Professor Craig Pennell

© 2018 Association for Child and Adolescent Mental Health. Background: The neuropeptide and hormone oxytocin is known to have a significant impact on social cognition and behaviour in humans. There is growing concern regarding the influence of exogenous oxytocin (OT) administration in early life on later social and emotional development, including autism spectrum disorder (ASD). No study has examined offspring development in relation to the dose of exogenous oxytocin administered during labour. Methods: Between 1989 and 1992, 2,900 mothers were recruited prior to the 18th week of pregnancy, delivering 2,868 live offspring. The Child Behaviour Checklist was used to measure offspring behavioural difficulties at ages 5, 8, 10, 14 and 17¿years. Autism spectrum disorder was formally diagnosed by consensus of a team of specialists. At 20¿years, offspring completed a measure of autistic-like traits, the Autism Spectrum Quotient (AQ). Oxytocin exposure prior to birth was analysed using categorical and continuous approaches (maternal oxytocin dose) with univariate and multivariate statistical techniques. Results: Categorical analyses of oxytocin exposure prior to birth demonstrated no group differences in any measures of child behaviour. A small in magnitude dose¿response association was observed for clinically significant total behaviour symptoms (adjusted odds ratio 1.03; 95% CI: 1.01¿1.06, p¿<.01). Exogenous oxytocin administration prior to birth was not associated with ASD (OR: 0.64; 95% CI: 0.15¿2.12, p¿=.46) or high levels of autistic-like traits (p¿=.93), as assessed by the AQ. Conclusions: This study is the first to investigate longitudinal mental health outcomes associated with the use of oxytocin-based medications during labour. The results do not provide evidence to support the theory that exogenous OT has a clinically significant negative impact on the long-term mental health of children.

© 2017, Springer-Verlag GmbH Germany. Aims/hypothesis: Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits. Methods: Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway. Results: In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (ß¿±¿SE 0.014¿±¿0.004 [mmol/l], p¿=¿1.5¿×¿10-3) and higher fasting insulin (0.030¿±¿0.005 [loge pmol/l], p¿=¿2.0¿×¿10-10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the ß-Klotho (KLB) locus on fasting insulin (0.030¿±¿0.011 loge pmol/l, uncorrected p¿=¿0.006), results in the replication cohorts and combined meta-analyses were non-significant. Conclusions/interpretation: In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis. Trial registration: Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses¿ Health Study).

© 2018 Macmillan Publishers Limited. part of Springer Nature. All rights reserved. Background:Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.Participants and methods:A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight).Results:Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10 â '8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG.Conclusions:We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

© 2018, The Publisher. In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.

© 2018 Macmillan Publishers Limited, part of Springer Nature Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10-6) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.

© J.A.M. van Eekelen et al., 2012. Genetic risk for depressive disorders is poorly understood despite consistent suggestions of a high heritable component. Most genetic studies have focused on risk associated with single variants, a strategy which has so far only yielded small (often non-replicable) risks for depressive disorders. In this paper we argue that more substantial risks are likely to emerge from genetic variants acting in synergy within and across larger neurobiological systems (polygenic risk factors). We show how knowledge of major integrated neurobiological systems provides a robust basis for defining and testing theoretically defensible polygenic risk factors. We do this by describing the architecture of the overall stress response. Maladaptation via impaired stress responsiveness is central to the aetiology of depression and anxiety and provides a framework for a systems biology approach to candidate gene selection. We propose principles for identifying genes and gene networks within the neurosystems involved in the stress response and for defining polygenic risk factors based on the neurobiology of stressrelated behaviour. We conclude that knowledge of the neurobiology of the stress response system is likely to play a central role in future efforts to improve genetic prediction of depression and related disorders.

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10 -60) and 9q31.2 (P = 2.2 × 10 -33), we identified 30 new menarche loci (all P < 5 × 10 -8) and found suggestive evidence for a further 10 loci (P < 1.9 × 10 -6). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing. © 2010 Nature America, Inc. All rights reserved.

Objectives: To describe trends in mode of delivery, to identify significant factors which affected mode of delivery, and to describe how these factors and their impact have changed over time. Design: Total population birth cohort. Setting: Western Australia 1984-2003. Participants: The analysis was restricted to all singleton infants delivered at 37-42 weeks of gestation with a cephalic presentation (n = 432 327). Methods: Logistic regression analyses were undertaken to estimate significant independent risk factors separately for elective and emergency caesarean sections compared with vaginal delivery (spontaneous and instrumental), adjusting for potential confounding variables. Main outcome measures: Trends in mode of delivery, demographic factors, and pregnancy and delivery complications. Estimated likelihood of elective caesarean section compared with vaginal delivery and emergency caesarean section compared with vaginal delivery. Results: Between 1984-88 and 1999-2003, the likelihood of women having an elective caesarean section increased by a factor of 2.35 times (95% CI 2.28-2.42) and the likelihood of an emergency caesarean section increased 1.89 times (95% CI 1.83-1.96). These caesarean section rate increases remained even after adjustment for their strong associations with many sociodemographic factors, obstetric risk factors, and obstetric complications. Rates of caesarean section were higher in older mothers, especially those older than 40 years of age (elective caesarean section, OR 5.42 [95% CI 4.88-6.01]; emergency caesarean section, OR 2.67 [95% CI 2.39-2.97]), and in nulliparous women (elective caesarean section, OR 1.54 [95% CI 1.47-1.61]; emergency caesarean section, OR 3.61 [95% CI 3.47-3.76]). Conclusions: Our data show significant changes in mode of delivery in Western Australia from 1984-2003, with an increasing trend in both elective and emergency caesarean section rates that do not appear to be explained by increased risk or indication. © RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology.

Objective To evaluate the relative contribution of cord occlusion length intervals between occlusions and experimental duration on oxidative stress in the fetal lamb brain. Design Acute, partially exteriorised fetal lambs with intermittent total cord occlusion. Setting The Vivarium of Westmead Hospital, University of Sydney, Australia and The Chinese University of Hong Kong. Main outcome measures Arterio-venous differences in the concentration of organic hydroperoxides, measured in paired samples of carotid arterial and jugular venous blood, as an index of oxidative stress in the brain. Methods Thirty-two fetal lambs were exposed to graded hypoxia, induced by intermittent total umbilical cord compression of 30 seconds, 60 seconds and 90 seconds duration, occurring every minute for a total of 27 occlusions over 81 minutes. Three sham experiments were also performed. In addition to organic hydroperoxides, carotid arterial blood samples were also assayed in 15 animals (two sham) for oxygen saturation, pH, hypoxanthine, xanthine and urate concentrations. A causal model for oxidative stress was defined: occlusions leading to hypoxia with a rise in hypoxanthine; reperfusion during intervals between occlusions leading to the accelerated production of xanthine and uric acid and the generation of oxygen free radicals, which in turn, are responsible for the rise in lipid peroxidation. Path analysis was performed to assess the strength of the relationships between these variables and the cord occlusion length, the interval between occlusions and the duration of the experiment. Results Sham experiments showed no change in organic hydroperoxide production. Following 30-second umbilical cord occlusions a sixfold drop in mean organic hydroperoxides was observed between carotid arterial and jugular venous levels. In contrast, following occlusions of 60 seconds duration (or longer) a median 20-fold increase in organic hydroperoxide production was observed. Path analysis revealed a strong indirect pathway from occlusion length ¿ hypoxanthine ¿ urate and weak positive pathways from oxygen saturation¿ urate and from interval between occlusions ¿ urate. After accounting for these pathways reflecting oxidative stress, a strong direct path remained from time from first occlusion ¿ organic hydroperoxide production. Conclusions Peroxidation of lipids in the brain occurs under conditions of severe hypoxia and reperfusion associated with intermittent umbilical cord occlusions of 60 seconds or longer. The path analysis supported the causal model as originally defined, with the exception that the indirect pathway via pH was found to be trivial.

A prospective trial to determine the accuracy and precision of the Boehringer Mannheim Accusport® handheld lactate meter in measuring plasma lactate levels in umbilical cord blood and neonatal blood microsamples was performed in the labour ward and the neonatal intensive care unit of the Nepean Hospital. Specimens were collected from the umbilical arrery of 160 consecutive deliveries covering gestations from 26 to 42 weeks, and from 110 umbilical artery catheters covering a range of gestations from 26 to 41 weeks. Serum was also obtained from an exchange transfusion for coefficient of variation analysis. Blood was simultaneously tested for lactic acid concentration on the Boehringer Mannheim (BM) Accusport® held lactate meter acid the Radiometer ABL 625® blood-gas machine. Clinical data from the mother and baby were recorded together with the full blood-gas analysis for comparison with the lactate measures. Coefficients of variation for the BM Accusport® lactate meter were established by a further 120 samples of plasma lactate at 6 concentrations from 1 to 20 mmol/L. The stability of measurements with the BM lactate meter over a wide range of temperatures was ascertained by repeated sampling of known concentrations of plasma lactate from 0.5°C to 37°C. The BM Accusport® lactate meter was found to be accurate from 1 mmol/L to 20 mmol/L with a Passing Bablok regression line y = 0.004 + 0.915 x (95% CI of slope of 0.889 to 0.946 acid intercept -0.138 to 0.094) for whole blood, and y = 0.200 + 1.000 x (95% CI of slope 0.989 to 1.018 and intercept 0.080 to 0.222) for plasma. Between run coefficient of variation (CV) was calculated to be 1.23% to 5.53% over the clinically significant range (2.2-19.3 mmol/L). The BM lactate meter was accurate from 5 to 37°C. At 0.5°C the BM lactate meter significantly underestimated the plasma lactate concentration. There was no significant effect of haematocrit (41.5 to 62%), gestation, or operator on the accuracy of the BM lactate meter. The Accusport® handheld lactate meter is an accurate, commerciailv available, method of measuring plasma lactate levels in only 60 seconds at the point-of-care. It requires only 15µL of blood and is significantly cheaper than other assay methods. The BM lactate meter is well suited to assess lactic acidaemia of fetal scalp and neonatal blood samples to help quantify hypoxic stress in the perinatal period.