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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.
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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.
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