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International Perinatal Care Unit, Institute of Child Health, University College London, London WC1N 1EH
3 To whom correspondence should be addressed. E-mail: ipu{at}ich.ucl.ac.uk.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • micronutrients • neonatal mortality • neonatal morbidity • developing countries
There has been a growing realization by international agencies and policy makers in developing countries that the neonatal period warrants special focus. First, perinatal and neonatal mortality represent a sizable problem. More than 9 million deaths occur before or just after birth each year, 98% of them in developing countries (1). About 56 of every 1000 infants die in the perinatal period (from 22 wk gestation to age 7 d) and about 34 of every 1000 liveborn babies suffer neonatal death (from birth to age 1 mo). Neonatal deaths account for two-thirds of deaths in infancy and 40% of deaths before age 5 y. The World Bank estimates that perinatal deaths account for 7.3% of the global burden of disease (1), a figure that exceeds the combined global burden of disease due to malaria and all vaccine-preventable infections.
Second, infants with neonatal problems or malnutrition are less likely to attain their full potential. Low-birth-weight (LBW) 4 infants (<2500 g) seem to perform less well on later educational and intelligence tests than do infants of normal birth weight (2), and there is growing evidence for and interest in the importance of intrauterine health for future cognitive development.
Other benefits too are linked to improved newborn care. When neonatal mortality rates fall, women tend to space their pregnancies, thus contributing to the demographic transition from high to low mortality and fertility. Because postneonatal causes of infant mortality (from 1 mo to 1 y) have been reduced, neonatal—and especially early neonatal—deaths now represent a much larger proportion of the overall infant mortality rate. Further reductions in infant mortality will depend on improving care for newborn infants.
Perinatal and neonatal mortality
Stillbirths and early neonatal deaths may be underreported by as much as 40% (3). The relative invisibility of perinatal death also contributes to an underestimation by policy makers of stillbirths as a public health problem. Only in recent years has the health of newborn infants in developing countries attracted attention from governments and international agencies. There may also be a tradition of seclusion of mothers and newborn infants within the home, which can leave them isolated from care if needed (4).
Despite the difficulties in collecting reliable mortality data in developing countries, more information is available about newborn health status around the world today than was the case even a few years ago. Exercises such as demographic and health surveys give reasonable estimates of neonatal mortality and may allow estimation of stillbirths. The Save the Children estimates provide the best indication of current levels of neonatal mortality (Table 1). However, because of large margins of error they indicate orders of magnitude rather than precise values and they cannot be used to assess trends over time. Neonatal and perinatal mortality are reported as highest in Africa (42/1000 and 76/1000, respectively), with some areas reaching as high as 200. This is >20 times that of Western Europe (1). Although perinatal mortality rates are lower in Asia, the size of the populations in countries such as India, Bangladesh and Pakistan means that 60% of all perinatal deaths occur there.
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Direct causes of stillbirths include hypoxia during labor; asphyxia during delivery; infections such as HIV, malaria, maternal syphilis and chorioamnionitis; and congenital anomalies. A death may result from multiple causes, and assignment of cause of death in the neonatal period is difficult. World Health Organization statistics (1) suggest that infections (pneumonia, neonatal tetanus, sepsis and diarrhea) are responsible for about 42%, complications during pregnancy and delivery (complications of preterm birth, asphyxia, and birth injuries) for about 42% and congenital anomalies 11%. The remaining 5% die from other causes such as jaundice and hemorrhagic disease of the newborn. Bang et al. (5) recently reported a large study of neonatal morbidity in rural India where the neonatal mortality rate was 52 per 1000 livebirths. They found that 48% of neonates had high-risk morbidities, 72% had low-risk morbidities and 18% gained <300 g over the first month. Seventeen percent of infants developed a clinical picture suggestive of sepsis.
LBW is a key indirect cause of neonatal mortality. However, it represents a conflation of two outcomes—preterm birth and small for gestational age (SGA). Around 75% of term LBW infants are born in Asia, particularly south-central Asia, and the global prevalence of SGA is about 16%, or 20 million infants per year (1). Twenty years ago it was noted that the higher prevalence rates of LBW in some developing countries were largely attributable to higher rates of SGA at term (6). Reductions in levels of term SGA should, it was thought, lead to improvements in neonatal outcome. The SGA—itself the presumptive result of intrauterine growth retardation (IUGR)—might be amenable to changes in maternal nutritional status. However, the connection between SGA and IUGR is not clearcut, and absolute weight may not indicate that an infant has experienced IUGR (7). A study of neonatal outcome in LBW infants in Bangladesh also suggested that preterm delivery, although associated with only one-third of LBW cases, was implicated in three-fourths of deaths (8). Finally, the practicalities of increasing birth weight at a population level remain questionable.
Hypothermia is another indirect cause of neonatal death that occurs throughout the world and in all climates. A recent study from a large rural population in Nepal revealed that only 64% of newborn infants had been wrapped within half an hour of birth and that 93% were bathed, often with cold water, within the first hour (9). These behaviors may present a formidable risk to LBW infants.
Can improvements in maternal multiple micronutrient status lead to improvements in perinatal and neonatal mortality?
The present body of work on multiple micronutrient interventions is not sufficient for us to draw conclusions on their effects on neonatal well-being. Because studies have generally concentrated on single micronutrients and a range of outcomes, we summarize the findings for individual nutrients. We limit our discussion to outcomes for the infant, particularly birth weight, preterm delivery and neonatal mortality.
Vitamins. Vitamin A. In animal models, vitamin A deficiency has been associated with reduced fetal survival and reversible squamous metaplasia of the respiratory tract epithelium. An association with gestational duration (10) has not been confirmed (11): serum vitamin A, serum retinol binding protein and fetal liver retinol levels are lower in preterm infants, but this is probably effect rather than cause (12– 15). Serum vitamin A levels probably do not correlate with maternal infection or neonatal Apgar scores (16). The trials of antenatal vitamin A supplementation have been carried out either in developing countries or with selected poor or malnourished women in industrialized countries. A possible effect on preterm birth (17) has not been replicated: the large cluster randomized trial in Nepal showed no effect of vitamin A supplementation on neonatal mortality or mortality in the first 6 mo (18), although subanalysis suggests that there may have been a trend toward an effect (19).
Thiamin. The potential role of thiamin as an antiteratogenic nutrient has been inconclusively explored in animal models. Although thiamin intake has been linked with birth weight on the basis of dietary assessment in the first trimester (20), there has been no observational association of thiamin levels with stillbirth. We know of no observational studies from developing countries and no trials of supplementation.
Riboflavin. Riboflavin intake has been weakly correlated with gestational duration on the basis of dietary assessment in the first trimester (20). We know of no observational studies from developing countries and no trials of supplementation.
Vitamin B-6 (pyridoxine). Pyridoxine appears to play an important role in the development of the central nervous system. Gestational pyridoxine deficiency in the rat has been associated with impaired physical and neuromotor development and neurological symptoms (21). A possible association of pyridoxine deficiency with lower Apgar scores was reported several times (22– 24). A Cochrane review of trials of intrapartum supplementation for effects on neonatal outcome includes no relevant studies (23).
Vitamin B-12 (cobalamin). The megaloblastic anemia of cobalamin deficiency highlights its association with defects in DNA synthesis, cell multiplication and metabolism. Low serum cobalamin levels have been associated with preterm birth (26). Severe gestational deficiency may also be associated with intrauterine death (27). We know of no trials of supplementation with respect to neonatal outcome.
Folic acid. The key role of folate in DNA synthesis means that deficiency is associated with dysfunction in rapidly dividing cells. The relationship between periconceptional folate deficiency and neural tube defects is now well established as is the benefit of supplementation. Observational studies have suggested that lower maternal serum folate levels are associated with preterm birth (28). A large U.S. study suggests an association between higher maternal serum folate at 30 wk gestation and higher Apgar scores (16). There is some evidence that supplementation prolongs gestation (29). A Cochrane review (25) of trials in nonanemic women found no association between folate supplementation and stillbirth or preterm delivery. We know of no previous trials that look at neonatal mortality but await the publication of one from southern Nepal.
Vitamin C (ascorbic acid). The involvement of ascorbate in collagen stabilization and protection from reactive oxygen species supports a role for it in maintaining membranes: lower plasma and leukocyte ascorbate have been associated with premature rupture of membranes (30), and serum ascorbate concentrations have been weakly positively associated with gestational duration (20). We know of no trials that have looked at neonatal outcome.
Vitamin D (cholecalciferol). Routine supplementation has not been an issue: the focus has generally been on populations at risk of neonatal hypocalcemia. We know of no trials that have looked at general neonatal outcome.
Vitamin E (tocopherol). The antioxidant properties of tocopherol may protect membranes from damage by reactive oxygen species. Tocopherol deficiency has also been associated with malformation and fetal death (31). Studies have found no association between maternal plasma or serum tocopherol and gestational duration (10) or Apgar scores (16), and we know of no trials that have looked at neonatal outcome.
Minerals. Zinc. Because zinc interacts with >300 enzymes and proteins, the effects of deficiency are wide ranging. Zinc deficiency in animal models has been associated with fetal wastage, stillbirth, delivery complications and neonatal death (32– 34). This relates at least to some degree to the deleterious effects of deficiency on DNA synthesis, skeletal abnormalities and growth and central nervous system malformations (35– 37). However, much of this work was done in the presence of severe zinc deficiency. In a situation of marginal deficiency, no effects were seen on pregnancy outcome or fetal malformation, although there may be an association with preterm rupture of membranes (38, 39). The knowledge that maternal acrodermatitis enteropathica (an inborn defect of zinc absorption associated with severe hypozincemia) leads to a reversible propensity for fetal malformation led to wider concern about the possibility of zinc deficiency in the general population (40). Indeed, lower zinc intakes have been associated with preterm delivery (41). The observational studies on zinc in pregnancy are, however, confusing. A central issue is the interpretation of plasma or serum zinc levels during pregnancy. It was suggested early on that gestational plasma or serum zinc concentrations are not always useful indicators of zinc status (42– 44). Maternal plasma zinc levels decline during gestation to a plateau in the third trimester (45) and may be difficult to interpret unless sampling time, laboratory methods and the underlying zinc status of the population are accounted for.
Some studies found lower maternal plasma zinc to be a risk factor for congenital malformations (46– 52); another did not (53). One study found lower maternal plasma zinc to be a risk factor for preterm delivery (54); others did not (55, 56). Maternal leucocyte zinc has been put forward as a better indicator of status, and some studies found a positive association with intrauterine growth (44, 57, 58); other studies did not (56, 59).
Some supplementation trials have shown that supplementation reduces the incidence of preterm delivery (60– 62), increases gestation duration (60, 61, 63– 66) and improves Apgar scores (61). Again, however, other studies demonstrate no effect on preterm delivery (63, 64, 67– 70), gestational duration (70) or Apgar scores (68, 71). Beneficial effects may only be seen in poorer populations (72), a suggestion supported by a Cochrane review of 5 trials (73). Although the results of three trials have since been published (66, 69, 70), disaggregation on the basis of developing or industrialized or poor or affluent populations has not clarified the issue. Gestational zinc supplementation could have longer-term effects on mortality because of benefits to immunocompetence. In the short term, however, two supplementation studies in poor U.S. populations found no effect on perinatal deaths (71), stillbirths, neonatal deaths or admission for special care (60). Of more concern, a recent study in Bangladesh randomly allocated 559 pregnant women to zinc (30 mg daily) or placebo (cellulose) from 4 mo gestation to delivery. At follow-up infants in the placebo group had higher scores on mental and psychomotor development indices than did those in the zinc-supplemented group (74).
Iron. That gestational iron supplementation improves hematological indices is not in question (75). The U-shaped relation of gestational anemia with fetal outcome makes assumptions about benefits questionable, however, and the ethics of placebo-controlled trials in a situation where supplementation is routinely recommended cloud the subject further. A recent trial of supplementation showed reductions in both fetal loss and neonatal mortality (76), but a Cochrane review of routine iron supplementation in pregnancy did not draw conclusions about either beneficial or harmful effects to mother or infant (77).
Copper. Copper deficiency affects many cuproenzymes, leading to defects in ATP production; lipid peroxidation; hormone activation; angiogenesis; and abnormalities of vasculature, skeleton and lung (78). Although maternal serum copper level rises over pregnancy (79), its validity as an index of copper status is questionable (80). One study found an association of low maternal plasma copper with preterm rupture of membranes (81). Cord serum copper has been negatively associated with preterm delivery (82). We know of no supplementation trials.
Iodine. Iodine-dependent thyroid hormones increase cell proliferation, synapse formation and microtubular assembly. The beneficial effect of iodine supplementation on endemic cretinism and goiter has been well established, and deficiency disorders are now understood to manifest across a spectrum that includes the subclinical. A trial in Zaire suggested improvements in infant mortality as well (83); this is supported by a study of lower quality from Algeria (84).
Magnesium. Lower serum magnesium levels have been questionably associated with preterm labor (85). Some magnesium supplementation studies have shown benefits to rates of preterm birth (86– 88); others have not (89– 91). Supplementation seems to have no effect on Apgar scores (89) or admission for special care (89, 91). A Cochrane review of six controlled trials (heavily weighted by two studies) concludes that supplementation starting before the third trimester results in a lower incidence of preterm birth. No significant effect was found on fetal or neonatal mortality (92).
Selenium. Selenium participates in antioxidant cellular protection and energy metabolism. Frank deficiency is associated with a juvenile cardiomyopathy and a chondrodystrophy. Plasma selenium has been found to be higher in preterm than term infants (84). There is a putative association of deficiency with neonatal respiratory morbidity (93). Little evidence exists for direct effects of deficiency on the fetus other than in conjunction with iodine deficiency (94), and we know of no supplementation trials.
Multiple micronutrients. It is tempting to aggregate the possible beneficial effects of individual micronutrients described above and to add the findings of dietary intake studies that suggest a relationship between the intake of a range of micronutrients and rates of LBW. However, to generalize from observational studies is unwise. The results of two multiple micronutrient supplementation trials have been published. A double-blind randomized controlled trial in Hungary involving 4753 women and three supplemental combinations of vitamins and minerals suggested improvements in stillbirth rates (95). A double-blind, factorial randomized controlled trial in Tanzania suggested improvements in fetal death rates (without concomitant changes in gestational duration) (96). The study involved only women with HIV infection.
What is the role of micronutrients in neonatal morbidity?
The evidence for the contribution of micronutrient deficiencies to perinatal mortality and duration of gestation is limited. For the important question of whether micronutrient deficiencies also increase the risk of common neonatal morbidities, there is hardly any evidence. We have already noted the probable, although unproven, value of micronutrients such as magnesium, zinc and folate in prevention of preterm birth and thereby the neonatal problems of prematurity and also the value of maternal cholecalciferol supplements in reducing neonatal hypocalcemia in vulnerable populations. What is the role of micronutrient deficiencies in increasing or exacerbating the major clinical problems facing neonatal health professionals in a developing country? The most important are asphyxia leading to neonatal encephalopathy, hypothermia, sepsis and metabolic problems such as hypoglycemia and hyperbilirubinemia. For many reasons these conditions have hardly been studied in developing countries. Most deliveries take place at home; definitions of morbidity states are controversial; morbidity patterns show a complex temporal relationship in the hours and days after birth; and diagnostic methods are often unavailable, expensive or insensitive. In addition, follow-up studies to look at neurodevelopmental sequelae and cognitive outcomes in infants are difficult to manage and suffer from high dropout rates.
Asphyxia leading to neonatal encephalopathy. Ellis et al. (97) reported the largest study of the epidemiology of neonatal encephalopathy and fresh stillbirths in a developing country setting in Kathmandu, Nepal. When analyzing risk factors, they observed an association between neonatal encephalopathy and a maternal blood hemoglobin value of <8 g/dL (odds ratio [OR] 2.6; 95% confidence intervals [CI]: 1.0–7.0), and also an increased risk among mothers whose thyroid stimulating hormone was raised (OR 2.1; 95% CI: 1.1–3.8), suggesting a possible link with subclinical iodine deficiency. The California Cerebral Palsy project also observed that magnesium sulfate, used for the treatment of preeclamptic toxemia and to arrest premature labor, appeared to protect against cerebral palsy in very LBW infants (OR 0.08; 95% CI: 0.02–0.67) (98), but other groups have failed to confirm these findings. One might speculate that magnesium deficiency could predispose to neonatal encephalopathy, leading to increased cerebral palsy rates in neonatal survivors, but randomized controlled trials will be needed to test this hypothesis. No prospective trial of magnesium supplements in pregnancy has yet been reported.
Hypothermia. In many poor communities there is little doubt that care practices with regard to drying, wrapping and bathing infants in the first hours after birth make neonatal hypothermia a common phenomenon (5). Infants transferred to hospital are also more likely to be hypothermic on arrival. Continuous ambulatory monitoring of LBW term infants born in the winter months and routinely managed on a postnatal ward in Kathmandu showed that all infants studied were hypothermic in the first 12 h and showed significantly increased cold stress (an increased peripheral-core temperature difference) throughout the first 24 h after birth (99).
Breast-feeding undoubtedly lowers the risk of hypothermia and cold stress through maternal contact, but whether micronutrient deficiencies alter the metabolic response to hypothermia or cold stress has not been studied. The key to the survival of animals under conditions of hypoxia and hypothermia lies in an inherent ability to down-regulate their cellular metabolic rate to new hypometabolic steady states in a way that balances the ATP demand and supply pathways (100). Micronutrient status may well affect these metabolic processes.
Neonatal sepsis. Numerous studies have explored the link between micronutrient deficiency and the risk of infection in children and adults (101). Full-term newborn infants possess most elements of a mature immune system, and additional protection comes through passive immunity from transplacental transfer of antibodies and, if breast-fed, from ingestion of immunoglobulin-rich colostrum. Infants also receive micronutrients in utero. Nonetheless, newborn infants are immunocompromised: they have yet to build up their own active immunological memory, both cellular and humoral, processes that could plausibly be affected by micronutrient imbalance. Serious neonatal infection is typically caused by a wide range of organisms as in other immunocompromised states. This makes diagnosis difficult even in centers of excellence with access to the latest molecular diagnostic methods, so that studies to elucidate associations between infection vulnerability and micronutrient status are problematic.
In South Africa, a randomized, double-blind, placebo-controlled trial to investigate the effect of vitamin A supplementation on the incidence and severity of respiratory infections in LBW infants during their first year of life showed no evidence of improvement in neonatal or postneonatal respiratory problems (102). Neonatal vitamin A supplementation may play a role in lowering morbidity rates associated with pneumococcal disease by delaying the age at which colonization occurs. In South India, infants were randomly assigned to receive two 7000-µg retinol equivalent doses of vitamin A or placebo orally at birth, and nasopharyngeal specimens were collected at ages 2, 4 and 6 mo (103). The odds of colonization were 27% lower in the treatment group than in the placebo group. A clinical trial of vitamin C in newborn sepsis has shown that significant improvement in chemotaxis and random migration of neutrophils may justify the inclusion of vitamin C as an adjunct to the therapy of neonatal sepsis (104).
It does seem likely that micronutrients such as zinc, iron, copper and vitamins A and C, shown to play a key role in immune mechanisms in children and adults, will in newborns also affect epithelial integrity, acute phase protein responses or cytokine messaging to build an appropriate cellular response to an invasive organism. Ongoing trials of multiple micronutrient supplementation for pregnant women in poor communities should throw light on these infectious and immune processes.
Neonatal hypoglycemia and hyperbilirubinemia. Metabolic adaptation in the immediate postnatal period is accompanied by an increased risk of hypoglycemia. A study in Nepal found that neonatal hypoglycemia was common in apparently healthy infants, especially among those who were LBW, had a low ponderal index or a high ratio of head circumference to birth weight (105). Forty-one percent of newborn infants experienced mild (blood glucose <2.6 mmol/L) and 11% moderate hypoglycemia (<2.0 mmol/L). New risk factors identified were raised maternal thyroid stimulating hormone and maternal anemia, suggesting a possible link to micronutrient deficiencies. Alternative fuels are important in the metabolic assessment of neonates, and they might provide effective cerebral metabolism even during moderate hypoglycemia. In Nepal, hypoglycemic infants were found to have lower levels of alternative fuels through either reduced availability or increased consumption (106). SGA and postterm infants increased counterregulatory ketogenesis with early neonatal hypoglycemia, but hypothermia, male gender and low infant thyroxine were associated with impaired counterregulation after birth. Again, micronutrient deficiencies might plausibly affect these processes.
Benign hyperbilirubinemia occurs in most newborn infants in their first week but may in some babies reach levels that predispose to the risk of neurodevelopmental sequelae such as kernicterus. Micronutrient or mineral levels might affect the role of bilirubin binding proteins or the process of bilirubin excretion. One study in Israel found no association between cord zinc, copper and iron levels and the risk of benign hyperbilirubinemia (107), but no such studies have been reported from deficient populations in Africa or south Asia.
Translating knowledge into community effectiveness trials and policy action
Effective nutrition interventions must demonstrate effect in poor, rural communities. Interventions require an evidence base for efficacy but also for affordability, acceptability and scalability through existing national organizations. The large number of research efficacy trials on micronutrients has resulted in almost no policy changes in developing countries, perhaps because community effectiveness issues have been insufficiently addressed. At present only iron and folic acid supplementation are routinely recommended in pregnancy. In Nepal, our recent survey of a large rural population showed that only 20% of mothers were given any antenatal supplements and only 4% of women received a full 3-mo supply. Once tablets are received, compliance is often poor.
Demand versus supply issues. Supply of effective micronutrient supplements is only part of the challenge; demand factors are of equal importance. Perinatal events have spiritual meaning and interpretation in all cultures, and traditional beliefs about causation (or "ethnophysiology") may be at odds with biomedical theory. For example, "eating down," whereby mothers either restrict food intake or maintain it at prepregnancy levels, is reported widely in south Asia. One interpretation is that mothers are thereby avoiding the potentially prolonged labor associated with larger infants; an alternative explanation is that mothers believe consumed food occupies the "baby growing space" and that dietary restriction will allow their baby to grow more effectively. The common assignation of foods to "hot" and "cold" categories and the need to balance them lead to an emphasis on cold foods during pregnancy, which is itself a hot state.
Decisions about dietary preferences and use of antenatal services also depend on the status and role of women. In societies where marriage is universal, occurs young and is often arranged, decisions about pregnancy are usually made by the mother-in-law or husband. A key policy question is how to change decision making and behavior in relation to nutrition in pregnancy in these settings. Conventional health and nutrition education approaches are probably much less effective than is widely appreciated (108). Participatory approaches working with mothers or women's groups anecdotally seem more appropriate but have not been evaluated with randomized controlled trials (109).
Dietary interventions or micronutrient bullets? The efficacy of giving food to malnourished pregnant mothers is not in doubt, but the lack of success and scalability of pregnancy food supplementation programs since the 1960s led policy makers to seek more immediate benefits from micronutrient supplementation strategies. The Gambia trial (110), however, reopens the debate because the effect of a daily energy biscuit taken in pregnancy on perinatal mortality was substantial. There is a strong argument for reexamining the effect and sustainability of nutrition education interventions to improve dietary intake before and during pregnancy using randomized controlled community effectiveness trials. Such trials attempt to balance the competing aims of efficacy and sustainability so as to produce a worthwhile effect in a large population, ideally through public sector provision, and as inexpensively as possible.
Priority issues for research
Policy is primarily influenced, if at all, by large-scale randomized, controlled trials that demonstrate convincing health benefits. One strategic issue is whether researchers and funding groups should set up much larger, simpler trials (involving tens of thousands of pregnant women) with relatively clear and simple outcomes. Perinatal mortality is not particularly easy to measure in communities where there is no birth registration, but community-based monitoring systems can be set up at relatively low cost and perinatal mortality rates provide the most convincing outcome indicator for a micronutrient or nutrition intervention in a large scale trial.
We suggest five areas for research that seem to have high relevance for nutrition policy:
Conclusion
The evidence base for individual micronutrient effects on neonatal mortality and morbidity is patchy and often contradictory and confusing. There is a pressing need for randomized controlled trials of multiple micronutrient supplementation in pregnant mothers who have suboptimal nutrition, in which outcomes for mothers and their infants, both short and long term, are monitored closely. Balanced micronutrient supplementation in pregnancy is potentially a highly cost-effective intervention that could be scaled up rapidly even in the poorest communities. Good clinical science demands, however, that the effects of such an intervention be thoroughly and rigorously evaluated before large-scale programs are established.
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FOOTNOTES |
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2 Anthony Costello receives financial support for his research from The UK Department for International Development, The Wellcome Trust, the World Health Organisation, and UNICEF. David Osrin receives financial support from a project grant of The Wellcome Trust.
4 Abbreviations used: IUGR, intrauterine growth retardation; LBW, low birth weight; SGA, small for gestational age.
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LITERATURE CITED |
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