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Low first-trimester hemoglobin and low birth weight, preterm birth and small for gestational age newborns
International Journal of Gynecology and Obstetrics (2007) 98, 124–128
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / i j g o
CLINICAL ARTICLE
Low first-trimester hemoglobin and low birth weight, preterm birth and small for gestational age newborns A. Ren ⁎, J. Wang, R.W. Ye, S. Li, J.M. Liu, Z. Li Institute of Reproductive and Child Health, Peking University Health Science Center, Beijing, China Received 13 December 2006; received in revised form 11 May 2007; accepted 16 May 2007
KEYWORDS Hemoglobin; Anemia; Pregnancy; Low birth weight; Preterm birth; Small for gestational age
Abstract Objective: To examine the relationship between first-trimester hemoglobin (Hb) concentration and risk of low birth weight (LBW), preterm birth and small for gestational age (SGA). Methods: Data were obtained from a population-based prenatal care program in China. A total of 88,149 women who delivered during 1995–2000 and had their Hb measured in the first trimester were selected as study subjects. Results: The prevalence of anemia (Hb b 110 g/L) was 22.1% in the first trimester. The risk of LBW, preterm birth and SGA was increased steadily with the decrease of first-trimester Hb concentration. After controlling for confounding factors, women with Hb 80–99 g/L had significantly higher risk for LBW (OR = 1.44, 95% CI 1.17–1.78), preterm birth (OR = 1.34, 95% CI 1.16–1.55) and SGA (OR = 1.13, 95% CI 0.98–1.31) than women with Hb 100–119 g/L. No elevated risk was noted for women with Hb ≥ 120 g/L. Conclusion: Low first-trimester Hb concentration increases the risk of LBW, preterm birth and SGA. © 2007 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Studies on the relationship between maternal hemoglobin (Hb) level and adverse pregnancy outcomes have been inconsistent. Some studies have found that low maternal Hb level increases the risk of low birth weight (LBW) or preterm birth [1–3]. Others have found a U-shaped relationship, i.e., Hb value at either the low or the high end increases the risk [4–9]. In
⁎ Corresponding author. 38 Xueyuan Rd, Haidian District, Institute of Reproductive and Child Health, Peking University Health Science Center, Beijing 100083, China. Tel.: +86 10 8280 5040; fax: +86 10 8280 1141. E-mail address: [email protected] (A. Ren).
addition, some studies have found no association between Hb level and the risk of adverse pregnancy outcomes [10–12]. These inconsistencies may stem from the differences in gestational age at which Hb was measured. Although some studies used Hb values measured in the first trimester [1,6], many studies used Hb values determined in the second or third trimester [4,8,13]. In addition, some studies did not provide information on trimesters at which Hb measurement was done [5,12]. One study used the lowest Hb measurement during pregnancy [7]. Maternal plasma volume expands as the pregnancy progresses: little increase is seen before 10 weeks’ gestation, followed by a progressive rise to maximum volume at about 34–36 weeks’ gestation, beyond which little or no further increase occurs [14]. Therefore, the effect of Hb concentration on pregnancy outcomes may be
0020-7292/$ - see front matter © 2007 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2007.05.011
Low hemoglobin and birth weight, preterm birth and small for gestational age newborns Table 1
Characteristics of women with and without anemia in the first trimester in a Chinese population, 1996–2000
Characteristics
Non-anemic (N = 68,820)a
Anemic (N = 19,329)a
P
Maternal age Gestational weeks at 1st visit Maternal BMI at 1st visit Education College High school Middle school or lower Gravidity 1 2 ≥3 Parity Primipara Multipara
25.7 ± 2.8 9.3 ± 2.0
26.1 ± 3.2 9.4 ± 2.0
b 0.001 b 0.001
20.4 ± 2.5
20.3 ± 2.4
b 0.001
7855 (11.4) 57,113 (83.1) 3719 (5.4)
1352 (7.0) 15,736 (81.5) 2223 (11.5)
34,766 (50.5) 23,763 (34.5) 10,288 (14.9)
7897 (40.9) 6594 (34.1) 4837 (25.0)
63,412 (92.1) 5406 (7.9)
16,121 (83.4) 3206 (16.6)
b 0.001
b 0.001
b 0.001
Data are expressed as mean ± standard deviation or n (%). For some of the characteristics, numbers do not add to 68,820 for non-anemic or 19,329 for anemic women due to missing data.
a
confounded by plasma expansion if second- or thirdtrimester Hb values are used. In addition, most published reports treated Hb concentration as a binary or threecategory variable in their analyses, probably due to limited sample size [3,4,10,12,15]. The crude classification of Hb concentration may mask the nature of the relationship between Hb concentration and pregnancy outcomes. Moreover, many published studies were done in areas where iron supplements are routinely given to pregnant women [11,12,15]. Possible effects of maternal anemia on adverse pregnancy outcomes would be reduced in these populations [16], and larger samples would be needed to detect a small difference with statistical significance. The present study used a large sample from a populationbased prenatal care program in China, where anemia prevalence is high and no routine iron supplementation is given. The aim was to examine the association between firsttrimester Hb concentration and the risk of LBW, preterm birth, and small for gestational age (SGA). Table 2
125
2. Materials and methods Data for this study were obtained from a universal populationbased prenatal care program implemented in Wuxi City and Taicang City, Jiangsu Province, and Ningbo City and Haiyan County, Zhejiang Province, China. Women entered this program either at premarital health assessment or at any stage of pregnancy. At entry, demographic and obstetric information was collected, and Hb concentration was determined by using standard methods. Relevant obstetric information at subsequent prenatal visits and data on pregnancy outcomes were collected. In the database, the woman’s name and address were not recorded, so confidentiality was ensured. In the present study, subjects were those who delivered a liveborn singleton infant of at least 28 weeks’ gestation from January 1, 1995, through December 31, 2000, and had their Hb measured at the first prenatal visit in the first trimester. A total of 102,484 women were identified; among these, 14,335 were excluded due to either late entry into prenatal care or missing information on Hb or birth weight. The final sample size was 88,149 (86% of 102,484). Anemia was defined as Hb b 110 g/L, LBW as birth weight b 2500 g, and preterm birth as b 37 completed weeks of gestation. Infants were considered SGA when the age-adjusted birth weight was below the tenth percentile according to a national survey in 1998 [17]. If a subject had two abnormalities, such as LBW and preterm delivery, each was considered an independent outcome, and the subject was included in both categories. All parameters were expressed as mean ± standard deviation or numbers and percentages. Student’s t-test was used to test differences in means, and χ2 test was employed to test differences in proportions. The Mantel–Haenszel test for linear association was used to assess linear trend between Hb level and rates of selected outcome variables. To evaluate the association between Hb level and the risk of adverse pregnancy outcomes, odds ratios (OR) for each Hb group relative to the reference group were estimated with 95% confidence intervals (95% CI). Multiple logistic regression was used to adjust for potential confounding factors. P b 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 11.5 (SPSS Inc., Chicago, IL).
3. Results The mean Hb concentration at first prenatal visit in the first trimester was 117.8 g/L. Overall, 21.9% of women were anemic, 99.4% of them had mild anemia (Hb 80–109 g/L) and
Severity of first-trimester anemia and birth outcomes in a Chinese population, 1996–2000
Group
Non-anemic Anemic Mildly anemic Severely anemic
N
68,820 19,329 19,219 110
Low birth weight
Preterm birth a
Small for gestational age a
%
AOR (95% CI)
%
AOR (95% CI)
%
AOR (95% CI)b
1.8 2.2⁎ 2.1 4.5†
1.00 1.16 (1.03–1.30) 1.15 (1.03–1.29) 2.14 (0.78–5.83)
4.4 4.9⁎ 4.9 9.1†
1.00 1.17 (1.09–1.27) 1.17 (1.08–1.26) 1.93 (0.94–3.99)
4.4 5.1⁎ 5.1 7.3†
1.00 1.11 (1.03–1.20) 1.11 (1.03–1.19) 1.54 (0.71–3.33)
AOR, adjusted odds ratio; CI, confidence interval. Non-anemic, hemoglobin ≥110 mg/L; mildly anemic, hemoglobin 80–109 mg/L; severely anemic, hemoglobin b80 mg/L. a Adjusted for maternal age, education, gravidity and BMI. b Adjusted for education, gravidity and BMI. *P ≤ 0.001, compared with non-anemic group. † P for trend ≤ 0.001 (non-anemic, mildly anemic, and severely anemic groups).
126
A. Ren et al.
Table 3 Mean birth weight, relative risk for preterm birth, low birth weight, and small for gestational age by first-trimester hemoglobin level in a Chinese population, 1996–2000 Hb (g/L) b 80 80–99 100–119 120–139 140–159 ≥ 160
N
110 3828 44,028 35,687 4299 197
Low birth weight
Preterm birth a
Small for gestational age a
%
AOR (95% CI)
%
AOR (95% CI)
%
AOR (95% CI)b
4.5 2.7 1.8 1.9 1.5 1.0⁎
2.16 (0.79–5.89) 1.44 (1.17–1.78) 1.00 1.08 (0.97–1.20) 0.90 (0.70–1.17) 0.78 (0.19–3.15)
9.1 5.7 4.4 4.4 4.1 3.0†
1.86 1.34 1.00 0.98 0.91 0.42
7.3 5.5 4.7 4.3 4.2 3.0‡
1.49 1.13 1.00 0.98 0.99 0.61
(0.90–3.84) (1.16–1.55) (0.91–1.04) (0.77–1.06) (0.14–1.33)
(0.69–3.23) (0.98–1.31) (0.91–1.05) (0.84–1.16) (0.22–1.65)
AOR, adjusted odds ratio; CI, confidence interval. Adjusted for maternal age, education, gravidity and BMI. b Adjusted for education, gravidity and BMI. P for trend, ⁎ = 0.006, † = 0.003, ‡ b 0.001. a
0.6% had severe anemia (Hb b 80 g/L). The mean birth weight was 3345.9 ± 432.9 g. LBW, preterm birth, and SGA were found in 1.9%, 4.5%, and 4.5% of births, respectively. Women with first-trimester anemia tended to have lower educational level and to be of higher gravidity and higher parity than women without anemia (Table 1). Anemic and non-anemic women had similar mean age, mean gestational age at first prenatal visit, and mean body mass index (BMI); although differences in these variables were statistically significant because of the large sample size, the absolute differences were negligible. Women with first-trimester anemia had higher rates of LBW, preterm birth, and SGA than women without anemia (Table 2). First-trimester anemia was associated with 16% higher risk for LBW, 17% higher risk for preterm birth after adjusting for maternal age, education, gravidity and BMI, and 11% higher risk for SGA after adjusting for education, gravidity and BMI. When women with mild and severe anemia were compared with women without anemia, a clear gradient in both the rate and the risk of adverse pregnancy outcomes was noted (Table 2). While mild anemia was associated with a 15%–17% higher risk for LBW and preterm birth and about 10% higher risk for SGA, severe anemia was associated with an even higher risk, although none of these ORs were statistically significant because of the small number of severely anemic women. Frequencies of LBW, preterm birth, and SGA also showed a clear linear trend against Hb concentrations (Table 3). Of women with Hb b 80 g/L, 4.5% had LBW, 9.1% had preterm birth, and 7.3% had SGA, whereas of women with Hb ≥160 g/L, 3.0% had preterm birth and SGA, and 1.0% had LBW. The risk of LBW, preterm birth and SGA increased with decreasing Hb concentration after adjusting for confounding factors by using multivariate logistic regression, although only the 80–99 g/L subgroup was statistically significant for LBW and preterm birth. No elevated risk was noted for women with Hb ≥120 g/L (Table 3).
4. Discussion In this Chinese population, rates of LBW, preterm birth, and SGA increased with the decrease in first-trimester Hb concentration, and low but not high Hb concentration was
associated with elevated risk of LBW, preterm birth, and SGA. These findings are consistent with those of a hospitalbased study in Nepal [18]. In that study, frequency of LBW decreased with hematocrit values measured in the first trimester. In a recent Israeli study, a linear association was also found between the severity of anemia and the risk of adverse pregnancy outcomes [1]: women with mild anemia had 10% higher risk for LBW and 20% higher risk for preterm birth, and women with severe anemia had 60% elevated risk for both LBW and preterm birth. A U-shaped relationship between Hb concentration and the risk of adverse pregnancy outcomes was noted in several studies. In a study from the UK, a U-shaped relationship was found between maternal Hb values and the risk of LBW and preterm birth [7]. However, the Hb values used were the lowest measurements during pregnancy. Since maternal Hb values decline with the progression of pregnancy and reach their nadir around 34–36 weeks’ gestation [14], Hb values used in the study were most likely those measured in late second trimester or early third trimester. Poor maternal plasma expansion in the latter half of pregnancy, which causes high Hb concentration, is associated with poor pregnancy outcomes [13]. Therefore, the results of this study are probably confounded by gestational age at Hb measurement. A study conducted in Shanghai, China found a U-shaped relationship between early first-trimester Hb level and the risk of preterm birth, LBW, and SGA [6]. However, their results were not adjusted for potential confounders. In a study from India, Hb concentration was found to be associated with the risk of LBW in a U-shaped manner [5], but information on gestational age at Hb measurement was not available. The relationships between Hb concentration and the risk of LBW and preterm birth seem different depending on gestational age at which Hb or hematocrit was measured. A recent meta-analysis found that early pregnancy anemia is associated with increased risk of LBW and preterm birth, while late pregnancy anemia is inversely associated with LBW and preterm birth [19]. In the Nepali study, the association between low hematocrit values and the risk of LBW was much stronger in the first trimester than in the third trimester, and no association was found in the second trimester [18]. In an earlier study, low hematocrit in early pregnancy was associated with a higher rate of preterm birth, whereas high
Low hemoglobin and birth weight, preterm birth and small for gestational age newborns hematocrit in later pregnancy was associated with higher rate [20]. Therefore, future studies should take gestational age at Hb measurement into consideration in examining the relationships between maternal Hb and adverse pregnancy outcomes to avoid confounding bias, as also suggested by other researchers [10,18,20]. Iron deficiency is the most common cause of anemia, especially in developing countries. In the present population, hookworm infection, malaria, and thalassemia are rare and therefore contribute little to the prevalence of anemia. During the study period, folic acid supplementation was widely promoted. Sixty to seventy percent of pregnant women took folic acid in the first trimester, and their blood folate levels in early pregnancy were comparable to those in some developed countries [21]. Therefore, anemia is less likely to be caused by hookworm infection, malaria, or folate deficiency in this population. In addition, China has no public health policy on routine iron supplementation, and iron supplements are prescribed only for pregnant women who are diagnosed as anemic. Thus, it is reasonable to assume that the vast majority of anemic cases in this population were due to iron deficiency. The finding that low first-trimester Hb level increases the risk of adverse pregnancy outcomes indicates the need for the prevention of early pregnancy anemia in this population where no iron supplementation policy is in place. WHO, UNICEF and International Nutritional Anemia Consultative (INACG) recommend that women be supplemented with iron (with folic acid) for six months during pregnancy [22], without mentioning when supplementation should begin. In most developing countries, women initiate their prenatal care late, often at second or third trimester [18,23]. Hence, it would be too late to prevent first-trimester anemia if iron supplements are prescribed at the first prenatal visit. Firsttrimester anemia develops mainly because of low or depleted iron reserves before women enter pregnancy [24]. Thus, increasing iron intake before pregnancy is critical to prevent anemia in early pregnancy. Preventive supplementation, i.e., long-term intermittent iron supplementation before pregnancy, has been proposed. A study conducted in Vietnam has shown that weekly supplementation with iron three to six months before pregnancy is effective in building iron reserves and in reducing the risk of first-trimester anemia [25]. The study is population-based, and the prenatal care program covers about 98% of pregnant women. Therefore, the possibility of selection bias was minimal when compared with many other studies that recruit subjects from tertiary hospitals, to which complicated pregnancies may be referred. Moreover, Hb was measured in the first trimester. At this time, maternal plasma has expanded little, and the Hb level should reflect body iron status. Limitations existed in the present study. Because Hb measurement was performed at multiple sites, random errors may have occurred more in our study than in a controlled study. However, random error may have diminished, rather than exaggerated, the observed ORs [2]. Although the sample size in the present study is large, not many pregnant women had very low or very high Hb values, resulting in low power to detect a statistically significant difference in the rates of low birth weight, preterm birth, and SGA between the extremes of the Hb subgroup with the reference subgroup. However, the clear trend between Hb levels and
127
the rates of adverse pregnancy outcomes indicates an association between the two. In conclusion, low first-trimester Hb concentration increases the risk of LBW, preterm birth, and SGA in this Chinese population.
References [1] Levy A, Fraser D, Katz M, Mazor M, Sheiner E. Maternal anemia during pregnancy is an independent risk factor for low birthweight and preterm delivery. Eur J Obstet Gynecol Reprod Biol 2005;122:182–6. [2] 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;96:741–8. [3] Scholl TO, Hediger ML, Fischer RL, Shearer JW. Anemia vs iron deficiency: increased risk of preterm delivery in a prospective study. Am J Clin Nutr 1992;55:985–8. [4] Chang SC, O’Brien KO, Nathanson MS, Mancini J, Witter FR. Hemoglobin concentrations influence birth outcomes in pregnant African-American adolescents. J Nutr 2003;133:2348–55. [5] Malhotra M, Sharma JB, Batra S, Sharma S, Murthy NS, Arora R. Maternal and perinatal outcome in varying degrees of anemia. Int J Gynecol Obstet 2002;79:93–100. [6] 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. [7] Steer P, Alam MA, Wadsworth J, Welch A. Relation between maternal haemoglobin concentration and birth weight in different ethnic groups. BMJ 1995;310:489–91. [8] Knottnerus JA, Delgado LR, Knipschild PG, Essed GG, Smits F. Haematologic parameters and pregnancy outcome. A prospective cohort study in the third trimester. J Clin Epidemiol 1990;43:461–6. [9] Murphy JF, O’Riordan J, Newcombe RG. Relation of haemoglobin levels in first and second trimesters to outcome of pregnancy. Lancet 1986;1:992–4. [10] Xiong X, Buekens P, Fraser WD, Guo Z. Anemia during pregnancy in a Chinese population. Int J Gynecol Obstet 2003;83:159–64. [11] Harding K, Evans S, Newnham JP. The prediction of pregnancy outcome by haemoglobin measurement before 20 weeks’ gestation. J Obstet Gynaecol 1997;17:33–8. [12] Lao TT, Pun TC. Anaemia in pregnancy—is the current definition meaningful? Eur J Obstet Gynecol Reprod Biol 1996;68:53–8. [13] Huisman A, Aarnoudse JG. Increased 2nd trimester hemoglobin concentration in pregnancies later complicated by hypertension and growth retardation. Early evidence of a reduced plasma volume. Acta Obstet Gynecol Scand 1986;65:605–8. [14] Hytten F. Blood volume changes in normal pregnancy. Clin Haematol 1985;14:601–12. [15] Hamalainen 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;22:271–5. [16] Rasmussen K. Is there a causal relationship between iron deficiency or iron-deficiency anemia and weight at birth, length of gestation and perinatal mortality? J Nutr 2001;131: 590S–601S [discussion 601S–603S]. [17] Mi J, Lin L, Liu Y, Zhang X, Cao L. A national sampling survey on birth weight in 1998 in China: mean value and standard deviation. Zhonghua Yu Fang Yi Xue Za Zhi 2002;36:154–7. [18] Bondevik GT, Lie RT, Ulstein M, Kvale G. Maternal hematological status and risk of low birth weight and preterm delivery in Nepal. Acta Obstet Gynecol Scand 2001;80:402–8. [19] Xiong X, Buekens P, Alexander S, Demianczuk N, Wollast E. Anemia during pregnancy and birth outcome: a meta-analysis. Am J Perinatol 2000;17:137–46.
128 [20] Lu ZM, Goldenberg RL, Cliver SP, Cutter G, Blankson M. The relationship between maternal hematocrit and pregnancy outcome. Obstet Gynecol 1991;77:190–4. [21] Ren A, Zhang L, Hao L, Li Z, Tian Y, Li Z. Comparison of blood folate levels among pregnant Chinese women in areas with high and low prevalence of neural tube defects. Public Health Nutrition in press. doi:10.1017/PHN2006890. [22] Stoltzfus RJ, Dreyfuss ML. Guidelines for the use of iron supplements to prevent and treat iron deficiency anemia (INACG, WHO, UNICEF). Washington, D.C.: ILSI Press; 2003. [23] Van Bogaert LJ. Anaemia and pregnancy outcomes in a South African rural population. J Obstet Gynaecol 2006;26:617–9.
A. Ren et al. [24] 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:S65–76. [25] 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:S95–108.
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / i j g o
CLINICAL ARTICLE
Low first-trimester hemoglobin and low birth weight, preterm birth and small for gestational age newborns A. Ren ⁎, J. Wang, R.W. Ye, S. Li, J.M. Liu, Z. Li Institute of Reproductive and Child Health, Peking University Health Science Center, Beijing, China Received 13 December 2006; received in revised form 11 May 2007; accepted 16 May 2007
KEYWORDS Hemoglobin; Anemia; Pregnancy; Low birth weight; Preterm birth; Small for gestational age
Abstract Objective: To examine the relationship between first-trimester hemoglobin (Hb) concentration and risk of low birth weight (LBW), preterm birth and small for gestational age (SGA). Methods: Data were obtained from a population-based prenatal care program in China. A total of 88,149 women who delivered during 1995–2000 and had their Hb measured in the first trimester were selected as study subjects. Results: The prevalence of anemia (Hb b 110 g/L) was 22.1% in the first trimester. The risk of LBW, preterm birth and SGA was increased steadily with the decrease of first-trimester Hb concentration. After controlling for confounding factors, women with Hb 80–99 g/L had significantly higher risk for LBW (OR = 1.44, 95% CI 1.17–1.78), preterm birth (OR = 1.34, 95% CI 1.16–1.55) and SGA (OR = 1.13, 95% CI 0.98–1.31) than women with Hb 100–119 g/L. No elevated risk was noted for women with Hb ≥ 120 g/L. Conclusion: Low first-trimester Hb concentration increases the risk of LBW, preterm birth and SGA. © 2007 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Studies on the relationship between maternal hemoglobin (Hb) level and adverse pregnancy outcomes have been inconsistent. Some studies have found that low maternal Hb level increases the risk of low birth weight (LBW) or preterm birth [1–3]. Others have found a U-shaped relationship, i.e., Hb value at either the low or the high end increases the risk [4–9]. In
⁎ Corresponding author. 38 Xueyuan Rd, Haidian District, Institute of Reproductive and Child Health, Peking University Health Science Center, Beijing 100083, China. Tel.: +86 10 8280 5040; fax: +86 10 8280 1141. E-mail address: [email protected] (A. Ren).
addition, some studies have found no association between Hb level and the risk of adverse pregnancy outcomes [10–12]. These inconsistencies may stem from the differences in gestational age at which Hb was measured. Although some studies used Hb values measured in the first trimester [1,6], many studies used Hb values determined in the second or third trimester [4,8,13]. In addition, some studies did not provide information on trimesters at which Hb measurement was done [5,12]. One study used the lowest Hb measurement during pregnancy [7]. Maternal plasma volume expands as the pregnancy progresses: little increase is seen before 10 weeks’ gestation, followed by a progressive rise to maximum volume at about 34–36 weeks’ gestation, beyond which little or no further increase occurs [14]. Therefore, the effect of Hb concentration on pregnancy outcomes may be
0020-7292/$ - see front matter © 2007 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2007.05.011
Low hemoglobin and birth weight, preterm birth and small for gestational age newborns Table 1
Characteristics of women with and without anemia in the first trimester in a Chinese population, 1996–2000
Characteristics
Non-anemic (N = 68,820)a
Anemic (N = 19,329)a
P
Maternal age Gestational weeks at 1st visit Maternal BMI at 1st visit Education College High school Middle school or lower Gravidity 1 2 ≥3 Parity Primipara Multipara
25.7 ± 2.8 9.3 ± 2.0
26.1 ± 3.2 9.4 ± 2.0
b 0.001 b 0.001
20.4 ± 2.5
20.3 ± 2.4
b 0.001
7855 (11.4) 57,113 (83.1) 3719 (5.4)
1352 (7.0) 15,736 (81.5) 2223 (11.5)
34,766 (50.5) 23,763 (34.5) 10,288 (14.9)
7897 (40.9) 6594 (34.1) 4837 (25.0)
63,412 (92.1) 5406 (7.9)
16,121 (83.4) 3206 (16.6)
b 0.001
b 0.001
b 0.001
Data are expressed as mean ± standard deviation or n (%). For some of the characteristics, numbers do not add to 68,820 for non-anemic or 19,329 for anemic women due to missing data.
a
confounded by plasma expansion if second- or thirdtrimester Hb values are used. In addition, most published reports treated Hb concentration as a binary or threecategory variable in their analyses, probably due to limited sample size [3,4,10,12,15]. The crude classification of Hb concentration may mask the nature of the relationship between Hb concentration and pregnancy outcomes. Moreover, many published studies were done in areas where iron supplements are routinely given to pregnant women [11,12,15]. Possible effects of maternal anemia on adverse pregnancy outcomes would be reduced in these populations [16], and larger samples would be needed to detect a small difference with statistical significance. The present study used a large sample from a populationbased prenatal care program in China, where anemia prevalence is high and no routine iron supplementation is given. The aim was to examine the association between firsttrimester Hb concentration and the risk of LBW, preterm birth, and small for gestational age (SGA). Table 2
125
2. Materials and methods Data for this study were obtained from a universal populationbased prenatal care program implemented in Wuxi City and Taicang City, Jiangsu Province, and Ningbo City and Haiyan County, Zhejiang Province, China. Women entered this program either at premarital health assessment or at any stage of pregnancy. At entry, demographic and obstetric information was collected, and Hb concentration was determined by using standard methods. Relevant obstetric information at subsequent prenatal visits and data on pregnancy outcomes were collected. In the database, the woman’s name and address were not recorded, so confidentiality was ensured. In the present study, subjects were those who delivered a liveborn singleton infant of at least 28 weeks’ gestation from January 1, 1995, through December 31, 2000, and had their Hb measured at the first prenatal visit in the first trimester. A total of 102,484 women were identified; among these, 14,335 were excluded due to either late entry into prenatal care or missing information on Hb or birth weight. The final sample size was 88,149 (86% of 102,484). Anemia was defined as Hb b 110 g/L, LBW as birth weight b 2500 g, and preterm birth as b 37 completed weeks of gestation. Infants were considered SGA when the age-adjusted birth weight was below the tenth percentile according to a national survey in 1998 [17]. If a subject had two abnormalities, such as LBW and preterm delivery, each was considered an independent outcome, and the subject was included in both categories. All parameters were expressed as mean ± standard deviation or numbers and percentages. Student’s t-test was used to test differences in means, and χ2 test was employed to test differences in proportions. The Mantel–Haenszel test for linear association was used to assess linear trend between Hb level and rates of selected outcome variables. To evaluate the association between Hb level and the risk of adverse pregnancy outcomes, odds ratios (OR) for each Hb group relative to the reference group were estimated with 95% confidence intervals (95% CI). Multiple logistic regression was used to adjust for potential confounding factors. P b 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 11.5 (SPSS Inc., Chicago, IL).
3. Results The mean Hb concentration at first prenatal visit in the first trimester was 117.8 g/L. Overall, 21.9% of women were anemic, 99.4% of them had mild anemia (Hb 80–109 g/L) and
Severity of first-trimester anemia and birth outcomes in a Chinese population, 1996–2000
Group
Non-anemic Anemic Mildly anemic Severely anemic
N
68,820 19,329 19,219 110
Low birth weight
Preterm birth a
Small for gestational age a
%
AOR (95% CI)
%
AOR (95% CI)
%
AOR (95% CI)b
1.8 2.2⁎ 2.1 4.5†
1.00 1.16 (1.03–1.30) 1.15 (1.03–1.29) 2.14 (0.78–5.83)
4.4 4.9⁎ 4.9 9.1†
1.00 1.17 (1.09–1.27) 1.17 (1.08–1.26) 1.93 (0.94–3.99)
4.4 5.1⁎ 5.1 7.3†
1.00 1.11 (1.03–1.20) 1.11 (1.03–1.19) 1.54 (0.71–3.33)
AOR, adjusted odds ratio; CI, confidence interval. Non-anemic, hemoglobin ≥110 mg/L; mildly anemic, hemoglobin 80–109 mg/L; severely anemic, hemoglobin b80 mg/L. a Adjusted for maternal age, education, gravidity and BMI. b Adjusted for education, gravidity and BMI. *P ≤ 0.001, compared with non-anemic group. † P for trend ≤ 0.001 (non-anemic, mildly anemic, and severely anemic groups).
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Table 3 Mean birth weight, relative risk for preterm birth, low birth weight, and small for gestational age by first-trimester hemoglobin level in a Chinese population, 1996–2000 Hb (g/L) b 80 80–99 100–119 120–139 140–159 ≥ 160
N
110 3828 44,028 35,687 4299 197
Low birth weight
Preterm birth a
Small for gestational age a
%
AOR (95% CI)
%
AOR (95% CI)
%
AOR (95% CI)b
4.5 2.7 1.8 1.9 1.5 1.0⁎
2.16 (0.79–5.89) 1.44 (1.17–1.78) 1.00 1.08 (0.97–1.20) 0.90 (0.70–1.17) 0.78 (0.19–3.15)
9.1 5.7 4.4 4.4 4.1 3.0†
1.86 1.34 1.00 0.98 0.91 0.42
7.3 5.5 4.7 4.3 4.2 3.0‡
1.49 1.13 1.00 0.98 0.99 0.61
(0.90–3.84) (1.16–1.55) (0.91–1.04) (0.77–1.06) (0.14–1.33)
(0.69–3.23) (0.98–1.31) (0.91–1.05) (0.84–1.16) (0.22–1.65)
AOR, adjusted odds ratio; CI, confidence interval. Adjusted for maternal age, education, gravidity and BMI. b Adjusted for education, gravidity and BMI. P for trend, ⁎ = 0.006, † = 0.003, ‡ b 0.001. a
0.6% had severe anemia (Hb b 80 g/L). The mean birth weight was 3345.9 ± 432.9 g. LBW, preterm birth, and SGA were found in 1.9%, 4.5%, and 4.5% of births, respectively. Women with first-trimester anemia tended to have lower educational level and to be of higher gravidity and higher parity than women without anemia (Table 1). Anemic and non-anemic women had similar mean age, mean gestational age at first prenatal visit, and mean body mass index (BMI); although differences in these variables were statistically significant because of the large sample size, the absolute differences were negligible. Women with first-trimester anemia had higher rates of LBW, preterm birth, and SGA than women without anemia (Table 2). First-trimester anemia was associated with 16% higher risk for LBW, 17% higher risk for preterm birth after adjusting for maternal age, education, gravidity and BMI, and 11% higher risk for SGA after adjusting for education, gravidity and BMI. When women with mild and severe anemia were compared with women without anemia, a clear gradient in both the rate and the risk of adverse pregnancy outcomes was noted (Table 2). While mild anemia was associated with a 15%–17% higher risk for LBW and preterm birth and about 10% higher risk for SGA, severe anemia was associated with an even higher risk, although none of these ORs were statistically significant because of the small number of severely anemic women. Frequencies of LBW, preterm birth, and SGA also showed a clear linear trend against Hb concentrations (Table 3). Of women with Hb b 80 g/L, 4.5% had LBW, 9.1% had preterm birth, and 7.3% had SGA, whereas of women with Hb ≥160 g/L, 3.0% had preterm birth and SGA, and 1.0% had LBW. The risk of LBW, preterm birth and SGA increased with decreasing Hb concentration after adjusting for confounding factors by using multivariate logistic regression, although only the 80–99 g/L subgroup was statistically significant for LBW and preterm birth. No elevated risk was noted for women with Hb ≥120 g/L (Table 3).
4. Discussion In this Chinese population, rates of LBW, preterm birth, and SGA increased with the decrease in first-trimester Hb concentration, and low but not high Hb concentration was
associated with elevated risk of LBW, preterm birth, and SGA. These findings are consistent with those of a hospitalbased study in Nepal [18]. In that study, frequency of LBW decreased with hematocrit values measured in the first trimester. In a recent Israeli study, a linear association was also found between the severity of anemia and the risk of adverse pregnancy outcomes [1]: women with mild anemia had 10% higher risk for LBW and 20% higher risk for preterm birth, and women with severe anemia had 60% elevated risk for both LBW and preterm birth. A U-shaped relationship between Hb concentration and the risk of adverse pregnancy outcomes was noted in several studies. In a study from the UK, a U-shaped relationship was found between maternal Hb values and the risk of LBW and preterm birth [7]. However, the Hb values used were the lowest measurements during pregnancy. Since maternal Hb values decline with the progression of pregnancy and reach their nadir around 34–36 weeks’ gestation [14], Hb values used in the study were most likely those measured in late second trimester or early third trimester. Poor maternal plasma expansion in the latter half of pregnancy, which causes high Hb concentration, is associated with poor pregnancy outcomes [13]. Therefore, the results of this study are probably confounded by gestational age at Hb measurement. A study conducted in Shanghai, China found a U-shaped relationship between early first-trimester Hb level and the risk of preterm birth, LBW, and SGA [6]. However, their results were not adjusted for potential confounders. In a study from India, Hb concentration was found to be associated with the risk of LBW in a U-shaped manner [5], but information on gestational age at Hb measurement was not available. The relationships between Hb concentration and the risk of LBW and preterm birth seem different depending on gestational age at which Hb or hematocrit was measured. A recent meta-analysis found that early pregnancy anemia is associated with increased risk of LBW and preterm birth, while late pregnancy anemia is inversely associated with LBW and preterm birth [19]. In the Nepali study, the association between low hematocrit values and the risk of LBW was much stronger in the first trimester than in the third trimester, and no association was found in the second trimester [18]. In an earlier study, low hematocrit in early pregnancy was associated with a higher rate of preterm birth, whereas high
Low hemoglobin and birth weight, preterm birth and small for gestational age newborns hematocrit in later pregnancy was associated with higher rate [20]. Therefore, future studies should take gestational age at Hb measurement into consideration in examining the relationships between maternal Hb and adverse pregnancy outcomes to avoid confounding bias, as also suggested by other researchers [10,18,20]. Iron deficiency is the most common cause of anemia, especially in developing countries. In the present population, hookworm infection, malaria, and thalassemia are rare and therefore contribute little to the prevalence of anemia. During the study period, folic acid supplementation was widely promoted. Sixty to seventy percent of pregnant women took folic acid in the first trimester, and their blood folate levels in early pregnancy were comparable to those in some developed countries [21]. Therefore, anemia is less likely to be caused by hookworm infection, malaria, or folate deficiency in this population. In addition, China has no public health policy on routine iron supplementation, and iron supplements are prescribed only for pregnant women who are diagnosed as anemic. Thus, it is reasonable to assume that the vast majority of anemic cases in this population were due to iron deficiency. The finding that low first-trimester Hb level increases the risk of adverse pregnancy outcomes indicates the need for the prevention of early pregnancy anemia in this population where no iron supplementation policy is in place. WHO, UNICEF and International Nutritional Anemia Consultative (INACG) recommend that women be supplemented with iron (with folic acid) for six months during pregnancy [22], without mentioning when supplementation should begin. In most developing countries, women initiate their prenatal care late, often at second or third trimester [18,23]. Hence, it would be too late to prevent first-trimester anemia if iron supplements are prescribed at the first prenatal visit. Firsttrimester anemia develops mainly because of low or depleted iron reserves before women enter pregnancy [24]. Thus, increasing iron intake before pregnancy is critical to prevent anemia in early pregnancy. Preventive supplementation, i.e., long-term intermittent iron supplementation before pregnancy, has been proposed. A study conducted in Vietnam has shown that weekly supplementation with iron three to six months before pregnancy is effective in building iron reserves and in reducing the risk of first-trimester anemia [25]. The study is population-based, and the prenatal care program covers about 98% of pregnant women. Therefore, the possibility of selection bias was minimal when compared with many other studies that recruit subjects from tertiary hospitals, to which complicated pregnancies may be referred. Moreover, Hb was measured in the first trimester. At this time, maternal plasma has expanded little, and the Hb level should reflect body iron status. Limitations existed in the present study. Because Hb measurement was performed at multiple sites, random errors may have occurred more in our study than in a controlled study. However, random error may have diminished, rather than exaggerated, the observed ORs [2]. Although the sample size in the present study is large, not many pregnant women had very low or very high Hb values, resulting in low power to detect a statistically significant difference in the rates of low birth weight, preterm birth, and SGA between the extremes of the Hb subgroup with the reference subgroup. However, the clear trend between Hb levels and
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the rates of adverse pregnancy outcomes indicates an association between the two. In conclusion, low first-trimester Hb concentration increases the risk of LBW, preterm birth, and SGA in this Chinese population.
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