Community and International Nutrition

Preconception Hemoglobin and Ferritin Concentrations Are Associated with Pregnancy Outcome in a Prospective Cohort of Chinese Women1
Alayne G. Ronnenberg,2 Richard J. Wood,* Xiaobin Wang, Houxun Xing,** Chanzhong Chen, Dafang Chen,** Wenwei Guang,** Aiqun Huang,** Lihua Wang, and Xiping Xu
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
ABSTRACT Prenatal anemia and iron deciency are associated with adverse birth outcomes, but no previous studies have examined the relation between preconception anemia, iron deciency, and pregnancy outcome in healthy women. We measured hemoglobin (Hb), ferritin, transferrin receptor (TfR), and vitamins B-6, B-12, and folate concentrations before pregnancy in 405 Chinese women (median time from sample collection to gestation end 316 d). Both mild (95 Hb 120 g/L) and moderate (Hb 95 g/L) anemia were signicantly associated with lower birthweight (139 and 192 g, respectively); iron-deciency anemia alone (Hb 120 g, ferritin 12 g/L, no B-vitamin deciency) was associated with a 242-g decrease in birthweight. Both low ( 12 g/L) and high ( 60 g/L) ferritin were also signicantly associated with lower birthweight (106 and 123 g, respectively). The risks of low birthweight (LBW) and fetal growth restriction (FGR) were signicantly 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 inammation, 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-deciency anemia, was associated with reduced infant growth and increased risk of adverse pregnancy outcome in Chinese women. J. Nutr. 134: 2586 2591, 2004. KEY WORDS:

Downloaded from jn.nutrition.org by guest on March 10, 2011

anemia

China

ferritin

pregnancy

transferrin receptor

Anemia may occur in as many as half of pregnant women worldwide (1). Although iron deciency is a common cause of anemia, especially in women of reproductive age, anemia may also result from other causes, including deciencies 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 deciency per se and anemia not associated with iron deciency 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,
1 Supported in part by grants 1R01 HD32505 and 1R01 HD41702 from the National Institute of Child Health and Human Development; and 1R01 ES08337 and P01 ES06198 from the National Institute of Environmental Health Science. 2 To whom correspondence should be addressed. E-mail: ronnenberg@comcast.net.

only a fraction of maternal anemia is related to iron deciency alone (7,11). Unraveling the possible independent pregnancy risks associated with anemia and iron deciency may improve the effectiveness of nutrition interventions (9,10). It was suggested that anemia and iron depletion that occur very early in gestation could inuence 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 reect 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 preg-

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.

0022-3166/04 $8.00 2004 American Society for Nutritional Sciences. Manuscript received 16 June 2004. Initial review completed 2 July 2004. Revision accepted 2 August 2004. 2586

ANEMIA AND BIRTH OUTCOME IN CHINESE WOMEN

2587

nancy, 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 deciency 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 inammation, 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 inammation (12). Plasma TfR is elevated in iron deciency and was shown to be an early and sensitive measure of tissue iron deciency (13). Recently, the ratio of TfR ( g/L) to ferritin ( g/L) was also used to identify more clearly persons with functional iron deciency (14). We previously reported a high prevalence of B-vitamin deciencies, 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 deciency, whereas only 17% of women with anemia had evidence of depleted iron stores. We subsequently reported that B-vitamin deciencies 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. SUBJECTS AND METHODS
Subjects. The current study is part of a prospective study of the effects of shift work on reproductive health among women textile workers in Anhui, China. The study protocols were approved by the Human Subject Committee of the Chinese Institutions involved in the study and by the Institutional Review Board of the Harvard School of Public Health. The eligibility criteria for enrollment were as follows: 1) full-time, newly married female employees; 2) aged 20 34 y; and 3) had obtained permission to have a child. Women were excluded if they: 1) were already pregnant before enrollment; 2) had tried unsuccessfully to become pregnant for at least 1 y at any time in the past; or 3) planned to change jobs or move out of the city over the 1-y course of follow-up. Of the 575 women originally enrolled in the study, 405 women who gave birth to live infants and for whom Hb data were available were included in the current analysis. The 170 women who were excluded did not differ signicantly from the study cohort in terms of sociodemographic characteristics or available baseline biomarker concentrations (P 0.05). 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 20C in China until shipped on dry ice to the Harvard School of Public Health, where it was stored at 70C 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 g/L) by ferritin (in g/L). Elevated plasma TfR was dened as a concentration 8.3 mg/L (19). An elevated RF ratio was dened as 500 (20). Vitamin deciencies [folate 6.8 nmol/L (3 g/L); vitamin B-12 258 pmol/L (300 pg/mL); and vitamin B-6 30 nmol/L of pyridoxal-5 -phosphate] were dened 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 dened as crown-heel length and was measured shortly after delivery. Birthweight ratio was dened as an infants 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 dened as the spontaneous delivery of a live infant before 37 completed wk (259 d) of gestation. Low birthweight (LBW) was dened as the birth of a live infant weighing 2500 g. Fetal growth restriction (FGR) was dened as a birthweight ratio 85% (21,22).

Downloaded from jn.nutrition.org by guest on March 10, 2011

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 classied 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 g/L was considered indicative of depleted iron 60 g/L was considered norstores (1), ferritin 12 g/L and mal, and ferritin 60 g/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 deciency anemia and anemia not related to iron deciency, we created 5 groups: group 1 included 131 anemic (Hb 120 g/L) women with ferritin 12 g/L and no evidence of B-vitamin deciency; group 2 included 109 anemic women with at least 1 B-vitamin deciency but 12 ferritin 12 g/L; group 3 included 28 women with ferritin g/L but no evidence of B-vitamin deciency; group 4 included 29 women with both ferritin 12 g/L and evidence of at least 1 B-vitamin deciency; 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 identied using multiple linear regression. Adjusted (leastsquares) 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 signicance refers to P 0.05. Statistical analyses were performed using SAS for Windows, release 8.2.

2588

RONNENBERG ET AL.

RESULTS A total of 405 women were included in the study (Table 1). Women tended to be young, lean, and anemic; mean Hb was 108.5 g/L, and nearly 80% had Hb 120 g/L. The geometric mean ferritin concentration was 29.9 g/L; nearly 18% of women had ferritin concentrations indicative of depleted iron stores ( 12 g/L). Elevated TfR and an RF ratio 500 were detected in 9.8 and 14.8% of women, respectively; 91% of women with an elevated RF ratio also had depleted iron stores. The median time from blood sampling to delivery was 316 d; 75% of women gave birth within 382 d of blood sampling. Thus, given a typical 280-d gestational period, most blood samples were obtained within 1 to 4 mo of conception. A total of 33 infants (8.2%) were classied as LBW, 27 (6.7%) as preterm, and 56 (13.8%) as FGR. Although many infants met criteria for multiple birth outcomes, distinct categories were still apparent, i.e., 31 infants were classied as both LBW and FGR, but only 9 of those were also born preterm. Both low ferritin and elevated TfR were signicantly associated with Hb concentration (Table 2), although an RF ratio 500 was not. Deciencies of vitamins B-6 and B-12 were

TABLE 1
Characteristics of the study population, Anqing, China1
Variable Age, y Height, m Weight, kg BMI, kg/m2 Maternal Hb, g/L Maternal ferritin, g/L RF ratio Infant birth weight, g Infant birth length, cm Infant head circumference, cm Infant gestational age, wk n 405 405 405 405 405 359 359 405 370 359 405 24.9 1.58 49.2 19.8 108.5 29.9 159.0 3116 50.0 33.5 39.6 % Hb, g/L 95 g/L ( 10th percentile) 95 Hb 120 120 Ferritin, g/L 12 12 ferritin 60 60 ( 80th percentile) High transferrin receptor, (TfR 8.3 mg/L) High RF ratio, (TfR: ferritin 500) Education completed Middle school or less High school College or above Rotating work shift Exposure to Passive smoking Dust Noise Work stress No use of vitamin/mineral supplements LBW infants ( 2500 g) Preterm infants ( 37 wk gestation completed) FGR infants 40 275 90 63 221 75 35 53 295 111 3 390 271 397 382 167 399 33 27 56 9.9 67.9 22.2 17.5 61.6 20.9 9.8 14.8 72.1 27.1 0.7 95.3 66.3 97.1 93.4 36.2 97.8 8.1 6.7 13.8 1.5 0.05 5.9 2.1 13.0 2.4 2.9 480 2.4 1.8 1.7

1 Values are means SD or %. Ferritin and the ratio of transferrin receptor (TfR) to ferritin (RF ratio) are presented as geometric means, n 359.

also associated with Hb. Among the 40 women with Hb 95 g/L, 5 had depleted iron stores but no B-vitamin deciency, 17 had a B-vitamin deciency but ferritin 12 g/L, 9 had both depleted iron stores and a vitamin deciency, and 9 had no evidence of B-vitamin deciency or iron depletion. Of the 297 women who had some degree of anemia, 19% also had ferritin 12 g/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. The covariate-adjusted relations between Hb (as a continuous variable) and birth outcomes were estimated using the LOESS procedure; the relation between birthweight and Hb is displayed graphically in Figure 1. This plot suggests at least 2 separate slopes, i.e., a relatively steep slope from the lowest Hb value ( 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). Both mild and moderate maternal anemia were associated with reductions in all 3 measures of infant growth (Table 3). The most profound association was noted for birthweight, with mild anemia associated with a 139-g decrease and moderate anemia associated with a 192-g decrease in birthweight. Both low and high ferritin categories were also signicantly associated with lower birthweight (106 and 123 g, respectively) compared with women with an intermediate ferritin concentration. When we divided anemic women into groups based on their ferritin and B-vitamin status, we found that all forms of anemia were generally associated with some degree of growth decit. The most pronounced decrements were observed for iron-deciency anemia without concurrent B-vitamin deciency; infants in this group were 242 g lighter on average than those born to nonanemic women. Infants born to vitamindecient anemic women who had ferritin 12 g/L and those born to anemic women with both low ferritin and a vitamin deciency 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 ( 0.89; SE 0.4; P 0.03) but the RF ratio (as either a continuous or binary variable) was not signicantly associated with any birth outcome. Logistic regression was used to assess the association between Hb and ferritin categories and adverse birth outcomes (Table 4). Moderate anemia (Hb 95 g/L) was signicantly associated with increased risk of LBW and FGR. In adjusted models, the risk of LBW was 6.5 times greater and the risk of FGR was nearly 5 times greater among women with moderate anemia compared with those without anemia. Although moderate anemia was associated with increased risk of preterm birth in a logistic model adjusted for nonnutrient covariates only (OR 3.9; 95% CI: 1.1, 14.1; P 0.04), this association was weakened by inclusion of B-vitamin deciencies in the model and was no longer signicant (OR 2.9; 95% CI: 0.8, 11.3; P 0.12). No signicant associations were observed between mild anemia (95 Hb 120 g/L) and LBW, preterm birth, or FGR. No signicant associations were observed between depleted iron stores (ferritin 12 g/L) and risk of preterm birth, LBW, or FGR in either the crude or adjusted model. However, the risk of FGR was nearly 3 times higher among infants born to women with elevated ferritin compared with those in the

Downloaded from jn.nutrition.org by guest on March 10, 2011

ANEMIA AND BIRTH OUTCOME IN CHINESE WOMEN

2589

TABLE 2
Associations among hemoglobin, ferritin, and B-vitamin status in Chinese women
Hb categories (g/L), n Variables associated with Hb concentration Hb n 95 40 95 Hb 120 n 257 % (n) Ferritin 12 g/L TfR 8.3 mg/L Vitamin B-6 deciency Vitamin B-12 deciency Folate deciency 35.0 (14) 22.5 (9) 42.5 (17) 22.5 (9) 22.5 (9) 16.7 (43) 9.7 (25) 24.1 (62) 16.7 (43) 22.2 (57) 9.7 (6) 1.6 (1) 14.5 (9) 11.3 (7) 14.5 (9) 0.29 0.59 0.39 0.37 0.22 0.17 0.22 0.15 0.17 0.16 0.10 0.01 0.01 0.03 0.17 359 Hb n 120 62 Adjusted associations1 SE P

1 The linear regression model with Hb as a continuous outcome variable was adjusted for all of the nutrition-related covariates and exposure to dust and work stress. The overall model was signicant, P 0.0001.

reference group. Elevated ferritin was also signicantly associated with more than double the risk of LBW in an unadjusted model, although the strength and signicance of the association was attenuated somewhat after adjustment for covariates. DISCUSSION Numerous previous studies reported a relation between prenatal maternal anemia, particularly iron-deciency anemia, and shortened gestation (25,26) and lower birthweight (5,27). Because of the unique design of the current study, in which the subjects were women who were attempting to become pregnant, blood samples were obtained before pregnancy; thus, they reect maternal Hb, ferritin, and B-vitamin status in the periconceptional period. To our knowledge, ours is the rst such prospective study to report an association between preconception maternal anemia and ferritin status and adverse pregnancy outcomes. Maternal anemia was signicantly associated with infant growth, including birthweight and the risk of LBW. The mean birthweights of infants born to women

FIGURE 1 Independent relation between birthweight and maternal prepregnancy Hb concentration (g/L) in Chinese women. Results were derived from generalized additive models using SPLUS 2000. The model was adjusted for maternal age, height, height-squared, BMI, education, work stress, maternal exposure to dust, noise, and passive smoking, infant gender, and gestational age. Dotted vertical lines at Hb concentrations of 95 and 120 g/L indicate the cutoff points for Hb categories in subsequent analyses.

with mild and moderate anemia were 144 and 199 g lower, respectively, than those of infants born to women without preconception anemia. In addition, women with moderate anemia before conception were 6 times as likely to deliver a LBW infant and 5 times more likely to have an infant with FGR. Although anemia per se was an important predictor of pregnancy outcome in our cohort, preconception iron-deciency anemia had a particularly strong effect on birthweight, i.e., infants born to women with preconception iron-deciency anemia and adequate B-vitamin status weighed on average 241 g less than those born to women without anemia. 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 ndings raise the question whether anemia in the periconceptional period may have an independent effect on infant growth, perhaps by inuencing hormone synthesis (28,29) or placental size or vascularization (30) required to sustain optimal fetal growth. Alternatively, women who were classied as moderately anemic before pregnancy may have developed more severe anemia during pregnancy, (31,32) leading to the observed growth decits. 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 g/L), a marker of depleted iron stores, was signicantly associated with reduced birthweight. However, elevated ferritin ( 60 g/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 (24,3336). Because ferritin is an acutephase protein, high ferritin concentration under these circumstances may not reect greater iron stores but rather may serve as a biomarker of acute or chronic inammation (37,38). Our ndings 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

Downloaded from jn.nutrition.org by guest on March 10, 2011

2590

RONNENBERG ET AL.

TABLE 3
Adjusted means for birth outcomes across categories of hemoglobin, ferritin, and anemia in Chinese women1,2
Category n Birthweight g Hemoglobin, g/L 95 95 Hb 120 1203 Ferritin, g/L 12 12 Ferritin 603 60 Anemia No iron or B-vitamin deciency B-vitamin deciency and no iron deciency Iron deciency and no B-vitamin deciency Both iron and B-vitamin deciencies No anemia3 40 275 90 63 221 75 131 109 28 29 62 3041 (2910, 3171)* 3094 (3044, 3145)* 3233 (3128, 3338) 3051 (2947,3154)** 3157 (3101, 3212) 3034 (2938,3130)** 3112 (3040, 3184)# 3091 (3011,3171)** 2990 (2836, 3145)* 3056 (2902, 3209)# 3232 (3126, 3337) Birth length cm 49.4 (48.7,50.1)** 50.0 (49.7, 50.2)# 50.3 (49.7, 50.8) 49.6 (49.0, 50.1)# 50.1 (49.8, 50.4) 49.8 (49.2, 50.3) 50.0 (49.6, 50.4) 50.0 (48.9, 50.3) 49.2 (48.3,50.0)** 49.7 (48.9, 50.5) 50.3 (49.7, 50.8) Head circumference cm 33.0 (32.4, 33.5)* 33.4 (33.2,33.6)** 33.9 (33.4, 34.3) 33.3 (32.9, 33.8) 33.4 (33.2, 33.7) 33.4 (33.0, 33.8) 33.4 (33.1, 33.7)# 33.3 (33.0,33.6)** 32.8 (32.2, 33.5)* 33.6 (33.0, 34.3) 33.9 (33.4, 34.3)

1 Values are least-squares means (95% CI). Means are adjusted for maternal age, height and height-squared, BMI, education, exposure to dust, noise, and passive smoking, work stress, infant gender, and gestational age (linear and quadratic terms). 2 Symbols indicate different from the reference group: * P 0.01; ** P 0.05; # P 0.1. 3 Reference group.

Downloaded from jn.nutrition.org by guest on March 10, 2011

dust induces lung inammation 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 inammation, such as C-reactive protein, which would have allowed us to study more directly the association between inammation 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 deciency (3,42 44). We found that preconception anemia that was not related to iron deciency 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 decient in at least 1 B vitamin, and 33% had B-vitamin deciencies without evidence of depleted iron stores. Because of the relatively small number of adverse preg-

nancy outcomes in this cohort, we did not have sufcient statistical power to estimate the association between nonirondeciency 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 deciency without depleted iron stores was signicantly associated with a decrease in birthweight of 141 g. In addition, we reported previously that B-vitamin deciencies 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 deciency 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

TABLE 4
Adjusted OR for preterm birth, LBW, and FGR by hemoglobin (Hb) and ferritin (Ft) categories in Chinese women1
Preterm birth (n Category Hemoglobin, g/L 95 95 Hb 120 1202 Ferritin, g/L 123 12 Ferritin 602 60 n % OR 95% CI 27) P % LBW (n OR 33) P % FGR (n OR 56) P

95% CI

95% CI

40 275 90 63 221 75

15.0 5.1 7.8 11.1 5.0 9.3

2.9 0.7 1.0 2.3 1.0 1.9

0.8, 11.3 0.3, 1.9 0.8, 6.5 0.7, 5.5

0.12 0.50 0.12 0.24

17.5 7.6 5.6 6.4 6.8 16.0

6.5 2.0 1.0 0.7 1.0 2.2

1.6, 26.7 0.7, 5.9 0.2, 2.4 0.9, 5.7

0.009 0.22 0.55 0.09

25.0 13.1 11.1 12.7 11.3 22.7

4.6 1.4 1.0 1.2 1.0 2.7

1.5, 13.5 0.7, 3.2 0.5, 2.8 1.3, 5.6

0.006 0.36 0.75 0.008

1 Logistic regression models were adjusted for maternal age, height and height-squared, BMI, education, exposure to dust, noise, and passive smoking, work stress, infant gender, and gestational age (linear and quadratic terms), and deciency of folate, vitamin B-12, and vitamin B-6. Preterm birth and FGR models were adjusted for all of the covariates above except for gestational age. Percentages are provided for convenience only. P-values refer to the logistic regression models. 2 Reference group. 3 Because of unavailable ferritin data for some women, the number of cases was reduced slightly in this subset: n 31 cases for LBW, 25 cases for preterm birth, and 50 cases for FGR.

ANEMIA AND BIRTH OUTCOME IN CHINESE WOMEN

2591

efforts to assess and combat the multiple causes of anemia in women of reproductive age appear warranted. LITERATURE CITED
1. DeMaeyer, E. & Adiels-Tegman, M. (1985) The prevalence of anaemia in the world. World Health Stat. Q. 38: 302316. 2. Murphy, J. F., ORiordan, J., Newcombe, R. G., Coles, E. C. & Pearson, J. F. (1986) Relation of haemoglobin levels in rst and second trimesters to outcome of pregnancy. Lancet 1: 992995. 3. Scholl, T. O., Hediger, M. L., Fischer, R. L. & Shearer, J. W. (1992) Anemia vs iron deciency: increased risk of preterm delivery in a prospective study. Am. J. Clin. Nutr. 55: 985988. 4. Zhou, L. M., Yang, W. W., Hua, J. Z., Deng, C. Q., Tao, X. & Stoltzfus, R. J. (1998) Relation of hemoglobin measured at different times in pregnancy to preterm birth and low birth weight in Shanghai, China. Am. J. Epidemiol. 148: 998 1006. 5. Agarwal, K. N., Agarwal, D. K. & Mishra, K. P. (1991) Impact of anaemia prophylaxis in pregnancy on maternal haemoglobin, serum ferritin and birth weight. Indian J. Med. Res. 94: 277280. 6. Tchernia, G., Blot, I., Rey, A. & Papiernik, E. (1983) [Maternal iron and folate deciencies. Effects on the newborn infant]. Sem. Hop. 59: 416 420. 7. Rasmussen, K. (2001) Is there a causal relationship between iron deciency or iron-deciency anemia and weight at birth, length of gestation and perinatal mortality? J. Nutr. 131: 590S 601S; discussion 601S 603S. 8. Cogswell, M. E., Parvanta, I., Ickes, L., Yip, R. & Brittenham, G. M. (2003) Iron supplementation during pregnancy, anemia, and birth weight: a randomized controlled trial. Am. J. Clin. Nutr. 78: 773781. 9. Allen, L. H. (1997) Pregnancy and iron deciency: unresolved issues. Nutr. Rev. 55: 91101. 10. Allen, L. H. (2000) Anemia and iron deciency: effects on pregnancy outcome. Am. J. Clin. Nutr. 71: 1280S1284S. 11. Allen, L. H., Rosado, J. L., Casterline, J. E., Lopez, P., Munoz, E., Garcia, O. P. & Martinez, H. (2000) Lack of hemoglobin response to iron supplementation in anemic Mexican preschoolers with multiple micronutrient deciencies. Am. J. Clin. Nutr. 71: 14851494. 12. Nielsen, O. J., Andersen, L. S., Hansen, N. E. & Hansen, T. M. (1994) Serum transferrin receptor levels in anaemic patients with rheumatoid arthritis. Scand. J. Clin. Lab. Investig. 54: 75 82. 13. Carriaga, M. T., Skikne, B. S., Finley, B., Cutler, B. & Cook, J. D. (1991) Serum transferrin receptor for the detection of iron deciency in pregnancy. Am. J. Clin. Nutr. 54: 10771081. 14. Olivares, M., Walter, T., Cook, J. D., Hertrampf, E. & Pizarro, F. (2000) Usefulness of serum transferrin receptor and serum ferritin in diagnosis of iron deciency in infancy. Am. J. Clin. Nutr. 72: 11911195. 15. Ronnenberg, A. G., Goldman, M. B., Aitken, I. W. & Xu, X. (2000) Anemia and deciencies of folate and vitamin B-6 are common and vary with season in Chinese women of childbearing age. J. Nutr. 130: 27032710. 16. Ronnenberg, A. G., Goldman, M. B., Chen, D., Aitken, I. W., Willett, W. C., Selhub, J. & Xu, X. (2002) Preconception folate and vitamin B(6) status and clinical spontaneous abortion in Chinese women. Obstet. Gynecol. 100: 107113. 17. Ronnenberg, A. G., Goldman, M. B., Chen, D., Aitken, I. W., Willett, W. C., Selhub, J. & Xu, X. (2002) Preconception homocysteine and B vitamin status and birth outcomes in Chinese women. Am. J. Clin. Nutr. 76: 13851391. 18. Wang, X., Chen, C., Wang, L., Chen, D., Guang, W. & French, J. (2003) Conception, early pregnancy loss, and time to clinical pregnancy: a populationbased prospective study. Fertil. Steril. 79: 577584. 19. Yeung, G. S., Kjarsgaard, J. C. & Zlotkin, S. H. (1998) Disparity of serum transferrin receptor measurements among different assay methods. Eur. J. Clin. Nutr. 52: 801 804. 20. Akesson, A., Bjellerup, P., Berglund, M., Bremme, K. & Vahter, M. (2002) Soluble transferrin receptor: longitudinal assessment from pregnancy to postlactation. Obstet. Gynecol. 99: 260 266. 21. Kramer, M. S., Platt, R., Yang, H., McNamara, H. & Usher, R. H. (1999) Are all growth-restricted newborns created equal(ly)? Pediatrics 103: 599 602. 22. Wang, X., Zuckerman, B., Pearson, C., Kaufman, G., Chen, C., Wang, G.,

Niu, T., Wise, P. H., Bauchner, H. & Xu, X. (2002) Maternal cigarette smoking, metabolic gene polymorphism, and infant birth weight. J. Am. Med. Assoc. 287: 195202. 23. World Health Organization (1992) The Prevalence of Anaemia in Women: A Tabulation of Available Information, 2nd ed. WHO, Geneva Switzerland. 24. Tamura, T., Goldenberg, R. L., Johnston, K. E., Cliver, S. P. & Hickey, C. A. (1996) Serum ferritin: a predictor of early spontaneous preterm delivery. Obstet. Gynecol. 87: 360 365. 25. Klebanoff, M. A., Shiono, P. H., Selby, J. V., Trachtenberg, A. I. & Graubard, B. I. (1991) Anemia and spontaneous preterm birth. Am J Obstet. Gynecol. 164: 59 63. 26. Scholl, T. O. & Hediger, M. L. (1994) Anemia and iron-deciency anemia: compilation of data on pregnancy outcome. Am. J. Clin. Nutr. 59: 492S500S discussion 500S501S. 27. Singla, P. N., Tyagi, M., Kumar, A., Dash, D. & Shankar, R. (1997) Fetal growth in maternal anaemia. J. Trop. Pediatr. 43: 89 92. 28. Wheeler, T., Sollero, C., Alderman, S., Landen, J., Anthony, F. & Osmond, C. (1994) Relation between maternal haemoglobin and placental hormone concentrations in early pregnancy. Lancet 343: 511513. 29. Allen, L. H. (2001) Biological mechanisms that might underlie irons effects on fetal growth and preterm birth. J. Nutr. 131: 581S589S. 30. Bazaz, G., Mirchandani, J. J. & Chitra, S. (1979) Placenta in intrauterine growth retardation. J. Obstet. Gynaecol. India 29: 805 810. 31. Ho, C. H., Yuan, C. C. & Yeh, S. H. (1987) Serum ferritin, folate and cobalamin levels and their correlation with anemia in normal full-term pregnant women. Eur. J. Obstet. Gynecol. Reprod. Biol. 26: 713. 32. Casanueva, E., Pfeffer, F., Drijanski, A., Fernandez-Gaxiola, A. C., Gutierrez-Valenzuela, V. & Rothenberg, S. J. (2003) Iron and folate status before pregnancy and anemia during pregnancy. Ann. Nutr. Metab. 47: 60 63. 33. Tamura, T., Goldenberg, R. L., Hou, J., Johnston, K. E., Cliver, S. P., Ramey, S. L. & Nelson, K. G. (2002) Cord serum ferritin concentrations and mental and psychomotor development of children at ve years of age. J. Pediatr. 140: 165170. 34. Scholl, T. O. (1998) High third-trimester ferritin concentration: associations with very preterm delivery, infection, and maternal nutritional status. Obstet. Gynecol. 92: 161166. 35. Goldenberg, R. L., Tamura, T., DuBard, M., Johnston, K. E., Copper, R. L. & Neggers, Y. (1996) Plasma ferritin and pregnancy outcome. Am. J. Obstet. Gynecol. 175: 1356 1359. 36. Goldenberg, R. L., Mercer, B. M., Miodovnik, M., Thurnau, G. R., Meis, P. J., Moawad, A., Paul, R. H., Bottoms, S. F., Das, A., Roberts, J. M., McNellis, D. & Tamura, T. (1998) Plasma ferritin, premature rupture of membranes, and pregnancy outcome. Am. J. Obstet. Gynecol. 179: 1599 1604. 37. Brailsford, S., Lunec, J., Winyard, P. & Blake, D. R. (1985) A possible role for ferritin during inammation. Free Radic. Res. Commun. 1: 101109. 38. Kuvibidila, S., Yu, L. C., Ode, D. L., Warrier, R. P. & Mbele, V. (1994) Assessment of iron status of Zairean women of childbearing age by serum transferrin receptor. Am. J. Clin. Nutr. 60: 603 609. 39. Scholl, T. O. & Reilly, T. (2000) Anemia, iron and pregnancy outcome. J. Nutr. 130: 443S 447S. 40. Li, D., Zhong, Y. N., Rylander, R., Ma, Q. Y. & Zhou, X. Y. (1995) Longitudinal study of the health of cotton workers. Occup. Environ. Med. 52: 328 331. 41. Rylander, R. (1990) Health effects of cotton dust exposures. Am. J. Ind. Med. 17: 39 45. 42. Alper, B. S., Kimber, R. & Reddy, A. K. (2000) Using ferritin levels to determine iron-deciency anemia in pregnancy. J. Fam. Pract. 49: 829 832. 43. Antelman, G., Msamanga, G. I., Spiegelman, D., Urassa, E. J., Narh, R., Hunter, D. J. & Fawzi, W. W. (2000) Nutritional factors and infectious disease contribute to anemia among pregnant women with human immunodeciency virus in Tanzania. J. Nutr. 130: 1950 1957. 44. Hinderaker, S. G., Olsen, B. E., Lie, R. T., Bergsjo, P. B., Gasheka, P., Bondevik, G. T., Ulvik, R. & Kvale, G. (2002) Anemia in pregnancy in rural Tanzania: associations with micronutrients status and infections. Eur. J. Clin. Nutr. 56: 192199.

Downloaded from jn.nutrition.org by guest on March 10, 2011