Small for gestation and growth hormone therapy
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《美国医学杂志》
Centre for Child Health, Sir Ganga Ram Hospital, New Delhi, India
Abstract
3 to 10% of neonates are born small for gestation (SGA). This usually occurs because of intrauterine growth retardation (IUGR). After birth most SGA infants show good catch-up growth and normalize their height and weight. About 10% of them continue to remain short (<-2SD) and do not achieve normal adult height, resulting in psychosocial problems. The mechanism of short stature in these children is poorly understood. Infants who do not show catch-up growth usually have an alteration in the GH-IGF-I axis. Diagnostic and management criteria for short stature in SGA were ill-defined in the past. Growth hormone (GH) therapy for improving height in these children has been approved by the FDA. GH therapy leads to growth acceleration and normalization of height during childhood. Long term GH treatment normalizes adult height above -2 SDS in 85% children, and 98% achieve an adult height within their target height range. GH therapy is safe in SGA children, but it is important to monitor for side effects.
Keywords: Growth hormone; Short stature; Small for gestational age
Small for gestation (SGA) is defined as a birth weight or length, more than 2 SD below the mean for the gestational age and sex, for a reference population. Intrauterine growth retardation (IUGR) is a pathophysiological term that refers to the growth deceleration in-utero. A fetus with IUGR could be AGA (appropriate for gestation) or SGA at birth. SGA refers to the birth size irrespective of the growth velocity in the uterus, although most SGA babies have IUGR.
Prevalence
3-10% babies worldwide are born SGA. In USA, 8.6% of live births are SGA.[1] Data collected from two hospitals in Kolkata reported that the proportion of infants weighing less than 2,001 g is approximately 10%, the dependence of this proportion on maternal age and parity being similar to the studies conducted elsewhere, suggesting a definite biological significance of the phenomenon.[2]
Factors Influencing Size of Babies at Birth
The birth size of babies is influenced by a number of factors. They are enumerated further.
1. Maternal factors
Nutrition of the mother : Malnutrition is a common cause of IUGR in developing countries like India. Malnutrition during the early part of pregnancy leads to impaired cell growth and multiplication. This results in fetus which is symmetrically small ( proportionate SGA ). Malnutrition in the later part of pregnancy results in small cell size but normal proliferation. The fetus has a larger head and small body since the blood flow is directed towards the development of the brain at the cost of the rest of the body (brain sparing phenomenon).[3] This has been referred to as asymmetric IUGR .
Maternal illness: Chronic vascular disease and hypoxemia in the mother, secondary to diseases like asthma, sickle cell anemia etc. results in IUGR.[4] Perinatal hypertension results in SGA babies.[5],[6]
Environmental toxins : Cigarette smoking, alcohol ingestion and intake of drugs like heroin etc. during pregnancy result in SGA babies.[7],[8]
Infections: Bacterial, protozoal and viral infections such as CMV and rubella in the mother also influence the size of babies at birth.
2. Placental factors
Compromise of utero-placental blood flow, infarction, abruption of placenta result in fetal hypoxemia and IUGR.
3. Fetal factors
Genetic syndromes such as Russell Silver, de Lange, Williams, Bloom and Johnson Blizzard syndrome are associated with SGA. Chromosomal abnormalities such as Down and Turner syndromes, congenital malformations and twin pregnancies can result in SGA babies.
4. Genetic factors
The size of the parents, especially the mother, affects the size of the baby at birth. Constitutional SGA has been reported as a common cause of SGA in Indian babies.[9]
The causes of SGA are listed in table1.
Endocrine Regulation of Fetal Growth
Insulin regulates the secretion of IGF-I prenatally, whereas postnatally IGF-I secretion is controlled by the GH-IGF-I axis. Insulin along with IGF-I and IGF-II is responsible for the growth of the fetus.[10],[11] Insulin primarily affects the adiposity of the fetus. IGF- II is the primary hormone responsible for early growth of the fetus, and after organogenesis, IGF-I is more important for fetal growth. IGF-I production in the fetus is influenced more by nutrition than by endocrine factors.[11] Low levels of IGF-I and IGFBP-3 are found in SGA babies.[10],[12]
Growth hormone (GH) and thyroid hormones do not affect the prenatal size of the fetus, and deficiency of these hormones does not result in small size babies. After birth, the levels of IGF-I and GH rise significantly in most SGA babies and are probably responsible for the catch-up growth.[13] There is a significant correlation between leptin levels, and size of the fetus at birth. The fat mass determines the leptin levels, hence leptin levels are low in SGA babies. The influence of leptin levels on postnatal growth is unknown.[14],[15]
Growth Pattern of SGA Children
About 85-90% babies who are born SGA show catch-up growth soon after birth, as soon as they are removed from the intrauterine environment. Catch-up growth is the acceleration in growth of SGA babies after birth. This results in the infant reaching a length and weight = or > the 3rd percentile (-2 SD). Maximum catch-up growth usually occurs in the first 6 months of life but may continue up to 2 years.[16] It occurs sooner in term babies compared with preterm babies. 10% of SGA babies fail to show catch-up growth despite good nutrition after birth. They continue to grow at a percentile that is lower than -2 SD and their target height percentile.
The degree of catch-up growth correlates with the birth length, weight and target height. Infants with severe growth retardation are less likely to show catch-up growth. SGA babies with birth length more than -2 SD below the mean have a 7 times higher risk of having short final height, and those with a birth weight more than -2 SD below mean have a 5 times higher risk, indicating that birth length has greater influence on final height than the weight. Of the infants who do not show catch-up growth, 50% end up as short adults. They constitute 14-22% of short adults.[17],[18]
Pubertal and Bone Maturation of SGA Children
SGA children usually enter puberty slightly earlier than their peers. In prepubertal SGA children, an exaggerated adrenarche is observed compared to AGA children, which tends to persist through puberty.[19] Accelerated bone maturation during puberty may be present. Bone age in SGA children is not a good predictor of final height in SGA children. Growth spurt during puberty is blunted compared to other adolescents. This could result in worsening of their short stature.
Metabolic Abnormalities in SGA Babies
Long term follow-up of babies born SGA reveals that they are at a higher risk of developing metabolic problems later in life, such as impaired glucose tolerance, type 2 diabetes mellitus, metabolic syndrome, hypertension, dyslipidemia and cardiovascular disease. [20],[21],[22],[23],[24],[25],[26],[27],[28]
Hormonal Determinants of Short Stature in SGA
SGA infants usually have low levels of insulin, IGF-I and IGFBP-3 at birth. Levels of these hormones rise in babies who show catch-up growth. Infants who do not show catch-up growth usually have an alteration in the GH-IGF-I axis that is poorly understood. 60% of these children show low spontaneous GH secretion over 24 hours. Some children may have classic GH deficiency demonstrated by poor response to provocative stimulation and low levels of IGF-I and IGFBP-3, whereas others may demonstrate normal stimulated levels of GH on provocation, with low levels of IGF-I and IGFBP-3, suggestive of GH insensitivity. High normal GH and IGF-I levels, suggestive of some degree of IGF-I insensitivity have also been demonstrated in some children. It is possible that a combination of these factors may be operating, resulting in short stature. [29],[30],[31],[32],[33],[34]
Management of Short Stature in SGA
There are two major factors which prevent SGA children from achieving their target heights:
1. Failure to show catch-up growth
2. Blunted pubertal growth spurt
To help these children achieve normal stature, it is important that they have good catch-up growth.
Growth Hormone (GH) Therapy in SGA
Human GH has been used to help short SGA children achieve catch-up growth. In July 2001, GH was approved by the US Food and Drug Administration (FDA) for the long term treatment of growth failure in children who are born SGA and do not achieve catch-up growth by 2 years of age at dosages up to 0.48 mg/kg/wk. Initial trials with GH therapy did not show a good response probably because low doses of GH were used and administration of the drug was infrequent. A number of multicenter trials have been carried out with GH therapy for SGA babies who do not show catch-up growth, over the last few years. GH was used irrespective of their GH status. Both high and low dose GH and continuous and discontinuous treatment have been used in these children. A summary of the studies of GH therapy in SGA children is given in table2.
de Zegher et al studied the effect of high doses of GH (0.2 or 0.3 IU/kg/day) for a short duration of 2 years in short SGA children without catch-up growth.[35] Mean age of the subjects at the start of GH was 5.4 years, with height -3.7 SDS, and height after adjustment for mid-parental height -2.9 SDS. Height increased by an average of 2.5 SD during 2 years of GH treatment. Treatment was stopped after 2 years. After discontinuation of GH therapy, there was a slight decline in height SDS by 0.4 and 0.3 in the first and second year respectively. After the initial slowing, there was a stabilization at the higher height (-1 SDS) and weight levels during the following years. This suggested that short term therapy was beneficial in improving the predicted adult height.
Sas et al from Netherlands reported that 5 year treatment of non-GH deficient SGA children without catch-up growth at a dose of 3 or 6 IU/M2/day resulted in normalization of height during childhood, followed by growth along the target height percentile and improvement of height SDS and predicted adult height.[36] The difference in height SDS gain in the low and high dose group was not statistically significant, except in children who remained prepubertal during the study. Height SDS gain was better in the high dose group. No major adverse events were observed and body proportions of these children remained normal. Fasting insulin increased but HbA1c remained normal and none of the children developed diabetes mellitus. Effects were similar in the low and high dose groups. The mean BA/CA ratio was higher than 1 for both dose groups but predicted adult height improved despite the skeletal maturation.
Recent studies have reported the adult height (AH) of short SGA children who received GH therapy. Van Pareren et al reported the effect of long term (mean duration of 7.5 years) continuous GH therapy on the AH of 54 children born SGA, who received low or high dose GH therapy in a randomized double blind dose response trial.[37] This study concluded that long term GH treatment in SGA children resulted in normalization of AH (above -2 SDS) in 85% children, and 98% children reached an AH within their target height range. The improvement in AH SDS was significantly greater in the GH treated SGA group compared with the untreated (control) SGA group (-2.3 vs. -1.1). The AH SDS was not significantly different in the low and high dose group, and the improvement in height SDS was similar in children with partial GH deficiency and non-GH deficient SGA children. There were no significant side effects reported during the course of treatment.
Carel et al conducted a controlled trial to study the effect of GH administration on short adolescents born SGA.[38] 168 short children born SGA (age 10.5 yr for girls and 12.5 yr for boys) were randomly assigned to receive either 0.067 mg/kg/d GH until attainment of AH or no treatment. Mean height prior to treatment was -3.2 SDS. Treatment duration was 2.7 ± 0.6 years. AH was -2.7 ± 0.9 vs -2.1 ± 1.0 SDS in the control and treated groups, respectively (p < 0.005). Height gain was 0.5 ± 0.8 and 1.1 ± 0.9 SDS in the control and treated groups respectively (p = 0.002). This study suggested that the potential for spontaneous catch-up in short adolescents born SGA is limited, but the treatment had a positive effect on outcome, with 0.6 SDS units difference between the treated and control groups, corresponding to +4 cm or +18% more growth in treated than control patients during the study, bringing half of these short adolescents into the normal adult height range. Treated children were closer to target height and more likely to have adult heights in the normal range than controls. The dose was higher, and the treatment duration was shorter (6 months to 3.2 years) than in previous studies.
An epianalysis of 6 year growth response to GH treatment of non GH deficient SGA children was done by Zegher et al.[39] 4 multicenter studies which included 139 short SGA GH-treated children and 49 untreated children were analyzed. The analysis revealed that GH was an effective treatment for normalizing short stature in non-GH deficient SGA children during early childhood and puberty. Both low dose continuous and high dose discontinuous therapy with GH were equally effective. Discontinuous therapy produced rapid normalization of height and shorter duration of treatment, and the continuous slow dose regime needed 3 times more shots and 50% more GH.
Metabolic Effects and Adverse Events due to GH Therapy in SGA Children
GH therapy results in positive metabolic effects in SGA children. [40],[41],[42],[43]
Effect on height and body mass index (BMI) : BMI improved in treated children. Long term treatment led to an increase in height and weight but no change in the body fat compared to controls.
Cardiovascular risk factors : The lipid profile was normal prior to initiation of GH therapy. GH therapy led to a decrease in the total (TC) and LDL cholesterol and improved the TC:HDL ratio. HDL cholesterol remained unchanged. Blood pressure measurement revealed increase in systolic and decrease in the diastolic BP in SGA children compared to age-matched controls. GH treatment resulted in a significant decrease in the systolic BP and diastolic BP showed a further decrease during treatment. BP changes were greater in GH deficient children compared to the non-GH deficient children.
Effect on carbohydrate metabolism: Long term GH treatment resulted in an increase in the fasting and glucose stimulated insulin levels. Fasting blood glucose showed a small but significant rise in the first year. There was no further increase after 6 years. HbA1c remained unchanged during treatment. There was no increase in the children with impaired glucose tolerance and none of them developed diabetes mellitus. Once GH therapy was discontinued, fasting blood glucose and insulin levels returned to the pretreatment levels.
Summary of Effects of GH Therapy in SGA Children with no Catch-up Growth
GH therapy in short SGA children with no catch-up growth normalizes adult stature and results in an adult height that is within the target range.
Results are better if treatment is started at a younger age, although some improvement in height is found even if treatment is started during adolescence.
Both, low dose continuous and high dose discontinuous treatment are almost equally effective.
Higher doses are preferred in those with severe growth retardation and low dose continuous therapy is preferred in those with GH deficiency.
Benefits of GH therapy are similar in GH deficient and non-GH-deficient SGA children.
Treatment is reasonably safe with no significant side effects. The risk of developing diabetes or accelerated bone maturation is minimal with high or low doses of GH.
Evaluation of Short SGA Children
Evaluation of short SGA children should consist of the standard evaluation performed for short children. Genetic syndromes and chromosomal disorders should be ruled out if suspected. Bone age for skeletal maturation should be done, although it is not a good predictor of adult height in SGA children. Provocative testing for GH deficiency should be done in these children if suspicion of GH deficiency is present, based on clinical or biochemical findings. It is helpful in identifying the underlying cause of short stature and in predicting response to therapy. It is not necessary to perform provocative tests in every child. Baseline IGF-I and IGFBP-3 levels must be done in all short SGA children. It is important for monitoring GH therapy and serves as a useful screen for GH deficiency.
Patient selection for GH therapy
SGA children who have not shown catch-up growth till 2-3 years of age
Height <-2 SDS for the population
Predicted adult height at least 1.0 SDS below target height to eliminate the influence of familial short stature
Catch-up growth is better if treatment is started at a younger age and it is more cost effective
Dosage and monitoring of therapy
Currently available data suggest that higher dosage of 0.48 mg/kg/wk (0.2 IU/kg/d) is efficacious and safe at initiation of therapy when rapid catch-up growth is desired. Lower doses can be used if long term therapy is planned.
Prior to starting treatment, BP should be checked, samples should be drawn for fasting lipid profile, fasting and post-prandial blood glucose and fasting insulin. In children who are obese with signs of insulin resistance and a family history of diabetes, glucose tolerance test with insulin levels must be performed. BP should be monitored and the above tests should be performed every 3 months to 1 year, depending on the degree of risk, along with the routine laboratory investigations done while monitoring GH therapy.
Key Messages
10% children born SGA do not show catch-up growth and end up as short adults.
Lack of catch-up growth in these children is probably due to abnormality of the GH-IGF axis.
GH therapy leads to growth acceleration and normalization of height during childhood.
Long term GH treatment normalizes AH (above -2 SDS) in 85% children, and 98% achieve an AH within their target height range.
GH therapy is safe in SGA children, but it is important to monitor for side effects.
References
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8. Wright JT, Waterson EJ, Barrison IG et al. Alcohol consumption, pregnancy, and low birthweight. Lancet 1986; 93: 663-665.
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13. Ozkan H, Aydin A, Demir N et al. Associations of IGF-I, IGFBP-I and IGFBP-3 on intrauterine growth and early catch-up growth. Biol Neonate 1999; 76 : 274-282.
14. Harigaya A, Nagashima K, Nako Y, Morikawa A. Relationship between concentration of serum leptin and fetal growth. J Clin Endocrinol Metab 1997; 82: 3281-3284.
15. Koistinen HA, Koivisto VA, Andersson S, Karonen SL, Kontula K, Oksanen L, Teramo KA. Leptin concentration in cord blood correlates with intrauterine growth. J Clin Endocrinol Metab 1997; 82 : 3328-3330.
16. Hediger MI, Overpeck MD, Maurer KR, Kuczmanski RJ, McGlynn A, Davis WW. Growth of infants and young children born small or large for gestational age: findings from the third national health and nutrition examination survey. Arch Pediatr Adolesc Med 1998; 152: 1225-1231.
17. Karlberg J, Albertsson-Wikland K. Growth in full-term small-for-gestational-age infants: from birth to final height. Pediatr Res 1995; 38: 733-739.
18. Hokken-Koelega ACS, de Ridder MAJ, van Lemmen RJ, den Hartog H, de Muinck Keizer-Schrama SMPF, Drop SLS. Children born small for gestational age: do they catch-up Pediatr Res 1995; 38: 267-271.
19. Veening MA, van Weissenbruch MM, Roord JJ, de Delemarre-van Waal HA Pubertal development in children born small for gestational age. J Pediatr Endocrinol Metab 2004; 17: 1497-1505.
20. Hofman L, Cutfield WS, Robinson EM et al. Insulin resistance in short children with intrauterine growth retardation. J Clin Endocrinol Metab 1997; 82: 402-406.
21. Law CM, Shiell AW. Is blood pressure inversely related to birth weight The strength of evidence from a systematic review of the literature. J Hypertens 1996; 14 : 935-941.
22. Bhargava SK, Sachdev HS, Fall CH, Osmond C, Lakshmy R, Barker DJ, Biswas SK, Ramji S, Prabhakaran D, Reddy KS. Relation of serial changes in childhood body-mass index to impaired glucose tolerance in young adulthood. N Engl J Med 2004; 350: 865-875.
23. Arends NJ, Boonstra VH, Duivenvoorden HJ, Hofman PL, Cutfield WS, Hokken-Koelega AC. Reduced insulin sensitivity and the presence of cardiovascular risk factors in short prepubertal children born small for gestational age (SGA). Clin Endocrinol (Oxf) 2005; 62: 44-50.
24. Phipps K, Barker DJ, Hales CN et al. Fetal growth and impaired glucose tolerance in men and women. Diabetologia 1993; 36: 225-228.
25. Barker DJP, Hales CN, Fall CHD et al. Type 2 (noninsulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 1993; 36: 62-67.
26. Barker DJ. Fetal origins of coronary heart disease. Br Med J 1995; 311 : 171-174.
27. Fall CH, Vijayakumar M, Barker DJ, Osmond C, Duggleby S. Weight in infancy and prevalence of coronary heart disease in adult life. Br Med J 1995; 310: 17-19.
28. Hattersley AT, Tooke JE. The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 1999; 353 : 1789-1792.
29. Rochiccioli P, Tauber M, Moisan V, Pienkowski C. Investigation of growth hormone secretion in patients with intrauterine growth retardation. Acta Paediatr Scand Suppl 1989; 349 : 42-46.
30. de Waal WJ, Hokken-Koelega ACS, Stijnen T, de Muinck Keizer-Schrama SMPF, Drop SLS, and the Dutch Working Group on Growth Hormone. Endogenous and stimulated GH secretion, urinary GH excretion, and plasma IGF-I and IGF-II levels in prepubertal children with short stature after intrauterine growth retardation. Clin Endocrinol 1994; 41 : 621-630.
31. Boguszewski M, Rosberg S, Albertsson-Wikland K. Spontaneous 24-hour growth hormone profiles in prepubertal small for gestational age children. J Clin Endocrinol Metab 1995; 80 : 2599-2606.
32. Ackland FM, Stanhope R, Eyre C, Hamill G, Jones J, Preece MA. Physiological growth hormone secretion in children with short stature and intra-uterine growth retardation. Horm Res 1988; 30: 241-245.
33. Stanhope R, Ackland F, Hamill G et al. Physiological growth hormone secretion and response to growth hormone treatment in children with short stature and intrauterine growth retardation. Acta Paediatr Scand 1989; 349 : 47-52.
34. Leger J, Noel M, Limal JM, Czernichow P. Growth factors and intrauterine growth retardation. II. Serum growth hormone, insulin-like growth factor (IGF) I, and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects: prospective study from birth to two years of age. Study Group of IUGR. Pediatr Res 1996; 40: 101-107.
35. de Zegher F, Du Caju MV, Heinrichs C et al. Early, discontinuous, high dose growth hormone treatment to normalize height and weight of short children born small for gestational age: results over 6 years. J Clin Endocrinol Metab 1999; 84 : 1558-1561.
36. Sas T, de Waal W, Mulder P et al. Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose-response trial. J Clin Endocrinol Metab 1999; 84: 3064-3070.
37. Van Pareren Y, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega A. Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: Results of a randomized, double-blind, dose-response GH trial. J Clin Endocrinol Metab 2003; 88: 3584 - 3590.
38. Carel JC, Chatelain P, Rochiccioli P, Chaussain J. Improvement in adult height after growth hormone treatment in adolescents with short stature born small for gestational age: Results of a randomized controlled study. J Clin Endocrinol Metab 2003; 88: 1587-1593.
39. de Zegher F, Wikland KA, Hartmut A, Chatelain P, Chaussain J, Lofstrom A, Jonsson B, Rosenfeld R. Growth hormone treatment of short children born small for gestational age: Growth responses with Continuous and Discontinuous regimens over 6 years. J Clin Endocrinol Metab 2000; 85(8) : 2816-21; 88: 3584-3590.
40. Sas T, Mulder P, Hokken-Koelega A. Body composition, blood pressure, and lipid metabolism before and during long-term growth hormone (GH) treatment in children with short stature born small for gestational age either with or without GH deficiency. J Clin Endocrinol Metab 2000; 85: 3786-3792.
41. Leger J, Garel C, Fjellestad-Paulsen A et al. Human growth hormone treatment of short-stature children born small for gestational age: effect on muscle and adipose tissue mass during a 3-year treatment period and after 1 year's withdrawal. J Clin Endocrinol Metab 1998; 83: 3512-3516.
42. Sas TC, Gerver WJ, De Bruin R et al. Body proportions during 6 years of GH treatment in children with short stature born small for gestational age participating in a randomised, double-blind, dose-response trial. Clin Endocrinol (Oxf) 2000; 53: 675-681.
43. Sas T, Mulder P, Aanstoot HJ et al. Carbohydrate metabolism during long-term growth hormone treatment in children with short stature born small for gestational age. Clin Endocrinol (Oxf) 2001; 54: 243-251.(Arya Archana Dayal)
Abstract
3 to 10% of neonates are born small for gestation (SGA). This usually occurs because of intrauterine growth retardation (IUGR). After birth most SGA infants show good catch-up growth and normalize their height and weight. About 10% of them continue to remain short (<-2SD) and do not achieve normal adult height, resulting in psychosocial problems. The mechanism of short stature in these children is poorly understood. Infants who do not show catch-up growth usually have an alteration in the GH-IGF-I axis. Diagnostic and management criteria for short stature in SGA were ill-defined in the past. Growth hormone (GH) therapy for improving height in these children has been approved by the FDA. GH therapy leads to growth acceleration and normalization of height during childhood. Long term GH treatment normalizes adult height above -2 SDS in 85% children, and 98% achieve an adult height within their target height range. GH therapy is safe in SGA children, but it is important to monitor for side effects.
Keywords: Growth hormone; Short stature; Small for gestational age
Small for gestation (SGA) is defined as a birth weight or length, more than 2 SD below the mean for the gestational age and sex, for a reference population. Intrauterine growth retardation (IUGR) is a pathophysiological term that refers to the growth deceleration in-utero. A fetus with IUGR could be AGA (appropriate for gestation) or SGA at birth. SGA refers to the birth size irrespective of the growth velocity in the uterus, although most SGA babies have IUGR.
Prevalence
3-10% babies worldwide are born SGA. In USA, 8.6% of live births are SGA.[1] Data collected from two hospitals in Kolkata reported that the proportion of infants weighing less than 2,001 g is approximately 10%, the dependence of this proportion on maternal age and parity being similar to the studies conducted elsewhere, suggesting a definite biological significance of the phenomenon.[2]
Factors Influencing Size of Babies at Birth
The birth size of babies is influenced by a number of factors. They are enumerated further.
1. Maternal factors
Nutrition of the mother : Malnutrition is a common cause of IUGR in developing countries like India. Malnutrition during the early part of pregnancy leads to impaired cell growth and multiplication. This results in fetus which is symmetrically small ( proportionate SGA ). Malnutrition in the later part of pregnancy results in small cell size but normal proliferation. The fetus has a larger head and small body since the blood flow is directed towards the development of the brain at the cost of the rest of the body (brain sparing phenomenon).[3] This has been referred to as asymmetric IUGR .
Maternal illness: Chronic vascular disease and hypoxemia in the mother, secondary to diseases like asthma, sickle cell anemia etc. results in IUGR.[4] Perinatal hypertension results in SGA babies.[5],[6]
Environmental toxins : Cigarette smoking, alcohol ingestion and intake of drugs like heroin etc. during pregnancy result in SGA babies.[7],[8]
Infections: Bacterial, protozoal and viral infections such as CMV and rubella in the mother also influence the size of babies at birth.
2. Placental factors
Compromise of utero-placental blood flow, infarction, abruption of placenta result in fetal hypoxemia and IUGR.
3. Fetal factors
Genetic syndromes such as Russell Silver, de Lange, Williams, Bloom and Johnson Blizzard syndrome are associated with SGA. Chromosomal abnormalities such as Down and Turner syndromes, congenital malformations and twin pregnancies can result in SGA babies.
4. Genetic factors
The size of the parents, especially the mother, affects the size of the baby at birth. Constitutional SGA has been reported as a common cause of SGA in Indian babies.[9]
The causes of SGA are listed in table1.
Endocrine Regulation of Fetal Growth
Insulin regulates the secretion of IGF-I prenatally, whereas postnatally IGF-I secretion is controlled by the GH-IGF-I axis. Insulin along with IGF-I and IGF-II is responsible for the growth of the fetus.[10],[11] Insulin primarily affects the adiposity of the fetus. IGF- II is the primary hormone responsible for early growth of the fetus, and after organogenesis, IGF-I is more important for fetal growth. IGF-I production in the fetus is influenced more by nutrition than by endocrine factors.[11] Low levels of IGF-I and IGFBP-3 are found in SGA babies.[10],[12]
Growth hormone (GH) and thyroid hormones do not affect the prenatal size of the fetus, and deficiency of these hormones does not result in small size babies. After birth, the levels of IGF-I and GH rise significantly in most SGA babies and are probably responsible for the catch-up growth.[13] There is a significant correlation between leptin levels, and size of the fetus at birth. The fat mass determines the leptin levels, hence leptin levels are low in SGA babies. The influence of leptin levels on postnatal growth is unknown.[14],[15]
Growth Pattern of SGA Children
About 85-90% babies who are born SGA show catch-up growth soon after birth, as soon as they are removed from the intrauterine environment. Catch-up growth is the acceleration in growth of SGA babies after birth. This results in the infant reaching a length and weight = or > the 3rd percentile (-2 SD). Maximum catch-up growth usually occurs in the first 6 months of life but may continue up to 2 years.[16] It occurs sooner in term babies compared with preterm babies. 10% of SGA babies fail to show catch-up growth despite good nutrition after birth. They continue to grow at a percentile that is lower than -2 SD and their target height percentile.
The degree of catch-up growth correlates with the birth length, weight and target height. Infants with severe growth retardation are less likely to show catch-up growth. SGA babies with birth length more than -2 SD below the mean have a 7 times higher risk of having short final height, and those with a birth weight more than -2 SD below mean have a 5 times higher risk, indicating that birth length has greater influence on final height than the weight. Of the infants who do not show catch-up growth, 50% end up as short adults. They constitute 14-22% of short adults.[17],[18]
Pubertal and Bone Maturation of SGA Children
SGA children usually enter puberty slightly earlier than their peers. In prepubertal SGA children, an exaggerated adrenarche is observed compared to AGA children, which tends to persist through puberty.[19] Accelerated bone maturation during puberty may be present. Bone age in SGA children is not a good predictor of final height in SGA children. Growth spurt during puberty is blunted compared to other adolescents. This could result in worsening of their short stature.
Metabolic Abnormalities in SGA Babies
Long term follow-up of babies born SGA reveals that they are at a higher risk of developing metabolic problems later in life, such as impaired glucose tolerance, type 2 diabetes mellitus, metabolic syndrome, hypertension, dyslipidemia and cardiovascular disease. [20],[21],[22],[23],[24],[25],[26],[27],[28]
Hormonal Determinants of Short Stature in SGA
SGA infants usually have low levels of insulin, IGF-I and IGFBP-3 at birth. Levels of these hormones rise in babies who show catch-up growth. Infants who do not show catch-up growth usually have an alteration in the GH-IGF-I axis that is poorly understood. 60% of these children show low spontaneous GH secretion over 24 hours. Some children may have classic GH deficiency demonstrated by poor response to provocative stimulation and low levels of IGF-I and IGFBP-3, whereas others may demonstrate normal stimulated levels of GH on provocation, with low levels of IGF-I and IGFBP-3, suggestive of GH insensitivity. High normal GH and IGF-I levels, suggestive of some degree of IGF-I insensitivity have also been demonstrated in some children. It is possible that a combination of these factors may be operating, resulting in short stature. [29],[30],[31],[32],[33],[34]
Management of Short Stature in SGA
There are two major factors which prevent SGA children from achieving their target heights:
1. Failure to show catch-up growth
2. Blunted pubertal growth spurt
To help these children achieve normal stature, it is important that they have good catch-up growth.
Growth Hormone (GH) Therapy in SGA
Human GH has been used to help short SGA children achieve catch-up growth. In July 2001, GH was approved by the US Food and Drug Administration (FDA) for the long term treatment of growth failure in children who are born SGA and do not achieve catch-up growth by 2 years of age at dosages up to 0.48 mg/kg/wk. Initial trials with GH therapy did not show a good response probably because low doses of GH were used and administration of the drug was infrequent. A number of multicenter trials have been carried out with GH therapy for SGA babies who do not show catch-up growth, over the last few years. GH was used irrespective of their GH status. Both high and low dose GH and continuous and discontinuous treatment have been used in these children. A summary of the studies of GH therapy in SGA children is given in table2.
de Zegher et al studied the effect of high doses of GH (0.2 or 0.3 IU/kg/day) for a short duration of 2 years in short SGA children without catch-up growth.[35] Mean age of the subjects at the start of GH was 5.4 years, with height -3.7 SDS, and height after adjustment for mid-parental height -2.9 SDS. Height increased by an average of 2.5 SD during 2 years of GH treatment. Treatment was stopped after 2 years. After discontinuation of GH therapy, there was a slight decline in height SDS by 0.4 and 0.3 in the first and second year respectively. After the initial slowing, there was a stabilization at the higher height (-1 SDS) and weight levels during the following years. This suggested that short term therapy was beneficial in improving the predicted adult height.
Sas et al from Netherlands reported that 5 year treatment of non-GH deficient SGA children without catch-up growth at a dose of 3 or 6 IU/M2/day resulted in normalization of height during childhood, followed by growth along the target height percentile and improvement of height SDS and predicted adult height.[36] The difference in height SDS gain in the low and high dose group was not statistically significant, except in children who remained prepubertal during the study. Height SDS gain was better in the high dose group. No major adverse events were observed and body proportions of these children remained normal. Fasting insulin increased but HbA1c remained normal and none of the children developed diabetes mellitus. Effects were similar in the low and high dose groups. The mean BA/CA ratio was higher than 1 for both dose groups but predicted adult height improved despite the skeletal maturation.
Recent studies have reported the adult height (AH) of short SGA children who received GH therapy. Van Pareren et al reported the effect of long term (mean duration of 7.5 years) continuous GH therapy on the AH of 54 children born SGA, who received low or high dose GH therapy in a randomized double blind dose response trial.[37] This study concluded that long term GH treatment in SGA children resulted in normalization of AH (above -2 SDS) in 85% children, and 98% children reached an AH within their target height range. The improvement in AH SDS was significantly greater in the GH treated SGA group compared with the untreated (control) SGA group (-2.3 vs. -1.1). The AH SDS was not significantly different in the low and high dose group, and the improvement in height SDS was similar in children with partial GH deficiency and non-GH deficient SGA children. There were no significant side effects reported during the course of treatment.
Carel et al conducted a controlled trial to study the effect of GH administration on short adolescents born SGA.[38] 168 short children born SGA (age 10.5 yr for girls and 12.5 yr for boys) were randomly assigned to receive either 0.067 mg/kg/d GH until attainment of AH or no treatment. Mean height prior to treatment was -3.2 SDS. Treatment duration was 2.7 ± 0.6 years. AH was -2.7 ± 0.9 vs -2.1 ± 1.0 SDS in the control and treated groups, respectively (p < 0.005). Height gain was 0.5 ± 0.8 and 1.1 ± 0.9 SDS in the control and treated groups respectively (p = 0.002). This study suggested that the potential for spontaneous catch-up in short adolescents born SGA is limited, but the treatment had a positive effect on outcome, with 0.6 SDS units difference between the treated and control groups, corresponding to +4 cm or +18% more growth in treated than control patients during the study, bringing half of these short adolescents into the normal adult height range. Treated children were closer to target height and more likely to have adult heights in the normal range than controls. The dose was higher, and the treatment duration was shorter (6 months to 3.2 years) than in previous studies.
An epianalysis of 6 year growth response to GH treatment of non GH deficient SGA children was done by Zegher et al.[39] 4 multicenter studies which included 139 short SGA GH-treated children and 49 untreated children were analyzed. The analysis revealed that GH was an effective treatment for normalizing short stature in non-GH deficient SGA children during early childhood and puberty. Both low dose continuous and high dose discontinuous therapy with GH were equally effective. Discontinuous therapy produced rapid normalization of height and shorter duration of treatment, and the continuous slow dose regime needed 3 times more shots and 50% more GH.
Metabolic Effects and Adverse Events due to GH Therapy in SGA Children
GH therapy results in positive metabolic effects in SGA children. [40],[41],[42],[43]
Effect on height and body mass index (BMI) : BMI improved in treated children. Long term treatment led to an increase in height and weight but no change in the body fat compared to controls.
Cardiovascular risk factors : The lipid profile was normal prior to initiation of GH therapy. GH therapy led to a decrease in the total (TC) and LDL cholesterol and improved the TC:HDL ratio. HDL cholesterol remained unchanged. Blood pressure measurement revealed increase in systolic and decrease in the diastolic BP in SGA children compared to age-matched controls. GH treatment resulted in a significant decrease in the systolic BP and diastolic BP showed a further decrease during treatment. BP changes were greater in GH deficient children compared to the non-GH deficient children.
Effect on carbohydrate metabolism: Long term GH treatment resulted in an increase in the fasting and glucose stimulated insulin levels. Fasting blood glucose showed a small but significant rise in the first year. There was no further increase after 6 years. HbA1c remained unchanged during treatment. There was no increase in the children with impaired glucose tolerance and none of them developed diabetes mellitus. Once GH therapy was discontinued, fasting blood glucose and insulin levels returned to the pretreatment levels.
Summary of Effects of GH Therapy in SGA Children with no Catch-up Growth
GH therapy in short SGA children with no catch-up growth normalizes adult stature and results in an adult height that is within the target range.
Results are better if treatment is started at a younger age, although some improvement in height is found even if treatment is started during adolescence.
Both, low dose continuous and high dose discontinuous treatment are almost equally effective.
Higher doses are preferred in those with severe growth retardation and low dose continuous therapy is preferred in those with GH deficiency.
Benefits of GH therapy are similar in GH deficient and non-GH-deficient SGA children.
Treatment is reasonably safe with no significant side effects. The risk of developing diabetes or accelerated bone maturation is minimal with high or low doses of GH.
Evaluation of Short SGA Children
Evaluation of short SGA children should consist of the standard evaluation performed for short children. Genetic syndromes and chromosomal disorders should be ruled out if suspected. Bone age for skeletal maturation should be done, although it is not a good predictor of adult height in SGA children. Provocative testing for GH deficiency should be done in these children if suspicion of GH deficiency is present, based on clinical or biochemical findings. It is helpful in identifying the underlying cause of short stature and in predicting response to therapy. It is not necessary to perform provocative tests in every child. Baseline IGF-I and IGFBP-3 levels must be done in all short SGA children. It is important for monitoring GH therapy and serves as a useful screen for GH deficiency.
Patient selection for GH therapy
SGA children who have not shown catch-up growth till 2-3 years of age
Height <-2 SDS for the population
Predicted adult height at least 1.0 SDS below target height to eliminate the influence of familial short stature
Catch-up growth is better if treatment is started at a younger age and it is more cost effective
Dosage and monitoring of therapy
Currently available data suggest that higher dosage of 0.48 mg/kg/wk (0.2 IU/kg/d) is efficacious and safe at initiation of therapy when rapid catch-up growth is desired. Lower doses can be used if long term therapy is planned.
Prior to starting treatment, BP should be checked, samples should be drawn for fasting lipid profile, fasting and post-prandial blood glucose and fasting insulin. In children who are obese with signs of insulin resistance and a family history of diabetes, glucose tolerance test with insulin levels must be performed. BP should be monitored and the above tests should be performed every 3 months to 1 year, depending on the degree of risk, along with the routine laboratory investigations done while monitoring GH therapy.
Key Messages
10% children born SGA do not show catch-up growth and end up as short adults.
Lack of catch-up growth in these children is probably due to abnormality of the GH-IGF axis.
GH therapy leads to growth acceleration and normalization of height during childhood.
Long term GH treatment normalizes AH (above -2 SDS) in 85% children, and 98% achieve an AH within their target height range.
GH therapy is safe in SGA children, but it is important to monitor for side effects.
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