Follow-up to Adult Height of a Cohort of Subjects Born Small for the Gestational Age and Treated With Growth Hormone
Follow-up to Adult Height of a Cohort of Subjects Born Small for the Gestational Age and Treated With Growth Hormone
This non-interventional study for prospective follow up of a cohort of 220 subjects born
 small for gestational age (SGA) is planned for the purpose of finding out if normalisation of
 adult height is associated or not with metabolic alterations and if true, their magnitude and
 relevance as well as to detect warnings throughout the treatment period that may be useful
 for prevention or therapy. This study would help in answering the question if the SGA and
 growth hormone (GH) association results in insulin resistance and if affirmative, who
 develops it as well as its impact on other metabolic parameters that precedes type 2
 diabetes.
The small for gestational age (SGA) concept includes babies born to term whose weight and/or
 height is lower than two standard deviations (SD) below the mean. Pathologically short
 stature is understood as a stature of 2.5 SD below the mean for their age and an expected
 adult height adjusted to the parental height of one SD below the mean. These SGA children
 with a pathological short stature after four years of age are unsuitable for GH treatment. In
 fact, there is no other efficient treatment for short stature and insufficient development of
 these children other than GH. In addition to short stature, the SGA syndrome also includes
 resistance to insulin with the consequent risk of developing type 2 diabetes and other
 interrelated metabolic alterations like dyslipidemia and hypertension; and the
 glucose-insulin-insulin growth factors (IGFs)-proteins transport axis regulate growth as well
 as foetal metabolism and development. Independent from the possible maternal environmental
 causes, those born with SGA have low levels of somatomedin C (IGF-I) and its transport
 protein [Insulin-like growth factor binding protein 3 (IGFBP-3)] as well as fasting
 hyperinsulinemia. The low levels of IGF-1 and IGFBP-3 persist in those that do not present a
 catch-up growth and the insulin resistance is secondary to the somatotrope axis. Treatment
 with GH increases IGF-I and IGFBP3 levels but also the plasmatic level of fasting insulin and
 the long term net result of this combination is unknown.

 An analysis has shown, that although during the first 2 years of GH treatment, there are no
 signs of glucose intolerance even though there is less sensitivity to insulin, there could be
 a greater incidence of type 2 diabetes in deficient children that have been treated with GH
 for a longer period. Treatment with GH, of children born SGA that have not caught-up their
 growth at 4 years of age, in the majority of cases achieves a good initial growth speed
 increase in order to continue to grow within normal limits and end up with an adult height
 that falls within normal. This is achieved with an authorised daily dose of 0.035 mg/kg (1
 mg/m2/day). However, the question regarding the possible metabolic consequences of GH
 treatment of those born SGA remains unanswered in both forms, to find out if GH treatment
 increases or reduces resistance to insulin and other associated metabolic parameters and
 therefore, the risk of developing type 2 diabetes. Continued monitoring to adult height of a
 cohort of subjects born with SGA and treated with GH is the most efficient, easy and
 comfortable tool for answering that question.

 OBJECTIVES

 Primary objective:

 -  To quantify the evolution of insulin sensitivity from the start of treatment with GH
 until adult stature is reached. Sensitivity or resistance to insulin is calculated using
 the HOMA-IR model (Homeostasis Model Assessment for Insulin Resistance) which is a
 reliable and easy mathematical model that uses the following formula: insulinemia
 (μU/ml) x glycemia (mmol/l)/22.5.

 Secondary objectives:

 -  To find predictive factors for the possible changes in insulin sensitivity and its
 complex associated obesity, hypertension and high triglycerides type dyslipidemia with
 low high density lipoprotein (HDL)-cholesterol. For this, a relation between these
 metabolic factors and auxological parameters is to be identified.

 a. The following are considered independent or predictive variables:

 -  Speed of growth in cm/ year

 -  Standard deviations of height

 -  IGF-I in ng/ml

 -  IGFBP-3 in ng/ml b. The dependent variables will be:

 -  HOMA-IR value

 -  Triglycerides rate in mg/dl / HDL-cholesterol in mg/dl

 -  Blood pressure in mmHG

 -  Body mass index

 This is an observational study of a single cohort, without the possibility of a control group
 because those born with SGA, who experience a catch-up growth and enter normal auxology
 within the first four years of life are not subjected to a paediatric follow-up similar to
 those that do not catch-up to normal auxology and are treated with GH. Therefore, the same
 auxological and metabolic test results are not available in standard care. The collection of
 said parameters requires an "ad hoc" intervention and the study would be experimental or
 interventional. The observation period of this study encompasses from the start of treatment
 with GH up to a year after finishing the treatment for any reason. The starting age as well
 as the time treatment is ended will vary per subject. However, most subjects finish treatment
 once adulthood is reached. In accordance with clinical studies, the average observation
 period will probably be about 10 years. After the basal data is made available, the
 collection of data afterwards will be carried out once a year per subject.
Inclusion Criteria:

 -  Children with growth disorder (current height <-2.5 SD and height adjusted to parental
 stature <-1 SD) in children born SGA with a weight and/or length at birth below -2 SD,
 that has not experimented a growth catch-up (growth speed <0 SD during the last year)
 at 4 years old or afterwards were enrolled in the study

 -  Children undergoing treatment with somatropin from Serono

 -  Children whose parent or legal guardians, as well as the subject himself if 12 or more
 years old have given written permission to access their records

 Exclusion Criteria:

 -  Children with closed epiphysis

 -  Children with known hypersensitivity to somatropin or to any excipients present in the
 injection powder or solvent

 -  Subjects with active neoplasms. Any anti-tumoral treatment must be completed prior to
 starting treatment with somatropin

 -  Subjects with evidence of progression or relapse of a subjacent intracranial lesion

 -  Subjects with acute critical diseases such as those that present complications after
 open heart surgery, abdominal surgery, polytraumatisms, acute respiratory failure or
 similar conditions