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© 2006 American Society for Nutrition J. Nutr. 136:2345-2349, September 2006

Nutrient Requirements and Optimal Nutrition

Preconception Maternal Iron Status Is a Risk Factor for Iron Deficiency in Infant Rhesus Monkeys (Macaca mulatta)1

Gabriele R. Lubach* and Christopher L. Coe

Harlow Center for Biological Psychology, University of Wisconsin, Madison, WI

* To whom correspondence should be addressed. E-mail: grlubach{at}wisc.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Iron deficiency is the most common micronutrient deficiency during pregnancy, and maternal anemia has been associated with poor pregnancy outcomes. However, it is still not clear how directly maternal iron status is linked to the infant's iron status postpartum. We investigated the impact of maternal iron deficiency on the hematological status of infant rhesus monkeys. Two groups of females, 8 iron deficient and 8 iron sufficient were assessed through pregnancy and for 6 mo postpartum. At conception, 4 females in each group were provided an iron-enriched diet. Iron status of the infant at birth reflected the preconception status of the mother, regardless of diet. Serum ferritin (Ft) concentrations were significantly higher in infants born to iron-sufficient mothers and were correlated with maternal transferrin saturation at entrance to the study (r = 0.52, P < 0.04). Infant iron status continued to reflect prenatal conditions through 6 mo of age. Our study confirmed the importance of iron sufficiency in gravid female monkeys for ensuring their infants' normal hematological development postpartum. A dietary intervention during pregnancy with only a moderate addition of iron was not sufficient to prevent the offspring from developing iron deficiency. These findings stress the importance of improving iron nutriture prior to conception.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Iron deficiency (ID)2 is the single most common micronutrient deficiency worldwide, estimated to affect >2 billion people, and, in over one-half of them, this deficiency leads to iron-deficiency anemia (IDA) (1). Iron deficiency is the most prevalent single-nutrient deficiency in pregnant women, and IDA may result in poor pregnancy outcomes (2–4). Studies have linked maternal IDA with low birth weight infants, preterm delivery, and increased neonatal morbidity and mortality (5,6). The following study used a nonhuman primate model to further investigate the influence of preterm iron status of the mother on the infant's hematological status postpartum.

The metabolic demands of pregnancy greatly increase the need for iron, starting in the second trimester with the expansion of the maternal red cell mass, and become more pronounced through the third trimester with rapid fetal growth. It has been estimated that human pregnancy requires ~1000 mg of iron, of which about one-half is utilized by the fetus and placenta (7,8). Although the cessation of menstruation saves some iron that would normally be lost, most healthy adult women have only 200–300 mg of storage iron available when they enter pregnancy (9). There is also evidence of increased iron absorption during the latter part of pregnancy, with the amount of absorption related to maternal iron status (10). The lower the iron stores, the higher the absorption of iron. To understand the consequences of these pregnancy-induced changes for females with different iron status, monkeys were selected on the basis of being iron sufficient (IS) or deficient at conception.

In both humans and rhesus monkeys, the majority of iron transport from the mother to her fetus occurs during the third trimester. It is during this period that the fetus receives the bulk of the maternal iron (9), and those stores at term must be sufficient to fulfill the iron needs of the growing infant during the first 4–6 mo of life. Low iron stores at birth make the infant more vulnerable to developing IDA. However, it is often thought that iron transport to the fetus is extremely efficient, and can compensate for poor maternal iron status (8,11,12). This association is still not clear, and there is conflicting information regarding correlations between maternal and newborn iron stores (2,13–16). We tested this directly in the current experiment by feeding the IS and ID females either an iron-rich or marginal diet, and then evaluating the hematological development of their infants postpartum. Some studies in humans have reported a positive association between prenatal iron supplementation and increased infant iron stores (17–20). The controversy is important to resolve because IDA can impact several domains in the developing infant, including growth, energy levels, and motor and cognitive performance (21–24).

Iron supplementation is now recommended for all pregnant women, although the optimal amount has still not been clearly identified (14,15,19,25–27). The primary goal of supplementation has often been to prevent or treat iron deficiency during pregnancy to reduce the incidence of preterm delivery and low birth weight infants (28). Even less is known about the iron needs of gravid monkeys, although it has been repeatedly documented that IDA is common in developing infant monkeys (29,30).

The present study was designed to explore this issue of prenatal supplementation through the provision of extra iron in the normal food allotment. The rhesus monkey is an excellent model for addressing issues involving the maternal-to-fetal transfer of iron because, like humans, rhesus monkeys have a hemochorial placenta, a fairly long gestation period, and produce single offspring. Furthermore, the mechanisms and timing of placental iron transfer are similar (12,31). Like human infants, rhesus monkeys are most likely to become iron deficient prior to being weaned onto solid foods and during periods of rapid growth (29,30).


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Animals and housing. Sixteen adult multiparous female rhesus monkeys (Macaca mulatta), born and housed at the Harlow Primate Laboratory (University of Wisconsin), were selected from a larger group (n = 30) that had been screened for general health status with an iron panel [iron, total iron binding capacity, percent transferrin saturation (TSAT)], and a complete blood count (CBC). Females were designated as either iron sufficient (IS, n = 8) or iron deficient (ID, n = 8) based on their TSAT, with levels <30% considered indicative of iron deficiency, and then were assigned to the diets (see below). The TSAT median of 30% was chosen to include some borderline iron-deficient females. Screening generally was done within 2 menstrual cycles prior to conception. Iron status groups were matched for age and parity (Table 1).


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  		TABLE 1 Characteristics of female rhesus monkeys at entrance to study1

 
Females were time-mated with a single male to allow for an estimation of date of conception ± 2 d. Following breeding, the females were returned to standardized housing in the animal quarters. The housing room contained double rows of stainless steel caging (each cage 0.9 x 0.9 x 0.9 m), where each pregnant female and then mother-infant dyad lived until the infants were weaned at 6 mo of age. Temperature (21 ± 3°C) was controlled, and lights were maintained on a 24-h schedule of 14 h light and 10 h dark. Monkeys consumed water ad libitum. They were weighed monthly throughout pregnancy. The experimental protocol was evaluated and approved by the University of Wisconsin Institutional Animal Care and Use Committee. Care and treatment of monkeys at the Harlow Primate Laboratory are designed to meet and exceed the guidelines in the NIH Guide for the Care and Use of Laboratory Animals.

    Diet. As stated above, one aim of this project was to study the effect of providing iron-enriched feed during pregnancy. Therefore, the female monkeys were further divided into 2 subgroups, matched for age and parity, and consumed either a standard diet (IS-St, ID-St) or an iron-enriched diet (IS-En, ID-En) throughout pregnancy and lactation (Table 2). All monkeys were fed twice daily with a standardized ration of commercial biscuits, consisting of ~200 g of feed in the morning and another 20 g in the afternoon. Based on consumption patterns and to preclude uncontrolled amounts of food accumulating, it is standard practice in our laboratory to provide the main portion of the food in the morning and a smaller portion in the afternoon. Food intake was evaluated every 2 wk (see below). The standard feed was Purina Monkey Diet 5037 Jumbo (PMI Nutrition International), which contained a minimum of 180 mg/kg iron (as per PMI). The iron-enriched biscuits were Purina Monkey Diets 5038A and 5038B, containing a minimum of 240 mg/kg iron (diet A) or 285 mg/kg iron (diet B). The original purpose of the study was to evaluate the 3 different diets. Based on the subsequent results, it became evident that the 2 enriched diets had very similar effects. Iron concentration was measured in unidentified, coded batches by PMI for verification. Both diets were identical in all other ingredients, except copper (see Table 2). The copper concentration was increased in proportion to the additional iron because dietary copper deficiencies can reduce iron uptake (32). All biscuits were weighed prior to feeding because of the larger size of the 5037 biscuit. All monkeys received fruit, 3 d/wk, in the afternoons.


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  		TABLE 2 Number of monkeys in each diet group and composition of Purina Monkey Diet1

 
    Food and iron consumption. Pregnant females were fed a fixed amount of food relative to body weight. Monkeys in captivity eat ~2–4% of their weight in food daily, and the amount consumed by monkeys in this study was appropriate for their body weights. Twice a month, counts of biscuits eaten on that day were recorded. Approximately one-half of the females in the study consumed their full allotment regularly. The other half had one or more biscuits left ~50% of the time. Variation in eating patterns was consistent among the groups and not related to maternal iron status or infant outcome. We estimated actual iron consumption on the basis of biscuits consumed daily (Table 2). Although the 2 enriched diets varied slightly in the amount of added iron, this did not affect birth weights (533.0 g ± 13.3 for diet A and 548.7 g ± 17.1 for diet B) or the iron status of the infants. Therefore, data from mothers and infants in the 2 iron-enriched groups were combined.

    Hematology. Maternal blood samples were collected every 2 mo during pregnancy and lactation for a CBC and iron panel. In addition, a postparturition sample was obtained 2–3 d after delivery for an iron chemistry panel. All samples were obtained in the morning, 3–4 h after feeding, into both serum and EDTA-treated vacutainer tubes. Monkeys were not sedated for this collection. Samples were also collected from the infants while they were being held. Thereafter, blood was collected at 2, 4, and 6 mo of age for CBCs and iron panels. All CBCs were processed with an automated system (Coulter Counter) in the clinical laboratory of the Wisconsin National Primate Research Center. Measures included: white blood count (WBC), red blood count (RBC), hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelets, and red cell distribution width (RDW). Serum iron concentration, total iron binding capacity (TIBC), percent transferrin saturation (TSAT), and ferritin (Ft) were measured by a local commercial laboratory (General Medical Laboratories), using the "ferrochrome without prior precipitation" method (Beckman CX7s), and the VITROS Ferritin assay (ECI Immunodiagnotstic System, Ortho-Clinical Diagnostics). Equipment was calibrated daily with quality control (QC) materials, and instrumentation standards were maintained within 2 SD of those QC values. Serum Ft concentrations were measured in both the mothers and infants at birth and at weaning.

    Statistical analysis. All analyses were done using Super ANOVA, version 1.11 (Abacus Concepts). Data were analyzed by 2-factor ANOVA, considering maternal iron status (IS, ID) and diet (St, En) as between factors. For those measures that were taken at multiple stages of pregnancy (first, second, and third trimester) or at multiple ages of infancy (2, 4, and 6 mo), repeated-measure ANOVA was conducted. Regression analyses were conducted to examine the associations between maternal and infant iron status. Post hoc analyses were conducted using both Fisher's Protected LSD and Scheffé's tests when interactions were significant. One serum Ft concentration was clearly an outlier (3 SD from the mean) and was not included, following the recommendation of Winsor (33). Differences were considered significant at P < 0.05. Values in the text are means ± SEM.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Maternal characteristics. Weight gains did not differ between the groups. The TSAT increased in both groups over time but was higher in the IS females (39.7 ± 2.04) than in the ID females (30.4 ± 2.28) (P < 0.03). Serum iron levels tended to increase over time (P = 0.07) but diet had no effect, and the greater concentrations may reflect the increased absorption of iron that typically occurs during pregnancy (25). After conception, the IS and ID groups did not differ in any hematological measures, and diet did not affect these variables. It is possible that the pregnancy-induced changes in the hematology, including increased iron absorption, obscured the initial preconception differences in iron status between groups. All values were within the normal range for our colony [Hb = 131 ± 1.5 (IS) and 134 ± 1.7 (ID) g/L; MCV = 72.5 ± 0.37 (IS) and 71.1 ± 0.40 (ID) fL].

    Birth outcome. Deliveries and gestation lengths were normal for all infants (170.4 ± 1.2 d). Interestingly, the ID mothers gave birth to larger infants (541 g ± 11.09 for ID and 503 g ± 13.56 for IS groups, P < 0.05). Nevertheless, the diets did not affect birth weight.

Iron status of the infants at birth reflected the preconception iron status of the mothers, regardless of the diets consumed. Serum ferritin concentrations, which provide one index of storage iron, were higher in infants born to IS mothers (P < 0.02) (Fig. 1). Infant ferritin levels were also correlated with the maternal TSAT at entrance to the study (P < 0.04; r = 0.52). There was no correlation with gestation length, but there was a trend toward a negative correlation with birth weight (r = –0.46, P < 0.08). This relation suggests that the faster growing fetuses may have utilized more iron in utero or that the slightly larger infants from the ID mothers did not have as much iron available. At birth, serum Ft concentrations in the mothers and infants were not significantly correlated.


Figure 1
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  		Figure 1  Serum ferritin concentrations of monkeys at birth according to maternal preconception iron status (IS and ID) and type of diet (St and En). Values are means + SEM, n = 4 (IS-St), 4 (IS-En), 3 (ID-St), and 5 (ID-En). The effect of maternal iron status was significant, (a > b) P < 0.02.

 
    Infant hematological development. The infants' iron status continued to reflect that of the mothers through the first 6 mo of development (Table 3). Infants born to IS mothers, had higher Hb, hematocrit (Hct), iron, and TSAT than those born to ID mothers. Diet was an additional factor affecting MCV levels at 6 mo in the ID group (P < 0.05) (Fig. 2), which may reflect the infants consumption of some of the feed by that age. Infant weight and rate of growth through 6 mo of age did not differ among the 4 groups.


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  		TABLE 3 Hematology and iron chemistry in infant rhesus monkeys from IS and ID mothers1

 

Figure 2
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  		Figure 2  Infant monkeys MCV at 2, 4, and 6 mo of age according to maternal preconception iron status (IS and ID) and type of diet (St and En). Values are means, n = 4 (IS-St), 4 (IS-En), 3 (ID-St), and 5 (ID-En). Infants born to IS mothers had significantly higher MVC levels across the first 6 mo of life, *P < 0.05. The En diet had a significant effect on the MCV levels of the ID group at 6 mo of age (a > b), P < 0.05.

 
By 6 mo of age, the infants' blood profiles indicated their growth-related needs had exceeded dietary intake, and the low TSAT (Table 3) and low Ft levels suggested that iron stores were dramatically depleted. Ferritin decreased in all infants so much that the differences by preconception maternal status were no longer significant (Fig. 1). In addition, the Ft concentrations at this age were no longer influenced by maternal diet. Serum Ft levels at weaning did not correlate with levels at birth, or with the mothers' Ft levels at weaning, but were primarily a reflection of growth.

    Sample size. Given the small number of mothers and infants evaluated in this study, it seemed appropriate to statistically assess the magnitude of the effect of the main variables and to project sample sizes that might be needed to replicate findings. The division of females into IS or ID groups based on their TSAT yielded an effect size of 3.49 (CI of 4.81–1.79). Given virtually no overlap in this grouping variable, a total of only 4 females per iron status group would be required to yield similar group distinctions with a power of 0.80, and alpha set at 0.05. An evaluation of one of the primary outcome measures, the infant Ft levels at birth, yielded an effect size of 1.42 (CI of 2.43–0.26). With the observed difference between infants based on the status of their mothers, a total study size of 14 infants would be sufficiently powered at 0.80 to find a similar neonatal effect at P = 0.05.


   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
Our study has confirmed the important influence of prenatal maternal iron status on the developing infant's hematological status postpartum. Females that entered the pregnancy ID were more likely to have offspring that progressed to IDA, although none of the infants were born ID. A dietary intervention during pregnancy with only moderate additions of iron did not appear to be sufficient to prevent their offspring from developing iron deficiency. In addition, infant iron status at birth reflected that of the mother prior to conception. The failure of the iron enrichment to more fully compensate may reflect some restriction of the placental transfer of iron, or the extremely high demands of the rapidly growing infant, which taxes the iron stored as Ft and Hb.

The amount of iron added to the enriched diets possibly served the therapeutic benefit of preventing anemia in the gravid female during pregnancy. However, the low serum Ft concentrations at parturition suggest that little iron was available as a reserve. In a recent study on pregnant women receiving between 20 and 80 mg of iron daily, it was found that the low-dose group had low Ft levels throughout gestation and through 8-wk postpartum (15).

Despite the compromised iron status of infants born to monkeys that were ID at conception, they were not growth-restricted in utero. In fact, their slightly larger size at birth may have increased their iron disadvantage, because more iron may have been utilized in utero. The reason for the size difference is unclear, because iron supplementation often increases birth weight. Sample sizes were not based on birth weight as an outcome measure in this study; nonetheless, iron deficiency may lead to a compensatory increase in placental size (34,35) leading to enhanced growth. In human infants, serum iron levels and other hematological measures decline as postnatal growth increases. A similar trend was evident in the monkeys, with iron levels, TSAT, and MCV declining precipitously through 6 mo of age. Older infants were considered to be ID when their serum Ft concentration was <15 µg/L (25). Based on this criterion, infants of the ID mothers were most at risk for IDA as they grew and used up available stores. Although the ID infants had consistently worse hematological profiles than the IS infants, their rate of growth was not impacted at this level of iron deficiency. Rapid growth can accelerate iron depletion, but that does not appear to have been the case here (36,37).

Although the 8 females assigned to the preconception ID group had only a marginal deficiency prior to pregnancy, 3 of their infants developed a profound IDA based on their hematological profiles (12). This 37.5% prevalence, or 18.7% of the total 16 infants, may seem high, but worldwide it is estimated that between 30 and 80% of human infants go through a period of IDA (1,38). In many parts of the world, infant iron deficiency is part of a larger spectrum of undernutrition and disease. However, even in countries where food is plentiful, high incidences of iron deficiency can be found (36). The prevalence and magnitude of the iron deficiency in our monkeys was also in keeping with 2 previous reports on iron deficiency in rhesus monkey infants during this period of rapid postpartum growth (29,30).

Many women may not have their pregnancy confirmed until well into the first trimester, and it is only then that nutritional supplementation may be initiated. In fact, the majority of women do not start iron supplementation until wk 12 of pregnancy (25). However, iron sufficiency is especially important during the first trimester for fetal growth and development (39), and our research further emphasizes the importance of preconception iron status for postnatal infant health. The benefits of supplementation during human pregnancy are already known (18), but the high iron demands of pregnancy make it difficult to compensate when iron supplements are started late in pregnancy. It may be necessary, therefore, to implement supplementation prior to pregnancy to build up reserves (40). Our findings stress the importance of improving iron nutriture prior to pregnancy in the rhesus monkey, and of considering preventive iron supplementation for women of reproductive age.


   ACKNOWLEDGMENTS
 
Drs. Dorrance Haught and Daniel Hopkins of PMI Nutrition International supplied the iron-enriched diet for this study. Special acknowledgments are due to Ms. J. Scheffler for assistance with the hematological testing. Our appreciation to Ms. H. Crispen for help in the sample collection, and to Dr. B. Lozoff, PI, Brain and Behavior in Early Iron Deficiency Program Project, for help with conceptual issues.


   FOOTNOTES
 
1 This research was supported by grants from the NIH (AI46521 and HD38305). Back

2 Abbreviations used: CBC, complete blood count; En, enriched; Ft, ferritin; Hb, hemoglobin; ID, iron deficient; IDA, iron-deficiency anemia; IS, iron sufficient; MCV, mean corpuscular volume; St, standard; TSAT, transferrin saturation. Back

Manuscript received 10 February 2006. Initial review completed 15 March 2006. Revision accepted 20 June 2006.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

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