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Studies of the effects of intrauterine growth failure among very low birthweight (VLBW < 1.5 kg) preterm children have mainly pertained to childhood (Sung et al, 1993; Pena et al, 1988; Robertson et al, 1990; Calame et al, 1986). Results have been confounded by the fact that some researchers have compared the children to control children of similar birthweight, whereas others compared them to control children of similar gestational age.
Robertson et al (1990) in Canada examined school performance at 8 years of preterm, small for gestational age VLBW infants and compared it to that of VLBW children born appropriate for gestational age. The IUGR children did not differ in school performance when compared to either birthweight- or gestational-age-matched controls. All the VLBW groups had significantly inferior outcomes when compared to a normal-birthweight control group.
In Cleveland we compared the school age outcomes of a cohort of 51 VLBW children who were born IUGR (with birthweights less than-2 SD for gestational age), to 198 VLBW born appropriate for gestational age. The groups did not differ in maternal socio-demographic characteristics, with the exception that more mothers of the appropriately grown (AGA) children were married (67% vs. 48%, respectively). Mothers of the IUGR children had a significantly higher rate of pregnancy hypertension. More IUGR than AGA children were multiple births (31% vs. 9%) and IUGR children had a significantly higher gestational age (32 vs. 29 wks) and lower birthweight (1113 g vs. 1192 g) compared to the AGA population. The AGA children had significantly more neonatal problems including lower 5-minute Apgar scores and a higher incidence of respiratory distress syndrome and apnea of prematurity. The populations thus differed in maternal marital status, birthweight, gestational age, and the rates of neonatal problems. No overt intrauterine infections were diagnosed.
At 8 years of age AGA children had higher rates of cerebral palsy (25% vs. 6%), but this difference was not significant. No significant differences in intelligence, language, visual-motor abilities, fine motor abilities, and academic achievement were noted between the AGA and IUGR children.
Based on the literature reported, we
conclude that intrauterine growth retardation does not appear to impose an added
disadvantage at school age over and above that of very low birthweight.
In general, the follow-up studies report overall normal intelligence with a trend to lower scores among IUGR subjects. Despite the limitations of the literature reviewed, there is no consistent evidence of a detrimental effect of IUGR on the mental and behavioral outcomes of adolescents or adults. The rates of major handicap are low, although there tend to be higher rates of minimal cerebral dysfunction, as evidenced by learning and subtle neurological and behavioral problems in IUGR children with normal intelligence. Three of the studies noted a decrease in the rates of abnormal neurodevelopment with increasing age (Douglas and Gear, 1976; Hawdon et al, 1990; Westwood et al, 1983) which could be associated with an amelioration of subtle neurological dysfunction after the onset of puberty. Support for this hypothesis is the work of Soorani-Lunsing (1993), who reported that onset of puberty was associated with a decrease in the rates of neurologic dysfunction, including fine manipulative disability, coordination problems, choreiform dyskinesia and hypotonia. She hypothesized that general maturational changes during puberty, as well as specific hormonal changes in estrogen secretion, might play a role in improving outcome.
The review of the literature reveals that ongoing detrimental effects of socio-environmental deprivation throughout the lifespan play a much greater role in determining outcome than any potential effect of intrauterine growth failure on the developing nervous system (Douglas and Gear, 1976; Hawdon et al, 1990; Drillien, 1970; Westwood et al, 1983; Illsley and Mitchell, 1984; Neligan et al, 1976; Low et al, 1992; Martyn et al, 1996; Stein et al, 1972). Warshaw (1985) has suggested that rather than representing serious pathology, IUGR may be an adaptation in which the size of the fetus is maintained appropriate to the availability of nutrients. The most consistent biologic predictors of poor later mental development and behavior in IUGR children are hypoxic ischemic injury and subnormal brain growth (Westwood et al, 1983; Berg, 1989; Ounsted et al, 1988; Harvey et al, 1982; Parkinson et al, 1981). Brain growth, as measured by the sonographic biparietal diameter or by head circumference after birth, is usually less affected than weight or length, resulting in "asymmetric" growth failure (Cooke et al, 1977; Kramer et al, 1989). This "brain sparing" may be protective when growth is restricted in utero, and outcome may be affected when this mechanism fails. This is especially evident when brain growth (head size) fails to catch up during infancy and childhood (Hack et al, 1989, 1991; Babson and Henderson, 1974; Lipper et al, 1981).
Thus, with the exception of extreme
IUGR affecting brain growth, and hypoxic ischemic injury, IUGR seems to have little or no
measurable effect on mental performance and behavior in adolescence or adulthood. However,
since IUGR occurs more often in deprived environmental circumstances, it can serve as a
marker for the associated poor outcomes throughout life.
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In follow-up studies of older children it becomes more and more difficult to separate prenatal and postnatal effects. Other major problems are diminishing statistical power and potential biases due to sample attrition.
Most studies of long-term outcomes of IUGR are relatively old. Considerable improvements have been made in the last few years in obstetric and emergency newborn care in industrialized countries. This means that the factors that recent survivors have been exposed to and the risks they entail could be substantially different from those of earlier study populations.
If head sparing can be observed in some IUGR babies, it is usually relative, i.e. head size is also affected, but to a lesser extent than weight and height. The extent to which head size is reduced seems closely related to the degree of growth retardation and no attempt has yet been made to dissociate the two and their effect on mental and behavioral development.
Effects of IUGR seem closely associated with accompanying factors; it is not always clear whether these should be treated as confounding factors and controlled for or not. Factors like socioeconomic status are clearly confounding factors, because they exist before and after IUGR occurs and are unlikely to be on the causal pathway between growth retardation and cognitive outcome. Asphyxia is a transient phenomenon and a factor that is likely to be on the causal pathway between IUGR and later outcomes. Where it is, at least partly, avoidable, it is of interest to know what specific outcomes, or what proportion of them, are attributable to asphyxia. If one wishes to assess the effect of IUGR in areas where factors like asphyxia are still less amenable to treatment, it seems more appropriate not to control for them.
Environmental circumstances can both
enhance and reduce developmental differences and other consequences. Mothers have been
observed for instance to react in a dichotomous way to the abnormal cries of malnourished
children, some devoting more time and attention to them, some less. Favorable
socio-economic conditions can have a protective effect, whereas under unfavorable
socioeconomic conditions, adverse effects can be amplified. The general conclusion from
Hack's review of the literature is that, while IUGR can produce disadvantages in childhood
that are significant, at least in statistical terms, these tend to be most consistent and
marked from the preschool years through adolescence and gradually overridden by
environmental influences in the long-term.
Among the commonly used indicators, a length deficit
at an early age seems to be the best predictor of motor and mental development. Effects
associated with ponderal index could be attributable mainly to length or height. Advocates
of ponderal index argue that it provides the best reflection of the timing of the insult,
and that this in turn could be of prognostic importance.