Big Data—Small Children: Adult Height in Preterm Infants Treated With GH

This year marks the thirty-fifth anniversary of the release of a biosynthetic human growth hormone (hGH). The first product, somatrem, had an additional methionine at the N-terminal (1). It has subsequently been replaced by somatropin (rhGH) which has the same sequence as pituitary growth hormone (GH). This year is also the thirty-fifth anniversary of pharmaceutical company–sponsored registries, which collected data from rhGH-treated patients. These two facts are connected. Before 1985, the only hGH available was purified from cadaver pituitaries (2). Supplies were limited, and that meant that only the most severely affected children with GH deficiency (GHD) could be treated. When an association between use of human pituitary GH and Creutzfeldt-Jakob disease was recognized (3), pituitary hGH was withdrawn. Only rhGH is used today. Quantities of hGH are now essentially unlimited and new indications have been explored. Because many more patients could be treated, the U.S. Food and Drug Administration asked Genentech to commit to a postmarketing surveillance study of children treated with somatrem. This study, eventually called the National Cooperative Growth Study (NCGS) was the first registry of patients receiving recombinant GH preparations (4, 5). Several other pharmaceutical companies now market rhGH, and many of them also sponsor registries to track data on the patients treated with their GH product. The KIGS (Pfizer International Growth Database) is one of these. KIGS and NCGS are the two largest GH registries. Together, they have long term data on approximately 150 000 children who received rhGH.

The registries are particularly useful for (1) identifying rare safety signals (2), assessing risks in patients with complex medical problems, and (3) gathering long-term outcome data that are not practical to collect in a controlled trial. While there is now a luxury of data on daily rhGH use, a registry of patients using a new long-acting formulation might provide information on whether differences in the pharmacokinetics and pharmacodynamics between these formulations and daily rhGH leads to unexpected changes in long-term efficacy or adverse events.

The paper by Boguszenwski et al (6) in this issue of The Journal of Clinical Endocrinology & Metabolism reporting adult height in children born prematurely is an example of the type of question that can be explored using these databases. They report on 586 infants born prematurely who were treated with rhGH for short stature until they reached adult height. Adult height was defined using decreasing growth rate and if available, bone age. The patients were divided into 2 groups based on size at birth: AGA (appropriate for gestational age, n = 482) and SGA (small for gestational age, n = 104). Most (66%) of the AGA children had GH deficiency, defined as a maximum stimulated GH <7 µg/L. In contrast, only 9 of the SGA met these criteria for GH deficiency.

The paper contains several interesting observations:

• 1) The higher proportion of children with GHD in the AGA group supports the belief that pituitary GH does not have a major role in prenatal growth.

• 2) As a group, the AGA patients gained more height than the SGA patients. This finding illustrates, the two uses of hGH (as replacement therapy and as pharmacotherapy) and suggests greater effectiveness in the former.

• 3) The most discouraging observation is how old children (both AGA and SGA) were when they began treatment. Many publications (including this one), report that in children with different diagnoses that the age when hGH treatment starts and the duration of treatment are important variables determining total height gain. Additionally, beginning hGH between ages 2 and 4 years is specifically recommended for SGA children (7). Still, most children in this study were older than 8 years when they began rhGH. Only a few SGA children began hGH before age 4.

Normal growth is the result of many factors, including nutrition, lack of chronic illness, as well as an appropriate endocrine milieu. Poor growth can be the first sign of many serious illnesses. A simple chart of height and weight compared to normal children can be highly informative: reassuring in many cases and an early sign of chronic illness in others. There are special considerations for children born prematurely. In the immediate postnatal period, they do not grow as fast as their counterparts who remain in utero. Once their acute problems resolve, they should show catch-up growth. This catch-up growth should be complete by 2 years. Short stature beyond age 2 years in a former preterm infant needs careful evaluation.

Abbreviations

Abbreviations
 
• AGA

  appropriate for gestational age

 
• GH

  growth hormone

 
• GHD

  growth hormone deficiency

 
• hGH

  human growth hormone

 
• KIGS

  Pfizer International Growth Database

 
• NCGS

  National Cooperative Growth Study

 
• rhGH

  somatropin

 
• hGH

  human growth hormone

 
• SGA

  small for gestational age

Additional Information

Disclosure Summary: Consultant for Ipsen US, 2016-2018.

Data Availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

References