The University of Western Australia

UWA Staff Profile

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Craig Pennell

Assoc/Prof Craig Pennell

Associate Professor
Women's and Infants' Health, School of

Contact details
School of Women's and Infants' Health
The University of Western Australia (M550)
35 Stirling Highway
+61 8 9381 3031
MB BS Adel., PhD W.Aust., FRANZCOG
Associate Professor Craig Pennell graduated in medicine with honours in 1993 from Adelaide University. After three years in the Royal Australian Army, he pursued training in Obstetrics and Gynaecology in Sydney. This was followed by three years of subspecialty training in Maternal-Fetal Medicine in Perth and fifteen months of subspecialty training in Toronto, Canada. Whilst completing his specialty and subspecialty training, he completed a PhD in Fetal Physiology evaluating the role of lactate measurement in the prediction of fetal hypoxic-ischaemic brain injury during labour. His convocation for Doctor of Philosophy (with Distinction) was in 2004. In October 2003 Dr Pennell was awarded the Athelstan and Amy Saw Research Fellowship from the University of Western Australia to undertake postdoctoral research in molecular genetics at the Samuel Lunenfeld Research Institute in Toronto. He returned to Perth in April 2005 and completed the examination process for certification as a subspecialist in Maternal Fetal Medicine in October 2006. When Dr Pennell returned to Australia he established the Perinatal Genomic Research Initiative within the School of Women’s and Infants’ Health (SWIH) at The University of Western Australia.

As the Associate Professor in Maternal Fetal Medicine at (The University of Western Australia at King Edward Memorial Hospital in Perth) his current position includes clinical maternal fetal medicine, undergraduate and postgraduate teaching and research with collaborators in Perth, Toronto, Alberta, and three multinational genetics consortiums: 1) the Preterm Birth Genome Project (PGP) led by the World Health Organisation in Geneva; 2) the Early Growth Genetics (EGG) consortium; and 3) the Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium). In 2008, he received the Faculty of Medicine, Dentistry and Health Sciences award for Undergraduate teaching to small groups.

Associate Professor Pennell currently has 80 publications, two book chapters and five PhD students.
Key research
Preterm Birth Genome Project
Developmental Origins of Health and Disease (DOHAD)
Adams, L. A., et al. (2012). "Cholesteryl ester transfer protein gene polymorphisms increase the risk of fatty liver in females independent of adiposity." J Gastroenterol Hepatol 27(9): 1520-1527.
BACKGROUND AND AIM: Environmental factors including excessive caloric intake lead to disordered lipid metabolism and fatty liver disease (FLD). However, FLD demonstrates heritability suggesting genetic factors are also important. We aimed to use a candidate gene approach to examine the association between FLD and single nucleotide polymorphisms (SNPs) in lipid metabolism genes in the adolescent population-based Western Australian Pregnancy (Raine) Cohort. METHODS: A total 951 seventeen year-olds underwent hepatic ultrasound, anthropometric and biochemical characterization, DNA extraction and genotyping for 57 SNPs in seven lipid metabolism genes (ApoB100, ATGL, ABHD5, MTTP, CETP, SREBP-1c, PPARalpha). Associations were adjusted for metabolic factors and Bonferroni corrected. RESULTS: The prevalence of FLD was 16.2% (11.4% male vs 21.2% female, P=0.001). Multivariate analysis of metabolic factors found suprailiac skinfold thickness (SST) to be the major predictor of FLD in females and males (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.08-1.15, P=1.7x10(-10) and OR 1.17, 95%CI 1.13-1.22, P=2.4x10(-11) , respectively). In females, two SNPs in linkage disequilibrium from the CETP gene were associated with FLD: rs12447924 (OR 2.16, 95%CI 1.42-3.32, P=0.0003) and rs12597002 (OR=2.22, 95%CI 1.46-3.41 P=0.0002). In lean homozygotes, the probability of FLD was over 30%, compared with 10-15% in lean heterozygotes and 3-5% in lean wild-types. However, these associations were modified by SST, such that for obese individuals, the probability of FLD was over 30% in all genotype groups. CONCLUSIONS: Cholesteryl ester transfer protein gene polymorphisms are associated with an increased risk of FLD in adolescent females. The effect is independent of adiposity in homozygotes, thereby placing lean individuals at a significant risk of FLD.

Adams, L. A., et al. (2013). "Association Between Liver-Specific Gene Polymorphisms and Their Expression Levels With Nonalcoholic Fatty Liver Disease." Hepatology 57(2): 590-600.
Genetic factors account for a significant proportion of the phenotypic variance of nonalcoholic fatty liver disease (NAFLD); however, very few predisposing genes have been identified. We aimed to (1) identify novel genetic associations with NAFLD by performing a genome-wide association study (GWAS), and (2) examine the biological expression of the strongest genetic associations in a separate cohort. We performed GWAS of a population-based cohort (Raine Study) of 928 adolescents assessed for NAFLD by ultrasound at age 17. Expression of genes with single nucleotide polymorphisms (SNPs) that were associated with NAFLD at a significance level of P < 10(-5) was examined in adults with NAFLD and controls by quantifying hepatic messenger RNA (mRNA) expression and serum levels of protein. After adjustment for sex and degree of adiposity, SNPs in two genes expressed in liver were associated with NAFLD adolescents: group-specific component (GC) (odds ratio [OR], 2.54; P = 1.20 x 10(-6)) and lymphocyte cytosolic protein-1 (LCP1) (OR, 3.29; P = 2.96 x 10(-6)). SNPs in two genes expressed in neurons were also associated with NAFLD: lipid phosphate phosphatase-related protein type 4 (LPPR4) (OR, 2.30; P = 4.82 x 10(-6)) and solute carrier family 38 member 8 (SLC38A8) (OR, 3.14; P = 1.86 x 10(-6)). Hepatic GC mRNA was significantly reduced (by 83%) and LCP1 mRNA was increased (by 300%) in liver biopsy samples from patients with NAFLD compared to controls (P < 0.05). Mean serum levels of GC protein were significantly lower in patients with NAFLD than controls (250 +/- 90 versus 298 +/- 90, respectively; P = 0.004); GC protein levels decreased with increasing severity of hepatic steatosis (P < 0.01). Conclusion: The association between GC and LCP1 SNPs and NAFLD as well as altered biological expression implicate these genes in the pathogenesis of NAFLD. (HEPATOLOGY 2013;57:590-600)

Artigas, M. S., et al. (2011). "Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function." Nature Genetics 43(11): 1082-U1070.
Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 x 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

Ayonrinde, O. T., et al. (2011). "Gender-specific differences in adipose distribution and adipocytokines influence adolescent nonalcoholic fatty liver disease." Hepatology 53(3): 800-809.
Nonalcoholic fatty liver disease (NAFLD) is a predominantly adult-diagnosed disorder. Knowledge regarding the epidemiology, phenotype, and metabolic risk factors, during adolescence is limited. We sought to determine the prevalence, phenotype, and predictors of NAFLD in 1170 community-based adolescents in the Western Australian Pregnancy Cohort (Raine) Study (the Raine Cohort) who underwent a cross-sectional assessment that included questionnaires, anthropometry, cardiovascular examinations, blood tests, and abdominal ultrasound examinations. Among the 1170 adolescents assessed, the prevalence of NAFLD was 12.8%. Females compared with males had a significantly higher prevalence of NAFLD (16.3% versus 10.1%, P = 0.004) and central obesity (33.2% versus 9.9%, P < 0.05). The severity of hepatic steatosis was associated with the body mass index, waist circumference, subcutaneous adipose tissue thickness (SAT), serum leptin level, homeostasis model assessment for insulin resistance score (P < 0.001 for all), and serum alanine aminotransferase level (P < 0.005) in both genders, but it was associated with increasing visceral adipose tissue thickness (VAT; P < 0.001) and decreasing serum adiponectin levels (P < 0.05) in males alone. Males and females with NAFLD had similar amounts of SAT (P > 0.05); however, in comparison with females with NAFLD, males with NAFLD had greater VAT, a more severe metabolic phenotype with higher glucose levels and systolic blood pressure and lower adiponectin and high-density lipoprotein cholesterol levels (P < 0.001 for all), and greater measures of liver injury (alanine aminotransferase and aspartate aminotransferase, P < 0.001 for all). Similarly, metabolic syndrome was more common in males than females with NAFLD (24% versus 8%, P = 0.01). Suprailiac skinfold thickness predicted NAFLD independently of the body mass index, insulin resistance, and VAT. CONCLUSION: Gender differences in adolescent NAFLD are related to differences in adipose distribution and adipocytokines. The male phenotype of NAFLD is associated with more adverse metabolic features and greater visceral adiposity than the female phenotype despite the lower prevalence of NAFLD.

Barker, A., et al. (2011). "Association of Genetic Loci With Glucose Levels in Childhood and Adolescence A Meta-Analysis of Over 6,000 Children." Diabetes 60(6): 1805-1812.
OBJECTIVE-To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents.
RESEARCH DESIGN AND METHODS-A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose.
RESULTS-Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced p-cell function, as indicated by homeostasis model assessment of beta-cell function. Analysis using a weighted risk score showed an increase [beta (95% CI)] in fasting glucose level of 0.026 mrnol/L (0.021-0.031) for each unit increase in the score.
CONCLUSIONS-Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards. Diabetes 60:1805-1812, 2011

Benyamin, B., et al. (2013). "Childhood intelligence is heritable, highly polygenic and associated with FNBP1L." Mol Psychiatry.
Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17 989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 x 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 x 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 x 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.Molecular Psychiatry advance online publication, 29 January 2013; doi:10.1038/mp.2012.184.

Biggio, J., et al. (2008). "A call for an international consortium on the genetics of preterm birth." Am J Obstet Gynecol 199(2): 95-97.

Bonilla, C., et al. (2012). "Vitamin B-12 Status during Pregnancy and Child's IQ at Age 8: A Mendelian Randomization Study in the Avon Longitudinal Study of Parents and Children." PLoS One 7(12).
Vitamin B-12 is essential for the development and maintenance of a healthy nervous system. Brain development occurs primarily in utero and early infancy, but the role of maternal vitamin B-12 status during pregnancy on offspring cognitive function is unclear. In this study we assessed the effect of vitamin B-12 status in well-nourished pregnant women on the cognitive ability of their offspring in a UK birth cohort (ALSPAC). We then examined the association of SNPs in maternal genes FUT2 (rs492602) and TCN2 (rs1801198, rs9606756) that are related to plasma vitamin B-12, with offspring IQ. Observationally, there was a positive association between maternal vitamin B-12 intake and child's IQ that was markedly attenuated after adjustment for potential confounders (mean difference in offspring IQ score per doubling of maternal B-12 intake, before adjustment: 2.0 (95% CI 1.3, 2.8); after adjustment: 0.7 (95% CI -0.04, 1.4)). Maternal FUT2 was weakly associated with offspring IQ: mean difference in IQ per allele was 0.9 (95% CI 0.1, 1.6). The expected effect of maternal vitamin B-12 on offspring IQ, given the relationships between SNPs and vitamin B-12, and SNPs and IQ was consistent with the observational result. Our findings suggest that maternal vitamin B-12 may not have an important effect on offspring cognitive ability. However, further examination of this issue is warranted.

Boraska, et al. (2012). "Genome-wide meta-analysis of common variant differences between men and women." Hum Mol Genet. EPub ahead of Print(EPub ahead of Print).

Boraska, V., et al. (2012). "Genome-Wide Association Study to Identify Common Variants Associated with Brachial Circumference: A Meta-Analysis of 14 Cohorts." PLoS One 7(3).
Brachial circumference (BC), also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS) meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men) of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p<0.05) in the age-adjusted strata for men and across both sexes. In this first GWAS meta-analysis for BC to date, we have not identified any genome-wide significant signals and do not observe robust association of previously established obesity loci with BC. Large-scale collaborations will be necessary to achieve higher power to detect loci underlying BC.

Bradfield, J. P., et al. (2012). "A genome-wide association meta-analysis identifies new childhood obesity loci." Nature Genetics 44(5): 526-+.
Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (>= 95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 x 10(-6) in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 x 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 x 10(-9); OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous metaanalysis of adult BMI1.

Cousminer, D. L., et al. (2013). "Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity." Hum Mol Genet.
The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 x 10-8) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.

Davidoff, D. F., et al. (2013). "Twin-twin transfusion syndrome and twin anemia-polycythemia sequence in a monochorionic triamniotic pregnancy." Twin Res Hum Genet 16(3): 3.

Elks, C. E., et al. (2010). "Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies." Nat Genet 42(12): 1077-1085.
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 x 10) and 9q31.2 (P = 2.2 x 10(3)(3)), we identified 30 new menarche loci (all P < 5 x 10) and found suggestive evidence for a further 10 loci (P < 1.9 x 10). 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.

Fernandez-Rhodes, L., et al. (2013). "Association of Adiposity Genetic Variants With Menarche Timing in 92,105 Women of European Descent." Am J Epidemiol.
Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)2), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970-2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9-17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.

Ferreira, M. A. R., et al. (2011). "Identification of IL6R and chromosome 11q13.5 as risk loci for asthma." Lancet 378(9795): 1006-1014.
Background We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease.
Methods We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26 475), and these were tested in an additional 25 358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset.
Findings Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57 800): rs4129267 (OR 1.09, combined p=2.4x10(-8)) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1.09, p=1.8x10(-8)) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1.33, p=7x10(-4)), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2.
Interpretation The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma.

Freathy, R. M., et al. (2010). "Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight." Nat Genet 42(5): 430-435.
To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113 g (95% CI 89-137 g) lighter at birth than the 24% with zero or one alleles (P(trend) = 7 x 10(-30)). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.

Gracie, S., et al. (2011). "An integrated systems biology approach to the study of preterm birth using "-omic" technology--a guideline for research." BMC Pregnancy Childbirth 11: 71.
Preterm birth is the leading cause of neonatal mortality and perinatal morbidity. The etiology of preterm is multi-factorial and still unclear. As evidence increases for a genetic contribution to PTB, so does the need to explore genomics, transcriptomics, proteomics and metabolomics in its study. This review suggests research guidelines for the conduct of high throughput systems biology investigations into preterm birth with the expectation that this will facilitate the sharing of samples and data internationally through consortia, generating the power needed to study preterm birth using integrated "-omics" technologies. The issues to be addressed include: (1) integrated "-omics" approaches, (2) phenotyping, (3) sample collection, (4) data management-integrative databases, (5) international consortia and (6) translational feasibility. This manuscript is the product of discussions initiated by the "-Omics" Working Group at the Preterm Birth International Collaborative Meeting held at the World Health Organization, Geneva, Switzerland in April 2009.

Gracie, S. K., et al. (2010). "All Our Babies Cohort Study: recruitment of a cohort to predict women at risk of preterm birth through the examination of gene expression profiles and the environment." BMC Pregnancy Childbirth 10: 87.
BACKGROUND: Preterm birth is the leading cause of perinatal morbidity and mortality. Risk factors for preterm birth include a personal or familial history of preterm delivery, ethnicity and low socioeconomic status yet the ability to predict preterm delivery before the onset of preterm labour evades clinical practice. Evidence suggests that genetics may play a role in the multi-factorial pathophysiology of preterm birth. The All Our Babies Study is an on-going community based longitudinal cohort study that was designed to establish a cohort of women to investigate how a women's genetics and environment contribute to the pathophysiology of preterm birth. Specifically this study will examine the predictive potential of maternal leukocytes for predicting preterm birth in non-labouring women through the examination of gene expression profiles and gene-environment interactions. METHODS/DESIGN: Collaborations have been established between clinical lab services, the provincial health service provider and researchers to create an interdisciplinary study design for the All Our Babies Study. A birth cohort of 2000 women has been established to address this research question. Women provide informed consent for blood sample collection, linkage to medical records and complete questionnaires related to prenatal health, service utilization, social support, emotional and physical health, demographics, and breast and infant feeding. Maternal blood samples are collected in PAXgene RNA tubes between 18-22 and 28-32 weeks gestation for transcriptomic analyses. DISCUSSION: The All Our Babies Study is an example of how investment in clinical-academic-community partnerships can improve research efficiency and accelerate the recruitment and data collection phases of a study. Establishing these partnerships during the study design phase and maintaining these relationships through the duration of the study provides the unique opportunity to investigate the multi-causal factors of preterm birth. The overall All Our Babies Study results can potentially lead to healthier pregnancies, mothers, infants and children.

Hammond, G., et al. (2013). "Changes in risk factors for preterm birth in Western Australia 1984-2006." BJOG.
OBJECTIVE: To characterise changing risk factors of preterm birth in Western Australia between 1984 and 2006. DESIGN: Population-based study. SETTING: Western Australia. POPULATION: All non-Aboriginal women giving birth to live singleton infants between 1984 and 2006. METHODS: Multinomial, multivariable regression models were used to assess antecedent profiles by preterm status and labour onset types (spontaneous, medically indicated, prelabour rupture of membranes [PROM]). Population attributable fraction (PAF) estimates characterized the contribution of individual antecedents as well as the overall contribution of two antecedent groups: pre-existing medical conditions (including previous obstetric history) and pregnancy complications. MAIN OUTCOME MEASURE: Antecedent relationships with preterm birth, stratified by labour onset type. RESULTS: Marked increases in maternal age and primiparous births were observed. A four-fold increase in the rates of pre-existing medical complications over time was observed. Rates of pregnancy complications remained stable. Multinomial regression showed differences in antecedent profiles across labour onset types. PAF estimates indicated that 50% of medically indicated preterm deliveries could be eliminated after removing six antecedents from the population; estimates for PROM and spontaneous preterm reduction were between 10 and 20%. Variables pertaining to previous and current obstetric complications (previous preterm birth, previous caesarean section, pre-eclampsia and antepartum haemorrhage) were the most influential predictors of preterm birth and adverse labour onset (PROM and medically indicated). CONCLUSIONS: Preterm antecedent profiles have changed markedly over the 23 years studied. Some changes may be attributable to true change, others to advances in surveillance and detection. Still others may signify change in clinical practice.

Hart, R., et al. (2012). "Periodontal disease: a potential modifiable risk factor limiting conception." Human Reproduction EPub ahead of print.

Henderson, J. J., et al. (2011). "Preterm birth aetiology 2004-2008. Maternal factors associated with three phenotypes: spontaneous preterm labour, preterm pre-labour rupture of membranes and medically indicated preterm birth." J Matern Fetal Neonatal Med.
Objectives: To (1) investigate the current distribution of PTB phenotypes; (2) identify factors associated with spontaneous preterm labour (SPTL), PPROM, and indicated PTB; (3) investigate the relationship of gestational age (ga) with each PTB phenotype. Methods: Retrospective review of all live, singleton births 23(+0) to 36(+6) weeks ga at an obstetric referral centre 2004-2008. Results: A total of 4,522 PTBs were included (SPTL 31.7%, PPROM 27.4%, indicated 40.8%). PTB phenotype distribution differed between ga groups (<27 weeks: SPTL 45%, PPROM 32%, indicated 23%; 27-33 weeks: SPTL 30%, PPROM 32%, indicated 39%; 34-36 weeks: SPTL 32%, PPROM 24%, indicated 44%, p < 0.001). Between 34-36 weeks', demographic factors were significantly different between PTB phenotypes (age >/=35: SPTL 13.8%, PPROM 15.4%, indicated 21.6%; Caucasian ethnicity: SPTL 61.6%, PPROM 69.0%, indicated 70.2%; Assisted Reproductive Technology (ART): SPTL 2.8%, PPROM 1.9%, indicated 9.3%; all p < 0.001). Between 27-33 weeks' PTB phenotype was associated with smoking (SPTL 24.9%, PPROM 29.3%, indicated 20.2%; p = 0.002) and ART (SPTL 2.3%, PPROM 1.6%, indicated 5.0%; p = 0.002). Demographic factors were not associated with PTB phenotype at 23-26 weeks. Conclusions: The increase in PTB rates may be explained by medical indications at late preterm gestations, primarily in older, Caucasian women requiring fertility assistance. Interventions to reduce the rate of PTB need to be targeted to this high-risk population.

Henderson, J. J., et al. (2011). "Transcervical Foley catheter should be used in preference to intravaginal prostaglandins for induction of labor with an unfavorable cervix." Am J Obstet Gynecol 205(1): e19-20.

Horikoshi, M., et al. (2013). "New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism." Nature Genetics 45(1): 76-U115.
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood(1). Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits(2). In an expanded genome-wide association metaanalysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

Huang, R. C., et al. (2012). "DNA methylation of the IGF2/H19 imprinting control region and adiposity distribution in young adults." Clin Epigenetics 4(1).

Hunter, T. J., et al. (2012). "Factors influencing survival in pre-viable preterm premature rupture of membranes." J Matern Fetal Neonatal Med.
Objective: An observational study of a consecutive case series of pre-viable PPROM (16-24 gestational weeks) was performed between 2001 and 2007 in a single tertiary centre to identify factors that predict neonatal survival. Methods: Detailed obstetric, ultrasound and neonatal data were abstracted from clinical records. Univariate, multivariate and receiver operator curve (ROC) analyses were performed to identify predictors of neonatal survival to discharge. Results: A total of 143 cases of PPROM were identified. Survival to discharge was less with PPROM at 16-20 weeks than 20-24 weeks (17% versus 39%; p = 0.042). GA at PPROM, latency, mode of delivery and electronic foetal monitoring (EFM) were all significant, independent, predictors of survival (p < 0.05). Ultrasound assessed amniotic fluid index (AFI) was a poor predictor of survival (area under ROC = 0.649, 95% CI = 0.532-0.766). A multivariable predictive model, including GA at PPROM, latency, mode of delivery and EFM had an area under the ROC of 0.954 (95% CI = 0.916-0.993, sensitivity 97%, specificity 89% and accuracy 92%). Conclusion: Pre-viable PPROM has a poor prognosis, though modern neonatal management techniques may improve survival in late pre-viable PPROM. The predictive model generated from this consecutive case series of this rare condition provides valuable data for counselling patients with this condition.

Ikram, M. A., et al. (2012). "Common variants at 6q22 and 17q21 are associated with intracranial volume." Nat Genet 44(5): 539-544.
During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.

Kamara, M., et al. (2013). "The risk of placenta accreta following primary elective caesarean delivery - a case control study." BJOG Accepted for Publication.

Kilpelainen, T. O., et al. (2011). "Obesity-susceptibility loci have a limited influence on birth weight: a meta-analysis of up to 28,219 individuals." Am J Clin Nutr 93(4): 851-860.
BACKGROUND: High birth weight is associated with adult body mass index (BMI). We hypothesized that birth weight and BMI may partly share a common genetic background. OBJECTIVE: The objective was to examine the associations of 12 established BMI variants in or near the NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, BCDIN3D, SH2B1, FTO, MC4R, and KCTD15 genes and their additive score with birth weight. DESIGN: A meta-analysis was conducted with the use of 1) the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk, Hertfordshire, Fenland, and European Youth Heart Study cohorts (n(max) = 14,060); 2) data extracted from the Early Growth Genetics Consortium meta-analysis of 6 genome-wide association studies for birth weight (n(max) = 10,623); and 3) all published data (n(max) = 14,837). RESULTS: Only the MTCH2 and FTO loci showed a nominally significant association with birth weight. The BMI-increasing allele of the MTCH2 variant (rs10838738) was associated with a lower birth weight (beta +/- SE: -13 +/- 5 g/allele; P = 0.012; n = 23,680), and the BMI-increasing allele of the FTO variant (rs1121980) was associated with a higher birth weight (beta +/- SE: 11 +/- 4 g/allele; P = 0.013; n = 28,219). These results were not significant after correction for multiple testing. CONCLUSIONS: Obesity-susceptibility loci have a small or no effect on weight at birth. Some evidence of an association was found for the MTCH2 and FTO loci, ie, lower and higher birth weight, respectively. These findings may provide new insights into the underlying mechanisms by which these loci confer an increased risk of obesity.

Knight, B. S., et al. (2007). "The impact of murine strain and sex on postnatal development after maternal dietary restriction during pregnancy." J Physiol 581(Pt 2): 873-881.
The objective of this study was to characterize offspring responses to maternal dietary restriction (DR) in two phylogenetically distant strains of mice: A/J and C57BL/6J (B6). Pregnant mice were fed 100% or 70% of ad libitum between 6.5 and 17.5 days (d) gestation. Offspring were fed 100% ad libitum postweaning. All comparisons were made to strain and sex matched controls. Male DR-B6 offspring initially grew slower than controls; however, by 77 d and 182 d they were significantly heavier (P<0.05). Further, they had an increase percentage fat mass (+70%, P<0.01) by 182 d and were glucose intolerant at both 80 d (P<0.001) and 186 d (P<0.05). In contrast, weight, %Fat mass and glucose tolerance in DR-A/J males during postnatal life were not different from controls. Female DR-B6 mice showed catch-up growth during the first 77 d of life; however, their weight, %Fat mass and glucose tolerance were not different from controls at 80 d and 186 d. Although female DR-A/J were heavier than controls at 182 d (P<0.05), their %Fat mass and glucose tolerance were not different from controls at 182 d and 186 d. The observed strain and sex differences offer a unique opportunity to begin to define gene-environment interactions that contribute to developmental origins of health and disease.

Knight, B. S., et al. (2007). "Strain differences in the impact of dietary restriction on fetal growth and pregnancy in mice." Reprod Sci 14(1): 81-90.
The association between suboptimal intrauterine environment and developmental origins of adult health and disease is variable, suggesting that genotype may contribute to eventual outcome. The objective of this study was to characterize maternal and fetal responses to maternal dietary restriction during pregnancy in 2 phylogenetically distant strains of mice. Pregnant A/J (n=35) and C57BL/6J (B6) (n=36) mice underwent either a 30% dietary restriction (DR) from day 6.5 until day 17.5 of gestation or were fed ad libitum. Seven mothers from each strain and diet were randomly selected for dissection on day 18.5 to assess fetal body and organ weights and maternal endocrine status through the collection of serum to measure progesterone, corticosterone, cortisol, and estradiol levels. The remaining mice were allowed to deliver spontaneously to assess gestational effects. Both strains showed similar responses to maternal DR during pregnancy in terms of reductions in maternal weight gain during pregnancy, reductions in fetal body weight, increased pup death within 24 hours of birth, and decreased placental 11beta-HSD2 protein expression. The impact of maternal DR was greater in B6 mice than A/J when assessing reductions in fetal kidney weight, embryo-placenta ratio, increases in placental weight, fetal brain-liver ratio, and maternal corticosterone and cortisol levels. Moreover, preterm delivery was significantly increased in DR B6 mice compared to DR A/J mice. The observed strain variations in response to dietary restriction may offer a unique opportunity to investigate gene-environment interactions associated with developmental origins of adult health and disease.

Knight, B. S., et al. (2009). "Developmental regulation of cardiovascular function is dependent on both genotype and environment." Am J Physiol Heart Circ Physiol 297(6): H2234-2241.
Adverse developmental environments can increase the risk of adult cardiovascular disease, but not all individuals are affected, suggesting the importance of genotype. Genetically distinct mouse strains allow the genetic dissection of complex traits; however, they have not been used to evaluate the developmental origins of adult cardiovascular disease. Our objective was to determine the effect of prenatal nutrient restriction (R) on adult cardiovascular function in A/J (AJ) and C57BL/6J (B6) mice and whether a postnatal high-fat (HF) diet exacerbates these effects. Pregnant AJ and B6 mice underwent a 30% R or ad libitum diet, and their offspring underwent a HF or control diet. Hypertension (+17 mmHg; P<0.001) was observed in B6R mice at 9 wk, and their arterial pressure tended to remain high at 25 wk (+13 mmHg; not significant). In AJR mice, the normal decrement in arterial pressure over this age range in this strain was abolished. Heart rate prematurely increased in B6R and decreased in AJR (all; P<0.05) mice from 9 to 25 wk. There was no effect of postnatal HF diet on these relationships. The Tei index (from a 26-wk microultrasound) was increased in both AJR and B6R mice (all; P<0.05), suggesting an improved global myocardial performance. Neither R nor HF alone changed diastolic (ratio of E wave to A wave) or systolic (%fractional shortening) function in either strain; however, R and HE combined improved diastolic function in B6 (P<0.05) but not in AJ mice. Therefore, there are strain-dependent alterations in adult cardiovascular function in response to prenatal nutrient restriction. Unexpectedly, a postnatal HF diet did not exacerbate the effects of prenatal nutrient restriction on postnatal cardiovascular outcomes.

Langridge, A. T., et al. (2013). "Maternal conditions and perinatal characteristics associated with autism spectrum disorder and intellectual disability." PLoS One 8(1): e50963.
BACKGROUND: As well as being highly comorbid conditions, autism spectrum disorders (ASD) and intellectual disability (ID) share a number of clinically-relevant phenomena. This raises questions about similarities and overlap in diagnosis and aetiological pathways that may exist for both conditions. AIMS: To examine maternal conditions and perinatal factors for children diagnosed with an ASD, with or without ID, and children with ID of unknown cause, compared with unaffected children. METHODS: The study population comprised all live singleton births in Western Australia (WA) between January 1984 and December 1999 (N = 383,153). Univariate and multivariate multinomial logistic regression models were applied using a blocked modelling approach to assess the effect of maternal conditions, sociodemographic factors, labour and delivery characteristics and neonatal outcomes. RESULTS: In univariate analyses mild-moderate ID was associated with pregnancy hypertension, asthma, urinary tract infection, some types of ante-partum haemorrhage, any type of preterm birth, elective C-sections, breech presentation, poor fetal growth and need for resuscitation at birth, with all factors showing an increased risk. Severe ID was positively associated with poor fetal growth and need for resuscitation, as well as any labour or delivery complication. In the multivariate analysis no maternal conditions or perinatal factors were associated with an increased risk of ASD without ID. However, pregnancy hypertension and small head circumference were associated with a reduced risk (OR = 0.64, 95% CI: 0.43, 0.94; OR = 0.58, 95% CI: 0.34, 0.96, respectively). For ASD with ID, threatened abortion before 20 weeks gestation and poor fetal growth were associated with an increased risk. CONCLUSION: Findings show that indicators of a poor intrauterine environment are associated with an elevated risk of ID, while for ASD, and particularly ASD without ID, the associations are much weaker. As such, these findings highlight the importance of accounting for the absence or presence of ID when examining ASD, if we are to improve our understanding of the causal pathways associated with these conditions.

Lu, Y., et al. (2013). "Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus." Nature Genetics Advanced online publication.

Mackey, D. A., et al. (2012). "Role of the TCF4 Gene Intronic Variant in Normal Variation of Corneal Endothelium." Cornea 31(2): 162-166.
PURPOSE: : To identify early features of Fuchs endothelial dystrophy (FED) in carriers of the rs613872(G) transcription factor 4 gene (TCF4) aged 20 to 21 years. METHODS: : Prospective cohort study of people aged 20 to 21 years previously enrolled in the Western Australia Pregnancy (Raine) Cohort. Specular microscopy was performed using a noncontact specular microscopy (EM-3000; Tomey, Nagoya, Japan). Individual genotype data were extracted from the genome-wide Illumina 660 Quad Array. Analysis of the association between the rs613872 risk allele in TCF4 and specular microscopic measurements was conducted. RESULTS: : Association between the rs613872 risk allele and corneal endothelial cell density (CD) as well as the coefficient of variation in cell shape was the main outcome measure. Genotype and specular microscopic data were available for a total of 445 participants (46% women). The median CD was 2851 and 2850 cells per square millimeter in the right and left eyes, respectively. No significant differences between intereye variability in endothelial CD were seen (right eye to left eye correlation = 0.64); however, a significant difference in variability of endothelial CD between men and women was observed (male: OD, 2839 +/- 124 cells/mm and OS, 2845 +/- 124 cells/mm vs. female: OD, 2838 +/- 134 cells/mm and OS, 2842 +/- 132 cells/mm; OD, P = 0.0013 and OS, P = 0.0016). Eleven individuals were homozygous for the rs613872 risk allele. We found no association between rs613872 genotype and CD or coefficient of variation. One of 11 homozygous GG individuals was found to have a gutta in 1 sample field on specular microscopy, whereas 2 of 297 TT individuals also had a gutta each in 1 sample field. CONCLUSIONS: : We were unable to detect an association between TCF4 rs613872 genotype and the variation in corneal endothelial CD or variation in cell morphology in a healthy young adult population.

McDonald, S. W., et al. (2013). "The All Our Babies pregnancy cohort: design, methods, and participant characteristics." Bmc Pregnancy and Childbirth 13.
Background: The prospective cohort study design is ideal for examining diseases of public health importance, as its inherent temporal nature renders it advantageous for studying early life influences on health outcomes and research questions of aetiological significance. This paper will describe the development and characteristics of the All Our Babies (AOB) study, a prospective pregnancy cohort in Calgary, Alberta, Canada designed to examine determinants of maternal, infant, and child outcomes and identify barriers and facilitators in health care utilization.
Methods: Women were recruited from health care offices, communities, and through Calgary Laboratory Services before 25 weeks gestation from May 2008 to December 2010. Participants completed two questionnaires during pregnancy, a third at 4 months postpartum, and are currently being followed-up with questionnaires at 12, 24, and 36 months. Data was collected on pregnancy history, demographics, lifestyle, health care utilization, physical and mental health, parenting, and child developmental outcomes and milestones. In addition, biological/serological and genetic markers can be extracted from collected maternal and cord blood samples.
Results: A total of 4011 pregnant women were eligible for recruitment into the AOB study. Of this, 3388 women completed at least one survey. The majority of participants were less than 35 years of age, Caucasian, Canadian born, married or in a common-law relationship, well-educated, and reported household incomes above the Calgary median. Women who discontinued after the first survey (n=123) were typically younger, non-Caucasian, foreign-born, had lower education and household income levels, were less likely to be married or in a common-law relationship, and had poor psychosocial health in early pregnancy. In general, AOB participants reflect the pregnant and parenting population at local and provincial levels, and perinatal indicators from the study are comparable to perinatal surveillance data.
Conclusions: The extensive and rich data collected in the AOB cohort provides the opportunity to answer complex questions about the relationships between biology, early experiences, and developmental outcomes. This cohort will contribute to the understanding of the biologic mechanisms and social/environmental pathways underlying associations between early and later life outcomes, gene-environment interactions, and developmental trajectories among children.

McKnight, C. M., et al. (2012). "Birth of a cohort - the first 20 years of the Raine study." Medical Journal of Australia 197(11-12): 608-610.

Middelberg, R. P., et al. (2012). "Loci affecting gamma-glutamyl transferase in adults and adolescents show age x SNP interaction and cardiometabolic disease associations." Human Molecular Genetics 21(2): 446-455.
Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in an intergenic region of chromosome 1, P = 3.9 x 10(-8); rs944002 in C14orf73 on chromosome 14, P = 4.7 x 10(-13); rs340005 in RORA on chromosome 15, P = 2.4 x 10(-8)), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum P(HET) = 5.6 x 10(-12) at rs6519520). Pathway analysis of significant and suggestive single-nucleotide polymorphism associations showed significant overlap between genes affecting GGT and those affecting common metabolic and inflammatory diseases, and identified the hepatic nuclear factor (HNF) family as controllers of a network of genes affecting GGT. Our results reinforce the disease associations of GGT and demonstrate that control by the GGT1 locus varies with age.

Mishra, A., et al. (2012). "Genetic variants near PDGFRA are associated with corneal curvature in Australians." Invest Ophthalmol Vis Sci 53(11): 7131-7136.
PURPOSE: Irregularity in the corneal curvature (CC) is highly associated with various eye disorders such as keratoconus and myopia. The sample had limited power to find genomewide significant (5 x 10(-8)) hits but good power for replication. Thus, an attempt was made to test whether alleles in the FRAP1 and PDGFRA genes, recently found to be associated with CC in Asian populations, also influence CC in Australians of North European ancestry. Results of initial genomewide association studies (GWAS) for CC in Australians were also reported. METHODS: Two population-based cohorts of 1788 Australian twins and their families, as well as 1013 individuals from a birth cohort from Western Australia, were genotyped using genomewide arrays. Following separate individual analysis and quality control, the results from each cohort underwent meta-analysis. RESULTS: Meta-analysis revealed significant replication of association between rs2114039 and corneal curvature (P = 0.0045). The SNP rs2114039 near PDGFRA has been previously implicated in Asians. No SNP at the FRAP1 locus was found to be associated in our Australian samples. No SNP surpassed the genomewide significance threshold of 5 x 10(-8). The SNP with strongest association was rs2444240 (P = 3.658 x 10(-7)), which is 31 kb upstream to the TRIM29 gene. CONCLUSIONS: A significant role of the PDGFRA gene in determining corneal curvature in the Australian population was confirmed in this study, also highlighting the putative association of the TRIM29 locus with CC.

Möller, M., et al. (2013). "Cervilenz™ is an effective tool for screening cervical-length in comparison to transvaginal ultrasound." J Matern Fetal Neonatal Med. 26(4).

Mook-Kanamori, D. O., et al. (2011). "Variants near CCNL1/LEKR1 and in ADCY5 and fetal growth characteristics in different trimesters." J Clin Endocrinol Metab 96(5): E810-815.
CONTEXT: A recent genome-wide association study identified variants near CCNL1/LEKR1 (rs900400) and in ADCY5 (rs9883204) to be associated with birth weight. We examined the associations of these variants with fetal growth characteristics in different trimesters, with a main interest in the timing of the associations and the affected body proportions. METHODS: We used data from two prospective cohort studies from fetal life onward in The Netherlands and Australia. Repeated fetal ultrasound examinations were performed to measure head circumference (HC), abdominal circumference (AC), femur length (FL), and estimated fetal weight (EFW). Analyses were based on a total group of 3909 subjects. RESULTS: The C-allele of rs900400 was associated in second trimester with smaller fetal HC and FL, and in third trimester with smaller HC, AC, FL, and EFW. For each C-allele, the combined effect estimate for EFW in third trimester was -18.6 g (95% confidence interval, -27.5, -9.7 g; P = 4.2 x 10(-5)). The C-allele of rs9883204 was not associated with fetal growth characteristics in second trimester but was associated with restriction of all growth characteristics, except HC, in third trimester and at birth. For each C-allele, the combined effect estimate was -16.9 g (95% confidence interval, -26.8, -7.0 g; P = 8.4 x 10(-4)) for EFW in third trimester. Both genetic variants were associated with lower birth and placenta weight. CONCLUSIONS: Our results suggest that a genetic variant of rs900400 leads to symmetric growth restriction from early pregnancy onward, whereas a genetic variant of rs9883204 leads to asymmetric growth restriction, characterized by a relatively larger HC, from third trimester.

Myatt, L., et al. (2012). "A Standardized Template for Clinical Studies in Preterm Birth." Reproductive Sciences 19(5).

Newnham, J. P., et al. (2009). "Treatment of periodontal disease during pregnancy: a randomized controlled trial." Obstet Gynecol 114(6): 1239-1248.
OBJECTIVE: To investigate whether treating periodontal disease prevents preterm birth and other major complications of pregnancy. METHODS: This single-center trial was conducted across six obstetric sites in metropolitan Perth, Western Australia. Pregnant women identified by history to be at risk (n=3,737) were examined for periodontal disease. Approximately 1,000 women with periodontal disease were allocated at random to receive periodontal treatment commencing around 20 weeks of gestation (n=542) or 6 weeks after the pregnancy was completed (controls; n=540). The treatment included mechanical removal of oral biofilms together with oral hygiene instruction and motivation at a minimum of three weekly visits, with further visits if required. RESULTS: There were no differences between the control and treatment groups in preterm birth (9.3% compared with 9.7%, odds ratio [OR] 1.05, 95% confidence interval [CI 0.7-1.58], P=.81), birth weight (3,450 compared with 3,410 g, P=.12), preeclampsia (4.1% compared with 3.4%, OR 0.82, 95% CI 0.44-1.56, P=.55), or other obstetric endpoints. There were four unexplained stillbirths in the control group and no pregnancy losses in the treated group (P=.12). Measures of fetal and neonatal well-being were similar in the two groups, including abnormalities in fetal heart rate recordings (P=.26), umbilical artery flow studies (P=.96), and umbilical artery blood gas values (P=.37). The periodontal treatment was highly successful in improving health of the gums (P<.01). CONCLUSION: The evidence provided by the present study does not support the hypothesis that treatment of periodontal disease during pregnancy in this population prevents preterm birth, fetal growth restriction, or preeclampsia. Periodontal treatment was not hazardous to the women or their pregnancies. CLINICAL TRIAL REGISTRATION:,, NCT00133926. LEVEL OF EVIDENCE: I.

Newnham, J. P., et al. (2009). "Early life origins of obesity." Obstet Gynecol Clin North Am 36(2): 227-244, xii.
There is increasing evidence that obesity has its origins in early life. Predisposition is based on interactions between the genome and environmental influences acting through epigenetic modifications. Individuals most at risk are those whose ancestral line has made a rapid transition from a traditional to a Westernized style of life. The process involves not only metabolism, but also behavior. As a result, those people who are most at risk of obesity may be those least likely to respond to educational programs based on lifestyle modification. Understanding the mechanisms and pathways that underpin the early origins of obesity is vital if we are to make progress in addressing this major problem of modern life.

O'Leary, C. M., et al. (2007). "Trends in mode of delivery during 1984-2003: can they be explained by pregnancy and delivery complications?" BJOG 114(7): 855-864.
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.

Paracchini, S., et al. (2011). "Analysis of dyslexia candidate genes in the Raine cohort representing the general Australian population." Genes Brain Behav 10(2): 158-165.
Several genes have been suggested as dyslexia candidates. Some of these candidate genes have been recently shown to be associated with literacy measures in sample cohorts derived from the general population. Here, we have conducted an association study in a novel sample derived from the Australian population (the Raine cohort) to further investigate the role of dyslexia candidate genes. We analysed markers, previously reported to be associated with dyslexia, located within the MRPL19/C2ORF3, KIAA0319, DCDC2 and DYX1C1 genes in a sample of 520 individuals and tested them for association with reading and spelling measures. Association signals were detected for several single nucleotide polymorphisms (SNPs) within DYX1C1 with both the reading and spelling tests. The high linkage disequilibrium (LD) we observed across the DYX1C1 gene suggests that the association signal might not be refined by further genetic mapping.

Paternoster, L., et al. (2012). "Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis." Nature Genetics 44(2): 187-192.
Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 x 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 x 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 x 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.

Pennell, C. E., et al. (2010). "Authors' Reply - Induction of labour in nulliparous women with an unfavourable cervix." BJOG 117(7).

Pennell, C. E., et al. (2009). "Induction of labour in nulliparous women with an unfavourable cervix: a randomised controlled trial comparing double and single balloon catheters and PGE2 gel." BJOG 116(11): 1443-1452.
OBJECTIVE: To compare the efficacy and patient satisfaction of three methods of labour induction (double balloon catheters, single balloon catheters and prostaglandin gel) in term nulliparous women with unfavourable cervices. DESIGN: Randomised controlled trial. POPULATION: A total of 330 nulliparous women with unfavourable cervices induced at term. METHODS: Three cervical ripening study arms were used: double balloon catheter (107 women); 16F Foley catheter (110 women) and PGE(2) gel (2 mg) (113 women). MAIN OUTCOME MEASURES: Caesarean section, induction to delivery interval, adverse reactions and patient satisfaction. RESULTS: There was no difference in caesarean delivery rates between groups (double balloon 43%, single balloon 36%, PGE(2) 37%, P = 0.567). The induction to delivery interval was longer in the double balloon group (median 24.5; 95% CI 23.7, 30.6 hours) than the single balloon (23.2; 20.8, 25.8 hours) or PGE(2) (23.8; 21.7, 26.8 hours) (P = 0.043). Uterine hyperstimulation occurred in 14% of the PGE(2) group with none occurring with mechanical cervical ripening. Cord blood gases were worse in the PGE(2) group: median arterial pH double balloon 7.26 (range 7.03-7.40); single balloon 7.26 (7.05-7.44); PGE(2) 7.25 (6.91-7.41) (P = 0.050). Cervical ripening with the single balloon catheter was associated with significantly less pain (pain score > or =4: double balloon 55%, single balloon 36%, PGE(2) 63%, P < 0.001). CONCLUSIONS: Labour induction in nullipara with unfavourable cervices results in high caesarean delivery rates. Although all methods in this study had similar efficacy, the single balloon catheter offers the best combination of safety and patient comfort.

Pennell, C. E., et al. (2007). "Genetic epidemiologic studies of preterm birth: guidelines for research." Am J Obstet Gynecol 196(2): 107-118.
Over the last decade, it has become increasingly apparent that the cause of preterm birth is multifactorial, involving both genetic and environmental factors. With the development of new technologies capable of probing the genome, exciting possibilities now present themselves to gain new insight into the mechanisms leading to preterm birth. This review aims to develop research guidelines for the conduct of genetic epidemiology studies of preterm birth with the expectation that this will ultimately facilitate the comparison of data sets between study cohorts, both nationally and internationally. Specifically, the 4 areas addressed in this review includes: (1) phenotypic criteria, (2) study design, (3) considerations in the selection of control populations, and (4) candidate gene selection. This article is the product of discussions initiated by the authors at the 3rd International Workshop on Biomarkers and Preterm Birth held at the University of California, Los Angeles, Los Angeles, CA, in March 2005.

Pennell, C. E., et al. (2007). "Authors Reply - Genetic epidemiology studies of preterm birth: studies for disease or of 'resuce birth'." Am J Obstet Gynecol 197(4).

Pennell, C. E., et al. (2009). Approaches to Evaluate Gene-Environment Interactions Underlying the Developmental Origins of Health and Disease. Early Life Origins of Human Health and Disease. J. P. Newnham and M. G. Ross, Karger.

Pennell, C. E. and M. B. Tracy (1999). "A new method for rapid measurement of lactate in fetal and neonatal blood." Aust N Z J Obstet Gynaecol 39(2): 227-233.
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 NepeanHospital. Specimens were collected from the umbilical artery 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 and 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 degrees C to 37 degrees 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 and 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 degrees C. At 0.5 degrees 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, commercially available, method of measuring plasma lactate levels in only 60 seconds at the point-of-care. It requires only 15 microL 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.

Pennell, C. E., et al. (2013). "Preterm Birth Genome Project (PGP) -- validation of resources for preterm birth genome-wide studies." J Perinat Med 41(1): 45-49.
We determined a series of quality control (QC) analyses to assess the usability of DNA collected and processed from different countries utilizing different DNA extraction techniques prior to genome-wide association studies (GWAS). The quality of DNA collected utilizing four different DNA extraction techniques and the impact of shipping DNA at different temperatures on array performance were evaluated. Fifteen maternal-fetal pairs were used from four countries. DNA was extracted using four approaches: whole blood, blood spots with whole genome amplification (WGA), saliva and buccal swab. Samples were sent to a genotyping facility, either on dry ice or at room temperature and genotyped using Affymetrix SNP array 6.0. QC measured included extraction techniques, effect of shipping temperatures, accuracy and Mendelian concordance. Significantly fewer (50 % ) single nucleotide polymorphisms (SNPs) passed QC metrics for buccal swab DNA (P < 0.0001) due to missing genotype data (P < 0.0001). Whole blood or saliva DNA had the highest call rates (99.2 0.4 % and 99.3 0.2 % , respectively) and Mendelian concordance. Shipment temperature had no effect. DNA from blood or saliva had the highest call rate accuracy, and buccal swabs had the lowest. DNA extracted from blood, saliva and blood spots were found suitable for GWAS in our study.

Reynolds, R. M., et al. (2012). "Analysis of baseline hypothalamic-pituitary-adrenal activity in late adolescence reveals gender specific sensitivity of the stress axis." Psychoneuroendocrinology.
Dysfunctional regulation of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as an important biological mechanism underlying stress-related diseases; however, a better understanding of the interlinked neuroendocrine events driving the release of cortisol by this stress axis is essential for progress in preventing or halting irreversible development of adverse HPA-function. We aimed to investigate basal HPA-activity in a normal population in late adolescence, the time of life believed to overlap with HPA-axis maturation and establishment of a lasting set point level of HPA function. A total of 1258 participants (mean age 16.6 years) recruited from the Western Australian Pregnancy (Raine) Cohort provided fasting morning blood and saliva samples for basal HPA activity assessment. Irrespective of gender, linear regression modelling identified a positive correlation between the main components of the HPA-cascade of events, ACTH, total cortisol and free cortisol in saliva. Corticosteroid binding globulin (CBG) was inversely associated with free cortisol in saliva, an effect most clearly observed in boys. ACTH levels were lower, but cortisol levels were higher in girls than in boys. Girls may also be exposed to more bioactive cortisol, based on higher average free cortisol measured in saliva at awakening. These relatively higher female free cortisol levels were significantly reduced by oral contraceptive use, eliminating the gender specific difference in salivary cortisol. Free plasma cortisol, calculated from total circulating cortisol and CBG concentrations, was also significantly reduced in girls using oral contraceptives, possibly via an enhancing effect of oral contraceptives on blood CBG content. This study highlights a clear gender difference in HPA activity under non-stressful natural conditions. This finding may be relevant for research into sex-specific stress-related diseases with a typical onset in late adolescence.

Robinson, M., et al. (2011). "Prenatal stress and risk of behavioral morbidity from age 2 to 14 years: The influence of the number, type, and timing of stressful life events." Development and Psychopathology 23(2): 507-520.
The maternal experience of stressful events during pregnancy has been associated with a number of adverse consequences for behavioral development in offspring, but the measurement and interpretation of prenatal stress varies among reported studies. The Raine Study recruited 2900 pregnancies and recorded life stress events experienced by 18 and 34 weeks' gestation along with numerous sociodemographic data. The mother's exposure to life stress events was further documented when the children were followed-up in conjunction with behavioral assessments at ages 2, 5, 8, 10, and 14 years using the Child Behavior Checklist. The maternal experience of multiple stressful events during pregnancy was associated with subsequent behavioral problems for offspring. Independent (e.g., death of a relative, job loss) and dependent stress events (e. g., financial problems, marital problems) were both significantly associated with a greater incidence of mental health morbidity between age 2 and 14 years. Exposure to stressful events in the first 18 weeks of pregnancy showed similar associations with subsequent total and externalizing morbidity to events reported at 34 weeks of gestation. These results were independent of postnatal stress exposure. Improved support for women with chronic stress exposure during pregnancy may improve the mental health of their offspring in later life.

Robinson, M., et al. (2010). "Child behaviour following low to moderate maternal drinking in pregnancy Reply." Bjog-an International Journal of Obstetrics and Gynaecology 117(12): 1564-1565.

Robinson, M., et al. (2010). "Low-moderate prenatal alcohol exposure and risk to child behavioural development: a prospective cohort study." Bjog-an International Journal of Obstetrics and Gynaecology 117(9): 1139-1150.
To examine the association of fetal alcohol exposure during pregnancy with child and adolescent behavioural development.
The Western Australian Pregnancy Cohort (Raine) Study recruited 2900 pregnancies (1989-91) and the 14-year follow up was conducted between 2003 and 2006.
Tertiary obstetric hospital in Perth, Western Australia.
The women in the study provided data at 18 and 34 weeks of gestation on weekly alcohol intake: no drinking, occasional drinking (up to one standard drink per week), light drinking (2-6 standard drinks per week), moderate drinking (7-10 standard drinks per week), and heavy drinking (11 or more standard drinks per week).
Longitudinal regression models were used to analyse the effect of prenatal alcohol exposure on Child Behaviour Checklist (CBCL) scores over 14 years, assessed by continuous z-scores and clinical cutoff points, after adjusting for confounders.
Main outcome measure
Their children were followed up at ages 2, 5, 8, 10 and 14 years. The CBCL was used to measure child behaviour.
Light drinking and moderate drinking in the first 3 months of pregnancy were associated with child CBCL z-scores indicative of positive behaviour over 14 years after adjusting for maternal and sociodemographic characteristics. These changes in z-score indicated a clinically meaningful reduction in total, internalising and externalising behavioural problems across the 14 years of follow up.
Our findings do not implicate light-moderate consumption of alcohol in pregnancy as a risk factor in the epidemiology of child behavioural problems.

Robinson, M., et al. (2013). "Hypertensive diseases of pregnancy predict parent-reported difficult temperament in infancy." J Dev Behav Pediatr 34(3): 174-180.
OBJECTIVE: Recent research has linked hypertensive diseases of pregnancy with adverse neurodevelopmental outcomes in childhood and adulthood. This study aimed to establish whether such effects are observed in infancy. METHODS: This was a prospective pregnancy cohort study of 2,785 pregnancies with complete data on hypertensive diseases of pregnancy. Mothers completed a validated Australian adaptation of the Toddler Temperament Scale when the children were 1 year of age (n = 2,384). Algorithms were used to classify children as difficult, slow to warm up, intermediate high, intermediate low, or easy, on the basis of their temperament scores. We then grouped difficult and intermediate-high infants together and compared them with easy, intermediate-low, and slow-to-warm-up infants. We used a multivariable logistic regression model and adjusted for known biomedical, sociodemographic, and psychological factors from the pre- and postnatal period that may influence child behavioral development. RESULTS: After adjusting for confounders, mothers who were diagnosed with gestational hypertension (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.06-1.75) or preeclampsia (OR, 2.23; 95% CI, 1.18-4.23) were more likely to report that their infants were in the difficult or intermediate-high classifications in the first year of life compared with infants born to mothers without gestational hypertension or preeclampsia. CONCLUSION: These data suggest that the link between maternal hypertensive diseases of pregnancy and child behavioral development begins in the first year of life.

Robinson, M., et al. (2011). "The over-estimation of risk in pregnancy." Journal of Psychosomatic Obstetrics and Gynecology 32(2): 53-58.
The concept of risk is especially salient to obstetric care. Unknown factors can still be responsible for peri-natal morbidity and mortality in circumstances that appeared to present little risk, while perfectly healthy infants are born in high-risk circumstances: a contradiction that patients and providers struggle with on a daily basis. With such contradictions comes the potential for the over-estimation of risk during pregnancy in order to assure a positive outcome. Understanding and addressing the estimation of risk during pregnancy requires acknowledging the history of obstetric risk in addition to understanding risk-related psychological theory. A relationship of trust between provider and patient is vital in addressing risk over-estimation, as is encouraging the development of self-efficacy in patients. Ultimately obstetric care is complex and efforts to avoid pre-natal risk exposure based on heightened perceptions of threat may do more harm than the perceived threat itself.
Robinson, M., et al. (2013). "Delivery at 37 weeks' gestation is associated with a higher risk for child behavioural problems." Aust N Z J Obstet Gynaecol 53(2).

Robinson, M., et al. (2013). "Pre-pregnancy maternal overweight and obesity increase the risk for affective disorders in offspring." Journal of the Developmental Origins of Health and Disease 4(1): 6.

Rogers, M. S., et al. (2001). "Oxidative stress in the fetal lamb brain following intermittent umbilical cord occlusion: a path analysis." BJOG 108(12): 1283-1290.
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.

Ronald, A., et al. (2011). "Prenatal Maternal Stress Associated with ADHD and Autistic Traits in early Childhood." Front Psychol 1: 223.
Research suggests that offspring of mothers who experience high levels of stress during pregnancy are more likely to have problems in neurobehavioral development. There is preliminary evidence that prenatal maternal stress (PNMS) is a risk factor for both autism and attention deficit hyperactivity disorder (ADHD), however most studies do not control for confounding factors and no study has investigated PNMS as a risk factor for behaviors characteristic of these disorders in early childhood. A population cohort of 2900 pregnant women were recruited before their 18th week of pregnancy and investigated prospectively. Maternal experience of stressful life events was assessed during pregnancy. When offspring were age 2 years, mothers completed the child behavior checklist. Multiple regression showed that maternal stressful events during pregnancy significantly predicted ADHD behaviors in offspring, after controlling for autistic traits and other confounding variables, in both males (p = 0.03) and females (p = 0.01). Similarly, stressful events during pregnancy significantly predicted autistic traits in the offspring after controlling for ADHD behaviors and confounding variables, in males only (p = 0.04). In conclusion, this study suggests that PNMS, in the form of typical stressful life events such as divorce or a residential move, show a small but significant association with both autistic traits and ADHD behaviors independently, in offspring at age 2 years, after controlling for multiple antenatal, obstetric, postnatal, and sociodemographic covariates. This finding supports future research using epigenetic, cross-fostering, and gene-environment interaction designs to identify the causal processes underlying this association.

Rye, M. S., et al. (2012). "Genome-wide association study to identify the genetic determinants of otitis media susceptibility in childhood." PLoS One 7(10): e48215.
BACKGROUND: Otitis media (OM) is a common childhood disease characterised by middle ear inflammation and effusion. Susceptibility to recurrent acute OM (rAOM; >/=3 episodes of AOM in 6 months) and chronic OM with effusion (COME; MEE >/=3 months) is 40-70% heritable. Few underlying genes have been identified to date, and no genome-wide association study (GWAS) of OM has been reported. METHODS AND FINDINGS: Data for 2,524,817 single nucleotide polymorphisms (SNPs; 535,544 quality-controlled SNPs genotyped by Illumina 660W-Quad; 1,989,273 by imputation) were analysed for association with OM in 416 cases and 1,075 controls from the Western Australian Pregnancy Cohort (Raine) Study. Logistic regression analyses under an additive model undertaken in GenABEL/ProbABEL adjusting for population substructure using principal components identified SNPs at CAPN14 (rs6755194: OR = 1.90; 95%CI 1.47-2.45; P(adj-PCA) = 8.3x10(-7)) on chromosome 2p23.1 as the top hit, with independent effects (rs1862981: OR = 1.60; 95%CI 1.29-1.99; P(adj-PCA) = 2.2x10(-5)) observed at the adjacent GALNT14 gene. In a gene-based analysis in VEGAS, BPIFA3 (P(Gene) = 2x10(-5)) and BPIFA1 (P(Gene) = 1.07x10(-4)) in the BPIFA gene cluster on chromosome 20q11.21 were the top hits. In all, 32 genomic regions show evidence of association (P(adj-PCA)<10(-5)) in this GWAS, with pathway analysis showing a connection between top candidates and the TGFbeta pathway. However, top and tag-SNP analysis for seven selected candidate genes in this pathway did not replicate in 645 families (793 affected individuals) from the Western Australian Family Study of Otitis Media (WAFSOM). Lack of replication may be explained by sample size, difference in OM disease severity between primary and replication cohorts or due to type I error in the primary GWAS. CONCLUSIONS: This first discovery GWAS for an OM phenotype has identified CAPN14 and GALNT14 on chromosome 2p23.1 and the BPIFA gene cluster on chromosome 20q11.21 as novel candidate genes which warrant further analysis in cohorts matched more precisely for clinical phenotypes.

Rye, M. S., et al. (2011). "FBXO11, a regulator of the TGFbeta pathway, is associated with severe otitis media in Western Australian children." Genes Immun 12(5): 352-359.
Otitis media (OM) is a common childhood disease characterised by middle ear inflammation following infection. Susceptibility to recurrent acute OM (rAOM) and chronic OM with effusion (COME) is highly heritable. Two murine mutants, Junbo and Jeff, spontaneously develop severe OM with similar phenotypes to human disease. Fine-mapping of these mutants identified two genes (Evi1 and Fbxo11) that interact with the transforming growth factor beta (TGFbeta) signalling pathway. We investigated these genes, as well as four Sma- and Mad-related (SMAD) genes of the TGFbeta pathway, as candidate rAOM/COME susceptibility genes in two predominantly Caucasian populations. Single-nucleotide polymorphisms (SNPs) within FBXO11 (family-based association testing Z-Score=2.61; P(best)=0.009) were associated with severe OM in family-based analysis of 434 families (561 affected individuals) from the Western Australian Family Study of OM. The FBXO11 association was replicated by directed analysis of Illumina 660W-Quad Beadchip data available for 253 cases and 866 controls (OR=1.55 (95% CI 1.28-1.89); P(best)=6.9 x 10(-6)) available within the Western Australian Pregnancy Cohort (Raine) Study. Combined primary and replication results show P(combined)=2.98 x 10(-6). Neither cohort showed an association with EVI1 variants. Family-based associations at SMAD2 (P=0.038) and SMAD4 (P=0.048) were not replicated. Together, these data provide strong evidence for FBXO11 as a susceptibility gene for severe OM.

Scerri, T. S., et al. (2012). "The dyslexia candidate locus on 2p12 is associated with general cognitive ability and white matter structure." PLoS One 7(11): e50321.
Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of dyslexia and SLI genetic risk factors for association with two measures of general cognitive abilities, or IQ, (verbal and non-verbal) in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N>5,000). Only the MRPL19/C2ORF3 locus showed statistically significant association (minimum P = 0.00009) which was further supported by independent replications following analysis in four other cohorts. In addition, a fifth independent sample showed association between the MRPL19/C2ORF3 locus and white matter structure in the posterior part of the corpus callosum and cingulum, connecting large parts of the cortex in the parietal, occipital and temporal lobes. These findings suggest that this locus, originally identified as being associated with dyslexia, is likely to harbour genetic variants associated with general cognitive abilities by influencing white matter structure in localised neuronal regions.

Skouen, J., et al. (2012). "Genetic variation in the beta-2 adrenergic receptor is associated with chronic musculoskeletal complaints in adolescents." Eur J Pain.

Sloboda, D. M., et al. (2007). "Age at menarche: Influences of prenatal and postnatal growth." J Clin Endocrinol Metab 92(1): 46-50.
OBJECTIVE: The objective of this study was to determine the influence of birth weight and postnatal weight gain on age at menarche. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study where girls from the West Australian Pregnancy (Raine) Cohort Study were followed prospectively from fetal life (18 wk of pregnancy) to adolescence (12-14 yr). MAIN OUTCOME MEASURE: Age at menarche was the main outcome measure. RESULTS: Growth status at birth was judged by expected birth weight ratio (EBW; a ratio of observed infant's birth weight over median birth weight appropriate for maternal age, weight, height, parity, infant sex, and gestational age). Postnatal growth status was judged by body mass index (BMI). Both EBW (P = 0.020) and BMI in childhood (8 yr of age) (P < 0.001) were associated with age at menarche. Menarche occurred earlier in girls with lower EBW and higher BMI. CONCLUSIONS: We have demonstrated for the first time that both birth weight and weight gain in childhood are associated with age at menarche. Weight gain before birth and subsequent weight gain up to the age of 8 yr were found to have opposing influences on the timing of menarche. Lower EBW combined with higher BMI during childhood predicted early age at menarche, and this relationship existed across normal birth weight and BMI ranges.

Sovio, U., et al. (2011). "Association between common variation at the FTO locus and changes in body mass index from infancy to late childhood: the complex nature of genetic association through growth and development." Plos Genetics 7(2): e1001307.
An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We meta-analyzed associations between the FTO locus (rs9939609) and BMI in samples, aged from early infancy to 13 years, from 8 cohorts of European ancestry. We found a positive association between additional minor (A) alleles and BMI from 5.5 years onwards, but an inverse association below age 2.5 years. Modelling median BMI curves for each genotype using the LMS method, we found that carriers of minor alleles showed lower BMI in infancy, earlier adiposity rebound (AR), and higher BMI later in childhood. Differences by allele were consistent with two independent processes: earlier AR equivalent to accelerating developmental age by 2.37% (95% CI 1.87, 2.87, p = 10(-20)) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10(-23)). We also fitted a linear mixed effects model to relate genotype to the BMI curve inflection points adiposity peak (AP) in infancy and AR. Carriage of two minor alleles at rs9939609 was associated with lower BMI at AP (-0.40% (95% CI: -0.74, -0.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (-4.72% (-5.81, -3.63), p = 10(-17)), supporting cross-sectional results. Overall, we confirm the expected association between variation at rs9939609 and BMI in childhood, but only after an inverse association between the same variant and BMI in infancy. Patterns are consistent with a shift on the developmental scale, which is reflected in association with the timing of AR rather than just a global increase in BMI. Results provide important information about longitudinal gene effects and about the role of FTO in adiposity. The associated shifts in developmental timing have clinical importance with respect to known relationships between AR and both later-life BMI and metabolic disease risk.

Taal, H. R., et al. (2012). "Common variants at 12q15 and 12q24 are associated with infant head circumference." Nature Genetics 44(5): 532-+.
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.

Tyrrell, et al. (2012). "Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight." Hum Mol Genet EPub ahead of Print.

van Eekelen, J. A. M., et al. (2011). "Identification and genetic determination of an early life risk disposition for depressive disorder: Atypical stress-related behaviour in early childhood." Australian Journal of Psychology 63(1): 6-17.
Progress in psychiatric genetics has been slow despite evidence of high heritability for most mental disorders. We argue that greater use of early detectable intermediate traits (endophenotypes) with the highest likely aetiological significance to depression, rather than complex clinical phenotypes, would be advantageous. Longitudinal data from the Western Australian Pregnancy Cohort (Raine) Study were used to identify an early life behavioural endophenotype for atypical hypothalamic-pituitary-adrenocortical function in adolescence, a neurobiological indicator of anxiety and depression. A set of descriptors representing rigid and reactive behaviour at age 1 year discriminated those in the top 20% of the free salivary cortisol exposure at age 17 years. Genetic association analysis revealed a male-sensitive effect to variation in three specific single nucleotide polymorphisms within selected genes underpinning the overall stress response. Furthermore, support for a polygenic effect on stress-related behaviour in childhood is presented.

Verhoeven, V. J. M., et al. (2013). "Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia." Nature Genetics 45(3): 314-318.
Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.

Warrington, N. M., et al. (2013). "Modelling BMI trajectories in children for genetic association studies." PLoS One 8(1): e53897.
BACKGROUND: The timing of associations between common genetic variants and changes in growth patterns over childhood may provide insight into the development of obesity in later life. To address this question, it is important to define appropriate statistical models to allow for the detection of genetic effects influencing longitudinal childhood growth. METHODS AND RESULTS: Children from The Western Australian Pregnancy Cohort (Raine; n=1,506) Study were genotyped at 17 genetic loci shown to be associated with childhood obesity (FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, ETV5, SEC16B, LYPLAL1, TFAP2B, MTCH2, BCDIN3D, NRXN3, SH2B1, MRSA) and an obesity-risk-allele-score was calculated as the total number of 'risk alleles' possessed by each individual. To determine the statistical method that fits these data and has the ability to detect genetic differences in BMI growth profile, four methods were investigated: linear mixed effects model, linear mixed effects model with skew-t random errors, semi-parametric linear mixed models and a non-linear mixed effects model. Of the four methods, the semi-parametric linear mixed model method was the most efficient for modelling childhood growth to detect modest genetic effects in this cohort. Using this method, three of the 17 loci were significantly associated with BMI intercept or trajectory in females and four in males. Additionally, the obesity-risk-allele score was associated with increased average BMI (female: beta=0.0049, P=0.0181; male: beta=0.0071, P=0.0001) and rate of growth (female: beta=0.0012, P=0.0006; male: beta=0.0008, P=0.0068) throughout childhood. CONCLUSIONS: Using statistical models appropriate to detect genetic variants, variations in adult obesity genes were associated with childhood growth. There were also differences between males and females. This study provides evidence of genetic effects that may identify individuals early in life that are more likely to rapidly increase their BMI through childhood, which provides some insight into the biology of childhood growth.

Webb, T. R., et al. (2012). "X-Linked Megalocornea Caused by Mutations in CHRDL1 Identifies an Essential Role for Ventroptin in Anterior Segment Development." Am J Hum Genet 90(2): 247-259.
X-linked megalocornea (MGC1) is an ocular anterior segment disorder characterized by an increased cornea diameter and deep anterior chamber evident at birth and later onset of mosaic corneal degeneration (shagreen), arcus juvenilis, and presenile cataracts. We identified copy-number variation, frameshift, missense, splice-site and nonsense mutations in the Chordin-like 1 gene (CHRDL1) on Xq23 as the cause of the condition in seven MGC1 families. CHRDL1 encodes ventroptin, a bone morphogenic protein antagonist with a proposed role in specification of topographic retinotectal projections. Electrophysiological evaluation revealed mild generalized cone system dysfunction and, in one patient, an interhemispheric asymmetry in visual evoked potentials. We show that CHRDL1 is expressed in the developing human cornea and anterior segment in addition to the retina. We explored the impact of loss of ventroptin function on brain function and morphology in vivo. CHRDL1 is differentially expressed in the human fetal brain, and there is high expression in cerebellum and neocortex. We show that MGC1 patients have a superior cognitive ability despite a striking focal loss of myelination of white matter. Our findings reveal an unexpected requirement for ventroptin during anterior segment development and the consequences of a lack of function in the retina and brain.

White, C. R., et al. (2010). "Benefits of introducing universal umbilical cord blood gas and lactate analysis into an obstetric unit." Aust N Z J Obstet Gynaecol 50(4): 318-328.
BACKGROUND: Current evidence suggests that umbilical arterial pH analysis provides the most sensitive reflection of birth asphyxia. However, there's debate whether umbilical cord blood gas analysis (UC-BGA) should be conducted on some or all deliveries. AIM: The aim of this study was to evaluate the impact of introducing universal UC-BGA at delivery on perinatal outcome. METHODS: An observational study of all deliveries > or =20 weeks' gestation at a tertiary obstetric unit between January 2003 and December 2006. Paired UC-BGA was performed on 97% of deliveries (n = 19,646). Univariate and adjusted analysis assessed inter-year UC-BGA differences and the likelihood of metabolic acidosis and nursery admission. RESULTS: There was a progressive improvement in umbilical artery pH, pO(2), pCO(2), base excess and lactate values in univariate and adjusted analyses (P < 0.001). There was a significant reduction in the newborns with an arterial pH <7.10 (OR = 0.71; 95%CI 0.53-0.95) and lactate >6.1 mmol/L (OR = 0.37; 95%CI 0.30-0.46). Utilising population specific 5th and 95th percentiles, there was a reduction in newborns with arterial pH less than 5th percentile (pH 7.12; OR = 0.75; 95%CI 0.59-0.96) and lactate levels greater than 95th percentile (6.7 mmol/L; OR = 0.37; 95%CI 0.29-0.49). There was a reduction in term (OR = 0.65; 95%CI 0.54-0.78), and overall (OR = 0.75; 95%CI 0.64-0.87) nursery admissions. These improved perinatal outcomes were independent of intervention rates. CONCLUSIONS: These data suggest that introduction of universal UC-BGA may result in improved perinatal outcomes, which were observed to be independent of obstetric intervention. We suggest that these improvements might be attributed to provision of biochemical data relating to fetal acid-base status at delivery influencing intrapartum care in subsequent cases.

White, C. R., et al. (2012). "Accurate prediction of hypoxic-ischaemic encephalopathy at delivery: a cohort study." J Matern Fetal Neonatal Med.
Abstract Objective: Hypoxic-ischaemic encephalopathy (HIE) is a major acute neurologic manifestation of perinatal asphyxia associated with significant mortality and morbidity. The study aimed to develop a simple, accurate method of predicting HIE at delivery. Methods: Between January 2003 and December 2009, all HIE cases were identified from the 38,404 deliveries at a single tertiary centre. Receiver operating curve (ROC) analysis and multivariate logistic regression assessed the ability of clinical and biochemical assessments to predict HIE. Results: Sixty neonates met the HIE criteria: 39 were moderate-severe HIE. Univariate analyses identified clinical neonatal markers (Apgar scores and neonatal resuscitation level) to be better HIE predictors than biochemical markers (umbilical artery pH, base excess and lactate values). Multivariable models using two to four predictors had areas under ROC curves up to 0.98, sensitivities up to 93% and specificities up to 99%. For moderate-severe HIE, the most effective predictor was neonatal resuscitation level and arterial lactate (ROC 0.98, sensitivity 85%, specificity 99%). Conclusion: The combination of umbilical arterial lactate and neonatal resuscitation level provides a rapid and accurate method of predicting moderate-severe HIE that can identify neonates at birth that may benefit from tertiary care and neuroprotective therapies.

White, C. R., et al. (2012). "Evaluation of selection criteria for validating paired umbilical cord blood gas samples: an observational study." BJOG 119(7): 857-865.
OBJECTIVE: To compare six validation criteria for umbilical cord blood gas (UCBG) values in vigorous and nonvigorous neonates. DESIGN: Retrospective cohort study. SETTING: Single tertiary obstetric centre, King Edward Memorial Hospital (KEMH), Perth, Western Australia. SAMPLE: A total of 37,763 consecutive deliveries at >23 weeks of gestation. METHODS: Six validation criteria were compared to evaluate the proportion of deliveries with 'valid' UCBG data; and the proportion of vigorous and nonvigorous neonates with metabolic acidaemia. MAIN OUTCOMES: Proportion of deliveries with 'valid' UCBG values; proportions of vigorous and nonvigorous neonates with normal, borderline and abnormal UCBG values. RESULTS: The criteria based on KEMH 5th centile arteriovenous pH and Pco(2) differences resulted in a higher proportion of neonates with 'valid' UCBG values than the previously described Westgate and Kro criteria. The increase in 'valid' UCBG values occurred across the entire study population including vigorous and nonvigorous neonates. Among neonates with short-term neonatal complications there was an increase in nonvigorous neonates with umbilical artery metabolic acidaemia. There was no corresponding increase in vigorous neonates diagnosed with abnormal UCBG values. CONCLUSIONS: Use of the KEMH criteria results in an increase in the proportion of nonvigorous term neonates with UCBG data considered 'valid' to aid clinicians in the management of the neonate shortly after delivery. This change occurs without increasing the rate of false-positive diagnoses of acidaemia in vigorous neonates. The KEMH 'validation' criteria were developed from an entire presenting population and provide a simple algorithm that can be universally applied to identify neonates with nonphysiological UCBG values.

White, C. R. H., et al. (2013). "Attitudes and barriers to the introduction of umbilical cord blood gas and lactate analysis at birth." Aust N Z J Obstet Gynaecol ePub ahead of print.

White, C. R. H., et al. (2012). "The effect of time, temperature and storage device on umbilical cord blood gas and lactate measurement: a randomized controlled trial." Journal of Maternal-Fetal & Neonatal Medicine 25(6): 587-594.
Objective: Umbilical cord blood gas analysis has a significant and growing role in early neonatal assessment. Factors often delay analysis of cord blood allowing values to change. Consequently, this study evaluates the impact of time, temperature and method of storage on umbilical blood gas and lactate analyses. Methods: Umbilical cord segments from 80 singleton deliveries were randomized to: cords at room temperature (CR), cords stored on ice (CI), syringes at room temperature (SR) or syringes stored on ice (SI). Analysis occurred every 15 minutes for one-hour. Mixed model analysis of variance allowing for repeated measures was utilized. Results: Cord arterial pH deteriorated in CR, CI, and SI within 15 minutes (p <= 0.001), with SR stable until 60 minutes (p = 0.002). Arterial pCO(2) remained stable in SR and CI, increased in SI (p = 0.002; 45 minutes) and decreased in CR (p < 0.001; 45 minutes). Arterial base excess deteriorated in CR and SI (p = 0.009; 15 minutes), SR (p < 0.001; 30 minutes), and CI (p < 0.001; 45 minutes). Arterial lactate levels increased within 15 minutes in all groups (p < 0.001). Conclusions: Cord blood gas values change rapidly after delivery. Smallest changes were seen in SR group. Data suggest that analyses should be conducted as soon as possible after delivery.

Whitehouse, A. J., et al. (2011). "CNTNAP2 variants affect early language development in the general population." Genes Brain Behav 10(4): 451-456.
Early language development is known to be under genetic influence, but the genes affecting normal variation in the general population remain largely elusive. Recent studies of disorder reported that variants of the CNTNAP2 gene are associated both with language deficits in specific language impairment (SLI) and with language delays in autism. We tested the hypothesis that these CNTNAP2 variants affect communicative behavior, measured at 2 years of age in a large epidemiological sample, the Western Australian Pregnancy Cohort (Raine) Study. Singlepoint analyses of 1149 children (606 males and 543 females) revealed patterns of association which were strikingly reminiscent of those observed in previous investigations of impaired language, centered on the same genetic markers and with a consistent direction of effect (rs2710102, P = 0.0239; rs759178, P = 0.0248). On the basis of these findings, we performed analyses of four-marker haplotypes of rs2710102-rs759178-rs17236239-rs2538976 and identified significant association (haplotype TTAA, P = 0.049; haplotype GCAG, P = .0014). Our study suggests that common variants in the exon 13-15 region of CNTNAP2 influence early language acquisition, as assessed at age 2, in the general population. We propose that these CNTNAP2 variants increase susceptibility to SLI or autism when they occur together with other risk factors.

Whitehouse, A. J., et al. (2012). "CNTNAP2 variants affect early language development in the general population." Genes Brain Behav 11(4): 501.

Whitehouse, A. J., et al. (2012). "Perinatal testosterone exposure and autistic-like traits in the general population: a longitudinal pregnancy-cohort study." J Neurodev Disord 4(1): 25.
ABSTRACT: BACKGROUND: Increased prenatal testosterone exposure has been hypothesized as a mechanism underlying autism spectrum disorders (ASD). However, no studies have prospectively measured prenatal testosterone exposure and ASD. The current study sought to determine whether testosterone concentrations in umbilical cord blood are associated with a clinical diagnosis of ASD in a small number of children and with autistic-like traits in the general population. METHODS: Umbilical cord blood was collected from 707 children. Samples were analyzed for total (TT) and bioavailable (BioT) testosterone concentrations. Parent report indicated that five individuals had a clinical diagnosis of ASD. Those participants without a diagnosis were approached in early adulthood to complete the Autism-Spectrum Quotient (AQ), a self-report measure of autistic-like traits, with 184 males (M = 20.10 years; SD= 0.65 years) and 190 females (M = 19.92 years; SD=0.68 years) providing data. RESULTS: The BioT and TT concentrations of the five children diagnosed with ASD were within one standard-deviation of the sex-specific means. Spearman's rank-order coefficients revealed no significant correlations between TT levels and scores on any AQ scale among males (rho range: -.01 to .06) or females (rho value range: -.07 to .01). There was also no significant association between BioT or TT concentrations and AQ scores among males (rho value range: -.07 to .08) or females (rho value range: -.06 to .12). Males were more likely than females to have 'high' scores (upper decile) on the AQ scale relating pattern and detail processing. However, the likelihood of a high score on this scale was unrelated to BioT and TT concentrations in both males and females. CONCLUSIONS: These findings indicate that testosterone concentrations from umbilical cord blood are unrelated to autistic-like traits in the general population. However, the findings do not exclude an association between testosterone exposure in early intrauterine life and ASD.

Whitehouse, A. J., et al. (2012). "Do hypertensive diseases of pregnancy disrupt neurocognitive development in offspring?" Paediatr Perinat Epidemiol 26(2): 101-108.
Whitehouse AJO, Robinson M, Newnham JP, Pennell CE. Do hypertensive diseases of pregnancy disrupt neurocognitive development in offspring? Paediatric and Perinatal Epidemiology 2012; 26: 101-108. The current study sought to determine whether hypertensive diseases of pregnancy (gestational hypertension and pre-eclampsia) are associated with neurocognitive outcomes in middle childhood. Participants were members of the Western Australian Pregnancy Cohort (Raine) Study. Data were available for 1389 children (675 females; mean age = 10.59 years; SD = 0.19). Twenty-five per cent of these participants were offspring of pregnancies complicated by either gestational hypertension (n = 279), or pre-eclampsia (n = 34). Verbal ability at age 10 years was assessed with the Peabody Picture Vocabulary Test - Revised (PPVT-R), and non-verbal ability with Ravens Colored Progressive Matrices (RCPM). Separate multivariable regression analyses, incorporating sociodemographic, antenatal, obstetric and postnatal covariates, investigated the effect of a two- (normotensive pregnancy vs. hypertensive pregnancy) and three-level (normotensive pregnancy vs. gestational hypertension vs. pre-eclampsia) predictor variable on PPVT-R and RCPM scores. Offspring of pregnancies complicated by maternal hypertension (gestational hypertension or pre-eclampsia) had a mean PPVT-R score that was 1.83 ([95% confidence interval (CI) -3.48, -0.17], P = 0.03) points lower than children from normotensive pregnancies. Multivariable regression analysis also identified a significant inverse association between the three-level predictor variable and offspring PPVT-R scores (P = 0.02). Gestational hypertension (without pre-eclampsia) reduced offspring PPVT-R scores by 1.71 points [95% CI -3.39, -0.03] and pre-eclampsia led to a reduction of 3.53 points [95% CI -8.41, 1.35], although this latter association did not achieve statistical significance. There was no effect of the two- (P = 0.99) or three-level (P = 0.92) predictor variable on RCPM scores. Maternal hypertensive diseases of pregnancy are a risk factor for a small reduction in offspring verbal ability.

Whitehouse, A. J. O., et al. (2011). "Brief Report: A Preliminary Study of Fetal Head Circumference Growth in Autism Spectrum Disorder." Journal of Autism and Developmental Disorders 41(1): 122-129.
Fetal head circumference (HC) growth was examined prospectively in children with autism spectrum disorder (ASD). ASD participants (N = 14) were each matched with four control participants (N = 56) on a range of parameters known to influence fetal growth. HC was measured using ultrasonography at approximately 18 weeks gestation and again at birth using a paper tape-measure. Overall body size was indexed by fetal femur-length and birth length. There was no between-groups difference in head circumference at either time-point. While a small number of children with ASD had disproportionately large head circumference relative to body size at both time-points, the between-groups difference did not reach statistical significance in this small sample. These preliminary findings suggest that further investigation of fetal growth in ASD is warranted.

Whitehouse, A. J. O., et al. (2010). "Maternal life events during pregnancy and offspring language ability in middle childhood: The Western Australian Pregnancy Cohort Study." Early Human Development 86(8): 487-492.
Background: There is accumulating evidence for a link between maternal stress during pregnancy and later behavioural and emotional problems in children. Little research has examined other developmental outcomes.
Aim: To determine the effect of maternal stress during pregnancy on offspring language ability in middle childhood.
Study design: Longitudinal pregnancy cohort-study.
Subjects: A total of 2900 mothers were recruited prior to the 18th week of pregnancy, delivering 2868 live births. The language ability of just under half of the offspring cohort (n = 1309; 45.6% of original sample) was assessed in middle childhood (Mean age = 10;7, Standard deviation = 0;2, range: 9;5-11;11).
Outcome measures: Language ability was measured using the Peabody Picture Vocabulary Test-Revised (PPVT-R). The main predictor variable was the frequency of 10 typically 'stressful' life events experienced by mothers during early and/or late pregnancy. Children were allocated to four groups according to whether they were exposed to high maternal stress (>= 2 life events) during early pregnancy only, late pregnancy only, both, or neither.
Results: Mixed-effects regression analyses revealed no association between the maternal experience of two or more stressful life events at any time-point during pregnancy and PPVT-R scores. Repeating the regression analyses with more lenient (>= 1 life events) or strict (>= 3 life events) thresholds for defining high-levels of maternal stress did not alter the pattern of findings.
Conclusions: Maternal experience of typically stressful life events during pregnancy has a negligible effect on vocabulary development to middle childhood. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Yazar, S., et al. (2013). "Raine Eye Health Study: Design, methodology and baseline prevalence of ophthalmic disease in a birth-cohort study of young adults. ." Opthalmic Genetics Accepted for Publication.
Funding received
2013 – 2015The International Preterm Birth Genome Project (CI-A)
National Health and Medical Research Council (APP1042267)
Chief Investigators: Pennell, Moses, Menon, Williams, Merialdi

2013Western Australian Preterm Birth Family Genetic Study
Channel Seven Telethon Trust
Undisclosed Amount
Chief Investigator: Pennell

2011 – 2016Early Risk Factors for Autism (CI-E)
National Health & Medical Research Council (APP1003424)
Chief Investigator: Whitehouse, Mayberry, Dissanayake, Hickey, Pennell

2010 – 2015Gene Environment Interactions Underlying DOHaD
Canadian Institutes of Health Research (MOP-82893)
Chief Investigator: Lye, Adams, Beilin, Briollais, Matthews, Newnham Olynyk, Palmer, Pennell

2010 – 2015A Murine Model to Investigate the Mechanisms Underlying DOHaD
Canadian Institutes of Health Research(MOP-81238)
Chief Investigators: Lye, Adamson, Matthews, Pennell

2010 – 2013Risk Factors for NAFLD: genes, early development and environment (CI – D)
National Health & Medical Research (APP634445)
Chief Investigator: Adams

2009 – 2012Telethon Western Australian Preterm Birth Genome Project
Channel Seven Telethon Trust
Undisclosed Amount
Chief Investigator: Pennell

2009 – 2011 An Investigation of Common Genes Influencing Cardiovascular
Disease and Depression in Early Life
National Heart Foundation (Australia) Grant in Aid (Application ID 572674)
Chief Investigators: McCaskie, Beilin, Mattes, Palmer, Pennell, Davey-Smith,

2008 – 2012Preterm Birth and Health Outcomes (Chief Investigator)
Alberta Heritage Foundation for Medical Research
Chief Investigators: Benzies, Bocking, Dolan, Guilbert, Lee, Leew, Lye, Lyon, Magill-Evans, McNeil, Metz, Mitchell, Newburn-Cook, Olson, Pennell, Schopflocher, Slater, Somerville, Tough, Wood, Yee

2007 – 2010 Gene-Environment Interactions Underlying the Developmental Origins of Health and Disease (Co-Investigator)
Canadian Institutes of Health Research
Chief Investigator: Lye
Co-Investigators: Beilin, Briollais, Challis, Doherty, Mathews, Newnham, Ozcelik, Palmer, Pennell, Siminovitch, Stanley, Zubrick

2006 – 2009A Murine Model to Investigate the Mechanisms Underlying Developmental Origins of Health and Disease (Co-Investigator)
Canadian Institutes of Health Research
Chief Investigator: Lye
Co-Investigators: Pennell, Adamson, Rossant, Challis, Danska, Mathews, Osborne

2008 – 2009 Preterm Birth Genome Project (Chief Investigator) World Health Organisation
Chief Investigators: Menon, Williams, Pennell, Vadillo-Ortega, Ha, Merialdi, Thorsen, Dolan

2008 – 2009 Preterm Birth Genome Project (Chief Investigator)
March of Dimes
Chief Investigators: Menon, Williams, Pennell, Vadillo-Ortega, Ha, Merialdi, Thorsen, Dolan

2005 – 2008 The Diagnosis of True Preterm Labour (Chief Investigator)
The March of Dimes Birth Defects Foundation
Chief Investigators: Lye, Pennell, Bocking

2009 – 2011A genome-wide search for genes underlying the developmental origins of health and disease (CI-A)
National Health and Medical Research Council, 2009-2011
Chief Investigators: Pennell, Palmer, Beilin, Newnham, Lye & Davey-Smith

2008 – 2012Phenotypic effects from birth to adolescence of putative causal genetic variants (Co-Investigator)
National Institutes for Health
Chief Investigator: Davey-Smith
Co-Investigators: Beilin, Day, Evans, Gaunt, Glasser, Hallal, Horta, Lawlor, Lye, Newnham, Pennell

2006 – 2007Identifying Genetic Markers of Periodontal Disease-Associated Pre-term Birth
(Chief Investigator)
Raine Medical Foundation, The University of Western Australia
Chief Investigator: Pennell
Co-Investigators: Lye, Newnham

2004 – 2006The Diagnosis of True Preterm Labour (Chief Investigator)
The Physicians Services Incorporated Foundation, Toronto
Chief Investigator: Pennell
Co-Investigators: Lye, Bocking

2002 – 2003New Interventions to Improve Fetal Lung Development in the Presence of Oligohydramnios (Chief Investigator)
Fotheringham Research Fellowship
Royal Australian and New Zealand College of Obstetrics and Gynaecology
Chief Investigator: Pennell
Co-Investigators: Newnham, Moss

2006 – 2007The effect of early life stress on adolescent HPA function and mental health
Women and Infants Research Foundation
Chief Investigator: van Eekelen
Co-Investigators: Pennell, Mattes

2001 – 2003Induction of Labour with an Unfavourable Cervix: The Balloon Trial
(Chief Investigator)
Women and Infants Research Foundation
Chief Investigator: Pennell
Co-Investigator: Dickinson

2000Fetal Monitoring in the Growth Restricted Ovine Fetus (Chief Investigator)
Australian Women and Children’s Research Foundation
Chief Investigator: Pennell PhD project

1999Biochemical and Physiologic Predictors of Neuronal Injury after Repeated Cord Occlusion in the Sheep Fetus Australian Women and Children’s Research Foundation (Chief Investigator) – PhD project
Australian Women and Children’s Research Foundation
Chief Investigator : Pennell
Honours and awards
2012Aspire Professional Development Award
The University of Western Australia

2008Award for Excellence in Teaching - Team Teaching in a Clinical and/or Practicum Setting. Faculty of Medicine, Dentistry and Health Sciences,
The University of Western Australia

2004Athelstan and Amy Saw Postdoctoral Research Fellowship
The University of Western Australia

2004Distinction for Doctorate in Philosophy
The University of Western Australia

2002Presidents Presenter Award
The Society for Gynecologic Investigation

2002 – 2003Fotheringham Research Fellowship
Royal Australian and New Zealand College of Obstetrics and Gynaecology

2001 – 2003Forrest Fellowship in Maternal Fetal Medicine
Women and Infants Research Foundation

2000Young Investigator Award
Perinatal Society of Australia and New Zealand

1999Nepean Medal for Research
Wentworth Area Health Service

1993Bachelor of Medicine and Bachelor of Surgery with Honours
Adelaide University

1989The Wood Jones and Herbert John Wilkinson Prize in Anatomy
The University of Adelaide

1988The Christopher and John Campbell Prize for Biochemistry
The University of Adelaide

1987Elder Prize for First Year Examination for the degrees of Bachelor of Medicine and Bachelor of Surgery
The University of Adelaide
Previous positions
Scientific Director of the Western Australian Pregnancy (Raine) Study (2008 - 2012)
1.US Patent 60/641,875. Markers of Preterm Labour, SJ Lye and CE Pennell, 2005 (Expired)
2.US Patent 60/785,145. Markers of Preterm Labour, SJ Lye and CE Pennell, 2006 (Expired)
3.Australian Patent AU2011900984. Methods of Diagnosing Preterm Birth and Oligonucleotides for Use in Same, Pennell CE, Ang QW, 2011 (Applied for, Provisional)
Current external positions
Scientific Director, The Preterm Birth Genome Project

Board Member, Western Australian Pregnancy (Raine) Study

Professor, University of Toronto

Secretary General, Preterm Birth International Collaborative (PREBIC)
Useful links
New and noteworthy
In 2012, Associate Professor Pennell was awarded over $1.2 million by the National Health and Medical Research Council (NHMRC) to further the research of the Preterm Birth Genome Project.
Current projects
The Preterm Birth Genome Project (PGP) was established in 2007, and is a multinational research project combining the knowledge of clinicians, scientists and clinical academics from Europe, Australia, North America, South America, Africa and Asia. The Project is coordinated by the World Health Organisation, and is supported by The University of Western Australia, The University of Toronto, The University of Texas Medical Branch, University of Vanderbilt and other leading universities. The Project has received funding from the Australian Federal Government (in excess of AUD1.2M), Government of Mexico, March of Dimes, the World Health Organisation, and philanthropic organisations. The PGP team have developed and implemented guidelines for conducting genetic epidemiology studies into preterm birth; as part of this, optimal and minimum phenotypic dataset requirements have been identified. (Pennell, C. E., B. Jacobsson, et al. (2007). "Genetic epidemiologic studies of preterm birth: guidelines for research." Am J Obstet Gynecol 196(2): 107-118.)
The Project is comprised of five key phases. Phase one of the project is complete, and has successfully identified the optimal sample type, collection methods and sample transport protocols, and confirmed that the multinational consortium can work together effectively. The results of Phase I have been published in the Journal of Perinatal Medicine (Pennell, C. E., F. Vadillo-Ortega, et al. (2012). "Preterm Birth Genome Project (PGP) - validation of resources for preterm birth genome-wide studies." J Perinat Med.)
Phase two of the Project is complete, and the manuscript is under preparation. Novel genetic regions that are associated with early spontaneous preterm birth have been identified. Replication studies are near completion.
Phase three aims to investigate the genetics of preterm birth in a global context. In this phase, 1000 cases and 1000 controls from six distinct populations will be analysed, totalling 6000 cases and 6000 controls; Caucasian, Indian, Hispanic, African, African-American and Han Chinese. Funding has been obtained from the Australian Government to fund the collection and genotyping of 1000 cases and 1000 controls. The World Health Organisation and March of Dimes are also providing financial support for Phase Three. Additional funding to enable the PGP research team to evaluate preterm birth risk genes in the five study populations is still being sought.
Phase four will examine the genetic interplay between the maternal and fetal genomes, and the effects of this on the timing of delivery and occurrence of preterm birth.
Phase five will investigate the gene environment interactions associated with preterm birth.
Research profile
Research profile and publications

The University of Western Australia

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