Sarah Mathai

Increased Adiposity in Adults Born Preterm and Their Children

Background Preterm birth is associated with abnormalities in growth, body composition, and metabolism during childhood, but adult data are scarce and none exist for their offspring. We therefore aimed to examine body composition and cardiovascular risk factors in adults born preterm and their children. Methods A cohort of 52 adults (aged 35.7 years, 54% female, 31 born preterm) and their term-born children (n=61, aged 8.0 years, 54% female, 60% from a preterm parent) were studied. Auxology and body composition (whole-body dual-energy X-ray absorptiometry) were measured, and fasting blood samples taken for metabolic and hormonal assessments. Results Adults born preterm had greater abdominal adiposity, displaying more truncal fat (p=0.006) and higher android to gynoid fat ratio (p=0.004). Although women born preterm and at term were of similar weight and BMI, men born preterm (n=8) were on average 20 kg heavier (p=0.010) and of greater BMI (34.2 vs 28.4 kg/m2; p=0.021) than men born at term (n=16). Adults born preterm also displayed a less favourable lipid profile, including lower HDL-C concentrations (p=0.007) and greater total cholesterol to HDL-C ratio (p=0.047). Children of parents born preterm tended to have more body fat than the children of parents born at term (21.3 vs 17.6%; p=0.055). Even after adjustment for mean parental BMI, children of parents born preterm had altered fat distribution, with more truncal fat (p=0.048) and greater android to gynoid fat ratio (p=0.009). Conclusions Adults born preterm, particularly men, have markedly increased fat mass and altered fat distribution. A similar increase in abdominal adiposity was observed in the term born offspring of parents born preterm, indicating that adverse outcomes associated with preterm birth may extend to the next generation.

A novel therapeutic paradigm to treat congenital hypothyroidism

Objective  To determine the effectiveness of a novel therapeutic paradigm to treat congenital hypothyroidism (CH) incorporating variable initial doses of L‐T4 based on the underlying aetiology and frequent monitoring, up to 2 years of age.

Neurodevelopmental and body composition outcomes in children with congenital hypothyroidism treated with high-dose initial replacement and close monitoring

BACKGROUND Despite newborn screening and early levothyroxine replacement, there are continued reports of mild neurocognitive impairment in children with congenital hypothyroidism (CHT). In Auckland, New Zealand, cases are identified by a neonatal screening program with rapid institution of high-dose levothyroxine replacement (10-15 μg/kg·d), producing prompt normalization of thyroid function. Subsequently, frequent monitoring and dose alterations are performed for 2 years. We aimed to assess whether the Auckland treatment strategy prevents impairment of intellectual and motor development. METHODS This study encompassed all children with CHT born in 1993-2006 in Auckland and their siblings. Neurocognitive assessments included the following: 1) intelligence quotient via Weschler Preschool and Primary Scale of Intelligence III or Weschler Intelligence Scale for Children IV; 2) Movement Assessment Battery for Children; and 3) Beery Developmental Test of Visual-Motor Integration. Body composition was assessed by dual-energy x-ray absorptiometry. RESULTS Forty-four CHT cases and 53 sibling controls aged 9.6 ± 3.9 years were studied. Overall intelligence quotient was similar among CHT cases and controls (95.2 vs 98.6; P = .20), and there were also no differences in motor function. Severity of CHT did not influence outcome, but greater time to normalize free T4 was associated with worse motor balance. There were no differences in anthropometry or body composition between groups. CONCLUSIONS These findings suggest that a strategy of rapidly identifying and treating infants with CHT using high-dose levothyroxine replacement is associated with normal intellectual and motor development. The subtle negative impact on motor function associated with time to normalize free T4 levels is consistent with benefit from rapid initial correction.

Maturity onset diabetes of the young in India - a distinctive mutation pattern identified through targeted next-generation sequencing

To establish and utilize a Next‐Generation Sequencing (NGS)‐based strategy to screen for maturity onset diabetes of the young (MODY) gene mutations in subjects with early‐onset diabetes.

Pre-Pubertal Children Born Post-Term Have Reduced Insulin Sensitivity and Other Markers of the Metabolic Syndrome

Background There are no data on the metabolic consequences of post-term birth (≥42 weeks gestation). We hypothesized that post-term birth would adversely affect insulin sensitivity, as well as other metabolic parameters and body composition in childhood. Methods 77 healthy pre-pubertal children, born appropriate-for-gestational-age were studied in Auckland, New Zealand: 36 born post-term (18 boys) and 41 (27 boys) born at term (38–40 weeks gestation). Primary outcome was insulin sensitivity measured using intravenous glucose tolerance tests and Bergman’s minimal model. Other assessments included fasting hormone concentrations and lipid profiles, body composition from whole-body dual-energy X-ray absorptiometry, 24-hour ambulatory blood pressure monitoring, and inflammatory markers. Results Insulin sensitivity was 34% lower in post-term than in term children (7.7 vs. 11.6 x10-4·min-1·(mU/l); p<0.0001). There was a compensatory increase in acute insulin response among post-term children (418 vs 304 mU/l; p=0.037), who also displayed lower glucose effectiveness than those born at term (2.25 vs 3.11 x10-2·min-1; p=0.047). Post-term children not only had more body fat (p=0.014) and less fat-free mass (p=0.014), but also had increased central adiposity with more truncal fat (p=0.017) and greater android to gynoid fat ratio (p=0.007) compared to term controls. Further, post-term children displayed other markers of the metabolic syndrome: lower normal nocturnal systolic blood pressure dipping (p=0.027), lower adiponectin concentrations (p=0.005), as well as higher leptin (p=0.008) and uric acid (p=0.033) concentrations. Post-term boys (but not girls) also displayed a less favourable lipid profile, with higher total cholesterol (p=0.018) and LDL-C (p=0.006) concentrations, and total cholesterol to HDL-C ratio (p=0.048). Conclusions Post-term children have reduced insulin sensitivity and display a number of early markers of the metabolic syndrome. These findings could have important implications for the management of prolonged pregnancies. Future studies need to examine potential impacts later in life, as well as possible underlying mechanisms.

White Matter Protection with Insulin-Like Growth Factor 1 and Hypothermia Is Not Additive after Severe Reversible Cerebral Ischemia in Term Fetal Sheep

Moderate cerebral hypothermia significantly improves survival without disability from perinatal hypoxia-ischemia. However, protection is partial. Insulin-like growth factor 1 (IGF-1) plays a key role in oligodendrocyte survival and myelination. The purpose of this study was to test the hypothesis that the combination of IGF-1 plus hypothermia could reduce postischemic white matter damage compared with hypothermia alone. Unanesthetized near-term fetal sheep received 30 min of cerebral ischemia, followed by either an infusion of 3 µg of IGF-1 intracerebroventricularly from 4.5 to 5.5 h plus cooling from 5.5 to 72 h (IGF-1 + hypothermia; n = 8), vehicle infusion plus cooling from 5.5 to 72 h (vehicle + hypothermia; n = 12), sham cooling plus sham infusion (ischemia control; n = 12) or sham ischemia (n = 5). The fetal extradural temperature was reduced from 39.4 ± 0.1°C to between 30 and 33°C. White matter was assessed after 5 days. Ischemia was associated with severe loss of CNPase-positive oligodendrocytes in white matter compared with sham ischemia (380 ± 138 vs. 1,180 ± 152 cells/field; mean ± SD; p < 0.001). Delayed hypothermia reduced cell loss (847 ± 297 cells/field, p < 0.01, vs. ischemia control), but there was no significant difference between vehicle + hypothermia and IGF-1 + hypothermia (1,015 ± 211 cells/field; NS). Ischemia was associated with increased caspase 3 expression in white matter (216 ± 41 vs. 19 ± 18 cells/field; p < 0.001). Hypothermia reduced numbers of activated caspase 3-positive cells (116 ± 81 cells/field; p < 0.05), with no significant difference between vehicle + hypothermia and IGF-1 + hypothermia (91 ± 27 cells/field; NS). In conclusion, delayed cotreatment with IGF-1 plus hypothermia after ischemia was associated with an improvement in white matter damage similar to that achieved by hypothermia alone.

Sirolimus therapy for congenital hyperinsulinism in an infant with a novel homozygous KCNJ11 mutation.

Abstract Background: Congenital hyperinsulinism results in refractory hypoglycemia. If a therapy with diazoxide has been unresponsive this has been treated by subtotal pancreatectomy in the past. This therapeutic option poses an increased risk of developing diabetes at a later stage. There have been a few case reports on the use of sirolimus in such situations in the recent past. Case presentation: Our patient was started on sirolimus very early, on day 29 of life and at the age of 14 months is doing well on sirolimus therapy. His growth and development have been good and he has not had any major complications so far. Genetic testing showed a novel KCNJ11 homozygous mutation on next generation sequencing and the parents were heterozygous carriers. Conclusions: We report the successful use of sirolimus in the management of diazoxide unresponsive congenital hyperinsulinism with diffuse pancreatic involvement. We believe this is the youngest patient to be initiated on sirolimus so far.

A single antenatal course of betamethasone adversely affects glucose regulation in adulthood and the next generation in childhood

Methods A cohort of 52 adults (aged 35.7 years, 46% men, 23 born after steroid treatment) and their term-born children (n=61, aged 8.0 years, 52% boys, 49% from a parent born after steroid treatment), was recruited in Auckland. Insulin sensitivity and secretion were assessed using hyperglycaemic clamps in adults, and HOMA-IR in children. Other assessments included DXA-derived body composition, lipid profile, adipokines, and 24-hour ambulatory blood pressure monitoring.

Preterm birth is associated with an intergenerational effect on cardio‐metabolic risk

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Early markers of the metabolic syndrome in children born post-term

We recently showed from a Swedish cohort that nearly half of boys born post-term (≥42 weeks gestation) were overweight or obese at 16 years of age. We hypothesized that post-term children would display features of insulin resistance and the metabolic syndrome even in their pre-pubertal years. 90 healthy pre-pubertal children aged 4–11 years, with birth weight appropriate-for-gestational-age were studied: 36 children born post-term (18 boys and 18 girls) and 54 children (36 boys and 18 girls) born at term (38–40 weeks). Insulin sensitivity was measured using Bergman’s minimal model. Other assessments included fasting lipid and hormonal profiles, body composition using whole-body dual-energy x-ray absorptiometry, and 24-hour ambulatory blood pressure monitoring. Insulin sensitivity was reduced in post-term children (8.44±0.74 vs 13.55±0.89 x10-4·min−1·(mU/L); p<0.0001). Post-term children had an adverse lipid profile, with higher total cholesterol (4.26±0.17 vs 3.92±0.11 mmol/l; p=0.023) and LDL (2.51±0.13 vs 2.25±0.08 mmol/l; p=0.016) concentrations. Further changes suggestive of the metabolic syndrome among post-term children included an increased android to gynoid fat ratio (0.74±0.03 vs 0.61±0.02; p=0.026), and a reduction in the normal nocturnal systolic blood pressure dip (8.2±1.0 vs 13.8±1.0%; p=0.016). Post-term children also had higher serum leptin (7.18±0.91 vs 3.67±0.41 ng/ml; p=0.011), lower adiponectin (8226±693 vs 10536±556 ng/ml; p=0.046), and lower IGFBP1 (9.56±1.06 vs 18.03±1.59 ng/ml; p=0.032) concentrations. Our study shows for the first time that post-term children have early features of the metabolic syndrome, including reduced insulin sensitivity, adverse lipid profile, and increased abdominal adiposity.