Anita Hokken-Koelega

Children Born Small for Gestational Age: Do They Catch Up?

ABSTRACT: Postnatal growth of 724 (423 premature, 301 full-term) small for gestational age infants (SGA. birth length less than the third length percemile (P3) for gestational age) was studied for the first 2 y of lile. The study group consisted of all SGA infants who had been admitted over a period of 8 y at the Departments of Neonatology of three University Hospitals in The Netherlands with exclusion of infants with well defined causes for growth retardation, such as chromosomal disorders, syndromes, severe malformations, or complications during the neonatal period or later on. The aim of the study was to describe postnatal growth of SGA infants and to find predictive factors for catch-up growth ≥P3 during the first 2 y of life. The majority (around 85%) of the healthy SGA infants showed catch-up growth to a height ≥P3 during the first 2 y of life. The percentage of premature SGA infants with catch-up growth ≥P3 at 2 y of age (82.5%) was not significantly different from that of full-term SGA infants (87.5%). Birth length SDS was more sensitive than birth weight SDS in predicting catch-up ≥P3 in premature SGA infants. In contrast, birth weight SDS was the best predictor for catch-up >P3 in full-term SGA infants. Gestational age, multiple birth, and sex were not significantly associated with catch-up in height ≥P3. For children with a length still below P3 at 3 or 6 mo of age, the actual length SDS at that age appeared positively associated with catch-up ≥P3. In SGA premature infants there was also a positive association between the weight gain during the first 6 mo and the catch-up growth ≥P3. SGA children with short stature (height <P3) at 2 y of age need further investigation.

Timing and Tempo of First-Year Rapid Growth in Relation to Cardiovascular and Metabolic Risk Profile in Early Adulthood

CONTEXT Growth during infancy appears to be an important determinant of cardiovascular disease and type 2 diabetes later in life. OBJECTIVES To specify which period in the first year of life is related to determinants of cardiovascular disease and type 2 diabetes in early adulthood and to investigate the association between tempo of first-year weight gain (>0.67 SDs) and these determinants. DESIGN, SETTING, AND PARTICIPANTS Observational study using longitudinal data collected in the Programming Factors for Growth and Metabolism (PROGRAM) study of 217 healthy participants, aged 18 to 24 years, including a relatively large sample of participants born small for gestational age and participants with short stature, performed at a medical center in The Netherlands between August 2004 and September 2007. The association of cardiovascular disease and type 2 diabetes with tempo of weight gain was assessed in a subgroup of 87 participants. MAIN OUTCOME MEASURES Associations between periods of first-year growth and tempo of weight gain and determinants of cardiovascular disease and type 2 diabetes in early adulthood. RESULTS Weight gain in the first 3 months of life was inversely associated with insulin sensitivity (beta, -0.223; 95% confidence interval [CI], -0.386 to -0.060) and serum high-density lipoprotein cholesterol level (beta, -0.053; 95% CI, -0.090 to -0.016) and positively associated with waist circumference (beta, 1.437; 95% CI, 0.066 to 2.808), acute insulin response (beta, 0.210; 95% CI, 0.024 to 0.395), ratio of total cholesterol to high-density lipoprotein cholesterol (beta, 0.052; 95% CI, 0.010 to 0.094), and level of triglycerides (beta, 0.066; 95% CI, 0.003 to 0.129) in early adulthood. Rapid weight gain during the first 3 months of life resulted in a higher percentage of body fat, more central adiposity, and reduced insulin sensitivity in early adulthood than when slower weight gain occurred during the entire first year. CONCLUSION Rapid weight gain in the first 3 months of life is associated with several determinants of cardiovascular disease and type 2 diabetes in early adulthood.

Recommendations for the diagnosis and management of Prader-Willi syndrome

OBJECTIVE The objective of the study was to provide recommendations for the diagnosis and management of Prader-Willi syndrome throughout the life span to guide clinical practice. PARTICIPANTS An open international multidisciplinary expert meeting was held in October 2006 in Toulouse, France, with 37 invited speakers and session chairs (see Acknowledgments) and 85 additional registered participants. The meeting was supported by an unrestricted educational grant from Pfizer. EVIDENCE Invited participants with particular expertise reviewed the published evidence base for their specialist topic and unpublished data from personal experience, previous national and international PWS conferences, and PWS Association clinical advisory groups. Sessions covered epidemiology, psychiatric, and behavioral disorders; breathing and sleep abnormalities; genetics; endocrinology; and management in infancy, childhood, transition, and adulthood. CONSENSUS PROCESS This included group meetings including open discussion after each session. The guidelines were written by the Scientific Committee (authors), using the conclusions provided by the sessions chairs and summary provided by each speaker, including incorporation of changes suggested after review by selected meeting participants (see Acknowledgments). CONCLUSIONS The diagnosis and management of this complex disorder requires a multidisciplinary approach with particular emphasis on the importance of early diagnosis using accredited genetic testing, use and monitoring of GH therapy from early childhood, control of the food environment and regular exercise, appropriate management of transition, consideration of group home placement in adulthood, and distinction of behavioral problems from psychiatric illness.

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

OBJECTIVE The pathophysiological mechanisms underlying the failure of catch up‐growth in children with short stature after Intrauterine growth retardation (IUGR) remain obscure. Since GH secretion disturbances might play a role in the growth retardation of these children we have Investigated various aspects of the GH/IGF axis.

Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: preliminary report of 3 countries participating in the EU SAGhE study

CONTEXT The long-term mortality in adults treated with recombinant GH during childhood has been poorly investigated. Recently released data from the French part of the European Union Safety and Appropriateness of GH treatments in Europe (EU SAGhE) study have raised concerns on the long-term safety of GH treatment. OBJECTIVE To report preliminary data on long-term vital status and causes of death in patients with isolated GH deficiency or idiopathic short stature or born small for gestational age treated with GH during childhood, in Belgium, The Netherlands, and Sweden. DESIGN Data were retrieved from national registries of GH-treated patients and vital status from National Population Registries. Causes of death were retrieved from a National Cause of Death Register (Sweden), Federal and Regional Death Registries (Belgium), or individual patient records (The Netherlands). PATIENTS All patients diagnosed with isolated GH deficiency or idiopathic short stature or born small for gestational age started on recombinant GH during childhood from 1985-1997 and who had attained 18 yr of age by the end of 2010 were included. Vital status was available for approximately 98% of these 2,543 patients, corresponding to 46,556 person-years of observation. MAIN OUTCOME MEASURE Vital status, causes of death, age at death, year of death, duration of GH treatment, and mean GH dose during treatment were assessed. RESULTS Among 21 deaths identified, 12 were due to accidents, four were suicides, and one patient each died from pneumonia, endocrine dysfunction, primary cardiomyopathy, deficiency of humoral immunity, and coagulation defect. CONCLUSIONS In these cohorts, the majority of deaths (76%) were caused by accidents or suicides. Importantly, none of the patients died from cancer or from a cardiovascular disease.

Adrenal function in sick very preterm infants

Some very preterm neonates admitted to the neonatal intensive care unit show circulatory and respiratory problems that improve after administration of steroids. It is unclear whether these symptoms could be caused by adrenal insufficiency. The objective of our study was to investigate the cortisol levels and the cortisol release from the adrenals after ACTH in very preterm infants with and without severe illness and to find whether a relation exists between adrenal function and outcome. An ACTH test (0.5 μg) was performed on d 4 in 21 very preterm infants (gestational age, 25.6–29.6 wk; birth weight, 485–1265 g). Baseline cortisol and 17-hydroxyprogesterone (17OHP) levels and the cortisol levels 30, 60, and 120 min after ACTH administration were measured. The Score for Neonatal Acute Physiology was used to measure illness severity. All infants showed an increase in cortisol levels after ACTH, but the cortisol levels were significantly lower in the ventilated more severely ill infants. After adjusting for birth weight and gestational age, the mean baseline cortisol levels and cortisol/17OHP ratios were significantly lower and the 17OHP levels significantly higher in the ventilated infants compared with the nonventilated infants. Patients with an adverse outcome had significantly lower baseline cortisol/17OHP ratios and 60-min cortisol levels during ACTH testing (p = 0.002 and p = 0.03, respectively). These data suggest an insufficient adrenal response to stress in sick ventilated very preterm infants with gestational ages younger than 30 wk compared with nonventilated less sick preterm infants. Further studies are required to investigate whether supplementation with physiologic doses of hydrocortisone may benefit the outcome.

One single dose of etomidate negatively influences adrenocortical performance for at least 24 h in children with meningococcal sepsis

ObjectiveTo investigate the effect of one single bolus of etomidate used for intubation on adrenal function in children with meningococcal sepsis.DesignRetrospective study conducted between 1997 and 2004.SettingUniversity-affiliated paediatric intensive care unit (PICU).Patients and participantsSixty children admitted to the PICU with meningococcal sepsis, not treated with steroids.InterventionsAdrenal hormone concentrations were determined as soon as possible after PICU admission, and after 12 h and 24 h. To assess disease severity, PRISM score and selected laboratory parameters were determined.Measurements and main resultsOn admission, before blood was drawn, 23 children had been intubated with etomidate, 8 without etomidate and 29 were not intubated. Children who were intubated had significantly higher disease severity parameters than those not intubated, whereas none of these parameters significantly differed between children intubated with or without etomidate. Children who received etomidate had significantly lower cortisol, higher ACTH and higher 11-deoxycortisol levels than those who did not receive etomidate. Arterial glucose levels were significantly lower in children who were intubated with etomidate than in non-intubated children. When children were intubated with etomidate, cortisol levels were 3.2 times lower for comparable 11-deoxycortisol levels. Eight children died, seven of whom had received etomidate. Within 24 h cortisol/ACTH and cortisol/11-deoxycortisol ratios increased significantly in children who received etomidate, but not in children who did not, resulting in comparable cortisol/ACTH ratios with still significantly lowered cortisol/11-deoxycortisol ratios 24 h after admission.ConclusionsOur data imply that even one single bolus of etomidate negatively influences adrenal function for at least 24 h. It might therefore increase risk of death.

Serum Anti-Mullerian Hormone Levels in Healthy Females: A Nomogram Ranging from Infancy to Adulthood

CONTEXT Anti-müllerian hormone (AMH) is an accurate marker of ovarian reserve. However, sufficiently large sets of normative data from infancy to the end of reproductive life are scarce. OBJECTIVE This study was an assessment of serum AMH levels in healthy females. SUBJECTS In 804 healthy females ranging from infancy until the end of the reproductive period, serum AMH levels were measured with an enzyme-linked immunometric assay. All adults had regular menstrual cycles. The majority was proven fertile and none of them had used oral contraceptive pills prior to study inclusion. RESULTS In the total cohort, AMH was inversely correlated with age (r = -0.24; P < 0.001). The age at which the maximum AMH value was attained was at 15.8 yr. In girls younger than 15.8 yr, serum AMH and age were positively correlated (r = +0.18; P = 0.007). Thereafter AMH levels remained stable (r = -0.33; P = 0.66), whereas from the age of 25.0 yr onward, an inverse correlation between AMH and age (r = -0.47; P < 0.001) was observed. At any given age, considerable interindividual differences in serum AMH levels were observed. CONCLUSION During infancy AMH levels increase, whereas during adolescence, a plateau until the age of 25 yr was observed. From the age of 25 yr onward, serum AMH levels correlate inversely with age, implying that AMH is applicable as a marker of ovarian reserve only in women of 25 yr old and older. Our nomogram may facilitate counseling women on their reproductive potential.

Reduced insulin sensitivity and the presence of cardiovascular risk factors in short prepubertal children born small for gestational age (SGA)

Background  Epidemiological studies have shown that the metabolic syndrome, a combination of type 2 diabetes mellitus, hypertension, dyslipidaemia and a high body mass index (BMI), occurs more frequently among adults who were born with a low birth weight. Because insulin is thought to play a key role in the pathogenesis of this syndrome we investigated insulin sensitivity and risk factors for cardiovascular disease in short prepubertal children born small for gestational age (SGA).

Growth Hormone Research Society Workshop Summary: Consensus Guidelines for Recombinant Human Growth Hormone Therapy in Prader-Willi Syndrome

Context: Recombinant human GH (rhGH) therapy in Prader-Willi syndrome (PWS) has been used by the medical community and advocated by parental support groups since its approval in the United States in 2000 and in Europe in 2001. Its use in PWS represents a unique therapeutic challenge that includes treating individuals with cognitive disability, varied therapeutic goals that are not focused exclusively on increased height, and concerns about potential life-threatening adverse events. Objective: The aim of the study was to formulate recommendations for the use of rhGH in children and adult patients with PWS. Evidence: We performed a systematic review of the clinical evidence in the pediatric population, including randomized controlled trials, comparative observational studies, and long-term studies (>3.5 y). Adult studies included randomized controlled trials of rhGH treatment for ≥ 6 months and uncontrolled trials. Safety data were obtained from case reports, clinical trials, and pharmaceutical registries. Methodology: Forty-three international experts and stakeholders followed clinical practice guideline development recommendations outlined by the AGREE Collaboration (www.agreetrust.org). Evidence was synthesized and graded using a comprehensive multicriteria methodology (EVIDEM) (http://bit.ly.PWGHIN). Conclusions: Following a multidisciplinary evaluation, preferably by experts, rhGH treatment should be considered for patients with genetically confirmed PWS in conjunction with dietary, environmental, and lifestyle interventions. Cognitive impairment should not be a barrier to treatment, and informed consent/assent should include benefit/risk information. Exclusion criteria should include severe obesity, uncontrolled diabetes mellitus, untreated severe obstructive sleep apnea, active cancer, or psychosis. Clinical outcome priorities should vary depending upon age and the presence of physical, mental, and social disability, and treatment should be continued for as long as demonstrated benefits outweigh the risks.