individual care as technological advances lead to smaller, robust and cheaper electronic injection devices. In contrast, in the present study compliance estimated by caregiver-report showed no correlation with growth response. This method is broadly similar to retrospective patient questionnaires or GH prescription data used in previous studies [6–11]. Although a higher GHreq should also indicate better compliance, caregivers may not admit to having failed to use the appropriate amount of GH, and therefore GHreq is likely to overestimate compliance. In other conditions, consistent with our findings, such studies are reported to overestimate adherence to drug treatment, whether due to forgetfulness, embarrassment or fear of recrimination [12]. Our study indicates that patient and/or parent reported compliance (GHreq) is an unreliable measure of GH treatment compliance. This is consistent with the finding that in children requiring antibiotic prophylaxis after urinary tract infection, 97% of parents reported giving antibiotics every day, but only 69% of urine samples were positive [13]. Understanding compliance is important as clinicians are generally unable to accurately predict treatment adherence [14], and non-compliance can mislead medical practitioners regarding the efficacy of treatment and lead to invasive testing for other causes of poor growth. Further, compliance is not an end in itself. Only one previous study (reported solely in abstract form) has examined the quantitative relationship between compliance and linear growth [7]. The present study demonstrates for the first time that missing more than one GH dose a week can compromise longitudinal growth. Importantly, we showed a continuous relationship between missed doses and growth. In other words there was no apparent threshold effect, and missing more than one GH dose each week would likely affect growth. There are few validated strategies to improve adherence to GH treatment. Reduction of injection frequency with depot GH would likely improve compliance, as seen with other depot injectable therapies such as GnRH agonists [15], but is not possible at present. Since the pain of injections has been reported to be a References 1. Donovan JL (1995) Patient decision making: the missing ingredient in compliance research. Int J Technol Assess Health Care 11: 443–455. 2. Main KM, Jorgensen JT, Hertel NT, Jensen S, Jakobsen L (1995) Automatic needle insertion diminishes pain during growth hormone injection. Acta Paediatr 84: 331–334. 3. Haverkamp F, Johansson L, Dumas H, Langham S, Tauber M, et al. (2008) Observations of nonadherence to recombinant human growth hormone therapy in clinical practice. Clin Ther 30: 307–316. 4. Cromer BA, Tarnowski KJ (1989) Noncompliance in adolescents: a review. J Dev Behav Pediatr 10: 207–215. 5. Allen DB (2006) Growth hormone therapy for short stature: is the benefit worth the burden? Pediatrics 118: 343–348. 6. Hunter I, deVries C, Morris A, MacDonald T, Greene S (2000) Human growth hormone therapy: poor adherence equals poor growth [abstract]. Arch Dis Child 82: A8. 7. Desrosiers P, O’Brien F, Blethen S (2005) Patient outcomes in the GHMonitor: the effect of delivery device on compliance and growth. Pediatr Endocrinol Rev 2: 327–331. 8. Oyarzabal M, Aliaga M, Chueca M, Echarte G, Ulied A (1998) Multicentre survey on compliance with growth hormone therapy: what can be improved? Acta Paediatr 87: 387–391. 9. Kapoor RR, Burke SA, Sparrow SE, Hughes IA, Dunger DB, et al. (2008) Monitoring of concordance in growth hormone therapy. Arch Dis Child 93: 147–148. Compliance with GH Treatment in New Zealand concern [2], strategies to reduce pain such as automatic pens or use of finer injection needles may be beneficial. Oyarzabal et al showed in a multicentre survey that users of automatic pens were significantly more compliant with GH treatment than those using conventional syringes [8]. Although there are no data on GH, in other settings daily drug reminder charts [16], financial incentives [17,18], provision of enhanced support and education for patients and their families on the benefits of therapy and consequences of non-compliance may improve adherence rates [19]. However, parents receive relatively consistent support and education in New Zealand, both centrally, at the time of induction and around GH deliveries, and from paediatricians and clinic nurses, and thus improved education is unlikely to suffice. The finding of a higher incidence of non-compliance among the indigenous Maori community is of concern. Maori children have a higher burden of many diseases as well as higher rates of complications during treatment of other chronic illnesses such as diabetes [20,21]. Previous authors have acknowledged that Maori also display poorer compliance with medical treatments [21], so that developing culturally safe ways to improve adherence to long- term treatment regimens will be critical to improving outcomes in vulnerable groups [20]. In conclusion, the present study strongly suggests that poor- compliance is one of the most common factors underlying suboptimal growth during GH therapy, and should be actively evaluated and managed before considering other illnesses that can affect growth or partial GH resistance. It is critical to find ways to improve families’ compliance with GH treatment. Author Contributions Conceived and designed the experiments: WSC PLH AJG. Performed the experiments: TD KR. Analyzed the data: JGBD ER. Wrote the paper: JGBD WSC AJG. Revised the paper and contributed to discussion: JGBD WSC PLH AJG ER KR. 10. Smith SL, Hindmarsh PC, Brook CG (1993) Compliance with growth hormone treatment–are they getting it? Arch Dis Child 68: 91–93. 11. Rosenfeld RG, Bakker B (2008) Compliance and persistence in pediatric and adult patients receiving growth hormone therapy. Endocr Pract 14: 143–154. 12. Christensen DB (1978) Drug-taking compliance: a review and synthesis. Health Serv Res 13: 171–187. 13. Smyth AR, Judd BA (1993) Compliance with antibiotic prophylaxis in urinary tract infection. Arch Dis Child 68: 235–236. 14. Kardas P (2002) Patient compliance with antibiotic treatment for respiratory tract infections. J Antimicrob Chemother 49: 897–903. 15. Marcus SF, Ledger WL (2001) Efficacy and safety of long-acting GnRH agonists in in vitro fertilization and embryo transfer. Hum Fertil 4: 85–93. 16. Gabriel M, Gagnon JP, Bryan CK (1977) Improved patients compliance through use of a daily drug reminder chart. Am J Public Health 67: 968–969. 17. Giuffrida A, Torgerson DJ (1997) Should we pay the patient? Review of financial incentives to enhance patient compliance. BMJ 315: 703–707. 18. Barclay E (2009) Text messages could hasten tuberculosis drug compliance. Lancet 373: 15–16. 19. U.S. Office of Inspector General (1990) Medication regimens: causes of noncompliance. Report OEI-04-89-89121. 20. Carter P, Cutfield W, Hofman P, Gunn A, Wilson D, et al. (2008) Ethnicity and social deprivation independently influence metabolic control in children with type 1 diabetes. Diabetologia 51: 1835–1842. 21. McCreanor T, Nairn R (2002) Tauiwi general practitioners’ talk about Maori health: interpretative repertoires. N Z Med J 115(1167): U272. PLoS ONE | www.plosone.org 3 January 2011 | Volume 6 | Issue 1 | e16223