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Definitions and classifications
Causes and mechanisms
Prevention
Working Group members: LS Bakketeig¹, N Butte², M de Onis³, M Kramer4, A O'Donnell5, JA Prada6, and HJ Hoffman7
¹National Institute of Public
Health, Department of Population Health Sciences, P.O. Box 4404 Torshov, N-0403 Oslo,
Norway;
2Children's Nutrition Research Center,
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA;
³Nutrition Unit, World Health Organization, 20
Avenue Appia, 1211 Geneva 27, Switzerland;
4Departments of Pediatrics and of
Epidemiology and Biostatistics, McGill University, Faculty of Medicine, Montreal, Quebec,
Canada;
5Centro de Estudios sobre Nutricion
Infantil, Buenos Aires, Argentina;
6Children's Hospital Medical Center,
P.O. Box 670541, Cincinnati, Ohio 45267-0541, USA;
7Epidemiology, Statistics, and Data
System Branch, National Institute on Deafness and other Communication Disorders, National
Institute of Health. Bethesda, MD 20892-7180. USA
Current available estimates confirm that intrauterine growth retardation (IUGR) is a major public health problem world-wide. The prevalence of IUGR in most developing countries is above the international cut-off point for triggering public health action, and population-wide strategies are therefore urgently needed. Being born small for gestational age (SGA), which is usually defined as having a birth weight below the 10th centile of an accepted reference, is often used as a proxy for IUGR. SGA and IUGR are not synonymous, however. Some SGA infants may merely represent the lower tail of the 'normal' fetal growth distribution, while other infants who have been affected in utero by an inadequate nutritional milieu or other growth-inhibiting influences may nevertheless have a birth weight that is 'appropriate' for gestational age (AGA).
Variations in fetal growth over the entire distribution of birth weight may have both etiologic and prognostic importance. In individual cases, however, it is usually very difficult to determine whether an observed birth weight that is low for gestational age is the result of true in utero growth restriction or represents a 'normally small' infant. Classification of IUGR is therefore based on the established cut-off for SGA. The higher the prevalence of low birth weight (LBW) in a given population, the greater the likelihood that the majority are a result of IUGR.
Because classification of LBW as due to preterm birth or IUGR requires valid estimates of gestational age (GA), attention is required to improving the availability and quality of GA estimates on a population-wide basis in developing countries. This includes, where feasible, recording early in pregnancy the mother's recall of the date her last normal menstrual period began and the training of birth attendants (traditional birth attendants, midwives, nurses, and physicians) in the physical assessment of the newborn (Dubowitz, Ballard, or Capurro scores). In developed countries, early (< 20 weeks) ultrasound examination has improved the validity and reliability of GA assessment, although evidence from randomized trials does not demonstrate improvement in maternal or fetal/infant outcomes with routine early ultrasound.
An international fetal growth reference curve should be developed based on pooled data from countries in different geographic regions where fetal growth is believed optimal. Care should be taken to ensure that such a reference fits with the new infant growth reference currently being developed under WHO auspices. Further research is needed to identify those determinants of fetal growth that influence mortality, morbidity, and performance independently of their effects on growth. Although it is quite clear that the use of sex-specific reference curves is justifiable, additional research is needed using large populations and ultrasound confirmation of GA to assess whether infants of different races born at a particular weight for gestational age are at substantially different risks for important health outcomes. Similar research is needed to determine whether infants who are born small because their mothers are primiparous or of short stature or living at high altitude are at the same risk for adverse sequelae as those of equivalent size who are small because, for example, their mothers have pre-eclampsia or smoke cigarettes. Until this information is available, the use of a single, sex-specific international reference has much to recommend it.
Application of the international fetal growth reference curve will vary according to its specific clinical and public health uses or purposes. Criteria for diagnosis of fetal growth restriction (e.g., SGA) should be related to evidence of increased risk for perinatal mortality and/or other indices of adverse outcomes. The new reference should provide percentiles [(e.g., 3rd, 5th, 10th, 15th, 25th, 50th (median), 75th, 85th, 90th, 95th, and 97th)] as well as z-scores [(e.g., -3, -2, -1, 0 (mean), 1, 2, and 3 SD)], so that health planners and practitioners can use the most appropriate cutoff based on local circumstances.
Proportionality at birth may be
related to adverse outcomes. Thus there is a need to develop reference data for birth
length and head circumference in relation to GA, and for birth weight in relation to birth
length. Because the concepts of 'wasting' and 'stunting' have proven useful for
categorizing undernourished infants and older children, an attempt should be made to
quantify the mortality and morbidity risks associated with 'wasted' and 'stunted' newborns
and to develop indicators for their classification.
The etiologic determinants of IUGR must be considered with respect to two measures of effect: the relative risk (the ratio of the risk of IUGR in women exposed to the determinant to the risk in those who are unexposed) and the etiologic fraction (the proportion of IUGR in a given population that is attributable to the determinant). From a clinical perspective, relative risk is the more important measure, because it allows an estimate of an individual woman's risk of delivering a growth-retarded infant. But from a public health perspective, the etiologic fraction is the effect measure of major interest and, because it depends on the prevalence of the determinant in the population, it will differ substantially from one population to another. Thus, the importance of a given determinant will vary between developed and developing countries and between the rich and the poor within countries.
Most of the evidence on etiologic determinants is based on observational studies and systematic overviews or meta-analyses of such studies. In developing countries, the major determinants of IUGR are nutritional: low gestational weight gain (primarily due to inadequate energy intake), low pre-pregnancy BMI (reflecting chronic maternal undernutrition), and short maternal stature (principally due to undernutrition and infection during childhood). Gastroenteritis, intestinal parasitosis, and respiratory infections are prevalent in developing countries and may also have an important impact. Malaria is a major determinant in countries where that disease is endemic. Cigarette smoking is an increasingly important factor in some settings.
In developed countries, cigarette smoking is far and away the most important etiologic determinant, but low gestational weight gain and low pre-pregnancy BMI are also determinants. The etiologic roles of pre-eclampsia, short stature, genetic factors, and alcohol and drug use during pregnancy are well-established but quantitatively less important. Socioeconomic disparities in IUGR risk within developed countries are largely attributable to socioeconomic gradients in smoking, weight gain and maternal stature. In poor urban areas where cocaine abuse is highly prevalent, this may also be important.
The etiologic role of micronutrients in IUGR remains to be clarified. The best evidence concerning their importance derives from randomized trials and from systematic overviews of those trials contained in the Cochrane Collaboration Pregnancy and Childbirth database. Unfortunately, there are few supplementation or fortification trials in developing country settings where deficiencies in these micronutrients are prevalent. Trials are required to define the possible etiologic roles of iron, calcium, vitamin D, and vitamin A, especially in developing countries. The evidence concerning folate, magnesium, and zinc also looks sufficiently promising to justify further investigation.
The physiologic and molecular
mechanisms by which nutritional or other determinants affect fetal growth are incompletely
understood. Growth is determined not only by substrate availability but also by the
integrity of physiologic processes necessary to ensure transfer of nutrients and oxygen to
the developing fetus. Expansion of maternal plasma volume, maintenance of uterine blood
flow, and development of adequate placentation are key physiologic mechanisms required for
optimal fetal growth. All substances used by the fetus are transported by the placenta:
some (like oxygen and most other gases) by passive diffusion, others by facilitated
transport proteins (e.g., Glut 1 for glucose), and still others (e.g., amino acids) by
active energy-dependent transport processes. Insulin-like growth factors (IGFs) are
important mediators of substrate incorporation into fetal tissue. IGF1 appears
to induce cell differentiation, including (perhaps) oligodendrocyte development in the
brain, whereas IGF2 may function to stimulate mitosis. It remains uncertain
whether these physiologic and molecular mechanisms are merely the final common pathways
for genetic or environmental determinants of IUGR, or whether they themselves vary
(favorably or pathologically) independently of those determinants.
A systematic review of 126 available randomized controlled trials (RCTs) has been carried out to summarize the efficacy of 36 prenatal interventions aimed at reducing IUGR. Strategies include prenatal care modalities, protein/energy supplementation, treatment of anemia, vitamin/mineral supplementation, fish oil supplementation, and prevention and treatment of hypertensive disorders, fetal compromise, and infection. Based on this review, few statistically significant reductions in the risk of IUGR have been demonstrated with these interventions. However, the point estimate (average effect) associated with some interventions suggests a potential effect of considerable magnitude; these interventions should be further evaluated by targeting populations at risk for IUGR, increasing sample size, and addressing coexisting factors limiting growth. Studies should be conducted in developed as well as developing countries.
Systematic reviews provide strong evidence of benefit only for the following interventions: balanced protein/energy supplementation, strategies to reduce maternal smoking, and antimalarial prophylaxis. In Jamaica, antibiotic administration to prevent urinary tract infections further reduced an already low prevalence of IUGR. Improvement of maternal nutrition should be a priority, especially in developing countries. Unless maternal undernutrition is severe, the effect of balanced protein/energy supplementation on birth weight is likely to be modest » 100 g). Reduction in maternal smoking should be encouraged, both by individual clinicians (using behavioral modification techniques, for example) and by policy makers (e.g., taxes on cigarettes and other tobacco products). Antimalarial chemoprophylaxis should be provided in endemic areas, particularly to primigravidae, although more research is needed to elucidate the ideal timing of treatment, combination of agents, and safety for the fetus.
The effectiveness of other interventions has not been demonstrated, but further research is required based on limited, suggestive results from RCTs. 'Packages' of combined interventions and community-based (cluster randomization) approaches should be explored. Potentially adverse effects of these interventions also require careful assessment.
Maternal supplementation of iron, zinc, folate, and magnesium should be rigorously evaluated, as these interventions may affect fetal growth, as well as preterm delivery and necrologic outcomes. It is important to target women deficient in the nutrient of interest to maximize the chance of detecting a beneficial effect. In this regard, the possibility of coexisting nutrient deficiencies limiting fetal growth must be considered. Two trials of iron supplementation conducted in developed countries have shown no effect on IUGR; it remains to be seen whether routine iron supplementation affects IUGR in populations with a high prevalence of anemia. A RTC the effect of vitamin A supplementation during pregnancy is currently under way in Nepal. Unlike food fortification with vitamin A, however, supplementation might have adverse safety implications, and caution is required to avoid teratogenic or other adverse effects.
In countries where multiple deficiencies and pathologies exist, it may be difficult to demonstrate a significant effect with a single intervention. For example, malaria and other parasitic infections, malnutrition, and anemia coexist in many developing countries. An appropriate combination of anti-anemic (iron-folate) and antimicrobial/antiparasitic agents tested in population-based trials may have a greater chance of showing a reduction in IUGR.
Antibiotic treatment of genito-urinary tract infections appears to be a promising area for perinatal research, although the impact may be greater for preterm delivery than for impaired fetal growth. The efficacy and safety of drug treatment remain to be demonstrated. A few older and methodologically weaker trials of abdominal decompression have reported large reductions in IUGR. In selected developed country settings, strategies to improve blood flow to the uterus may merit further testing.
RCTs aimed at other putative causes of IUGR have been disappointing. For example, efforts to prevent and treat hypertensive disorders have not significantly reduced IUGR. Trials using antiplatelet agents in high-risk women have yielded only modest benefits, while trials of betablockers have suggested a potential for harm. Prenatal care and nutritional education interventions have not heretofore been shown to impact significantly on IUGR, but better approaches are required (e.g., community-wide interventions to promote optimal weight gain and discourage 'eating down').
Future research in the prevention and treatment of IUGR should be based on sound epidemiologic and other scientific evidence. Rigorous randomization procedures (including concealment of treatment allocation) and efforts to minimize losses to follow-up fare required to ensure high methodological quality. Without randomization there is a high risk of bias due to confounding. Sample sizes should be planned with sufficient power to detect significant impacts on IUGR and other fetal/infant outcomes. Study designs should also include practical measures to assess gestational age, as well as potential obstetric complications or other adverse outcomes.
Lastly, while systematic reviews of
RCTs represent the most objective way to evaluate the effectiveness of health care
interventions, the available data are limited. Moreover, there are problems related to the
size of the trials, their heterogeneity, settings, and methodologic quality. Findings from
observational studies should not be totally discounted, but rather tested in RCTs whenever
possible.