking an irondecient state, and with the increase in iron absorption. Later in pregnancy, indirect evidence suggests that fetal demands for iron drive the changes in iron absorption and metabolism in pregnancy. Indeed, a greater fetal iron deposit near term lowers maternal iron status.95 In maternal ID, the syncytiotrophoblast reacts as if hypoxic by increasing the cytochrome C reductase, as well as the divalent metal transporter, the transferrin receptors, and the ferroportin levels. There are also favorable interactions with other nutrients that increase iron transport, like copper content that is increased in ID and acts as ceruloplasmin-iron-oxidase, as well as through oxidases similar to hephaestin. All these changes favor iron transfer to the fetus. On the other hand, as indicated above, fetal liver iron levels regulate the production of hepcidin by the mother favoring maternal iron absorption and possibly placental expression/function of ferroportin. All the changes in iron metabolism and erythropoiesis, and the forces modifying them during the dierent gestational ages, makes the second trimester and early third trimester particularly vulnerable times for the mother and the fetus; during this time they are at increased risk for the development of ID as well as for an overreaction to excess iron absorption/ availability leading to oxidative stress and excessive erythropoiesis resulting in hemoconcentration, higher blood viscosity, and poor placental perfusion, with the consequence of premature delivery, low birth weight, smallness for gestational age, and preeclampsia.64,65,69 Generally, these conditions are detected at or near term becase this is the time when they are explored but they, most probably, occurred earlier.95,96 It is interesting to note a higher ratio of liver/total body copper in the rst trimester of pregnancy, even though iron requirements are lowest during early gestation. The functional meaning of this is not entirely clear, but the article by Dr. H. McArdle in the present supplement, covers the role of the placenta in fetal iron status in detail.70 Besides these carefully concerted mechanisms aimed at protecting fetal iron status and favoring maternal iron absorption and erythropoiesis, which aect the fetal iron endowment, the practices of antenatal supplementation and the many factors that aect pregnancy duration and fetal development, the management of delivery, especially the timing of cord clamping, can modify the iron endowS10

ment of the newborn. In another article in the present supplement, Dr. Chaparro expands on this last important step in the reproductive process and describes its eects on the newborn.97 INTERVENTIONS TO IMPROVE MATERNAL AND NEWBORN IRON STATUS PRIOR TO AND DURING PREGNANCY Eciency, eectiveness, and safety for the mother and the infant As indicated above, primary interventions to improve the health and iron status of mothers and their newborns prior to and during pregnancy should start prior to conception and during the mothers own fetal development. Later, interventions are aimed at the following: safeguarding and, if needed, improving the mothers nutrient intake and utilization; reducing toxic exposures; avoiding teenage pregnancies and short intergenesic intervals; and controlling infections (i.e., HIV, malaria, Helicobacter pylori, hookworm and other intestinal parasites, schistosomiasis, sexually transmitted infections, etc.). An adequate dietary intake of macro- and micronutrients during a womans lifetime, beginning during her own fetal development, ensures the future mother enters pregnancy with adequate development and nutrient status; thus, attaining adequate nutrient reserves should be the primary aim of any intervention. Unfortunately, in low socioeconomic populations, where intergenerational poor nutrition and a hostile environment exist, fetal and early childhood malnutrition and inadequate development increase reproductive risk for the adult woman. Similarly, an inadequate body mass index at conception, or early in pregnancy, and poor weight gain during pregnancy, as well as obesity prior to conception and excessive gestational weight gain and adiposity, increase gestational risk and negatively aect iron status, birth weight, and maternal health.98100 It is obvious that adequate protein, energy, and vitamin and mineral status prior to and throughout pregnancy are favorable for ensuring a positive pregnancy outcome, including the newborns iron endowment. The literature also indicates there is suggestive, but controversial, evidence for favorable eects related to increased intake of omega-3 fatty acids on gestation and on the newborn.101,102 Within this general picture, inadequate iron nutrition is particularly important. Still focusing on this element, the risk of ID and of entering pregnancy with poor iron reserves is particularly serious among teenagers and women with multiple pregnancies, especially if the intergenesic period is short.98 Even in otherwise well-nourished WRA, about 2035% present with depleted iron stores and, even in the United
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States, more than 50% of women have less than 300 mg iron reserves or <5 mg of iron per kg body weight.41 Cereal-based diets with poor consumption of meats (heme iron) and of vitamin C-containing foods in the meal, and normal, but abundant, menstrual ows contribute to this picture.103,104 Chronic infections and conditions such as hookworm, Helicobacter pylori, HIV, malaria, and diverse chronic inammatory conditions are additional contributors to inadequate iron status. Other intestinal parasites aecting food intake and gastrointestinal functions and iron sequestration also increase ID risk. Therefore, control of these factors favors maternal iron status prior to and during pregnancy. Some antihelminthic agents are recommended only after the rst trimester as a precaution against birth defects, even though there is currently no evidence to indicate they pose such a risk. A recent study on antimalarial treatments and ironfolic acid supplementation during pregnancy conducted in malarial African countries provides important information on the positive eects and safety of these combined measures.105 Interestingly, on the side of excess nutrition, obesity is associated with increased hepcidin production and poor regulation of its interaction with other molecules involved in iron metabolism, which can lead to ID.99,100 Also, the regulatory function of hepcidin seems to be impaired in preeclamptic states, some of which are induced by excessive iron intake during gestation.106 Equally important is the fact that excessive iron intake can impair the absorption of other minerals, like zinc,107 and reduce the nutritional status of antioxidant vitamins C and E,108 favoring oxidative processes caused by excess iron leading to defective placental development. This is in addition to the previously mentioned risk that subclinical vitamin C deciency can cause premature rupture of amniotic membranes, leading to premature delivery. Excess vitamin A early in pregnancy has been associated with cranial and heart birth defects.60,109 The literature on studies of the eect of antenatal supplementation with iron, iron plus folic acid, or with iron plus other minerals and vitamins is abundant and includes dierent doses and forms of iron administration. Several reviews on this topic have been or are about to be published very soon.95,96,110113 This topic is covered in greater detail in the present supplement by Dr. T. Scholl116; thus, the information presented here is painted in broad strokes. a) In contrast with the eects of antenatal supplementation, there is a scarcity of studies on targeted, preventive supplementation with iron and folic acid to WRA in preparation for pregnancy, yet, its impact on gestation and newborn characteristics is astounding. Some of the documents reviewed in
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b)

c)

d)

e)

preparation for a 2007 Global Conference in Manila that resulted in the WHO recommendation of targeted, preventive, weekly ironfolic acid prepregnancy supplementation of WRA who may become pregnant, as pioneered by the Western Pacic Regional Oce of the World Health Organization (WPRO/WHO) and within it by Dr. T. Cavalli-Sforza, have been published, together with a WHO position statement.19,115118 There is also a scarcity of longitudinal studies that explore the impact of antenatal iron supplementation on the health and iron status of the newborn at birth and later. The studies approaching this important question directly and indirectly show a positive eect of maternal iron status on the iron status of the newborn and suggest that this benet results in improved long-term growth, development, and health.119121 However, a careful balance between the benets of increased iron intake and the negative eects of excessive iron intake (e.g., in areas with chronic hyperendemic malaria and possibly in populations with other chronic infections) must be recognized and be kept in mind. This balance is critical, particularly in non-anemic or mildly anemic women of childbearing age (pregnant or not and iron-decient or not). Both ID and excess iron alter mitochondrial function and carry risks because of oxidative stress; particularly during pregnancy, excess iron can produce hemoconcentration, which also carries risk.58,65,122126 The implications of excess maternal iron in terms of the newborns iron endowment and its long-term eects, while controlling for other independent factors, needs further exploration. In terms of antenatal iron supplementation, the data comparing iron and folic acid with multivitamin and mineral supplementation show mild-tomoderate advantages of the latter, particularly in developing countries where multiple micronutrient deciencies are prevalent.112 There is ongoing debate regarding the advantages of daily or preventive, intermittent supplementation prior to and during pregnancy. WHO recommends a weekly preventive supplement of iron and folic acid to women of reproductive age in areas where the prevalence of ID in that age group is greater than 20%.120 It appears that intermittent supplementation during pregnancy is as eective as daily, compliance is higher, it produces less undesirable side eects and hemoconcentration, and it is safer.95,127 The impact of dierent strategies directed towards the community (schools, community groups, social
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marketing, mass communication strategies, general stores and/or pharmacies, etc.), as well as towards the supplement prescribers and healthcare providers in centers aimed at improving safety, reducing undesirable side eects, fostering compliance with supplement intake, and improving gestational and neonatal health is not well dened, although examples abound demonstrating the positive eects of such interventions in terms of the iron status of WRA. f) There is very little information on the acceptability and logistics (cost, implementation strategies, etc.) of dierent forms of iron compounds and their modes of administration.

PATERNAL INFLUENCES The genetic and epigenetic (nutritional, age-related, and toxicologically induced) paternal characteristics are gaining recognition as important components of reproductive outcomes through genetic imprinting. Folate and zinc nutrition, as well as chronic mild lead intoxication and smoke exposure, are known to aect sperm quality and phenotypic expressions in the newborn.136140 Moreover, maternal exposure to secondary smoke from paternal smoking results in low birth weight and, consequently, lower iron endowment of the newborn with its associated long-term negative consequences.141 CONCLUSION

Timing of cord clamping and its eect on the newborn and infant The next important condition that inuences both the newborns weight and its iron endowment is the timing and conditions in which the cord is clamped after delivery. Moss and Monset-Couchard128 reviewed the available information on placental transfusion from 1885 to 1996 and concluded that delayed clamping resulted in signicant increments in newborns blood volume and that placental transfusion did not harm the baby, be it at term and healthy or premature and of low weight, but that given the number of uncontrolled variables in most studies more research considering specic conditions was needed. The safety of delayed cord clamping has been amply documented even under adverse circumstances of perinatal health.129133 The importance of the best obstetric practice, including the timing of cord clamping, has been neglected as a factor inuencing birth weight and the benet-to-risk ratio for preventing ID and anemia in the newborn and young infant. In the present supplement, Dr. C.M. Chaparro97 addresses how delayed cord clamping inuences the iron legacy of the newborn and young infant. The benets of delayed cord clamping are shown in an important number of publications demonstrating the signicant benets and very small risk associated with this practice. Regarding birth weight, the volume of placental transfusion averages around 60 mL, with signicant variation depending on how and when cord clamping is performed and other variables, including the gestational age at delivery, vaginal or cesarean birth, timing of clamping, and the position of the newborn in relation to the placenta.134 The benets of delayed cord clamping in terms of hematological and iron nutrition status have been clearly demonstrated131135 in healthy newborns as well as in low-birth-weight newborns, in whom it may be of greater benet.
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Iron endowment of the newborn is partially protected by the placental transport of iron. In spite of this protective function, iron endowment depends on multiple factors that include intergenerational characteristics of the mother and father, gestational health and nutrition, duration of pregnancy, and management of delivery. Interventions aimed at improving pre-pregnancy and gestational nutrition and health, and delayed cord ligation can signicantly improve the iron endowment of the newborn. It is recommended that these interventions be applied worldwide. Acknowledgments Dr. Kenneth J. Carpenter is thanked for his scientic and editorial comments on this manuscript. Declaration of interest. The author has no relevant interests to declare. REFERENCES
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