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Nutritional interventions to prevent intrauterine growth retardation: Evidence from randomized controlled trials

Annex: Systematic reviews included

M de Onis1, J Villar² and M Gülmezoglu³

Correspondence: Dr M de Onis

¹Nutrition Unit, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland; ²UNDP/UNFPA/WHO World Bank Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland;
³National Perinatal Epidemiology Unit, Oxford, UK

This report summarizes the evidence from systematic reviews of randomized controlled trials on the effectiveness of nutritional interventions aimed at reducing intrauterine growth retardation (IUGR). There were 12 interventions including protein-energy, vitamin, mineral, and fish oil supplementation, as well as the prevention and treatment of anemia and hypertensive disorders. A primary concern is the limited data supporting the effectiveness of recommended nutritional interventions during pregnancy, some of which are widely used even in women without nutritional deficiencies. Overall, with the exception of perhaps balanced protein/energy supplementation (typical odds ratio: 0.77; 95 per cent confidence interval: 0.58 to 1.01), no effective nutritional interventions for reducing the risk of IUGR have been demonstrated. Other interventions, such as zinc, folate and magnesium supplementation during gestation, merit further research which should be conducted among populations at risk of IUGR, using larger sample sizes, and addressing coexisting factors limiting fetal growth. Appropriate combinations of interventions should be a priority for evaluation as it is unlikely that a single factor will reduce a multicausal outcome like IUGR that is so dependent on socioeconomic disparities.


Current available estimates confirm that the prevalence of intrauterine growth retardation (IUGR) in most developing countries is above the international cutoff point for triggering public health action (de Onis et al, 1997). Fetuses suffering growth impairment face an increased risk for intrauterine complications and, after birth, negative short- and long-term health outcomes (Balcazar H & Haas JD, 1991; Villar et al, 1990a; Williams et al, 1982; Øyen et al, 1995; Low et al, 1992; Parkinson CE, Wallis S & Harvey DR, 1981; Villar et al, 1984; Barker, 1991). IUGR is a crucial element in the intergenerational vicious cycle of poverty, growth failure, disease and malnutrition. The implications of this vicious cycle are enormous for the human and socio-economic development of affected populations. Effective interventions aimed at preventing impaired fetal growth are therefore urgently needed.

Randomized controlled trials (RCTs) are widely recognized to be the most objective and rigorous available method to evaluate the effectiveness of health care interventions (Villar and Carroli, 1996). Systematic reviews of randomized controlled trials provide an excellent tool for summarizing the results of interventions (Chalmers, 1989). By following a rigorous methodology they reduce bias, improve reliability and accuracy of conclusions, and can establish if trial results are consistent and generalizable across populations, settings and treatment variations. Methodological issues such as the type and sources of data, the size of included trials, the heterogeneity of trials, and their methodological qualities influence the strength of conclusions (Villar et al, 1997a; Jeng et al, 1995; Villar et al, 1995).

A comprehensive review of the evidence from 126 RCTs evaluating 36 prenatal interventions aimed at preventing or treating impaired fetal growth has recently been published by us elsewhere (Gülmezoglu et al, 1997). Strategies reviewed included care and advice during pregnancy, nutrition supplementation, and prevention and treatment of hypertensive disorders, fetal compromise, and infection. This paper summarizes, for the purposes of the IDECG/IUNS Workshop on Causes and Consequences of IUGR, the results of this comprehensive review (Gülmezoglu et al, 1997) and presents an in-depth analysis of nutritional interventions evaluated in RCTs.


The effectiveness of interventions was evaluated using systematic reviews of randomized controlled trials included in the Cochrane Pregnancy and Childbirth Database (Keirse et al, 1995). As part of a systematic review, meta-analysis provides a statistical synthesis, which increases power and reduces imprecision in the estimation. Results are expressed as typical odds ratios with 95% confidence intervals (Chalmers, 1989).

For identification of relevant trials in pregnancy and childbirth to be included in the systematic reviews a comprehensive search strategy continuously operates (Keirse et al, 1995). Identified trials are then sent to individual reviewers for consideration for inclusion. The most important aspect of a trial is whether it has prevented systematic errors (bias) or not. These can be inadequate concealment of allocation of treatments, execution of the intervention, and detection of outcomes. Trials with serious potential for bias at any one of the above points are given weak methodological quality scores. These and other aspects such as sample size and inconsistencies among various trials are discussed in the text and influence the conclusions of the systematic reviews.

For the present overview of nutritional interventions aimed at preventing IUGR, all systematic reviews have been updated up to March 1997 by contacting the individual reviewers of the Pregnancy and Childbirth Collaborative Review Group to inquire about any new trials that have been identified since the most recent update. We identified 2 new trials-one on maternal nutritional supplementation and another on maternal zinc supplementation-which, although not included in the calculations of the typical odds ratios to avoid changing the methodology, are reported in the results and considered in the discussion. The title and author of each systematic review included in this paper are provided in an Annex to facilitate its location in The Cochrane Pregnancy and Childbirth Database and the Pregnancy and Childbirth Module of The Cochrane Database of Systematic Reviews.

We have included those systematic reviews reporting at least one of the following outcomes:

- Low birth weight (< 2500 g) differentiating preterm delivery: Term-LBW.

- Small-for-gestational age (SGA): Birth weight less than a percentile value (usually 10th) for either of the population studied or another population. Some reported this outcome as IUGR.

- Low weight for gestational age (LW-GA): Similar to SGA but using 'low weight' instead of 'small'.

- Percent deviation from estimated fetal weight at a given gestational age (e.g. 15%, 20% less than expected for a specific gestational age).

- Mean birth weight (MBW)

We excluded those systematic reviews that involved screening and diagnostic methods, and multiple pregnancies. Systematic reviews that combined low birth weight with preterm delivery and gave the outcome only as LBW without any information on preterm delivery have also been excluded.

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