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Effects of intrauterine growth retardation on mental performance and behavior, outcomes during adolescence and adulthood


School age outcomes of young adolescents with intrauterine growth failure (Table 1)
Late adolescent and adult outcomes of low birthweight and intrauterine growth failure
Effects of IUGR on the development of very low birthweight children
Discussion and conclusion
References
Discussion


M. Hack

Correspondence: Dr Maureen Hack

Case Western Reserve University, Rainbow Babies & Childrens Hospital, University Hospitals of Cleveland, 11100 Euclid Ave., Cleveland, OH 44106-6010, USA

Studies of the long-term effects of intrauterine growth retardation on mental performance and behavior are reviewed. The results of the majority of studies suggest that, if effects of prematurity and of other associated complicating factors are controlled for, effects of IUGR per se, that can sometimes be demonstrated at an earlier age, become diluted by socio-environmental conditions at later stages in life and no longer appear to have a detrimental effect on mental and behavioral outcomes in adolescence and adulthood.

Studies of the long-term effects of intrauterine growth retardation (IUGR) on mental performance and behavior have provided varying and often conflicting results. This is mainly due to the heterogeneity of the populations that have been studied, including different definitions and varying causes of IUGR, differences in perinatal and neonatal complications associated with the gestational age of the child, and differences in the quality of neonatal care. Initial reports of the consequences of IUGR included children with major congenital malformations and children with intrauterine infections, who are known to have very poor developmental outcomes (Allen, 1984; Warkany et al, 1966). Furthermore postnatal conditions may confound the effects of IUGR on later mental performance and behavior. These include subnormal nutrition and growth during infancy and early childhood, and the social and environmental conditions of the family (Allen, 1984; Smeriglio, 1989). Reported heterogeneity of outcomes of IUGR is further influenced by the fact that some studies are population based, whereas others include only selected high-risk hospital populations. Many studies include both preterm and term children, and some include multiple births. The loss to follow-up sometimes exceeds 50%, thus populations followed might not be representative of the original population.

The majority of available reports of adolescent and adult outcomes of IUGR populations pertain to births that occurred prior to the development of current methods of perinatal and neonatal care, when infant mortality was very high. Furthermore, between 1940 and 1960, various practices of newborn care caused iatrogenic sequelae that had a detrimental effect on outcomes. These included prolonged starvation of babies, unrestricted use of oxygen that resulted in blindness, followed by a period of restricted use of oxygen resulting in higher death rates and cerebral palsy, and the widespread use of antibiotics, especially sulfa drugs causing kernicterus and streptomycin causing dearness (Hack et al, 1979; Douglas and Gear, 1976). Current methods of perinatal care include antenatal surveillance of intrauterine growth failure and associated fetal distress, optimal timing of delivery, adequate neonatal resuscitation and the prevention and treatment of neonatal complications associated with IUGR such as hypoglycemia and polycythemia (Kramer et al, 1990; Hawdon et al, 1990; Tenovuo et al, 1988). There is currently a greater awareness of the importance of the home environment and socioeconomic status of the family as determinants of childhood and adult outcomes (Sameroff et al, 1993).

This report will review the published literature on the mental performance and behavior of adolescent and adult persons who experienced intrauterine growth retardation.

School age outcomes of young adolescents with intrauterine growth failure (Table 1)

Drillien (1970) in Scotland compared 10- to 12-year-old IUGR children born 1953-1958 at term gestation to normal birthweight controls. The results were confounded by the fact that mothers of IUGR children tended to be of lower social class and of shorter stature than mothers of normal birthweight children, and that mothers of children with birthweights < 2000 g had higher rates of severe toxemia and chronic illness. No differences in intelligence were found among IUGR children of the middle to upper working classes, whereas IUGR children of mothers in the lower working classes had lower intelligence scores than normal birthweight children.

Hill (1978) in the USA, examined children born 1964-1965 who were clinically malnourished or 'dysmature' at term birth, and compared them to normal controls. At 12 to 14 years of age the IUGR children had significantly lower mean IQ scores, 42% had either mental retardation or learning difficulties and 27% required special education compared to none of the controls. Although children with chromosomal anomalies and congenital malformations were excluded from study, the IUGR children had a history of neonatal complications including low Apgar scores and hypoglycemia, which might have affected the later outcomes.

Table 1a. Adolescent and adult outcomes of IUGR

Author

Country

Year of birth

Age (yrs)

Population description

IUGR

Control

(1) Adolescent outcomes

Drillien '70

Scotland

'53-'55

10-12

IUGR (< 10th percentile) born at 38-41 wks gestation

Mean IQ
Mid SES 111 (n=21)
Low SES 93 (n=46)

Mean IQ
Mid SES 111 (n=44)
Low SES 102 (n=30)

Lagerstrom '91

Sweden Regional

'54-'56

13

Low birthweight (< 2.5 kg) compared to 2.5 kg children born at > 37 wks gestation

(n=8)
Mean IQ 82

(n=763)
Mean IQ 101

Hill '78

USA

'64-'65

12-14

Middle/High SES Clinical assessment of IUGR and "wasting"

(n=3)
Mean IQ 104*
Special Ed 27%
Cerebral palsy 3%
Seizures 6%

(n=73)
Mean IQ 121* (p <.05)
Special Ed 0%
Cerebral palsy 0%
Seizures 0%

Westwood '83

Canada

'60-'66

13-19

Excluded asphyxia, intrauterine infections and malformations. Birthweight < - 2 SD for gestation at > 37 wks gestation

(n=33)
Mean IQ 104*
Math 88*

(n=33)
Mean IQ 109* (p =.05)
Math 94* (p=.011)
(Differences not significant when SES controlled)

Rantakallio '85

Finland Regional

1966

14

Regional study of 12,000 births. Included term and preterm children

Rates of mental retardation and subnormal school performance (with or without cerebral palsy or epilepsy) significantly higher at birthweight < 25th percentile for gestational age.

Illsey '84

Scotland Regional

'69-'70

10

Singleton IUGR (birthweight < 10th percentile) born at > 37 weeks gestation

(n=64, both IUGR and controls) IQ scores of term IUGR children similar to controls but they had poorer perceptuomotor skills.

Hawdon '90

England Regional

'73-'74

10-11

Singleton group, birthweight< -2 SD of gestation (36-42 wks).

(n=30)
Two children severely retarded.
Of the remaining: Mean IQ 95
Reading quotient 92

(n=30)
None retarded
Mean IQ 97
Reading quotient 92






Family and environmental factors were significant determinants of outcome.

Pryor '95

New
Zealand
Regional

'72-'73

15

IUGR (< 10th percentile at > 37 weeks gestation), singleton. Excluded malformations and neonatal problems.

(n=91)
Mean IQ 101*
Reading scores were similar. IUGR had significantly more inattention and total problem behaviors.

(n=1037)
Mean IQ 109* (p <.05)

Low '92

Canada

'78-'82

9-11

Study of high risk children including IUGR (< 10th percentile). 50% of population lost to follow-up

Term IUGR (n=39)
Learning deficits 46%
Preterm IUGR (n=38)
Learning deficits 50%

Term (n=65)
Learning deficits 25%
Preterm (n=76)
Learning deficits 32%

Nilsen '84

Norway

'62-'63

18

Birthweight< 2.5 kgm. singleton mares examined when conscripted to the military. Excluded Malformation. IUGR birthweight < 10th percentile for gestation.

IUGR (n=29)
2 (7%) unfit for service.
No significant differences in intelligence compared to controls.

Paz '95 Israel
'70-'71
17
IUGR-birthweight < 3rd percentile at > 37 weeks gestation. 90% followed. Tested prior to army conscription. Excluded malformations and infections.

IUGR

CONTROL







Malen
=30

Female
n=34

Male
n=872

Female
n=771






IQ
Neur. Abn.

105
10%

103
9%

109
7%

107
5%

Table 1b. Adolescent and adult outcomes of IUGR

Author

Country

Year of birth

Age (yrs)

Description of population

Outcomes

(2) Late adolescent and young adults outcomes

Martyn '96

England
Regional

'20-'43

48-74

50% of survivors still in the region. Compared birthweight < 5.5 lb (n = 74) to larger birthweight survivors

No significant difference in cognitive function or its; decline with age.

Stein '72

Holland
Regional

'44-'46

18

Retrospective cohort study of 7 famine areas compared to 11 areas without famine. 98% of males tested at induction to military service.

Maternal famine during pregnancy and birthweight had no effect on the rates of severe or mild mental retardation or on IQ.

Douglas '76

England
National

1946

18

80 of 163 < 2 kgm birthweight singletons survived to age 18 years. 84% examined and matched to normal birthweight controls

No significant differences in mental or behavioral handicaps. IQ of < 2000 gm group 93 vs 97 for controls. No significant effect of IUGR on outcomes.

Baker '87

Denmark

'59-'61

18

Report on 94 of 857 < 2.5 kgm, term and preterm

No difference between LBW or IUGR groups and controls.

Westwood et al (1983) in Canada, reported outcomes in 13- to 19-year-old children, born 1960-1966 at term gestation, who had severe IUGR (below -2SD birthweight for gestation). Children with intrauterine infections, major congenital malformations and severe asphyxia, as well as twins, were excluded from study. Of an eligible cohort of 118 children, only 33 (28%) were followed to adolescence. Results revealed significantly lower IQ scores among the IUGR children as compared to controls, but these differences were not significant after controlling for socio-economic status of the families. There were, however, significant differences on arithmetic achievement scores. This population had previously been followed to 8 years of age by Fitzhardinge, at which time greater differences were reported between the IUGR population and controls (Fitzhardinge and Steven, 1972). Westwood hypothesized that the improved outcomes documented during adolescence resulted from resolution of some difficulties with increasing age and maturity (Westwood et al, 1983).

Rantakallio (1988) in Finland examined the effect of intrauterine growth failure on the school performance of a regional population of 12,000 children born in 1966. At 14 years of age, children with a birthweight for gestational age below the median (25th-75th centile) had significantly higher rates of educational subnormality, including mental retardation, cerebral palsy, epilepsy, and delayed or no schooling. The rates of subnormality were higher for preterm than for term born IUGR children, and highest for the children whose birthweight percentiles were more than - 2 SD below the mean.

Lagerstrom in Sweden similarly examined the regional outcome of IUGR children born between 1954 and 1956. In this population, only 7 of the 780 children born at term gestation (> 37 weeks) weighed < 2.5 kg at birth. At 13 years of age, these 7 children had significantly poorer scores on measures of school performance, including intelligence, language, and mathematics (Lagerstrom et al, 1991).

Illsley in Scotland, examined the outcomes of a regional population of children born during 1969 and 1970. At 10 years of age, term born IUGR children had IQ scores similar to the normal birthweight controls but had poorer scores on tests of sensorimotor performance (Illsley and Mitchell, 1984).

Hawdon et al (1990) in England, examined the outcomes of a regional population of children born 1973-1974. Thirty singleton boys out of an initial population of 53 children born at term gestation were examined at 10-11 years of age. Intrauterine growth failure was defined as birthweight below - 2 SD for gestational age. Two (7%) of the boys were severely retarded and excluded from further analyses. The remaining children had similar IQ and reading scores when compared to matched controls. Significant correlations between lower z-scores and behaviors suggestive of attention deficit disorder were noted when the severity of weight for gestation was examined via z-scores (indicating the deviation of the child's birthweight from the mean of gestational age). However, although the groups had been matched for social class (father's occupation and marital status of the mother), the mothers of the IUGR group were significantly shorter in stature, smoked more, had higher rates of fetal distress and birth complications, higher scores on questionnaires indicating 'neuroticism' and 'malaise', and the ratings of their involvement in the home were lower, with significantly higher punishment scores. When multivariate analyses were performed, the severity of intrauterine growth failure was the poorest predictor of outcome, and predicted only the behaviors 'distractibility' and 'approachability'. The two best predictors of outcome were maternal intelligence and the ordinal position of the child, followed by maternal height and the family's occupational class. Neligan et al (1976) had reported on a similar population born in the same area 10 years previously who had poorer outcome at age 5-7 years. Hawdon hypothesized that the improved outcomes of his IUGR population were due to improved neonatal care, consideration of the effects of socio-environmental factors and the possibility that some findings might disappear as adolescence approaches.

Low et al (1992) in Canada examined the outcomes of 50% of a hospital population of IUGR children born 1978-1982 who were followed to 9-11 years of age. Both term and preterm children with IUGR (weight less than the 10th percentile for gestational age) had significantly higher rates of learning difficulties compared to children who were appropriately grown at birth. Socio-economic status, as measured by parental education and paternal occupation, and rating of the child's inattention, also had a significant independent association with learning problems.

Pryor et al (1995) examined 91 singleton IUGR children (weight less than the 10th percentile at > 37 weeks gestation) born 1972-1973, and compared them to 1037 normal birthweight controls. With the exception of one child, all had a normal neonatal course and none of the IUGR children had malformations. At 15 years of age the IUGR children had significantly lower mean WISC.R IQ scores, although their reading scores were similar. Overall behavior and inattention, as measured on a behavior problem checklist, differed significantly between groups.

Agarwal et al (1995) examined the combined effects of low birthweight (< 2.5 kg) and childhood malnutrition on tests of cognitive function at age 10-12 in a population of Indian boys. Results revealed that the effect of IUGR was confounded by ongoing malnutrition during infancy and early childhood. Children malnourished during infancy, irrespective of whether they were of low birthweight, had deficits in memory tests, lower scores for abilities related to personal and current information, orientation, and conditional learning.

Mervis et al (1995) used a case control method to assess the association between low birthweight, intrauterine growth failure and mental retardation at 10 years of age in the metropolitan Atlanta Developmental Disability Study in the USA. With full term normal birthweight children as the reference population, the odds ratio for mild mental retardation (IQ 50-69) for children born weighing 1.5 to 2.49 kg at term gestation was 2.2 (95% Confidence Intervals, 1.2, 4.0) and the odds ratio for severe mental retardation (IQ < 50) was 3.7 (95 C.I. 1.7, 7.9). It is unclear whether children with intrauterine infections were excluded from the population.

Late adolescent and adult outcomes of low birthweight and intrauterine growth failure

The majority of studies on adult outcomes of children born with low birthweight (< 2.5 kg) include both term and preterm children. Prior to the 1960's the mortality of preterm infants was extremely high, and low-birthweight populations included mainly borderline preterm and term survivors, but only one report specifies the gestational age of the children at birth (Paz et al, 1995).

The longest follow-up study is by Martyn et al (1996), who reported on the relationship between fetal growth and cognitive function in middle and late adult life. His population included 1576 singleton men and women, aged 48-74 years, born to married mothers between the years 1920 and 1943 in Herefordshire, Preston and Sheffield, England, on whom birth measurements were available, and who were still living in the area at the time of the follow-up study. The population represented 47% of those who were invited to participate in the study at middle age. Only 74 of the participants weighed less than 5.5 pounds at birth and only 84 were born at less than 38 weeks gestation. The study assessed cognitive function, and its decline with age, by measuring the difference between a vocabulary test, which remains stable with age (the Mill Hill test), and the AH 4 test which measures logical, verbal and numerical reasoning and declines with age. Although cognitive function tended to be higher with increasing birthweight, the results of the study revealed no significant association between body size, or body proportion, at birth and cognitive function, or its decline with age. However, subjects who had a larger biparietal diameter at birth, had significantly higher AH 4 scores. This finding persisted even when adjustment was made for the subject's age and social class and when the subjects born before 38 weeks gestation were excluded from analysis. The authors could not explain this finding since no significant relationship between cognitive function and other head measurements (circumference or occipital frontal diameter), or their relationship to other body measurements was found. They concluded that, "by the time the baby reaches adulthood environmental factors in postnatal life may overshadow any effect of the intrauterine experience".

Stein et al (1972) studied the effects of prenatal exposure to famine in Holland during World War II (1944-1945). The study population included 125,000 males born in 7 famine-stricken areas and 11 areas not exposed to famine, on whom psychological and educational tests were performed at induction into the military at 18-19 years of age. Ninety-six percent of the births were located for the study. The authors noted a decrease in mean birthweight and birthweight below 2000 g during the famine, however there were no differences in intelligence, measured by the Raven Progressive Matrices Test, or in the rates of mild or severe mental retardation, between subjects from the famine and control areas. Stein et al concluded that starvation during pregnancy had no effects on intelligence and that there was no clear association between mean birthweight and intelligence. During the famine, births decreased more among the lower than among the higher social classes, whereas after the famine, there was a compensatory increase in births among the lower social classes. Social class effects might thus have affected the mean intelligence scores both during and after the famine. Stein also noted that the population might represent a selective survival of the fittest or that postnatal experiences might have had a compensatory effect on the outcomes.

Douglas and Gear (1976) followed 80 of 163 singleton survivors with birthweight less than 2000 g who participated in the 1959 longitudinal British Birth Cohort Child Development Study. Sixty-seven subjects (84%) were tested at 18 years of age and compared to matched controls with normal birthweight. Although significant differences in academic performance had been noted at 8 years of age, no significant differences in the rates of mental or behavioral handicaps were noted later. At the age of 15 years the low birthweight children had a mean IQ of 93 compared to 97 for the normal birthweight controls, but this difference was not statistically significant. Douglas noted that the results might have been confounded by the fact that, although the groups had initially been matched by social class, the home circumstances of the control families improved over the years, "possibly due to a greater drive and social responsibility among these families". A similar divergence of social circumstances between the low birthweight and control families over time was noted by Illsley and Mitchell (1984).

Nilsen et al (1984) in Norway examined the outcomes of a hospital population of children born 1962-1963 with birthweights < 2500 g, when they were conscripted to the army at the age of 18 years. Twenty-nine children had birthweights below the 10th centile for gestation; two of them were considered unfit for military service. No differences in intelligence scores were noted between the remaining 27 IUGR subjects and controls.

Paz et al (1995) reported on the outcomes of 17-year-old IUGR (< 3rd percentile for gestation) term subjects born in Jerusalem, Israel, who were tested prior to conscription to the army. The IUGR subjects had significantly lower IQ scores when compared to controls, but when the scores were adjusted for perinatal risk factors and socio-demographic status, the differences remained significant for females only. The conclusions that can be drawn from this study are limited by the: small number of IUGR children (30 males and 34 females), the exclusion of severely handicapped children from the army evaluation, and the greater likelihood of females with low education achievement to be exempt from conscription to the army. Significantly more of the IUGR males (40% versus 23% for normal birth weight controls) had low educational achievement defined as education less than 12 years or attending a special educational school. For females, the rates were 15% versus 6%, respectively. IUGR birth had no effect on having an IQ < 85 when multivariate analysis was performed to control for confounding variables such as ethnic origin, parental education, social class and birth order.


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