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* Institute of Human Nutrition, University of Southampton, UK, The Aga Khan University, Department of Paediatrics, Karachi, Pakistan and ** Department of Obstetrics and Gynecology, Khon Kaen University, Thailand
2 To whom correspondence should be addressed. E-mail: A.A.Jackson{at}soton.ac.uk.
Across the world there is a high prevalence of adverse outcomes to pregnancy, which can be life threatening for both the mother and her baby. For the mother, poor nutritional status, infection, stresses at home and at work all contribute, separately or together, to increasing her risk of ill health and limiting her ability to provide an adequate supply of nutrients to the developing fetus. Suboptimal fetal growth is associated with higher fetal mortality, as well as neonatal and infant morbidity and mortality. Infants who are born small have greater risk of poor physical and neurocognitive development and greater risk of ill health during later life. These outcomes represent the final common pathway of a complex mix of biological and social interactions. Effective interventions to prevent or manage adverse pregnancy outcomes requires a clear understanding of both the underlying processes and their interactions, which are the fundamental causes of the problems, or act as important modulators of the process. This understanding is required to determine the extent to which effective interventions might be generic, or require approaches for which the contextual relations play a major part.
A workshop was convened to consider these problems July 18–19, 2002, under the sponsorship of the United States Agency for International Development and the Wellcome Trust, at Merton College Oxford. The objective of the workshop was to review our understanding of the role of nutrition in the promotion of reproductive health and pregnancy outcomes, with a specific focus on the role micronutrients might play. Any successful pregnancy requires the net deposition of tissue within the mother, the placenta and the fetus; thus there is a fundamental relationship between the nutritional status of the mother and her ability to transfer nutrients to the fetus at the appropriate time during pregnancy. However, the mother's ability to achieve effective and timely transfer may be constrained by factors other than her immediate dietary intake or overall nutritional status. The mother may have her own demands for nutrients that compete with the needs of the fetus. In a younger woman the needs to complete her own growth and development have to be satisfied. Stresses of life impose their own nutritional demands. The stresses may be biological in origin due to infection of inflammatory challenges, but may equally well be the result of a high workload, psychological or social stresses. It is well recognized that different stresses can alter the handling of nutrients within the body and their availability to the tissues. What is less clear is the extent to which different environmental exposures may operate upon the individual through a limited range of final common pathways.
If we are to be successful in identifying and introducing interventions that will improve reproductive health we need to understand the extent to which the individual factors interact. How does the mother's dietary intake and her ability to cope or interact with infection and other stresses change her reproductive competence? In experimental models, which explore the effects of nutrients upon reproductive health, it is not unusual for conclusions to be drawn from extreme dietary manipulations that are seldom found amongst human populations. It is less clear the extent to which modest changes in dietary exposure limit function and lead to significant risk of adverse pregnancy outcome.
The central task of the workshop was to review the evidence relating micronutrient status to adverse pregnancy outcomes. The workshop was organized by a Scientific Committee in six sessions to address the question: "If nutritional considerations were included as an explicit and integral part of health delivery, to what extent would it be possible to reduce adverse pregnancy outcomes?" Individual sessions were devoted to consideration of "Infection and Inflammation" (A. Tomkins and R. Goldenberg), "Metabolic Problems" (J. King and C. Keen), "Lifestyle Factors" (R. Goldenberg and J. King), and "Fetal and Infant Growth and Outcomes" (C. Keen and A. Jackson). The meeting began with three overviews of maternal nutrition and adverse pregnancy outcomes. Kramer (1) presented the epidemiology, Keen et al. (2) the plausibility of micronutrient deficiencies playing a significant role in adverse pregnancy outcomes and Villar et al. (3, 4) the evidence from randomized controlled trials that nutritional interventions can prevent adverse outcomes. These were followed by a presentation from Rouse (5) on the economics of nutrition interventions to prevent adverse pregnancy outcomes The discussion during the final session used the evidence presented during the workshop to identify the important outstanding issues that need to be addressed for nutrition to have a significant impact upon reproductive health. Individual members of the Scientific Committee accepted responsibility for the organization of each different session and prior to the workshop participants were asked to prepare a review of the state of understanding in their area of special interest. These documents were circulated and discussed prior to the workshop, and were available as background documents for more detailed discussion during the workshop itself. The participants represented a wide range of experience, and the workshop sought to promote in depth discussion across disciplinary boundaries. This supplement contains the background papers prepared for the workshop. It is clear that the pattern of adverse influences may vary between populations in the developed and developing world, but for all locations micronutrient status appears as a fundamental consideration, which can modulate the response to other adverse environmental exposures.
Much maternal morbidity can be directly related to infection, which in turn might be either caused by or lead to micronutrient deficiencies. However, difficulties in characterizing micronutrient status are compounded by changes in plasma levels of micronutrients that take place as a normal part of an inflammatory response, but with newer approaches to assessing overall nutrition and inflammatory status it seems possible that these problems can be overcome (6, 7). There is now strong evidence that maternal infection, especially ascending infection, plays a significantly greater role in maternal, fetal and newborn morbidity than has been acknowledged (8, 9). It is less clear the extent to which improved micronutrient status would lead to greater resistance to infection or improved response to treatment (10). Important outstanding questions include the extent to which effective treatment of infection adequately leads to improved micronutrient status, the extent to which improving micronutrient status is a prerequisite for maintaining resistance to infection, or whether problems with infection and micronutrient status would need to be addressed simultaneously.
Weight changes in the mother and growth in length and weight of the fetus represent a positive energy balance and net accumulation of macronutrients. Metabolic problems during pregnancy may well be reflected in, or a consequence of, perturbations in macronutrient homeostasis (11, 12). However, the processes through which the relative partitioning of macronutrients within the mother, and between the mother and the fetus, are influenced directly by micronutrient status is not sufficiently clear. The extent to which dietary interventions can be used to directly influence the mother's ability to supply the fetus are exemplified by the complex metabolic interactions that take place between a woman and her environment in the metabolism of calcium and vitamin D during pregnancy and lactation (13). The most widely used nutritional intervention during pregnancy is supplementation with iron and folic acid, and even here there is much to be learnt about how to ensure that programs are effective in improving pregnancy outcomes without undue adverse effects (14).
The support provided by different societies to women during pregnancy varies widely. Plausible mechanisms through which a range of stresses, including psychological stress, might influence micronutrient status or in turn be influenced by the micronutrient status of the mother exist (15). Stresses, which at first sight appear widely diverse, social stress and substance abuse might operate through similar mechanisms and metabolic processes that are sensitive to modulation by micronutrient status (16). The size of a mother, her ability to achieve adequate energy balance in a life situation that demands strenuous physical work and her ability to replete nutrient reserves during successive pregnancies, which may be closely spaced, contribute to the outcome of a pregnancy (17– 19). All of these factors impact upon the mother's health and capability to deliver nutrients to the fetus, but as stressors might, directly or indirectly, interact with the micronutrient status of the mother and/or the fetus.
The evidence is now clear that suboptimal fetal growth is associated with higher fetal mortality, neonatal morbidity and mortality. Small size at birth is associated with greater susceptibility to infection and both altered postnatal growth and neurocognitive development. Nutrition, acting either directly, or through specific endocrine mechanisms is a major determinant of the pace and balance of fetal growth (20), with effects that have adverse consequence later in infancy and childhood. Modest changes to maternal diet, from very early in pregnancy, or even in the preconceptual period, can have marked effect on the ability of the fetus and newborn to withstand other infective or physical environmental stresses (21, 22).
There was a growing consensus among participants, representing diverse disciplinary groups, that suitable nutrition-based interventions can substantially improve the health of mothers and their infants, but on the basis of current knowledge of the biological processes the issue of when and how to intervene remains an empirical question. The consensus at the workshop was that although a desire to intervene to improve pregnancy outcomes exists, significant gaps in our understanding make it difficult to be sure which intervention(s) would be effective. Filling these knowledge gaps will require both basic and applied research, before such interventions can be recommended for large scale programs in developing countries. What is increasingly clear is that interventions during or late in pregnancy are less likely to exert the significant effect required. Effective interventions are likely to be required at a much earlier stage than previously considered, certainly before mid-pregnancy, and for some interventions probably during the preconceptual period. This awareness presents significant challenges both to basic science and the application of that understanding to populations. The biological, clinical and public health questions that need to be answered have similarities across all communities and are relevant to a wide range of disciplines. The workshop concluded that the fundamental nature of the questions being posed, and the wide relevance of the application of the understanding to be obtained, justifies a major collaborative program of research that would integrate understanding across a wide range of disciplinary groups.
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FOOTNOTES |
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LITERATURE CITED |
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 TOP LITERATURE CITED |
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1. Kramer, M. S. (2003) The epidemiology of adverse pregnancy outcomes: an overview. J. Nutr. 133: 1592S–1596S.
2. Keen, C. L., Clegg, M. S., Hanna, L. A., Lanoue, L. Rogers, J. M., Daston, G. P., Oteiza, P. & Uriu-Adams, J. Y. (2003) The plausibility of micronutrient deficiencies being a significant contributing factor to the occurrence of pregnancy complications. J. Nutr. 133: 1597S–1605S.
3. Villar, J., Merialdi, M., Gülmezoglu, A. M., Abalos, E., Carroli, G., Kulier, R, & de Onis M. (2003) Nutritional interventions during pregnancy for the prevention and treatment of maternal morbidity and preterm delivery: an overview of randomized controlled trials. J. Nutr. 133: 1606S–1625S.
4. Villar, J., Merialdi, M., Gülmezoglu, A. M., Abalos, E., Carroli, G., Kulier, R, & de Onis M. (2003) Characteristics of randomized controlled trials included in systematic reviews of nutritional interventions reporting maternal morbidity, mortality, preterm delivery, intra-uterine growth restriction & small for gestational age and birth weight outcomes. J. Nutr. 133: 1632S–1639S.
5. Rouse, D. J. (2003) Potential cost-effectiveness of nutritional interventions to prevent adverse pregnancy outcomes in the developing world. J. Nutr. 133: 1640S–1644S.
6. Goldenberg, R. L. (2003) The plausibility of micronutrient deficiency in relationship to perinatal infection. J. Nutr. 133: 1645S–1648S.
7. Tomkins, A. (2003) Assessing micronutrient status in the presence of inflammation. J. Nutr. 133: 1649S–1656S.
8. Bergström, S. (2003) Infection-related morbidities in the mother, fetus and neonate. J. Nutr. 133: 1656S–1660S.
9. Romero, R., Chaiworapongsa, T. & Espinoza, J. (2003) Intrauterine infection, premature birth and the fetal inflammatory response syndrome. J. Nutr. 133: 1668S–1673S.
10. Steketee, R. W. (2003) Pregnancy, nutrition and parasitic diseases. J. Nutr. 133: 1661S–1667S.
11. Catalano, P. M., Kirwan, J. P., Haugel-de Mouzon, S. & King J. (2003) Gestational diabetes and insulin resistance: its role in the short and long-term implications for mother and fetus. J. Nutr. 133: 1674S–1683S.
12. Roberts, J. M., Balk, J., Bodnar, L. M. Belizán, J. M., Bergel, E. & Martinez, A. (2003) Nutrient involvement in preeclampsia. J. Nutr. 133: 1684S–1692S.
13. Prentice, A. (2003) Micronutrients and the bone mineral content of the mother, fetus and newborn. J. Nutr. 133: 1693S–1699S.
14. Casanueva, E. & Viteri, F. (2003) Iron and oxidative stress in pregnancy. J. Nutr. 133: 1700S–1708S.
15. Hobel, C & Culhane J. (2003) Role of psychosocial and nutritional stress on poor pregnancy outcome. J. Nutr. 133: 1709S–1717S.
16. Cogswell, M. E., Weisberg P. & Spong, C. (2003) Cigarette smoking, alcohol use, and adverse pregnancy outcomes—implications for micronutrient supplementation? J. Nutr. 133: 1722S–1731S.
17. Shaw, G. M. (2003) Strenuous work, nutrition, and adverse pregnancy outcomes: a brief review. J. Nutr. 133: 1718S–1721S.
18. King, J. C. (2003) The risk of maternal nutritional depletion and poor outcomes increases in early or closely spaced pregnancies. J. Nutr. 133: 1732S–1736S.
19. Neggers, Y. & Goldenberg, R. L. (2003) Some thoughts on body mass index, micronutrient intakes and pregnancy outcome. J. Nutr. 133: 1737S–1740S.
20. Gluckman, P. J. & Pinal, C. S. (2003) The regulation of fetal growth by the somatotrophic axis. J. Nutr. 133: 1741S–1746S.
21. Fall, C. H. D., Yajnik, C. S., Rao, S., Davies A. A., Brown, N & Farrant, J. J. W. (2003) Micronutrients and fetal growth. J. Nutr. 133: 1747S–1756S.
22. de L Costello, A. M. & Osrin, D. (2003) Micronutrient status during pregnancy and outcomes for newborn infants in developing countries. J. Nutr. 133: 1757S–1764S.
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