Previous - Next
Immunocompetence
Mortality and morbidity
Body size, composition and physical performance
Maturation
Policy implications
Research needs
Working Group members: A Ferro-Luzzi¹, A Ashworth², R Martorell³ and N Scrimshaw4
Correspondence: IDECG Secretariat, c/o Nestlé Foundation, POB 581, 1010 Lausanne, Switzerland
¹Instituto Nazionale della
Nutrizione, Rome, Italy;
²Centre for Human Nutrition, London School of
Hygiene and Tropical Medicine, Keppel Street, London;
³Department of International Health, The Rollins
School of Public Health of Emory University, Atlanta, Georgia 30322;
4UNU Food and Nutrition Program,
Charles Street Station, POB 500, Boston, MA 02114-0500
Most immune functions have been shown to be impaired in SGA children in the relatively small number of studies that have been reported. Modifying factors include the magnitude of the weight deficit at term, patterns of infant feeding, the age at which the subjects were tested, and the type of assessment used. In general, the greater the fetal growth retardation the more impaired is immunocompetence, and there is a significant improvement in immune responses as IUGR infants age. Some SGA infants may completely outgrow the immunodeficiency observed in the first year of life whereas others continue to exhibit impaired immune responses for many years, with observed effects in some infants to at least 9 years of age. The effect of IUGR may not be detectable when strong antigenic stimuli are used, but with weaker antigens a reduced antibody response can be observed.
IUGR infants have fewer mature
thymocytes and less clear demarcation between the cortex and medulla of the thymus.
Preterm infants have reduced levels of IgG at birth that is thought to be a reflection of
the limited time available for transfer of immunoglobulins from the mother to the infant,
mostly in the last trimester of pregnancy. In IUGR infants, the placental transfer of IgG
is impaired even though sufficient time is available for the process. Impairments of
lymphocyte response to mitogenic stimulation and IgG production in vitro have been
demonstrated in IUGR infants compared with term infants whose birth weights are in the
normal range. Most of these studies come from a single laboratory. More extensive
investigations are needed to reinforce the finding that IUGR lowers immunity and
resistance to infections. There have been few trials of the potential benefits for
immunocompetence of post-natal dietary supplementation of IUGR infants. Zinc
supplementation of preterm LBW infants in rural India improved immune response, and in
Brazil zinc supplementation was associated with reduced diarrheal morbidity in term LBW
infants.
In developing countries with a high prevalence of LBW, IUGR infants comprise the majority of neonatal deaths. To quantify the relative risk of neonatal death, 10 data sets with birth-weight specific mortalities were examined for populations in which IUGR infants would have comprised the majority of low weight births. Although there were large differences in neonatal mortality among these populations (range 1.7 to 39.0 per 1000 live births), reflecting differences in socioeconomic status, health care and probably differing etiologies of IUGR, the relative risk of death in each 500 g birth-weight interval was quite similar across populations. Infants weighing 2000-2499 g were approximately 4 times more likely to die in the neonatal period than infants weighing 2500-2999 g, and the latter were 2.5 times more likely to die than infants weighing 3000-3499 g. Interventions that reduce the incidence of IUGR can therefore be expected to reduce neonatal mortality. In developing countries with high rates of IUGR, this reduction could be substantial.
The association between IUGR and increased mortality extends into the postneonatal period and includes sudden infant death syndrome, particularly in developing countries with a high rate of IUGR. The slope of the relationship between birthweight and mortality is less steep in the postneonatal compared with the neonatal period. This in part reflects the different distribution of death by cause under and over one month of age. In the neonatal period other causes including congenital abnormalities and complications surrounding delivery predominate, while deaths from infections are more important in the postneonatal period. In most developing countries a large proportion of infants weighing 2000-2499 g can be considered IUGR. A high proportion of term births are between 2500-2999 g and most of these will also be IUGR. Interventions that reduce the incidence of IUGR can therefore be expected to reduce postneonatal mortality as well as neonatal mortality.
For 5 populations with birth-weight specific postneonatal mortalities, the relative risks of death in each 500 g birth-weight interval were again quite consistent despite postneonatal mortality rates ranging from 2.4-69.0 per 1000 live births. The risk of postneonatal death in infants weighing 2000-2499 g was twice that of infants 2500-2999 g, and the latter were at twice the risk of postneonatal death of infants weighing 3000-3499 g.
An increased risk of morbidity has also been observed in IUGR infants in community-based studies in developing countries, where diarrheal diseases and acute respiratory infections are the major causes of mortality. Families with IUGR infants tend to be more disadvantaged in income, housing, parental education etc. than families of appropriately grown infants, and thus their infants may be more exposed to infection and receive inferior medical care when ill. Consequently higher mortality and morbidity in IUGR infants could be due, at least in part, to their adverse environment. In a few studies in which socioeconomic and other likely confounders could be controlled, an increased risk of morbidity of about 30% remained.
The risks of morbidity and mortality
may differ depending on body proportions of infants at birth, i.e. stunted and/or wasted,
but only limited data are available. Stunted LBW infants have higher neonatal mortality
than wasted newborns. In Guatemala higher diarrheal rates in the first two months of life
were reported in IUGR infants with an adequate ponderal index, and who therefore can be
assumed to be mainly stunted, than those who were born thin. Because of the possible
differential effects of birth dimensions on mortality and morbidity, it is recommended
that IUGR infants be characterized by body proportions at birth.
General gaps in the literature and study biases
While there are a number of studies of the effects of IUGR on body size during infancy and childhood, almost all are from industrialized countries. Very little is known anywhere about effects of IUGR on body composition (i.e. fatness, fat free mass), physical performance (i.e. work capacity, strength), and maturation.
Loss to follow-up can be considerable in many studies, particularly those which span many years. In long-term studies of IUGR and non-IUGR subjects there is the concern that losses may be greater among IUGR subjects because they are more frequently born to disadvantaged families. Thus investigators need to make special efforts to minimize losses due to incomplete follow-up and to account for those that do occur. It is essential to compare the socio-economic and other characteristics of those lost to follow-up in longitudinal studies with those remaining in the study in order to identify possible sources of bias.
Growth
In the poorest developing countries, a large proportion of the entire population may suffer from some degree of prenatal growth retardation as measured by length and weight. IUGR newborns in industrialized countries show some catch- up in growth during the first one to two years of life relative to their own percentile/Z-score at birth. After about two years of life, IUGR subjects maintain their achieved place in the distribution, i.e. their Z-score remains unchanged.
Catch-up growth relative to the reference population does not occur in IUGR infants in poor developing countries, except for an initial transient phase which is not enough to compensate for the prenatal deficit. In these countries, both IUGR and non-IUGR groups suffer from postnatal growth retardation, i.e. mean Z-scores relative to the reference population become more negative throughout the first two to three years of life. However, the postnatal decline in Z-scores for length and weight is less for IUGR than for non-IUGR term subjects.
IUGR newborns who are born thin in developing countries (i.e. disproportionate, low ponderal index), may constitute approximately half of all IUGR infants, as illustrated by studies from Guatemala. Under favorable conditions this group tends to gain weight quickly and thus to achieve a weight proportionate to length a few months after birth.
The catch-up in growth during the first two years of life, which occurs in industrialized countries is still not enough to fully compensate for prenatal growth retardation. Thus, IUGR subjects remain short during childhood and adolescence relative to those who are born at term without IUGR. Differences in body size in both males and females at 17-19 years of age are about 5 cm in height and 5 kg in weight relative to non-IUGR subjects. In the only long-term study from a developing country the effects of IUGR on body size in Guatemala were of a magnitude similar to that in industrialized countries. In Guatemala, the shortest group at adolescence is that of IUGR subjects who are born with adequate ponderal indices and can be assumed to have been stunted in utero.
Body composition
Because of their smaller size, IUGR cases have smaller body fat and fat free masses as young adults. Only a few of the studies have examined body composition to explore whether IUGR cases have a tendency to be fatter. The limited available evidence does not support this conclusion.
Physical performance, work capacity, and strength
In Guatemala, IUGR cases at
adolescence have a lower fat free mass, a major determinant of work capacity, as well as
reduced strength compared to non-IUGR subjects. Nothing more has been reported about the
effects of IUGR on physical performance.
Very little is known about effects
of IUGR on maturation. The limited existing evidence suggests that there are no
differences in the timing of peak height velocity and sexual maturation with respect to
non-IUGR subjects. Also, skeletal ages are similar in IUGR and non-IUGR subjects.
There are critical periods of both prenatal and postnatal development during which malnutrition can exert lasting effects, and both periods should receive attention in preventive programs.
- The adverse consequences of IUGR are well established and frequently serious. Thus appropriate multifaceted preventive actions with mothers before and during pregnancy should have a high priority.
-IUGR infants are at higher risk of dying.
-IUGR infants are more likely to remain small than those of normal birth weight. They will need the special attention of primary health, nutrition and social services during infancy and early childhood.
Since IUGR infants are likely to be
susceptible to infections because of impaired immunity, measures to reduce the risk of
infections such as immunization and improved sanitation as well as enhanced immune status
through improved nutrition have particular importance. Breast feeding has multiple
benefits in this regard.
- The greatest need for research relating to the adverse effects of IUGR on infancy and childhood is in the developing countries, where IUGR is much more widespread and its multifactorial nature more diverse and less well understood, where the implications for survival and optimal function in the community are likely to be more profound, and where postnatal circumstances and environmental conditions are more adverse to compensatory growth.
- Little is known anywhere about the short- and long-term effects of IUGR on body composition, physical performance and maturation. Thus future studies are needed in both industrialized and developing countries to address these aspects.
- It is important to note that in developing countries most newborns, and not just those below an arbitrary cut-off for IUGR, are likely to suffer from substantial prenatal growth retardation. It is important, therefore, that the relationship between birth weight and later life outcomes be assessed along the whole continuum of birth weights.
- Further studies are needed to asses the functional significance of the effects of IUGR on parameters such as adult body size, body composition, physical work capacity, work productivity and implications for reproductive performance and obstetric risks. Moreover, studies of the effects of IUGR should include direct measures of socioeconomic success such as adult income, wealth, occupation, social mobility and educational achievement as well as cognitive and health status. Smaller body mass and impaired performance are likely to be permanent outcomes of IUGR in developing countries.