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ABSTRACT INTRODUCTION
Background: Anemia is a leading cause of maternal deaths and Anemia remains a significant health problem globally, ac-
adverse pregnancy outcomes in developing countries.
Am J Clin Nutr 2016;103:495–504. Printed in USA. Ó 2016 American Society for Nutrition 495
small-for-gestational-age and preterm births. Previous meta- as subjects. We included studies that examined maternal he-
analyses have not comprehensively studied the association be- moglobin, hematocrit, or anemia status measured in the first or
tween maternal anemia and adverse pregnancy outcomes by second trimester during pregnancy and pregnancy and perinatal
both geographic region and national income category despite the outcomes. Anemia was defined as the exposure variable with
wide variation in anemia burden within and between regions and hemoglobin concentrations ,11 g/dL or hematocrit ,33% (18).
national income categories (1, 2). To our knowledge, no pre- We included studies that reported any hemoglobin or hematocrit
vious study has estimated the population-attributable fraction cutoffs. Birth and health outcomes including preterm delivery
(PAF) of adverse pregnancy outcomes for maternal anemia. An (defined as a birth before 37 wk of gestation), low birth weight
understanding of these outcomes, the current trends in maternal (defined as weight ,2500 g), small for gestational age (defined
anemia, and the association of maternal anemia with adverse as birth weight below the sex-specific 10th percentile of the
pregnancy outcomes at the regional level and stratified by in- gestational age), perinatal mortality [defined as deaths including
come is essential to inform policies and program development to death of a fetus .22 wk of gestation (stillbirth)], early neonatal
prevent maternal anemia and improve maternal and child health mortality (,7 d of life), neonatal mortality (defined as death of
outcomes. a neonate in the first month of life), gestational diabetes, pre-
In this study, we aimed to conduct a systematic review with eclampsia, and cesarean delivery were included in our studies.
a meta-analysis of published cohort studies of low birth weight, We excluded cross-sectional and case-control studies because
preterm birth, small for gestational age, perinatal mortality, these trials do not allow for the assessment of the temporal as-
neonatal mortality, gestational diabetes, preeclampsia, and mode sociation between exposure and outcome. Studies that considered
of delivery according to maternal anemia status in low- and high-risk subjects with HIV, AIDS, heart disease, or diabetes at
middle-income countries. To assess the role of maternal anemia baseline were not included in our review. A small sample size
at the population level, we estimated the PAF for selected adverse may introduce bias in the estimation of an effect size; therefore,
dropping studies that reporting ORs, and pooled estimates of birth weight and preterm delivery were substantially higher in
low birth weight, preterm birth, and perinatal mortality showed low-income countries than in upper-middle-income countries.
similar results to those in the analysis with the OR conversion Stratification by geographic region revealed increased risk of
(Supplemental Table 8). low birth weight and preterm delivery in anemic pregnant
women in South Asia than in East-West Asia and the African
and South American regions. However, the result was not sta-
Stratified analyses tistically significant (P . 0.05).
The study showed moderate heterogeneity in the low-birth-
weight outcome and severe heterogeneity in the preterm birth and
small-for-gestational-age outcomes. To examine these hetero- Prevalence of anemia
geneities, we conducted stratified analyses according to study Figure 2 presents the random-effects estimate for maternal
designs, sample sizes, confounding adjustments, country-income anemia during pregnancy by country-income category. Preva-
categories, study locations, and maternal ages shown in Table 2 lence was estimated from 28 recent surveys and 25 countries
and Supplemental Table 9. The RR differed according to the with a pooled prevalence of 42.7% (95% CI: 37.0%, 48.4%) in
subgroup analysis by country-income category. Risks of low low- and middle-income countries. There were slight differences
MATERNAL ANEMIA AND PREGNANCY OUTCOMES 499
TABLE 1
Summary, publication bias, and trim-and-fill estimates
Summary estimates Trim-and-fill estimates1
Low birth weight 17 1.31 (1.13, 1.51)2 65.7 0.03 4 1.18 (1.02, 1.37)
Preterm birth 13 1.63 (1.33, 2.01)2 88.2 0.05 0 1.63 (1.33, 2.01)
Small for gestational age 5 0.87 (0.63, 1.20)2 95.0 0.41 0 0.87 (0.63, 1.20)
Perinatal mortality 12 1.51 (1.30, 1.76)3 0.0 ,0.001 5 1.43 (1.24, 1.65)
Neonatal mortality 2 2.72 (1.19, 6.25)3 0.0 0.72 0 2.72 (1.19, 6.25)
Gestational diabetes 2 1.02 (0.86, 1.21)3 19.8 0.16 0 1.02 (0.86, 1.21)3
Preeclampsia 1 2.66 (0.61, 11.52)4 NA5 NA 0 2.66 (0.61, 11.52)
Cesarean delivery 1 1.68 (0.76, 3.72)4 NA NA 0 1.68 (0.76, 3.72)
1
Trim-and-fill method simulated studies that were likely to be missing from the literature because of publication or
other forms of bias. Trim-and-fill RRs estimate what the pooled RRs would be if the missing studies were included in the
analysis.
2
On the basis of random-effects methods.
3
On the basis of fixed-effects methods.
4
No pooling method was used because there was only a single study.
5
NA, not applicable.
When the substantial heterogeneity in 95% prediction intervals sistent regional variation in risks of low birth weight, preterm birth,
was accounted for, the results indicated that the association and perinatal mortality. Highest risk of perinatal mortality at-
between anemia and risks of low birth weight, preterm birth, and tributable to maternal anemia was shown in Ghana, Pakistan, India,
small for gestational age became insignificant. These results do and Malawi. Greater risk of low birth weight was also observed in
not necessarily indicate that there is no impact of maternal Pakistan, Bangladesh, and Ghana.
anemia on birth outcomes. However, the results do indicate that In some low-income and lower-middle-income countries, the
there is still substantial uncertainty about the significance of the control of infectious diseases such as HIV, AIDS, and malaria has
association. Our findings expand significantly on the recent meta- not yet been achieved, and health-service delivery, access, and
analysis of Haider et al. (13), which collapsed findings across effective coverage and access to affordable care are limited (11,
countries and accessed only limited information on birth out- 39–45). In previous studies anemia, malnutrition, and malaria
comes. We compared risks of preterm birth and low birth weight during pregnancy were shown to be significant risks to both
separately for low- or middle-income countries rather than con- maternal and neonatal health (2, 8, 11, 37). However, many low-
ducting a combined comparison against high-income countries. In income countries are facing challenges in implementing im-
addition, we presented information on pregnancy outcomes by munization, malaria control, and nutrition support programs (5,
geographic regions and country-income categories in recognition 46, 47). The war in Afghanistan and internal conflict in Pakistan
of the substantially differing patterns of prevalence and birth targeted female health workers, and thus, many parts of these
outcomes in these country categories. Our study showed a con- areas are severely affected by workforce-related barriers to the
502 RAHMAN ET AL.
TABLE 3
LBW, PTB, and PNM attributed to maternal anemia1
LBW PTB PNM
Country Prevalence, % RR (95% CI) PAF, % RR (95% CI) PAF, % RR (95% CI) PAF, %
2
Overall 42.7 1.31 (1.13, 1.51) 12.1 1.63 (1.33, 2.01) 19.0 1.51 (1.30, 1.76) 17.9
Country-income category2
Low-income 45.4 1.72 (1.32, 2.25) 24.6 2.73 (1.29, 5.79) 44.0 1.60 (1.15, 2.23) 21.4
Lower middle-income 39.8 1.12 (0.94, 1.33) 4.6 1.36 (0.97, 1.91) 12.5 1.44 (1.18, 1.76) 14.9
Upper middle-income 37.1 1.27 (0.89, 1.79) 9.1 1.20 (1.00, 1.44) 4.9 1.63 (1.18, 2.25) 18.9
Region2
South Asia 48.6 1.36 (1.11, 1.66) 14.9 2.03 (1.23, 3.36) 33.4 2.05 (1.18, 3.55) 38.8
East-West Asia 39.9 1.27 (0.89, 1.79) 9.8 1.20 (1.00, 1.44) 5.3 1.63 (1.18, 2.25) 20.1
Africa and South America 43.5 1.32 (0.76, 2.29) 12.5 1.24 (1.12, 1.37) 9.5 1.43 (1.19, 1.72) 15.8
Country specific3
Bangladesh 49.6 1.80 (1.18, 2.27) 28.6 — — — —
Pakistan 40.0 2.10 (1.56, 2.82) 30.6 3.95 (3.04, 5.13) 54.1 2.25 (1.14, 4.44) 42.4
India 59.0 1.13 (0.92, 1.38) 7.1 1.63 (0.88, 3.04) 27.1 1.70 (0.66, 4.38) 29.2
China 28.9 1.15 (0.70, 1.89) 5.5 1.14 (1.01 1.28) 0.9 1.63 (1.18, 2.25) 15.4
Nepal 47.6 1.24 (0.97, 1.58) 10.3 0.93 (0.62, 1.39) 23.5 — —
Iran 14.0 2.00 (1.08, 3.70) 12.3 2.61 (1.33, 5.10) 18.4 — —
Peru 28.8 — — 1.24 (1.12, 1.37) 6.5 1.40 (1.14, 1.73) 10.3
resolution of their maternal and child health issues (5). Cost is low- and middle-income countries, and thus, the results of review
another barrier to accessing health services in low-income are not applicable to high-income countries. We only included
countries (48, 49), and many poor households may avoid con- studies that measured hemoglobin during the first or second
sulting doctors during pregnancy to minimize financial risks trimester and may have overlooked some studies that addressed
associated with high-treatment costs. Consequently, these women the effect of anemia in the third trimester. However, a recent
may be unaware of their nutritional status during pregnancy. meta-analysis suggested that anemia during the third trimester is
Service delivery, effective coverage, and access and affordable not a potential risk factor for adverse birth outcomes, and its
care during pregnancy can be ensured by introducing universal exclusion was unlikely to have biased this review (8). We defined
health coverage plans (43, 45, 48, 49). For example, in Ghana, anemia on the basis of WHO standard thresholds based on he-
Indonesia, Uganda, and China, after health insurance was in- moglobin [anemic: ,10–11 g hemoglobin/dL or hematocrit
troduced, the burden of treatment costs sharply decreased and ,30–34%; nonanemic: .11 g hemoglobin/dL) (18), but some
access to care increased (48, 50). Ensuring access to compre- studies did not use these categorizations. Different definitions
hensive, integrated primary care and maternal and child health and categorizations can lead to variations in RRs or ORs even
services through better health-financing methods will help to within a single data set. However, in our systematic review, al-
ensure that women understand their nutritional status and are most all studies used WHO cutoffs except for 5 studies from
able to act earlier in pregnancy to minimize worst risks associated Ghana, Bangladesh, India, China, and Turkey. We performed
with maternal anemia. a pooled analysis separately in which thresholds proposed by the
Our study had several strengths. We used comprehensive WHO and other thresholds according to the definitions of the
search techniques and validated systematic review methods, original studies. Despite different definitions, there was no sig-
followed a predesigned protocol, and observed the Meta-analysis nificant difference in pooled estimates between WHO thresholds
of Observational Studies in Epidemiology (15) and Preferred and others. This stable pooled estimate may have been because
Reporting Items for Systematic Reviews and Meta-Analyses (17) only 5 studies used different cutoffs to those recommended by
guidelines, which strengthened the review quality and conclu- the WHO. We also had to use estimated RRs for 7 studies that
sions. We investigated the possible association between maternal reported ORs, which were converted to RRs for the meta-analysis.
anemia and birth and health outcomes by region, country-income There was risk that the variance of the derived RRs could have
category, and specific countries. In the meta-analysis, appropriate been underestimated in the proposed conversion methodology
statistical techniques were used to estimate the pooled preva- of Zhang (15, 21). However, we performed a sensitivity analysis
lence, RR, and presence of bias. that excluded the affected studies and showed negligible effect
Despite these strengths, limitations of this systematic review on the results. Finally, we did not include gray literature, which
and meta-analysis must be considered. We included studies from may have contained smaller null-result studies that were not
MATERNAL ANEMIA AND PREGNANCY OUTCOMES 503
accepted for publication, but we adjusted for this publication 11. Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B,
bias with the use of the trim-and-fill method and showed little Newman RD. Epidemiology and burden of malaria in pregnancy.
Lancet Infect Dis 2007;7:93–104.
effect on our results from the inclusion of possible imputed 12. Ouédraogo S, Koura GK, Bodeau-Livinec F, Accrombessi MM,
negative studies. Massougbodji A, Cot M. Maternal anemia in pregnancy: assessing the
In conclusion, maternal anemia is a risk factor for adverse effect of routine preventive measures in a malaria-endemic area. Am J
birth and perinatal health outcomes in low-and middle-income Trop Med Hyg 2013;88:292–300.
13. Haider BA, Olofin I, Wang M, Spiegelman D, Ezzati M, Fawzi WW.
countries. Significantly higher risk of low birth weight and pre- Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes:
term birth were observed in low-income countries and in South systematic review and meta-analysis. BMJ 2013;346:f3443.
Asian countries despite the greater priority and larger investment 14. Rasmussen K. Is there a causal relationship between iron deficiency or
on maternal and child health programs in recent decades. On the iron-deficiency anemia and weight at birth, length of gestation and
perinatal mortality? J Nutr 2001;131:590S–601S; discussion 601S-603S.
basis of our review findings, we advocate that greater attention be
15. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D,
placed on the impact of maternal and child health programs on Moher D, Becker BJ, Sipe TA, Thacker SB. Meta-analysis of obser-
anemia-related outcomes in low-income countries. With the vational studies in epidemiology: a proposal for reporting. Meta-
management of maternal anemia during pregnancy in low-income analysis Of Observational Studies in Epidemiology (MOOSE) group.
countries, a substantial proportion of anemia-related adverse JAMA 2000;283:2008–12.
16. World Bank. World Bank list of economies [Internet]. 2014 [cited 2014
pregnancy outcomes could be avoided. Feb 24]. Available from: http://data.worldbank.org/about/country-
classifications/country-and-lending-groups.
We thank Miwako Segawa for her help with the electronic search strategies
17. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group.
and retrieval of articles. Preferred reporting items for systematic reviews and meta-analyses: the
The authors’ responsibilities were as follows—MMR: contributed to the PRISMA statement. PLoS Med 2009;6:e1000097.
statistical analysis, interpretation of the data, and wrote the first draft of the 18. World Health Organization. Vitamin and Mineral Nutrition In-