FE Viteri, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, 2909, Oakland, CA 94609, USA. E-mail: firstname.lastname@example.org, Phone: +1-510-450-7938, Fax: +1-510-450-7910.
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 influences 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 briefly addressed, as are some important aspects of antenatal nutritional interventions that include iron.
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 affect 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 pre-pregnancy 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 infant's 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 influences her reproductive performance and the health of her offspring begins with her own characteristics at birth and continues with the effects 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 identified as a gestational risk factor for a mother and her baby.2 Other important modifiers that influence 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 specific 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 newborn's 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 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 neonate's health and development and the newborn's 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-sufficient 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
Table 1. Iron requirements, costs, and savings during pregnancy and at delivery.
Requirements, costs, and savings
Amount of iron (mg)
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 200–250 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 significantly 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).
A strong association exists between fetal growth (size), duration of pregnancy, and the newborn's iron endowment. The original and groundbreaking studies by Widdowson7 on the trace elements of the fetus demonstrated, indirectly, that anything affecting fetal growth and time of delivery would affect 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.8–10
Table 2. Fetal total body mineral contents at different gestational ages.
In summary, the many factors affecting 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 newborn's iron endowment. The mother's iron status prior to and during pregnancy, as well as interventions aimed at maintaining and improving maternal health and iron nutrition, can also change the offspring's 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 affect iron endowment at birth. The often neglected paternal influences on the course of pregnancy and thus the endowment at birth are briefly 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. Specifically, the biochemical indicators of the iron status of non-pregnant WRA are unique in that they can measure with accuracy the different metabolic stages of this metal, from its absorption, transport once absorbed, utilization in heme formation, storage, reutilization, and its deficit or excess at the cellular level.11–13 Important and simple surrogates indicating a prolonged deficit of iron are the measurement of hemoglobin (Hb) concentration and the characteristics of red blood cells. Unfortunately, they lack the desired specificity. 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 Children's Hospital Oakland Research Institute). This non-invasive device effectively 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 defining mild-to-moderate iron deficiency (ID) in pregnancy? Unfortunately, not that well. There is overwhelming evidence indicating that the 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 definition of gestational anemia and of hemoconcentration, as well as that of ID and excess, are not that well defined, 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 woman's 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 µg/L) at the beginning of pregnancy developed gestational anemia later in pregnancy more than five 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 offspring. 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 deficient, and even in industrial societies close to half have unsatisfactory iron reserves.20,21
The specificity with which iron status is measured during pregnancy is limited because of several changes that affect 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-sufficient. In these studies, women received the following daily doses of iron supplements from early pregnancy: 20–80 mg,22 100 mg,23 and 200 mg24, 50–200 mg,26 or placebo23,24. Despite the various levels of iron supplementation, in the Milman sample,22 there were no differences 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 differ from those reported by Scanlon27 in a cross-sectional 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 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 modified in the direction of having lower iron status up to gestational weeks 30–32; 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 iron-binding capacity lower. Free erythrocyte protoporphyrins rose moderately at the same gestational weeks. Hb concentrations also dropped moderately in both groups until about gestational weeks 30–32, when those in the supplemented groups rose while those in the placebo groups continued to fall. Most other indicators tended to improve after weeks 32–34 in the supplemented group only.
Table 3. Evolution of the mean blood values of selected iron nutrition indicators during pregnancy in normal women receiving antenatal iron supplements.a
Blood and serum values were taken from references 22–27 cited in this paper. At higher altitudes, due to lower oxygen tensions, the Hb levels, erythrocyte numbers and hematocrit increase and derived parameters are affected.
1st T. = About First Trimester (12 weeks); 2nd T = About Second Trimester (24 weeks); 3rdT = About Third Trimester (36 weeks).
MCV, MeanCorpuscular Volume; MCH, Mean corpuscular Hemoglobin; MCHC, Mean corpuscular Hemoglobin Concentration.
Distribution of women with different 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 different amounts of bone marrow iron (** 0, TRACE, +, ++. +++ respectively).
NOTE: 9 weeks post-partum the % distribution of women with the different amounts of bone marrow iron were: for the placebo group 9, 17, 32, 42, and 0. The % distribution of women in the different categories for the supplemented group was 0, 0, 8, 71 and 21, indicating a significant 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.
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 modifications in iron metabolism and in several of the indicators of iron nutritional status during pregnancy that need clarification. Notably, even though these indicators suggest an iron-deficient state, particularly late in gestation (week 36), the incorporation of absorbed iron into Hb was lower than in the iron-deficient, non-pregnant women,24 which suggests effective competition for iron utilization from the feto-placental unit.
The cutoff 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 with the Hb levels reported as predictors of pregnancy outcome. Specifically, several studies indicate that the outcome of pregnancy is best when maternal Hb levels during the second and third trimesters are higher than 90–100 g/L and lower than 125 g/L.30–36 The lower concentrations are below the CDC/WHO cutoff levels for anemia (110 g/L in the first 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 first 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, effect on raising the incidence of premature delivery or low birth weight, including small-for-gestational-age (SGA) deliveries.38–40 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 cutoff 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 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 400–450 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 different 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, first 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 their deficit in mg/kg. This method is extremely useful and sufficiently accurate and precise, except at the extremes of iron excess and deficiency. 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 deficient, yet the cumulative frequency line is completely straight without showing any deviation in the deficient status compared to the sufficient 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 deficiency. 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 affects 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 (HIFα2) and gestational-associated hormonal changes also modify erythropoietic activity.51–53
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 mother's 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 confidence.
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 deficient 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, technological 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 different 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 influence pregnancy outcome?
There is evidence that supports a negative effect of ID anemia early in pregnancy on increasing the risk of premature delivery and low birth weight37 and of non-ID anemia during pregnancy affecting 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 effects from iron and micronutrient supplementation prior to and during pregnancy on infant birth weight and on gestation in general.2,19,54–57 However, many studies fail to show clearly beneficial effects 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 effects 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.61–64 Risk of low birth weight, premature delivery, and of small-for-gestational-age deliveries have been documented among pregnant women with hemoconcentration, especially during the second and early third trimesters.33,36,58,65–69
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 placenta's role in iron regulation provided here. However, it should be noted that the health and habits of the male parent, especially smoking and some specific nutrient deficiencies (i.e., folate and zinc) must not be ignored, since there is a risk of defective DNA in sperm that can affect 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 pre-pregnancy and periconceptional deficiencies can impair implantation and if implantation occurs, can affect all placental functions. By day 6 of fertilization, uterine implantation takes place, and by days 5–6 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 amnion-chorion 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.72–74
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 7–8 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 amnion-chorionic 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 first trimester of gestation, the major organ systems develop; during the second trimester (weeks 13–24) rapid growth and maturation 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 fetal-placental and maternal demands for iron increase. Fetal ferritin levels increase faster after week 30,8 indicating a drastic change in the fetus's 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 hypoxia-inducible factors, in coordination with iron-based increased reactive oxygen species, possibly modulate trophoblastic invasion of the decidua, leading to adequate placentation.80–82
Hypoxia augments the production of hypoxia-inducible 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 transferrin-binding and fetal transport.83–88 However, the oxidative environment, including the iron contents, must be controlled to avoid excessive stress that can induce placental pathology.88–93
On the maternal side, erythropoietic acceleration starts slowly at about gestational week 14 and accelerates until it stabilizes at about week 28–30. This coincides with the decline in maternal hepcidin production, with the changes in maternal biomarkers mimicking an iron-deficient 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 different 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 first 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 affect the fetal iron endowment, the practices of antenatal supplementation and the many factors that affect pregnancy duration and fetal development, the management of delivery, especially the timing of cord clamping, can modify the iron endowment 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 effects on the newborn.97
INTERVENTIONS TO IMPROVE MATERNAL AND NEWBORN IRON STATUS PRIOR TO AND DURING PREGNANCY
Efficiency, effectiveness, 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 mother's own fetal development. Later, interventions are aimed at the following: safeguarding and, if needed, improving the mother's 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 woman's 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 affect iron status, birth weight, and maternal health.98–100
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 newborn's iron endowment. The literature also indicates there is suggestive, but controversial, evidence for favorable effects 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 20–35% present with depleted iron stores and, even in the United 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 flows contribute to this picture.103,104
Chronic infections and conditions such as hookworm, Helicobacter pylori, HIV, malaria, and diverse chronic inflammatory conditions are additional contributors to inadequate iron status. Other intestinal parasites affecting 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 first 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 iron–folic acid supplementation during pregnancy conducted in malarial African countries provides important information on the positive effects 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 deficiency 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 effect of antenatal supplementation with iron, iron plus folic acid, or with iron plus other minerals and vitamins is abundant and includes different doses and forms of iron administration. Several reviews on this topic have been or are about to be published very soon.95,96,110–113 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 effects 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 preparation for a 2007 Global Conference in Manila that resulted in the WHO recommendation of targeted, preventive, weekly iron–folic acid pre-pregnancy supplementation of WRA who may become pregnant, as pioneered by the Western Pacific Regional Office of the World Health Organization (WPRO/WHO) and within it by Dr. T. Cavalli-Sforza, have been published, together with a WHO position statement.19,115–118
b) 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 effect of maternal iron status on the iron status of the newborn and suggest that this benefit results in improved long-term growth, development, and health.119–121 However, a careful balance between the benefits of increased iron intake and the negative effects 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-deficient 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.58,65,122–126 The implications of excess maternal iron in terms of the newborn's iron endowment and its long-term effects, while controlling for other independent factors, needs further exploration.
c) In terms of antenatal iron supplementation, the data comparing iron and folic acid with multivitamin and mineral supplementation show mild-to-moderate advantages of the latter, particularly in developing countries where multiple micronutrient deficiencies are prevalent.112
d) 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 effective as daily, compliance is higher, it produces less undesirable side effects and hemoconcentration, and it is safer.95,127
e) The impact of different strategies directed towards the community (schools, community groups, social 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 effects, fostering compliance with supplement intake, and improving gestational and neonatal health is not well defined, although examples abound demonstrating the positive effects 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 different forms of iron compounds and their modes of administration.
Timing of cord clamping and its effect on the newborn and infant
The next important condition that influences both the newborn's 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 significant increments in newborn's 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 specific conditions was needed. The safety of delayed cord clamping has been amply documented even under adverse circumstances of perinatal health.129–133
The importance of the best obstetric practice, including the timing of cord clamping, has been neglected as a factor influencing birth weight and the benefit-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 influences the iron legacy of the newborn and young infant.
The benefits of delayed cord clamping are shown in an important number of publications demonstrating the significant benefits and very small risk associated with this practice. Regarding birth weight, the volume of placental transfusion averages around 60 mL, with significant 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 benefits of delayed cord clamping in terms of hematological and iron nutrition status have been clearly demonstrated131–135 in healthy newborns as well as in low-birth-weight newborns, in whom it may be of greater benefit.
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 affect sperm quality and phenotypic expressions in the newborn.136–140 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
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 significantly improve the iron endowment of the newborn. It is recommended that these interventions be applied worldwide.
Dr. Kenneth J. Carpenter is thanked for his scientific and editorial comments on this manuscript.
Declaration of interest. The author has no relevant interests to declare.