Publications by authors named "Francois Audibert"

143 Publications

Association Between Human Papillomavirus Infection Among Pregnant Women and Preterm Birth.

JAMA Netw Open 2021 Sep 1;4(9):e2125308. Epub 2021 Sep 1.

Department of Social and Preventive Medicine, Université de Montréal, Montreal, Québec, Canada.

Importance: Preterm birth remains a leading cause of perinatal mortality and lifelong morbidity worldwide. The cause of most preterm births is unknown, although several infectious processes have been implicated.

Objective: To assess whether human papillomavirus (HPV) infection, a frequent infection among women of childbearing age, is associated with preterm birth.

Design, Setting, And Participants: The prospective HERITAGE cohort study was conducted at 3 academic hospitals in Montreal, Québec, Canada, among 899 pregnant women recruited between November 8, 2010, and October 16, 2016. Follow-up was completed on June 15, 2017. Statistical analysis was conducted from February 6, 2020, to January 21, 2021.

Exposures: Vaginal HPV DNA detection in the first and third trimesters of pregnancy and placental HPV infection.

Main Outcomes And Measures: The main outcome was preterm birth (defined as a live birth or stillbirth between 20 weeks and 0 days and 36 weeks and 6 days of gestation). The association between HPV DNA detection and preterm birth was measured using logistic regression. Odds ratios (ORs) and 95% CIs were adjusted by inverse probability of treatment weights of the propensity score.

Results: The study included 899 women (mean [SD] age, 31.3 [4.6] years [range, 19-47 years]) with singleton pregnancies. A total of 378 women (42.0%) had HPV DNA detected in vaginal samples collected during the first trimester, and it was detected in 91 of 819 placentas (11.1%) at delivery. Fifty-five participants experienced preterm birth (38 spontaneous and 17 medically indicated). Persistent vaginal HPV-16/18 detection was significantly associated with all preterm births (adjusted OR [aOR], 3.72; 95% CI, 1.47-9.39) and spontaneous preterm births (aOR, 3.32; 95% CI, 1.13-9.80), as was placental HPV infection (all preterm births: aOR, 2.53; 95% CI, 1.06-6.03; spontaneous preterm births: aOR, 2.92; 95% CI, 1.09-7.81). Results were similar when restricting the analysis to participants without a history of cervical intraepithelial neoplasia treatment.

Conclusions And Relevance: The study's results suggest that persistent HPV-16/18 infection is associated with an increased risk of preterm birth, independent of cervical treatment. Future studies should investigate the association of HPV vaccination and vaccination programs with the risk of preterm birth.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.25308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444026PMC
September 2021

The plasma antioxidant vitamin status of the INTAPP cohort examined: The unsuspected importance of β-carotene and γ-tocopherol in preeclampsia.

Pregnancy Hypertens 2021 Aug 12;25:213-218. Epub 2021 Jun 12.

Department of Medicine, Faculty of Medicine, Laval University, Quebec, Quebec, Canada; Endocrinology and Nephrology Research Axis, CHU of Quebec-Laval University, Quebec, Quebec, Canada.

Objective: Examine the levels of plasma antioxidant vitamins before and during a treatment with placebo or vitamin E + C supplement to prevent preeclampsia (PE).

Study Design: Per-protocol analysis of a subset group of pregnant women (n = 295) from the International Trial of Antioxidants for the Prevention of PE (INTAPP) randomized case-control study. Normotensive receiving placebo or vitamins (n = 115 and 87 respectively) were compared to gestational hypertension (GH) without proteinuria (n = 30 and 27) and PE (n = 21 and 15). Vitamin quantification was performed at 12-18, 24-26 and 32-34 weeks of gestation.

Main Outcome Measures: Coenzyme (Co) Q, β-carotene and vitamins E (α and γ forms) plasma levels.

Results: Vitamin E + C supplementation was found to increase the α-tocopherol levels by 40% but was associated with a 57% decrease in the γ-tocopherol isoform for all study groups (p < 0.001). The β -carotene was lower in the PE than in the normotensive and GH groups (p < 0.001) while the level of CoQ remained unaffected.

Conclusions: A more personalized approach that target the suboptimal levels of specific antioxidants without disturbing the α/γ-tocopherol ratio could be a more successful approach to counteract oxidative stress in PE.
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http://dx.doi.org/10.1016/j.preghy.2021.06.009DOI Listing
August 2021

Maternal vitamin D, oxidative stress, and pre-eclampsia.

Int J Gynaecol Obstet 2021 Sep 21;154(3):444-450. Epub 2021 Jan 21.

Department of Obstetrics and Gynecology, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada.

Objective: To examine the associations between risk of pre-eclampsia and pregnancy levels of maternal 25-hydroxyvitamin D (25[OH]D) and oxidative stress biomarkers.

Methods: A nested case-control study (n = 99; 34 cases; 65 controls) within a prospective pregnancy cohort. Maternal 25(OH)D and oxidative stress markers (six isomers of F -isoprostanes; F -isoPs) were measured in plasma at 12-18 and 24-26 gestational weeks. Vitamin D deficiency was defined as 25[OH]D less than 50 nmol/L.

Results: Maternal vitamin D deficiency was associated with increased 8-iso-PGF (P = 0.037), 15(R)-PGF (P = 0.004), (±)5-iPF -VI (P = 0.026) at 12-18 weeks. Vitamin D deficiency was inversely associated with 8-iso-PGF (P = 0.019) and (±)5-iPF -VI isomer (P = 0.010) at 24-26 weeks. Both maternal vitamin D deficiency (adjusted odds ratio [aOR], 4.79; 95% confidence interval [CI], 1.67-13.75) and increased (±)5-iPF -VI (aOR, 2.46; 95% CI, 1.16-5.22) at 24-26 weeks were associated with risk of pre-eclampsia. However, the interaction test between 25(OH)D and (±)5-iPF -VI was not significant (P = 0.143).

Conclusion: Plasma 25(OH)D below 50 nmol/L was associated with increased oxidative stress levels during pregnancy as measured by two F -isoP isomers, including the well-studied marker 8-iso-PGF . Whether vitamin D-induced oxidative stress mediates the risk of pre-eclampsia warrants future study.
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http://dx.doi.org/10.1002/ijgo.13559DOI Listing
September 2021

Validation and development of models using clinical, biochemical and ultrasound markers for predicting pre-eclampsia: an individual participant data meta-analysis.

Health Technol Assess 2020 12;24(72):1-252

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management.

Objectives: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers.

Design: This was an individual participant data meta-analysis of cohort studies.

Setting: Source data from secondary and tertiary care.

Predictors: We identified predictors from systematic reviews, and prioritised for importance in an international survey.

Primary Outcomes: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia.

Analysis: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for -statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using and τ. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals.

Results: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary -statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia.

Limitations: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data.

Conclusion: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings.

Future Work: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate.

Study Registration: This study is registered as PROSPERO CRD42015029349.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780127PMC
December 2020

External validation of prognostic models predicting pre-eclampsia: individual participant data meta-analysis.

BMC Med 2020 11 2;18(1):302. Epub 2020 Nov 2.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting.

Methods: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis.

Results: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%.

Conclusions: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice.

Trial Registration: PROSPERO ID: CRD42015029349 .
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http://dx.doi.org/10.1186/s12916-020-01766-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604970PMC
November 2020

Hypertension Canada's 2020 Comprehensive Guidelines for the Prevention, Diagnosis, Risk Assessment, and Treatment of Hypertension in Adults and Children.

Can J Cardiol 2020 05;36(5):596-624

Service de néphrologie, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Quebec, Canada.

Hypertension Canada's 2020 guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children provide comprehensive, evidence-based guidance for health care professionals and patients. Hypertension Canada develops the guidelines using rigourous methodology, carefully mitigating the risk of bias in our process. All draft recommendations undergo critical review by expert methodologists without conflict to ensure quality. Our guideline panel is diverse, including multiple health professional groups (nurses, pharmacy, academics, and physicians), and worked in concert with experts in primary care and implementation to ensure optimal usability. The 2020 guidelines include new guidance on the management of resistant hypertension and the management of hypertension in women planning pregnancy.
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http://dx.doi.org/10.1016/j.cjca.2020.02.086DOI Listing
May 2020

Antibodies to human papillomavirus types 6, 11, 16 and 18: Vertical transmission and clearance in children up to two years of age.

EClinicalMedicine 2020 Apr 7;21:100334. Epub 2020 Apr 7.

Department of Social and Preventive Medicine, Université de Montréal, Montreal, Canada.

There is a paucity of data on the dynamics of human papillomavirus (HPV) antibodies in children. We aimed to describe the vertical transmission and clearance of antibodies against HPV6, 11, 16 and 18 in children. We used data from pregnant women recruited into the HERITAGE cohort study between 2009 and 2012 who were positive for HPV-DNA at baseline. Dried blood spots were collected during the first trimester in pregnant participants, and at birth, 6, 12, and 24 months of age in children. The level of total immunoglobulin G (IgG) against HPV6, 11, 16 and 18 were measured using Luminex immunoassays. Spearman's coefficients were used to correlate HPV antibody levels between newborns and mothers. Panel and Kaplan-Meier graphics described antibody dynamics in the first 24 months of life. Antibodies from newborns and mothers ( = 58 pairs) were moderately to highly correlated with coefficients of 0·81 (95% confidence intervals (CI):0·70-0·88), 0·68 (95% CI:0·5-0·80), 0·90 (95% CI:0·83-0·94) and 0·85 (95% CI:0·76-0·91) against HPV6, 11, 16 and 18, respectively. In newborns seropositive at birth, anti-HPV antibodies were cleared by 80% and 100% at 12 and 24 months, respectively. Only two children presented detectable HPV antibodies at 24 months. The first child had no detectable antibodies at birth and the second presented increasing levels after two undetected measures. Correlation between mother and newborn IgG antibodies against HPV suggests vertical transfer. Most children cleared anti-HPV antibodies within six to 12 months. The Canadian Institutes of Health Research (CIHR).
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http://dx.doi.org/10.1016/j.eclinm.2020.100334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201033PMC
April 2020

Chirurgie fœtale : le passé, le présent et l'avenir.

J Obstet Gynaecol Can 2019 Dec;41 Suppl 2:S290-S292

Division de médecine foeto-maternelle, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Qc.

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http://dx.doi.org/10.1016/j.jogc.2019.10.014DOI Listing
December 2019

Fetal Surgery: Past, Present, and Future Perspectives.

J Obstet Gynaecol Can 2019 Dec;41 Suppl 2:S287-S289

Division of Maternal and Fetal Medicine, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, QC.

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http://dx.doi.org/10.1016/j.jogc.2019.08.039DOI Listing
December 2019

Left Superior Vena Cava in the Fetus: A Rarely Isolated Anomaly.

Pediatr Cardiol 2020 Feb 13;41(2):230-236. Epub 2019 Nov 13.

Department of Fetal and Pediatric Cardiology, Université de Montréal - Sainte-Justine University Hospital, Montreal, QC, Canada.

The frequency of chromosomal anomalies among fetuses with isolated persistent left superior vena cava (PLSVC) is still debated. The objective of the present study was to assess the prevalence of genetic and morphological anomalies identified in fetuses with PLSVC. We conducted a single-center retrospective study including all fetuses diagnosed with a PLSVC between 2010 and 2017. PLSVC was categorized as isolated or associated according to antenatal diagnosis of associated congenital heart defects, hypoplastic aortic isthmus, abnormal venous/arterial connections, and extracardiac anomalies. Among 229 fetuses diagnosed with PLSVC, 39 cases (17%) were strictly isolated and no syndromic/genetic anomaly or aortic coarctation was diagnosed. Seventy-two fetuses had a cardiovascular defect with a rate of genetic anomalies of 22%, 29 had an extracardiac malformation, and 89 had both an extracardiac and a cardiovascular defect. Among fetuses with abnormal development of the arterial/venous system as the only associated anomaly such as aberrant right subclavian artery or absent ductus venosus, 22% had a genetic anomaly. Overall, sixty-five fetuses or infants had a genetic concern, including 23 aneuploidies, 15 pathogenic micro-deletions/duplications, and 5 variants of unknown significance; 12 patients had VACTERL association, and 12 heterotaxy syndrome. Seven infants had an aortic coarctation diagnosed at birth.In conclusion, a thorough prenatal ultrasound examination is paramount, and the identification of variants of the venous/arterial system in addition to PLSVC should raise suspicion for genetic or morphologic abnormalities. Invasive prenatal diagnosis with array-CGH should be offered when PLSVC is non-isolated, after a detailed ultrasound evaluation in a tertiary center.
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http://dx.doi.org/10.1007/s00246-019-02246-5DOI Listing
February 2020

Renal functional markers in extremely premature infants with and without twin-twin transfusion syndrome.

J Perinatol 2020 02 15;40(2):256-262. Epub 2019 Oct 15.

Division of Neonatology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, McGill University, 1001 Décarie, B05.2513, Montreal, QC, Canada.

Objective: Describe renal function of preterm infants <29 weeks of gestational age (GA) with twin-twin transfusion syndrome (TTTS) who received laser therapy.

Design: Retrospective analysis of premature TTTS compared with dichorionic-diamniotic (di-di) twins from 2006 to 2015. Primary outcome was biomarkers of renal injury.

Results: Thirty-three TTTS-laser and 101 di-di newborns with similar GA at birth (26.4 ± 1.4 vs 26.9 ± 1.6 weeks, p = 0.07) were included. Creatinine and urea levels were higher in TTTS-laser group at day of life (DOL) 2-7 (123.5 ± 12.4 vs 75.8 ± 2 μmol/L, p = 0.0001 and 11.9 ± 1.1 mmol/L vs 8.7 ± 0.3 mmol/L, p = 0.0001) and DOL 8-14, (98.1 ± 14.2 vs 64.8 ± 2.3 μmol/L, p = 0.0001 and 9.1 ± 1.2 vs 5.4 ± 0.3 mmol/L, p = 0.0001). There was a significant effect of TTTS status on creatinine level at DOL 8-14.

Conclusion: In extremely preterm with TTTS treated by laser, biomarkers of renal function were higher compared with di-di twins in the first 2 weeks of life.
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http://dx.doi.org/10.1038/s41372-019-0524-5DOI Listing
February 2020

Exploration of the effect of human papillomavirus (HPV) vaccination in a cohort of pregnant women in Montreal, 2010-2016.

Heliyon 2019 Aug 14;5(8):e02150. Epub 2019 Aug 14.

Department of Social and Preventive Medicine, Université de Montréal, Sainte-Justine University Hospital Centre, Montreal, Canada.

HPV vaccination efficacy has been shown in clinical trials but it is important to verify population level vaccine effectiveness (VE). We aimed to explore VE and herd effect using HPV infection data from a cohort study of Canadian pregnant women. We analyzed the baseline data of the HERITAGE study, which includes pregnant women recruited in Montreal between 2010-2012 and 2015-2016. Cervicovaginal samples self-collected in the first trimester were tested for 36 HPV types. Vaccination status was self-reported. VE and 95% confidence intervals (CI) were estimated by comparing the prevalence of HPV between vaccinated and unvaccinated women. Herd effect was explored by comparing HPV prevalence in unvaccinated women between the 2 recruitment periods. Adjusted ORs (95%CI) were estimated using exact logistic regression. The proportion of vaccinated women with at least one dose of 4vHPV was 7.5%. Although most of them were vaccinated after the onset of sexual activity, a high VE was found for HPV-16/18 (86.1% (95%CI: 15.0-99.7)). For HPV-6/11/16/18 and for HPV-31/33/45, VE was 61.9% (-23.5-92.6) and 57.0% (-47.7-92.0%), respectively. We also observed a non-statistically significant reduction in the prevalence of HPV-6/11/16/18 and HPV-31/33/45 among unvaccinated women recruited during the second recruitment period (adjusted OR: 0.8 (0.4-1.8) and 0.8 (0.3-1.7), respectively).
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http://dx.doi.org/10.1016/j.heliyon.2019.e02150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704337PMC
August 2019

Prospective head-to-head comparison of accuracy of two sequencing platforms for screening for fetal aneuploidy by cell-free DNA: the PEGASUS study.

Eur J Hum Genet 2019 11 23;27(11):1701-1715. Epub 2019 Jun 23.

Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

We compared clinical validity of two non-invasive prenatal screening (NIPS) methods for fetal trisomies 13, 18, 21, and monosomy X. We recruited prospectively 2203 women at high risk of fetal aneuploidy and 1807 at baseline risk. Three-hundred and twenty-nine euploid samples were randomly removed. The remaining 1933 high risk and 1660 baseline-risk plasma aliquots were assigned randomly between four laboratories and tested with two index NIPS tests, blind to maternal variables and pregnancy outcomes. The two index tests used massively parallel shotgun sequencing (semiconductor-based and optical-based). The reference standard for all fetuses was invasive cytogenetic analysis or clinical examination at birth and postnatal follow-up. For each chromosome of interest, chromosomal ratios were calculated (number of reads for chromosome/total number of reads). Euploid samples' mean chromosomal ratio coefficients of variation were 0.48 (T21), 0.34 (T18), and 0.31 (T13). According to the reference standard, there were 155 cases of T21, 49 T18, 8 T13 and 22 45,X. Using a fetal fraction ≥4% to call results and a chromosomal ratio z-score of ≥3 to report a positive result, detection rates (DR), and false positive rates (FPR) were not statistically different between platforms: mean DR 99% (T21), 100%(T18, T13); 79%(45,X); FPR < 0.3% for T21, T18, T13, and <0.6% for 45,X. Both methods' negative predictive values in high-risk pregnancies were >99.8%, except for 45,X(>99.6%). Threshold analysis in high-risk pregnancies with different fetal fractions and z-score cut-offs suggested that a z-score cutoff to 3.5 for positive results improved test accuracy. Both sequencing platforms showed equivalent and excellent clinical validity.
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http://dx.doi.org/10.1038/s41431-019-0443-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871532PMC
November 2019

Whole exome sequencing identifies novel predisposing genes in neural tube defects.

Mol Genet Genomic Med 2019 01 10;7(1):e00467. Epub 2018 Nov 10.

IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Background: Neural tube defects (NTD) are among the most common defects affecting 1:1000 births. They are caused by a failure of neural tube closure during development. Their clinical presentation is diverse and dependent on the site and severity of the original defect on the embryonic axis. The etiology of NTD is multifactorial involving environmental factors and genetic variants that remain largely unknown.

Methods: We have conducted a whole exome sequencing (WES) study in five new NTD families and pooled the results with WES data from three NTD families and 43 trios that were previously investigated by our group. We analyzed the data using biased candidate gene and unbiased gene burden approaches.

Results: We identified four novel loss-of-function variants in three genes, MTHFR, DLC1, and ITGB1, previously associated with NTD. Notably, DLC1 carried two protein truncating variants in two independent cases. We also demonstrated an enrichment of variants in MYO1E involved in cytoskeletal remodeling. This enrichment reached borderline significance in a replication cohort supporting the association of this new candidate gene to NTD.

Conclusion: These data provide some key insights into the pathogenic mechanisms of human NTD and demonstrate the power of next-generation sequencing in deciphering the genetics of this complex trait.
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http://dx.doi.org/10.1002/mgg3.467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382446PMC
January 2019

Outcomes of extremely premature infants with twin-twin transfusion syndrome treated by laser therapy.

J Perinatol 2018 11 3;38(11):1548-1555. Epub 2018 Sep 3.

Department of Pediatrics, Division of Neonatology, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada.

Objective: To compare short-term and long-term outcomes of preterm infants born at <29 weeks of gestational age (GA) with twin-twin transfusion syndrome (TTTS) treated with laser therapy to preterm twin infants without TTTS.

Design: Retrospective case-control study comparing 33 preterm TTTS twins to 101 preterm diamniotic-dichorionic (di-di) twins born at our institution between 2006 and 2015.

Results: GA at birth were 26.4 ± 1.4 weeks (TTTS) and 26.9 ± 1.6 weeks (di-di) (p = 0.07). TTTS premature newborns were less exposed to antenatal steroids (p = 0.01), more frequently born by C-section (p = 0.005), received more surfactant therapy (p = 0.004, and were smaller for GA (p < 0.001). When adjusted for antenatal steroids and birth weight, TTTS status was not associated with increased mortality (HR 1.66, 95% CI 0.77-3.56, p = 0.20). No differences were found on neurodevelopmental outcomes at 18 months of corrected GA.

Conclusion: Premature TTTS newborns treated with fetal laser therapy had similar survival and neurodevelopmental outcomes compared to preterm di-di twins without TTTS.
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http://dx.doi.org/10.1038/s41372-018-0202-zDOI Listing
November 2018

F-isoprostanes and fatty acids profile in early pregnancy complicated by pre-existing diabetes.

Prostaglandins Leukot Essent Fatty Acids 2018 08 19;135:115-120. Epub 2018 Jul 19.

Axe endocrinologie et néphrologie, Centre de recherche du CHU de Québec-Université Laval, et Centre de recherche en endocrinologie, métabolisme et inflammation (CREMI), Université Laval, Québec G1V 4G2, Canada; Département de Kinésiologie, Faculté de médecine, Université Laval, Québec G1K 7P4, Canada. Electronic address:

Background: Diabetes and pregnancy are both associated with oxidative stress, characterized by an increase of F-isoprostanes from the non-enzymatic oxidation of arachidonic acid, a n - 6 polyunsaturated fatty acid (PUFA). We hypothesized that pregnant women with pre-existing diabetes will be characterized by elevated levels of specific F-isoPs isomers and altered PUFA composition in plasma early pregnancy when compared to normoglycemic controls.

Methods: Plasma samples from 23 women with uncomplicated pregnancies and 11 women with pre-existing diabetes in pregnancy were collected between 12 and 18 weeks of pregnancy (MIROS cohort). Six F-isoprostanes isomers were measured by high-performance liquid chromatography coupled to tandem mass spectrometry. Fatty acids concentrations in plasmatic phospholipids were measured by gas chromatography coupled to a flame ionization detector.

Results: F-isoprostanes, specifically the 8-iso-15(R)-PGFα levels, were 67% higher in diabetic than normoglycemic pregnancies (p = 0.026). The total n - 6 PUFA and arachidonic acid level did not differ between study groups. In contrast, total n - 3 level was 32% lower in diabetic pregnancies than in controls (p = 0.002); EPA(20:5) and DHA(22:6) being specifically reduced (p = 0.035 and p = 0.003 respectively). Delta-6-desaturase (D6D) activity index, calculated using fatty acid ratios, was 9% lower in pre-existing diabetes than in controls (p = 0.042).

Conclusions: Pre-existing diabetes in early pregnancy displays a distinctive F-isoprostanes profile when compared to other pathologies of pregnancy, such as preeclampsia, as previously assessed in the same cohort.
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http://dx.doi.org/10.1016/j.plefa.2018.07.008DOI Listing
August 2018

No. 363-Investigation and Management of Non-immune Fetal Hydrops.

J Obstet Gynaecol Can 2018 08;40(8):1077-1090

Montréal, QC.

Objective: To describe the current investigation and management of non-immune fetal hydrops with a focus on treatable or recurring etiologies.

Outcomes: To provide better counselling and management in cases of prenatally diagnosed non-immune hydrops.

Evidence: Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in 2017 using key words (non-immune hydrops fetalis, fetal hydrops, fetal therapy, fetal metabolism). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, observational studies, and significant case reports. Additional publications were identified from the bibliographies of these articles. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to September 2017. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinicalpractice guideline collections, clinical trial registries, and national and international medical specialty societies.

Benefits, Harms, And Costs: These guidelines educate readers about the causes of non-immune fetal hydrops and its prenatal counselling and management. It also provides a standardized approach to non-immune fetal hydrops, emphasizing the search for prenatally treatable conditions and recurrent genetic etiologies.

Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care.

Recommendations:
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http://dx.doi.org/10.1016/j.jogc.2017.12.011DOI Listing
August 2018

Large-for-Gestational-Age May Be Associated With Lower Fetal Insulin Sensitivity and β-Cell Function Linked to Leptin.

J Clin Endocrinol Metab 2018 10;103(10):3837-3844

Sainte-Justine Hospital Research Center, University of Montreal, Montreal, Quebec, Canada.

Context: Fetal overgrowth is associated with increased risk for type 2 diabetes in adulthood. It is unclear whether there are alterations in insulin sensitivity and β-cell function in early life.

Objective: To determine whether large-for-gestational-age (LGA) (birth weight > 90th percentile), an indicator of fetal overgrowth, is associated with altered fetal insulin sensitivity and β-cell function.

Study Design, Population, And Outcomes: In the Design, Development, and Discover birth cohort in Canada, we studied 106 pairs of LGA and optimal-for-gestational-age (OGA; birth weight, 25th to 75th percentiles) infants matched by maternal ethnicity, smoking status, and gestational age. Cord plasma glucose-to-insulin ratio was used as an indicator of fetal insulin sensitivity, and proinsulin-to-insulin ratio was used as an indicator of β-cell function. Cord plasma leptin and high-molecular-weight (HMW) adiponectin concentrations were measured.

Results: Comparisons of infants who were born LGA vs OGA, adjusted for maternal and newborn characteristics, showed that cord blood insulin, proinsulin, and leptin concentrations were significantly higher, whereas HWM adiponectin concentrations were similar. Glucose-to-insulin ratios were significantly lower (15.4 ± 28.1 vs 22.0 ± 24.9; P = 0.004), and proinsulin-to-insulin ratios significantly higher (0.73 ± 0.82 vs 0.60 ± 0.78; P = 0.005) in LGA vs OGA newborns, indicating lower insulin sensitivity and β-cell function in LGA newborns. These significant differences were almost unchanged after further adjustment for cord blood adiponectin levels but disappeared upon additional adjustment for cord blood leptin levels.

Conclusions: This study demonstrates that LGA may be associated with decreases in both fetal insulin sensitivity and β-cell function. The alterations appear to be linked to elevated leptin levels.
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http://dx.doi.org/10.1210/jc.2018-00917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179169PMC
October 2018

N° 363 - Évaluation et prise en charge de l'anasarque fœtoplacentaire non immune.

J Obstet Gynaecol Can 2018 08 3;40(8):1091-1107. Epub 2018 Jul 3.

Montréal (Qc).

Objectif: Décrire les méthodes actuelles d'évaluation et de prise en charge de l'anasarque fœtoplacentaire non immune en mettant l'accent sur les étiologies traitables ou récurrentes. RéSULTATS: Offrir de meilleurs services de conseil et de prise en charge en cas d'anasarque fœtoplacentaire non immune diagnostiquée en période prénatale. DONNéES: La littérature publiée a été récupérée au moyen de recherches menées dans PubMed, MEDLINE, CINAHL, et la Bibliothèque Cochrane en 2017 à l'aide de mots-clés (« non-immune hydrops fetalis », « fetal hydrops », « fetal therapy », « fetal metabolism »). Les articles retenus portaient sur des revues systématiques, des essais cliniques contrôlés, randomisés ou non, des études observationnelles et des études de cas importantes. D'autres publications ont été repérées dans les bibliographies de ces articles. Aucune restriction de date ou de langue n'a été employée. Les recherches ont été mis à jour régulièrement, et les résultats ont été incorporés à la directive clinique jusqu'en septembre 2017. Nous avons également tenu compte de la littérature grise (non publiée) trouvée sur les sites Web d'organismes d'évaluation des technologies de la santé et d'autres organismes liés aux technologies de la santé, dans des collections de directives cliniques et des registres d'essais cliniques, et obtenue auprès d'associations nationales et internationales de médecins spécialistes. AVANTAGES, INCONVéNIENTS ET COûTS: La présente directive clinique renseigne les lecteurs sur les causes de l'anasarque fœtoplacentaire non immune ainsi que sur son évaluation et sa prise en charge. Elle propose également une approche standardisée d'évaluation et de prise en charge, et met l'accent sur la recherche des conditions traitables en période prénatale et des étiologies génétiques récurrentes.

Valeurs: La qualité des données probantes a été évaluée en fonction des critères décrits dans le rapport du Groupe d'étude canadien sur les soins de santé préventifs. RECOMMANDATIONS.
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http://dx.doi.org/10.1016/j.jogc.2018.06.005DOI Listing
August 2018

Maternal Circulating Placental Growth Factor and Neonatal Metabolic Health Biomarkers in Small for Gestational Age Infants.

Front Endocrinol (Lausanne) 2018 25;9:198. Epub 2018 Apr 25.

Department of Obstetrics and Gynecology, University of Sherbrooke, Sherbrooke, QC, Canada.

Small for gestational age (SGA) infants are at increased risk of type 2 diabetes in adulthood. It is unknown whether any prenatal biomarkers are helpful for identifying SGA infants with altered metabolic health profile at birth or later life. In a nested study of 162 SGA (birth weight < 10th percentile) and 161 optimal birth weight (25th-75th percentiles) control infants in the 3D (design, develop and discover) birth cohort in Canada, we assessed whether maternal circulating placental growth factor (PlGF), a biomarker of placental function, is associated with metabolic health biomarkers in SGA infants. Main outcomes were cord plasma insulin, proinsulin, insulin-like growth factor-I (IGF-I), leptin, and high-molecular weight (HMW) adiponectin concentrations. Maternal PlGF concentrations at 32-35 weeks of gestation were substantially lower in SGA versus control infants ( < 0.001), so as were cord plasma proinsulin ( = 0.005), IGF-I ( < 0.001), leptin ( < 0.001), and HMW adiponectin ( = 0.002) concentrations. In SGA infants with both low (<25th percentile) and normal maternal PlGF concentrations, cord plasma IGF-I and leptin concentrations were lower than control infants, but the decreases were to a greater extent in SGA infants with low maternal PlGF. Cord blood leptin levels were lower comparing SGA infants with low vs. normal maternal PlGF levels ( = 0.01). SGA infants with low maternal circulating PlGF levels at late gestation were characterized by greater decreases in cord blood IGF-I and leptin concentrations. Maternal circulating PlGF appears to be associated with neonatal metabolic health profile in SGA infants.
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http://dx.doi.org/10.3389/fendo.2018.00198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996905PMC
April 2018

Association of pre-eclampsia with SOD2 Ala16Val polymorphism among mother-father-infant triads.

Int J Gynaecol Obstet 2018 Aug 30;142(2):221-227. Epub 2018 May 30.

Department of Obstetrics and Gynecology, Sainte-Justine Hospital Research Center, University of Montreal, Montreal, QC, Canada.

Objective: To determine whether pre-eclampsia is associated with polymorphisms in superoxide dismutase (SOD) genes among mother-father-infant triads.

Methods: We did this follow-up cohort study at 17 urban hospitals in Canada between October 1, 2008, and September 30, 2010. We recruited Canadian participants who had participated in the International Trial of Antioxidant Supplementation for the Prevention of Pre-eclampsia. Saliva specimens were collected for DNA extraction. The SOD1 +35A/C (rs2234694) and SOD2 Ala16Val C/T (rs4880) single-nucleotide polymorphisms (SNPs) were genotyped.

Results: Dual presence of the SOD2 Ala16Val TT variant among mother-father pairs (n=657) was associated with an increased risk of pre-eclampsia when compared with the absence of the TT variant among the mother-father pairs (7/48 [14.6%] vs 11/339 [3.2%]; adjusted odds ratio 6.80, 95% confidence interval 2.32-19.95; P<0.001). By contrast, presence of a single T variant in mother-father pairs (16/270 [5.9%]) or mother-infant pairs (8/179 [4.5%]) was not associated with pre-eclampsia. The SOD1 +35A/CSNP was not associated with pre-eclampsia.

Conclusion: The SOD2 Ala16Val SNP might be involved in paternal influence on the maternal predisposition to pre-eclampsia. Genotyping of mother-father pairs could be a promising strategy to identify pre-eclampsia genes.
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http://dx.doi.org/10.1002/ijgo.12528DOI Listing
August 2018

Factors associated to early intrauterine fetal demise after laser for TTTS by preoperative fetal heart and Doppler ultrasound.

Prenat Diagn 2018 06 6;38(7):523-530. Epub 2018 Jun 6.

Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, CHU Sainte-Justine, Montreal University, Montreal, Québec, Canada.

Objective: To determine the prognostic value of fetal Doppler and echocardiographic parameters for intrauterine fetal demise (IUFD) within 24 hours and within 1 week after laser coagulation in monochorionic pregnancies complicated by twin-twin transfusion syndrome.

Method: This retrospective study correlated the preoperative hemodynamic and echocardiography parameters to the outcome in fetuses with twin-twin transfusion syndrome undergoing laser therapy.

Results: One hundred and twelve laser coagulations were performed between February 2006 and June 2015. The total (single and double) IUFD rate was 27.7%. Further, 59% of IUFD occurred within 24 hours and 74.4% occurred within 1 week after laser. The following were associated to IUFD within 24 hours: the middle cerebral arterial pulsatility index in the donor, abnormal umbilical artery (UA) end diastolic flow, increased middle cerebral artery peak systolic velocity, and right ventricular myocardial performance index (RV-MPI) z-score in the recipient. For IUFD within 1 week were the pulsatility index in the donor UA and the recipient abnormalities in UA, ductus venosus, middle cerebral artery-peak systolic velocity, and RV-MPI z-score.

Conclusion: Following laser was early IUFD that was associated with Doppler findings suggesting donor cerebroplacental redistribution, and recipient overload cardiomyopathy, such as abnormal ductus venosus and UA Dopplers as well as an increase of RV-MPI.
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http://dx.doi.org/10.1002/pd.5280DOI Listing
June 2018

Hypertension Canada's 2018 Guidelines for the Management of Hypertension in Pregnancy.

Can J Cardiol 2018 05 1;34(5):526-531. Epub 2018 Mar 1.

Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada; O'Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada; Departments of Medicine, Obstetrics and Gynecology, and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.

We present Hypertension Canada's inaugural evidence-based Canadian recommendations for the management of hypertension in pregnancy. Hypertension in pregnancy is common, affecting approximately 7% of pregnancies in Canada, and requires effective management to reduce maternal, fetal, and newborn complications. Because of this importance, these guidelines were developed in partnership with the Society of Obstetricians and Gynaecologists of Canada with the main common objective of improving the management of women with hypertension in pregnancy. Guidelines for the diagnosis, assessment, prevention, and treatment of hypertension in adults and children are published separately. In this first Hypertension Canada guidelines for hypertension in pregnancy, 7 recommendations for the management of nonsevere and severe hypertension in pregnancy are presented. For nonsevere hypertension in pregnancy (systolic blood pressure 140-159 mm Hg and/or diastolic blood pressure 80-109 mm Hg), we provide guidance for the threshold for initiation of antihypertensive therapy, blood pressure targets, as well as first- and second-line antihypertensive medications. Severe hypertension (systolic blood pressure ≥ 160 mm Hg and/or diastolic blood pressure ≥ 110 mm Hg) requires urgent antihypertensive therapy to reduce maternal, fetal, and newborn adverse outcomes. The specific evidence and rationale underlying each of these guidelines are discussed.
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http://dx.doi.org/10.1016/j.cjca.2018.02.021DOI Listing
May 2018

Au-delà de l'aneuploïdie : pour une approche canadienne moderne en matière de dépistage prénatal.

J Obstet Gynaecol Can 2018 Mar;40(3):276-278

Département d'obstétrique et de gynécologie, Faculté de médecine, CHU Sainte-Justine Université de Montréal, Montréal (Qc).

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http://dx.doi.org/10.1016/j.jogc.2018.01.013DOI Listing
March 2018

Beyond Fetal Aneuploidy: A Call For A Contemporary Canadian Approach To Prenatal Screening.

J Obstet Gynaecol Can 2018 Mar;40(3):273-275

Department of Obstetrics and Gynecology, Faculty of Medicine, CHU Sainte-Justine Université de Montréal, Montréal, QC.

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http://dx.doi.org/10.1016/j.jogc.2018.01.006DOI Listing
March 2018

Effect of maternal age on the risk of preterm birth: A large cohort study.

PLoS One 2018 31;13(1):e0191002. Epub 2018 Jan 31.

Division of Obstetric Medicine, Department of Obstetrics and Gynecology CHU Sainte Justine, Montréal, Québec, Canada.

Background: Maternal age at pregnancy is increasing worldwide as well as preterm birth. However, the association between prematurity and advanced maternal age remains controversial.

Objective: To evaluate the impact of maternal age on the occurrence of preterm birth after controlling for multiple known confounders in a large birth cohort.

Study Design: Retrospective cohort study using data from the QUARISMA study, a large Canadian randomized controlled trial, which collected data from 184,000 births in 32 hospitals. Inclusion criteria were maternal age over 20 years. Exclusion criteria were multiple pregnancy, fetal malformation and intra-uterine fetal death. Five maternal age categories were defined and compared for maternal characteristics, gestational and obstetric complications, and risk factors for prematurity. Risk factors for preterm birth <37 weeks, either spontaneous or iatrogenic, were evaluated for different age groups using multivariate logistic regression.

Results: 165,282 births were included in the study. Chronic hypertension, assisted reproduction techniques, pre-gestational diabetes, invasive procedure in pregnancy, gestational diabetes and placenta praevia were linearly associated with increasing maternal age whereas hypertensive disorders of pregnancy followed a "U" shaped distribution according to maternal age. Crude rates of preterm birth before 37 weeks followed a "U" shaped curve with a nadir at 5.7% for the group of 30-34 years. In multivariate analysis, the adjusted odds ratio (aOR) of prematurity stratified by age group followed a "U" shaped distribution with an aOR of 1.08 (95%CI; 1.01-1.15) for 20-24 years, and 1.20 (95% CI; 1.06-1.36) for 40 years and older. Confounders found to have the greatest impact were placenta praevia, hypertensive complications, and maternal medical history.

Conclusion: Even after adjustment for confounders, advanced maternal age (40 years and over) was associated with preterm birth. A maternal age of 30-34 years was associated with the lowest risk of prematurity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791955PMC
February 2018

Prenatal vitamin D status and offspring's growth, adiposity and metabolic health: a systematic review and meta-analysis.

Br J Nutr 2018 02 11;119(3):310-319. Epub 2018 Jan 11.

1Centre hospitalier universitaire Sainte-Justine Research Center,Montreal,QC H3T 1C5,Canada.

In this systematic review and meta-analysis of observational studies, we aimed to estimate the associations between prenatal vitamin D status and offspring growth, adiposity and metabolic health. We searched the literature in human studies on prenatal vitamin D status and offspring growth in PubMed, up to July 2017. Studies were selected according to their methodological quality and outcomes of interest (anthropometry, fat mass and diabetes in offspring). The inverse variance method was used to calculate the pooled mean difference (MD) with 95 % CI for continuous outcomes, and the Mantel-Haenszel method was used to calculate the pooled OR with 95 % CI for dichotomous outcomes. In all, thirty observational studies involving 35 032 mother-offspring pairs were included. Vitamin D status was evaluated by circulating 25-hydroxyvitamin D (25(OH)D) level. Low vitamin D status was based on each study's cut-off for low 25(OH)D levels. Low prenatal vitamin D levels were associated with lower birth weight (g) (MD -100·69; 95 % CI -162·25, -39·13), increased risk of small-for-gestational-age (OR 1·55; 95 % CI 1·16, 2·07) and an elevated weight (g) in infant at the age of 9 months (g) (MD 119·75; 95 % CI 32·97, 206·52). No associations were observed between prenatal vitamin D status and other growth parameters at birth, age 1 year, 4-6 years or 9 years, nor with diabetes type 1. Prenatal vitamin D may play a role in infant adiposity and accelerated postnatal growth. The effects of prenatal vitamin D on long-term metabolic health outcomes in children warrant future studies.
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http://dx.doi.org/10.1017/S0007114517003646DOI Listing
February 2018

Vitamin A and E Nutritional Status in Relation to Leptin, Adiponectin, IGF-I and IGF-II in Early Life - a Birth Cohort Study.

Sci Rep 2018 01 8;8(1):100. Epub 2018 Jan 8.

Department of Nutrition, Sainte-Justine Hospital Research Center, University of Montreal, Montreal, H3T 1C5, Canada.

The metabolic health effects of vitamin A and E nutritional status in early life are largely unknown. We assessed whether vitamin A and vitamin E nutritional status may affect circulating leptin, adiponectin, insulin-like growth factor (IGF)-I and IGF-II levels in early life in humans. In a singleton birth cohort (n = 248), vitamin A and E nutritional status in fetuses/newborns were assessed by cord plasma concentrations of retinol, β-carotene, α- and γ-tocopherols. The primary outcomes were cord plasma leptin, adiponectin, IGF-I and IGF-II concentrations. Cord plasma retinol was significantly positively correlated to IGF-I in girls (r = 0.42, P < 0.0001) but not in boys (r = 0.14, P = 0.11). Adjusting for maternal and newborn's characteristics, one log unit increase in cord plasma retinol was associated with a 28.0% (95% CI: 11.1-47.5%) increase in IGF-I in girls (P < 0.001) but not in boys (P = 0.75). One log unit increment in cord plasma α-tocopherol was associated with a 6.6% (0.4-12.3%) decrease in adiponectin (P = 0.04), while one log unit increment in cord plasma γ-tocopherol was associated with a 21.2% (4.7-34.8%) decrease in leptin (P = 0.01). There may be a sex-specific association between retinol and IGF-I, a negative association between α-tocopherol and adiponectin, and a negative association between γ-tocopherol and leptin in early life in humans.
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http://dx.doi.org/10.1038/s41598-017-18531-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758521PMC
January 2018

Genomic study of severe fetal anomalies and discovery of GREB1L mutations in renal agenesis.

Genet Med 2018 07 26;20(7):745-753. Epub 2017 Oct 26.

CHU Sainte-Justine, Montreal, Quebec, Canada.

Purpose: Fetal anomalies represent a poorly studied group of developmental disorders. Our objective was to assess the impact of whole-exome sequencing (WES) on the investigation of these anomalies.

Methods: We performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies, including renal a/dysgenesis, VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities), brain anomalies, suspected ciliopathies, multiple major malformations, and akinesia.

Results: A molecular diagnosis was obtained in 19 cases (19%). In 13 of these cases, the diagnosis was not initially suspected by the clinicians because the phenotype was nonspecific or atypical, corresponding in some cases to the severe end of the spectrum of a known disease (e.g., MNX1-, RYR1-, or TUBB-related disorders). In addition, we identified likely pathogenic variants in genes (DSTYK, ACTB, and HIVEP2) previously associated with phenotypes that were substantially different from those found in our cases. Finally, we identified variants in novel candidate genes that were associated with perinatal lethality, including de novo mutations in GREB1L in two cases with bilateral renal agenesis, which represents a significant enrichment of such mutations in our cohort.

Conclusion: Our study opens a window on the distinctive genetic landscape associated with fetal anomalies and highlights the power-but also the challenges-of WES in prenatal diagnosis.
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http://dx.doi.org/10.1038/gim.2017.173DOI Listing
July 2018

Comparison of first-tier cell-free DNA screening for common aneuploidies with conventional publically funded screening.

Prenat Diagn 2017 12 21;37(12):1238-1244. Epub 2017 Nov 21.

Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, Québec City, Quebec, Canada.

Objective: This study evaluates the impact of offering cell-free DNA (cfDNA) screening as a first-tier test for trisomies 21 and 18.

Methods: This is a prospective study of pregnant women undergoing conventional prenatal screening who were offered cfDNA screening in the first trimester with clinical outcomes obtained on all pregnancies.

Results: A total of 1198 pregnant women were recruited. The detection rate of trisomy 21 with standard screening was 83% with a false positive rate (FPR) of 5.5% compared with 100% detection and 0% FPR for cfDNA screening. The FPR of cfDNA screening for trisomies 18 and 13 was 0.09% for each. Two percent of women underwent an invasive diagnostic procedure based on screening or ultrasound findings; without the cfDNA screening, it could have been as high as 6.8%. Amongst the 640 women with negative cfDNA results and a nuchal translucency (NT) ultrasound, only 3 had an NT greater or equal to 3.5 mm: one had a normal outcome and two lost their pregnancy before 20 weeks.

Conclusions: cfDNA screening has the potential to be a highly effective first-tier screening approach leading to a significant reduction of invasive diagnostic procedures. For women with a negative cfDNA screening result, NT measurement has limited clinical utility.
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http://dx.doi.org/10.1002/pd.5174DOI Listing
December 2017
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