Screening and testing practices for Lynch syndrome in Nova Scotians with endometrial cancer: a descriptive study.

BACKGROUND: Identifying people with Lynch syndrome, a genetic condition predisposing those affected to colorectal, endometrial and other cancers, allows for implementation of risk-reducing strategies for patients and their families. The goal of this study was to describe screening and testing practices for this condition among people with endometrial cancer in Nova Scotia, Canada, and to determine the prevalence of Lynch syndrome in this population. METHODS: All patients diagnosed with endometrial cancer in Nova Scotia between May 1, 2017, and Apr. 30, 2020 were identified through a provincial gynecologic oncology database. Patients from out of province were excluded. We collected age, body mass index, tumour mismatch repair protein immunohistochemistry results, personal and family histories, and germline testing information for all patients. RESULTS: We identified 465 people diagosed with endometrial cancer during the study period. Most were aged 51 years or older, and had obesity and low-grade early-stage endometrioid tumours. Tumour immunohistochemistry testing was performed in 444 cases (95.5%). Based on local criteria, 189 patients were eligible for genetic counselling, of whom 156 (82.5%) were referred to medical genetics. Of the 98 patients who underwent germline testing, 9 (9.2%) were diagnosed with Lynch syndrome. INTERPRETATION: The prevalence of Lynch syndrome was at least 1.9% (9/465) in this population. Our results illustrate successful implementation of universal tumour testing; however, there remains a gap in access to genetic counselling.

Epidemiology of spinal muscular atrophy caused by SMN1 deletions in Maritime Canada.

Spinal muscular atrophy (SMA), caused primarily by deletions in SMN1, leads to progressive loss of lower motor neurons. Newborn screening for SMA is under consideration for the Maritime Newborn Screening Program. The incidence of this disease has not been explored in Maritime Canada which includes the provinces of Nova Scotia (NS), New Brunswick (NB), and Prince Edward Island (PEI). In this retrospective chart review, patients were identified from the IWK Clinical Genomics Lab and Maritime Medical Genetics Service databases for SMN1 genetic testing between 2000 and 2020. The incidence of SMA in Maritime Canada was 1:11,900. Among patients born between 2000 and 2020, NB and PEI had lower proportions of type 1 SMA (12% and 0%, respectively) when compared to NS (50%). The majority of type 1 patients had 2 copies of SMN2, the majority of type 2 patients had 3 copies, and the majority of type 3 patients had 4 copies. There was a delay to molecular diagnosis for all subtypes, longest in type 3. This study provides the best available SMA epidemiology in Maritime Canada and expands our understanding of the pattern of disease severity relative to SMN2 copy number in this region.

Clinical application of fetal genome-wide sequencing during pregnancy: position statement of the Canadian College of Medical Geneticists.

PURPOSE AND SCOPE: The aim of this position statement is to provide recommendations for Canadian healthcare professionals regarding the use of genome-wide sequencing (GWS) in the context of diagnostic testing of the fetus during pregnancy. This statement was developed to facilitate clinical translation of GWS as a prenatal diagnostic test and the development of best practices in Canada, but the applicability of this document is broader and aims to help professionals in other healthcare systems. METHODS OF STATEMENT DEVELOPMENT: A multidisciplinary group was assembled to review existing literature on fetal GWS for genetic diagnosis in the context of suspected monogenic diseases and to make recommendations relevant to the Canadian context. The statement was circulated for comments to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors on 19 February 2021. RESULTS AND CONCLUSIONS: The use of prenatal GWS is indicated for the investigation of multiple fetal anomalies. Its use in the context of isolated fetal anomaly should be guided by available resources and current evidence, which is continually changing. During pregnancy, GWS should be ordered by, or in collaboration with, a medical geneticist. It should be used following detailed phenotyping to interrogate known disease genes, preferably using a trio approach, following detailed fetal phenotyping. Testing should be done with an overall aim to help in the management of the pregnancy, delivery and postnatal care. It should be guided by personal utility of the test for the pregnant person and clinical utility for pregnancy and birth management, as outlined herein. Genetic counselling is crucial in making the parental decision an informed decision. Chromosomal microarray analysis should be completed in parallel or prior to GWS and should be preceded by Quantitative Fluorescent PCR (QF-PCR) for detection of common aneuploidies. In normal circumstances, only pathogenic and likely pathogenic variants with a high likelihood of being associated with the identified fetal anomalies should be reported. Reporting of secondary findings, defined as purposeful analysis of variants in a set of medically actionable genes, should not, by default, be performed in the prenatal context. Laboratories should only report incidental findings that reveal risk of a significant Mendelian condition during infancy and childhood. Should a laboratory have a policy for reporting incidental findings in medically actionable adult-onset conditions, they should only be reported with explicit opt-in consent signed by the tested individuals. Genetic counselling is crucial in disclosing the test results and the implications the results may have for the fetus. It should be emphasised that negative results do not rule out a genetic diagnosis nor guarantee a good prognosis. Postnatal phenotyping and reanalysis of existing data should be considered. Families should be given the opportunity to participate in research studies as appropriate. These recommendations will be routinely re-evaluated as knowledge of the diagnostic and clinical utility of fetal GWS during pregnancy improves.

The Effect of Fetal Trisomy 21 on Adverse Perinatal Obstetrical Outcomes in Nova Scotia, 2000-2019.

OBJECTIVE: To understand the risks associated with trisomy 21 in pregnancy in order to inform obstetrical care and improve outcomes. METHODS: A population-based retrospective cohort study was undertaken of all pregnancies involving a fetus with trisomy 21 in Nova Scotia, Canada, from 2000 to 2019. Cases were identified from the provincial laboratory genetics database, linked to the Nova Scotia Atlee Perinatal Database for pregnancy outcomes, and compared with the general obstetrical population. RESULTS: A total of 350 pregnancies were identified, of which 23% were ongoing pregnancies in which trisomy 21 was diagnosed prenatally and 24% involved diagnoses made after delivery. Compared with the general obstetrical population, women with ongoing pregnancies affected by trisomy 21 were more likely to be older (mean age 34 vs. 29 y), multiparous (67% vs. 55%), and in a relationship (79% vs. 68%). Trisomy 21 was associated with a significantly increased risk of preterm birth (<37 weeks; 24.1% vs. 8.3%); small for gestational age (<10th percentile; 21.7% vs. 8.2%); cesarean delivery (31.5% vs. 27.1%); and combined perinatal/neonatal mortality (8.0% vs. 0.8%) (P < 0.001 for all). CONCLUSION: Trisomy 21 is associated with significant adverse perinatal and neonatal risks. Population screening to identify trisomy 21 can be used to optimize perinatal outcomes with appropriate fetal surveillance in these pregnancies.

Molar and nonmolar triploidy: Recurrence or bad luck.

In triploid pregnancies, the parental origin of the extra genome determines the phenotype and placental and fetal outcomes. Molecular genetics and placental pathology enable differentiation of molar vs nonmolar pregnancy to guide future planning.

Fetal Exome Sequencing on the Horizon.

Prenatal whole exome sequencing has recently been introduced. It is evolving and although not currently ready for everyday clinical practice, it will likely become part of the diagnostic arsenal available to clinicians caring for couples carrying a pregnancy for which fetal anomalies have been identified. This commentary discusses what it is, its indications, its benefits, and its limitations.

Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada.

BACKGROUND: The aim of this guideline is to provide updated recommendations for Canadian genetic counsellors, medical geneticists, maternal fetal medicine specialists, clinical laboratory geneticists and other practitioners regarding the use of chromosomal microarray analysis (CMA) for prenatal diagnosis. This guideline replaces the 2011 Society of Obstetricians and Gynaecologists of Canada (SOGC)-Canadian College of Medical Geneticists (CCMG) Joint Technical Update. METHODS: A multidisciplinary group consisting of medical geneticists, genetic counsellors, maternal fetal medicine specialists and clinical laboratory geneticists was assembled to review existing literature and guidelines for use of CMA in prenatal care and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the CCMG membership-at-large for feedback and, following incorporation of feedback, was approved by the CCMG Board of Directors on 5 June 2017 and the SOGC Board of Directors on 19 June 2017. RESULTS AND CONCLUSIONS: Recommendations include but are not limited to: (1) CMA should be offered following a normal rapid aneuploidy screen when multiple fetal malformations are detected (II-1A) or for nuchal translucency (NT) ≥3.5 mm (II-2B) (recommendation 1); (2) a professional with expertise in prenatal chromosomal microarray analysis should provide genetic counselling to obtain informed consent, discuss the limitations of the methodology, obtain the parental decisions for return of incidental findings (II-2A) (recommendation 4) and provide post-test counselling for reporting of test results (III-A) (recommendation 9); (3) the resolution of chromosomal microarray analysis should be similar to postnatal microarray platforms to ensure small pathogenic variants are detected. To minimise the reporting of uncertain findings, it is recommended that variants of unknown significance (VOUS) smaller than 500 Kb deletion or 1 Mb duplication not be routinely reported in the prenatal context. Additionally, VOUS above these cut-offs should only be reported if there is significant supporting evidence that deletion or duplication of the region may be pathogenic (III-B) (recommendation 5); (4) secondary findings associated with a medically actionable disorder with childhood onset should be reported, whereas variants associated with adult-onset conditions should not be reported unless requested by the parents or disclosure can prevent serious harm to family members (III-A) (recommendation 8).The working group recognises that there is variability across Canada in delivery of prenatal testing, and these recommendations were developed to promote consistency and provide a minimum standard for all provinces and territories across the country (recommendation 9).

Incidence and Carrier Frequency of CFTR Gene Mutations in Pregnancies With Echogenic Bowel in Nova Scotia and Prince Edward Island.

OBJECTIVE: Fetal echogenic bowel (echogenic bowel) is associated with cystic fibrosis (CF), with a reported incidence ranging from 1% to 13%. Prenatal testing for CF in the setting of echogenic bowel can be done by screening parental or fetal samples for pathogenic CFTR variants. If only one pathogenic variant is identified, sequencing of the CFTR gene can be undertaken, to identify a second pathogenic variant not covered in the standard screening panel. Full gene sequencing, however, also introduces the potential to identify variants of uncertain significance (VUSs) that can create counselling challenges and cause parental anxiety. To provide accurate counselling for families in the study population, the incidence of CF associated with echogenic bowel and the carrier frequency of CFTR variants were investigated. METHODS: All pregnancies for which CF testing was undertaken for the indication of echogenic bowel (from Nova Scotia and Prince Edward Island) were identified (January 2007-July 2017). The CFTR screening and sequencing results were reviewed, and fetal outcomes related to CF were assessed. RESULTS: A total of 463 pregnancies with echogenic bowel were tested. Four were confirmed to be affected with CF, giving an incidence of 0.9% in this cohort. The carrier frequency of CF among all parents in the cohort was 5.0% (1 in 20); however, when excluding parents of affected fetuses, the carrier frequency for the population was estimated at 4.1% (1 in 25). CFTR gene sequencing identified an additional VUS in two samples. CONCLUSION: The incidence of CF in pregnancies with echogenic bowel in Nova Scotia and Prince Edward Island is 0.9%, with an estimated population carrier frequency of 4.1%. These results provide the basis for improved counselling to assess the risk of CF in the pregnancy, after parental carrier screening, using Bayesian probability. Counselling regarding VUSs should be undertaken before gene sequencing.

Factors Associated with Trial of Labour and Mode of Delivery in Robson Group 5: A Select Group of Women With Previous Caesarean Section.

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.

Adverse Perinatal Conditions Associated With Prenatally Detected Fetal Echogenic Bowel in Nova Scotia.

OBJECTIVE: This study sought to estimate the association of adverse perinatal outcomes with pregnancies complicated by fetal echogenic bowel. METHODS: Data for pregnancies complicated with echogenic bowel identified in the second trimester were derived from the tertiary referral IWK Health Centre (Halifax, NS) Viewpoint Ultrasound Database augmented by medical chart review. The study was undertaken between 2003 and 2014. Rates of positive cytomegalovirus and toxoplasmosis infection were determined using maternal serology and amniocentesis results. Rates of intrauterine growth restriction, abnormal karyotype, cystic fibrosis, antenatal bleeding, and bowel abnormalities were also determined. Neonatal information included newborn urine culture results and postnatal genetic testing. Univariate analyses compared rates of infection with isolated echogenic bowel and echogenic bowel with other ultrasound findings, with statistical significance set at P <0.05. RESULTS: There were 422 pregnancies identified prenatally with echogenic bowel (82% had isolated echogenic bowel). Of these, 92 (22%) had at least one of the foregoing associated abnormalities. Three percent of women had serologic test results positive for cytomegalovirus or toxoplasmosis, with <1% documented newborn infections. Cystic fibrosis and other genetic diagnoses were observed in 8%, intrauterine growth restriction in 14%, antenatal bleeding in 19%, and bowel abnormalities in 3% of the cases of echogenic bowel. Pregnancies with isolated echogenic bowel had an 80% reduction in risk for these significant outcomes, in contrast to a four- to 11-fold increased risk of specific outcomes when additional ultrasound findings were present. CONCLUSION: An overall rate of adverse conditions of 22% with prenatally detected echogenic bowel serves to inform women and health care providers and emphasizes the importance of careful screening fetal ultrasound studies and timely referral for comprehensive assessment with findings of echogenic bowel for evaluation for associated findings.

Association Between Factor V Leiden Mutation, Small for Gestational Age, and Preterm Birth: A Systematic Review and Meta-Analysis.

OBJECTIVE: To estimate the association of a maternal factor V Leiden (FVL) mutation with SGA and preterm birth. DATA SOURCES: We performed a search of PubMed, Embase, Scopus, CINAHL, and the Cochrane Library from inception to April 2016 for cohort and case-control studies of women with FVL mutation and associated outcomes of SGA and preterm birth that included a reference group without FVL mutation. Additional studies were identified from reference lists of relevant research and review articles. STUDY SELECTION: Two authors (JKB, AMO) independently examined the abstracts of the potentially eligible studies, and full texts of eligible studies were retrieved for further evaluation. Disagreements were resolved by consensus. We identified 42 studies suitable for inclusion in the meta-analysis. DATA EXTRACTION: Thirty-two studies evaluated SGA, and 18 studies assessed preterm birth. Study quality was assessed using the Newcastle Ottawa Scale. A random effects model with inverse variance weighting was used to calculate pooled ORs and 95% CIs. Subgroup analyses were performed by study design. DATA SYNTHESIS: The overall OR associating FVL mutation with SGA was significant (OR 1.40, 95% CI 1.18 to 1.67). Analysis of 13 cohort studies resulted in an OR of 1.20 (95% CI 1.03 to 1.41), and data from 19 case-control studies yielded an OR of 1.86 (95% CI 1.35 to 2.56). There was no significant association between FVL mutation and preterm birth (OR 1.17, 95% CI 1.00 to 1.37) when all groups were studied, but the association was significant for case-control studies alone (OR 1.40, 95% CI 1.05 to 1.86). CONCLUSION: There is an increased risk for SGA in pregnancies complicated by FVL mutation in both cohort and case-control study designs. The risk of preterm birth with FVL mutation is less clear, although there is conflicting evidence from cohort and case-control studies regarding the risk of preterm birth associated with FVL mutation.

Joint SOGC-CCMG Opinion for Reproductive Genetic Carrier Screening: An Update for All Canadian Providers of Maternity and Reproductive Healthcare in the Era of Direct-to-Consumer Testing.

OBJECTIVE: This guideline was written to update Canadian maternity care and reproductive healthcare providers on pre- and postconceptional reproductive carrier screening for women or couples who may be at risk of being carriers for autosomal recessive (AR), autosomal dominant (AD), or X-linked (XL) conditions, with risk of transmission to the fetus. Four previous SOGC- Canadian College of Medical Geneticists (CCMG) guidelines are updated and merged into the current document. INTENDED USERS: All maternity care (most responsible health provider [MRHP]) and paediatric providers; maternity nursing; nurse practitioner; provincial maternity care administrator; medical student; and postgraduate resident year 1-7. TARGET POPULATION: Fertile, sexually active females and their fertile, sexually active male partners who are either planning a pregnancy or are pregnant (preferably in the first trimester of pregnancy, but any gestational age is acceptable). OPTIONS: Women and their partners will be able to obtain appropriate genetic carrier screening information and possible diagnosis of AR, AD, or XL disorders (preferably pre-conception), thereby allowing an informed choice regarding genetic carrier screening and reproductive options (e.g., prenatal diagnosis, preimplantation genetic diagnosis, egg or sperm donation, or adoption). OUTCOMES: Informed reproductive decisions related to genetic carrier screening and reproductive outcomes based on family history, ethnic background, past obstetrical history, known carrier status, or genetic diagnosis. SOGC REPRODUCTIVE CARRIER SCREENING SUMMARY STATEMENT (2016): Pre-conception or prenatal education and counselling for reproductive carrier screening requires a discussion about testing within the three perinatal genetic carrier screening/diagnosis time periods, which include pre-conception, prenatal, and neonatal for conditions currently being screened for and diagnosed. This new information should be added to the standard reproductive carrier screening protocols that are already being utilized by the most responsible maternity provider through the informed consent process with the patient. (III-A; GRADE low/moderate) SOGC OVERVIEW OF RECOMMENDATIONS QUALITY AND GRADE: There was a strong observational/expert opinion (quality and grade) for the genetic carrier literature with randomized controlled trial evidence being available only for the invasive testing. Both the Canadian Task Force on Preventive Health Care quality and classification and the GRADE evidence quality and grade are provided. EVIDENCE: MEDLINE; PubMed; government neonatal screening websites; key words/common reproductive genetic carrier screened diseases/previous SOGC Guidelines/medical academic societies (Society of Maternal-Fetal Medicine [SMFM]; American College of Medical Genetics and Genomics; American College of Obstetricians and Gynecologists [ACOG]; CCMG; Royal College Obstetrics and Gynaecology [RCOG] [UK]; American Society of Human Genetics [ASHG]; International Society of Prenatal Diagnosis [ISPD])/provincial neonatal screening policies and programs; search terms (carrier screening, prenatal screening, neonatal genetic/metabolic screening, cystic fibrosis (CF), thalassemia, hemoglobinopathy, hemophilia, Fragile X syndrome (FXS), spinal muscular atrophy, Ashkenazi Jewish carrier screening, genetic carrier screening protocols, AR, AD, XL). SEARCH PERIOD: 10 years (June 2005-September 2015); initial search dates June 30, 2015 and September 15, 2015; completed final search January 4, 2016. Validation of articles was completed by primary authors RD Wilson and I De Bie. BENEFITS, HARMS, AND COST: Benefits are to provide an evidenced based reproductive genetic carrier screening update consensus based on international opinions and publications for the use of Canadian women, who are planning a pregnancy or who are pregnant and have been identified to be at risk (personal or male partner family or reproductive history) for the transmission of a clinically significant genetic condition to their offspring with associated morbidity and/or mortality. Harm may arise from having counselling and informed testing of the carrier status of the mother, their partner, or their fetus, as well as from declining to have this counselling and informed testing or from not having the opportunity for counselling and informed testing. Costs will ensue both from the provision of opportunities for counselling and testing, as well as when no such opportunities are offered or are declined and the birth of a child with a significant inherited condition and resulting morbidity/mortality occurs; these comprise not only the health care costs to the system but also the social/financial/psychological/emotional costs to the family. These recommendations are based on expert opinion and have not been subjected to a health economics assessment and local or provincial implementation will be required. GUIDELINE UPDATE: This guideline is an update of four previous joint SOGC-CCMG Genetic Screening Guidelines dated 2002, 2006, 2008, and 2008 developed by the SOGC Genetic Committee in collaboration with the CCMG Prenatal Diagnosis Committee (now Clinical Practice Committee). 2016 CARRIER SCREENING RECOMMENDATIONS.

Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies.

OBJECTIVE: To provide updated information on the pre- and post-conception use of oral folic acid with or without a multivitamin/micronutrient supplement for the prevention of neural tube defects and other congenital anomalies. This will help physicians, midwives, nurses, and other health care workers to assist in the education of women about the proper use and dosage of folic acid/multivitamin supplementation before and during pregnancy. EVIDENCE: Published literature was retrieved through searches of PubMed, Medline, CINAHL, and the Cochrane Library in January 2011 using appropriate controlled vocabulary and key words (e.g., folic acid, prenatal multivitamins, folate sensitive birth defects, congenital anomaly risk reduction, pre-conception counselling). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from 1985 and June 2014. Searches were updated on a regular basis and incorporated in the guideline to June 2014 Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Costs, risks, and benefits: The financial costs are those of daily vitamin supplementation and eating a healthy folate-enriched diet. The risks are of a reported association of dietary folic acid supplementation with fetal epigenetic modifications and with an increased likelihood of a twin pregnancy. These associations may require consideration before initiating folic acid supplementation. The benefit of folic acid oral supplementation or dietary folate intake combined with a multivitamin/micronutrient supplement is an associated decrease in neural tube defects and perhaps in other specific birth defects and obstetrical complications. VALUES: The quality of evidence in the document was rated using the criteria described in the Report of the Canadian Task Force on Preventative Health Care (Table 1). Summary Statement In Canada multivitamin tablets with folic acid are usually available in 3 formats: regular over-the-counter multivitamins with 0.4 to 0.6 mg folic acid, prenatal over-the-counter multivitamins with 1.0 mg folic acid, and prescription multivitamins with 5.0 mg folic acid. (III) Recommendations 1. Women should be advised to maintain a healthy folate-rich diet; however, folic acid/multivitamin supplementation is needed to achieve the red blood cell folate levels associated with maximal protection against neural tube defect. (III-A) 2. All women in the reproductive age group (12-45 years of age) who have preserved fertility (a pregnancy is possible) should be advised about the benefits of folic acid in a multivitamin supplementation during medical wellness visits (birth control renewal, Pap testing, yearly gynaecological examination) whether or not a pregnancy is contemplated. Because so many pregnancies are unplanned, this applies to all women who may become pregnant. (III-A) 3. Folic acid supplementation is unlikely to mask vitamin B12 deficiency (pernicious anemia). Investigations (examination or laboratory) are not required prior to initiating folic acid supplementation for women with a risk for primary or recurrent neural tube or other folic acid-sensitive congenital anomalies who are considering a pregnancy. It is recommended that folic acid be taken in a multivitamin including 2.6 ug/day of vitamin B12 to mitigate even theoretical concerns. (II-2A) 4. Women at HIGH RISK, for whom a folic acid dose greater than 1 mg is indicated, taking a multivitamin tablet containing folic acid, should be advised to follow the product label and not to take more than 1 daily dose of the multivitamin supplement. Additional tablets containing only folic acid should be taken to achieve the desired dose. (II-2A) 5. Women with a LOW RISK for a neural tube defect or other folic acid-sensitive congenital anomaly and a male partner with low risk require a diet of folate-rich foods and a daily oral multivitamin supplement containing 0.4 mg folic acid for at least 2 to 3 months before conception, throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues. (II-2A) 6. Women with a MODERATE RISK for a neural tube defect or other folic acid-sensitive congenital anomaly or a male partner with moderate risk require a diet of folate-rich foods and daily oral supplementation with a multivitamin containing 1.0 mg folic acid, beginning at least 3 months before conception. Women should continue this regime until 12 weeks' gestational age. (1-A) From 12 weeks' gestational age, continuing through the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues, continued daily supplementation should consist of a multivitamin with 0.4 to 1.0 mg folic acid. (II-2A) 7. Women with an increased or HIGH RISK for a neural tube defect, a male partner with a personal history of neural tube defect, or history of a previous neural tube defect pregnancy in either partner require a diet of folate-rich foods and a daily oral supplement with 4.0 mg folic acid for at least 3 months before conception and until 12 weeks' gestational age. From 12 weeks' gestational age, continuing throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues, continued daily supplementation should consist of a multivitamin with 0.4 to 1.0 mg folic acid. (I-A). The same dietary and supplementation regime should be followed if either partner has had a previous pregnancy with a neural tube defect. (II-2A).

Objectif : Offrir des renseignements à jour sur l'utilisation pré et postconceptionnelle d'acide folique par voie orale, avec ou sans supplément de multivitamines / micronutriments, aux fins de la prévention des anomalies du tube neural et d'autres anomalies congénitales. Ces renseignements aideront les médecins, les sages-femmes, les infirmières et les autres professionnels de la santé à contribuer aux efforts de sensibilisation des femmes quant à l'utilisation et aux posologies adéquates de la supplémentation en acide folique / multivitamines, avant et pendant la grossesse. Résultats : La littérature publiée a été récupérée par l'intermédiaire de recherches menées dans PubMed, Medline, CINAHL et la Cochrane Library en janvier 2011 au moyen d'un vocabulaire contrôlé et de mots clés appropriés (p. ex. « folic acid ¼, « prenatal multivitamins ¼, « folate sensitive birth defects ¼, « congenital anomaly risk reduction ¼, « pre-conception counselling ¼). Les résultats ont été restreints aux analyses systématiques, aux études observationnelles et aux essais comparatifs randomisés / essais cliniques comparatifs publiés en anglais entre 1985 et juin 2014. Les recherches ont été mises à jour de façon régulière et intégrées à la directive clinique jusqu'en juin 2014. La littérature grise (non publiée) a été identifiée par l'intermédiaire de recherches menées dans les sites Web d'organismes s'intéressant à l'évaluation des technologies dans le domaine de la santé et d'organismes connexes, dans des collections de directives cliniques, dans des registres d'essais cliniques, et auprès de sociétés de spécialité médicale nationales et internationales. Coûts, risques et avantages : Les coûts financiers sont ceux de la supplémentation quotidienne en vitamines et de la consommation d'un régime alimentaire santé enrichi en folate. Les risques sont ceux qui sont liés à une association signalée entre la supplémentation alimentaire en acide folique et des modifications épigénétiques fœtales / la probabilité accrue d'obtenir une grossesse gémellaire. Ces associations pourraient devoir être prises en considération avant la mise en œuvre d'une supplémentation en acide folique. La supplémentation en acide folique par voie orale (ou l'apport alimentaire en folate combiné à un supplément de multivitamines / micronutriments) a pour avantage de mener à une baisse connexe du taux d'anomalies du tube neural et peut-être même des taux d'autres complications obstétricales et anomalies congénitales particulières. Valeurs : La qualité des résultats est évaluée au moyen des critères décrits par le Groupe d'étude canadien sur les soins de santé préventifs (Tableau). Déclaration sommaire 1. Au Canada, les comprimés de multivitamines comptant de l'acide folique sont habituellement offerts en 3 formats : multivitamines régulières en vente libre comptant de 0,4 à 0,6 mg d'acide folique, multivitamines prénatales en vente libre comptant 1,0 mg d'acide folique et multivitamines d'ordonnance comptant 5,0 mg d'acide folique. (III) Recommandations 1. Les femmes devraient se voir conseiller de maintenir un régime alimentaire santé riche en folate; la mise en œuvre d'une supplémentation en acide folique / multivitamines s'avère cependant requise pour leur assurer l'obtention des taux érythrocytaires de folate qui sont associés à l'octroi d'une protection maximale contre les anomalies du tube neural. (III-A) 2. Toutes les femmes en âge de procréer (12-45 ans) qui sont toujours fertiles (la grossesse demeure possible) devraient se voir offrir, dans le cadre de leurs consultations gynécologiques de dépistage (renouvellement de la contraception, test de Pap, examen gynécologique annuel), des services de counseling au sujet des avantages de l'acide folique administré sous forme d'une supplémentation multivitaminique, et ce, qu'elles envisagent ou non de connaître une grossesse. Puisqu'un si grand nombre de grossesses se manifestent de façon inattendue, cette recommandation s'applique à toutes les femmes qui pourraient devenir enceintes. (III-A) 3. La supplémentation en acide folique est peu susceptible de masquer la carence en vitamine B12 (anémie pernicieuse). La tenue d'explorations (examen ou épreuves de laboratoire) n'est pas requise avant la mise en œuvre d'une supplémentation en acide folique chez les femmes exposées à des risques d'anomalies du tube neural (ou d'autres anomalies congénitales sensibles à l'acide folique) primaires ou récurrentes qui envisagent une grossesse. Il est recommandé que l'acide folique soit administré sous forme de multivitamines comptant également 2,6 µg/jour de vitamine B12, de façon à atténuer toutes les préoccupations (même celles qui sont théoriques). (II-2A) 4. Les femmes exposées à des RISQUES ÉLEVÉS (pour lesquelles une dose d'acide folique supérieure à 1 mg s'avère indiquée) qui prennent des multivitamines contenant de l'acide folique devraient être avisées de respecter les consignes d'utilisation du produit en question et de ne pas prendre plus d'une dose quotidienne de supplément multivitaminique; ces femmes devraient plutôt prendre des comprimés additionnels ne contenant que de l'acide folique pour obtenir la dose requise. (II-2A) 5. Pendant au moins les deux à trois mois précédant la conception, tout au long de la grossesse et pendant de quatre à six semaines à la suite de l'accouchement (ou tant et aussi longtemps que se poursuit l'allaitement), les femmes qui sont exposées à un FAIBLE RISQUE d'anomalie du tube neural ou d'autres anomalies congénitales sensibles à l'acide folique et qui comptent un partenaire masculin également exposé à un faible risque doivent adopter un régime alimentaire composé d'aliments riches en folate et prendre un supplément multivitaminique oral quotidien contenant 0,4 mg d'acide folique. (II-2A) 6. À partir d'au moins trois mois avant la conception, les femmes qui sont exposées à un RISQUE MODÉRÉ d'anomalie du tube neural ou d'autres anomalies congénitales sensibles à l'acide folique et qui comptent un partenaire masculin également exposé à un risque modéré doivent adopter un régime alimentaire composé d'aliments riches en folate et prendre un supplément multivitaminique oral quotidien contenant 1 mg d'acide folique. Ces femmes devraient poursuivre l'utilisation de cette posologie jusqu'à l'atteinte d'un âge gestationnel de 12 semaines. (1-A) À partir de 12 semaines d'âge gestationnel, tout au long du reste de la grossesse et pendant de quatre à six semaines postpartum (ou tant et aussi longtemps que se poursuit l'allaitement), la supplémentation quotidienne utilisée devrait être composée d'une multivitamine contenant de 0,4 à 1,0 mg d'acide folique. (II-2A) 7. Pendant au moins trois mois avant la conception et jusqu'à l'atteinte d'un âge gestationnel de 12 semaines, les femmes qui sont exposées à un RISQUE ÉLEVÉ ou accru d'anomalie du tube neural et qui comptent un partenaire masculin présentant des antécédents personnels d'anomalie du tube neural (ou encore en présence d'antécédents personnels ou familiaux de grossesse affectée par une anomalie du tube neural chez l'un ou l'autre des partenaires) doivent adopter un régime alimentaire composé d'aliments riches en folate et prendre un supplément oral quotidien de 4 mg d'acide folique. À partir de 12 semaines d'âge gestationnel, tout au long du reste de la grossesse et pendant de quatre à six semaines postpartum (ou tant et aussi longtemps que se poursuit l'allaitement), la supplémentation quotidienne utilisée devrait être composée d'une multivitamine contenant de 0,4 à 1,0 mg d'acide folique. (I-A) Le même régime alimentaire et de supplémentation devrait être respecté en présence d'antécédents personnels ou familiaux de grossesse affectée par une anomalie du tube neural chez l'un ou l'autre des partenaires. (II-2A).

RETIRED: Technical Update: Preimplantation Genetic Diagnosis and Screening

This document has been archived because it contains outdated information. It should not be consulted for clinical use, but for historical research only. Please visit the journal website for the most recent guidelines.

Ce document a été archivé, car il contient des informations périmées. Il ne devrait pas être consulté pour un usage clinique, mais uniquement pour des recherches historiques. Veuillez consulter le site web du journal pour les directives les plus récentes.

RETIRED: Current status in non-invasive prenatal detection of Down syndrome, trisomy 18, and trisomy 13 using cell-free DNA in maternal plasma.

This document has been archived because it contains outdated information. It should not be consulted for clinical use, but for historical research only. Please visit the journal website for the most recent guidelines.

Mosaic tetrasomy 5p resulting from an isochromosome 5p marker chromosome: case report and review of literature.

We report on the fifth case, and oldest reported patient, of an individual affected with mosaic tetrasomy 5p resulting from an isochromosome 5p [i(5)(p10)] marker chromosome. A syndrome of mosaic tetrasomy 5p is defined, and includes the following features seen in the reported cases: developmental delay, seizures, ventriculomegaly (other brain anomalies), small stature/growth delay and mosaic pigmentary skin changes. Other findings include various dysmorphic facial features as well as hand and foot anomalies. This syndrome is likely more common than suggested in the literature, as the clinical presentation can be variable, and the chromosome anomaly is unlikely to be found on routine karyotype of peripheral blood lymphocytes. The i(5)(p10) marker chromosome is found only as a mosaic anomaly, with levels ranging from 0% to 10% in cultured lymphocytes to 12-85% in cultured skin fibroblasts. Microarray analysis performed on unstimulated lymphocytes from the patient in this report did not detect any evidence of the chromosome abnormality, indicating that this methodology may not be useful as a diagnostic tool in this disorder. Diagnosis of the mosaic tetrasomy 5p syndrome will rely on good clinical assessment, and appropriate cytogenetic studies, including analysis of skin fibroblasts. A child with unexplained developmental delay, seizures, hypotonia, and ventriculomegaly with or without dysmorphic features should be assessed carefully for pigmentary changes of the skin. If a diagnosis of mosaic 5p tetrasomy is suspected, karyotype of cultured fibroblasts in addition to routine cytogenetic analysis, to look for this marker chromosome is warranted.

Family history screening: use of the three generation pedigree in clinical practice.

With a growing understanding of genetic disorders in the scientific and lay literature, it is becoming increasingly important to consider risk factors based on family history and ethnicity for identifying individuals for whom genetic testing is indicated and will be most beneficial. A pedigree helps to identify patients and families who have an increased risk for genetic disorders, to optimize counselling, screening, and diagnostic testing, with the goal of disease prevention or early diagnosis and management of the disease. Information should be updated periodically as new information regarding family history is acquired. This review was designed to provide a rationale for and an approach to obtaining a three-generation pedigree for patients who are seen as new assessments or those under ongoing care by primary care or specialist physicians, as well to summarize some resources available for constructing a useful pedigree.

Preimplantation genetic testing.

OBJECTIVE: To review the techniques and indications of preimplantation genetic testing, including preimplantation genetic diagnosis and screening. OPTIONS: Limited to an introductory discussion about the genetic aspects of preimplantation reproductive techniques. OUTCOMES: This update does not discuss in detail the adverse outcomes that have been recorded in association with assisted reproductive technologies. EVIDENCE: The Cochrane Library and Medline were searched for articles relating to preimplantation testing that were published from 1990 to February 2008, using the following terms: preimplantation genetic diagnosis, preimplantation genetic screening, and in vitro fertilization. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Additional publications were identified from the bibliographies of these articles. Randomized controlled trials were considered evidence of the highest quality, followed by cohort studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and from national and international medical specialty societies. VALUES: This update is a consensus of the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada. The recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS: This update educates readers about new genetic concepts, directions, and technology. The major harms and costs identified are those of assisted reproductive technologies. SPONSOR: The Society of Obstetricians and Gynaecologists of Canada. CONCLUSIONS: Preimplantation genetic diagnosis is an alternative to prenatal diagnosis for the detection of genetic disorders in couples at risk of transmitting a genetic condition to their offspring. Preimplantation genetic screening has been proposed to improve the effectiveness of in vitro fertilization in women of advanced maternal age or in couples with recurrent miscarriage or implantation failure, but the benefits of this approach are debated. RECOMMENDATIONS: The recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. 1. Before preimplantation genetic diagnosis is performed, genetic counselling must be provided to ensure that patients fully understand the risk of having an affected child, the impact of the disease on an affected child, and the benefits and limitations of all available options for preimplantation and prenatal diagnosis. (III-A) 2. Couples should be informed that preimplantation genetic diagnosis can reduce the risk of conceiving a child with a genetic abnormality carried by one or both parents if that abnormality can be identified with tests performed on a single cell. (II-2B) 3. Invasive prenatal testing to confirm the results of preimplantation genetic diagnosis is encouraged because the methods used for preimplantation genetic diagnosis have technical limitations that include the possibility of a false negative result. (II-2B) 4. Before preimplantation genetic screening is performed, thorough education and counselling must be provided to ensure that patients fully understand the limitations of the technique, the risk of error, and the lack of evidence that preimplantation genetic screening improves live-birth rates. (III-A) 5. Available evidence does not support the use of preimplantation genetic screening as currently performed to improve live-birth rates in patients with advanced maternal age, recurrent implantation failure, or recurrent pregnancy loss. (I-D).

Successful outcome in pregnancy with arterial tortuosity syndrome.

BACKGROUND: Arterial tortuosity syndrome is a rare, autosomal recessive, severe, connective tissue disorder caused by a mutation in the SLC2A10 gene. We describe the pregnancy and delivery with this high-risk connective tissue disorder involving generalized abnormalities of the vasculature. CASE: A woman with an undefined connective tissue disorder was referred for tertiary prenatal care. Diagnostic imaging demonstrated multiple pulmonary artery aneurysms and arterial tortuosity, consistent with a clinical diagnosis of arterial tortuosity syndrome. With a team considering all potential complications, a delivery plan was undertaken involving cesarean delivery and intensive perioperative and postpartum monitoring. The outcome was optimal for mother and neonate. Concurrent molecular testing demonstrated homozygosity for the SLC2A10 gene. CONCLUSION: Optimal maternal, fetal and neonatal outcomes were obtained with comprehensive multidisciplinary care and close maternal and fetal surveillance.