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This paper summarizes the evidence from randomize controlled trials of the effectiveness of nutritional interventions to prevent intrauterine growth retardation. As a first conclusion, there is an enormous gap between the magnitude of the problem of IUGR (de Onis et al, 1997) and the quality and size of the RCTs that evaluated nutritional strategies to prevent it. Furthermore, we question whether a single intervention is likely to reduce the rate of a multicausal outcome like IUGR that is so dependent on socioeconomic disparities. Thus, appropriate combinations of interventions should be a priority for evaluation in the context of large, methodologically sound trials.

Of the 12 nutritional interventions reviewed, only balanced protein/energy supplementation seems to marginally improve mean birth weight and decrease the number of small-for-gestational age babies, which supports early evidence from non-randomized analyses (Lechtig et al, 1975). Unfortunately, the evidence to date provides limited information on neonatal mortality and the benefit on neurocognitive and physical development remains unclear.

The modest benefits achieved on fetal growth might be explained by the rather small increases in net energy intake achieved in the trials; non-compliance and dietary replacement could play a role in these small net increases. It could be argued that if an effect is seen despite this marginal increase in intake, there may be a biological association between supplementation and fetal growth. These considerations raise the question of the appropriate timing and dosage of the interventions considering that long-standing social and nutritional deprivation are difficult to overcome by a nutritional intervention during few months in the course of a pregnancy. Villar & Rivera's report on the supplementation during two consecutive pregnancies and the interim lactation period suggests that the likelihood of improving fetal growth in chronically malnourished populations may be greater with such long-term interventions (Villar and Rivera, 1988). This study was not randomized and no definite conclusions can be drawn from it but it should be kept in mind in designing similar interventions.

It has been hypothesized that increasing the birth weight may theoretically increase the likelihood of cephalopelvic disproportion in labor (Garner et al, 1992), however, empirical evidence from the recent Gambia trial (Ceesay et al, 1997) demonstrates that the impact of nutritional supplementation on head circumference is very small, thus minimizing concerns about the risk of cephalopelvic disproportion. Improving maternal nutritional status benefits overall women's health and may assist maternal growth in adolescent pregnancies with poor nutrition, and hence could have a positive effect on fetal growth. Efforts to improve women's nutrition should be a priority, especially in developing countries.

Nutritional advice appears effective in increasing pregnant women's energy and protein intakes, but the implications for fetal or infant health cannot be judged from the available trial (Kafatos et al, 1989). There is evidence from a recent RCT that pregnant women do increase knowledge when it is provided through health education interventions but the implementation and impact of this advice is limited (Belizán et al, 1995). Moreover, nutritional advice can only be beneficial if it is possible to increase nutritional intake, which may be difficult in most impoverished populations. The systematic reviews on isocaloric balanced protein supplementation and high-protein supplementation during pregnancy provide no evidence of benefit on fetal growth and suggest that such supplements (i.e., without energy supplementation) may even be harmful (Table 3). This conclusion appears to apply even to undernourished women.

The evidence provided by the only small trial conducted on vitamin D supplementation suggests a potential beneficial effect on fetal growth in vulnerable groups, such as pregnant Asian women living in sunless climates. Larger trials, studying the effects of vitamin D supplementation on substantive neonatal and maternal outcomes, and its safety comparing different dosage schedules, could be considered to clarify further the role of supplementation.

Zinc supplementation at closes of 25 mg/day seems to have a tendency towards reducing term-LBW, mainly reflecting the effect observed in the Alabama trial (Goldenberg et al, 1995). Women in this trial had relatively low plasma zinc concentrations in early pregnancy and most of the effect is concentrated among women with a body mass index less than 26 kg/m2. In conclusion, there are 4 RCTs including 1400 women on this subject and the available data provide no convincing case for routine zinc supplementation during pregnancy. More trials are needed in selected communities at high risk of being zinc deficient, as well as in populations from developing countries where poor fetal growth is highly prevalent.

The available evidence suggests that magnesium supplementation at doses of 15 mmol/day may have beneficial effects in preventing IUGR, however, the data are currently insufficient to justify routine magnesium supplementation during pregnancy. In view of the methodological limitations of the two available trials, it is important that further, better designed trials be conducted to assess whether the current evidence reflects bias or a real beneficial effect. The suggestion that in utero exposure to magnesium sulphate could be protective against cerebral palsy in very low birth weight infants is encouraging and further evaluation is justified (Nelson and Grether, 1995).

Concerning antianemic supplements, there seems to be no evidence currently to recommend routine as opposed to selective iron supplementation in well-nourished populations and there are inadequate data from populations where iron deficiency is common; thus, it is urgent that it be adequately tested in anemic populations or in populations where anemia is believed to contribute to perinatal morbidity and mortality. Unfortunately, considering the widespread use of iron supplements., it is unlikely that a placebo controlled trial can be ethically justified in such populations. Furthermore, iron supplements are indicated for maternal reasons in populations with high prevalence of anemia (Villar and Bergsjø, 1997).

Folate supplementation seems to reduce the incidence of term-LBW despite the methodological limitations of the trials. There are plausible mechanisms through which such an effect could operate and the evidence therefore deserves further testing. Where there is evidence that megaloblastic anemia in pregnancy is a common problem, routine supplementation with folate may well be justified, however, better controlled trials in populations in which folate deficiency is common are needed before any firm recommendations in this regard can be made. In developing countries folate supplementation could be important because folate deficiency frequently co-exists with iron deficiency, and it may be relevant to antimalarial chemoprophylaxis studies or programs (Fleming et al, 1986, 1984).

At present it is not possible to make any firm conclusions about the role of fish oil in pregnancy based on the limited available: evidence and large, randomized, placebo-controlled trials will be required in order to assess reliably the potential benefits and adverse effects. Also, compliance with fish oil supplementation may be a problem because of its unpleasant taste. Similarly, the available data are too few to reach any conclusion about the differential effects of low and high salt intake during pregnancy on substantive pregnancy outcomes and any attempt to manipulate salt intake during pregnancy should be strongly discouraged. Finally, the results of calcium supplementation studies do not provide evidence of a significant effect on IUGR (Carroll et al, 1994; Bucher et al, 1996).


a) Implications for practice:

It is surprising how limited data are supporting the effectiveness of nutritional interventions during pregnancy, some of which are of widespread use even in women without nutritional deficiencies. However, it is obvious that women manifesting nutritional deficits can only benefit from reversing such situation. On the basis of the evidence reviewed here, only balanced protein/energy supplementation has additional potential beneficial effects on reducing the incidence of IUGR.

b) Priority areas for further research:

In poor societies with high rates of IUGR, where multiple pathologies coexist, it may be difficult to achieve beneficial results by testing a single intervention. Malaria and other parasites, malnutrition and anemia coexist in many developing countries and the presence of such a combination of conditions is worse than each one of them alone. According to the evidence reviewed in this paper, an appropriate combination of antianemic (iron-folate) and antimicrobial/antiparasitic agents that can be tested in population-based trials may have greater chance of showing a beneficial effect on IUGR. Zinc and magnesium supplementation should also be rigorously evaluated.

c) Methodological considerations for future research:

Trials should be conducted on promising interventions based on sound epidemiological or basic science background information and following rigorous randomization procedures to ensure high methodological quality; sample sizes should be adequate to detect any impact on substantial outcomes even if they are not large enough to show an effect on perinatal mortality; practical workable measures to assess gestational age or fetal growth prospectively and accurately should be established before initiating the trials (neonatal examination for more accurate evaluation of SGA/LBW could be used); data on any related adverse effects should be collected and reported.

Annex: Systematic reviews included

1.- In: Neilson JP, Crowther CA, Hodnett ED, Hofmeyr GJ, Keirse MJNC (eds.) Pregnancy and Childbirth Module of The Cochrane Database of Systematic Reviews. Available in The Cochrane Library [database on disk and CDROM]. The Cochrane Collaboration; Issue 2. Oxford: Update Software; 1997. Updated quarterly. Available from: Update Software, Oxford.

Kramer MS. Balanced protein/energy supplementation in pregnancy.
Kramer MS. Nutritional advice in pregnancy.
Kramer MS. Isocaloric balanced protein supplementation in pregnancy.
Kramer MS. High protein supplementation in pregnancy.
Mahomed K, Gulmezoglu AM. Vitamin D supplementation in pregnancy.

2.- In: Keirse MJNC, Renfrew MJ, Neilson JP, Crowther CA (eds.) Pregnancy and Childbirth Module of The Cochrane Pregnancy and Childbirth Database [database on disk and CDROM]. The Cochrane Collaboration; Issue 2. Oxford: Update Software; 1995.

Mahomed K. Routine zinc supplementation in pregnancy.
Keirse MJNC. Routine magnesium supplementation in pregnancy.
Mahomed K. Routine iron supplementation in pregnancy.
Mahomed K. Routine folate supplementation in pregnancy.
Duley L. Prophylactic fish oil in pregnancy.
Duley L. Routine calcium supplementation in pregnancy.
Duley L. Low vs high salt intake in pregnancy.

Acknowledgements - We express our gratitude to Ms Monika Blössner for her assistance in preparing this manuscript.


Balcazar H & Haas JD (1991): Retarded fetal growth patterns and early neonatal mortality in a Mexico city population. Bull. Pan. Am. Health Organ. 25, 55-63.

Barker DJP (1991): The intrauterine origins of cardiovascular and obstructive lung disease in adult life: The Mark Daniels lecture 1990. J. R. Coll. Physicians Load. 25, 129-33.

Baumslag N, Edelstein T & Metz J (1970): Reduction of incidence of prematurity by folic acid supplementation in pregnancy. Br. Med. 1, 16-17.

Belizán JM, Villar J. Bergel E et al (1997): Long-term effect of calcium supplementation during pregnancy on the blood pressure of the offspring: Follow up of a randomized controlled trial. Br. Med. J. 315, 281-285.

Belizán JM, Barros F, Langer A et al (1995): Impact of health education during pregnancy on behavior and utilization of health resources. Am. J. Obstet. Gynecol. 173, 894-9.

Belizán JM, Villar J, Gonzalez L, Campodonico L & Bergel E (1991): Calcium supplementation to prevent hypertensive disorders of pregnancy. N. Engl. J. Med. 325, 1399-1405.

Blackwell RQ, Chow BY, Chinn KSK, Blackwell BN & Hsu SC (1973): Prospective maternal nutrition study in Taiwan: rationale, study design, feasibility and preliminary findings. Nutrition Reports International. 517-32.

Brooke OG, Brown IRE, Bone CDM et al (1980): Vitamin D supplements in pregnant Asian women: effects on calcium status and fetal growth. Br. Med. J. 1, 751-4.

Bucher HC, Guyatt GH, Cook RJ et al (1996): Effect of calcium supplementation on pregnancy-induced hypertension and preeclampsia: a meta-analysis of randomized controlled trials. JAMA 275, 1113-7.

Carroli G, Duley L, Belizán JM & Villar J (1994): Calcium supplementation during pregnancy: a systematic review of randomised controlled trials. Br. J. Obstet. Gynaecol. 101, 753-8.

Ceesay SM, Prentice AM, Cole TJ, Foord F. Weaver LT, Poskitt EME & Whitehead RG (1997): Effects on birthweight and perinatal mortality of maternal dietary supplementation in a primary health care setting in rural Gambia. Br. Med. J. (in press).

Chalmers I (1989): Evaluating the effects of care during pregnancy and childbirth. In: Chalmers I, Enkin M, Keirse MJNC (eds). Effective Care in Pregnancy and Childbirth. Oxford University Press: Oxford, pp 3-65.

Cong KJ, Chi SL & Lui ON (1993): Calcium and pregnancy-induced hypertension. Chinese J. Obstet. Gynecol. 28, 657-9.

Dawson EB & McGanity WJ (1987): Protection of maternal iron stores in pregnancy J. Reprod. Med. 32, S. 478-87.

de Onis M, Blössner M & Villar J (1997): Levels and patterns of intrauterine growth retardation in developing countries. Eur. J. Clin. Nutr. 52:S1, 5-15.

Elwood PC, Harley TJL, Hughes SJ, Sweetnam PM, Gray OP & Davies DP (1981): Child growth (0-5 years), and the effect of entitlement to a milk supplement. Arch. Dis. Child 56, 831-5.

Fleming AF, Ghatoura GB, Harrison KA, Briggs ND & Dunn DT (1986): The prevention of anaemia in pregnancy in primigravidae in the guinea savanna of Nigeria. Ann. Trop. Med. Parasitol. 80, 211-33.

Fleming AF, Harrison KA, Briggs ND et al (1984): Anaemia in young primigravidae in the guinea savanna of Nigeria: sickle-cell trait gives partial protection against malaria. Ann. Trop. Med. Parasitol. 78, 395-404.

Fleming AF, Hendrickse JP de V & Allan NC (1968): The prevention of megaloblastic anaemia in pregnancy in Nigeria. J. Obstet. Gynaecol. Br. Cmmwlth. 75, 425-32.

Garner P & Gülmezoglu AM (1996): Routine antimalarial drug chemoprophylaxis during pregnancy in endemic malarious areas. In: Feng C, Garner P, Gelband H. Salinas R (eds). Tropical Diseases Module of The Cochrane Database of Systematic Reviews [updated 06 September 1996]. The Cochrane Collaboration; Issue 3. Update Software: Oxford.

Garner P. Kramer MS & Chalmers I (1992): Might efforts to increase birthweight in undernourished women do more harm than good? Lancet 340, 1021-3.

Giles PF, Harcourt AG & Whiteside MG (1971): The effect of prescribing folic acid during pregnancy on birth-weight and duration of pregnancy. A double-blind trial. Med. J. Aust. 2, 17-21.

Girija A, Geervani P & Rao GN (1984): Influence of dietary supplementation during pregnancy on lactation performance. J. Trop. Pediatr. 30, 79-83.

Goldenberg RL, Tamura T, Neggers Y et al (1995): The effect of zinc supplementation on pregnancy outcome. JAMA 274, 463-8.

Gülmezoglu M, de Onis M & Villar J (1997): Effectiveness of interventions to prevent or treat impaired fetal growth. Obstet. Gynecol. Surv. 52, 139-149.

Hemminki E & Rimpelä, U (1991): A randomized comparison of routine versus selective iron supplementation during pregnancy. J. Am. Coll. Nutr. 10, 3-10.

Hunt IF, Murphy NJ, Cleaver AE et al (1984): Zinc supplementation during pregnancy: effects on selected blood constituents and on progress and outcome of pregnancy in low-income women of Mexican descent. Am. J. Clin. Nutr. 40, 508-21.

Iyengar L (1971): Folic acid requirements of Indian pregnant women. Am. J. Obstet. Gynecol. 111, 13-16.

Iyengar L (1967): Effects of dietary supplements late in pregnancy on the expectant mother and her newborn. Indian J. Med. Res. 55, 85-9.

Jeng GT, Scott JR & Burmeister LF (1995): A comparison of meta-analytic results using literature vs. individual patient data: paternal cell immunisation for recurrent miscarriage. JAMA 274, 830-6.

Jønsson B, Hauge B, Falmer Larsen M & Hald F (1996): Zinc supplementation during pregnancy: a double blind randomised controlled trial. Acta Obstet. Gynecol. Scand. 75, 725-9.

Kafatos AG, Vlachonikolis IG & Codrington CA (1989): Nutrition during pregnancy: the effects of an educational intervention program in Greece. Am. J. Clin. Nutr. 50, 970-9.

Kardjati S, Kusin JA & de With C (1988): Energy supplementation in the last trimester of pregnancy in East Java: I. Effect on birth weight. Br. J. Obstet. Gynaecol. 95, 783-94.

Keirse MJNC, Renfrew MJ, Neilson JP & Crowther CA (eds) (1995): Pregnancy and Childbirth Module of The Cochrane Pregnancy and Childbirth Database [database on disk and CDROM]. The Cochrane Collaboration; Issue 2. Update Software: Oxford.

Kovacs L, Molnar BG, Huhn E & Bodis L (1988): Magnesium substitution in pregnancy. A prospective, randomized double-blind study. Geburts hilfe Frauenheilkd. 48, 595-600.

Kramer MS (1997): Balanced protein/energy supplementation in pregnancy. In: Neilson JP, Crowther CA, Hodnett ED, Hofmeyr GJ, Keirse MJNC (eds). Pregnancy and Childbirth Module of The Cochrane Database of Systematic Reviews. Available in The Cochrane Library [database on disk and CDROM]. The Cochrane Collaboration; Issue 2. Update Software: Oxford. Updated quarterly.

Lechtig A, Habicht JP, Delgado H, Klein RE, Yarbrough C & Martorell R (1975): Effects of food supplementation during pregnancy on birthweight. Pediatrics 56, 508-20.

Low J, Handley-Derry M, Burke S et al (1992): Association of intrauterine fetal growth retardation and reaming deficits at age 9 to 11 years. Am. J. Obstet. Gynecol. 167, 1499-505.

Lumley J (1995): Strategies for reducing smoking in pregnancy. In: Keirse MJNC, Renfrew MJ, Neilson JP, Crowther CA (eds). Pregnancy and Childbirth Module of The Cochrane Pregnancy and Childbirth Database [database on disk and CDROM]. The Cochrane Collaboration; Issue 2. Update Software: Oxford.

Mahomed K, James DK, Golding J &; McCabe R (1989): Zinc supplementation during pregnancy: a double blind randomised controlled trial. Br. Med. J. 299, 826-30.

Mardones-Santander F, Rosso P, Stekel A et al (1988): Effect of a milk-based food supplement on maternal nutritional status and fetal growth in underweight Chilean women. Am. J. Clin. Nutr. 47, 413-9.

Mora JO, de Navarro L, Clement J, Wagner M, de Paredes B & Herrera MG (1978): The effect of nutritional supplementation an calorie and protein intake of pregnant women. Nutr. Rep. Intl. 17, 217-28.

Mora JO, de Paredes B, Wagner M et al (1979): Nutritional supplementation and the outcome of pregnancy. 1. Birth weight. Am. J. Clin. Nutr. 32, 455-62.

Nelson KB & Grether JK (1995): Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight preterm infants? Pediatrics 95, 263-9.

Olsen SF, Sørensen JD, Secher NJ et al (1992): Randomised controlled trial of effect of fish-oil supplementation on pregnancy duration. Lancet 339, 1003-7.

Onwude JL, Hjartardottir H, Tuffnell D, Thornton JG & Lilford RJ (1992): Fish oil in high risk pregnancy: a randomised, double blind, placebo controlled trial. Proceedings of 26th British Congress of Obstetrics and Gynaecology, Manchester, UK, p 4-30.

Onwude JL, Lilford RJ, Hjartardottir H, Staines A & Tuffnell D (1995): A randomised double blind placebo controlled trial of fish oil in high risk pregnancy. Br. J. Obstet. Gynaecol. 102, 95-100.

Øyen N, Skjaerven R, Little R & Wilcot A (1995): Fetal growth retardation in Sudden Infant Death Syndrome (SIDS) babies and their siblings. Am. J. Epidemiol. 142, 84-90.

Parkinson CE, Wallis S & Harvey DR (1981): School achievement and behaviour of children who are small-for-dates at birth. Dev. Med. Child Neurol. 23, 41-50.

Rolschau J, Date J & Kristoffersen K (1979): Folic acid supplement and intrauterine growth. Acta Obstet. Gynecol. Scand. 58, 343-6.

Rush D, Stein Z & Susser M (1980a): A randomized controlled trial of prenatal nutritional supplementation in New York City. Pediatrics 65, 683-97.

Rush D, Stein Z & Susser M (1980b): Diet in pregnancy: a randomized controlled trial of nutritional supplements. Birth Defects 16, 1-187.

Sanchez-Ramos L, Briones DK, Kaunitz AM, DelValle GO, Gaudier FL & Walker CD (1994): Prevention of pregnancy-induced hypertension by calcium supplementation in angiotensin II-sensitive patients. Obstet. Gynecol. 84, 349-53.

Sibai BM, Villar MA & Bray E (1989): Magnesium supplementation during pregnancy: a double-blind randomized controlled clinical trial. Am J. Obstet. Gynecol. 161, 115-9.

Simmer K, Lort-Phillips L, James C & Thompson RPH (1991): A double-blind trial of zinc supplementation in pregnancy. Eur. J. Clin. Nutr. 45, 139-44.

Spatling L & Spatling G (1988): Magnesium supplementation in pregnancy. A double-blind study. Br. J. Obstet. Gynaecol. 95, 120-5.

Steegers EAP, Van Lakwijk HPJM, Jongsma HW et al (1991): (Patho)-physiological implications of chronic dietary sodium restriction during pregnancy; a longitudinal prospective randomized study. Br. J. Obstet. Gynaecol. 98, 980-7.

Tontisirin K, Booranasubkajom U, Hongsumarn A & Thewtong D (1986): Formulation and evaluation of supplementary foods for Thai pregnant women. Am. J. Clin. Nutr. 43, 931-9.

Villar J, Piaggio G, Carroli G & Donner A (1997a): Factors affecting the comparability between meta-analysis and large trials in perinatology. J Clin. Epidemiol. 50, 997-1002.

Villar J & Bergsjø P (1997b): Scientific basis for the content of routine antenatal care. Acta Obstet. Gynecol. Scan 76, 1-14.

Villar J & Carroli G (1996): Methodological issues of randomized controlled trials for the evaluation of reproductive health interventions. Prev. Med. 25, 365-75.

Villar J, Carroli G & Belizán JM (1995): Predictive ability of meta-analyses of randomised controlled trials. Lancet 345, 772-6.

Villar J & Repke JT (1990b): Calcium supplementation during pregnancy may reduce preterm delivery in high-risk populations. Am. J. Obstet. Gynecol. 163, 1124-31.

Villar J, de Onis M, Kestler E, Bolanos F, Cerezo R & Berendes H (1990a): The differential morbidity of the intrauterine growth retardahon syndrome. Am. J. Obstet. Gynecol 163, 151-7.

Villar J & Rivera J (1988): Nutritional supplementation during two consecutive pregnancies and the interim lactation period: Effect on birth weight. Pediatrics 81, 51-7.

Villar J, Repke J, Belizán JM & Pareja G (1987): Calcium supplementation reduces blood pressure during pregnancy: results of a randomized controlled trial. Obstet. Gynecol 70, 317-22.

Villar J, Smeriglio V, Martorell R. Brown CH & Klein RE (1984): Heterogenous growth and mental development of intrauterine growth-retarded infants during the first three years of life. Pediatrics 74, 783-91.

Williams RL, Creasy RK, Cunningham GC, Hawes WE, Norris FD & Tashiro M (1982): Fetal growth and perinatal viability in California. Obstet. Gynecol. 59, 624-32.

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