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Department of Environmental Health, Harvard School of Public Health, Boston;
* Mineral Bioavailability Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA;
Department of Pediatrics, Boston University School of Medicine and Boston Medical Center, Boston, MA;
** Institute for Biomedicine, Anhui Medical University, Anhui, China; and
Center for Ecogenetics and Reproductive Health, Beijing Medical University, Beijing, China
2To whom correspondence should be addressed. E-mail: ronnenberg{at}comcast.net.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Hb < 120 g/L) and moderate (Hb < 95 g/L) anemia were significantly associated with lower birthweight (139 and 192 g, respectively); iron-deficiency anemia alone (Hb < 120 g, ferritin < 12 µg/L, no B-vitamin deficiency) was associated with a 242-g decrease in birthweight. Both low (<12 µg/L) and high (
60 µg/L) ferritin were also significantly associated with lower birthweight (106 and 123 g, respectively). The risks of low birthweight (LBW) and fetal growth restriction (FGR) were significantly greater among women with moderate anemia compared with nonanemic controls [odds ratio (OR): 6.5; 95% CI: 1.6, 26.7; P = 0.009 and OR: 4.6; 95% CI: 1.5, 13.5; P = 0.006, respectively]. TfR and low ferritin were not associated with adverse birth outcome, but elevated ferritin, which could be a marker of inflammation, was associated with increased risk of LBW (OR: 2.2; 95% CI: 0.9, 5.7; P = 0.09) and FGR (OR: 2.7; 95% CI: 1.3, 5.6; P = 0.008). Preconception anemia, particularly iron-deficiency anemia, was associated with reduced infant growth and increased risk of adverse pregnancy outcome in Chinese women.
KEY WORDS: • anemia • China • ferritin • pregnancy • transferrin receptor
Anemia may occur in as many as half of pregnant women worldwide (1). Although iron deficiency is a common cause of anemia, especially in women of reproductive age, anemia may also result from other causes, including deficiencies of folate, vitamin B-12, and vitamin B-6. Numerous observational studies showed an association between anemia during pregnancy and adverse birth outcomes (2–4). Despite these well-known relations with anemia, less is known about the independent contributions of iron deficiency per se and anemia not associated with iron deficiency on pregnancy outcome. With few exceptions (5–8), studies in which supplemental iron was provided to pregnant women generally showed little improvement in birth outcomes, and routine iron supplementation during pregnancy remains controversial (9,10). The frequent failure of iron supplementation to improve pregnancy outcome may be related to the observation that in some populations, only a fraction of maternal anemia is related to iron deficiency alone (7,11). Unraveling the possible independent pregnancy risks associated with anemia and iron deficiency may improve the effectiveness of nutrition interventions (9,10).
It was suggested that anemia and iron depletion that occur very early in gestation could influence birth outcomes differently than if they occurred later in pregnancy (10). One advantage of assessing hematological indices before conception is that they are likely to reflect status in the periconceptional period. However, to our knowledge, no previous studies examined the relation between preconception hemoglobin (Hb),3 ferritin, and B-vitamin status and pregnancy outcome in apparently healthy women. Most studies that examined these relations generally assessed biomarker concentrations at various times throughout pregnancy. Interpretation of the relation between these measures and birth outcome can be challenging (7) because plasma volume expands during pregnancy, diluting Hb, ferritin, and vitamin concentrations even in well-nourished, nutrient-replete women. In addition, the use of low serum ferritin alone to assess iron deficiency can result in an underestimation of the true prevalence of depleted iron stores because this protein is also an acute-phase reactant that is elevated irrespective of body iron stores by infection or inflammation, which are common conditions in many populations. Better estimates of iron depletion under these conditions may be made by measuring soluble plasma transferrin receptor (TfR) concentration, which is unaffected by inflammation (12). Plasma TfR is elevated in iron deficiency and was shown to be an early and sensitive measure of tissue iron deficiency (13). Recently, the ratio of TfR (µg/L) to ferritin (µg/L) was also used to identify more clearly persons with functional iron deficiency (14).
We previously reported a high prevalence of B-vitamin deficiencies, anemia, and depleted iron stores in a cohort of young Chinese textile workers who were planning to become pregnant (15). Of these women, 44% had some evidence of at least 1 B-vitamin deficiency, whereas only 17% of women with anemia had evidence of depleted iron stores. We subsequently reported that B-vitamin deficiencies in this group were associated with clinical spontaneous abortion (16) and other adverse birth outcomes (17).
The purpose of the current prospective study was to examine the association between Hb, ferritin, and TfR concentrations assessed one time before conception in young Chinese women and infant growth and gestational age at birth in their infants.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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A detailed description of data collection can be found elsewhere (18). In brief, after obtaining informed consent, an interviewer administered a baseline questionnaire that collected sociodemographic information and health history. Women were followed-up during any ensuing pregnancy or up to 1 y after beginning to attempt pregnancy, and all pregnancy outcomes were recorded.
Measurements. At enrollment, single measurements of height and weight in light clothing were made to the nearest 0.1 cm and 0.1 kg, respectively, by trained study personnel, and blood samples were collected from nonfasting subjects via venipuncture into 10-mL EDTA-treated tubes by a trained research phlebotomist. A small aliquot of whole blood was used to obtain a single measurement of Hb concentration using an automated colorimetric procedure. The remaining blood was centrifuged, and plasma was obtained and stored at –20°C in China until shipped on dry ice to the Harvard School of Public Health, where it was stored at –70°C before nutritional analyses. Frozen samples were then transported to the Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, where plasma concentrations of folate and vitamins B-6 and B-12 were measured as previously described (15). Plasma ferritin and TfR concentrations in a subset of 359 women for whom adequate plasma samples were available were also measured at Tufts University as previously described (15).
The ratio of TfR to ferritin (RF ratio) was calculated by dividing TfR (in µg/L) by ferritin (in µg/L). Elevated plasma TfR was defined as a concentration >8.3 mg/L (19). An elevated RF ratio was defined as >500 (20). Vitamin deficiencies [folate <6.8 nmol/L (3 µg/L); vitamin B-12 < 258 pmol/L (300 pg/mL); and vitamin B-6 < 30 nmol/L of pyridoxal-5'-phosphate] were defined as in an earlier study (17). Because ferritin and the RF ratio have skewed distributions, these variable were converted to logarithms before means and SD were determined.
Major outcomes. Infant birthweight (g) was measured immediately after delivery. Infant length (cm) was defined as crown-heel length and was measured shortly after delivery. Birthweight ratio was defined as an infant’s observed birthweight divided by the mean birthweight of infants of the same gestational age within the cohort (21,22). Birthweight ratio was multiplied by 100 for convenience. Gestational age (d) was the number of days between d 1 of the last menstrual period and the day of delivery. Preterm delivery was defined as the spontaneous delivery of a live infant before 37 completed wk (259 d) of gestation. Low birthweight (LBW) was defined as the birth of a live infant weighing <2500 g. Fetal growth restriction (FGR) was defined as a birthweight ratio < 85% (21,22).
Statistical analysis
We created Hb and ferritin categories as follows: Hb 120 g/L was considered normal based on WHO guidelines (23) and was used as the referent; the middle category included those with Hb < 120 g/L but 95 g/L, which we classified as mild anemia, and the lowest Hb category (moderate anemia), which was also the 10th percentile, was determined in part on the basis of the results of the LOESS procedure (see below) and included women with Hb < 95 g/L. Plasma ferritin < 12 µg/L was considered indicative of depleted iron stores (1), ferritin 12 µg/L and < 60 µg/L was considered "normal," and ferritin 60 µg/L was considered elevated. This upper cutoff value corresponded to the 80th percentile and was similar to that used by Tamura et al. (24).
To determine the potential differential effects of iron deficiency anemia and anemia not related to iron deficiency, we created 5 groups: group 1 included 131 anemic (Hb < 120 g/L) women with ferritin 12 µg/L and no evidence of B-vitamin deficiency; group 2 included 109 anemic women with at least 1 B-vitamin deficiency but ferritin 12 µg/L; group 3 included 28 women with ferritin < 12 µg/L but no evidence of B-vitamin deficiency; group 4 included 29 women with both ferritin 12 µg/L and evidence of at least 1 B-vitamin deficiency; and group 5, which served as the reference group, included 62 women who were not anemic.
The equality of proportions across categories was assessed using 
2 analyses. The determinants of Hb concentration (as binary variables) were identified using multiple linear regression. Adjusted (least-squares) means (and their 95% CI), calculated across various Hb, ferritin, and anemia categories, were assessed using the general linear models procedure (proc GLM) of SAS. Means were adjusted for the following covariates: maternal age, height, height-squared, BMI, education, infant gender, gestational age (linear and quadratic terms), and maternal exposure to dust, noise, passive smoking and work stress.
We applied local regression to model Hb and ferritin concentration adjusted for birthweight, head circumference, and gestational age using the SAS LOESS procedure and plotted the predicted values from the LOESS model against observed maternal Hb. Results of the LOESS procedure for Hb and birthweight were graphically depicted using Sigma Plot graphical software (SPSS).
The risks of adverse pregnancy outcomes were assessed by TfR and RF ratio status (as binary variables) and across maternal Hb and ferritin categories using logistic regression and were expressed as odds ratios (OR) with their 95% CI. Logistic regression models were adjusted for the same covariates listed above. Statistical significance refers to P 0.05. Statistical analyses were performed using SAS for Windows, release 8.2.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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12 µg/L, 9 had both depleted iron stores and a vitamin deficiency, and 9 had no evidence of B-vitamin deficiency or iron depletion. Of the 297 women who had some degree of anemia, 19% also had ferritin < 12 µg/L, and 16% had an elevated RF ratio. Among the 35 women with elevated TfR, 57% also had low ferritin, and all but one was anemic.
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78 g/L) up to a concentration of 95 g/L, and a steady but much more gradual increase after this point. Similar relations were evident for other birth outcomes (not shown). Based in part on these diagrams, we divided Hb concentration into 3 categories for subsequent analyses. We added broken vertical lines to Figure 1 at 95 g/L and 120 g/L to illustrate the 3 categories. No linear relation was evident in the graphic depiction of the relation between ferritin and the birth outcomes as continuous variables (data not shown).
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12 µg/L and those born to anemic women with both low ferritin and a vitamin deficiency weighed 141 and 176 g less, respectively, than infants born to nonanemic women. Elevated TfR was associated with a 0.9 cm lower birth length (ß = –0.89; SE = 0.4; P = 0.03) but the RF ratio (as either a continuous or binary variable) was not significantly associated with any birth outcome.
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Hb <120 g/L) and LBW, preterm birth, or FGR.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The deleterious effects of maternal anemia on pregnancy outcomes that we observed are consistent with earlier studies showing that maternal anemia during pregnancy triples the risk of LBW (7). Our findings raise the question whether anemia in the periconceptional period may have an independent effect on infant growth, perhaps by influencing hormone synthesis (28,29) or placental size or vascularization (30) required to sustain optimal fetal growth. Alternatively, women who were classified as moderately anemic before pregnancy may have developed more severe anemia during pregnancy, (31,32) leading to the observed growth deficits. Unfortunately, we do not know whether prenatal micronutrient supplementation was implemented or whether nutritional status changed substantially throughout the course of pregnancy; thus we cannot speculate on which of these 2 pathways is more probable, although the issue deserves further study.
We found that low ferritin (<12 µg/L), a marker of depleted iron stores, was significantly associated with reduced birthweight. However, elevated ferritin (60 µg/L) was also associated with reduced birthweight and was a risk factor for LBW and FGR. Our observation of an association between pregnancy outcome and high ferritin levels before conception is consistent with numerous reports indicating an increased risk of adverse birth outcomes in women with elevated ferritin during pregnancy (24,33–36). Because ferritin is an acute-phase protein, high ferritin concentration under these circumstances may not reflect greater iron stores but rather may serve as a biomarker of acute or chronic inflammation (37,38). Our findings are particularly noteworthy because ferritin was measured in blood samples obtained before pregnancy; thus, the association between elevated ferritin and pregnancy outcome in our study was not due to pregnancy-related infections, such as chorioamnionitis, or to inadequate plasma volume expansion during pregnancy, both of which have been cited as possible reasons for the association (34,39). Exposure to cotton dust induces lung inflammation in textile workers (40,41) and is a possible cause of elevated ferritin in some of our textile factory workers. We did not have an independent measure of inflammation, such as C-reactive protein, which would have allowed us to study more directly the association between inflammation and adverse pregnancy outcomes, nor did we have dietary data, which would have helped to determine the role of micronutrient intake in nutritional status.
Several studies reported a high prevalence of anemia during pregnancy in the absence of iron deficiency (3,42–44). We found that preconception anemia that was not related to iron deficiency was common among women in this study. Only 20% of the women with anemia also had biochemical evidence of depleted iron stores, whereas nearly half of these same women were deficient in at least 1 B vitamin, and 33% had B-vitamin deficiencies without evidence of depleted iron stores. Because of the relatively small number of adverse pregnancy outcomes in this cohort, we did not have sufficient statistical power to estimate the association between noniron-deficiency anemia and adverse pregnancy outcomes, such as preterm birth or LBW, using logistic regression. However, we were able to show that anemia related to B-vitamin deficiency without depleted iron stores was significantly associated with a decrease in birthweight of 141 g. In addition, we reported previously that B-vitamin deficiencies are important independent determinants of adverse pregnancy outcomes in this cohort (17). These observations support the suggestion (7,11) that an important factor in the lack of improvement in birth outcomes observed in many iron-only supplementation programs may be that, in some populations, only a fraction of observed anemia is related to iron deficiency alone. Given the continuing high global prevalence of anemia in women of reproductive age and the apparent importance of anemia as a predictor of adverse pregnancy outcomes, greater public health efforts to assess and combat the multiple causes of anemia in women of reproductive age appear warranted.
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FOOTNOTES |
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3 Abbreviations used: Hb, hemoglobin; FGR, fetal growth restriction; LBW, low birthweight; OR, odds ratio; RF ratio, ratio of transferrin receptor to ferritin; TfR, transferrin receptor.
Manuscript received 16 June 2004. Initial review completed 2 July 2004. Revision accepted 2 August 2004.
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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