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Background: Screening for Trisomy 21 in Nova Scotia has traditionally included serum integrated prenatal screening (SIPS, maternal serum screening), and integrated prenatal screening (maternal serum screening with nuchal translucency, IPS) for those patients considered to be at high risk. In 2016, non-invasive prenatal testing (NIPT) became available as a funded second tier screen for pregnancies at high risk for Trisomy 21 in Nova Scotia.Objective: To compare pregnancy characteristics and number of diagnostic procedures performed for high risk of Trisomy 21 before and after introduction of funded NIPT in Nova Scotia.Methods: This population-based retrospective cohort study evaluated pregnancies with diagnostic testing and/or NIPT which were identified through the IWK Health Clinical Genomics Laboratory Database. Maternal chart review was performed for each pregnancy to confirm eligibility and collect demographic data. Descriptive statistics comparing number of diagnostic procedures and pregnancy characteristics were performed among two epochs – pre-NIPT (2012-2015) and post-NIPT (2016-2019) using Fisher’s exact test, and rates of Trisomy 21 confirmed by diagnostic testing between the two epochs were described.Results: The population incidence of Trisomy 21 remained stable and maternal demographics were similar between the two epochs; after the introduction of funded NIPT, the number of diagnostic procedures decreased, and when diagnostic testing was performed, the procedures were 6-fold more likely to confirm Trisomy 21 (95% CI 2.6-12.9) following high risk screening.Conclusion: The decrease in diagnostic procedures with an increase in the prenatal detection of Trisomy 21 demonstrated in this study illustrates the value of NIPT in a population with limited resources for first trimester screening.

PURPOSE Phase I trials are a crucial step in the evaluation of new cancer therapies. Historically, low rates of response (5%) and comparably high rates of death from toxicities (0.5%) have contributed to debates on the ethics and orientation of these trials. With the introduction of novel targeted therapies, a contemporary estimate is needed. METHODS We systematically searched PubMed, Embase, and ClinicalTrials.gov for reports of phase I oncology trials of single-agent targeted immunomodulators, molecularly targeted therapies, and antiangiogenic agents, published between January 2015 and July 2018. Adult and pediatric trials of solid and hematological malignancies were eligible. Treatment-related adverse events (grades 3, 4, and 5) and response rates (objective, complete, and partial) were extracted and analyzed. RESULTS One hundred and fifty-eight trial reports, covering 6,707 patients, were included. The rate of treatment-related deaths was 0.0% (95% CI, 0.0 to 0.1), while 13.2% of patients (9.5 to 17.3) experienced a grade 3 or 4 treatment-related toxicity. The combined objective response rate was 6.4% (4.6 to 8.5). Among trials using tumor biomarkers as eligibility criteria, the objective response rate was higher (12.0% [7.3 to 17.6] compared to 4.9% [2.5 to 5.7], P value < .01). The same was true of trials focusing on a single tumor type (13.4% [8.2 to 19.4]) compared to multiple tumor types (3.8% [2.5 to 5.3], P value < .01). CONCLUSION Reduced grade 5 risk and improved benefit appears to exist in modern phase I oncology trials, particularly in trials that target single tumor types and integrate biomarkers as eligibility criteria. These findings provide information to support informed consent discussions, highlight the need for improved reporting of phase I oncology trials, and provide direction for optimizing their design.

To investigate the relationship between birth weight for gestational age and health care utilization of term offspring from birth to 7 years.We used a population-based retrospective cohort study of infants (≥37 weeks' gestational age) born between 2003 and 2007 in the Canadian province of Nova Scotia (n = 42 050). Perinatal records were linked to provincial administrative health data from birth to age 7 years. The primary outcome was health care utilization (physician visits and hospital admissions) and costs. Birth weight was categorized as small for gestational age (SGA,10th percentile), appropriate for gestational age (AGA), or large for gestational age (LGA,90th percentile). Regression models adjusted for potential confounders were used to investigate the associations.Children born SGA had a higher number of specialist visits and hospital admissions, a longer length of stay for the birth admission, and, as a result, higher physician and hospital costs amounting to a cost differential of Can $1222 during the first 7 years of life compared with children born AGA. By contrast, health care use and costs did not differ between children born LGA and AGA.Former SGA term infants have a moderate increase in health care use and costs in early childhood compared with former AGA infants, and LGA birth at term is not associated with higher health care utilization.

OBJECTIVE To estimate the association between threatened preterm labour (TPTL) and perinatal outcomes of infants born at term. DESIGN A population-based cohort study of perinatal outcomes following TPTL

OBJECTIVES: To explore provincial variation in both excess and inadequate pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) and their impact on small- and large-for-gestational-age (SGA, LGA) infants. METHODS: Four provinces with a perinatal database capturing the required exposures participated: British Columbia (BC), Ontario (ON), Nova Scotia (NS), and Newfoundland and Labrador (NL). In multiple, concurrent retrospective studies, we included women ≥ 19 years, who gave birth from 22(+0) to 42(+6) weeks’ gestation, to a live singleton from April 2013–March 2014. From adjusted odds ratios, we calculated population attributable fractions (PAF) of SGA and LGA for BMI and GWG. RESULTS: The proportion of overweight and obese women increased from western to eastern Canada. In BC, ON, NS, and NL, the proportions of women who were overweight were 21.1%, 24.0%, 23.7%, and 25.4%, while obesity proportions were 14.2%, 18.1%, 24.2%, and 29.8%, respectively. Excess GWG affected 53.9%, 49.9%, 57.6%, and 65.6% of women, respectively. Excess GWG contributed to 29.5–42.5% of LGA, compared with the PAFs for overweight (6.8–12.0%) and obesity (13.2–20.6%). Inadequate GWG’s contribution to SGA (4.8–12.3%) was higher than underweight BMI’s (2.9–6.2%). CONCLUSION: In this interprovincial study, high and increasing proportions of women from west to east had excess pre-pregnancy BMI, and between half to two thirds had excess GWG. The contributions of GWG outside of recommendations to SGA and LGA were greater than that of low or high BMI. GWG is a potentially modifiable determinant of SGA and LGA across Canada. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.17269/s41997-018-0086-x) contains supplementary material, which is available to authorized users.

Objective To determine the proportion of women in Robson group 5 (RG5) who were eligible for a trial of labour after Caesarean (TOLAC) and, among eligible candidates, identify determinants of having a TOLAC and subsequent vaginal delivery (VD). Methods This population-based cohort study used data derived from the Nova Scotia Atlee Perinatal Database. Deliveries from 1998–2014 to women in RG5 (≥1 previous CS with a singleton term cephalic fetus) were included. Eligibility for a TOLAC was based on SOGC criteria. Multivariable logistic regression was used to identify characteristics independently associated with TOLAC and VD. The characteristics associated with VD were used in a logistic model to predict the theoretical probability of VD in women who did not have a TOLAC. Results Of the 15 111 deliveries in RG5, 75.3% were by CS. Of the 14 763 eligible women, 5488 (37.2%) had a TOLAC, of which 3739 (68.1%) resulted in VD. Predictors of VD included high area–level income and either a CS without labour or a spontaneous VD in the preceding pregnancy. While mode of previous delivery also predicted TOLAC among eligible women, high area–level income was associated with reduced odds of TOLAC. The probability of VD in women who did not undergo TOLAC was estimated to be 47.1%, and the lowest CS rate attainable in RG5 was estimated at 46.3%. Conclusions Sociodemographic factors such as income and previous mode of delivery were associated with the rates of TOLAC and subsequent VD in eligible women, and suggest that the Caesarean section rate in RG5 could be safely reduced.

OBJECTIVES: To determine associations between experiencing alcohol-related harm, sex, and sexual orientation among Canadian high school students. METHODS: We used data from the 2012 Atlantic Student Drug Use Survey (ASDUS), including a comprehensive six-category measure of sexual orientation and nine different alcohol-related harms for analyses. Simple logistic regression was used to determine the association between experiencing any of the nine harms and each specific alcohol-related harm and sexual orientation, stratified by sex. Analysis was limited to those who indicated they had consumed alcohol in the year prior to the survey. RESULTS: High rates of having any alcohol-related harm were seen among both males (41.7%) and females (46.0%) attending Atlantic Canadian high schools. Mostly heterosexual males had a lower odds ratio for experiencing any alcohol-related harm compared to heterosexual males. Mostly heterosexual females and bisexual females had higher odds ratios for experiencing any alcohol-related harm than heterosexual females. CONCLUSIONS: High rates of alcohol-related harm in this population suggest that youth may benefit from a harm reduction approach to alcohol use. While we found that mostly heterosexual and bisexual female youth experience higher levels of alcohol-related harm than heterosexual females, further research is required to confirm this association and to determine its relevance to harm reduction strategies.

Objective To better understand the pathogenesis of inflammatory-related diseases after menopause, we studied the adiposity-independent association between endogenous sex hormones and C-reactive protein (CRP), a biomarker of inflammation. Methods We conducted a secondary, cross-sectional analysis of baseline data from the Alberta Physical Activity and Breast Cancer Prevention Trial (2003-2007), including 319 healthy, postmenopausal women not using hormone therapy. Multivariable linear regression models related serum CRP levels to estrogens, androgens, and sex hormone-binding globulin (SHBG), all on the natural logarithmic scale. Models were adjusted for age, lipids, medication, and former menopausal hormone therapy use, and also for adiposity (body mass index [BMI], per cent body fat [via whole-body dual x-ray absorptiometry], or intra-abdominal fat area [via computed tomography]). Results Without adiposity adjustment, estrone, total estradiol, and free estradiol were significantly positively associated with CRP, whereas SHBG was significantly inversely associated with CRP. Of all adiposity measures, adjustment for BMI caused the greatest attenuation of CRP-estrogen associations; only free estradiol (β = 0.24, 95% confidence interval [CI] 0.06, 0.43) and SHBG (β = -0.37, 95% CI -0.60, -0.13) associations remained significant. Inverse associations between CRP-total testosterone became stronger with BMI adjustment (β = -0.20, 95% CI -0.40, -0.01). Differential associations across categories of BMI, former hormone therapy use, and years since menopause were suggestive, but not statistically significant (Pheterogeneity > 0.05). Conclusions Prospective and systems epidemiological studies are needed to understand whether or not the cross-sectional associations we observed, independent of adiposity, between CRP-SHBG, CRP-total testosterone, and CRP-free estradiol, are causal.

Introduction Neonatal hypoxic-ischemic encephalopathy (HIE) is associated with neonatal mortality, acute neurological injury, and long-term neurodevelopmental disabilities; however, the association between intrapartum factors and HIE remains unclear. Methods This population-based cohort study used linked obstetrical and newborn data derived from the Nova Scotia Atlee Perinatal Database (NSAPD, 1988–2015) and the AC Allen Perinatal Follow-Up Program Database (2006–2015) for all pregnancies with live, non-anomalous newborns ≥35 weeks gestation, not delivered by pre-labour cesarean section. Temporal trends in HIE incidence were described, and logistic regression estimated odds ratios (OR) with 95% confidence intervals (CI) for the association of intrapartum factors with HIE. Results The NSAPD identified 227 HIE cases in the population of 226 711 deliveries from 1988 to 2015. Women with clinical chorioamnionitis in labour (OR 8.0; 95% CI 3.9–16), emergency cesarean delivery (OR 10; 95% CI 7.6–14), shoulder dystocia (OR 3.5; 95% CI 2.1–5.7), placental abruption (OR 18; 95% CI 11–29), and cord prolapse (OR 30; 95% CI 15–61) were more likely to have newborns with HIE. Two-thirds of newborns with HIE had an abnormal intrapartum fetal heart rate tracing. The mortality rate among infants with HIE was 27% by 3 years of age. Neurodevelopmental outcomes in the surviving infants were normal in 43% and showed severe developmental delay in 40%. Conclusion Overall, the rate of HIE was low in infants born at ≥35 weeks gestation. The identification of associated intrapartum factors should promote increased surveillance in these clinical situations and emphasize the importance of careful management to optimize newborn outcomes.

The objective of the present study was to examine the association between birth by Caesarean section (CS) and otitis media (OM) in childhood. We assembled a retrospective cohort of children born between 2003 and 2007 in Nova Scotia and followed them through to 2014. The cohort was derived through a linkage of the Nova Scotia Atlee Perinatal Database with provincial administrative health data. Cox proportional hazards, negative binomial regression and logistic regression were used to examine the association between CS and OM. Among the 36,318 children, 27% were born by CS, and 78% had at least one OM episode (median 2 episodes). Children born by CS were at a slightly higher risk of OM (hazard ratio 1.06, 95% confidence interval (CI) 1.03, 1.09), had more OM episodes in the first 7 years of life (incidence rate ratio 1.04, 95% CI 1.01, 1.07), and were more likely to be above the 95th percentile for OM episodes than children born vaginally (odds ratio 1.10, 95% CI 0.99, 1.23). Our study shows that birth by CS is weakly associated with OM in childhood, but the clinical and public health impact of these findings is small.

Background The negative impact of exposures such as maternal obesity, excessive gestational weight gain, and hypertension in pregnancy on the health of the next generation has been well studied. Evidence from animal studies suggests that the effects of in utero exposures may persist into the second generation, but the epidemiological literature on the influence of pregnancy-related exposures across three generations in humans is sparse. Objectives This cohort was established to investigate associations between antenatal and perinatal exposures and health outcomes in women and their offspring. Population The cohort includes women who were born and subsequently had their own pregnancies in the Canadian province of Nova Scotia from 1980 onward. Design Intergenerational linkage of data in the Nova Scotia Atlee Perinatal Database was used to establish a population-based dynamic retrospective cohort. Methods The cohort has prospectively collected information on sociodemographics, maternal health and health behaviours, pregnancy health and complications, and obstetrical and neonatal outcomes for two generations of women and their offspring. Preliminary results As of October 2018, the 3G cohort included 14 978 grandmothers (born 1939-1986), 16 766 mothers or cohort women (born 1981-2003), and 28 638 children (born 1996-2018). The cohort women were generally younger than Nova Scotian women born after 1980, and as a result, characteristics associated with pregnancy at a younger age were more frequently seen in the cohort women; sampling weights will be created to account for this design effect. The cohort will be updated annually to capture future deliveries to women who are already in the cohort and women who become eligible for inclusion when they deliver their first child. Conclusions The 3G Multigenerational Cohort is a population-based cohort of women and their mothers and offspring, spanning a time period of 38 years, and provides the opportunity to study inter- and transgenerational associations across the maternal line.

Objective This study sought to determine the optimal timing of ultrasound in the third trimester to predict birth weight accurately in diabetic women with a singleton pregnancy. Methods A retrospective cohort study of all diabetic women with a singleton pregnancy treated in Halifax, Nova Scotia, was performed. Estimated fetal weight was derived from ultrasound measures using the Hadlock2 equation. The Mongelli equation was used to predict birth weight. The association between gestational age at ultrasound and accuracy of predicted birth weight was assessed, with accuracy as a continuous variable representing the difference between predicted and actual birth weight and as a categorical variable (with four gestational age categories) representing whether predicted birth weight was within, over, or under 250 g of actual birth weight Results The cohort of 943 women comprised 121 (12.8%) with type 1 diabetes, 111 (11.7%) with type 2 diabetes, and 711 (75.4%) with gestational diabetes. Ultrasound scans performed at term were the most accurate in predicting birth weight. At this gestational age, the mean difference between predicted and actual birth weight was −30 g (95% confidence interval −109 to −48). After adjusting for maternal body mass index, age, smoking, type of diabetes, and interval between ultrasound examination and delivery, accuracy improved as gestational age at ultrasound increased (P = 0.005). The odds of underpredicting or overpredicting birth weight were not significantly affected by the timing of the ultrasound examination. Conclusion Because the predictive accuracy of ultrasound prediction of birth weight improves with gestational age, fetal growth assessment at term is recommended to aid with delivery planning in women with diabetes.

Objective The primary objective of this study was to explore the association between weight cycling in the 6 months prior to pregnancy and gestational weight gain concordance with the 2009 Institute of Medicine guidelines for weight gain in pregnancy. Methods This was a prospective cohort study. Participants were women aged 18 years or older with a singleton pregnancy who had a prenatal appointment between April 1 and August 31, 2019. Eligible women completed a questionnaire that assessed their pre-pregnancy attempts to lose weight, measured with a modified version of the Weight Cycling subscale within the Revised Restraint Scale. After delivery, participants’ last recorded gestational weight before delivery, and corresponding gestational ages were obtained from prenatal records. Results One hundred and ninety-five pregnant women consented to participate in the study (a 95.6% response rate). Of them, 5 were excluded; therefore, 190 participants were included in the analysis. One-third of participants had attempted to lose weight in the 6 months before pregnancy. Logistic regression showed that for every one-unit increase in Weight Cycling score, the odds of excess gestational weight gain increased by a factor of 1.32. Conclusion Women's pre-conceptual efforts to enter pregnancy at a lower BMI should be approached in a manner that avoids pre-pregnancy weight cycling.

The mechanisms whereby regular exercise reduces chronic inflammation remain unclear. We investigated whether regular aerobic exercise alters basal levels of interleukin (IL)‐10 and IL‐4 in two randomized trials of physical activity. The Alberta Physical Activity and Breast Cancer Prevention Trial (ALPHA, n = 320) and the Breast Cancer and Exercise Trial in Alberta (BETA, n = 400) were two‐center, two‐armed randomized trials in inactive, healthy, postmenopausal women. Both trials included an exercise intervention prescribed five times/week and no dietary changes. In ALPHA, the exercise group was prescribed 225 min/week versus no activity in the controls. BETA examined dose‐response effects comparing 300 (HIGH) versus 150 (MODERATE) min/week. Plasma concentrations of IL‐10 and IL‐4 were measured at baseline, 6, and 12 months. Intention‐to‐treat (ITT) analysis was performed using linear mixed models adjusted for baseline biomarker concentrations. Circulating anti‐inflammatory cytokine levels decreased among all groups, with percent change ranging from −3.4% (controls) to −8.2% (HIGH) for IL‐4 and −1.6% (controls) to −7.5% (HIGH) for IL‐10. No significant group differences were found for IL‐4 (ALPHA P = 0.54; BETA P = 0.32) or IL‐10 (ALPHA P = 0.84; BETA P = 0.68). Some evidence for moderation of the effect of exercise by baseline characteristics was found for IL‐10 but not for IL‐4. Results from these two large randomized aerobic exercise intervention trials suggest that aerobic exercise does not alter IL‐10 or IL‐4 in a manner consistent with chronic disease and cancer prevention.

OBJECTIVES: Evidence suggests a beneficial effect of vitamin D on perinatal health; however, low vitamin D status is prevalent in pregnant women and neonates. The objective was to determine factors that are associated with vitamin D status of mothers in early pregnancy and neonates. METHODS: The study comprised 1,635 pregnant women from Quebec City and Halifax, Canada, 2002–2010. Vitamin D status was based on the concentration of 25-hydroxy-vitamin D [25(OH)D] determined with a chemiluminescence immunoassay in maternal sera collected at a median of 15 weeks’ gestation and in neonatal cord sera at delivery. A questionnaire with information on potential determinants was completed midpregnancy. RESULTS: A total of 44.8% of mothers and 24.4% of neonates had 25(OH)D concentrations

Infants follow a predictable trajectory of increased early crying. Frustration with crying is reported to be a trigger for abusive head trauma (AHT).To evaluate the impact of postpartum delivery of the educational program, the Period of PURPLE Crying (PURPLE), in a group of first-time mothers. The primary objective was to determine whether there was a change in knowledge about infant crying and shaking after exposure to PURPLE. Factors associated with change in knowledge were also examined.A total of 93 participants were recruited over a four-month period at a tertiary care hospital in Nova Scotia. Pre- and postintervention data were collected.Knowledge about infant crying increased significantly after program delivery (P=0.001). Low baseline crying knowledge was a significant predictor of increased knowledge about infant crying (P≤0.01). There was an insignificant decrease in shaking knowledge (P=0.5), which may have been the consequence of high baseline knowledge.An educational program for new parents appears to be warranted, especially with respect to improving knowledge about infant crying. This may have a positive benefit in AHT prevention. Additional studies are required to evaluate the impact of the program on other caregivers and on rates of AHT.Les nourrissons suivent une trajectoire prévisible d’augmentation des pleurs peu après la naissance. La frustration à l’égard de ces pleurs est considérée comme un déclencheur des traumatismes crâniens non accidentels (TCNA).Évaluer l’effet de la transmission d’un programme d’éducation postnatale, laLes chercheurs ont recruté 93 participantes sur une période de quatre mois dans un hôpital de soins tertiaires de la Nouvelle-Écosse. Ils ont colligé les données avant et après l’intervention.Les connaissances sur les pleurs des nourrissons augmentaient de manière significative après la prestation du programme (P=0,001). Le peu de connaissances sur les pleurs en début d’étude était un prédicteur important d’augmentation des connaissances sur les pleurs des nourrissons (P≤0,01). Il y avait une diminution non significative des connaissances sur les secousses (P=0,5), qui peut découler des connaissances importantes avant l’intervention.Un programme d’éducation pour les nouveaux parents semble justifié, particulièrement pour accroître les connaissances sur les pleurs des nourrissons. Il pourrait contribuer à prévenir les TCNA. Il faudra réaliser d’autres études pour évaluer l’effet du programme auprès d’autres personnes qui s’occupent de nourrissons et sur le taux de TCNA.

Background Vitamin D status, as measured by serum 25-hydroxyvitamin D (25(OH)D), has been shown in some studies to be inversely associated with gestational diabetes risk. Recently, it has been suggested that maternal smoking status may modify this relationship. We explored the association between 25(OH)D concentration and gestational diabetes and determined if there was an interaction between smoking and 25(OH)D. Methods A nested case–control study was conducted in Halifax, Nova Scotia and Quebec City, Quebec. Women were recruited before 20 weeks gestation and 25(OH)D was measured. Cases were women who developed gestational diabetes and controls were frequency matched to cases on study site, gestational age at blood draw, and season and year of blood draw. Logistic regression models estimated adjusted odds ratios (aOR) and 95% confidence intervals (CI). Models were tested for multiplicative and additive interaction, which was estimated by relative excess risk due to interaction (RERI). Results The study included 395 gestational diabetes cases and 1925 controls. Women who smoked during pregnancy and had 25(OH)D concentrations

Objective This study sought to identify barriers that prevent medical students from performing pelvic examinations in their obstetrics and gynaecology (Ob/Gyn) clinical clerkship rotations and to compare the perspectives of faculty, residents, nurses, and students regarding perceived barriers. Methods An electronic survey was distributed to third-year Dalhousie University (Halifax, NS) medical students on completion of their Ob/Gyn clerkship rotations in the 2015-2016 academic year and to Ob/Gyn nursing staff, faculty, and residents (Canadian Task Force Classification III). Results There were 82 responses, giving an overall response rate of 28%. Students reported performing an average of 9.2 speculum examinations, 3.8 cervical checks, and 2.8 bimanual examinations during their 6-week rotations. They reported being declined the opportunity to perform an examination an average of 7.1 times. Students perceived themselves to be more competent performing these examinations compared with staff perception of student competency. Students perceived resident interest in teaching, resident and staff time constraints, and patient willingness to have a medical student involved in their examination as frequent barriers. Faculty, residents, and nurses perceived student gender, patient willingness, difficulty of examination, and resident time constraints to be significant barriers. Conclusion This study is the first to examine multidisciplinary perspectives on perceived barriers to medical students performing pelvic examinations. Staff and students have different perceptions of a student's competence performing these examinations. Existing barriers are likely multifactorial.

ObjectiveTo examine the association between birth weight for gestational age and asthma in childhood and adolescence while controlling for potential confounders and considering smoking as an effect modifier.MethodsA retrospective cohort of all singleton term births in Nova Scotia, Canada, between 1989 and 1993 was identified in the provincial perinatal database and followed through 2014 by linking with administrative health data. The outcome, asthma, was defined as having one hospitalisation or two physician visits with an International Classification of Diseases code for asthma in a 2-year period. Birth weight was categorised as small (SGA), large (LGA) or appropriate (AGA) for gestational age. Multivariable-adjusted Cox proportional hazards models were used to examine the association between the birth weight for gestational age and asthma and to test for effect modification by maternal smoking in pregnancy.ResultsOf the 40 724 cohort children, 10.5% and 11.7% were born SGA and LGA, respectively, and the risk of developing asthma to age 18 years was 30.2%. The adjusted HRs for SGA and LGA (relative to AGA) and asthma were 1.07 (95% CI 1.02 to 1.14) and 0.96 (95% CI 0.91 to 1.02), respectively. Relative to AGA children born to non-smoking mothers, SGA children were not at increased risk of asthma (HR 1.02), whereas both AGA and SGA children born to smoking mothers were at significantly increased risk (HR 1.14 and 1.29, respectively).ConclusionsOur findings suggest that SGA in term infants is not associated with asthma in childhood in the absence of smoking in pregnancy.

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

Mammographic density, i.e., the radiographic appearance of the breast, is a strong predictor of breast cancer risk. To determine whether the association of breast density with breast cancer is modified by a first-degree family history of breast cancer (FHBC) in women of white and Asian ancestry, we analyzed data from four case–control studies conducted in the USA and Japan. The study population included 1,699 breast cancer cases and 2,422 controls, of whom 45 % reported white (N = 1,849) and 40 % Asian (N = 1,633) ancestry. To standardize mammographic density assessment, a single observer re-read all mammograms using one type of interactive thresholding software. Logistic regression was applied to estimate odds ratios (OR) while adjusting for confounders. Overall, 496 (12 %) of participants reported a FHBC, which was significantly associated with breast cancer risk in the adjusted model (OR 1.51; 95 % CI 1.23–1.84). There was a statistically significant interaction on a multiplicative scale between FHBC and continuous percent density (per 10 % density: p = 0.03). The OR per 10 % increase in percent density was higher among women with a FHBC (OR 1.30; 95 % CI 1.13–1.49) than among those without a FHBC (OR 1.14; 1.09–1.20). This pattern was apparent in whites and Asians. The respective ORs were 1.45 (95 % CI 1.17–1.80) versus 1.22 (95 % CI 1.14–1.32) in whites, whereas the values in Asians were only 1.24 (95 % CI 0.97–1.58) versus 1.09 (95 % CI 1.00–1.19). These findings support the hypothesis that women with a FHBC appear to have a higher risk of breast cancer associated with percent mammographic density than women without a FHBC.

Birth by caesarean section has been recently implicated in the aetiology of childhood obesity, but studies examining the association have varied with regard to their settings, designs, and adjustment for potential confounders. We conducted a systematic review and meta-analysis to summarize the available evidence and to explore study characteristics as sources of heterogeneity. A search of Medline, EMBASE, and Web of Science identified 28 studies. Random effects meta-analysis was used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). Caesarean section had a RR of 1.34 (CI 1.18-1.51) for obesity in the child compared with vaginal birth. The RR was lower for studies that adjusted for maternal pre-pregnancy weight than for studies that did not (1.29, CI 1.16-1.44 vs. 1.55, CI 1.11-2.17). Studies that examined multiple early life factors reported lower RRs than studies that specifically examined caesarean section (1.39, CI 1.23-1.57 vs. 1.23, CI 0.97-1.56). Effect estimates did not vary by child's age at obesity assessment, study design or country income. Children born by caesarean section are at higher risk of developing obesity in childhood. Findings are limited by a moderate heterogeneity among studies and the potential for residual confounding and publication bias.

Background/objective The association between maternal pre-pregnancy obesity and adverse child health outcomes is well described, but there are few data on the relationship with offspring health service use. We examined the influence of maternal pre-pregnancy obesity on offspring health care utilization and costs over the first 18 years of life. Methods This was a population-based retrospective cohort study of children (n = 35,090) born between 1989 and 1993 and their mothers, who were identified using the Nova Scotia Atlee Perinatal Database and linked to provincial administrative health data from birth through 2014. The primary outcome was health care utilization as determined by the number and cost of physician visits, hospital admissions and days, and high utilizer status (>95th percentile of physician visits). The secondary outcome was health care utilization by ICD chapter. Maternal pre-pregnancy weight was categorized as normal weight, overweight, or obese. Multivariable-adjusted regression models were used to examine the association between maternal weight status and offspring health care use. Results Children of mothers with pre-pregnancy obesity had more physician visits (10%), hospital admissions (16%), and hospital days (10%) than children from mothers of normal weight over the first 18 years of life. Offspring of mothers with obesity had C$356 higher physician costs and C$1415 hospital costs over 18 years than offspring of normal weight mothers. Children of mothers with obesity were 1.74 times more likely to be a high utilizer of health care and had higher rates of physician visits and hospital stays for nervous system and sense organ disorders, respiratory disorders, and gastrointestinal disorders compared to children of normal weight mothers. Conclusion Our findings suggest that maternal pre-pregnancy overweight and obesity are associated with slightly higher offspring health care utilization and costs in the first 18 years of life.

Objective This study sought to examine the maternal characteristics and outcomes of adolescent births in Nova Scotia. Methods The investigators conducted a retrospective population-based cohort study using the Nova Scotia Atlee Perinatal Database. Maternal characteristics and maternal and neonatal outcomes of singleton live births between 2006 and 2015 were compared between adolescent (aged 12 to 19) and adult (aged 20 to 35) women. Associations were examined using log-binomial regression models. Results Of the 35 111 births that occurred during the study period, 11% were to adolescent mothers. Compared with adult women, adolescents had higher rates of smoking and substance abuse and were of lower socioeconomic status. Adolescent mothers were more than twice as likely as women aged 20 to 35 to smoke during pregnancy. Adolescent women were significantly less likely to have gestational diabetes, need induction of labour, have an assisted vaginal delivery, require a Caesarean section, have a large-for-gestational age infant, or breastfeed at discharge compared with the 20 to 35 age group. Birth of a small-for-gestational age infant and other adverse neonatal outcomes were more frequently seen in adolescents compared with adult women in the unadjusted models, but this difference vanished in models adjusted for sociodemographic factors and smoking. Conclusion This study highlights disparities in socioeconomic characteristics and health behaviours between births in adolescent and adult mothers and suggests that a targeted multidisciplinary approach would be valuable for the pregnant adolescent. The role of antenatal support for pregnant adolescents is reinforced because sociodemographic factors and smoking accounted for differences in neonatal outcomes relative to adult women.

Background Weight gain during pregnancy has an important impact on maternal and neonatal health. Unlike the Institute of Medicine (IOM) recommendations for weight gain in singleton pregnancies, those for twin gestations are termed “provisional”, as they are based on limited data. The objectives of this study were to determine the neonatal and maternal outcomes associated with gaining weight below, within and above the IOM provisional guidelines on gestational weight gain in twin pregnancies, and additionally, to explore ranges of gestational weight gain among women who delivered twins at the recommended gestational age and birth weight, and those who did not. Methods A retrospective cohort study of women who gave birth to twins at ≥20 weeks gestation, with a birth weight ≥ 500 g was conducted in Nova Scotia, Canada (2003–2014). Our primary outcome of interest was small for gestational age (

BACKGROUND The rate of cesarean delivery is increasing in North America. Surgical site infection following this operation can make it difficult to recover, care for a baby and return home. We aimed to determine the incidence of surgical site infection to 30 days following cesarean delivery, associated risk factors and whether risk factors differed for predischarge versus postdischarge infection. METHODS We identified a retrospective cohort in Nova Scotia by linking the provincial perinatal database to hospital admissions and physician billings databases to follow women for 30 days after they had given birth by cesarean delivery between Jan. 1, 1997 and Dec. 31, 2012. Logistic regression with generalized estimating equations was used to determine risk factors for infection. RESULTS A total of 25 123 women had 33 991 cesarean deliveries over the study period. Of the 25 123, 923 had surgical site infections, giving an incidence rate of 2.7% (95% CI 2.54%-2.89%); the incidence decreased over time. Risk factors for infection (adjusted odds ratios ≥ 1.5) were prepregnancy weight 87.0 kg or more, gaining 30.0 kg or more during pregnancy, chorioamnionitis, maternal blood transfusion, anticoagulation therapy, alcohol or drug abuse, second stage of labour before surgery, delivery in 1997-2000 and delivery in a hospital performing 130-1249 cesarean deliveries annually. Women who gave birth earlier in the study period, those who gave birth in a hospital with 130-949 cesarean deliveries per year and those with more than 1 fetus were at a significantly higher risk for surgical site infection before discharge; women who smoked were at significantly higher risk for surgical site infection after discharge. INTERPRETATION Most risk factors are known before delivery, and some are potentially modifiable. Although the incidence of surgical site infection decreased over time, targeted clinical and infection prevention and control interventions could further reduce the burden of illness associated with this health-care-related infection.

Objective To identify factors known in mid-pregnancy to be associated with risk of macrosomia (≥4000 g) among non-diabetic women and to develop a risk score to allow early identification of women at high risk. Methods Data were obtained from a population-based perinatal database and a hospital laboratory database in Nova Scotia, Canada. The study included singleton live births born to non-diabetic women between 1998 and 2005. Logistic regression was used to identify risk factors significantly associated with macrosomia. Risk scoring systems were developed for nulliparous and parous women separately and validated using the C-statistic. Results Of the 23 857 mother-infant pairs included in the study, 16.7% of the infants were macrosomic. In nulliparous women, seven risk factors were identified, of which pre-pregnancy weight ≥90 kg with an OR of 4.8 (95% CI: 3.9 to 6.0) contributed a greater number of points to the risk score. The resulting risk score corresponded to a range of estimated risk of 0.2% to 47.0% and had a C-statistic of 0.70. In parous women, the most points were assigned to women with a previous large birth (OR: 3.7; 95% CI: 3.2–4.0) and a pre-pregnancy weight ≥90 kg (OR: 3.8; 95% CI: 3.1–4.7). The resulting risk score corresponded to a range of estimated risk of 0.4% to 88.0% and had a C-statistic of 0.75. Conclusions Macrosomia risk can be estimated by a simple calculation based on a woman's risk factor profile at mid-pregnancy.

Excess gestational weight gain (GWG) may predispose mothers to becoming overweight or obese. The aim of this study was to investigate the association between GWG, according to the American Institute of Medicine (IOM) guidelines, and postpartum weight retention (PPWR). A cohort of 12,875 women from Nova Scotia, Canada with at least two consecutively recorded pregnancies was identified through a population-based perinatal database between 1993 and 2010. GWG was calculated as the difference between delivery and prepregnancy weights. PPWR, analyzed as a continuous variable in linear regression models, was calculated via interpregnancy weight change. Fifty eight percent of the total study population gained in excess of the IOM guidelines. Mean PPWR, adjusted for age and prepregnancy body mass index (BMI) among women with excess GWG was 5.0 kg (95 % CI 4.9-5.2), greater than women with adequate (2.1 kg, 95 % CI 1.8-2.3) or inadequate GWG (0.3 kg, 95 % CI 0-0.7). Effect modification by prepregnancy BMI was observed; the relationship between excess GWG and increased PPWR was observed in all prepregnancy BMI categories, yet was greatest among underweight women (7.5 kg, 95 % CI 6.6-8.3). Effect modification by parity was also observed; in contrast to multiparous women, primiparous women who gained in excess of GWG guidelines retained more postpartum weight (5.3 kg, 95 % CI 5.1-5.5 vs. 4.3 kg, 95 % CI 4.0-4.7). This study demonstrates that excess GWG is associated with an increase in the amount of weight retained after pregnancy. Interventions targeted to promote optimal GWG are warranted.

Objective To examine the association between cesarean delivery and healthcare utilization and costs in offspring from birth until age 7 years. Study design A retrospective cohort study of singleton term births in the Canadian province of Nova Scotia between 2003 and 2007 followed until age 7 years was conducted using data from the Nova Scotia Atlee Perinatal Database and administrative health data. The main exposure was mode of delivery (cesarean delivery vs vaginal birth); the outcome was healthcare utilization and costs during the first 7 years of life. Associations were modeled using multiple regression adjusting for maternal prepregnancy weight and sociodemographic factors. Results In total, 32 464 births were included in the analysis. Compared with children born by vaginal birth, children born by cesarean delivery had more physician visits (incidence rate ratio 1.06, 95% CI 1.05-1.08) and longer hospital stays (incidence rate ratio 1.12, 95% CI 1.03-1.21) and were more likely to be high utilizers of physician visits (OR 1.23, 95% CI 1.10-1.37). Physician and hospital costs were $775 higher for children born by cesarean delivery compared with vaginal birth. Conclusions Cesarean delivery compared with vaginal birth is associated with small but statistically significant increases in healthcare utilization and costs during the first 7 years of life.

e14060 Background: Phase 1 clinical trials are a crucial step in the evaluation of new cancer therapies. However, critics cite a low rate of response to therapy (5%), together with a not insignificant risk of death from associated toxicities (0.5%), suggesting a risk-benefit ratio that may limit the ethics of inviting patients to participate in Phase 1 trials. With the introduction of novel targeted therapies, a contemporary estimate of the risks and benefits is needed. Methods: A systematic review was conducted. Eligible for inclusion were phase 1 trials in both adult and pediatric populations published between Jan 2015 to July 2018 of targeted immunomodulators, molecularly targeted therapies, and antiangiogenic agents for solid and hematological malignancies. We systematically searched PubMed and Embase. Rates of objective response (complete and partial), stable disease, and Grades 3, 4 and 5 treatment-related adverse events were extracted and pooled. The protocol was prospectively registered in PROSPERO (CRD42018100386). Results: 116 trials (109 adult, 6 pediatric, 1 mixed) met inclusion criteria. The studies reported on nearly 4300 patients (52% male, 48% female), ages ranging from 1 to 90. Most trials reported on molecularly targeted therapies (58%), followed by immunomodulators (33%). The combined overall objective response rate was 6% (95% CI 4% to 8%), with a complete response rate of 0.3% (0.1% to 0.7%) and a partial response rate of 5% (3% to 7%). The rate of stable disease was 34% (30% to 38%). Of the three types of therapies, the objective response rate appeared highest in the molecularly targeted therapies, at 8% (5% to 11%). Overall, the rate of treatment-related deaths was 0.02% (0% to 0.2%). Conclusions: Our results suggest that response rates for single agent, targeted phase I anti-cancer therapies are not materially different from estimates derived in the conventional chemotherapy setting. In an era where providers tout the benefits of precision medicine, this is an important consideration when counselling patients considering participation in phase I trials. Treatment-related death rates were very low, weakening criticism that participation puts patients at great risk. Reporting was highly inconsistent across included studies, highlighting a need to improve the quality of reporting in phase I trials.

Objectives To determine if variation in the prevalence of risk factors accounts for the increase in shoulder dystocia rates in Nova Scotia, and to estimate the proportion of deliveries recorded with shoulder dystocia that had supporting documentation in the medical chart. Methods A population-based retrospective cohort study was conducted using the Atlee Perinatal Database including all singleton vaginal cephalic deliveries between 1988 and 2017. Shoulder dystocia rates in five epochs were standardized to the distribution of risk factors observed in the cohort. To address our second objective, charts of 400 randomly selected deliveries coded with shoulder dystocia that occurred in Halifax between 2006 and 2015 were reviewed. Results Rates of shoulder dystocia as recorded in the Atlee Database were 1.4% in 1988-1992, 2.4% in 1993-1998, 3.4% in 1999-2005, 4.6% in 2006-2010, and 5.2% in 2011-2017. Changes in the distribution of risk factors such as prepregnancy weight, gestational weight gain, and diabetes did not account for the increase over time. Shoulder dystocia was explicitly documented in 95% of the 400 charts reviewed. Few charts (16%) contained documentation of a clinical sign associated with shoulder dystocia but most (90%) contained documentation of a maneuver executed in its management. Of the 81% of charts that noted severity, 69% were described as mild, with the frequency of mild cases increasing over time (p = 0.15). Conclusions Increased rates of shoulder dystocia do not appear to be a result of increased risk factor prevalence or over-coding. Further research is necessary to improve diagnosis and documentation.

Objectives To develop a tool to predict the risk of developing hypertension within twenty years postpartum. Methods A population-based cohort of 90,316 Nova Scotian women aged 15 to 55 who gave birth for the first time between 1988 and 2009 was studied. Data from the Nova Scotia Atlee Perinatal Database were linked to administrative data to identify new diagnoses of hypertension. Cox regression was used to model the risk of hypertension and estimate hazard ratios (HR) and 95% confidence intervals (CI). The model was simplified through backwards elimination, then translated into a risk score that could be easily tabulated. Results Pregnancy-related predictors included in our final model were: primiparity, gestational hypertension, preeclampsia, gestational age at delivery, delivery of a small- or large-for-gestational-age infant, gestational diabetes, multiple gestation, and breastfeeding. The strongest of these were hypertensive disorders of pregnancy. Adjusted HRs were 2.1 (95% CI 1.9-2.4) and 2.2 (95% CI 2.1-2.3) after one pregnancy complicated by preeclampsia and gestational hypertension, respectively, which rose to 4.9 (95% CI 3.2-7.5) and 4.1 (95% CI 3.6-4.6) if these disorders recurred in a subsequent pregnancy. Breastfeeding in two or more pregnancies was the strongest negative predictor (HR= 0.74, 95% CI 0.69-0.79). The c-statistic measuring the model's discrimination was 0.72. Predicted hypertension risks were consistent with observed rates across time. Conclusions Individualized predictions of hypertension risk up to 20years after pregnancy can be generated from clinical information routinely available at the time of pregnancy to identify women at a young age who may benefit from primary prevention.

Objectives To evaluate whether cervical dysplasia with or without loop electrosurgical excision procedure (LEEP) was associated with risk of preterm delivery. Methods This retrospective cohort study linked a provincial perinatal database and a provincial colposcopy database. All women aged ? 45years with a singleton delivery > 20 weeks’ gestation between 1995 and 2012 were included. The exposure groups included women with dysplasia treated with LEEP (Group 1) and women with dysplasia who were not treated (Group 2). The comparison group included women who did not have dysplasia or LEEP (Group 3). The primary outcome was rate of spontaneous preterm birth Results There were 4265 women in Group 1, 3147 women in Group 2, and 63345 unexposed (Group 3) women. Relative to the unexposed women, women in Group 1 were more likely to deliver preterm (aHR 1.22; CI 1.06-1.39), but women in Group 2 were not (aHR 1.01; CI 0.86-1.19). Subgroup analysis showed that untreated high grade dysplasia, but not low grade dysplasia, was not associated with sPTB (aHR 0.67, 95% CI 0.52-0.88). Conclusions Treatment with LEEP was associated with a higher risk of sPTB, and this association was not heterogeneous by grade. High grade dysplasia, but not low grade dysplasia, was associated with a higher risk of sPTB.

To maximize statistical power in studies of mammographic density and breast cancer, it is advantageous to combine data from several studies, but standardization of the density assessment is desirable. Using data from 4 case-control studies, we describe the process of reassessment and the resulting correlation between values, identify predictors of differences in density readings, and evaluate the strength of the association between mammographic density and breast cancer risk using different representations of density values. The pooled analysis included 1,699 cases and 2,422 controls from California (1990–1998), Hawaii (1996–2003), Minnesota (1992–2001), and Japan (1999–2003). In 2010, a single reader reassessed all images for mammographic density using Cumulus software (Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada). The mean difference between original and reassessed percent density values was −0.7% (95% confidence interval: −1.1, −0.3), with a correlation of 0.82 that varied by location (r = 0.80–0.89). Case status, weight status, age, parity, density assessment method, mammogram view, and race/ethnicity were significant determinants of the difference between original and reassessed values; in combination, these factors explained 9.2% of the variation. The associations of mammographic density with breast cancer and the model fits were similar using the original values and the reassessed values but were slightly strengthened when a calibrated value based on 100 reassessed radiographs was used.

Fruits and vegetables have been examined for their possible effects on the risk of bladder cancer, as they contain numerous nutrients, phytochemicals, and antioxidants with potentially anticarcinogenic properties. In a prospective analysis of 185,885 older adults participating in the Multiethnic Cohort Study, we examined whether the consumption of fruits and vegetables, or of nutrients concentrated in fruits and vegetables, was associated with bladder cancer risk. Cox proportional hazards models were used to calculate HRs and 95% CIs for bladder cancer in relation to dietary intakes. A total of 581 invasive bladder cancer cases (429 men and 152 women) were diagnosed over a mean follow-up period of 12.5 y. In women, total fruits and vegetables [HR = 0.35 (95% CI: 0.22, 0.56); highest vs. lowest quartile], total vegetables [HR = 0.49 (95% CI: 0.29, 0.83)], yellow-orange vegetables [HR = 0.48 (95% CI: 0.30, 0.77)], total fruits [HR = 0.54 (95% CI: 0.34, 0.85)], and citrus fruits [HR = 0.56 (95% CI: 0.34, 0.90)] were inversely associated with the risk of invasive bladder cancer in risk factor-adjusted models. In addition, women with the highest intakes of vitamins A, C, and E; the carotenoids α-carotene, β-carotene, and β-cryptoxanthin; and folate had a lower risk of bladder cancer. For men, no associations for fruits, vegetables, or nutrients were found overall, although inverse associations were observed for vegetable intake among current smokers, and in ethnic-specific analyses, for fruit and vegetable intake among Latinos specifically. Our findings suggest that greater consumption of fruits and vegetables may lower the risk of invasive bladder cancer among women and highlight the need for specific subgroup analyses in future studies.

Background The mode of delivery has recently gained attention as another potential perinatal risk factor for childhood obesity but results are conflicting. Objective To examine whether caesarean section is independently associated with childhood obesity after adjusting for a broad range of confounding factors. Methods The current study used a population-based survey in Grade 5 students linked to a provincial perinatal registry in the Canadian province of Nova Scotia. Associations between caesarean section and childhood overweight and obesity at age 10/11 years were examined using multiple logistic regression. Results Of the 4298 students who participated in the 2003 Children9s Lifestyle and School Performance Study (response rate 51.1%), 3426 (80%) could be linked with information in the Atlee Perinatal Database, and 2988 mother-child pairs (70%) had complete information on the exposure and outcome. Compared to vaginal delivery, caesarean section was associated with offspring obesity (OR) 1.49, 95% CI 1.10 to 2.00) in the univariate analysis. After adding maternal prepregnancy weight to the multiple regression model, the OR for obesity dropped from 1.48 to 1.20 (95% CI 0.87 to 1.65). When caesarean section with and without labour were considered separately, we found no statistically significant associations relative to the vaginal delivery group (OR 1.24, 95% CI 0.84 to 1.82 and OR 1.03, 95% CI 0.58 to 1.84). Conclusion Our results do not support a causal association between caesarean section and childhood obesity. Maternal prepregnancy weight was an important confounder in the association between caesarean delivery and childhood obesity and needs to be considered in future studies.

Background Oxidative stress may contribute to cancer aetiology through several mechanisms involving damage to DNA, proteins and lipids leading to genetic mutations and genomic instability. The objective of this study was to determine the effects of aerobic exercise on markers of oxidative damage and antioxidant enzymes in postmenopausal women. Methods The Alberta Physical Activity and Breast Cancer Prevention Trial (ALPHA) was a two-centre, two-armed randomised trial of 320 inactive, healthy, postmenopausal women aged 50–74 years. Participants were randomly assigned to a year-long exercise intervention (225 min/week) or a control group while being asked to maintain a normal diet. Fasting blood samples were obtained and plasma concentrations of two oxidative damage markers (8-hydroxy-2′-deoxyguanosine (8-OHdG) and 8-isoprostaglandin F2α (8-Iso-PGF2α)) and two antioxidant enzymes (superoxide dismutase and catalase) were measured at baseline, 6 months and 12 months. Intention-to-treat (ITT) and per-protocol analyses were performed using linear mixed models adjusted for baseline biomarker concentrations. A further exercise adherence analysis, based on mean minutes of exercise per week, was also performed. Results In the ITT and per-protocol analyses, the exercise intervention did not have any statistically significant effect on either oxidative damage biomarkers or antioxidant enzyme activity. Conclusions A year-long aerobic exercise intervention did not have a significant impact on oxidative stress in healthy, postmenopausal women. Trial registration number NCT00522262.

Study Objective To examine the association between gestational weight gain (GWG) and interpregnancy weight change (IPWC) in adolescent mothers (younger than 20 years), and to determine if this association differs from adult women (aged 20-35 years). Design Retrospective cohort study. Setting and Participants We included 3055 adolescents and 17,090 adult women with singleton pregnancies recorded in the Nova Scotia Atlee Perinatal Database with a subsequent pregnancy occurring between 2003 and 2014. Interventions and Main Outcome Measures GWG in the first pregnancy was categorized as below, within, or above the current Institute of Medicine recommendations. IPWC was defined as the difference between the prepregnancy weights of the 2 pregnancies. Analyses were adjusted for parity, body mass index in the first pregnancy, and time between pregnancies. Results Relative to adolescents with GWG within the recommendations, those who gained below had a 2.7 kg (95% confidence interval [CI], 1.4-3.9) lower mean IPWC whereas those who gained above had a 4.2 kg (95% CI, 3.3-5.1) higher mean IPWC. Smaller differences in IPWC between GWG categories were observed in adult women; relative to those with GWG within the recommendations, adults who gained below had a 1.3 kg (95% CI, 0.9-1.7) lower mean IPWC and those who gained above had a 2.9 kg (95% CI, 2.6-3.2) higher mean IPWC. Conclusion Mean IPWC differed across GWG categories and the differences were greater in adolescents than in adult women. This difference should be considered when assessing whether specific GWG recommendations are needed for adolescents.

To access publisher's full text version of this article click on the hyperlink at the bottom of the page We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression. National Institute for Health Research (NIHR) info:eu-repo/grantAgreement/EC/FP7/223175 Cancer Research UK C1287/A10118 C1287/A10710 C12292/A11174 C1281/A12014 C5047/A8384 C5047/A15007 C5047/A10692 C8197/A16565 US National Institutes of Health (NIH) CA128978 CA192393 CA116167 CA176785 US National Institutes of Health (NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer) CA116201 Post-Cancer GWAS initiative 1U19 CA148537 1U19 CA148065 1U19 CA148112 Post-Cancer GWAS initiative (GAME-ON initiative) US Department of Defense W81XWH-10-1-0341 Canadian Institutes of Health Research (CIHR) Komen Foundation for the Cure Breast Cancer Research Foundation Ovarian Cancer Research Fund

The objective of the current study was to determine the proportion of adverse perinatal outcomes that could be potentially prevented if maternal obesity were to be reduced or eliminated (population attributable risk fractions, PARF); and the number needed to treat (NNT) of overweight or obese women to prevent one case of adverse perinatal outcome. Data from the Atlee Perinatal Database on 66,689 singleton infants born in Nova Scotia, Canada, between 2004 and 2014, and their mothers were used. Multivariable-adjusted PARFs and NNTs of maternal pre-pregnancy weight status were determined for various perinatal outcomes under three scenarios: If all overweight and obese women were to i) become normal weight before pregnancy; ii) shift down one weight class; or iii) lose 10% of their body weight, significant relative reductions would be seen for gestational diabetes mellitus (GDM, 57/33/15%), hypertensive disorders of pregnancy (HDP, 26/16/6%), caesarean section (CS, 18/10/3%), and large for gestational age births (LGA, 24/14/3%). The NNT were lowest for the outcomes GDM, induction of labour, CS, and LGA, where they ranged from 13 to 73. The study suggests that a substantial proportion of adverse perinatal outcomes may be preventable through reductions in maternal pre-pregnancy weight.

Background:Few studies have examined the predictors of adherence separately for supervised and unsupervised exercise or in postmenopausal women over an extended time period. Here, we report the predictors of exercise adherence in the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial.Methods:The ALPHA trial randomized 160 postmenopausal women in Calgary and Edmonton, Canada to an exercise intervention that consisted of an average of 200 min/wk of supervised (123 minutes) and unsupervised (77 minutes) exercise over a 1-year period. Baseline data were collected on demographic, health-related fitness, quality of life, and motivational variables from the theory of planned behavior.Results:Participants completed an average of 95% of their supervised exercise and 79% of their unsupervised exercise. In multivariate analyses, 8.1% (P = .001) of the variance was explained for supervised exercise by being from Edmonton (β = 0.22; P = .004) and older (β = 0.15; P = .050). For unsupervised exercise, 21.1% (P < .001) of the variance was explained by being from Calgary (β = –0.39; P < .001), having a family history of breast cancer (β = 0.21; P = .003), and having higher vitality (β = 0.19; P = .011).Conclusions:Predictors of adherence may differ for supervised and unsupervised exercise, moreover, predicting adherence to supervised exercise may be particularly difficult in well-controlled efficacy trials.

Background : It is important to understand the adverse health sequelae that may result from the rising incidence of diabetes. Diabetics may have an increased risk for urothelial cancer but the evidence from prospective studies and ethnically diverse populations is sparse. Method : We examined this association in the Multiethnic Cohort (MEC) that was conducted in Hawaii and Los Angeles with nearly 186,000 participants in five ethnic groups. Over a median 10.7 years of follow-up, 918 incident cases of urothelial cancer (89% bladder and 11% other urinary tract sites) were identified through tumor registry linkages. Results : A self-reported diagnosis of diabetes was associated with an increased risk of urothelial cancer (relative risk=1.25; 95% confidence interval: 1.04–1.50). The association was not explained by body mass index, physical activity, or smoking. There was some suggestion that the risk was higher in women, Whites and African Americans, and past smokers. The risk associated with diabetes for in situ and localized cancer was similar to that for regional and distant cancer. Conclusion : This study demonstrates that the increased urothelial cancer risk with diabetes in this multiethnic population is very similar to that observed in mostly White or Asian populations. Whether or not the elevated risk is moderated by the degree of control of the hyperglycemia associated with diabetes will need to be determined in future studies.

Objective To identify factors that mediate or moderate the effects of exercise on postmenopausal sex hormone concentrations. Methods Postmenopausal women were randomized to 12 months of aerobic exercise for 200 min/week (n = 160) or to a control group (n = 160). Intention-to-treat analyses were performed using general linear models with sex hormone concentrations at 6 and 12 months as the outcome. Mediation by adiposity and insulin was investigated by examining changes in effect estimates after adjustment for changes in these factors over 12 months. Moderation was studied as the interaction between group assignment and eight baseline characteristics. Results Intervention effects on sex hormone–binding globulin (SHBG) and estradiol changes were attenuated with adjustment for change in overall body fat, while there was less attenuation adjusting for intra-abdominal fat change. Intervention effects on SHBG levels were unaffected by adjustment for insulin change. Significant interactions were identified between treatment and physical fitness (for SHBG and testosterone) and age (for testosterone), implying subgroup differences in intervention effect. Conclusions Our data suggest that overall fat loss partially mediated exercise-induced changes in estradiol and SHBG concentrations. No previous RCT in postmenopausal women has studied moderators of exercise-induced sex hormone changes; therefore, future studies are needed to corroborate our results.

Physical activity is a known modifiable lifestyle means for reducing postmenopausal breast cancer risk, but the biologic mechanisms are not well understood. Metabolic factors may be involved. In this study, we aimed to determine the effects of exercise on insulin resistance (IR) indicators, IGF1, and adipokines in postmenopausal women. The Alberta Physical Activity and Breast Cancer Prevention Trial was a two-armed randomized controlled trial in postmenopausal, inactive, cancer-free women. A year-long aerobic exercise intervention of 225 min/week (n=160) was compared with a control group asked to maintain usual activity levels (n=160). Baseline, 6- and 12-month serum levels of insulin, glucose, IGF1, IGF-binding protein 3 (IGFBP3), adiponectin, and leptin were assayed, and after data collection, homeostasis model assessment of IR (HOMA-IR) scores were calculated. Intention-to-treat analyses were performed using linear mixed models. The treatment effect ratio (TER) of exercisers to controls was calculated. Data were available on 308 (96.3%) women at 6 months and 310 (96.9%) women at 12 months. Across the study period, statistically significant reductions in insulin (TER=0.87, 95% confidence interval (95% CI)=0.81-0.93), HOMA-IR (TER=0.86, 95% CI=0.80-0.93), and leptin (TER=0.82, 95% CI=0.78-0.87), and an increase in the adiponectin/leptin ratio (TER=1.21, 95% CI=1.13-1.28) were observed in the exercise group compared with the control group. No significant differences were observed for glucose, IGF1, IGFBP3, adiponectin or the IGF1/IGFBP3 ratio. Previously inactive postmenopausal women who engaged in a moderate-to-vigorous intensity exercise program experienced changes in insulin, HOMA-IR, leptin, and adiponectin/leptin that might decrease the risk for postmenopausal breast cancer.

Objective Interventions for disease prevention should also be evaluated for quality of life (QoL) effects. Few exercise trials have examined QoL in the context of primary disease prevention. Here, we report the QoL outcomes from the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial. Methods The ALPHA trial was a randomized controlled trial in Calgary and Edmonton, Canada between May 2003 and July 2007 that compared an exercise intervention to a sedentary lifestyle among 320 sedentary, postmenopausal women. The exercise group was asked to perform moderate-to-vigorous intensity aerobic exercise 45 min/day, 5 days/week for 1 year. QoL was assessed by the short form-36 health survey. Results Compared to the control group, the exercise group maintained significantly better physical functioning ( p p p = 0.002), and bodily pain ( p = 0.020) by 4–5 points which exceeds the 3.0 minimally important difference for these scales. Changes in body composition partially mediated the intervention effects. Antidepressant use and the presence of comorbidities moderated some intervention effects. Conclusions A 1-year moderate-to-vigorous aerobic exercise program prevents declines in the physical aspects of QoL in postmenopausal women. Exercise may have a potentially important advantage for breast cancer prevention compared to other lifestyle or biomedical interventions.