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EVIDENCE-BASED PUBLIC HEALTH POLICY AND PRACTICE |
1 Division of Preventive Medicine and Public Health, University of Jaen, Jaen, Spain
2 Division of Preventive Medicine and Public Health, University of Cantabria, Santander, Spain
Correspondence to:
Dr M Delgado-Rodriguez, Division of Preventive Medicine and Public Health, University of Jaen, 23071 Jaen, Spain; mdelgado{at}ujaen.es
Accepted for publication 28 March 2007
 | ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Design: Case–control study.
Setting: University Hospital of Cantabria.
Study population: Cases were 322 mothers without anaemia delivering a singleton infant of less than 2500 g. Controls were 934 mothers without anaemia delivering a term non-small-for-gestational-age infant.
Data collection: Data on iron and folic acid supplementation were obtained from prenatal chart record and personal interview. Data on risk factors for LBW were also gathered.
Results: Agreement between the two sources of information was good (82% for folic acid and 94% for iron). Odds ratios yielded from the two sources were very close. Folic acid only (15 mg/day) was unrelated to LBW, whereas iron supplementation (80 mg ferrous sulphate) was associated with a lower risk of LBW (odds ratio (OR) 0.58, 95% CI 0.34 to 0.98), adjusted for smoking, maternal education, body mass index, obstetric diseases during pregnancy, weight gain during pregnancy, and previous LBW. The results of iron plus folic acid were similar to those for iron (OR 0.56, 95% CI 0.33 to 0.96). There was a significant trend towards a lower risk of LBW (p<0.001) with the duration of iron supplementation. After stratifying by the type of LBW, the trend was also significant for any kind of LBW.
Conclusions: Iron supplementation is associated with a lower risk of LBW in pregnant women without anaemia.
Two clinical trials in pregnant women without anaemia in developed countries have been reported. The first was performed on 275 low-income women from Cleveland, Ohio, United States, for whom data on birthweight were available for 213 women; the study reported a fourfold lower incidence of LBW (from 17% to 4%) in the treatment arm, 30 mg iron for approximately 10 weeks.10 The second trial, reported in 2006, randomly assigned US women eligible for the Special Supplemental Nutrition Program for Women, Infants and Children, into four arms in 1997–1999.11 Two arms were women without anaemia, 218 were assigned to receive iron (30 mg) and 211 were assigned to placebo. Data were reported on the outcomes of 166 and 168 women of the treatment and placebo arms, respectively. The frequency of several outcomes in the treatment and placebo groups were as follows: LBW 4.8% versus 9.5% (p = 0.09); small for gestational age (SGA) 10.8 versus 15.5% (p = 0.22); and preterm delivery 7.5% versus 13.9 (p = 0.05). Despite these results, there are doubts about the benefits of iron supplementation and therefore it is not fully endorsed.12 13 Currently available evidence is thus insufficient to support or reject this practice for the specific purposes of raising birthweight.14
Observational studies provide a lower evidence level than trials, although they can be useful in evaluating programmes in the field. We present the results of a case–control study to assess whether iron and folic supplementation among pregnant women without anaemia is associated with LBW.
| METHODS |
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| TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Eligibility criteria for cases were the delivery of a single live infant weighing less than 2500 g without congenital malformations during the study period, residence in the referral area of the hospital, receiving prenatal care (first visit in the first trimester and at least five visits during pregnancy), and without anaemia during pregnancy (anaemia was defined as a haemoglobin level less than 11 g/l regardless of gestational age). No woman declined to participate. A total of 322 cases were included; 187 were preterm and 108 were SGA.
The selection of controls was as follows. A random sample of one sixth of all women delivering at the hospital was drawn by using the following procedure: each month for the study period, all women delivering on five days, randomly selected in advance, were asked to participate (n = 1550). Forty-nine women had already been identified and included in the group of cases or they had a preterm or SGA infant, 11 women had infants with congenital malformations, 28 women declined participation, 528 did not receive adequate prenatal care (as defined for cases) and information on anaemia status was lacking, leaving 934 women in the control group.
Three sources of data were used: personal interviews (carried out within the three days after delivery), clinical charts, and prenatal care records. Information was obtained on the following variables: mother’s vital data (age at pregnancy, race, education level, marital status, socioeconomic class, and occupation, from interview), obstetric history (parity and abortions, from the prenatal care record), previous adverse perinatal outcomes, conditions during pregnancy (infections, preeclampsia, diabetes, and other obstetric conditions from the prenatal care record), birthweight (weight in grams in the delivery room), prescribed and over-the-counter drugs (from both prenatal care record and from interview), smoking during pregnancy (interview), and prenatal care (number of visits and date of first visit, from prenatal care record and interview in those receiving private care). Social class was coded in five main levels (ranging from I, the highest, to V, the lowest) according to the classification of the Spanish Society of Epidemiology,15 which is close to that of the Black Report.16 Information on iron and folic supplementation and other supplements was obtained from two sources: personal interview and prenatal care record. Data on the duration of intake were obtained by personal interview (this information was not included in the prenatal care record) after asking for the date of pregnancy when intake began and the date of pregnancy when medication was stopped. A woman was included in the group "taking supplements" if the duration of intake lasted at least one week.
Comparison of proportions was assessed by the Fisher’s exact test and the t-test was applied to compare means. The agreement between the data provided by the two sources of iron and folic supplementation was assessed by the kappa statistic. Associations between the supplements (from the two sources) and LBW were assessed by odds ratio (OR) and its 95% confidence interval (CI). Multiple risk factor-adjusted OR were estimated by means of logistic regression. To determine variables to be included in multivariate logistic regression analysis, the procedure described by Sun et al.17 was followed. Intermediate variables were discarded. Two stepwise models were run, one backward and another forward, allowing the entry of variables with p<0.2.18 19 We made a list of predictors of LBW identified in other studies. With information from stepwise models and the list of predictors, a saturated model was built, and by using a heuristic approach, variables that did not change the coefficient of birthweight by more than 10% were discarded.18 The objective was to have a parsimonious model retaining all important confounders. All analyses were repeated, stratifying by gestational age (preterm and term LBW) and SGA (yes/no). If substantial differences were found, they are mentioned as footnotes in tables and noted in the text. The Stata 8.0-SE statistical package (Stata Corp., College Station, Texas, USA) was used in analyses.
| RESULTS |
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| TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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What this paper adds Iron supplementation is associated with a lower risk of LBW in pregnant women without anaemia without increasing preeclampsia or gestational diabetes
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Policy implications The results suggest that a small-dose iron supplementation should be recommended to all pregnant women
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As folic acid and iron are commonly used simultaneously, the independent association of each supplementation was assessed separately (table 2). The results with both sources of information, interview and prenatal care chart, were similar. Women taking folic acid only did not show any relationship with LBW. The strength of the association between iron only and LBW was similar to that obtained with folic acid plus iron (very close OR) and approximately halved the risk of LBW.
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| DISCUSSION |
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| TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The benefits of iron supplementation in pregnant women have been studied in several trials. In three trials iron supplementation was compared with placebo and no distinction between anaemia and non-anaemia during pregnancy was made. In an Indian trial, it reduced the incidence of LBW,20 whereas in an American trial it increased birthweight and reduced preterm delivery but not SGA.11 In a third trial in Wisconsin (USA) on women with prepregnancy normal iron stores, however, no significant differences were seen in maternal or neonatal health, although the number of women was small.21
Concerns have been raised about the potential disadvantages of giving iron supplementation to women without anaemia.8 There have been two American trials on low-income women without anaemia. In the Cleveland trial women receiving a dose of 30 mg per day had a fourfold reduction (from 17% to 4%) in the risk of LBW, mainly preterm LBW;10 however, the study was not powered to detect any influence on SGA. In the Raleigh trial,11 the risk of LBW in the treatment group was halved, although the figure was not significant (p = 0.09). These results agree with ours. There is also evidence from a case–control study on all pregnant women (with and without anaemia) that iron supplementation prevents SGA.22
Regarding the association between folic acid and birthweight, a systematic review published in 1997,23 combining five trials (with 447 treated women versus 438 placebo), suggested that folic acid decreases term LBW (OR 0.60, 95% CI 0.37 to 0.97); most of the trials included in the review defined their populations poorly, did not give details of randomisation procedures, and did not take iron supplementation into account, although it was routine. It has been found that serum folate concentrations showed negative relationships with the incidence of foetal growth retardation as well as the birthweight of infants,24–26 although a previous study had shown that anaemia other than iron deficiency was unrelated to LBW and preterm delivery.1 In New Zealand, a case–control study of SGA folic acid supplementation also showed a reduced risk.22 In a Danish trial the effects of supplementing the diet with folic acid given preconceptionally or in the first half of pregnancy were a slight increase of birthweight and a decrease in the incidence of preterm labour, LBW and SGA; the greatest effect was seen in the groups receiving folic acid preconceptionally.27 Other trials have, however, failed to show any advantage of folic acid supplementation on birthweight.28 29
We have not reported the effect of supplementing other micronutrients on LBW. The number of women using these supplements was small (16 cases and 66 controls). The available trials have reported conflicting results. Two trials carried out in developing countries and comparing multiple micronutrient supplementation with folic acid plus iron have shown a decreased LBW in women with anaemia only30 and an increase in birthweight.31 Another trial showed a slight beneficial effect, although the results did not achieve statistical significance.32 Finally, another trial on semirural women in Mexico did not report a greater advantage over iron-only supplementation.33 A Cochrane review found that multiple micronutrient supplementations were not better than folic acid plus iron supplements.34
Our results suggest that iron but not folic acid supplementation in women without anaemia is associated with a lower risk of LBW. The main goal of iron supplementation is to avoid iron deficiency, which could cause LBW by several mechanisms.35 There is, however, a danger of adverse effects if iron is supplemented above the needs of pregnancy.8 Much of the information on the benefits of supplementation come from studies carried out in developing countries where malnutrition is common. Two trials on women without anaemia have recently been reported in the developed world showing the benefits of iron supplementation, one with data on 213 women10 and the other on 334 women11. Observational studies, such as ours, can provide useful information while waiting for a larger trial with enough statistical power to detect all the benefits and adverse effects in women without anaemia.
| FOOTNOTES |
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| REFERENCES |
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