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Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21211;
* Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853;
Nutrition, University of Zimbabwe, Harare, Zimbabwe; and
** Paediatrics and Child Health, University of Zimbabwe, Harare, Zimbabwe
2To whom correspondence should be addressed. E-mail: zvitambo{at}yahoo.com.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • HIV • neonate • infant • hemoglobin • ferritin
Iron deficiency is the most common cause of anemia worldwide; in children, it is associated with impaired behavioral and cognitive development (1). It is generally assumed that the infant born at term with an adequate birthweight has sufficient iron stores to meet its needs for the first 6 mo of life (2,3). However, in some populations, anemia may be prevalent at younger ages (4). Certain developmental opportunities occur only during a particular period of life; thus, it is urgent to prevent iron deficiency at as early an age as possible because the developmental deficit may be irremediable.
One method of preventing postnatal iron deficiency is to ensure that the infant begins life with a full endowment of iron. Transfer of iron from mother to the fetus is regulated by the placenta (5) and begins during the first trimester of gestation (6), with approximately two thirds of fetal accretion occurring during the third trimester (7,8). The total body iron content of infants born any time during the third trimester increases progressively with body weight and has been estimated to be 
75 mg/kg (7). However, babies born preterm or with low birthweight have smaller absolute amounts of iron and are prone to early postnatal iron deficiency (9). It was long believed that the acquisition of iron by the fetus is largely independent of maternal iron status (10–12), except perhaps when infants are born to severely anemic mothers (13); however, a number of studies have challenged this dogma (4,14–19). Part of this apparent discrepancy could be the lack of age-specific criteria for assessing anemia and iron status in early infancy or identifying infants who are at risk for early depletion of iron stores.
Iron is partitioned in the body, and is found primarily in the circulation as hemoglobin (Hb)4 (20). A minimal amount is present in muscle cells as myoglobin and in iron-containing enzymes and transport proteins. The remainder is found in storage mostly as ferritin and a small quantity as hemosiderin. In newborns, there is a high percentage of iron in Hb, but there is also a sizeable amount in body stores, and concentrations of Hb and plasma ferritin are relatively high at birth (2). Shortly thereafter, Hb begins a dramatic decline, as the breakdown of fetal red blood cells exceeds the formation of new erythrocytes. Iron (3.4 mg/g Hb) is released and salvaged by the reticuloendothelial system for later use. Measurement of either plasma ferritin or Hb concentration alone neglects the substantial contribution of the other to total body iron (TBI). The TBI content of the infant can be calculated as the sum of body storage iron (estimated from plasma ferritin concentration) and Hb iron. However this method has been applied only to relatively small samples of infants in well-nourished populations (17,21–27).
Our objective was to examine the relationship of TBI at birth to subsequent anemia in infancy and to maternal and fetal characteristics in a large sample of African infants. We measured plasma ferritin, Hb concentration and birthweight in Zimbabwean newborns and quantified the prenatally acquired iron endowment by estimating TBI at birth. We related this birth estimate of TBI to the development of postnatal anemia and examined the potential determinants of TBI, specifically maternal Hb concentration, preterm birth, the sex of the infant, HIV infection, maternal age, maternal mid-upper arm circumference and parity.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The study was carried out in Harare, the capital of Zimbabwe. Harare has a temperate climate, with a mean daily maximum temperature of 25°C and a minimum of 12°C, and four main seasons: early (June to August) and late (September to November) dry and early (December to February) and late (March to May) rainy. The common diet during the time of the study was maize meal porridge, with relishes of vegetables, peanuts and other legumes, and sometimes meat. Malaria is not endemic in the study area because of its high altitude of 1500 m. Helminth infection is rare throughout Zimbabwe. The prevalence of HIV infection among antenatal women ranges from 12 to 73% at sentinel sites throughout the country, with a national average of 35% (28).
Infants were enrolled between October 1998 and January 2000 in the Zimbabwe Vitamin A for Mothers and Babies Project (ZVITAMBO), a placebo-controlled clinical trial among 14,110 mother-baby pairs testing the efficacy of immediate postpartum maternal and/or neonatal vitamin A supplementation on infant mortality and mother-to-child HIV transmission. Pairs were recruited within 96 h of delivery at maternity clinics and hospitals in Harare and were eligible if neither the mother nor the baby had an acutely life-threatening condition and the infant was a singleton with birthweight > 1500 g. Written informed consent was obtained from the mother. We randomly selected a 34% subsample of babies overselecting for babies of HIV-positive mothers. Seven of every eight infants born to HIV-positive mothers and one of every ten born to HIV-negative mothers were identified by a computer program for a total of 2314 and 535 babies, respectively. Five babies received a neonatal blood transfusion and were excluded. Only infants with complete birth data (Hb, ferritin, birthweight and all potential determinants of TBI) were included in the analysis (n = 2021). Mothers and their babies were followed-up at 6 wk, 3 mo and every 3 mo until 12 mo of age by study midwives in a study clinic or at home; acutely ill patients were referred to a study physician, or directly to the hospital. Blood was collected at recruitment and follow-up, and Hb measured in baseline samples and repeated in infant samples from 3 mo of age onward. The study protocol was approved by the Medical Research Council of Zimbabwe, the Committee on Human Research of The Johns Hopkins Bloomberg School of Public Health, the Medicines Control Authority of Zimbabwe, and the Montreal General Hospital Research Ethics Committee.
Methods.
At recruitment (delivery), questionnaires were used to collect demographic and obstetric details. Gestational age was assessed using the method of Capurro (29). Birthweight was measured to the nearest 5 g using an electronic scale (Seca model 727, Hanover, MD). Maternal mid-upper arm circumference was measured to the nearest 0.1 cm. An infant feeding history was obtained by interview with the mother at each follow-up visit.
Maternal blood was collected by venipuncture and infant blood by venipuncture or heel stick. Hb was measured using the HemoCue hemoglobinometer (HemoCue, Mission Viejo, CA). We performed daily quality control of the HemoCue. Two 125-µL aliquots of EDTA-treated blood were pelleted using the Roche Specimen Preparation Kit (Roche Molecular Systems, Branchburg, NJ) and all remaining blood was centrifuged (890 x g, 5 min, room temperature), with the serum, plasma and infant cell pellets stored at -80°C for later analysis.
Plasma ferritin concentration was measured by enzyme immunoassay (Ramco Laboratories, Houston, TX). If plasma quantity was insufficient, serum was used. The interassay CV was 9.6 and 9.2% at 70 and 300 µg/L, respectively, and the intra-assay CV was 4.0 and 4.7%, respectively.
To determine maternal HIV status at recruitment, baseline samples were assayed in parallel by two ELISA for detecting antibody to both HIV 1 and 2 [GeneScreen (Sanofi Diagnostics Pasteur PRx, Johannesburg, South Africa) and Murex (Murex Diagnostics, Johannesburg, South Africa)]. The mother’s status was confirmed positive by concordant ELISA, or by Western blot when discordant, and repeated ELISA at the next visit. The baby of an HIV-positive mother was determined to be HIV-infected at birth by analyzing baseline cell pellets with Roche prototype qualitative DNA PCR which incorporates primer pairs sensitive in detecting all group M HIV virus types. This kit has been shown to have 100% sensitivity and specificity in detecting HIV in samples from ZVITAMBO women (30).
Calculation of TBI.
We calculated TBI as the sum of two components, Hb iron (HbI) and body storage iron (BSI), according to the method previously used in infants (17,21–27):
 | (1) |
where TBI is total body iron at birth, HbI is the quantity of circulating iron at birth in the form of Hb and BSI is the quantity of body storage iron at birth, with all values expressed in mg (molecular weight of iron is 55.847). Body iron also comprises iron in myoglobin, iron-containing enzymes and iron transport proteins. In the normal adult male, this quantity has been estimated to be 20% of HbI (20); however, limited data exist for estimating this quantity in infants, and it is not included in Eq. (1). Thus the estimation of TBI likely underestimates the total amount of body iron.
 | (2) |
where HbI is expressed in mg, 3.47 is the iron content (mg)/g Hb, BV is blood volume in L/kg body which we assumed to be 0.080 at birth (31), Hb is Hb concentration at birth (g/L) and body weight is birthweight (kg).
BSI was estimated from plasma ferritin concentration and the regression equation determined by Saarinen and Siimes (25):
 | (3) |
 | (4) |
where BSI is expressed in mg, plasma ferritin in µg/L, and body weight is birthweight (kg). Based on this equation, BSI is 0 when plasma ferritin is 22 µg/L. Thus, we considered plasma ferritin values 
22 µg/L to indicate depleted iron stores and assigned a numeric value of 0 mg to those neonates (n = 15).
Statistical analysis.
Our analytic approach was first to evaluate the predictive power of TBI by comparing the odds of postnatal anemia by birth quartile of TBI using the 
2 test. This was done for four postnatal time points, 3, 6, 9 and 12 mo of age. We explored various quantile categories of TBI, and quartile divisions provided the best balance of more detailed information and less statistical noise. We used regression analysis to assess the relationship of TBI with potential determinants, including: 1) maternal characteristics at delivery: Hb, HIV status, age, parity and mid-upper arm circumference; and 2) infant characteristics: gestational age, HIV status and sex. We constructed a multivariate model, adjusted for birthweight and postnatal age of the infant at recruitment, and retained independent variables that were potentially significant (P < 0.10). Interactions were considered potentially significant if their P-value was 0.15.
We defined infantile anemia as Hb < 105 g/L at 3 and 6 mo and < 100 g/L at 9 and 12 mo of age. The standard Hb cut-off value used for children is 110 g/L (10,20,32,33) and is currently recommended by the WHO for children 6 mo to 5 y old (34). However, several studies have suggested that during infancy, the WHO cut-off value may overestimate anemia (35–39). Recently it was reported that among iron-replete, breast-fed infants from Sweden and Honduras, 2 SD cut-off values for Hb at 4 and 6 mo of age were both 105 g/L and at 9 mo 100 g/L (40); therefore, we used these more stringent cut-off values. Using the WHO cut-off value, the relationship between TBI and anemia remained significant but was slightly less strong.
We defined categories for low birthweight (<2500 g), preterm birth (gestational age < 38 wk), parity (1, 2–4, 
5) and low maternal mid-upper arm circumference (< 23 cm) and modeled maternal age (y) as a continuous variable. We explored the effect of different categories of maternal Hb on TBI and combined categories with similar ß-values in the birthweight adjusted models. The categories reflect an upward adjustment in Hb of 7 g/L for altitude (41). Maternal Hb concentrations > 180 g/L were considered measurement error and excluded from the analysis (n = 2). Analyses were conducted with Stata 6.0 software (Stata, College Station, TX). Values in the text are means ± SD unless otherwise stated.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Of the 2021 sample infants, 1640 (81%) were born to HIV-positive mothers; of those 143 (8.7%) tested PCR positive for HIV at birth. Half of the newborns were girls (48.5%), and the majority (73.3%) were recruited within 24 h of their birth. Birthweight was 2932 ± 457 g and was greater (P < 0.001) in males (2992 ± 460 g) than in females (2869 ± 444 g). The maternal Hb concentration was 113 ± 20 g/L and maternal age was 25.3 ± 5.1 y. Birth Hb and ferritin were inversely correlated (Spearman r = - 0.149, P < 0.001).
By maternal report, all infants in this study were breast-fed for at least 6 mo, but only 3.5% were breast-fed exclusively (with or without medication) for at least 3 mo. Solid foods were introduced to 25% of the infants by 6 wk of age and to more than 33% by 3 mo, although very rarely did these foods include iron-rich sources (meat, poultry, eggs, fish or iron-fortified infant formula). The common infant foods were juice and porridge made from maize meal.
The overall prevalence of postnatal anemia in infants was high; 40% were anemic (Hb < 105 g/L) at 3 mo and 38% at 6 mo. The proportion with anemia at 9 and 12 mo (Hb < 100 g/L) remained high at 34 and 30%, respectively.
Estimated TBI.
Hb concentration at birth was 177 ± 24 g/L and the geometric mean (95% CI) plasma ferritin concentration was 212 (205–220) µg/L. Calculated values of HbI, BSI and TBI were normally distributed and were 144 ± 29, 65 ± 24, and 210 ± 41 mg, respectively. The 25th, 50th and 75th percentiles in TBI were 181.4, 208.7 and 235.8 mg, respectively.
TBI and the development of postnatal anemia.
There was an inverse relationship between TBI quartile and risk of anemia at all postnatal ages, and this dose-response relationship was strongest at 6 and 9 mo (Table 1). The odds of anemia were >3 times higher for babies in the lowest vs. the highest TBI quartile at 6, 9 and 12 mo. Birth Hb and ferritin and birthweight quartiles were less strongly and consistently related to postnatal anemia.
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Several infant and maternal characteristics were associated with TBI (Table 2). In multivariate analysis, the predicted change in TBI/kg increase in birthweight was 68 mg (P < 0.001). Preterm birth and parity were not independently associated with TBI after controlling for birthweight. Maternal age was best modeled as a continuous variable, and TBI decreased 25 mg for every 10-y decrease in maternal age (P = 0.033). After controlling for birthweight, a lower maternal mid-upper arm circumference was associated with a slightly higher TBI (P = 0.080). Maternal Hb concentration was positively associated with TBI. The relationship was nearly linear but a better fit was achieved using a log/log model (R = 0.5829, P < 0.001) (Fig. 1). At the mean level for all other independent variables (see Table 2), the relationship can be described as
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where TBI is expressed in mg and maternal Hb in g/L. The y-intercept at the mean level for all independent variables was 1.56 in the logged model and 20.71 in the original multivariate model (see Table 2). We examined further the relationship between maternal Hb and the components of TBI (HbI and BSI). Infant BSI leveled off at 100 g/L of maternal Hb, but the relationship between infant HbI and maternal Hb was approximately linear throughout the range of maternal Hb (Fig. 2).
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Plasma ferritin was used to estimate non-Hb body storage iron in newborns according to the method originally proposed by Saarinen and Siimes (25). A critical assumption is that the relationship between plasma ferritin and BSI is the same in infants as in adults. However, in defense of the equation, we determined BSI to be 22.4 mg/kg, which is in close agreement with the value of 25 mg/kg generally used to characterize the normal newborn (11). Another assumption in the estimation of TBI is that blood volume was 80 mL/kg and was the same for each infant. The timing of clamping of the umbilical cord can significantly affect the volume of blood transferred from the placenta to the newborn (and thus total body iron content) and hematologic indices soon after birth (42). We did not directly ascertain cord-clamping practices in this study; however, information from obstetricians in Harare indicates that cord clamping practice is consistent and immediately after delivery (P. Zvandasara, Department of Obstetrics and Gynaecology, University of Zimbabwe, personal communication). Furthermore, any variation that did occur in our study population is highly unlikely to confound the relationships we observed.
TBI predicted anemia better than each of its constituents (Hb, ferritin and birthweight). The observation of an inverse relationship between birth Hb and ferritin suggests that, at birth, body iron is partitioned between "active" and storage iron, and that the combination of Hb and ferritin in TBI is necessary to obtain an accurate assessment of neonatal iron status. To our knowledge, ours if the first study to characterize this correlation. The calculation of TBI also incorporates birthweight, which positively affects the total iron content at birth (7). It is noteworthy that preterm birth was not independently associated with TBI after controlling for birthweight. This is consistent with the common belief that although the premature infant has a smaller absolute amount of total body iron at birth than the full-term newborn, the proportion of iron to body weight remains relatively constant (2).
Our findings provide evidence that birth iron continues to predict risk of anemia for at least 12 postnatal months and highlight the potential of improving iron status via interventions during gestation or early infancy. Infants have a relatively high demand for iron because they are growing rapidly, and human milk is low in iron, even after accounting for bioavailability. The partial replacement of early breast milk with weaning foods low in iron, as is common in Zimbabwe, can further reduce nutritional iron (43). Thus, the iron reserves at birth are a critical factor determining the risk for iron deficiency during infancy. The difference in TBI from the median of the lowest quartile of the TBI distribution to the median of the highest quartile was 93 mg. Iron supplements at a dose of 12.5 mg/d are currently recommended for infants 6–12 mo of age if iron-rich foods are not regularly consumed (44). Assuming that 20% of supplemental iron is absorbed, 93 mg of additional birth endowment is equivalent to 5 wk of daily iron supplementation.
Maternal Hb was a strong linear predictor of TBI. Several studies demonstrated that moderate-to-severe anemia during pregnancy is associated with low birthweight (45,46) and preterm deliveries (47–50). However, in the present study, maternal Hb remained an independent predictor of infant iron status when birthweight was held constant, and these relations were not influenced by gestational age. Excluding low birthweight and preterm babies from the analysis did not change the association between maternal Hb and infant TBI (data not shown). We conclude that the association was independently attributable to the biological effect of the mother’s Hb on the iron status of the infant. This is consistent with increasing evidence that maternal iron deficiency in pregnancy has a negative effect on fetal iron stores (18,22,51–53) and that this effect persists into the postpartum year even among infants born at term with an adequate birthweight (4,14–17,19). Our results are unique, however, in the way we have defined infant iron status. We know of only one other study that compared maternal iron status with TBI calculated as the sum of HbI and BSI (17). They found no relationship between iron status in 81 Caucasian and Asian, predominantly Bangladeshi, women living in England measured at 37 wk gestation and their estimate of infant TBI at birth. However, they used cord ferritin and cord Hb to estimate BSI and HbI and reported an unusually low mean value for ferritin concentration (60 µg/L). Unlike our observations, TBI was unrelated to iron status at 6 mo or 1 y of age. The difference between our results and theirs may be explained in part by their small sample size and differences in methods of measurement. Ahmad et al. (18) measured TBI by chemical analysis in 15 aborted fetuses and showed a positive linear correlation between maternal Hb and the TBI content of the fetus. The TBI of fetuses of nonanemic mothers (Hb > 120 g/L) was 75 mg/kg fetal weight and was <65 mg/kg in those aborted by women with Hb < 90 g/L.
An unexpected observation was that even at high maternal Hb concentration (>130 g/L), infant TBI continued to increase. This was surprising because high Hb concentrations in pregnancy usually indicate poor plasma volume expansion, which is a risk factor for low birthweight, and are not believed to reflect iron status (54). An examination of the relationship between maternal Hb and the components of TBI provides a possible explanation for this phenomenon at the high range of maternal Hb. Above 100 g/L, BSI leveled off, suggesting that there is a threshold at which the infant’s iron stores no longer benefit from an increase in the mother’s iron status. However, infant HbI continued to increase as maternal Hb increased. Hb concentration is substantially heritable (55), and we speculate that the continuous linear relation between maternal and neonatal Hb reflects their genetic relationship. The relation between maternal Hb and neonatal storage iron showed the expected plateau at values > 100 g/L, consistent with an interpretation that maternal iron deficiency severe enough to cause anemia does so by compromising fetal iron acquisition.
The most likely cause of low Hb in these Zimbabwean women was iron deficiency. During pregnancy, iron requirements exceed the storage iron for most women (56). In the present study, among a subsample (n = 55) of HIV-negative, anemic (Hb < 120 g/L) mothers, 55% had depleted iron stores (ferritin < 12 µg/L, N. Mbuya et al., unpublished data). Malaria and helminth infection are rare in this population, and although HIV infection is associated with anemia (57), it did not modify the effect of maternal Hb on infant TBI. Because mother-infant pairs could have been enrolled up to 96 h after delivery, we considered blood loss during labor as a potential cause of low Hb in mothers (58). Blood loss was indeed significantly associated with maternal Hb, but it was not associated with infant TBI, and its inclusion had no influence in the multivariate model.
Another novel finding was that HIV-infected infants apparently had greater TBI. We cannot rule out that the transfer of iron from mother to fetus may be affected by HIV infection, but it seems unlikely that this relationship would be positive. We hypothesize that an inflammatory response to HIV exposure and infection is present at birth and that this response is greater among females. Ferritin, an acute phase protein, is increased during inflammation and infection (59) and is indirect evidence that high TBI for infected girls does not reflect a difference in iron status but rather suggests a difference in immune response between sexes. Sexual dimorphism has been demonstrated in many aspects of the immune system in adult rodents and humans (60,61), and in general, female mammals have greater humoral and cell-mediated immunity than males.
In bivariate analysis, maternal arm circumference was positively associated with TBI, but when birthweight was included in the model, the relationship between maternal arm circumference and TBI reversed direction. Mothers with larger arm circumference have larger babies with greater TBI, but after adjusting for birthweight, the remaining relationship between arm circumference and TBI was in the opposite direction because at a given birthweight, larger mothers have larger babies, and at a given birthweight, fatter babies are less iron-dense babies. The relationship between maternal age and TBI also reversed direction after adjusting for birthweight, possibly for the same reason. Primiparity was not retained after birthweight was included.
We conclude that we can make satisfactory estimates of the prenatally acquired iron endowment in epidemiologic studies of newborns. Furthermore, babies born with low birthweight or to mothers with low Hb fail to accrete sufficient iron during the fetal period and are born with less TBI, which confers a substantially greater risk of anemia from 3 to 12 mo of age. These findings suggest that improving maternal nutritional status to prevent anemia and low birthweight may be essential components of public health efforts to prevent iron deficiency anemia among young infants.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Present address: Division of Nutritional Sciences, Cornell University, Ithaca, NY.
4 Members of the ZVITAMBO Study Group, in addition to the named authors are: Henry Chidawanyika, Agnes Mahomva, Florence Majo, Edmore Marinda, Michael Mbizvo, Lawrence Moulton, Kuda Mutasa, Mary Ndhlovu, Robert Ntozini, Ellen Piwoz, Lidia Propper, Philipa Rambanepasi, Andrea Ruff, Naume Tavengwa, Brian Ward, Lynn Zijenah, Claire Zunguza, Partson Zvandasara; principal investigators are Kusum Nathoo and Jean Humphrey.
5 Abbreviations used: BSI, body storage iron; Hb, hemoglobin; HbI, hemoglobin iron; OR, odds ratio; TBI, total body iron.
Manuscript received 30 May 2003. Initial review completed 24 July 2003. Revision accepted 13 August 2003.
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LITERATURE CITED |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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