Maternal prepregnancy hemoglobin concentration has rarely been explored as a risk of poor birth outcomes. This study examined whether women with anemia before pregnancy would be at higher risk of preterm birth, low birth weight (LBW) and small-for-gestational-age (SGA) birth.
This retrospective cohort study was conducted on 70 895 Korean women who delivered a singleton in 1999, with their prepregnancy hemoglobin concentration measured at health examinations in 1997–1999. A logistic model was used to adjust for confounding variables and calculate odds ratios (ORs) and 95% confidence intervals (CIs).
In adjusted analysis, moderate-to-severe anemia (hemoglobin <100 g/l) before pregnancy was associated with preterm birth (OR, 1.53; 95% CI, 1.05–2.23; P=0.027), LBW (OR, 1.81; 95% CI, 1.24–2.64; P=0.002) and SGA (OR, 1.71; 95% CI, 1.35–2.17; P<0.001) when compared with prepregnancy hemoglobin of 120–149 g/l. Mild anemia (hemoglobin of 100–119 g/l) was also associated with LBW (OR, 1.21; 95% CI, 1.06–1.39; P=0.005) and SGA (OR, 1.15; 95% CI, 1.06–1.25; P=0.001). The risk of preterm birth, LBW and SGA across 11 prepregnancy hemoglobin groups depended on the severity of anemia (P for trend=0.042, 0.019, and 0.001, respectively). A high hemoglobin concentration (⩾150 g/l), however, was not associated with adverse birth outcomes.
Anemia, not high hemoglobin concentration, before pregnancy was associated with an elevated risk of preterm birth, LBW and SGA, and the risk increased with the severity of anemia in Korean women.
Anemia is a global public health problem affecting people in both developing and developed countries.1 The prevalence of anemia increases with maternal age in Korea.2 The high prevalence of anemia (24.4%) in black women at their fertile age is a public health concern in the United States.3
Preterm birth,4 low birth weight (LBW)5 and small for gestational age (SGA)6 are the leading causes of perinatal and early childhood mortality and morbidity. Although some studies have documented that maternal anemia increased the risk of adverse birth outcomes,7, 8, 9, 10, 11, 12, 13, 14, 15 inconsistent results on the relationship between maternal hemoglobin (Hb) concentration and adverse birth outcomes cast doubt on anemia, especially mild-to-moderate anemia, as a risk of poor birth outcomes.16, 17, 18, 19 Various studies have shown that a high Hb concentration was also significantly associated with poor birth outcomes.7, 8, 9, 17 Studies have suggested that maternal anemia is likely to have a less severe effect on birth outcomes than a high Hb concentration, particularly in developed countries.17, 20
Most previous studies have measured maternal hemoglobin during pregnancy. As the Hb concentration changes during pregnancy with fetal growth,21 the association between maternal Hb and adverse birth outcomes may vary depending on the gestational age at which maternal Hb is measured. It has rarely been evaluated whether women with anemia or high hemoglobin concentration when not pregnant would have poor birth outcomes.13
Through this large retrospective cohort study, we attempted to explore the association between prepregnancy Hb concentration, divided into 2, 4 and 11 groups, and the risk of preterm birth, LBW and SGA in Korean women.
Subjects and methods
Live birth data were obtained from Korea’s national birth register. A total of 558 016 mothers with a singleton birth in 1999 were individually identified. A cohort of 71 082 mothers, who had undergone health-screening examinations in 1997–1999 sponsored by the National Health Insurance Corporation on or before the first day of their last menstrual period, was established. In the end, a total of 70 895 mothers whose prepregnancy Hb concentration had been collected were recruited as the study population. This study was approved by the Institutional Review Board of Kwandong University Myoungji Hospital.
Birth outcomes and maternal variables
We defined preterm birth as a birth at less than 37 weeks of gestation, and LBW as infants weighing less than 2500 g at birth. SGA was defined as infants with weights below the tenth percentile of the gender-age-adjusted birth weight in Korea.22 The data on gestational age, birth weight, parity and maternal education status were obtained from the birth register. The birth register form is required by law to be filled out by parents. The body mass index was calculated by dividing weight (kg) by the square of height (m). We classified women into 2 groups (anemia (Hb<120 g/l) and no anemia (Hb⩾120 g/l)),1 4 groups (moderate-to-severe anemia (Hb<100 g/l), mild anemia (Hb of 100–119 g/l), normal (Hb of 120–149 g/l) and high hemoglobin (Hb⩾150 g/l)) and 11 groups by intervals of 10 g/l9, 10, 23, 24 from severe anemia (Hb<80 g/l) to the highest Hb group (⩾170 g/l) by prepregnancy Hb concentration. Hb categorization, particularly the grading of anemia, was based on the WHO guidelines.1, 25, 26 The data on height, weight, Hb concentration and health examination results (normal versus tuberculosis and other chest diseases, hypertension, hyperlipidemia, liver disease, diabetes, kidney disease, gynecologic disease, cervix cancer or other diseases suspected) were derived from the National Health Insurance Corporation health examinations, which, conducted by medical staff at local hospitals, followed a standard procedure.27
Maternal age, body mass index and Hb concentration were expressed as mean±s.d. The number and rate (%), and the rate’s exact binomial 95% confidence interval (CI) were calculated for preterm birth, LBW and SGA across the Hb groups. An independent samples t-test was applied to compare the differences in means, and the χ2-test was performed to examine differences in proportions. An unconditional logistic regression model was made to calculate odds ratios (ORs) and 95% CIs. The ORs were adjusted for mother’s age at delivery (years: <25, 25–29, 30–34 and ⩾35), body mass index (kg/m2: <18.5, 18.5–20.9, 21–22.9, 23–24.9, ⩾25.0), parity (0, 1, 2 or above), education level (middle-school graduation or below, high-school graduation, college graduation or over) and health examination results (normal or diseases suspected). Tests for linear trends across the Hb groups were also conducted with the Hb group as an ordinal variable. SAS version 9.2 for Windows (SAS Institute Inc., Cary, NC, USA) was used. The P-value was calculated with two-sided tests and a statistical significance level of 0.05 was applied.
The study population’s mean maternal age at delivery was 27.9±3.3 years. The mean body mass index and mean Hb concentration was 20.5±2.3 kg/m2 and 130.4±11.0 g/l, respectively, at the time of health examinations undertaken before pregnancy. Women with anemia (Hb<120 g/l) were 12.1% of subjects. Anemic women were slightly older (28.4±3.5 vs 27.9±3.3 years; P<0.001) and very modestly more obese (20.6±2.3 vs 20.5±2.3 kg/m2; P<0.001) than non-anemic women. Women with anemia tended to have a higher educational status, to be of higher parity and to have a greater prevalence of suspected diseases than women without anemia (Table 1). The numbers of severely anemic, moderately anemic and mildly anemic women were 50, 572 and 7959, respectively.
The proportion of preterm birth, LBW and SGA was the highest in women with moderate-to-severe anemia when the subjects were classified into four groups. The risk of LBW and SGA gradually increased with the severity of prepregnancy anemia among 11 groups of maternal Hb in the univariate analysis (Table 2).
In the adjusted analysis, anemic women had a more elevated risk of LBW and SGA than non-anemic women. Anemic women had an elevated risk of preterm birth with a borderline significance compared with non-anemic women. Moderate-to-severe anemic women had significantly increased ORs of preterm birth, LBW and SGA, and mildly anemic women also had increased ORs of LBW and SGA, relative to the normal Hb group (Table 3). The risk of adverse birth outcomes, particularly SGA, gradually increased with the severity of maternal anemia before pregnancy, except that no preterm birth was observed in severely anemic women (Table 3, Figure 1).
In this study, the risk of preterm birth, LBW and SGA increased with more severe maternal anemia before pregnancy. SGA was more consistently associated with the severity of anemia than preterm birth and LBW. High prepregnancy Hb concentration had no association with the risk of preterm birth, LBW or SGA.
Prepregnancy anemia and birth outcomes
The inconsistent results concerning the effect of maternal anemia for preterm birth and LBW may mainly come from the timing of Hb measurement. Few studies on maternal Hb for birth outcomes used Hb measured before pregnancy,13 but instead measured the mother’s Hb during pregnancy. Some studies did not specify the gestational age at which the maternal Hb was measured.18 Hb concentration in late pregnancy heavily reflects plasma volume changes.16, 21 Mild maternal anemia due to a large plasma expansion in the second or third trimester may have beneficial effects on birth outcomes, whereas high Hb concentration due to a poor plasma expansion in the second and third trimester may have harmful effects on birth outcomes. Although maternal anemia in the first trimester showed no relationship with the risk of preterm birth and LBW in one study,19 the maternal Hb values were categorized into only two groups, many studies have reported that maternal anemia in the first trimester or at the first antenatal visit was associated with an increased risk of adverse birth outcomes.10, 11, 12, 14, 15 The results of the present study suggest that anemia before pregnancy is also significantly associated with the risk of preterm birth and LBW.
Several studies have evaluated the association between maternal Hb anemia in early pregnancy or before pregnancy, and SGA. Maternal anemia in the first trimester was not associated with SGA in American11 or Finnish women.12 In Chinese women, first trimester anemia was not associated with SGA in some studies.10, 19 Both the Chinese studies in which the first trimester anemia was not associated with SGA had relatively small sample sizes10 or categorized maternal Hb into just two groups: anemia and non-anemia.19 In a large study among Chinese women, however, the first trimester anemia was associated with SGA.14 The risks of fetal growth restriction were significantly greater among women with moderate anemia before pregnancy (OR=4.6) compared with non-anemic controls in China.13 In our study in Korean women, prepregnancy anemia was associated with an increased risk of SGA, and the risk of SGA in relation to prepregnancy Hb clearly depended on the severity of anemia. The concept that maternal anemia in the first trimester or before pregnancy may be associated with SGA or fetal growth restriction in Chinese and Korean women, but not in European or American women, is obscure. We cannot definitively explain the discrepancies among studies in the association between maternal anemia and SGA, but it has been reported that the effects of Hb concentration on birth outcomes could differ by ethnicity.7, 16, 28 The optimal range of Hb concentration defined by a minimum incidence of unfavorable birth outcomes may vary among ethnic groups.7, 28
High Hb concentration and birth outcomes
The risk of poor perinatal outcomes increased in mothers with high Hb in some studies.7, 8, 9, 17, 23, 24, 28 Anemia was suggested to be less important than high Hb concentration during pregnancy in the genesis of LBW and preterm labor in developed countries.17, 20, 28 However, high Hb concentration in the second or third trimester, or the lowest measured Hb during pregnancy is likely associated with the disorders of plasma expansion.7, 9, 11, 17, 28 Maternal high Hb in late pregnancy may not be an independent risk factor for adverse birth outcomes, but a result of poor plasma expansion. Excluding those studies, many studies of developed countries, as well as developing countries, have documented that high Hb concentration in the first trimester or before pregnancy was not significantly associated with an elevated risk of preterm birth or LBW.10, 11, 12, 13, 14, 15 This study demonstrated that healthy women with a prepregnancy Hb in the higher tail-end were at no risk of preterm birth, LBW or SGA. However, several large studies in European and American women have shown that high Hb in the first trimester was associated with the risk of preterm birth,8 LBW,8 SGA11 and stillbirth.23 A high Hb concentration in the first trimester showed a more inconsistent effect on poor birth outcomes than anemia. Whether a high Hb concentration in early pregnancy or before pregnancy would have an elevated risk of adverse birth outcomes remains to be seen through further research.
Prepregnancy anemia as an independent risk factor
Although iron deficiency is considered to be the most common cause of anemia, other causes and nutrients may well have an important role in the genesis of anemia.29 Other causes of anemia such as hookworm infection, malaria, schistosomiasis and thalassemia are uncommon in Korea. Although those diseases were not specifically examined, tuberculosis and other chest diseases, hypertension, hyperlipidemia, liver disease, diabetes, kidney disease, gynecologic disease, cervix cancer and other diseases were checked at the health examinations and controlled in the adjusted analysis. When the analysis was restricted to women not suspected of having diseases other than anemia, the effect of prepregnancy Hb on birth outcomes barely changed (data not shown). Anemia may be attributed to low socioeconomic status. However, anemic women tended to be more educated than non-anemic women in this study, and maternal educational level was adjusted for in the analysis. Anemia during pregnancy could also be a marker for other maternal or fetal conditions connected to pregnancy, such as uterine bleeding, which may cause poor birth outcomes.10, 11 However, in our study with Hb measured before pregnancy, maternal anemia cannot be a marker for the deleterious conditions of pregnancy. Maternal anemia before pregnancy, therefore, could be an independent predictor of preterm birth, LBW and SGA rather than a marker or mediator of other underlying disorders or socioeconomic conditions, and could be mainly attributed to maternal nutrition in this study. However, anemia was defined by Hb concentration only, and neither iron nor any other nutrients were assessed in this study.
Timing of nutritional supplementation
The finding that prepregnancy anemia increases the risk of adverse pregnancy outcomes suggests that the prevention of anemia is needed before pregnancy for desirable birth outcomes. In Korea, it is customary to prescribe iron and folic acid supplements to pregnant women.30 The present study shows that Korean women, who are anemic before pregnancy, might suffer from poor birth outcomes despite iron and folic acid supplementation during pregnancy, Although data on the doses and duration of iron and folic acid supplementation before or during pregnancy were not collected and were not adjusted for. When to start nutritional supplementation for better birth outcomes is a topic of debate.30, 31 No evidence was found that iron supplementation with or without folic acid during pregnancy has a beneficial effect on birth outcomes.32 Some researchers have suggested that correction of anemia during pregnancy would be difficult and should therefore be prevented.33 Prepregnancy weekly supplementation could improve iron reserves effectively and favor better pregnancy outcomes.33, 34
Strengths and limitations of the study
This large cohort of 70 895 singleton pregnancies includes 2200 preterm births, 1943 LBW babies and 6044 SGA infants. Our efforts of classifying prepregnancy Hb concentrations into 11 groups to obtain more detailed results are the advantages of this study. Hb concentrations were measured before pregnancy, which minimizes the possibility of differential misclassification of the Hb level and confounding by hemodilution with gestational age. However, some limitations of this study require the reader’s attention. First, our subjects differed from women of other studies in some ways. In our study, the proportion of mothers under 20 years at delivery was only 0.2% of all subjects. Our subjects were ethnically very homogeneous, well-educated and tended to be nulliparous. Korean women are thinner on average than European or American women. The effect of maternal anemia or high Hb on some birth outcomes, therefore, might vary in different geographic areas or among ethnic groups. Second, smoking could be associated with Hb concentration and birth outcomes.11 As smoking status was missing among 70.6% of the subjects, it was not included in our analysis. Among women with smoking information, smoking status (current smoker, ex-smoker, non-smoker) was not associated with anemia (P=0.402), preterm birth (P=0.803), LBW (P=0.760) or SGA (P=0.483) in the χ2-analysis, and there was virtually no change in the association between prepregnancy Hb concentration and birth outcomes in the logistic model with or without smoking status (data not shown). It is, however, still a limitation that smoking was not adjusted for among all women in this study. Third, in this study no data was collected during pregnancy. Data on important maternal conditions during pregnancy that have significant effects on birth outcomes, such as gestational hypertension, gestational diabetes, changes in Hb concentration and weight gain during pregnancy, were not collected. It would have been helpful to adjust for these maternal conditions during pregnancy to better understand the effects of prepregnancy anemia on birth outcomes. Fourth, some sample sizes were small with a limited number of cases partly due to a narrow Hb concentration range. The results may thus have a limited statistical power with insufficient cases in some of the analyses.
Our results suggest that anemia, rather than high Hb concentration, before pregnancy increases the risk of preterm birth, LBW and SGA, and the risk increases with the severity of anemia in Korean women. When women are considering to become pregnant, it may result in positive birth outcomes to measure Hb concentration and to treat those who are anemic with iron supplementation before conception.
De Benoist B, McLean E, Cogswell M, Egli I, Wojdyla D (eds). Worldwide Prevalence of Anaemia 1993–2005: WHO Global Database on Anaemia. World Health Organization: Geneva, Switzerland, 2008.
Korea Centers for Disease Control and Prevention. In-depth Analyses of the Third National Health and Nutrition Examination Survey: Health Examination. (in Korean), Korea Centers for Disease Control and Prevention: Seoul, Korea, 2007.
Cusick SE, Mei Z, Freedman DS, Looker AC, Ogden CL, Gunter E et al. Unexplained decline in the prevalence of anemia among US children and women between 1988–1994 and 1999–2002. Am J Clin Nutr 2008; 88: 1611–1617.
Slattery MM, Morrison JJ . Preterm delivery. Lancet 2002; 360: 1489–1497.
McCormick MC . The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985; 312: 82–90.
Figueras F, Gardosi J . Intrauterine growth restriction: new concepts in antenatal surveillance, diagnosis, and management. Am J Obstet Gynecol 2011; 204: 288–300.
Garn SM, Ridella SA, Petzold AS, Falkner F . Maternal hematologic levels and pregnancy outcomes. Semin Perinatol 1981; 5: 155–162.
Murphy JF, O’Riordan J, Newcombe RG, Coles EC, Pearson JF . Relation of haemoglobin levels in first and second trimesters to outcome of pregnancy. Lancet 1986; 327: 992–994.
Steer P, Alam MA, Wadsworth J, Welch A . Relation between maternal haemoglobin concentration and birth weight in different ethnic groups. BMJ 1995; 310: 489–491.
Zhou LM, Yang WW, Hua JZ, Deng CQ, Tao X, Stoltzfus RJ . Relation of hemoglobin measured at different times in pregnancy to preterm birth and low birth weight in Shanghai, China. Am J Epidemiol 1998; 148: 998–1006.
Scanlon KS, Yip R, Schieve LA, Cogswell ME . High and low hemoglobin levels during pregnancy: differential risks for preterm birth and small for gestational age. Obstet Gynecol 2000; 96: 741–748.
Hämäläinen H, Hakkarainen K, Heinonen S . Anaemia in the first but not in the second or third trimester is a risk factor for low birth weight. Clin Nutr 2003; 22: 271–275.
Ronnenberg AG, Wood RJ, Wang X, Xing H, Chen C, Chen D et al. Preconception hemoglobin and ferritin concentrations are associated with pregnancy outcome in a prospective cohort of Chinese women. J Nutr 2004; 134: 2586–2591.
Ren A, Wang J, Ye RW, Li S, Liu JM, Li Z . Low first-trimester hemoglobin and low birth weight, preterm birth and small for gestational age newborns. Int J Gynaecol Obstet 2007; 98: 124–128.
Zhang Q, Ananth CV, Li Z, Smulian JC . Maternal anaemia and preterm birth: a prospective cohort study. Int J Epidemiol 2009; 38: 1380–1389.
Klebanoff MA, Shiono PH, Berendes HW, Rhoads GG . Facts and artifacts about anemia and preterm delivery. JAMA 1989; 262: 511–515.
Lu ZM, Goldenburg RL, Cliver SP, Cutter G, Blankson ML . The relationship between maternal hematocrit and pregnancy outcome. Obstet Gynecol 1991; 71: 190–194.
Malhotra M, Sharma JB, Batra S, Sharma S, Murthy NS, Arora R . Maternal and perinatal outcome in varying degrees of anemia. Int J Gynaecol Obstet 2002; 79: 93–100.
Xiong X, Buekens P, Fraser WD, Guo Z . Anemia during pregnancy in a Chinese population. Int J Gynaecol Obstet 2003; 83: 159–164.
Steer PJ . Maternal hemoglobin concentration and birth weight. Am J Clin Nutr 2000; 71 (5 Suppl), S1285–S1287.
Whittaker PG, Macphail S, Lind T . Serial hematologic changes and pregnancy outcome. Obstet Gynecol 1996; 88: 33–39.
Hong JS, Yi SW, Han YJ, Park YW, Nam CM, Kang HC et al. Fetal growth and neonatal mortality in Korea. Paediatr Perinat Epidemiol 2007; 21: 397–410.
Stephansson O, Dickman PW, Johansson A, Cnattingius S . Maternal hemoglobin concentration during pregnancy and risk of stillbirth. JAMA 2000; 284: 2611–2617.
Little MP, Brocard P, Elliott P, Steer PJ . Hemoglobin concentration in pregnancy and perinatal mortality: a London-based cohort study. Am J Obstet Gynecol 2005; 193: 220–226.
World Health Organization. Haemoglobin Concentrations for the Diagnosis of Anaemia and Assessment of Severity. Vitamin and Mineral Nutrition Information System. World Health Organization: Geneva, Switzerland, 2011, (WHO/NMH/NHD/MNM/11.1, http://www.who.int/vmnis/indicators/haemoglobin.pdf) (last accessed 3 March 2012).
De Maeyer EM, Dallman P, Gurney JM, Hallberg L, Sood SK, Srikantia SG Preventing and Controlling Iron Deficiency Anemia Through Primary Health Care. World Health Organization: Geneva, Switzerland, 1989.
Jee SH, Ohrr H, Sull JW, Yun JE, Ji M, Samet JM . Fasting serum glucose level and cancer risk in Korean men and women. JAMA 2005; 293: 194–202.
Blankson ML, Goldenberg RL, Cutter G, Cliver SP . The relationship between maternal hematocrit and pregnancy outcome: black-white differences. J Natl Med Assoc 1993; 85: 130–134.
Hisano M, Suzuki R, Sago H, Murashima A, Yamaguchi K . Vitamin B6 deficiency and anemia in pregnancy. Eur J Clin Nutr 2010; 64: 221–223.
Lee JI, Lee JA, Lim HS . Effect of time of initiation and dose of prenatal iron and folic acid supplementation on iron and folate nutriture of Korean women during pregnancy. Am J Clin Nutr 2005; 82: 843–849.
Beard JL . Effectiveness and strategies of iron supplementation during pregnancy. Am J Clin Nutr 2000; 71 (5 Suppl), 1288S–1294SS.
Peña-Rosas JP, Viteri FE . Effects and safety of preventive oral iron or iron+folic acid supplementation for women during pregnancy. Cochrane Database Syst Rev 2009; CD004736.
Viteri FE, Berger J . Importance of pre-pregnancy and pregnancy iron status: can long-term weekly preventive iron and folic acid supplementation achieve desirable and safe status? Nutr Rev 2005; 63 (12 Pt 2), S65–S76.
Berger J, Thanh HT, Cavalli-Sforza T, Smitasiri S, Khan NC, Milani S et al. Community mobilization and social marketing to promote weekly iron-folic acid supplementation in women of reproductive age in Vietnam: impact on anemia and iron status. Nutr Rev 2005; 63 (12 Pt 2), S95–S108.
This research was supported by a grant (number 03-03) from the Health Promotion Fund, Ministry of Health and Welfare, Korea. We thank the Korea Institute for Health and Social Affairs, the National Statistical Office and the National Health Insurance Corporation for providing data for the study.
The authors declare no conflict of interest.
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Cite this article
Yi, SW., Han, YJ. & Ohrr, H. Anemia before pregnancy and risk of preterm birth, low birth weight and small-for-gestational-age birth in Korean women. Eur J Clin Nutr 67, 337–342 (2013). https://doi.org/10.1038/ejcn.2013.12
- preterm birth
- low birth weight
- small for gestational age
- cohort studies
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