Valérie Désilets

Pre-conceptional Vitamin/Folic Acid Supplementation 2007: The Use of Folic Acid in Combination With a Multivitamin Supplement for the Prevention of Neural Tube Defects and Other Congenital Anomalies

OBJECTIVE To provide information regarding the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies, so that physicians, midwives, nurses, and other health care workers can assist in the education of women in the pre-conception phase of their health care. OPTION: Supplementation with folic acid and vitamins is problematic, since 50% of pregnancies are unplanned, and womens health status may not be optimal when they conceive. OUTCOMES Folic acid in combination with a multivitamin supplement has been associated with a decrease in specific birth defects. EVIDENCE Medline, PubMed, and Cochrane Database were searched for relevant English language articles published between 1985 and 2007. The previous Society of Obstetricians and Gynaecologists of Canada (SOGC) Policy Statement of November 1993 and statements from the American College of Obstetrics and Gynecology and Canadian College of Medical Geneticists were also reviewed in developing this clinical practice guideline. VALUES The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS Promoting the use of folic acid and a multivitamin supplement among women of reproductive age will reduce the incidence of birth defects. The costs are those of daily vitamin supplementation and eating a healthy diet. RECOMMENDATIONS 1. Women in the reproductive age group should be advised about the benefits of folic acid in addition to a multivitamin supplement during wellness visits (birth control renewal, Pap testing, yearly examination) especially if pregnancy is contemplated. (III-A) 2. Women should be advised to maintain a healthy diet, as recommended in Eating Well With Canadas Food Guide (Health Canada). Foods containing excellent to good sources of folic acid are fortified grains, spinach, lentils, chick peas, asparagus, broccoli, peas, Brussels sprouts, corn, and oranges. However, it is unlikely that diet alone can provide levels similar to folate-multivitamin supplementation. (III-A) 3. Women taking a multivitamin containing folic acid should be advised not to take more than one daily dose of vitamin supplement, as indicated on the product label. (II-2-A) 4. Folic acid and multivitamin supplements should be widely available without financial or other barriers for women planning pregnancy to ensure the extra level of supplementation. (III-B) 5. Folic acid 5 mg supplementation will not mask vitamin B12 deficiency (pernicious anemia), and investigations (examination or laboratory) are not required prior to initiating supplementation. (II-2-A) 6. The recommended strategy to prevent recurrence of a congenital anomaly (anencephaly, myelomeningocele, meningocele, oral facial cleft, structural heart disease, limb defect, urinary tract anomaly, hydrocephalus) that has been reported to have a decreased incidence following preconception / first trimester folic acid +/- multivitamin oral supplementation is planned pregnancy +/- supplementation compliance. A folate-supplemented diet with additional daily supplementation of multivitamins with 5 mg folic acid should begin at least three months before conception and continue until 10 to 12 weeks post conception. From 12 weeks post-conception and continuing throughout pregnancy and the postpartum period (4-6 weeks or as long as breastfeeding continues), supplementation should consist of a multivitamin with folic acid (0.4-1.0 mg). (I-A) 7. The recommended strategy(ies) for primary prevention or to decrease the incidence of fetal congenital anomalies will include a number of options or treatment approaches depending on patient age, ethnicity, compliance, and genetic congenital anomaly risk status. OPTION A: Patients with no personal health risks, planned pregnancy, and good compliance require a good diet of folate-rich foods and daily supplementation with a multivitamin with folic acid (0.4-1.0 mg) for at least two to three months before conception and throughout pregnancy and the postpartum period (4-6 weeks and as long as breastfeeding continues). (II-2-A) OPTION B: Patients with health risks, including epilepsy, insulin dependent diabetes, obesity with BMI >35 kg/m2, family history of neural tube defect, belonging to a high-risk ethnic group (e.g., Sikh) require increased dietary intake of folate-rich foods and daily supplementation, with multivitamins with 5 mg folic acid, beginning at least three months before conception and continuing until 10 to 12 weeks post conception. From 12 weeks post-conception and continuing throughout pregnancy and the postpartum period (4-6 weeks or as long as breastfeeding continues), supplementation should consist of a multivitamin with folic acid (0.4-1.0 mg). (II-2-A) OPTION C: Patients who have a history of poor compliance with medications and additional lifestyle issues of variable diet, no consistent birth control, and possible teratogenic substance use (alcohol, tobacco, recreational non-prescription drugs) require counselling about the prevention of birth defects and health problems with folic acid and multivitamin supplementation. The higher dose folic acid strategy (5 mg) with multivitamin should be used, as it may obtain a more adequate serum red blood cell folate level with irregular vitamin / folic acid intake but with a minimal additional health risk. (III-B) 8. The Canadian Federal Government could consider an evaluation process for the benefit/risk of increasing the level of national folic acid flour fortification to 300 mg/100 g (present level 140 mg/100 g). (III-B) 9. The Canadian Federal Government could consider an evaluation process for the benefit/risk of additional flour fortification with multivitamins other than folic acid. (III-B) 10. The Society of Obstetricians and Gynaecologists of Canada will explore the possibility of a Canadian Consensus conference on the use of folic acid and multivitamins for the primary prevention of specific congenital anomalies. The conference would include Health Canada/Congenital Anomalies Surveillance, Canadian College of Medical Geneticists, Canadian Paediatric Society, Motherisk, and pharmaceutical industry representatives. VALIDATION This is a revision of a previous guideline and information from other consensus reviews from medical and government publications has been used. SPONSOR The Society of Obstetricians and Gynaecologists of Canada.

Pregnancy Outcomes After Assisted Reproductive Technology

OBJECTIVE To review the effect of assisted reproductive technology (ART) on perinatal outcomes, to provide guidelines to optimize obstetrical management and counselling of Canadian women using ART, and to identify areas specific to birth outcomes and ART requiring further research. OPTIONS Perinatal outcomes of ART pregnancies in subfertile women are compared with those of spontaneously conceived pregnancies. Perinatal outcomes are compared between different types of ART. OUTCOMES This guideline discusses the adverse outcomes that have been recorded in association with ART, including obstetrical complications, adverse perinatal outcomes, multiple gestations, structural congenital abnormalities, chromosomal abnormalities, imprinting disorders, and childhood cancer. EVIDENCE The Cochrane Library and MEDLINE were searched for English-language articles from 1990 to February 2005, relating to assisted reproduction and perinatal outcomes. Search terms included assisted reproduction, assisted reproductive technology, ovulation induction, intracytoplasmic sperm injection (ICSI), embryo transfer, and in vitro fertilization (IVF). Additional publications were identified from the bibliographies of these articles as well as the Science Citation Index. Studies assessing gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT) were excluded since they are rarely used in Canada. All study types were reviewed. Randomized controlled trials were considered evidence of the highest quality, followed by cohort studies. Key studies and supporting data for each recommendation are summarized with evaluative comments and referenced. VALUES The evidence collected was reviewed by the Genetics Committee and the Reproductive Endocrinology Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) and quantified using the Evaluation of Evidence Guidelines developed by the Canadian Task Force on the Periodic Health Examination. BENEFITS, HARMS, AND COSTS The type and magnitude of benefits, harms, and costs expected for patients from guideline implementation. This guideline has been reviewed by the Genetics Committee and the Reproductive Endocrinology and Infertility Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada and the Board of the Canadian Fertility and Andrology Society. RECOMMENDATIONS 1. Spontaneous pregnancies in untreated infertile women may be at higher risk for obstetrical complications and perinatal mortality than spontaneous pregnancies in fertile women. Further research is required to clarify the contribution of infertility itself to adverse obstetrical and perinatal outcomes. (II-2A) 2. All men with severe oligozoospermia or azoospermia should be offered genetic/clinical counselling for informed consent and offered karyotyping for chromosomal abnormalities before attempting IVF-ICSI. They should be made aware of the availability of tests for Y chromosome microdeletion. Some patients may consider the option of donor insemination. (II-3B) 3. Couples exploring IVF-ICSI when the man has obstructive azoospermia should be offered genetic/clinical counselling for informed consent and offered genetic testing for alterations in genes associated with cystic fibrosis (CF) before attempting IVF-ICSI. (II-2A) 4. Pregnancies achieved by ovarian stimulation with gonadotropins and intrauterine insemination are at higher risk for perinatal complications, and close surveillance during pregnancy should be considered. It remains unclear if these increased risks are attributable to the underlying infertility, characteristics of the infertile couple, or use of assisted reproductive techniques. Multiple gestations remain a significant risk of gonadotropin treatment. (II-2A) 5. Pregnancies achieved by IVF with or without ICSI are at higher risk for obstetrical and perinatal complications than spontaneous pregnancies, and close surveillance during pregnancy should be considered. It remains unclear if these increased risks are attributable to the underlying infertility, characteristics of the infertile couple, or use of assisted reproductive techniques. (II-2A) 6. Women undergoing ART should be informed about the increased rate of obstetrical interventions such as induced labour and elective Caesarean delivery. (II-2A) 7. Couples suffering from infertility who are exploring treatment options should be made aware of the psychosocial implications of ART. Further research into the psychosocial impact of ART is needed. (II-2A) 8. Singleton pregnancies achieved by assisted reproduction are at higher risk than spontaneous pregnancies for adverse perinatal outcomes, including perinatal mortality, preterm delivery, and low birth weight, and close surveillance during pregnancy should be available as needed. (II-2A) 9. A significant risk of ART is multiple pregnancies. Infertile couples need to be informed of the increased risks of multifetal pregnancies. Although dichorionic twins are most common, the incidence of monochorionic twins is also increased. Risks of multiple pregnancies include higher rates of perinatal mortality, preterm birth, low birth weight, gestational hypertension, placental abruption, and placenta previa. Perinatal mortality in assisted conception twin pregnancies appears to be lower than in spontaneously conceived twin pregnancies. (II-2A) 10. When multifetal reduction is being considered for high-order multiple pregnancies, psychosocial counselling should be readily available. Careful surveillance for fetal growth problems should be undertaken after multifetal reduction. (II-2A) 11. To reduce the risks of multiple pregnancies associated with ART and to optimize pregnancy rates, national guidelines should be developed on the number of embryos replaced according to characteristics such as patients age and grade of embryos. (II-2A) 12. Further epidemiologic and basic science research is needed to help determine the etiology and extent of the increased risks to childhood and long-term growth and development associated with ART. (II-2A) 13. Discussion of options for prenatal screening for congenital structural abnormalities in pregnancies achieved by ART is recommended, including appropriate use of biochemical and sonographic screening. (II-2A) 14. Further epidemiologic and basic science research is needed to help determine the etiology and extent of the increased risks of congenital abnormalities associated with ART. (II-2A) 15. Couples considering IVF-ICSI for male-factor infertility should receive information, and if necessary formal genetic counselling, about the increased risk of de novo chromosomal abnormalities (mainly sex chromosomal anomalies) associated with their condition. Prenatal diagnosis by chorionic villus sampling (CVS) or amniocentesis should be offered to these couples if they conceive. (II-2A) 16. Further epidemiologic and basic science research is needed to help determine the etiology and extent of the increased risks of chromosomal abnormalities associated with ART. (II-2A) 17. Discussion of options for prenatal screening and testing for aneuploidy in pregnancies achieved by ART, adapted for maternal age and number of fetuses, is recommended, including appropriate use of biochemical and sonographic screening. (II-2A) 18. The precise risks of imprinting and childhood cancer from ART remain unclear but cannot be ignored. Further clinical research, including long-term follow-up, is urgently required to evaluate the prevalence of imprinting disorders and cancers associated with ART. (II-2A) 19. The clinical application of preimplantation genetic diagnosis must balance the benefits of avoiding disease transmission with the medical risks and financial burden of in vitro fertilization. Further ethical discussion and clinical research is required to evaluate appropriate indications for preimplantation genetic diagnosis. (III-B).

Obstetrical complications associated with abnormal maternal serum markers analytes.

OBJECTIVE To review the obstetrical outcomes associated with abnormally elevated or decreased level of one or more of the most frequently measured maternal serum marker analytes used in screening for aneuploidy. To provide guidance to facilitate the management of pregnancies that have abnormal levels of one of more markers and to assess the usefulness of these markers as a screening test. OPTIONS Perinatal outcomes associated with abnormal levels of maternal serum markers analytes are compared with the outcomes of pregnancies with normal levels of the same analytes or the general population. EVIDENCE The Cochrane Library and Medline were searched for English-language articles published from 1966 to February 2007, relating to maternal serum markers and perinatal outcomes. Search terms included PAPP-A (pregnancy associated plasma protein A), AFP (alphafetoprotein), hCG (human chorionic gonadotropin), estriol, unconjugated estriol, inhibin, inhibin-A, maternal serum screen, triple marker screen, quadruple screen, integrated prenatal screen, first trimester screen, and combined prenatal screen. All study types were reviewed. Randomized controlled trials were considered evidence of the highest quality, followed by cohort studies. Key individual studies on which the recommendations are based are referenced. Supporting data for each recommendation are summarized with evaluative comments and references. The evidence was evaluated using the guidelines developed by the Canadian Task Force on Preventive Health Care. VALUES The evidence collected was reviewed by the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada. BENEFITS, HARMS, AND COSTS The benefit expected from this guideline is to facilitate early detection of potential adverse pregnancy outcomes when risks are identified at the time of a maternal serum screen. It will help further stratification of risk and provide options for pregnancy management to minimize the impact of pregnancy complications. The potential harms resulting from such practice are associated with the so called false positive (i.e., uncomplicated pregnancies labelled at increased risk for adverse perinatal outcomes), the potential stress associated with such a label, and the investigations performed for surveillance in this situation. No cost-benefit analysis is available to assess costs and savings associated with this guideline. SUMMARY STATEMENTS: 1. An unexplained level of a maternal serum marker analyte is defined as an abnormal level after confirmation of gestational age by ultrasound and exclusion of maternal, fetal, or placental causes for the abnormal level. (III) 2. Abnormally elevated levels of serum markers are associated with adverse pregnancy outcomes in twin pregnancies, after correction for the number of fetuses. Spontaneous or planned mutifetal reductions may result in abnormal elevations of serum markers. (II-2) RECOMMENDATIONS: 1. In the first trimester, an unexplained low PAPP-A (< 0.4 MoM) and/or a low hCG (< 0.5 MoM) are associated with an increased frequency of adverse obstetrical outcomes, and, at present, no specific protocol for treatment is available. (II-2A) In the second trimester, an unexplained elevation of maternal serum AFP (> 2.5 MoM), hCG (> 3.0 MoM), and/or inhibin-A (> or =2.0 MoM) or a decreased level of maternal serum AFP (< 0.25 MoM) and/or unconjugated estriol (< 0.5 MoM) are associated with an increased frequency of adverse obstetrical outcomes, and, at present, no specific protocol for treatment is available. (II-2A) 2. Pregnant woman with an unexplained elevated PAPP-A or hCG in the first trimester and an unexplained low hCG or inhibin-A and an unexplained elevated unconjugated estriol in the second trimester should receive normal antenatal care, as this pattern of analytes is not associated with adverse perinatal outcomes. (II-2A) 3. The combination of second or third trimester placenta previa and an unexplained elevated maternal serum AFP should increase the index of suspicion for placenta accreta, increta, or percreta. (II-2B) An assessment (ultrasound, MRI) of the placental-uterine interface should be performed. Abnormal invasion should be strongly suspected, and the planning of delivery location and technique should be done accordingly. (III-C) 4. A prenatal consultation with the medical genetics department is recommended for low unconjugated estriol levels (<0.3 MoM), as this analyte pattern can be associated with genetic conditions. (II-2B) 5. The clinical management protocol for identification of potential adverse obstetrical outcomes should be guided by one or more abnormal maternal serum marker analyte value rather than the false positive screening results for the trisomy 21 and/or the trisomy 18 screen. (II-2B) 6. Pregnant woman who are undergoing renal dialysis or who have had a renal transplant should be offered maternal serum screening, but interpretation of the result is difficult as the level of serum hCG is not reliable. (II-2A) 7. Abnormal maternal uterine artery Doppler in association with elevated maternal serum AFP, hCG, or inhibin-A or decreased PAPP-A identifies a group of women at greater risk of IUGR and gestational hypertension with proteinuria. Uterine artery Doppler measurements may be used in the evaluation of an unexplained abnormal level of either of these markers. (II-2B) 8. Further research is recommended to identify the best protocol for pregnancy management and surveillance in women identified at increased risk of adverse pregnancy outcomes based on an abnormality of a maternal serum screening analyte. (III-A) 9. In the absence of evidence supporting any specific surveillance protocol, an obstetrician should be consulted in order to establish a fetal surveillance plan specific to the increased obstetrical risks (maternal and fetal) identified. This plan may include enhanced patient education on signs and symptoms of the most common complications, increased frequency of antenatal visits, increased ultrasound (fetal growth, amniotic fluid levels), and fetal surveillance (biophysical profile, arterial and venous Doppler), and cervical length assessment. (III-A) 10. Limited information suggests that, in women with elevated hCG in the second trimester and/or abnormal uterine artery Doppler (at 22-24 weeks), low-dose aspirin (60-81 mg daily) is associated with higher birthweight and lower incidence of gestational hypertension with proteinuria. This therapy may be used in women who are at risk. (II-2B) 11. Further studies are recommended in order to assess the benefits of low-dose aspirin, low molecular weight heparin, or other therapeutic options in pregnancies determined to be at increased risk on the basis of an abnormal maternal serum screening analyte. (III-A) 12. Multiple maternal serum markers screening should not be used at present as a population-based screening method for adverse pregnancy outcomes (such as preeclampsia, placental abruption, and stillbirth) outside an established research protocol, as sensitivity is low, false positive rates are high, and no management protocol has been shown to clearly improve outcomes. (II-2D) When maternal serum screening is performed for the usual clinical indication (fetal aneuploidy and/or neural tube defect), abnormal analyte results can be utilized for the identification of pregnancies at risk and to direct their clinical management. (II-2B) Further studies are recommended to determine the optimal screening method for poor maternal and/or perinatal outcomes. (III-A).

Delayed Child-Bearing

OBJECTIVE To provide an overview of delayed child-bearing and to describe the implications for women and health care providers. OPTIONS Delayed child-bearing, which has increased greatly in recent decades, is associated with an increased risk of infertility, pregnancy complications, and adverse pregnancy outcome. This guideline provides information that will optimize the counselling and care of Canadian women with respect to their reproductive choices. OUTCOMES Maternal age is the most important determinant of fertility, and obstetric and perinatal risks increase with maternal age. Many women are unaware of the success rates or limitations of assisted reproductive technology and of the increased medical risks of delayed child-bearing, including multiple births, preterm delivery, stillbirth, and Caesarean section. This guideline provides a framework to address these issues. EVIDENCE Studies published between 2000 and August 2010 were retrieved through searches of PubMed and the Cochrane Library using appropriate key words (delayed child-bearing, deferred pregnancy, maternal age, assisted reproductive technology, infertility, and multiple births) and MeSH terms (maternal age, reproductive behaviour, fertility). The Internet was also searched using similar key words, and national and international medical specialty societies were searched for clinical practice guidelines and position statements. Data were extracted based on the aims, sample, authors, year, and results. VALUES The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). SPONSOR The Society of Obstetricians and Gynaecologists of Canada. RECOMMENDATIONS 1. Women who delay child-bearing are at increased risk of infertility. Prospective parents, especially women, should know that their fecundity and fertility begin to decline significantly after 32 years of age. Prospective parents should know that assisted reproductive technologies cannot guarantee a live birth or completely compensate for age-related decline in fertility. (II-2A) 2. A fertility evaluation should be initiated after 6 months of unprotected intercourse without conception in women 35 to 37 years of age, and earlier in women > 37 years of age. (II-2A) 3. Prospective parents should be informed that semen quality and male fertility deteriorate with advancing age and that the risk of genetic disorders in offspring increases. (II-2A) 4. Women ≥ 35 years of age should be offered screening for fetal aneuploidy and undergo a detailed second trimester ultrasound examination to look for significant fetal birth defects (particularly cardiac defects). (II-1A) 5. Delayed child-bearing is associated with increased obstetrical and perinatal complications. Care providers need to be aware of these complications and adjust obstetrical management protocols to ensure optimal maternal and perinatal outcomes. (II-2A) 6. All adults of reproductive age should be aware of the obstetrical and perinatal risks of advanced maternal age so they can make informed decisions about the timing of child-bearing. (II-2A) 7. Strategies to improve informed decision-making by prospective parents should be designed, implemented, and evaluated. These strategies should provide opportunity for adults to understand the potential medical, social, and economic consequences of child-bearing throughout the reproductive years. (III-B) 8. Barriers to healthy reproduction, including workplace policies, should be reviewed to optimize the likelihood of healthy pregnancies. (III-C).

Prenatal Screening for Fetal Aneuploidy in Singleton Pregnancies

OBJECTIVE To develop a Canadian consensus document on maternal screening for fetal aneuploidy (e.g., Down syndrome and trisomy 18) in singleton pregnancies. OPTIONS Pregnancy screening for fetal aneuploidy started in the mid 1960s, using maternal age as the screening test. New developments in maternal serum and ultrasound screening have made it possible to offer all pregnant patients a non-invasive screening test to assess their risk of having a fetus with aneuploidy to determine whether invasive prenatal diagnostic testing is necessary. This document reviews the options available for non-invasive screening and makes recommendations for Canadian patients and health care workers. OUTCOMES To offer non-invasive screening for fetal aneuploidy (trisomy 13, 18, 21) to all pregnant women. Invasive prenatal diagnosis would be offered to women who screen above a set risk cut-off level on non-invasive screening or to pregnant women whose personal, obstetrical, or family history places them at increased risk. Currently available non-invasive screening options include maternal age combined with one of the following: (1) first trimester screening (nuchal translucency, maternal age, and maternal serum biochemical markers), (2) second trimester serum screening (maternal age and maternal serum biochemical markers), or (3) 2-step integrated screening, which includes first and second trimester serum screening with or without nuchal translucency (integrated prenatal screen, serum integrated prenatal screening, contingent, and sequential). These options are reviewed, and recommendations are made. EVIDENCE Studies published between 1982 and 2009 were retrieved through searches of PubMed or Medline and CINAHL and the Cochrane Library, using appropriate controlled vocabulary and key words (aneuploidy, Down syndrome, trisomy, prenatal screening, genetic health risk, genetic health surveillance, prenatal diagnosis). Results were restricted to systematic reviews, randomized controlled trials, and relevant observational studies. There were no language restrictions. Searches were updated on a regular basis and incorporated in the guideline to August 2010. 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 national and international medical specialty societies. The previous Society of Obstetricians and Gynaecologists of Canada guidelines regarding prenatal screening were also reviewed in developing this clinical practice guideline. VALUES The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS This guideline is intended to reduce the number of prenatal invasive procedures done when maternal age is the only indication. This will have the benefit of reducing the numbers of normal pregnancies lost because of complications of invasive procedures. Any screening test has an inherent false-positive rate, which may result in undue anxiety. It is not possible at this time to undertake a detailed cost-benefit analysis of the implementation of this guideline, since this would require health surveillance and research and health resources not presently available; however, these factors need to be evaluated in a prospective approach by provincial and territorial initiatives. RECOMMENDATIONS 1. All pregnant women in Canada, regardless of age, should be offered, through an informed counselling process, the option of a prenatal screening test for the most common clinically significant fetal aneuploidies in addition to a second trimester ultrasound for dating, assessment of fetal anatomy, and detection of multiples. (I-A) 2. Counselling must be non-directive and must respect a womans right to accept or decline any or all of the testing or options offered at any point in the process. (III-A) 3. Maternal age alone is a poor minimum standard for prenatal screening for aneuploidy, and it should not be used a basis for recommending invasive testing when non-invasive prenatal screening for aneuploidy is available. (II-2A) 4. Invasive prenatal diagnosis for cytogenetic analysis should not be performed without multiple marker screening results except for women who are at increased risk of fetal aneuploidy (a) because of ultrasound findings, (b) because the pregnancy was conceived by in vitro fertilization with intracytoplasmic sperm injection, or (c) because the woman or her partner has a history of a previous child or fetus with a chromosomal abnormality or is a carrier of a chromosome rearrangement that increases the risk of having a fetus with a chromosomal abnormality. (II-2E) 5. At minimum, any prenatal screen offered to Canadian women who present for care in the first trimester should have a detection rate of 75% with no more than a 3% false-positive rate. The performance of the screen should be substantiated by annual audit. (III-B) 6. The minimum standard for women presenting in the second trimester should be a screen that has a detection rate of 75% with no more than a 5% false-positive rate. The performance of the screen should be substantiated by annual audit. (III-B) 7. First trimester nuchal translucency should be interpreted for risk assessment only when measured by sonographers or sonologists trained and accredited for this service and when there is ongoing quality assurance (II-2A), and it should not be offered as a screen without biochemical markers in singleton pregnancies. (I-E) 8. Evaluation of the fetal nasal bone in the first trimester should not be incorporated as a screen unless it is performed by sonographers or sonologists trained and accredited for this service and there is ongoing quality assurance. (II-2E) 9. For women who undertake first trimester screening, second trimester serum alpha fetoprotein screening and/or ultrasound examination is recommended to screen for open neural tube defects. (II-1A) 10. Timely referral and access is critical for women and should be facilitated to ensure women are able to undergo the type of screening test they have chosen as first trimester screening. The first steps of integrated screening (with or without nuchal translucency), contingent, or sequential screening are performed in an early and relatively narrow time window. (II-1A) 11. Ultrasound dating should be performed if menstrual or conception dating is unreliable. For any abnormal serum screen calculated on the basis of menstrual dating, an ultrasound should be done to confirm gestational age. (II-1A) 12. The presence or absence of soft markers or anomalies in the 18- to 20-week ultrasound can be used to modify the a priori risk of aneuploidy established by age or prior screening. (II-2B) 13. Information such as gestational dating, maternal weight, ethnicity, insulin-dependent diabetes mellitus, and use of assisted reproduction technologies should be provided to the laboratory to improve accuracy of testing. (II-2A) 14. Health care providers should be aware of the screening modalities available in their province or territory. (III-B) 15. A reliable system needs to be in place ensuring timely reporting of results. (III-C) 16. Screening programs should be implemented with resources that support audited screening and diagnostic laboratory services, ultrasound, genetic counselling services, patient and health care provider education, and high quality diagnostic testing, as well as resources for administration, annual clinical audit, and data management. In addition, there must be the flexibility and funding to adjust the program to new technology and protocols. (II-3B).

Evaluation of Prenatally Diagnosed Structural Congenital Anomalies

OBJECTIVE To provide information to genetic counsellors, midwives, nurses, and physicians who are involved in the prenatal care of women dealing with prenatally diagnosed isolated or multiple structural congenital anomalies. OUTCOMES To provide better counselling for women and families who are dealing with the diagnosis of a fetal structural anomaly. EVIDENCE Published literature was retrieved through searches of PubMed or Medline, CINAHL, and the Cochrane Library for relevant articles using appropriate controlled vocabulary (e.g., structural congenital anomalies, prenatal ultrasound diagnosis of congenital anomalies, invasive testing results, and diagnosis of genetic syndromes; soft markers of aneuploidy were not included in this search) and key words. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and material from between 1985 and 2008 incorporated in the guideline. 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 national and international medical specialty societies. VALUES The evidence obtained was reviewed by the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC). Recommendations were quantified using the evaluation of evidence guidelines developed by the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS Findings of isolated or multiple fetal anomalies on prenatal ultrasound examination always lead to stressful times for women and families. Although a proportion of such anomalies can be explained by chromosomal abnormalities (aneuploidy, unbalanced translocation, deletions, or duplications), others may represent recognizable syndromes with another genetic basis (microdeletion or autosomal dominant, recessive, or X-linked inheritance). Providing accurate information and relevant reproductive genetic counselling to these women and families will allow them to make informed decisions. This is not easily accomplished because of the limited information available prenatally. This document does not provide an extensive description of every syndrome but rather a framework of reference. No cost-benefit analysis is provided. RECOMMENDATIONS 1. When a fetal structural anomaly is identified, the pregnant woman should be offered a timely consultation with a trained genetic counsellor and with a maternal-fetal medicine specialist and/or a medical geneticist. The counselling should be unbiased and respectful of the patients choice, culture, religion, and beliefs. (III-A) 2. Patients should be informed that prenatal ultrasound at 18 to 20 weeks can detect major structural anomalies in approximately 60% of such cases. (II-2A) 3. When a fetal structural anomaly is suspected or identified, a referral to a tertiary ultrasound unit should be made as soon as possible to optimize therapeutic options. (II-2A) 4. In ongoing pregnancies with fetal structural anomalies, ultrasound examination should be repeated (at a frequency depending on the anomaly) to assess the evolution of the anomaly and attempt to detect other anomalies not previously identified, as this may influence the counselling as well as the obstetrical or perinatal management. (II-2B) 5. Once a fetal structural anomaly is identified by 2-D ultrasound, other imaging techniques such as fetal echocardiography, 3-D obstetrical ultrasound, ultrafast fetal MRI, and, occasionally, fetal X-ray and fetal CT scan (using a low-dose protocol) may be helpful in specific cases. (II-2A) 6. Parental imaging should be considered in specific cases, depending on the fetal anomaly identified (e.g., potential dominant inheritance). (III-A) 7. Parental blood testing and invasive prenatal testing may also be required to clarify the diagnosis for a fetus with isolated or multiple structural anomalies. (II-2A) 8. Women should receive information regarding the abnormal ultrasound findings in a clear, sympathetic, and timely fashion, and in a supportive environment that ensures privacy. Referral to the appropriate pediatric or surgical subspecialist(s) should be considered to provide the most accurate information possible concerning the anomaly or anomalies and the associated prognosis. (II-2 B) 9. Parents should be informed that major or minor fetal structural anomalies, whether isolated or multiple, may be part of a genetic syndrome, sequence, or association, despite a normal fetal karyotype. (III-A) 10. If early or urgent postnatal management may be required, delivery at a centre that can provide the appropriate neonatal care should be considered. (III-A) 11. When any congenital structural anomaly has been identified prenatally, a comprehensive newborn assessment is essential for diagnosis and counselling on the etiology, prognosis, and recurrence risk for future pregnancies, especially when the etiology has not been clearly identified prenatally. (III-A) 12. In cases of termination of pregnancy, stillbirth, or neonatal death, the health professional should encourage the performance of a complete autopsy by a perinatal or pediatric pathologist to provide maximum information on the diagnosis and etiology of the structural fetal anomaly or anomalies. When a complete autopsy is refused, the health professional should encourage the performance of at least a partial or external autopsy (including X-rays and photographs). (III-A) VALIDATION: This committee opinion has been prepared by the Genetics Committee of the SOGC and approved by the Executive of the SOGC.

Carrier Screening for Thalassemia and Hemoglobinopathies in Canada

OBJECTIVE To provide recommendations to physicians, midwives, genetic counsellors, and clinical laboratory scientists involved in pre-conceptional or prenatal care regarding carrier screening for thalassemia and hemoglobinopathies (e.g., sickle cell anemia and other qualitative hemoglobin disorders). OUTCOMES To determine the populations to be screened and the appropriate tests to offer to minimize practice variations across Canada. EVIDENCE The Medline database was searched for relevant articles published between 1986 and 2007 on carrier screening for thalassemia and hemoglobinopathies. Key textbooks were also reviewed. Recommendations were quantified using the Evaluation of Evidence guidelines developed by the Canadian Task Force on Preventive Health Care. VALUES The evidence collected from the Medline search was reviewed by the Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists (CCMG) and the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC). BENEFITS, HARMS, AND COSTS Screening of individuals at increased risk of being carriers for thalassemia and hemoglobinopathies can identify couples with a 25% risk of having a pregnancy with a significant genetic disorder for which prenatal diagnosis is possible. Ideally, screening should be done pre-conceptionally. However, for a significant proportion of patients, the screening will occur during the pregnancy, and the time constraint for obtaining screening results may result in psychological distress. This guideline does not include a cost analysis. RECOMMENDATIONS 1. Carrier screening for thalassemia and hemoglobinopathies should be offered to a woman if she and/or her partner are identified as belonging to an ethnic population whose members are at higher risk of being carriers. Ideally, this screening should be done pre-conceptionally or as early as possible in the pregnancy. (II-2A) 2. Screening should consist of a complete blood count, as well as hemoglobin electrophoresis or hemoglobin high performance liquid chromatography. This investigation should include quantitation of HbA2 and HbF. In addition, if there is microcytosis(mean cellular volume < 80 fL) and/or hypochromia (mean cellular hemoglobin < 27 pg) in the presence of a normal hemoglobin electrophoresis or high performance liquid chromatography the patient should be investigated with a brilliant cresyl blue stained blood smear to identify H bodies. A serum ferritin (to exclude iron deficiency anemia) should be performed simultaneously. (III-A) 3. If a womans initial screening is abnormal (e.g., showing microcytosis or hypochromia with or without an elevated HbA2, or a variant Hb on electrophoresis or high performance liquid chromatography) then screening of the partner should be performed. This would include a complete blood count as well as hemoglobin electrophoresis or HPLC, HbA2 and HbF quantitation,and H body staining. (III-A) 4. If both partners are found to be carriers of thalassemia or an Hb variant, or of a combination of thalassemia and a hemoglobin variant, they should be referred for genetic counselling. Ideally,this should be prior to conception, or as early as possible in the pregnancy. Additional molecular studies may be required to clarify the carrier status of the parents and thus the risk to the fetus. (II-3A) 5. Prenatal diagnosis should be offered to the pregnant woman/couple at risk for having a fetus affected with a clinically significant thalassemia or hemoglobinopathy. Prenatal diagnosis should be performed with the patients informed consent. If prenatal diagnosis is declined, testing of the child should be done to allow early diagnosis and referral to a pediatric hematology centre, if indicated. (II-3A) 6. Prenatal diagnosis by DNA analysis can be performed using cells obtained by chorionic villus sampling or amniocentesis. Alternatively for those who decline invasive testing and are at risk of hemoglobin Barts hydrops fetalis (four-gene deletion alpha-thalassemia), serial detailed fetal ultrasound for assessment of the fetal cardiothoracic ratio (normal < 0.5) should be done in a centre that has experience conducting these assessments for early identification of an affected fetus. If an abnormality is detected, a referral to a tertiary care centre is recommended for further assessment and counselling. Confirmatory studies by DNA analysis of amniocytes should be done if a termination of pregnancy is being considered. (II-3A) 7. The finding of hydrops fetalis on ultrasound in the second or third trimester in women with an ethnic background that has an increased risk of alpha-thalassemia should prompt immediate investigation of the pregnant patient and her partner to determine their carrier status for alpha-thalassemia. (III-A) VALIDATION: This guideline has been prepared by the Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists (CCMG) and the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) and approved by the Board of Directors of the CCMG and the Executive and Council of the SOGC.

Prenatal screening for and diagnosis of aneuploidy in twin pregnancies.

OBJECTIVE To provide a Canadian consensus document with recommendations on prenatal screening for and diagnosis of fetal aneuploidy (e.g., Down syndrome and trisomy 18) in twin pregnancies. OPTIONS The process of prenatal screening and diagnosis in twin pregnancies is complex. This document reviews the options available to pregnant women and the challenges specific to screening and diagnosis in a twin pregnancy. OUTCOMES Clinicians will be better informed about the accuracy of different screening options in twin pregnancies and about techniques of invasive prenatal diagnosis in twins. EVIDENCE PubMed and Cochrane Database were searched for relevant English and French language articles published between 1985 and 2010, using appropriate controlled vocabulary and key words (aneuploidy, Down syndrome, trisomy, prenatal screening, genetic health risk, genetic health surveillance, prenatal diagnosis, twin gestation). Results were restricted to systematic reviews, randomized controlled trials, and relevant observational studies. Searches were updated on a regular basis and incorporated in the guideline to August 2010. 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 national and international medical specialty societies. The previous Society of Obstetricians and Gynaecologists of Canada guidelines regarding prenatal screening were also reviewed in developing this clinical practice guideline. VALUES The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). BENEFITS, HARMS, AND COSTS There is a need for specific guidelines for prenatal screening and diagnosis in twins. These guidelines should assist health care providers in the approach to this aspect of prenatal care of women with twin pregnancies. SUMMARY STATEMENTS 1. Fetal nuchal translucency combined with maternal age is an acceptable first trimester screening test for aneuploidies in twin pregnancies. (II-2) 2. First trimester serum screening combined with nuchal translucency may be considered in twin pregnancies. It provides some improvement over the performance of screening by nuchal translucency and maternal age by decreasing the false-positive rate. (II-3) 3. Integrated screening with nuchal translucency plus first and second trimester serum screening is an option in twin pregnancies. Further prospective studies are required in this area, since it has not been validated in prospective studies in twins. (III) 4. Non-directive counselling is essential when invasive testing is offered. (III) 5. When chorionic villus sampling is performed in non-monochorionic multiple pregnancies, a combination of transabdominal and transcervical approaches or a transabdominal only approach appears to provide the best results to minimize the likelihood of sampling errors. (II-2) Recommendations 1. All pregnant women in Canada, regardless of age, should be offered, through an informed counselling process, the option of a prenatal screening test for the most common clinically significant fetal aneuploidies. In addition, they should be offered a second trimester ultrasound for dating, assessment of fetal anatomy, and detection of multiples. (I-A) 2. Counselling must be non-directive and must respect a womans right to accept or decline any or all of the testing or options offered at any point in the process. (III-A) 3. When non-invasive prenatal screening for aneuploidy is available, maternal age alone should not be an indication for invasive prenatal diagnosis in a twin pregnancy. (II-2A) If non-invasive prenatal screening is not available, invasive prenatal diagnosis in twins should be offered to women aged 35 and over. (II-2B) 4. Chorionicity has a major impact on the prenatal screening process and should be determined by ultrasound in the first trimester of all twin pregnancies. (II-2A) 5. When screening is done by nuchal translucency and maternal age, a pregnancy-specific risk should be calculated in monochorionic twins. In dichorionic twins, a fetus-specific risk should be calculated. (II-3C) 6. During amniocentesis, both amniotic sacs should be sampled in monochorionic twin pregnancies, unless monochorionicity is confirmed before 14 weeks and the fetuses appear concordant for growth and anatomy. (II-2B) 7. Prior to invasive testing or in the context of twins discordant for an abnormality, selective reduction should be discussed and made available to those requesting the procedure after appropriate counselling. (III-B) 8. Monitoring for disseminated intravascular coagulopathy is not indicated in dichorionic twin pregnancies undergoing selective reduction. (II-2B).

Use of a DNA Method, QF-PCR, in the Prenatal Diagnosis of Fetal Aneuploidies

OBJECTIVE To provide Canadian health care providers with current information on the use of quantitative fluorescent polymerase chain reaction (QF-PCR) or equivalent technology in the prenatal diagnosis of fetal chromosomal abnormalities. OPTIONS Over the last few decades, prenatal diagnosis of fetal chromosomal abnormalities has relied on conventional cytogenetic analysis of cultured amniocytes, chorionic villi, or fetal blood. In the last few years, the clinical validity of a newer technique, QF-PCR, to detect the common aneuploidies has been reported by a number of investigators. This technique has the advantage of providing rapid results for the diagnosis or exclusion of aneuploidy in chromosomes 13, 18, 21, X or Y. It is now possible to choose standard chromosome analysis or QF-PCR for the prenatal diagnosis of chromosomal abnormalities, or to perform both tests, depending on the clinical indication for testing. This document reviews the clinical utility of QF-PCR and makes recommendations for its use in the care of Canadian patients. EVIDENCE Medline and PubMed were searched for articles published in English between January 2000 and December 2010 that presented data on the use of QF-PCR versus standard cytogenetic analysis of prenatal samples. A second search was done to identify publications in English that provided results of cytogenetic analysis performed on prenatal samples for women at an increased risk of fetal aneuploidy because of maternal age, abnormal prenatal screening results, or fetal soft ultrasound markers suggestive of an increased risk of aneuploidy. Publications were included if they provided detailed information on the abnormalities detected, regardless of whether or not rapid aneuploidy screening was undertaken. Results were restricted to systematic reviews, randomized controlled trials, and relevant observational 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 national and international medical specialty societies. VALUES The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). BENEFITS, HARMS, AND COSTS This guideline promotes the use of a rapid aneuploidy DNA test for women at increased risk of having a pregnancy affected by a common aneuploidy. This will have the benefit of providing rapid and accurate results to women at increased risk of fetal Down syndrome, trisomy 13, trisomy 18, sex chromosome aneuploidy or triploidy. It will also promote better use of laboratory resources and reduce the cost of prenatal diagnosis. However, a small percentage of pregnancies with a potentially clinically significant chromosomal abnormality will remain undetected by QF-PCR but detectable by conventional cytogenetics. Recommendations 1. QF-PCR is a reliable method to detect trisomies and should replace conventional cytogenetic analysis whenever prenatal testing is performed solely because of an increased risk of aneuploidy in chromosomes 13, 18, 21, X or Y. As with all tests, pretest counselling should include a discussion of the benefits and limitations of the test. In the initial period of use, education for health care providers will be required. (II-2A) 2. Both conventional cytogenetics and QF-PCR should be performed in all cases of prenatal diagnosis referred for a fetal ultrasound abnormality (including an increased nuchal translucency measurement > 3.5 mm) or a familial chromosomal rearrangement. (II-2A) 3. Cytogenetic follow-up of QF-PCR findings of trisomy 13 and 21 is recommended to rule out inherited Robertsonian translocations. However, the decision to set up a back-up culture for all cases that would allow for traditional cytogenetic testing if indicated by additional clinical or laboratory information should be made by each centre offering the testing according to the local clinical and laboratory experience and resources. (III-A) 4. Other technologies for the rapid detection of aneuploidy may replace QF-PCR if they offer a similar or improved performance for the detection of trisomy 13, 18, 21, and sex chromosome aneuploidy. (III-A).

Mid-Trimester Amniocentesis Fetal Loss Rate

OBJECTIVE To determine the postprocedure loss rate for mid-trimester genetic amniocentesis. OUTCOME Reduction of benign biopsy rates. BENEFITS To provide better advice for women about the risks and benefits of mid-trimester genetic amniocentesis, and to ensure that women are given sufficient information/counselling to make a decision about screening. SUMMARY STATEMENT The risk of postprocedure loss is unique to the individual and is based on multiple variables.