Three-Year Growth Response to Growth Hormone Treatment in Very Young Children Born Small for Gestational Age Data from KIGS

Transcription

1 ORIGINAL ARTICLE Endocrine Care Three-Year Growth Response to Growth Hormone Treatment in Very Young Children Born Small for Gestational Age Data from KIGS Margaret C. S. Boguszewski, Anders Lindberg, and Hartmut A. Wollmann Department of Pediatrics (M.C.S.B.), Federal University of Paraná, Curitiba PR , Brazil; Pfizer Inc (A.L.), Endocrine Care, SE Sollentuna, Sweden; and Pfizer Inc (H.A.W.), Endocrine Care, Berlin, Germany Context: Children born small for gestational age (SGA) with poor growth during the first years of life may remain short in stature during childhood and as adults. Objective: To evaluate the 3-year growth response to GH treatment in very young short children born SGA, and to test the existing predictions models for growth response developed for older SGA children. Setting: KIGS (The Pfizer International Growth Database). Patients: A total of 620 SGA children (birth length and/or weight below 2 SD score [SDS]) on GH treatment, 156 in the 2- to 4-year-old group (100 boys; median age, 3.3 y), and 464 in the 4- to 6-year-old group (284 boys; median age, 4.9 y). Results: Median values and - s are presented. Both groups presented a significant increase in height velocity during GH treatment. Median height SDS increased from 3.9 ( 5.4 to 2.9) at the start to 2.2 ( 3.8 to 1.0) at 3 years in the 2- to 4-year-old group (P.01) and from 3.4 ( 4.5 to 2.6) to 2.0 ( 3.3 to 0.9) in the 4- to 6-year-old group (P.01). Median weight SDS increased from 3.8 ( 5.9 to 2.4) to 2.1 ( 4.1 to 0.5) in the 2- to 4-year-old group (P.01). Respective values for the 4- to 6-year-old group were 3.1 ( 4.8 to 1.8) to 1.6 ( 3.1 to 0.1) SDS (P.01). First- and second-year growth response could be estimated by the SGA model. Conclusion: Very young children born SGA without spontaneous catch-up growth presented a significant improvement in height and weight during the 3 years of GH treatment. Growth response could be estimated by the SGA model. (J Clin Endocrinol Metab 99: , 2014) ISSN Print X ISSN Online Printed in U.S.A. Copyright 2014 by the Endocrine Society Received November 17, Accepted April 10, First Published Online April 23, 2014 GH therapy has been shown to be effective in improving height in short children born small for gestational age (SGA) (1 3). Among the patients characteristics found to be related to growth response, young age at the start of treatment was related to better growth response (4). GH treatment was approved by the US Food and Drug Administration (FDA) for children born SGA who fail to manifest catch-up growth by the age of 2 years and by the European Agency for the Evaluation of Medicinal Products for children older than 4 years of age. The consensus statement from the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society proposed that chronological age and height should be taken together for the decision of GH treatment: children born SGA with height below 2.5 SD score (SDS) at the age of 2 years or with height below 2 SDS at the age of 4 years should be eligible for GH treatment (5). Despite the recommendation for GH therapy at a Abbreviations: SDS, SD score; SGA, small for gestational age. doi: /jc J Clin Endocrinol Metab, August 2014, 99(8): jcem.endojournals.org 2683

2 2684 Boguszewski et al hgh Treatment in Very Young SGA Children J Clin Endocrinol Metab, August 2014, 99(8): young age, a recent review of the impact of GH therapy on adult height in short SGA children showed that chronological age at the start of therapy ranged from 7.9 to 10.7 years (6), and some short SGA children only came to medical attention when they were at puberty, with less time for GH treatment and the eventual need for postponement of puberty with the addition of GnRH analogs (7). Few studies are available on GH treatment for young short SGA children (8, 9), and a greater increase in height velocity was observed in those younger than 4 years of age (9). The present study was undertaken to evaluate the 3-year growth response to GH treatment in very young short children born SGA, with ages at the start of GH therapy from 2 to 4 years as approved by the FDA and after 4 years of age, the European indication. In addition, we tested in the very young SGA children the existing predictions models for growth response developed for SGA children with older ages. Patients and Methods Patients were selected from KIGS (The Pfizer International Growth Database), a large pharmacoepidemiological survey with children treated with rhgh (Genotropin; Pfizer Inc). In total, more than patients from 52 countries were enrolled in the database at the time of this study. For the present analysis, they were recruited between 1987 and June 2012 (75% of them after the year 2000) from 27 countries, of which seven countries contributed more than 80% of the patients. For this study, children were selected from three major KIGS diagnostic groups as coded by the managing physician: idiopathic short stature, and SGA/intrauterine growth restriction without or with minor dysmorphic stigma (10). The KIGS database was queried for children with birth length and/or weight below 2 SDS and with ages at the start of GH treatment older than 2 and less than 4 years or between 4 and 6 years. Gestational age was taken as reported by the treating physician. Exclusion criteria were: chromosomal disorders, genetic syndromes, malformations, maternal history of alcohol or drug addiction, bone dysplasia, and any treatment that could affect growth. A total of 156 patients (100 boys) were selected in the 2- to 4-year-old group and 464 children (284 boys) in the 4- to 6-year-old group. At the time of the KIGS founding in 1987, enrollment was independent from informed consent in many countries, but currently data are enrolled only after informed consent has been obtained by a local physician. Statistical methods Birth weight SDS was calculated using the reference of Niklasson et al (11). Calculations on height SDS were based on the longitudinal growth standards of Prader et al (12), and for weight SDS, the data reported by Freeman et al (13) were used. Rationale for these choices was explained elsewhere (14). Median values and - s are presented. Student s t test was used for comparisons of outcome measures when applicable; otherwise, Wilcoxon rank sum test was used, considering differences at less than 1% level as significant (P.01). The growth response of both patient groups was compared to the already published KIGS prediction models for SGA (4). Differences between observed and predicted height velocities are expressed in terms of Studentized residuals. The residual is calculated as the observed height velocity minus the predicted height velocity for each observation, and the Studentized residual is the residual divided by its SE. SAS version 8 for Sun Solarix (SAS Institute) was used for all statistical analyses. Results At baseline Table 1 shows baseline information of the two age groups of short SGA children. Both groups presented important short stature, but patients in the 2- to 4-year-old group were shorter and leaner than the older ones (Figure 1) and had lower adjusted parental height ( 2.8 vs 2.3 Table 1. Characteristics at Birth and at GH Start of Children Born SGA With Age Ranges From 2 4 and 4 6 Years SGA, ages 2 4 y SGA, ages 4 6 y N Median N Median Age, y a Gestational age, wk Birth weight SDS Birth length SDS Height SDS a Weight SDS a MPH SDS Ht-MPH SDS a Height velocity SDS a Bone age, y a Maximum GH peak, g/l IGF-1 SDS Abbreviations: MPH, midparental height; Ht-MPH, adjusted parental height. a P.01.

3 doi: /jc jcem.endojournals.org 2685 Figure 1. Height and weight SDS at start and during the first and third years of GH treatment in children born SGA with ages from 2 4 years and 4 6 years at start of GH therapy. SDS; P.001). For those children where height velocity before treatment was available, height velocity SDS was below zero, except for five patients (3%) in the 2- to 4-year-old group and 31 patients (7%) in the 4- to 6-yearold group. Seventy-eight children (50%) in the 2- to 4-year-old group and 196 (42.2%) in the 4- to 6-year-old group were born with gestational age 37 weeks. The preterm children in the 4- to 6-year-old group were younger at the start of therapy (4.8 vs 5.0 y; P.01), leaner (weight SDS, 3.41 vs 2.95; P.001), and had a lower adjusted parental height ( 2.44 vs 2.14; P.01) than the term ones. GH maximum peak to provocative tests was available for 100 SGA children in the 2- to 4-year-old group; 24% had peak values below 10 g/l, and 7% had peak values below 5 g/l. For the 253 children in the 4- to 6-year-old group with GH maximum peak available, respective numbers were 25.7 and 7.9%. There was no difference between the two groups regarding GH peak distribution. Growth response to GH treatment The GH doses and growth information during the 3-year period are shown in Table 2. The median GH doses used during the 3 years of treatment were constant in the groups, with a higher GH dose in the 2- to 4-year-old age group (P.001). The two SGA groups presented a significant increase in height velocity, higher in the 2- to 4-year-old group. As a result, in the 2- to 4-year-old group, median height SDS increased from 3.9 ( 5.4 to 2.9) SDS at the start of GH therapy to 2.2 ( 3.8 to 1.0) SDS at 3 years (Figure 1). This change is equivalent to 7.5 to 8.0 cm over the expected spontaneous increase in height. Respective values for the 4- to 6-year-old group were 3.4 ( 4.5 to 2.6) SDS to 2.0 ( 3.3 to 0.9) SDS (7.0 to 7.5 cm). Median weight SDS increased from 3.8 ( 5.9 to 2.4) at GH start in the 2- to 4-year-old group to 2.1 ( 4.1 to 0.5) SDS at 3 years of GH. Respective values for the 4- to 6-year-old group were 3.1 ( 4.8 to 1.8) to 1.6 ( 3.1 to 0.1) SDS (Figure 1). When evaluated by gender, girls in the 2- to 4-year-old group were shorter than boys at the start of treatment (56 girls/100 boys; height SDS, 4.18 vs 3.80; P.01) and presented a higher increase in height during the first year ( height SDS, 1.02 vs 0.87; P.05), with consequent disappearance of the significant difference in height at 3 years of treatment. Girls were also shorter than boys in the 4- to 6-yearold group (180 girls/284 boys; height SDS, 3.57 vs 3.33; P.01). However, in this group, boys presented higher height velocity during the first year of treatment (3.36 vs 2.74 SDS; P.01), and height SDS values were still significantly different at 3 years of therapy (girls, 2.15 SDS; vs boys, 1.93 SDS; P.05). Preterm children in the 2- to 4-year-old group received a higher GH dose than those born at term (0.38 vs 0.32; P.05). They presented higher height velocity SDS during the first year of therapy (2.49 vs 1.87; P.05), but this difference disappeared during the second and third years of treatment. These findings were not observed in the 4- to 6-yearold group. Prediction models The growth response of the very young children born SGA was compared with the prediction response from earlier published prediction models. Predicted height velocity and Studentized residual at 2 years were calculated using height velocity at 1 year. For the first year growth response, both groups of SGA children, ages 2 to 4 years and 4 to 6 years, were compared with the SGA model (Table 2 and Figure 2). The best predictors in the SGA model were GH dose, weight at the start of treatment, midparental height SDS, and age at treatment start the last with an inverse association. The observed height velocity for the second year was also estimated by the SGA model (Table 2). Discussion This study shows the growth-promoting effects of GH treatment in very young children born SGA without spontaneous catch-up growth using information from a large international database. Children born SGA older than 2

4 2686 Boguszewski et al hgh Treatment in Very Young SGA Children J Clin Endocrinol Metab, August 2014, 99(8): Table 2. Characteristics at GH Start and During the 3-Year Period of GH Treatment of Children Born SGA With Age Ranges From 2 4 Years and 4 6 Years SGA, age 2 4 y SGA, age 4 6 y N Median N Median At GH start GH dose, mg/kg/wk b Ht-MPH SDS b Height velocity, cm/y b At1yofGH GH dose, mg/kg/wk b Height SDS b Weight SDS b Ht-MPH SDS b Height velocity, cm/y b Predicted height velocity b Studentized residual At2yofGH GH dose, mg/kg/wk b Height SDS b Weight SDS b Ht-MPH SDS b Height velocity, cm/y b Predicted height velocity a b Studentized residual a At3yofGH GH dose, mg/kg/wk b Height SDS b Weight SDS b Ht-MPH SDS b Height velocity, cm/y Abbreviations: MPH, midparental height; Ht-MPH, adjusted parental height. Predicted height velocity was calculated using the SGA model (Ref. 14). a Predicted height velocity and Studentized residual at 2 years were calculated using height velocity at 1 year. b P.01. and younger than 6 years of age were included, and a significant improvement in height and weight gain during the 3 years of prepubertal GH treatment was observed. Few studies are available on GH treatment for young short Figure 2. Predicted height velocity to GH treatment using the SGA model (14) in short SGA children with ages from 2 4 years (left panel) and 4 6 years (right panel) at start of GH therapy. SGA children (8, 9). Argente et al (9) evaluated the effects of 2-year high-dose GH treatment (0.06 mg/kg/d, approximately 0.42 mg/kg/wk) in 81 SGA children from 14 centers in Spain. They showed a mean height gain of 2.1 SDS for chronological age after the 2-year period of treatment. Children under 4 years of age significantly increased more in height and weight during the first year of treatment compared with those aged 4 years or older. The gain in height of the younger children was maintained during all periods of follow-up. Growth velocity did not change significantly in the control group until GH treatment was started. Bergadá et al (8) evaluated 14 children born SGA with a mean age of 4.2 years at the start of GH treatment and a mean dose of 0.33 mg/kg/wk. After 2 years of GH treatment, all patients except one

5 doi: /jc jcem.endojournals.org 2687 achieved height in the normal range, with a mean height gain of 1.5 SDS. Weight and head circumference also improved. In the present study, a large group of very young children born SGA was evaluated during a 3-year period, and different GH doses were used. Thus, it represents a unique opportunity to evaluate the growth response to GH treatment in this special group of short children. All presented a significant increase in height velocity, higher in the 2- to 4-year-old group, reinforcing the benefits of treatment at a young age. Normal growth during the first year of life is extremely rapid, leading to a doubling or tripling of the birth weight and a 50% increase in body length. The infancy component of growth, to 3 to 4 years of age, is claimed to start in midgestation and to represent the postnatal continuation of fetal growth (15). Several studies are available on the subject of early postnatal growth in children born SGA, and most of them showed that around 85% of the SGA children revealed spontaneous catch-up growth during the first 2 years of life (16, 17). Catch-up growth can be documented as early as 12 weeks of age, and most of the total catch-up in height from birth to final height can be achieved by 2 months of age (18). Therefore, these data suggest that two subgroups of children born SGA can be recognized during the first years of life: those who catch-up rapidly and maintain their growth position, and those with poor growth during the initial few months of life. The latter group is likely to remain short during childhood and as adults. In the present study, the very young SGA children started GH treatment at a median age of 3.3 years, and all were below 2 SD for weight and/or height. Their growth velocity was below the mean expected for their age, suggesting that spontaneous catch-up growth did not occur. All responded well to GH treatment. With a careful monitoring of postnatal growth, especially during the first months of life, we believe that it is possible to identify the subgroup of SGA children who will not catch up spontaneously and to start GH treatment as early as by 2 years of age. Preterm SGA children have also been treated with positive results (19, 20). In our study, half of the 156 children in the 2- to 4-year-old group and 42% in the 4- to 6-yearold group were born with gestational age 37 weeks, reflecting the increasing incidence of prematurity during the last few decades (21). Sullivan et al (22) evaluated the postnatal growth trajectories of children born preterm from birth to 12 years of age and showed that growth differs among preterm children according to neonatal morbidity. All preterm children with different medical problems presented a rapid spontaneous increment in growth between birth and 18 months of age. After this age, children born preterm caught up in height by 8 years of age, but not the preterm born SGA, who remained short by 12 years. Preterm SGA had the smallest height and lowest weight by 12 years. In our study, no difference in height or weight at the start of GH treatment was observed between SGA children born at term and those born preterm in the 2- to 4-year-old group. However, in the 4- to 6-year-old group, the SGA preterm were leaner and had a lower adjusted parental height than those born at term, showing the long-term negative effects of prematurity and small size at birth on postnatal growth. Similar findings were reported by de Kort et al (23). Growth response to GH treatment was not different between term and preterm SGA infants. For this study, children were selected from three major KIGS diagnostic groups (idiopathic short stature, and SGA/intrauterine growth restriction without or with minor dysmorphic stigma). Given that these categories contained the most children in KIGS who are not GH deficient, it was not surprising that less than 30% had a GH maximum peak below 10 g/l and less than 10% had GH peaks below 5 g/l. When we removed these 27 children from the respective study groups, our results did not change. In addition, we could estimate the observed height velocity during GH treatment for the two young SGA groups using the SGA model published previously (4). In the model, the best predictors for the growth response were the GH dose (higher dose, better response), followed by age at the start of treatment (lower age, better response), the weight at the start of treatment, and midparental height SDS (both with positive relation) (4). GH secretion estimated by GH maximum peak during provocative tests did not enter the model. Recently, Carrascosa et al (24) found no difference in height gain to adult age among patients with different GH secretion status on GH treatment, including short children born SGA, suggesting that GH secretions estimated during provocative tests are of little help when GH therapy is decided. Considering the benefits of GH treatment and the care with safety issues, these findings reinforce the need for a continuous search for the best predictors of growth response and individualization of GH dosing (25). The GH dose was one of the most important predictors of growth response. Children in the youngest SGA group received a higher median GH dose during the 3 years of follow-up, approximately 0.35 mg/kg/wk, compared with 0.25 mg/kg/wk for the older group. Among them, those born preterm received the highest dose during the first year of GH treatment. Children in the 2- to 4-year-old group were leaner, shorter, and had a lower adjusted parental height than children in the 4- to 6-year-old group. These facts could explain in part why physicians decided on the early age to start treatment and on the higher GH dose for

6 2688 Boguszewski et al hgh Treatment in Very Young SGA Children J Clin Endocrinol Metab, August 2014, 99(8): the youngest patients, especially for those born preterm. However, it is important to emphasize that the dose range was within the recommended range (5), and it could be even higher in the 4- to 6-year-old group. In conclusion, in this observational database, very young children born SGA without spontaneous catch-up growth presented a significant improvement in height and weight gain during the 3 years of GH treatment. The growth response could be estimated by the SGA model published previously. Acknowledgments The authors express their thanks to all KIGS Investigators and their patients for contributing data to KIGS. KIGS is sponsored by Pfizer Inc. Address all correspondence and requests for reprints to: Margaret C. S. Boguszewski, Department of Pediatrics, Federal University of Paraná, Curitiba, Brazil, Rua General Carneiro, 181 (14 andar), Curitiba, PR, Brasil CEP margabogus@uol.com.br. This manuscript was funded by Pfizer Inc. Disclosure Summary: M.C.S.B. has received consultant fees as a member of the KIGS Steering Committee, Pfizer Inc. A.L. is a full-time employee of Pfizer Endocrine Care, Sollentuna, Sweden. H.A.W. is an employee of Pfizer Endocrine Care, Berlin, Germany. References 1. Boguszewski M, Albertsson-Wikland K, Aronsson S, et al. Growth hormone treatment of short children born small-for-gestational-age: the Nordic Multicentre Trial. Acta Paediatr. 1998;87: 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: Dahlgren J, Wikland KA; Swedish Study Group for Growth Hormone Treatment. Final height in short children born small for gestational age treated with growth hormone. Pediatr Res. 2005;57: Ranke MB, Lindberg A, Cowell CT, et al. Prediction of response to growth hormone treatment in short children born small for gestational age: analysis of data from KIGS (Pharmacia International Growth Database). J Clin Endocrinol Metab. 2003;88: Clayton PE, Cianfarani S, Czernichow P, Johannsson G, Rapaport R, Rogol A. Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab. 2007;92(3): Maiorana A, Cianfarani S. Impact of growth hormone therapy on adult height of children born small for gestational age. Pediatrics. 2009;124;e519 e Lem AJ, van der Kaay DC, de Ridder MA, et al. Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog: results of a randomized, dose-response GH trial. J Clin Endocrinol Metab. 2012;97(11): Bergadá I, Blanco M, Keselman A, Domené HM, Bergadá C. Growth hormone treatment in younger than six years of age short children born small for gestational age [in Spanish]. Arch Argent Pediatr. 2009;107(5): Argente J, Gracia R, Ibáñez L, et al. Improvement in growth after two years of growth hormone therapy in very young children born small for gestational age and without spontaneous catch-up growth: results of a multicenter, controlled, randomized, open clinical trial. J Clin Endocrinol Metab. 2007;92(8): Fujieda K,Tanaka T. Diagnosis of children with short stature: insights from KIGS. In: Ranke MB, Price DA, Reiter EO, eds. Growth Hormone Therapy in Pediatrics 20 Years of KIGS. Basel, Switzerland: Karger; 2007: Niklasson A, Ericson A, Fryer JG, Karlberg J, Lawrence C, Karlberg P. An update of the Swedish reference standards for weight, length and head circumference at birth for given gestational age ( ). Acta Paediatr Scand. 1991;80: Prader A, Largo RH, Molinari L, Issler C. Physical growth of Swiss children from birth to 20 years of age. First Zurich longitudinal study of growth and development. Helv Paediatr Acta Suppl. 1989; 52: Freeman JV, Cole TJ, Chinn S, Jones PR, White EM, Preece MA. Cross sectional stature and weight reference curves for the UK, Arch Dis Child. 1995;73: Lindber A, Ranke MB. Data analyses within KIGS. In: Ranke MB, Price DA, Reiter EO, eds. Growth Hormone Therapy in Pediatrics 20 Years of KIGS. Basel, Switzerland: Karger; 2007: Karlberg J. On the modelling of human growth. Stat Med. 1987; 6(2): Hokken-Koelega AC, De Ridder MA, Lemmen RJ, Den Hartog H, De Muinck Keizer-Schrama SM, Drop SL. Children born small for gestational age: do they catch up? Pediatr Res. 1995;38(2): Albertsson-Wikland K, Wennergren G, Wennergren M, Vilbergsson G, Rosberg S. Longitudinal follow-up of growth in children born small for gestational age. Acta Paediatr. 1993;82(5): Karlberg JP, Albertsson-Wikland K, Kwan EY, Lam BC, Low LC. The timing of early postnatal catch-up growth in normal, full-term infants born short for gestational age. Horm Res. 1997;48: Garcia RA, Longui CA, Kochi C, et al. First two years response to growth hormone treatment in very young preterm small for gestational age children. Horm Res. 2009;72(5): Boguszewski MC, Karlsson H, Wollmann HA, Wilton P, Dahlgren J. Growth hormone treatment in short children born prematurely data from KIGS. J Clin Endocrinol Metab. 2011;96(6): Pilling EL, Elder CJ, Gibson AT. Growth patterns in the growthretarded premature infant. Best Pract Res Clin Endocrinol Metab. 2008;22: Sullivan MC, McGrath MM, Hawes K, Lester BM. Growth trajectories of preterm infants: birth to 12 years. J Pediatr Health Care. 2008;22: de Kort SW, Willemsen RH, van der Kaay DC, Duivenvoorden HJ, Hokken-Koelega AC. Does preterm birth influence the response to growth hormone treatment in short, small for gestational age children? Clin Endocrinol (Oxf). 2009;70: Carrascosa A, Audí L, Fernández-Cancio M, et al. Height gain at adult-height age in 184 short patients treated with growth hormone from prepubertal age to near adult-height age is not related to GH secretory status at GH therapy onset. Horm Res Paediatr. 2013;79: Cohen P, Rogol AD, Howard CP, Bright GM, Kappelgaard AM, Rosenfeld RG. Insulin growth factor-based dosing of growth hormone therapy in children: a randomized, controlled study. J Clin Endocrinol Metab. 2007;92: