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* UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, CH–1211 Geneva 27, Switzerland, Centro Rosarino de Estudios Perinatales (CREP), WHO Collaborative Center in Maternal and Child Health, Rosario 2000, Argentina, ** Geneva Foundation for Medical Education and Research, Geneva, Switzerland and Department of Nutrition, World Health Organization, CH–1211 Geneva 27, Switzerland
3 To whom correspondence should be addressed. E-mail: merialdim{at}who.int.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • nutritional interventions • fetal growth • birth weight • small for gestational age • randomized controlled trials
Imbalances in maternal nutrition can adversely affect normal fetal growth and development. Impaired fetal growth is prevalent in developing countries and has been associated with negative short and long term outcomes such as increased perinatal morbidity and mortality, infant mortality and child hood morbidity. Children who experience impaired fetal growth are more likely to show poor cognitive development and neurologic impairment. Some chronic adult diseases are hypothesized to originate in utero: birth weight and other indicators of newborn health have been associated with the development of cardiovascular disease, high blood pressure, obstructive lung disease, diabetes, high cholesterol concentrations and renal damage (1).
Villar et al. (2) describe a conceptual framework for interpreting the results of clinical trials to evaluate nutrition interventions during pregnancy. For impaired fetal growth, two additional factors need to be added to this framework: assessment of fetal growth and the criteria used to classify abnormal fetal growth. This review focuses on the efficacy of nutrition interventions to correct nutrition deficiencies or act as "pharmacological agents" to prevent or treat impaired fetal growth.
Assessment of fetal growth
Fetal growth can be assessed retrospectively, using anthropometric measures of size at birth, or prospectively by serial clinical evaluations such as uterine height and ultrasound measurements of several fetal anatomical parameters. The use of reference data based on birth weight has its limitations. First, a cross-sectional approach, based on data collected at birth from infants born at various gestational ages, may not reflect the longitudinal growth of fetuses of the same ages. Second, the interpretation of the reference data is complicated by inaccuracies in the estimation of gestational age at delivery and by the pathological processes that could affect the size of infants born early in gestation (3, 4).
The main limitation to using ultrasound measurements has been the large coefficient of variation associated with ultrasound estimations of fetal weight (3,
5). The margin of error associated with measuring the size of single anatomical parameters, however, has been reduced and the reproducibility of these measurements has been shown to be very high. Intraobserver error was on average <1%, while interobserver error was 
1–2% in older studies (6). Intraclass correlation coefficients ranged from 0.982 to 0.997 in a recent study (7).
Classification of fetal growth
Several classifications systems have been proposed for newborn birth weight. The simplest is categorizing newborns <2500 gm as having a low birth weight (LBW) 4, but this classification does not differentiate between infants born small at term and infants who are small because they are born preterm. Reference charts of birth weight at different gestational ages classify infants as small for gestational age (SGA), usually when birth weight is below the 10th percentile for a given gestational age, adequate for gestational age (AGA) and large for gestational age (3, 8). Because it is based on percentile distributions, this classification may erroneously categorize some normal growth newborns in the lower tail of the normal fetal growth distribution as growth impaired. Thus, it is important that classifications of fetal growth are based on risk rather than on statistical parameters only.
Methods
We considered any systematic review of randomized controlled trials or individual trials of nutrition interventions during pregnancy to prevent or treat impaired fetal growth. The trials included pregnant women with or without any prior risk of adverse pregnancy outcome at assessment/screening. The main outcome measure was SGA or intrauterine growth restriction (IUGR), defined as birth weight less than a percentile value (usually 10th) for either the population studied or another population. Secondary outcomes included LBW (<2500 gm) and mean birth weight, which do not take into account the effect of gestational age at birth on birth weight.
The source of systematic reviews was the 2002 Issue 4 of the Cochrane Library (The Cochrane Library, 2002). We did not add to the meta-analyses of the Cochrane systematic reviews if a new trial was identified after the publication date of the systematic review. However, the results of new trials have been included and discussed accordingly.
Data extraction was done by two of the authors. Trial quality was assessed in the systematic reviews and the findings were considered by us before making recommendations about program action and research needs. Trials not included in the Cochrane reviews were assessed individually for methodological quality according to standard criteria used in Cochrane reviews (9).
Results
The results of 13 systematic reviews included in the last issue of the Cochrane Library and nine trials not included in those reviews were examined, giving 65 randomized clinical trials that are included in Annex Table 1 in the article by Villar et al. in this issue (10).
Table 1 shows the number of trials included in the systematic reviews and the results of the meta-analyses for SGA and LBW. Results of the meta-analyses are expressed as Typical Relative Risk (RR) and 95% confidence interval (CI). If the CI includes the value 1.0, the hypothesis that there is no difference in risk between the intervention and control groups cannot be rejected. Risk estimates for individual trials are presented as RR and 95%CI. For birth weight, the results of the meta-analyses are expressed as mean birth weight difference and 95%CI. If the CI includes 0.0, the hypothesis of no difference in birth weight between the intervention and control groups cannot be rejected.
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Balanced protein-energy. The systematic review of balanced protein energy supplementation in pregnancy (12) included 13 trials (Table 1). Six of the 13 trials reported SGA [See Annex Table 1 (10) Trials 4,6,7,8,12,15] and all reported a protective effect, although only one trial showed a statistically significant results [See Annex Table 1 (10) Trial 6]. The overall effect was a 32% reduction in SGA (Table 1), which is of clinical and public health relevance. Eleven trials reported birth weight as an outcome [See Annex Table 1 (10) Trials 3,4,5,7,8,10,12,13,15,17,18]. Infants born to mothers who received supplementation tended to be heavier than infants born to non supplemented mothers. However, the overall difference in mean birth weight was small and not significant (mean difference: 25.4 gm; 95%CI: -3.62, 54.5).
Isocaloric balanced protein and high protein. Only one of the three trials included in the systematic review of isocaloric balanced protein supplementation in pregnancy reported SGA as an outcome (13). This trial [See Annex Table 1 (10) Trial 11] showed an adverse effect of supplementation on the risk of SGA (Table 1). Three trials reported data on birth weight [See Annex Table 1 (10) Trials 11,17,18] and showed a reduction in mean birth weight in the supplemented group compared with the control group (mean difference -63.5 gm; 95%CI: -124.3, -2.86).
The effect of high protein supplementation on SGA was evaluated in one [See Annex Table 1 (10) Trial 15] of two trials included in the systematic review. High protein supplementation increased the risk of SGA (Table 1). The same trial—conducted among women of low socio economic status in the United States—showed a nonsignificant decrease in birth weight (mean difference: -58.4 gm; 95%CI: -146.2, 29.5). The other trial [See Annex Table 1 (10) Trial 9] that included 25 Indian women found no difference in the birth weight of infants born to mothers who received high protein supplements compared with those of mothers who did not. In the U.S. trial [See Annex Table 1 (10) Trial 16], the nutrition intervention was associated with a non statistically significant increase in neonatal death. These results suggest that high protein supplementation during pregnancy may be harmful to the fetus and should be avoided.
Energy protein restriction. The systematic review on energy protein restriction for high weight-for-height or weight gain during pregnancy included three trials (14). None of the trials reported data on LBW or SGA. Two trials reported data on birth weight [See Annex Table 1 (10) Trials 19,20] and the results show heterogeneity. The first trial—on 100 obese Egyptian women—found a reduction in birth weight associated with energy restriction compared with normal diet (mean difference: -450 gm; 95%CI: -624.7, -275.3). The second—on 182 obese Scottish women—found no difference in mean birth weight between infants born to women on a low energy diet and women receiving no intervention (mean difference: 6 gm; 95%CI: -121.5, 133.5). The overall results of the meta-analysis showed a reduction in mean birth weight associated with energy restriction (mean difference: -125 gm; 95%CI: -255.6, -49.5). However, these results must be treated cautiously because of the heterogeneity in the results of the individual trials.
Salt restriction. The systematic review for reduced salt intake compared with normal dietary salt or high salt intake in pregnancy (15) included two trials with data on reduced fetal growth. The latter was defined as LBW (<2500 gm) in one trial [See Annex Table 1 (10) Trial 22] and as birth weight for gestational age below the 10th percentile in the other trial [See Annex Table 1 (10) Trial 23a,23b]. The trial reporting SGA as an outcome did not show evidence of a differential effect, although the trend was for the risk of SGA to increase [See Annex Table 1 (10) Trial 23a,23b]. The trial reporting LBW (<2500 gm) [See Annex Table 1 (10) Trial 22] also found no effect, but the direction of the change was the opposite to that for SGA (Table 1).
Calcium. Eleven trials were included in the systematic review of calcium supplementation during pregnancy for preventing hypertensive disorders and related problems (16) and nine presented data on fetal growth. A study in India found no evidence of a differential effect of calcium supplementation on the incidence of SGA, which may have been influenced by the sample size being too small [See Annex Table 1 (10) Trial 31]. A U.S. study that was not included in the systematic review found no difference in the risk of SGA by supplement type but, as with the India study, the CI was wide (RR 1.01; 95%CI: 0.21–4.88) [See Annex Table 1 (10) Trial 33].
The majority of the calcium supplementation trials [See Annex Table 1 (10) Trials 24,25,26,33,34] presented data on LBW and tended to show a protective effect of calcium supplementation on fetal growth. The overall result showed a significant 17% reduction in the risk of LBW associated with calcium supplementation (Table 1).
The systematic review did not present data on mean birth weight. However, seven of the trials reported larger mean birth weights in neonates from calcium supplemented mothers compared with those of unsupplemented women [See Annex Table 1 (10) Trials 27–33]. The observed difference was statistically significant in 3 studies. Because two of the studies [See Annex Table 1 (10) Trials 24,31] reported heterogeneous effects of calcium supplementation on the rate of SGA, the results suggest that calcium supplementation may affect birth weight both through a direct effect on growth and by prolonging gestation.
Iron supplementation. The systematic review of iron supplementation in pregnancy included 20 trials that compared routine iron vs. no iron or placebo; conventional oral iron vs. slow release iron preparation; and selective versus routine iron in pregnancy (17). Data on SGA and LBW are reported only for the latter group and in only one trial [See Annex Table 1 (10) Trial 49]. The results are similar for both outcomes and show no difference in fetal growth by type of supplementation (Table 1).
One trial comparing routine iron versus placebo reported data on mean birth weight [See Annex Table 1 (10) Trial 45]. The authors found a small nonsignificant increase in mean birth weight among the infants of mothers who received iron supplementation compared with those who did not (mean difference: 30 gm; 95%CI: -90.0, 150.0).
One trial in the systematic review of treatment for iron deficiency anemia in pregnancy (18), in which intravenous iron versus regular oral iron was compared, included fetal growth outcomes [See Annex Table 1 (10) Trial 62]. Because of the small sample size, meaningful conclusions can not be drawn for either SGA (Table 1) or mean birth weight difference (mean difference: -119.3 gm; 95%CI: -312.1, 73.5). No cases of LBW were detected in either of the two groups.
Folate. Of the 21 trials included in the review of folate supplementation in pregnancy (19), 5 reported data on LBW [See Annex Table 1 (10) Trials 50,52,53,54,57]. There was statistically significant heterogeneity in the results (p 0.01) with only one trial reporting an increased risk of LBW, while the other trials tended to show a null or protective effect. Although not significant, the overall result shows a tendency toward a decrease in the risk of LBW associated with folic acid supplementation (Table 1). Only one trial presented data on mean birth weight and found a reduction in mean birth weight associated with folic acid supplementation in pregnancy (mean difference: -86.0 gm; 95%CI: -107.2, -64.8) [See Annex Table 1 (10) Trial 58].
Iron and folate supplementation. The review of iron and folate supplementation in pregnancy included eight trials (20) of which only one had data on LBW [See Annex Table 1 (10) Trial 61]. The relative risk of LBW associated with the intervention was high but, due to the small sample size and the absence of outcomes in the control group, the CI was very wide (Table 1).
Magnesium. Seven trials were included in the systematic review of magnesium supplementation in pregnancy (21). The effect of magnesium supplementation on fetal growth was assessed in terms of rates of SGA, LBW (<2000 or 2500 gm), very LBW (<1500 gm) and differences in mean birth weight between supplemented and placebo groups. The pooled estimate for the risk of SGA from the three trials that looked at this outcome [See Annex Table 1 (10) Trials 65,67,68] showed a significant overall risk reduction of 30% in the intervention group (Table 1). The pooled result of the four trials reporting LBW as an outcome [See Annex Table 1 (10) Trials 63–65,68,] showed the risk of LBW fell significantly by 33% following magnesium supplementation (Table 1). One trial reported a nonsignificant reduction in the risk of very LBW following magnesium supplementation [See Annex Table 1 (10) Trial 68].
Four trials [See Annex Table 1 (10) Trials 63,66,67,68] examined the difference in mean birth weight by supplement type and found that overall newborns in the magnesium supplementation group weighed 51 grams more than newborns of nonsupplemented mothers (mean difference 50.83 gm; 95%CI: 0.22, 101.84).
One of the studies in the systematic review had allocated patients to the magnesium and placebo groups using medical centers as units of randomization [See Annex Table 1 (10) Trial 65], which makes interpretation of the results problematical. The authors did not adjust for the cluster design, which might have affected the results of the meta-analysis. A sensitivity analysis that excluded this trial from the meta-analysis (20) showed the direction of the effect does not change, although the CI of the overall risk estimates included 1.0, which could be explained by the reduction in sample size (RR 0.90; 95%CI: 0.60–1.35 and RR 0.75; 95%CI: 0.46–1.22 respectively).
Fish oil. The systematic review on fish oil supplementation in pregnancy (22) has not been updated since 1995. This review, which includes three trials [See Annex Table 1 (10) Trials 70a,71,72], found an overall tendency toward an increased risk of birth weight below the 3rd or 5th percentile associated with fish oil supplementation (odds ratio 1.56; 95%CI: 0.56–4.35). We identified two articles published after the last update of the systematic review with data on fetal growth in relation to fish oil supplementation [See Annex Table 1 (10) Trials 69,70b]. Olsen et al. [See Annex Table 1 (10) Trial 70b] presented data from trials that compared giving pregnant women at risk of various pregnancy complications, including intrauterine growth impairment, fish oil versus olive oil supplements. Two trials examined the effect of fish oil supplements for preventing and treating IUGR. The prophylactic trial included women with IUGR (<5th percentile) in a previous pregnancy and found no effect on birth weight for gestational age below the 10th percentile (RR 1.13; 95%CI: 0.77–1.66). The therapeutic trial included women with suspected intrauterine growth impairment diagnosed by ultrasonically estimated fetal weight below the 10th percentile. No difference in birth weight adjusted by gestational age at delivery was found between the two supplement groups.
A Dutch trial among women with a history of intrauterine growth impairment (birth weight <10th percentile), with or without history of pregnancy induced hypertension, evaluated the effect of fish oil supplementation against placebo and found no difference in birth weight percentile distributions between the groups [See Annex Table 1 (10) Trial 69). The trial that compared fish oil versus placebo supplementation in women at high risk of pregnancy induced hypertension or asymmetrical intrauterine growth retardation [See Annex Table 1 (10) Trial 71] confirmed the results of the other studies by finding no difference in rates of birth weight below the 3rd percentile (RR 0.89; 95%CI: 0.48–1.64).
Zinc. The last update of the systematic review of zinc supplementation in pregnancy included seven trials (23). The meta analysis for three trials comparing zinc supplements versus placebo [See Annex Table 1 (10) Trials 77,79,85] showed no evidence of a differential effect on SGA by supplement type (Table 1). The meta-analysis for the five trials reporting LBW [See Annex Table 1 (10) Trials 77,78,80,83,85] showed a non significant reduction in risk of LBW associated with maternal zinc supplementation (Table 1).
Three trials reported mean birth weight as an outcome [See Annex Table 1 (10) Trials 77,80,84]. Overall, there was no difference in this outcome by supplement type (mean difference: 24.4 gm; 95%CI: -45.8, 94.6). The only trial that showed a positive effect of zinc supplementation on birth weight (mean difference: 126 gm; 95%CI: 12.1, 239.9), but not LBW rate (RR 0.62; 95%CI: 0.56–1.06) or gestational age rates (RR 0.86; 95%CI: 0.64–1.28) was conducted among low-income pregnant women in Alabama with low serum zinc concentrations at entry into prenatal care [See Annex Table 1 (10) Trial 77]. The effect of zinc supplementation on birth weight was more evident in women who were not overweight at the beginning of pregnancy. The results of this trial may be more relevant to populations similar to the one studied, such as populations in developing countries who are more at risk of zinc deficiency and not overweight (24). The results of three studies published after the last update of the review, and conducted in developing countries, did not find an effect of zinc supplementation on birth weight [See Annex Table 1 (10) Trials 74,82,81]. Caulfield et al. compared iron and folate supplementation with and without zinc and did not find differences by supplement type in birth weight or in the risk of LBW (RR 0.96; 95%CI: 0.50–1.86) [See Annex Table 1 (10) Trial 79]. Another trial with a similar study design, but higher dose of daily zinc supplementation, showed no difference in mean birth weight [See Annex Table 1 (10) Trial 81] However, the primary outcome of this study was not birth weight but the growth of fetal anatomical parameters assessed by ultrasonography. A positive effect of maternal zinc supplementation on fetal femur diaphysis growth was detected.
Osendarp et al. supplemented pregnant Bangladeshi women with 30 mg/d zinc or placebo [See Annex Table 1 (10) Trial 82]. No differences in mean birth weight or rates of low birth by supplement group were observed (RR 1.12; 95%CI: 0.90–1.41).
Vitamin D. The review of vitamin D supplementation during pregnancy (25) includes two clinical trials [See Annex Table 1 (10) Trials 86,89]. The first reported low weight for gestational age and birth weight as outcomes and found no evidence of a differential effect of vitamin D on either SGA (Table 1) or birth weight (mean difference: 123.0 gm 95%CI: -50.4, 296.4). In contrast, the second found that women who received 1000 IU vitamin A daily and 200,000 IU vitamin D in a single dose had, on average, a lower birth weight than women who received no supplementation (mean differences: -90.0 gm; 95%CI: -132.7, -47.3 and -250.0 gm; 95%CI: -292.4, -207.5, respectively).
Vitamin C and E. A trial of vitamins C and E supplementation among pregnant women at increased risk for preeclampsia reported a non significant reduced risk for SGA associated with vitamin supplementation (RR 0.74; 95%CI: 0.50–1.08) [See Annex Table 1 (10) Trial 87).
Discussion
Based on data from six trials that included more than 4000 women, the Cochrane review showed that balanced protein-energy supplementation reduced the overall risk of SGA by 30%.
Most of the trials were conducted in developing countries, thus the positive effect of this intervention is likely to be replicable in those settings. In contrast, a trial conducted among women in New York, U.S., without evidence of undernutrition, showed that high protein supplementation may negatively affect fetal growth and neonatal mortality.
Single micronutrient supplementation interventions have not been shown to affect size at birth, except magnesium supplementation which reduced the rate of both SGA by 30% in three trials including more than 1700 women. Methodological concerns about a large magnesium trial in the review suggest caution in interpreting those results. Calcium supplementation may reduce low birth weight, although it is likely to be related to prolonged gestation.
The biological importance of the effect of nutrition supplementation on other fetal growth parameters besides birth weight remains to be evaluated. Recently fetal ultrasonography has been used to evaluate nutrition interventions during pregnancy and the results from one clinical trial on maternal zinc supplementation showed a positive effect on fetal long bone growth despite no observed effect on birth weight [See Annex Table 1 (10) Trial 81). Focusing on outcomes other than birth weight may help identify the effects of nutrition interventions on specific growth components and suggest mechanistic hypotheses that might be further investigated in animal and in vitro studies. To acquire public health relevance, new outcome measures must have strong biological links with substantive outcomes such as severe morbidity or postnatal growth. Further research in this area is warranted, as suggested by recent findings of an inverse relationship between fetal femur length, assessed by ultrasonography during pregnancy, and blood pressure at 6 y old (26).
Most studies have relied on assessing gestational age based on the last menstrual period or postnatal newborn assessment that have limitations and may decrease their accuracy. Gestational age at birth is a major determinant of birth weight and its accurate determination is critical for the proper evaluation of nutrition interventions. Although this bias should be equally distributed among the comparison groups in large randomized clinical trials, the error in the outcome classification could increase the false negative results of some trials. Only one study has looked at the postnatal implications of nutrition interventions intended to affect fetal growth (27). These implications need to be considered because they relate to both the somatic and neurological development of the infant and child.
Presently, there is little evidence to support the implementation of specific nutrition public health interventions to prevent impaired fetal growth. The positive effect on impaired fetal growth shown by the systematic review of balanced protein energy supplementation suggests that this might be the only nutritional intervention for which a practical recommendation can be made. Kramer and Victoria (28) suggested that universal balanced protein energy supplementation be provided to women in areas with a high prevalence of maternal undernutrition to prevent impaired fetal growth. Moreover, intervening universally to all women is more likely to be effective than targeted energy supplementation to women considered at risk of undernutrition on the basis of anthropometrical screening.
The areas for further research include:
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FOOTNOTES |
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2 The views expressed in this document are solely the responsibility of the authors and do not necessarily represent the views of the World Health Organization or its Member States.
4 Abbreviations: CI, confidence interval; IUGR, intrauterine growth restriction; LBW, low birth weight; RR, relative risk; SGA, small for gestational age; WHO, World Health Organization.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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2. Villar, J., Merialdi, M., Gülmezoglu, A. M., Abalos, E., Carroli, G., Kulzer, R. & de Onis, M. (2003) Nutritional interventions during pregnancy for the prevention or treatment of maternal morbidity and preterm delivery: an overview of randomized controlled trials. J. Nutr. 133: 1606S–1625S.
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24. Caulfield, L. E., Zavaleta, N., Shankar, A. H. & Merialdi, M. (1998) Potential contribution of maternal zinc supplementation during pregnancy to maternal and child survival. Am. J. Clin. Nutr. 68: 499S–508S.[Abstract]
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