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7 Intrauterine growth retardation and familial short stature
7 Intrauterine growth retardation and familial short stature UDO E. HEINRICH
DEFINITION AND INCIDENCE OF INTRAUTERINE GROWTH RETARDATION
Traditionally, low birth weight has been associated with prematurity. Only in relatively recent years has it been accepted that low birth weight can also result from insufficient prenatal growth and that preterm infants with appropriate weight and infants which are small for their gestational age differ profoundly from the clinical point of view (Battaglia, 1970). Cut-off points for the definition of infants with intrauterine growth retardation (IUGR) differ widely: they include the third, the fifth birth weight percentile, 2 SD below the mean or the tenth percentile (Lubchenko et al, 1963; Gruenwald, 1966; Usher and McLean, 1969; Michaelis et al, 1970; Fitzhardinge and Stevens, 1972a,b). Since race, parity of the mother and sex of the infant influence birth weight, standards which are specific for these factors have been published (Kloosterman, 1970; Miller and Merritt, 1979). A reasonable definition for IUGR from reviewing the literature is the following: these are children whose birth lengths are below the tenth percentile and whose birth weights are equal to or below the tenth percentile according to sex and ethnic background. The currently used definition of IUGR has limitations, since many infants with birth weights and lengths below the tenth percentile are simply 'constitutionally small' and have not suffered from a pathological restriction of intrauterine growth. Criteria have been proposed to differentiate between infants with limited growth potential and infants who are really growth retarded. The ponderal index (PI) (Walther and Ramaekers, 1982) evaluates the ratio of soft tissue mass to skeletal frame and is determined in the neonate by the equation: PI = Weight (g) x 100 length 3 (cm) It is widely used and helps to define different forms of IUGR (Resnik, 1978; Wennergren et al, 1982; Miller, 1985; Ounsted et al, 1985; Visser et al, 1986; Wolfe et al, 1987): Bailli~re's Clinical Endocrinology and Metabolism-589 Vol. 6, No. 3, July 1992 Copyright © 1992, by Baillifre Tindall ISBN 0-7020-1620-9 All rights of reproduction in any form reserved
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1. Proportionate (symmetric) growth retardation. Birth length, weight and head circumference are all at the same percentile on growth charts. The PI is within the limits defined as normal (2.2-3.0) (Miller, 1981 ). The impairment of growth begins early in gestation (fetuses with chromosomal anomalies, genetic dwarfing syndromes and intrauterine infections, familial (constitutional) smallness). 2. Disproportionate (asymmetric) growth retardation. In these infants the birth weight is decreased but length and head circumference are on a higher percentile on growth charts. The PI is usually below the limits defined as normal. Negative influences interfering with normal intrauterine growth have been involved only after the 30th week of gestation (infants born to mothers with hypertension or toxaemia of pregnancy). The incidence of I U G R varies greatly with the population studied. Low socioeconomic conditions are associated with a high incidence of IUGR, whereas in developed countries an incidence of 4-7 per 100 births has been quoted.
DEFINITION OF FAMILIAL SHORT STATURE
Height for chronological age is below the population range but normal for the height of the parents. Growth velocity is normal, i.e. distant growth curves parallel the normal percentiles. Bone age development is in accordance to chronological age and the timing of puberty is normal. In the literature there is some confusion in the terminology, in that some investigators use the term 'constitutional short stature' for this group of short children; others even include children with 'constitutional delay of growth and adolescence' (CDGA) in this category. While a familial relationship is common to both entities, the latter children have retarded bone ages, a slowing of their 'tempo' of growth and development, late puberty and are usually of normal length at birth. Another important discriminating factor is the adult height to be expected. In familial short stature the adult height expectation is limited by the short stature of one or both of the parents. Children with C D G A tend to reach an adult height within the population range. In many cases there is an overlap of both entities: these children are small from birth onwards, have retarded bone ages and their midparental height is below the tenth percentile of the population range. They are characterized by a late puberty and they will finally reach an adult height in accordance with parental heights, albeit below the population range (so-called small delay). The term 'constitutional short stature' would be better discarded and replaced by the term 'familial short stature' to prevent confusion with the term 'constitutional delay of growth and adolescence'.
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AETIOPATHOLOGY OF IUGR
Normal fetal growth The rate of fetal weight gain increases from 5 g/day at 14-15 weeks of gestation to 10 g/day at 20 weeks and to 30-35 g/day at 32-34 weeks. The rate peaks at 33-36 weeks gestation at approximately 230 g/week and thereafter decreases, reaching zero or an actual loss at 41-42 weeks gestation (Rudolph, 1985). The position of the linear growth peak velocity is somewhat uncertain, probably about 20-24 weeks. Then a linear growth deceleration occurs and joins the infant's postnatal deceleration of length velocity at birth (Falkner, 1985). There are many factors influencing fetal growth. In the normal fetus sex and plurality, birth order, social and economic conditions, parental height and ethnic factors modulate size at birth. Genetic factors seem to play only a small part in determining birth weight (Ounsted and Ounsted, 1973). Ounsted and Ounsted termed the maternal effect on birth size 'maternal constraint' and showed that this effect is familial through the female line.
Intrauterine growth retardation I U G R is the result of many different disturbances. Conditions interfering with normal fetal growth and development have commonly been differentiated into fetal, placental, maternal and environmental factors. In many cases no underlying condition can be elucidated ('idiopathic' IUGR). Table i summarizes the factors which may interfere with fetal growth and development. Chromosomal aberrations are found in 5-15% and maternal disease is assumed to account for 25-30% of all cases of IUGR. Placental factors are relatively rare. The contribution of environmental factors is largely unknown. Maternal malnutrition is by far the most frequent cause of fetal growth retardation all over the world, but is exceedingly rare in developed countries. Congenital infections account for 1-2% of all cases. Maternal smoking and alcohol and drug addiction are well known causes of IUGR but their contribution to the overall number of cases is difficult to assess.
Chromosomal causes and primary growth failure syndromes In a high proportion of chromosomally abnormal fetuses intrauterine growth is impaired. The average birth weight at term in newborns with the Ullrich-Turner syndrome is 84%, in trisomy 13 80%, in trisomy 21 80-90%, and in trisomy 18 only 60% of the normal mean. Chromosomal deletions are also associated with reduced birth size (Polani, 1974). Severe growth retardation is also a feature of fetuses with triploidy (Doshi et al, 1983). In addition, there are a number of primary, in part genetically determined, syndromes with severe IUGR, including the Silver-Russell and the Seckel syndromes.
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Silver-Russell syndrome In 1953 and 1954 Silver and Russell independently described a new syndrome of small stature. While Silver observed asymmetrical features, Russell emphasized the prenatal smallness and the craniofacial dysostosis. It is now thought that the patients described by the two authors represent the same syndrome, which is characterized by IUGR, a small triangular face, a Table 1. Factors interfering with normal fetal growth and development.
Intrinsic fetal anomalies Chromosomal Trisomies 13, 18, 21 Deletions 4p-, 5p-, etc. Ullrich-Turner syndrome and variants Primary growth failure syndromes Silver-Russell syndrome Seckel syndrome Brachmann-de-Lange syndrome (Pankau et al, 1990) Bloom syndrome (German et al, 1984) Dubowitz syndrome (Dubowitz, 1965; Winter, 1986) Fanconi pancytopenia syndrome Osteochondrodysplasias Leprechaunism (Catani et al, 1987) Etc. Congenital infections Rubella Cytomegaly Toxoplasmosis Etc. Congenital anomalies Bilateral renal agenesis Defects of the neural axis Congenital heart disease Malformations of the GI tract Abnormalities of the placenta Abnormal implantation Vascular anomalies, e.g. haemangiomas, etc. Tumours of the placenta Progressive vascular disease Maternal disorders Cardiovascular disorders: hypertension, cardiac disease, preeclampsia, severe diabetes mellitus Maternal phenylketonuria (Lipson et al, 1984) Chronic respiratory diseases Chronic renal diseases Collagen diseases Anaemias Uterine malformations Drugs: alcohol, tobacco, narcotics abuse Therapeutic drugs Environmental factors Maternal malnutrition High altitude Occupational hazards Irradiation
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skull of large appearance with a prominent forehead and low set ears, a small mandible in relation to the maxilla, clinodactyly of the fifth finger, and a number of facultative features like asymmetry of the face and/or body and syndactyly of the second and third toes. The average birth weight in Tanner's patients (Tanner et al, 1975) was 3.1 SD below the mean. The children are usually very thin, but Davies et al (1988) found that in girls, in contrast to boys, there is a tendency to gain subcutaneous fat after puberty. Mature height in both sexes was about 3.6 sD below the mean for British children, corresponding to 142 cm for girls and 150.7 cm for boys. Growth velocity during childhood was normal but there was little catch-up growth during childhood and adolescence. An abnormal timing of puberty was originally described by Silver et al (1953), but could not be confirmed by Davies et al (1988), who found an essentially normal adolescent growth spurt that was slightly reduced in magnitude and occurred slightly earlier. While during early childhood bone age development is retarded, it catches up until puberty is reached (Tanner et al, 1975). Endocrinological studies in patients with Silver-Russell syndrome are usually normal; however, seven cases with growth hormone deficiency have been reported, four of which had additional pituitary abnormalities (Cassidy et al, 1986).
Seckel syndrome (microcephalic primordial dwarfism type I) The syndrome was defined by Seckel (1960) on the basis of 13 cases. His original definition included severe intrauterine and proportionate postnatal dwarfism, severe microcephaly, 'bird-headed' profile with receding forehead and chin, large and beaked nose, severe mental retardation and some other anomalies such as dislocation of the head of the radius. In 1982, Majewski and Goecke in analysing 60 cases from the literature then published, found that two-thirds of these did not meet the diagnostic criteria proposed by Seckel. Seckel syndrome has to be distinguished from clinically similar syndromes like the different types of osteodysplastic primordial dwarfism (types I-III) (Majewski and Spranger, 1976; Majewski et al, 1982a, 1982b) which are characterized by additional anomalies such as joint dislocations, shortened or bowed long bones (type I), elongated clavicles, cleft cervical vertebral arches, lumbar platyspondyly and abnormal pelvis (type III) or disproportionate shortness of forearms and legs in the first years of life, brachymesophalangy, brachymesocarpaly I, V-shaped flare of at least the distal femoral metaphyses, triangular shape of the distal femoral epiphyses, a high and narrow pelvis, proximal femoral epiphysiolysis and coxa vara (type II). Symptoms of type I and type III have been found together in some patients so that there is some controversy as to whether they may represent one entity (Haan et al, 1989). Average birth weights in patients with typical Seckel syndrome ranged from 1000 to 2055 g (Majewski and Goecke, 1982), postnatal height ranged between -5.1 and - 13.3 SD, head circumferences were between -4.1 and --14.3SD. All patients analysed by Majewski and Goecke were mentally
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retarded, nearly half with an intelligence quotient below 50. Bone age was retarded in all patients. Gross hormonal disturbances were not detected in any of the cases studied. Intrauterine infections
The most typical form of fetal infection causing fetal growth retardation is the rubella virus infection. Studies by Naeye and Blanc (1965) indicated that the rubella infection leads to a reduction of cell number and size in fetal organs. About 30% of infants with cytomegalovirus infection are growth retarded (McCracken et al, 1969). Other congenital virus infections (herpes simplex, varicella zoster) can also lead to growth retardation of the fetus (Waterton, 1979). Among congenital bacterial infections listeriosis, syphilis and toxoplasmosis may cause fetal growth retardation. Malaria, which seems to act largely through infestation of the placenta, is possibly the most important infectious cause of low birth weight world-wide (McGregor et al, 1983). Hormonal studies have so far revealed no abnormalities. Maternal addictions
Smoking The adverse effects of maternal smoking on fetal growth have been repeatedly demonstrated over the last 30 years. Birth weights of infants of mothers who smoke average about 200 g less than those of non-smoking mothers (Pirani, 1978). In a German perinatal study the proportion of low birth weight infants increased from 8.5% in non-smoking mothers to 16.7% in mothers who smoked more than ten cigarettes per day during pregnancy (Schwangerschaftsverlauf und Kindesentwicklung, 1977). As early as 1964, Miller and Hassanein showed that maternal smoking was associated with reductions of birth weight and length in infants born at term, but had no influence on the PI. This supports the view that smoking reduces the growth potential rather than impairing fetal nutrition. Children of mothers who smoked during pregnancy have reduced height and delayed educational attainment (Butler and Goldstein, 1973), which lends further support for this view. The mechanism of action of smoking on fetal growth is not clear. Nicotine may lead to vasoconstriction of uterine vessels with reduced perfusion of the intervillous space, resulting in a reduced oxygen transfer to the fetus. Hypoxia may further be aggravated by carbon monoxide which destroys the oxygen binding power of haemoglobin and myoglobin. Low concentrations of hydrocyanic acid in tobacco smoke may cause cellular anoxia by inactivating cytochrome oxidase.
Alcohol Growth retardation is a prominent feature of the embryo-fetal alcohol
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syndrome (Brander, 1938; Lemoine et al, 1968; Jones et al, 1973, 1974; Bierich et al, 1976; Oullette et al, 1977). The severity of growth retardation, dysmorphic features and of mental impairment is related to the quantity of alcohol consumed, but probably also to gestational timing and individual fetal response. Symptoms are marked in cases where the maternal intake exceeds 45 ml pure alcohol per day (Oullette et al, 1977). The common association of heavy smoking with heavy drinking may impose some problems in analysis. Retardation of length and weight are proportional (PI is usually normal), indicating an early onset of the injury. In the 24 cases described by Bierich et al (1976), mean birth weight was 1959 g, mean birth length 44.1 cm and mean head circumference 32.9cm. Postnatally there was a certain degree of catch-up of growth in length and to a lesser degree in weight, but a further retardation of skull growth, pointing to the disturbed brain development. Small head size at birth correlates with reduced mental performance later in life. In a retrospective and prospective study Olegard (1979) found an intelligence quotient below 85 in 58% and below 70 in 19% of cases. Characteristic craniofacial dysmorphic features present in addition to microcephaly are epicanthal folds, blepharophimosis, ptosis, maxillary hypoplasia, microgeny, a high arched palate and dysplasia of the external ear and a missing philtrum. Extracranial dysmorphic features include brachydactyly V and clinodactyly V, which also can be observed in other forms of IUGR. In eight of 24 cases Bierich et al (1976) found a funnelshaped chest. Cardiovascular malformations were detected in nine of 24 cases (six atrial septal defects, one ventricular septal defect, one hypertrophic subaortal stenosis, one aplasia of the right pulmonary artery) (L6ser et al, 1977). Mental retardation is a common feature of the syndrome. It appears to be due to structural abnormalities of the brain with leptomeningeal neuroglial heterotopia (surface heterotopia). The extent to which this brain malformation is specific for alcohol teratogenicity is presently unknown (Clarren et al, 1978). It appears that problems of brain morphogenesis can be the predominant effect of alcohol exposure in utero (Clarren et al, 1978; Jones et al, 1974) and may even occur as the only apparent abnormality. Heroin
Maternal heroin addiction is associated with both preterm and I U G R infants. The effect persists when allowance is made for differences in maternal nutrition (Naeye et al, 1973). That infections and other drugs may play a role in the effect of heroin and related drugs on fetal growth cannot, however, be excluded. INCIDENCE OF BIRTH DEFECTS IN N E W B O R N S WITH IUGR
Major birth defects are diagnosed in about 3-4% of infants during their first year of life (Centers for Disease Control, 1988). In a population based study,
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Khoury et al (1988) found a significantly higher risk of IUGR among infants with serious birth defects (relative risk 2.6). Similarly, in population based studies in the UK (Alberman et al, 1985; Powell et al, 1988), 10-20% of stillborn and liveborn infants weighing less than 2000 g had birth defects. Mili et al (1991), from the analysis of 11398 infants with serious birth defects (Metropolitan Atlanta Congenital Defects Program 1978-1988) found that the rate of birth defects varies greatly across the different birth weight categories. Of infants weighing less than 1500 g at birth, 16-17% had serious congenital defects, compared with about 3% of infants weighing 2500 g or more at birth. The findings suggest that low birth weight and birth defects may share common pathogenetic mechanisms. The association may be explained by two mechanisms: 1. 2.
Birth defects may predispose infants to low birth weight if they lead to IUGR, preterm delivery or both. Low birth weight and birth defects may coexist because of common underlying factors.
The first mechanism suggests that the presence of birth defects is a risk factor for I U G R and preterm delivery. Some authors have suggested that, for example in infants with congenital heart malformations, haemodynamic factors such as low oxygen saturation or perfusion may contribute to IUGR. Khoury et al (1988) found I U G R in 22.3 % of infants with major birth defects, most strikingly in infants with chromosomal anomalies and anencephaly, and the risk increased substantially as the number of defects increased. The second mechanism suggests that common factors may underlie the pathogenesis of I U G R and birth defects. Embryonic and fetal growth are regulated by the interaction between genes, nutritional and environmental influences, fetal and placental hormones, and growth factors (Milner and Hill, 1987, 1989). Teratogenic influences involved in the development of abnormal tissue include gene and chromosomal mutations, alterations of the intercellular communication or membrane properties, and the modulation of hormone receptors (Vainio, 1989). LONG-TERM GROWTH AND DEVELOPMENT OF CHILDREN WITH IUGR
In spite of an extremely heterogeneous aetiology there is relatively little variability in the postnatal growth patterns of children with IUGR. Most of the children show a certain degree of catch-up growth during the first 6 months of life, but rarely reach the final adult height of their normal birth weight peers (Fitzhardinge and Steven, 1972a; Westwood et al, 1983). The control of the growth spurt during the first months of life is not well understood. Colle et al (1976) followed the insulin response after an i.v. bolus of glucose in a group of 6-month-old infants with I U G R and demonstrated a significant correlation between linear growth during the first 6 months and the incremental insulin response. The infants with the lowest insulin response were those who had failed to attain a length above the tenth
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percentile for age. This led the authors to conclude that insulin may play a permissive role for the catch-up growth. However, the actual degree of height deficit at birth was another important determinant for the height attained at 6 months of age. Profound changes of perinatal care during the last decade have largely improved survival rates and reduced the rates of neurological handicaps in children with IUGR. Growth failure and other abnormalities can be diagnosed by ultrasound at an early stage of fetal development. There is marked improvement of early postnatal growth, but stature at 18 months (Fitzhardinge and Inwood, 1989) and 2 years (Tenovuo et al, 1987) has not shown an improvement over previous findings. In Fitzhardinge's study, 29% of the full-term and 44% of the pre-term infants were still below the fifth centile in length and weight at 18 months of age. Catch-up in both studies only occurred during the first 6 months of life. In contrast, in a retrospective study in 24 children with I U G R re-evaluated at a mean age of 5.5 years, Rochiccioli et al (1989) observed a rapid and early catch-up growth between the ages of 6 months and 3 years, followed by a decrease in growth velocity. The investigation of growth hormone secretion showed an abnormality in 66% and a high incidence of so called 'neurosecretory dysfunction' (37.5 %). Other investigators confirmed these results and showed decreased spontaneous growth hormone secretion or more subtle abnormalities in many of their patients with I U G R (Albertsson-Wikland et al, 1989; Stanhope et al, 1989).
GROWTH HORMONE TREATMENT IN CHILDREN WITH IUGR
In 1971 Tanner et al reported that three of 15 children with Silver-Russell syndrome gained more than 2cm on a regimen of 5-10 units of growth hormone per week over a period of 12 months. In 1972, Grunt et al confirmed these results showing that two out of six children with I U G R gained 2 cm on 4 units of growth hormone given three times per week over 12 months. Foley et al (1974) and Lanes et al (1979) were able to show that growth hormone given for i year increased the growth rates of children with I U G R in a dose-dependent manner. More recently, with the availability of recombinant growth hormone, the results of a number of studies have been presented demonstrating that growth hormone treatment with doses of 15 or 30unitsm -~week -1 (Stanhope et al, 1989), 0.3unitskg -1week -1 (Rochiccioli et al (1989) and 0.7 units kg -1 week -1 (Albertsson-Wikland et al, 1989) can significantly increase the short-term growth rate of children with IUGR. Stanhope admitted that during treatment bone maturation advanced rapidly and inappropriately so that there was no alteration in final height prognosis. Heterogeneity within the groups of children with IUGR has hitherto complicated analysis of treatment results. Job (1991) presented the preliminary results of a French multicentre study which included 95 prepubertal children with I U G R (mean birth length - 3.41 _+1.0 so, mean birth weight
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- 2 . 6 5 + 0.77 so), most of them without detectable cause or associated dysmorphic features. Forty-seven of the children received 0.4 units kg-1 week-1 and 48 received 1.2 units kg- a week- 1growth hormone for 2 years. There was an overall dose-effect relationship for the first 18 months, but the individual growth response in both dose regimens was extremely variable, with a tendency for an inadequate bone age maturation in both the tow and high dose groups. Thus, while there is some indication that growth hormone treatment may be beneficial for some children with IUGR, long-term observations will be needed to decide whether or not the gain in height will exceed the detrimental effect on bone maturation. SUMMARY
Intrauterine growth retardation (IUGR) is an important cause of small stature in children presenting to paediatric endocrinologists. I U G R has to be differentiated from familial ('constitutional') short stature, where the growth deficit is genetically determined and/or induced by smallness of the mother (maternal constraint). Intrinsic fetal anomalies such as chromosomal abnormalities, primary growth failure syndromes, congenital infections and congenital anomalies are of equal importance with maternal disorders, in particular chronic use of alcohol, tobacco and narcotics, and pregnancy complications like hypertension and pre-eclampsia, in causing fetal growth retardation. The relative importance of placental abnormalities and environmental factors (with the exception of malnutrition) appears to be small. Some catch-up growth of children with I U G R has been observed in about 70 % of all cases during the first year of life. Many I U G R children show major or minor birth defects which may be predisposing factors or may also coexist because of common underlying factors producing both small stature and structural anomalies. Since in most children with I U G R adult heights to be expected are below the population range, growth hormone treatment has been tried for many years, but the data available from the literature are not encouraging to date and need to be re-evaluated in controlled long-term trials.
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Lubchenko LO, Hansman C, Dressier B e t al (1963) Intrauterine growth as estimated from liveborn birthweight data at 24 to 42 weeks of gestation. Pediatrics 32: 793-800. McCracken GH, Shinefield HR, Cobb K, Rausen AR, Dische MR & Eichenwald HF (1969) Congenital cytomegalovirus inclusion disease. American Journal of Diseases of Children 117: 522-539. McGregor IA, Wilson E & Billewicz WZ (1983) Malaria infection of the placenta in the Gambia, West Africa; its incidence and relationship to stillbirth, birthweight and placental weight. Transactions of the Royal Society of Tropical Medicine and Hygiene 77: 223-244. Majewski F & Goecke T (1982) Studies of microcephalic primordial dwarfism. I. Approach to a delineation of the Seckel syndrome. American Journal of Medical Genetics 12: 7-21. Majewski F & Spranger J (1976) Ober einen neuen Typ des primordialen Minderwuchses: der brachymele primordiale Minderwuchs. Monatsschrift Kinderheilkunde 124: 499-503. Majewski F, Ranke M & Schinzel A (1982a) Studies of microcephalic primordial dwarfism. II. Osteodysplastic primordial dwarfism type II. American Journal of Medical Genetics 12: 23-35. Majewski F, Stoeckenius M & Kemperdick H (1982b) Studies of microcephalic primordial dwarfism. III. An intrauterine dwarf with platyspondyly and anomalies of pelvis and clavicles: osteodysplastic primordial dwarfism type III. American Journal of Medical Genetics 12: 37-42. Michaelis R, Schulte F & Nolte R (1970) Motor behaviour of small for gestational age newborn infants. Pediatrics 76: 208-215. Mili F, Edmonds LD, Khoury MJ & McClearn AB (1991) Prevalence of birth defects among low-birth-weight infants. American Journal of Diseases of Children 145: 1313-1318. Miller HC (1981) Intrauterine growth retardation: an unmet challenge. American Journal of Diseases of Children 135: 944-948. Miller HC (1985) Prenatal factors affecting intrauterine growth retardation. Clinics in Perinatology 12: 307. Miller HC & Merritt TA (1979) Fetal Growth in Humans, pp 31-57; 127-141. Chicago: Year Book Medical. Milner RDG & Hill DJ (1987) Interaction between endocrine and paracrine peptides in prenatal growth. European Journal of Pediatrics 146:113-122. Milner RDG & Hill DJ (1989) Fetal growth signals. Archives of Disease in Childhood64: 53-57. Naeye RL & Blanc W (1965) Pathogenesis of congenital rubella. Journal of the American Medical Association 194: 1277-1283. Naeye RL, Blanc W, Leblanc W & Khatamee MA (1973) Fetal complications of maternal heroin addiction: abnormal growth, infections, and episodes of stress. Journal of Pediatrics 83: 1055-1061. Oiegard R, Sabel KG, Aronsson B e t al (1979) Effects on the child of alcohol abuse during pregnancy. Retrospective and prospective studies. Acta Paediatrica Scandinavica. Supplement 275:112-121. Oullette EM, Rosett HL, Rosman NP & Weiner L (1977) Adverse effects on offspring of maternal alcohol abuse during pregnancy. New England Journal of Medicine 297: 528530. Ounsted M & Ounsted C (1973) On fetal growth rate. Clinics in Developmental Medicine, No. 46. London: Spastics International Medical Publications. Ounsted M, Moar VA & Scott A (1985) Risk factors associated with small-for-dates and large-fo:-dates infants. British Journal of Obstetrics and Gynaecology 92: 226. Pankau R, Johannson W & Meinicke P (1990) Das Brachmann-de Lange Syndrom bei 16 eigenen Patienten. Monatsschrift Kinderheilkunde 138: 72-76. Pirani BB (1978) Smoking during pregnancy. Obstetrical and Gynecological Survey 33: 1-13. Polani PE (1974) Chromosomal and other genetic influences on birth weight variation. Ciba Foundation Symposium 27: 127-160. Powell TG, Pharoah POD & Cooke RWI (1988) Congenital defects and care of low birth weight infants. Early Human Development 16: 173-183. Resnik R (1978) Maternal diseases associated with abnormal fetal growth. Journal of Reproductive Medicine 21: 315. Rochiccioli P, Tauber M, Moisan V & Pienkowski C (1989) Investigation of growth hormone secretion in patients with intrauterine growth retardation. Acta Paediatrica Scandinavica. Supplement 349: 42-46.
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Rudolph A (1985) Failure to thrive in the perinatal period. Acta Paediatrica Scandinavica. Supplement 319: 55--61. Russell A (1954) A syndrome of intrauterine dwarfism recognisable at birth with craniofacial dysostosis, disproportionately short arms and other abnormalities (5 examples). Proceedings of the Royal Society of Medicine 47: 1070. Schwangerschaftsverlauf und Kindesentwicklung (1977) Bisherige Ergebnisse eines seit 1964 gefrrderten Schwerpunktprogramms. DFG Forschungsbericht, pp 13-15, 60-66. Boppard: Harald Boldt. Seckel HPG (1960) Bird-headed Dwarfs. Springfield, IL: CC Thomas. Silver HK, Kiyasu N, George J & Deamer WC (1953) Syndrome of congenital hemihypertrophy, shortness of stature and urinary gonadotrophins. Pediatrics 12: 368. Stanhope R, Ackland F, Hamill G, Clayton J, Jones J & Preece MA (1989) Physiological growth hormone secretion and response to growth hormone treatment in children with short stature and intrauterine growth retardation. Acta Paediatrica Scandinavica. Supplement 349: 47-52. Tanner JM, Whitehouse RH, Hughes PCR & Vince FP (1971) Effect of growth hormone treatment for 1 to 7 years on the growth of 100 children with growth hormone deficiency, low birthweight, inherited smallness, Turner's syndrome, and other complaints. Archives of Disease in Childhood 46: 745-782. Tanner JM, Lejarraga H & Cameron N (1975) The natural history of the Silver-Russell syndrome: a longitudinal study of thirty-nine cases. Pediatric Research 9: 611-623. Tenovuo A, Kero P, Piekkala P, Korvenranta H, Sillanpaa M & Erkkola R (1987) Growth of 519 small for gestational age infants during the first two years of life. Acta Paediatrica Scandinavica 76: 636-646. Usher R & McLean F (1969) Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. Pediatrics 74: 901-910. Vainio H (1989) Carcinogenesis and teratogenesis may have common mechanisms. Scandinavian Journal of Work, Environment and Health 15: 13-17. Visser GHA, Huisman A, Saathof PWF et al (1986) Early fetal growth retardation. Obstetric background and recurrence rate. Obstetrics and Gynecology 67: 40. Walther FJ & Ramaekers LHJ (1982) Growth in early childhood of newborns affected by disproportionate intrauterine growth retardation. Acta Paediatrica Scandinavica 71: 651656. Waterton AP (1979)'Virus infections (other than rubella) during pregnancy. British Medical Journal 2: 564-566. Wennergren M, Karlsson K & Olsson T (1982) A scoring system for antenatal identification of fetal growth retardation. British Journal of Obstetrics and Gynaecology 89: 520. Westwood M, Kramer MS, Munz D, Lovett JM & Waiters GV (1983) Growth and development of full-term nonasphyxiated small-for-gestational-age newborns: follow-up through adolescence. Pediatrics 71: 376-382. Winter RM (1986) Dubowitz syndrome. Journal of Medical Genetics 23: 11-13. Wolfe HM, Gross TL & Sokol RJ (1987) Recurrent small for gestational age birth: perinatal risks and outcomes. American Journal of Obstetrics and Gynecology 157: 288.
DEFINITION AND INCIDENCE OF INTRAUTERINE GROWTH RETARDATION
Traditionally, low birth weight has been associated with prematurity. Only in relatively recent years has it been accepted that low birth weight can also result from insufficient prenatal growth and that preterm infants with appropriate weight and infants which are small for their gestational age differ profoundly from the clinical point of view (Battaglia, 1970). Cut-off points for the definition of infants with intrauterine growth retardation (IUGR) differ widely: they include the third, the fifth birth weight percentile, 2 SD below the mean or the tenth percentile (Lubchenko et al, 1963; Gruenwald, 1966; Usher and McLean, 1969; Michaelis et al, 1970; Fitzhardinge and Stevens, 1972a,b). Since race, parity of the mother and sex of the infant influence birth weight, standards which are specific for these factors have been published (Kloosterman, 1970; Miller and Merritt, 1979). A reasonable definition for IUGR from reviewing the literature is the following: these are children whose birth lengths are below the tenth percentile and whose birth weights are equal to or below the tenth percentile according to sex and ethnic background. The currently used definition of IUGR has limitations, since many infants with birth weights and lengths below the tenth percentile are simply 'constitutionally small' and have not suffered from a pathological restriction of intrauterine growth. Criteria have been proposed to differentiate between infants with limited growth potential and infants who are really growth retarded. The ponderal index (PI) (Walther and Ramaekers, 1982) evaluates the ratio of soft tissue mass to skeletal frame and is determined in the neonate by the equation: PI = Weight (g) x 100 length 3 (cm) It is widely used and helps to define different forms of IUGR (Resnik, 1978; Wennergren et al, 1982; Miller, 1985; Ounsted et al, 1985; Visser et al, 1986; Wolfe et al, 1987): Bailli~re's Clinical Endocrinology and Metabolism-589 Vol. 6, No. 3, July 1992 Copyright © 1992, by Baillifre Tindall ISBN 0-7020-1620-9 All rights of reproduction in any form reserved
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1. Proportionate (symmetric) growth retardation. Birth length, weight and head circumference are all at the same percentile on growth charts. The PI is within the limits defined as normal (2.2-3.0) (Miller, 1981 ). The impairment of growth begins early in gestation (fetuses with chromosomal anomalies, genetic dwarfing syndromes and intrauterine infections, familial (constitutional) smallness). 2. Disproportionate (asymmetric) growth retardation. In these infants the birth weight is decreased but length and head circumference are on a higher percentile on growth charts. The PI is usually below the limits defined as normal. Negative influences interfering with normal intrauterine growth have been involved only after the 30th week of gestation (infants born to mothers with hypertension or toxaemia of pregnancy). The incidence of I U G R varies greatly with the population studied. Low socioeconomic conditions are associated with a high incidence of IUGR, whereas in developed countries an incidence of 4-7 per 100 births has been quoted.
DEFINITION OF FAMILIAL SHORT STATURE
Height for chronological age is below the population range but normal for the height of the parents. Growth velocity is normal, i.e. distant growth curves parallel the normal percentiles. Bone age development is in accordance to chronological age and the timing of puberty is normal. In the literature there is some confusion in the terminology, in that some investigators use the term 'constitutional short stature' for this group of short children; others even include children with 'constitutional delay of growth and adolescence' (CDGA) in this category. While a familial relationship is common to both entities, the latter children have retarded bone ages, a slowing of their 'tempo' of growth and development, late puberty and are usually of normal length at birth. Another important discriminating factor is the adult height to be expected. In familial short stature the adult height expectation is limited by the short stature of one or both of the parents. Children with C D G A tend to reach an adult height within the population range. In many cases there is an overlap of both entities: these children are small from birth onwards, have retarded bone ages and their midparental height is below the tenth percentile of the population range. They are characterized by a late puberty and they will finally reach an adult height in accordance with parental heights, albeit below the population range (so-called small delay). The term 'constitutional short stature' would be better discarded and replaced by the term 'familial short stature' to prevent confusion with the term 'constitutional delay of growth and adolescence'.
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AETIOPATHOLOGY OF IUGR
Normal fetal growth The rate of fetal weight gain increases from 5 g/day at 14-15 weeks of gestation to 10 g/day at 20 weeks and to 30-35 g/day at 32-34 weeks. The rate peaks at 33-36 weeks gestation at approximately 230 g/week and thereafter decreases, reaching zero or an actual loss at 41-42 weeks gestation (Rudolph, 1985). The position of the linear growth peak velocity is somewhat uncertain, probably about 20-24 weeks. Then a linear growth deceleration occurs and joins the infant's postnatal deceleration of length velocity at birth (Falkner, 1985). There are many factors influencing fetal growth. In the normal fetus sex and plurality, birth order, social and economic conditions, parental height and ethnic factors modulate size at birth. Genetic factors seem to play only a small part in determining birth weight (Ounsted and Ounsted, 1973). Ounsted and Ounsted termed the maternal effect on birth size 'maternal constraint' and showed that this effect is familial through the female line.
Intrauterine growth retardation I U G R is the result of many different disturbances. Conditions interfering with normal fetal growth and development have commonly been differentiated into fetal, placental, maternal and environmental factors. In many cases no underlying condition can be elucidated ('idiopathic' IUGR). Table i summarizes the factors which may interfere with fetal growth and development. Chromosomal aberrations are found in 5-15% and maternal disease is assumed to account for 25-30% of all cases of IUGR. Placental factors are relatively rare. The contribution of environmental factors is largely unknown. Maternal malnutrition is by far the most frequent cause of fetal growth retardation all over the world, but is exceedingly rare in developed countries. Congenital infections account for 1-2% of all cases. Maternal smoking and alcohol and drug addiction are well known causes of IUGR but their contribution to the overall number of cases is difficult to assess.
Chromosomal causes and primary growth failure syndromes In a high proportion of chromosomally abnormal fetuses intrauterine growth is impaired. The average birth weight at term in newborns with the Ullrich-Turner syndrome is 84%, in trisomy 13 80%, in trisomy 21 80-90%, and in trisomy 18 only 60% of the normal mean. Chromosomal deletions are also associated with reduced birth size (Polani, 1974). Severe growth retardation is also a feature of fetuses with triploidy (Doshi et al, 1983). In addition, there are a number of primary, in part genetically determined, syndromes with severe IUGR, including the Silver-Russell and the Seckel syndromes.
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Silver-Russell syndrome In 1953 and 1954 Silver and Russell independently described a new syndrome of small stature. While Silver observed asymmetrical features, Russell emphasized the prenatal smallness and the craniofacial dysostosis. It is now thought that the patients described by the two authors represent the same syndrome, which is characterized by IUGR, a small triangular face, a Table 1. Factors interfering with normal fetal growth and development.
Intrinsic fetal anomalies Chromosomal Trisomies 13, 18, 21 Deletions 4p-, 5p-, etc. Ullrich-Turner syndrome and variants Primary growth failure syndromes Silver-Russell syndrome Seckel syndrome Brachmann-de-Lange syndrome (Pankau et al, 1990) Bloom syndrome (German et al, 1984) Dubowitz syndrome (Dubowitz, 1965; Winter, 1986) Fanconi pancytopenia syndrome Osteochondrodysplasias Leprechaunism (Catani et al, 1987) Etc. Congenital infections Rubella Cytomegaly Toxoplasmosis Etc. Congenital anomalies Bilateral renal agenesis Defects of the neural axis Congenital heart disease Malformations of the GI tract Abnormalities of the placenta Abnormal implantation Vascular anomalies, e.g. haemangiomas, etc. Tumours of the placenta Progressive vascular disease Maternal disorders Cardiovascular disorders: hypertension, cardiac disease, preeclampsia, severe diabetes mellitus Maternal phenylketonuria (Lipson et al, 1984) Chronic respiratory diseases Chronic renal diseases Collagen diseases Anaemias Uterine malformations Drugs: alcohol, tobacco, narcotics abuse Therapeutic drugs Environmental factors Maternal malnutrition High altitude Occupational hazards Irradiation
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skull of large appearance with a prominent forehead and low set ears, a small mandible in relation to the maxilla, clinodactyly of the fifth finger, and a number of facultative features like asymmetry of the face and/or body and syndactyly of the second and third toes. The average birth weight in Tanner's patients (Tanner et al, 1975) was 3.1 SD below the mean. The children are usually very thin, but Davies et al (1988) found that in girls, in contrast to boys, there is a tendency to gain subcutaneous fat after puberty. Mature height in both sexes was about 3.6 sD below the mean for British children, corresponding to 142 cm for girls and 150.7 cm for boys. Growth velocity during childhood was normal but there was little catch-up growth during childhood and adolescence. An abnormal timing of puberty was originally described by Silver et al (1953), but could not be confirmed by Davies et al (1988), who found an essentially normal adolescent growth spurt that was slightly reduced in magnitude and occurred slightly earlier. While during early childhood bone age development is retarded, it catches up until puberty is reached (Tanner et al, 1975). Endocrinological studies in patients with Silver-Russell syndrome are usually normal; however, seven cases with growth hormone deficiency have been reported, four of which had additional pituitary abnormalities (Cassidy et al, 1986).
Seckel syndrome (microcephalic primordial dwarfism type I) The syndrome was defined by Seckel (1960) on the basis of 13 cases. His original definition included severe intrauterine and proportionate postnatal dwarfism, severe microcephaly, 'bird-headed' profile with receding forehead and chin, large and beaked nose, severe mental retardation and some other anomalies such as dislocation of the head of the radius. In 1982, Majewski and Goecke in analysing 60 cases from the literature then published, found that two-thirds of these did not meet the diagnostic criteria proposed by Seckel. Seckel syndrome has to be distinguished from clinically similar syndromes like the different types of osteodysplastic primordial dwarfism (types I-III) (Majewski and Spranger, 1976; Majewski et al, 1982a, 1982b) which are characterized by additional anomalies such as joint dislocations, shortened or bowed long bones (type I), elongated clavicles, cleft cervical vertebral arches, lumbar platyspondyly and abnormal pelvis (type III) or disproportionate shortness of forearms and legs in the first years of life, brachymesophalangy, brachymesocarpaly I, V-shaped flare of at least the distal femoral metaphyses, triangular shape of the distal femoral epiphyses, a high and narrow pelvis, proximal femoral epiphysiolysis and coxa vara (type II). Symptoms of type I and type III have been found together in some patients so that there is some controversy as to whether they may represent one entity (Haan et al, 1989). Average birth weights in patients with typical Seckel syndrome ranged from 1000 to 2055 g (Majewski and Goecke, 1982), postnatal height ranged between -5.1 and - 13.3 SD, head circumferences were between -4.1 and --14.3SD. All patients analysed by Majewski and Goecke were mentally
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retarded, nearly half with an intelligence quotient below 50. Bone age was retarded in all patients. Gross hormonal disturbances were not detected in any of the cases studied. Intrauterine infections
The most typical form of fetal infection causing fetal growth retardation is the rubella virus infection. Studies by Naeye and Blanc (1965) indicated that the rubella infection leads to a reduction of cell number and size in fetal organs. About 30% of infants with cytomegalovirus infection are growth retarded (McCracken et al, 1969). Other congenital virus infections (herpes simplex, varicella zoster) can also lead to growth retardation of the fetus (Waterton, 1979). Among congenital bacterial infections listeriosis, syphilis and toxoplasmosis may cause fetal growth retardation. Malaria, which seems to act largely through infestation of the placenta, is possibly the most important infectious cause of low birth weight world-wide (McGregor et al, 1983). Hormonal studies have so far revealed no abnormalities. Maternal addictions
Smoking The adverse effects of maternal smoking on fetal growth have been repeatedly demonstrated over the last 30 years. Birth weights of infants of mothers who smoke average about 200 g less than those of non-smoking mothers (Pirani, 1978). In a German perinatal study the proportion of low birth weight infants increased from 8.5% in non-smoking mothers to 16.7% in mothers who smoked more than ten cigarettes per day during pregnancy (Schwangerschaftsverlauf und Kindesentwicklung, 1977). As early as 1964, Miller and Hassanein showed that maternal smoking was associated with reductions of birth weight and length in infants born at term, but had no influence on the PI. This supports the view that smoking reduces the growth potential rather than impairing fetal nutrition. Children of mothers who smoked during pregnancy have reduced height and delayed educational attainment (Butler and Goldstein, 1973), which lends further support for this view. The mechanism of action of smoking on fetal growth is not clear. Nicotine may lead to vasoconstriction of uterine vessels with reduced perfusion of the intervillous space, resulting in a reduced oxygen transfer to the fetus. Hypoxia may further be aggravated by carbon monoxide which destroys the oxygen binding power of haemoglobin and myoglobin. Low concentrations of hydrocyanic acid in tobacco smoke may cause cellular anoxia by inactivating cytochrome oxidase.
Alcohol Growth retardation is a prominent feature of the embryo-fetal alcohol
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syndrome (Brander, 1938; Lemoine et al, 1968; Jones et al, 1973, 1974; Bierich et al, 1976; Oullette et al, 1977). The severity of growth retardation, dysmorphic features and of mental impairment is related to the quantity of alcohol consumed, but probably also to gestational timing and individual fetal response. Symptoms are marked in cases where the maternal intake exceeds 45 ml pure alcohol per day (Oullette et al, 1977). The common association of heavy smoking with heavy drinking may impose some problems in analysis. Retardation of length and weight are proportional (PI is usually normal), indicating an early onset of the injury. In the 24 cases described by Bierich et al (1976), mean birth weight was 1959 g, mean birth length 44.1 cm and mean head circumference 32.9cm. Postnatally there was a certain degree of catch-up of growth in length and to a lesser degree in weight, but a further retardation of skull growth, pointing to the disturbed brain development. Small head size at birth correlates with reduced mental performance later in life. In a retrospective and prospective study Olegard (1979) found an intelligence quotient below 85 in 58% and below 70 in 19% of cases. Characteristic craniofacial dysmorphic features present in addition to microcephaly are epicanthal folds, blepharophimosis, ptosis, maxillary hypoplasia, microgeny, a high arched palate and dysplasia of the external ear and a missing philtrum. Extracranial dysmorphic features include brachydactyly V and clinodactyly V, which also can be observed in other forms of IUGR. In eight of 24 cases Bierich et al (1976) found a funnelshaped chest. Cardiovascular malformations were detected in nine of 24 cases (six atrial septal defects, one ventricular septal defect, one hypertrophic subaortal stenosis, one aplasia of the right pulmonary artery) (L6ser et al, 1977). Mental retardation is a common feature of the syndrome. It appears to be due to structural abnormalities of the brain with leptomeningeal neuroglial heterotopia (surface heterotopia). The extent to which this brain malformation is specific for alcohol teratogenicity is presently unknown (Clarren et al, 1978). It appears that problems of brain morphogenesis can be the predominant effect of alcohol exposure in utero (Clarren et al, 1978; Jones et al, 1974) and may even occur as the only apparent abnormality. Heroin
Maternal heroin addiction is associated with both preterm and I U G R infants. The effect persists when allowance is made for differences in maternal nutrition (Naeye et al, 1973). That infections and other drugs may play a role in the effect of heroin and related drugs on fetal growth cannot, however, be excluded. INCIDENCE OF BIRTH DEFECTS IN N E W B O R N S WITH IUGR
Major birth defects are diagnosed in about 3-4% of infants during their first year of life (Centers for Disease Control, 1988). In a population based study,
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Khoury et al (1988) found a significantly higher risk of IUGR among infants with serious birth defects (relative risk 2.6). Similarly, in population based studies in the UK (Alberman et al, 1985; Powell et al, 1988), 10-20% of stillborn and liveborn infants weighing less than 2000 g had birth defects. Mili et al (1991), from the analysis of 11398 infants with serious birth defects (Metropolitan Atlanta Congenital Defects Program 1978-1988) found that the rate of birth defects varies greatly across the different birth weight categories. Of infants weighing less than 1500 g at birth, 16-17% had serious congenital defects, compared with about 3% of infants weighing 2500 g or more at birth. The findings suggest that low birth weight and birth defects may share common pathogenetic mechanisms. The association may be explained by two mechanisms: 1. 2.
Birth defects may predispose infants to low birth weight if they lead to IUGR, preterm delivery or both. Low birth weight and birth defects may coexist because of common underlying factors.
The first mechanism suggests that the presence of birth defects is a risk factor for I U G R and preterm delivery. Some authors have suggested that, for example in infants with congenital heart malformations, haemodynamic factors such as low oxygen saturation or perfusion may contribute to IUGR. Khoury et al (1988) found I U G R in 22.3 % of infants with major birth defects, most strikingly in infants with chromosomal anomalies and anencephaly, and the risk increased substantially as the number of defects increased. The second mechanism suggests that common factors may underlie the pathogenesis of I U G R and birth defects. Embryonic and fetal growth are regulated by the interaction between genes, nutritional and environmental influences, fetal and placental hormones, and growth factors (Milner and Hill, 1987, 1989). Teratogenic influences involved in the development of abnormal tissue include gene and chromosomal mutations, alterations of the intercellular communication or membrane properties, and the modulation of hormone receptors (Vainio, 1989). LONG-TERM GROWTH AND DEVELOPMENT OF CHILDREN WITH IUGR
In spite of an extremely heterogeneous aetiology there is relatively little variability in the postnatal growth patterns of children with IUGR. Most of the children show a certain degree of catch-up growth during the first 6 months of life, but rarely reach the final adult height of their normal birth weight peers (Fitzhardinge and Steven, 1972a; Westwood et al, 1983). The control of the growth spurt during the first months of life is not well understood. Colle et al (1976) followed the insulin response after an i.v. bolus of glucose in a group of 6-month-old infants with I U G R and demonstrated a significant correlation between linear growth during the first 6 months and the incremental insulin response. The infants with the lowest insulin response were those who had failed to attain a length above the tenth
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percentile for age. This led the authors to conclude that insulin may play a permissive role for the catch-up growth. However, the actual degree of height deficit at birth was another important determinant for the height attained at 6 months of age. Profound changes of perinatal care during the last decade have largely improved survival rates and reduced the rates of neurological handicaps in children with IUGR. Growth failure and other abnormalities can be diagnosed by ultrasound at an early stage of fetal development. There is marked improvement of early postnatal growth, but stature at 18 months (Fitzhardinge and Inwood, 1989) and 2 years (Tenovuo et al, 1987) has not shown an improvement over previous findings. In Fitzhardinge's study, 29% of the full-term and 44% of the pre-term infants were still below the fifth centile in length and weight at 18 months of age. Catch-up in both studies only occurred during the first 6 months of life. In contrast, in a retrospective study in 24 children with I U G R re-evaluated at a mean age of 5.5 years, Rochiccioli et al (1989) observed a rapid and early catch-up growth between the ages of 6 months and 3 years, followed by a decrease in growth velocity. The investigation of growth hormone secretion showed an abnormality in 66% and a high incidence of so called 'neurosecretory dysfunction' (37.5 %). Other investigators confirmed these results and showed decreased spontaneous growth hormone secretion or more subtle abnormalities in many of their patients with I U G R (Albertsson-Wikland et al, 1989; Stanhope et al, 1989).
GROWTH HORMONE TREATMENT IN CHILDREN WITH IUGR
In 1971 Tanner et al reported that three of 15 children with Silver-Russell syndrome gained more than 2cm on a regimen of 5-10 units of growth hormone per week over a period of 12 months. In 1972, Grunt et al confirmed these results showing that two out of six children with I U G R gained 2 cm on 4 units of growth hormone given three times per week over 12 months. Foley et al (1974) and Lanes et al (1979) were able to show that growth hormone given for i year increased the growth rates of children with I U G R in a dose-dependent manner. More recently, with the availability of recombinant growth hormone, the results of a number of studies have been presented demonstrating that growth hormone treatment with doses of 15 or 30unitsm -~week -1 (Stanhope et al, 1989), 0.3unitskg -1week -1 (Rochiccioli et al (1989) and 0.7 units kg -1 week -1 (Albertsson-Wikland et al, 1989) can significantly increase the short-term growth rate of children with IUGR. Stanhope admitted that during treatment bone maturation advanced rapidly and inappropriately so that there was no alteration in final height prognosis. Heterogeneity within the groups of children with IUGR has hitherto complicated analysis of treatment results. Job (1991) presented the preliminary results of a French multicentre study which included 95 prepubertal children with I U G R (mean birth length - 3.41 _+1.0 so, mean birth weight
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- 2 . 6 5 + 0.77 so), most of them without detectable cause or associated dysmorphic features. Forty-seven of the children received 0.4 units kg-1 week-1 and 48 received 1.2 units kg- a week- 1growth hormone for 2 years. There was an overall dose-effect relationship for the first 18 months, but the individual growth response in both dose regimens was extremely variable, with a tendency for an inadequate bone age maturation in both the tow and high dose groups. Thus, while there is some indication that growth hormone treatment may be beneficial for some children with IUGR, long-term observations will be needed to decide whether or not the gain in height will exceed the detrimental effect on bone maturation. SUMMARY
Intrauterine growth retardation (IUGR) is an important cause of small stature in children presenting to paediatric endocrinologists. I U G R has to be differentiated from familial ('constitutional') short stature, where the growth deficit is genetically determined and/or induced by smallness of the mother (maternal constraint). Intrinsic fetal anomalies such as chromosomal abnormalities, primary growth failure syndromes, congenital infections and congenital anomalies are of equal importance with maternal disorders, in particular chronic use of alcohol, tobacco and narcotics, and pregnancy complications like hypertension and pre-eclampsia, in causing fetal growth retardation. The relative importance of placental abnormalities and environmental factors (with the exception of malnutrition) appears to be small. Some catch-up growth of children with I U G R has been observed in about 70 % of all cases during the first year of life. Many I U G R children show major or minor birth defects which may be predisposing factors or may also coexist because of common underlying factors producing both small stature and structural anomalies. Since in most children with I U G R adult heights to be expected are below the population range, growth hormone treatment has been tried for many years, but the data available from the literature are not encouraging to date and need to be re-evaluated in controlled long-term trials.
REFERENCES Alberman E, Benson J & Kani W (1985) Disabilities in survivors of low birth weight. Archives o f Disease in Childhood 60: 913-919. Albertsson-Wikland K and the Swedish Paediatric Study Group for Growth Hormone Treatment (1989) Growth hormone secretion and growth hormone treatment in children with intrauterine growth retardation. Acta Paediatrica Scandinavica. Supplement 349: 35-41. Battaglia FC (1970) Intrauterine growth retardation. American Journal o f Obstetrics and Gynecology 106: 1103-1114. Bierich JR, Majewski F, Michaelis R & Tillner I (1976) Uber das embryofetale Alkoholsyndrom. European Journal o f Pediatrics 121: 155-177. Brander T (1938) Ein Gesichtspunkt zur Frage 'Alkohol und Nachkommenschaft'. Z. menschl. Vererb u. Konstit. Lehre 22: 61.
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