Perinatal outcomes of Aboriginal women with mental health disorders.

OBJECTIVE: Maternal mental disorders have been associated with adverse perinatal outcomes such as low birthweight and preterm birth, although these links have been examined rarely among Australian Aboriginal populations. We aimed to evaluate the association between maternal mental disorders and adverse perinatal outcomes among Aboriginal births. METHODS: We used whole population-based linked data to conduct a retrospective cohort study (N = 38,592) using all Western Australia singleton Aboriginal births (1990-2015). Maternal mental disorders were identified based on the International Classification of Diseases diagnoses and grouped into six broad diagnostic categories. The perinatal outcomes evaluated were preterm birth, small for gestational age, perinatal death, major congenital anomalies, foetal distress, low birthweight and 5-minute Apgar score. We employed log-binomial/-Poisson models to calculate risk ratios and 95% confidence intervals. RESULTS: After adjustment for sociodemographic factors and pre-existing medical conditions, having a maternal mental disorder in the five years before the birth was associated with adverse perinatal outcomes, with risk ratios (95% confidence intervals) ranging from 1.26 [1.17, 1.36] for foetal distress to 2.00 [1.87, 2.15] for low birthweight. We found similar associations for each maternal mental illness category and neonatal outcomes, with slightly stronger associations when maternal mental illnesses were reported within 1 year rather than 5 years before birth and for substance use disorder. CONCLUSIONS: This large population-based study demonstrated an increased risk of several adverse birth outcomes among Aboriginal women with mental disorders. Holistic perinatal care, treatment and support for women with mental disorders may reduce the burden of adverse birth outcomes.

Maternal consumption of coffee and tea during pregnancy and risk of childhood ALL: a pooled analysis from the childhood Leukemia International Consortium.

PURPOSE: The early onset of childhood acute lymphoblastic leukemia (ALL) suggests that critical exposures occurring during pregnancy may increase risk. We investigated the effects of maternal coffee and tea consumption during pregnancy on ALL risk by pooling data from eight case-control studies participating in the Childhood Leukemia International Consortium. METHOD: Data on maternal coffee intake were available for 2,552 cases and 4,876 controls, and data on tea intake were available for 2,982 cases and 5,367 controls. Coffee and tea intake was categorized into 0, > 0-1, > 1-2, and > 2 cups/day, and covariates were combined and harmonized. Data on genetic variants in NAT2, CYP1A1, and NQO1 were also available in a subset. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression, and linear trends across categories were assessed. RESULTS: No association was seen with 'any' maternal coffee consumption during pregnancy, but there was evidence of a positive exposure-response; the pooled OR for > 2 cups/day versus none was 1.27 (95% CI 1.09-1.43), p trend = 0.005. No associations were observed with tea consumption. No interactions were seen between coffee or tea intake and age, maternal smoking or genotype, and there was little or no evidence that associations with coffee or tea differed among cases with and without chromosomal translocations. CONCLUSIONS: Despite some limitations, our findings suggest that high coffee intake during pregnancy may increase risk of childhood ALL. Thus, current advice to limit caffeine intake during pregnancy to reduce risk of preterm birth may have additional benefits.

A 17-Gene Genomic Prostate Score Assay Provides Independent Information on Adverse Pathology in the Setting of Combined Multiparametric Magnetic Resonance Imaging Fusion Targeted and Systematic Prostate Biopsy.

PURPOSE: Multiparametric magnetic resonance imaging and biopsy based molecular tests such as the 17-gene Oncotype DX® Genomic Prostate Score™ assay are increasingly performed to improve risk stratification in men with clinically localized prostate cancer. The prostate score assay was previously shown to be a significant independent predictor of adverse pathology findings at radical prostatectomy in men diagnosed by systematic biopsies only. Therefore, we investigated the ability of the prostate score assay to predict adverse pathology findings in the setting of magnetic resonance imaging guided prostate biopsy. MATERIALS AND METHODS: We identified men diagnosed with NCCN® (National Comprehensive Cancer Network®) very low, low or intermediate risk prostate cancer who underwent simultaneous multiparametric magnetic resonance imaging fusion targeted and systematic prostate biopsy with subsequent radical prostatectomy within 6 months. Prostate score assay testing was performed on biopsy tissue with the highest Gleason score. The primary outcome of the study was adverse pathology findings, defined as Gleason score 4 + 3 or greater disease and/or pT3+ at radical prostatectomy. Independent predictors of adverse pathology findings were determined in a multivariable model to adjust for clinical parameters. RESULTS: A total of 134 men were eligible for primary analysis. On univariable analysis the UCLA score, magnetic resonance imaging, prostate score assay results and biopsy Gleason score were significant predictors of adverse pathology findings. After multivariable adjustment prostate score assay values remained a significant predictor of adverse pathology results (prostate score assay per 20 U OR 3.28, 95% CI 1.74-6.62, p <0.001). A wide and overlapping distribution of prostate score assay results was seen across PI-RADS® (Prostate Imaging Reporting and Data System) version 2 scores. CONCLUSIONS: The prostate score assay result is an independent predictor of adverse pathology findings in patients who were diagnosed with very low, low or intermediate risk prostate cancer in the setting of multiparametric magnetic resonance imaging fusion prostate biopsy. This assay can be useful as an independent technology or an adjunct technology to multiparametric magnetic resonance imaging to individualize risk stratification of low and intermediate risk prostate cancer.

Parental smoking, maternal alcohol, coffee and tea consumption and the risk of childhood brain tumours: the ESTELLE and ESCALE studies (SFCE, France).

PURPOSE: To investigate whether parental smoking around the time of pregnancy or maternal consumption of beverages (alcohol, coffee, or tea) during pregnancy were associated with the risk of CBT. METHODS: We pooled data from two French national population-based case-control studies with similar designs conducted in 2003-2004 and 2010-2011. The mothers of 510 CBT cases (directly recruited from the national childhood cancer register) and 3,102 controls aged under 15 years, frequency matched by age and gender, were interviewed through telephone, which included questions about prenatal parental smoking and maternal consumption of alcohol, coffee and tea. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusted for age, sex and study of origin. RESULTS: No association was seen between CBT and the mother smoking or drinking alcohol, coffee, or tea during the index pregnancy. The OR between CBT and paternal smoking in the year before birth (as reported by the mother) was 1.25 (95% CI 1.03, 1.52) with an OR of 1.09 (0.99, 1.19) for every 10 cigarettes per day (CPD) smoked. The association between paternal smoking and CBT appeared to be stronger in children diagnosed before the age of five years (OR 1.52, 95% CI 1.14, 2.02) and for astrocytoma (OR 1.86, 95% CI 1.26, 2.74). CONCLUSION: We found some evidence of a weak association between paternal smoking in the year before the child's birth and CBT, especially astrocytomas. These findings need to be replicated in other samples, using similar classifications of tumour subtypes.

Factors related to pregnancy and birth and the risk of childhood brain tumours: The ESTELLE and ESCALE studies (SFCE, France).

Little is known of the causes of childhood brain tumors (CBT). The aims of this study were to investigate whether extremes of birth weight were associated with increased risk of CBT and whether maternal preconceptional folic acid supplementation or breastfeeding reduced the risk. In addition, other maternal characteristics and birth related factors were also investigated. We pooled data from two French national population-based case-control studies with similar designs conducted in 2003-2004 and 2010-2011. The mothers of 510 CBT cases (directly recruited from the national childhood cancer register) and 3,102 controls aged under 15 years, frequency matched by age and gender did a telephone interview, which focussed on demographic and perinatal characteristics, and maternal life style habits and reproductive history. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusted for age, sex, study of origin and relevant confounders. No association was found between CBT and birth weight or fetal growth. The use of preconceptional folic acid supplementation was rare (5.3% in cases and 7.8% in controls) and the OR was 0.8 (95% CI 0.5, 1.4). There was no association with breastfeeding, even prolonged (six months or more; OR 1.0, 95% CI 0.8, 1.4). Neither was there any association between CBT and other investigated factors (maternal body mass index, gestational weight gain, congenital abnormality, maternal reproductive history or use of fertility treatments. Although large, this study was underpowered for subtype analyses. Pooling data with other population-based studies may provide further insight into findings by CBT subtypes.

Risk of neuroblastoma, birth-related characteristics, congenital malformations and perinatal exposures: A pooled analysis of the ESCALE and ESTELLE French studies (SFCE).

Neuroblastoma (NB), an embryonic tumour arising from neural crest cells, is the most common malignancy among infants. The aetiology of NB is largely unknown. We conducted a pooled analysis to explore whether there is an association between NB and preconception and perinatal factors using data from two French national population-based case-control studies. The mothers of 357 NB cases and 1783 controls younger than 6 years, frequency-matched by age and gender, responded to a telephone interview that focused on demographic, socioeconomic and perinatal characteristics, childhood environment, life-style and maternal reproductive history. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals. After controlling for matching variables, study of origin and potential confounders, being born either small (OR 1.4 95% CI 1.0-2.0) or large (OR 1.5 95% CI 1.1-2.2) for gestational age and, among children younger than 18 months, having congenital malformations (OR 3.6 95% CI 1.3-8.9), were significantly associated with NB. Inverse associations were observed with breastfeeding (OR 0.7 95% CI 0.5-1.0) and maternal use of any supplements containing folic acid, vitamins or minerals (OR 0.5 95% CI 0.3-0.9) during the preconception period. Our findings reinforce the hypothesis that fetal growth anomalies and congenital malformations may be associated with an increased risk of NB. Further investigations are needed in order to clarify the role of folic acid supplementation and breastfeeding, given their potential importance in NB prevention.

Childhood folate, B6, B12, and food group intake and the risk of childhood brain tumors: results from an Australian case-control study.

PURPOSE: The etiology of childhood brain tumors (CBT) is poorly understood, but dietary factors could be involved. In this case-control study of CBT, the possible associations of childhood intake of dietary and supplemental folate, vitamin B6, and vitamin B12 with the risk of CBT were investigated, along with various food groups. METHODS: Cases diagnosed between 2005 and 2010 were identified from 10 pediatric oncology centers in Australia and controls by nationwide random-digit dialling. For study children of ages 3-14 years, diet in the year before diagnosis (or recruitment) was assessed using food frequency questionnaires. Folate intake was adjusted for bioavailability, and dietary micronutrient intake was energy-adjusted. Micronutrients and food groups were analyzed using logistic regression adjusting for relevant confounders. Principal components analysis was conducted to assess food group intake patterns for analysis. RESULTS: Food and micronutrient data were available for 216 cases and 523 controls. Folate intake was associated with a reduced risk of CBT overall (odds ratio for highest tertile vs. lowest: 0.63, 95% confidence interval 0.41, 0.97) and particularly low-grade gliomas (odds ratio for highest tertile vs. lowest: 0.52, 95% confidence interval 0.29, 0.92). Vitamin B6 and B12 intake was not associated with CBT risk, nor was processed meat. CONCLUSIONS: High folate intake during childhood may reduce the risk of CBT. This potentially important finding needs to be corroborated in other studies. If replicated, these results could have important implications for public health recommendations regarding diet during childhood.

Folate pathway gene polymorphisms, maternal folic acid use, and risk of childhood acute lymphoblastic leukemia.

BACKGROUND: Several studies suggest that maternal folic acid supplementation before or during pregnancy protects against childhood acute lymphoblastic leukemia (ALL). We investigated associations between ALL risk and folate pathway gene polymorphisms, and their modification by maternal folic acid supplements, in a population-based case-control study (2003-2007). METHODS: All Australian pediatric oncology centers provided cases; controls were recruited by national random digit dialing. Data from 392 cases and 535 controls were included. Seven folate pathway gene polymorphisms (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756 A>G, MTR 5049 C>A, CBS 844 Ins68, and CBS 2199 T>C) were genotyped in children and their parents. Information on prepregnancy maternal folic acid supplement use was collected. ORs were estimated with unconditional logistic regression adjusted for frequency-matched variables and potential confounders. Case-parent trios were also analyzed. RESULTS: There was some evidence of a reduced risk of ALL among children who had, or whose father had, the MTRR 66GG genotype: ORs 0.60 [95% confidence interval (CI) 0.39-0.91] and 0.64 (95% CI, 0.40-1.03), respectively. The ORs for paternal MTHFR 677CT and TT genotypes were 1.41 (95% CI, 1.02-1.93) and 1.81 (95% CI, 1.06-3.07). ORs varied little by maternal folic acid supplementation. CONCLUSIONS: Some folate pathway gene polymorphisms in the child or a parent may influence ALL risk. While biologically plausible, underlying mechanisms for these associations need further elucidation. IMPACT: Folate pathway polymorphisms may be related to risk of childhood ALL, but larger studies are needed for conclusive results.

Paternal intake of folate and vitamins B6 and B12 before conception and risk of childhood acute lymphoblastic leukemia.

PURPOSE: We investigated whether paternal dietary intake of folate before conception is associated with the risk of childhood acute lymphoblastic leukemia (ALL) in a nationwide case-control study. METHODS: Data on dietary folate intake during the 6 months before the child's conception were collected from 285 case fathers and 595 control fathers using a dietary questionnaire. Nutrient intake was quantified using a customized computer software package based on Australian food composition databases. Data on folate intake were analyzed using unconditional logistic regression, adjusting for study-matching variables, total energy, and potentially confounding variables. In a subset of 229 cases and 420 controls, data on vitamin B6 and vitamin B12 intake were also analyzed. RESULTS: No consistent associations were seen with paternal dietary intake of folate or vitamin B6. Higher levels of paternal dietary vitamin B12 were appeared to be associated with an increased risk of childhood ALL, with those in the highest tertile of consumption having an OR of 1.51 (0.97, 2.36). The use of supplements containing folate and vitamins B6 or B12 was rare. CONCLUSIONS: We did not find any biologically plausible evidence that paternal nutrition in the period leading up to conception was associated with childhood ALL. Our finding for vitamin B12 may be a chance finding, given the number of analyses performed, or be attributable to participation bias because parents with a tertiary education had the lowest level of B12 intake and tertiary education was more common among control than case parents.

QTc prolongation and family history of sudden death in a patient with desmin cardiomyopathy.

This case report describes a pregnant female patient who presented with new-onset congestive heart failure symptoms and prolonged QTc, with strong family history of sudden death. Endomyocardial biopsy and genetic testing revealed myocardial desmin accumulation and a previously described mutation in the DES (desmin) gene, as well as variants in two LQT genes, SCN5A and KCNH2. The case highlights the phenotypic variability for a particular desmin genotype, and the possible interaction of desminopathy with LQT variants not independently associated with large differences in current properties or QT prolongation from wild type.

Maternal consumption of coffee and tea during pregnancy and risk of childhood ALL: results from an Australian case-control study.

OBJECTIVES: To investigate whether maternal coffee and/or tea consumption during the last 6 months of pregnancy was associated with risk of childhood ALL. METHODS: Data on coffee and tea drinking during pregnancy from 337 case mothers and 697 control mothers were analyzed using unconditional multivariable logistic regression. A meta-analysis of our findings with those of previous studies was also conducted. RESULTS: There was little evidence of an overall association between maternal coffee consumption and risk of ALL: OR 0.89 (95% CI 0.61, 1.30), although there was some suggestion that higher levels of intake might increase the risk in children of non-smoking mothers: OR for 2+ cups/day = 1.44 (95% CI 0.85, 2.42); this was supported by our meta-analysis. Risk was also elevated among cases with chromosomal translocations. The overall OR for maternal tea consumption was 0.82 (95% CI 0.56, 1.18), although the OR for T-cell ALL was 0.21 (95% CI 0.08, 0.51). Among ALL cases with translocations, the ORs for tea consumption tended to be elevated: OR = 1.70 (95% CI 0.79-3.68) for 2+ cups/day. CONCLUSIONS: The observed increased risk associated with coffee and tea consumption may be confined to ALL with translocations. These associations should be explored further in large international consortia.

Maternal folate and other vitamin supplementation during pregnancy and risk of acute lymphoblastic leukemia in the offspring.

The Australian Study of Causes of Acute Lymphoblastic Leukemia in Children (Aus-ALL) was designed to test the hypothesis, raised by a previous Western Australian study, that maternal folic acid supplementation during pregnancy might reduce the risk of childhood acute lymphoblastic leukemia (ALL). Aus-ALL was a national, population-based, multicenter case-control study that prospectively recruited 416 cases and 1,361 controls between 2003 and 2007. Detailed information was collected about maternal use of folic acid and other vitamin supplements before and during the index pregnancy. Data were analyzed using logistic regression, adjusting for matching factors and potential confounders. A meta-analysis with the results of previous studies of folic acid supplementation was also conducted. We found weak evidence of a protective effect of maternal folate supplementation before pregnancy against risk of childhood ALL, but no evidence for a protective effect of its use during pregnancy. A meta-analysis including this and 2 other studies, but not the study that raised the hypothesis, also found little evidence that folate supplementation during pregnancy protects against ALL: the summary odds ratios (ORs) for folate supplementation were 1.06 [95% confidence interval (CI): 0.77-1.48] with reference to no folate supplementation and 1.02 (95% CI: 0.86-1.20) with reference to no vitamin supplementation. For vitamin supplementation in general, the summary OR from a meta-analysis of 5 studies-including Aus-ALL-was 0.83 (95% CI: 0.73-0.94). Vitamin supplementation in pregnancy may protect against childhood ALL, but this effect is unlikely to be large or, if real, specifically due to folate.

Development of hormone-dependent prostate cancer models for the evaluation of inhibitors of 17beta-hydroxysteroid dehydrogenase type 3.

17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) are responsible for the pre-receptor reduction/oxidation of steroids at the 17-position into active/inactive hormones, and the 15 known enzymes vary in their substrate specificity, localisation, and directional activity. 17beta-HSD Type 3 (17beta-HSD3) has been seen to be over-expressed in prostate cancer, and catalyses the reduction of androstenedione (Adione) to testosterone (T), which stimulates prostate tumour growth. Specific inhibitors of 17beta-HSD3 may have a role in the treatment of hormone-dependent prostate cancer and benign prostate hyperplasia, and also have potential as male anti-fertility agents. A 293-EBNA-based cell line with stable expression of transfected human 17beta-HSD3 was created and used to develop a whole cell radiometric TLC-based assay to assess the 17beta-HSD3 inhibitory potency of a series of compounds. STX2171 and STX2624 (IC(50) values in the 200-450nM range) were two of several active inhibitors identified. In similar TLC-based assays these compounds were found to be inactive against 17beta-HSD1 and 17beta-HSD2, indicating selectivity. A novel proof of concept model was developed to study the efficacy of the compounds in vitro using the androgen receptor positive hormone-dependent prostate cancer cell line, LNCaPwt, and its derivative, LNCaP[17beta-HSD3], transfected and selected for stable expression of 17beta-HSD3. The proliferation of the parental cell line was most efficiently stimulated by 5alpha-dihydrotestosterone (DHT), but the LNCaP[17beta-HSD3] cells were equally stimulated by Adione, indicating that 17beta-HSD3 efficiently converts Adione to T in this model. Adione-stimulated proliferation of LNCaP[17beta-HSD3] cells was inhibited in the presence of either STX2171 or STX2624. The compounds alone neither stimulated proliferation of the cells nor caused significant cell death, indicating that they are non-androgenic with low cytotoxicity. STX2171 inhibited Adione-stimulated growth of xenografts established from LNCaPwt cells in castrated mice in vivo. In conclusion, a primary screening assay and proof of concept model have been developed to study the efficacy of 17beta-HSD3 inhibitory compounds, which may have a role in the treatment of hormone-dependent cancer. Active compounds are selective for 17beta-HSD3 over 17beta-HSD1 and 17beta-HSD2, non-androgenic with low toxicity, and efficacious in both an in vitro proof of concept model and in an in vivo tumour model.