Lola Cartier

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).

Current Status in Non-Invasive Prenatal Detection of Down Syndrome, Trisomy 18, and Trisomy 13 Using Cell-Free DNA in Maternal Plasma

OBJECTIVE To provide a review of published studies on the use of cell-free fetal DNA in maternal plasma for the non-invasive diagnosis of Down syndrome, trisomy 18, and trisomy 13. EVIDENCE PubMed was searched for articles published between 2006 and October 2012, using appropriate key words (e.g., non-invasive prenatal diagnosis, Down syndrome, cell-free fetal DNA, aneuploidy screening). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated in the guideline to October 31, 2012. 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 studies reviewed were classified according to criteria described by the Canadian Task Force on Preventive Health Care, and the recommendations for practice were ranked according to this classification (Table 1). Recommendations 1. Non-invasive prenatal testing using massive parallel sequencing of cell-free fetal DNA to test for trisomies 21, 18, and 13 should be an option available to women at increased risk in lieu of amniocentesis. Pretest counselling of these women should include a discussion of the limitations of non-invasive prenatal testing. (II-2A) 2. No irrevocable obstetrical decision should be made in pregnancies with a positive non-invasive prenatal testing result without confirmatory invasive diagnostic testing. (II-2A) 3. Although testing of cell-free fetal DNA in maternal plasma appears very promising as a screening test for Down syndrome and other trisomies, studies in average-risk pregnancies and a significant reduction in the cost of the technology are needed before this can replace the current maternal screening approach using biochemical serum markers with or without fetal nuchal translucency ultrasound. (III-A).

Pregnancy Outcomes After Assisted Human Reproduction

OBJECTIVE To review the effect of assisted human reproduction (AHR) on perinatal outcomes, to identify areas requiring further research with regard to birth outcomes and AHR, and to provide guidelines to optimize obstetrical management and counselling of prospective Canadian parents. OUTCOMES This document compares perinatal outcomes of different types of AHR pregnancies with each other and with those of spontaneously conceived pregnancies. Clinicians will be better informed about the adverse outcomes that have been documented in association with AHR, including obstetrical complications, adverse perinatal outcomes, multiple gestations, structural congenital abnormalities, chromosomal abnormalities, and imprinting disorders. EVIDENCE Published literature was retrieved through searches of MEDLINE and the Cochrane Library from January 2005 to December 2012 using appropriate controlled vocabulary and key words (assisted reproduction, assisted reproductive technology, ovulation induction, intracytoplasmic sperm injection, embryo transfer, and in vitro fertilization). Results were not restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies; studies of all designs published in English from January 2005 to December 2012 were reviewed, and additional publications were identified from the bibliographies of these articles. Searches were updated on a regular basis and incorporated in the guideline to August 2013. 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 in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Summary Statements 1. There is increasing evidence that infertility or subfertility is an independent risk factor for obstetrical complications and adverse perinatal outcomes, even without the addition of assisted human reproduction. (II-2) 2. The relative risk for an imprinting phenotype such as Silver-Russell syndrome, Beckwith-Wiedemann syndrome, or Angelman syndrome is increased in the assisted reproduction population, but the actual risk for one of these phenotypes to occur in an assisted pregnancy is estimated to be low, at less than 1 in 5000. The exact biological etiology for this increased imprinting risk is likely heterogeneous and requires more research. (II-2) Recommendations 1. All men with severe oligozoospermia or azoospermia (sperm count < 5 million/hpf) should be offered genetic/clinical counselling, karyotype assessment for chromosomal abnormalities, and Y-chromosome microdeletion testing prior to in vitro fertilization with intracytoplasmic sperm injection. (II-2A) 2. All men with unexplained obstructive azoospermia should be offered genetic/clinical counselling and genetic testing for cystic fibrosis prior to in vitro fertilization with intracytoplasmic sperm injection. (II-2A) 3. Multiple pregnancy is the most powerful predictive factor for adverse maternal, obstetrical, and perinatal outcomes. Couples should be thoroughly counselled about the significant risks of multiple pregnancies associated with all assisted human reproductive treatments. (II-2A) 4. The benefits and cumulative pregnancy rates of elective single embryo transfer support a policy of using this protocol in couples with good prognosis for success, and elective single embryo transfer should be strongly encouraged in this population. (II-2A) 5. To reduce the incidence of multiple pregnancy, health care policies that support public funding for assisted human reproduction, with regulations promoting best practice regarding elective single embryo transfer, should be strongly encouraged. (II-2A) 6. Among singleton pregnancies, assisted reproductive technology is associated with increased risks of preterm birth and low birth weight infants, and ovulation induction is associated with an increased risk of low birth weight infants. Until sufficient research has clarified the independent roles of infertility and treatment for infertility, couples should be counselled about the risks associated with treatment. (II-2B) There is a role for closer obstetric surveillance of women who conceive with assisted human reproduction. (III-L) 7. There is growing evidence that pregnancy outcomes are better for cryopreserved embryos fertilized in vitro than for fresh embryo transfers. This finding supports a policy of elective single embryo transfer for women with a good prognosis (with subsequent use of cryopreserved embryos as necessary), and may reassure women who are considering in vitro fertilization. (II-2A) 8. Women and couples considering assisted human reproduction and concerned about perinatal outcomes in singleton pregnancies should be advised that (1) intracytoplasmic sperm injection does not appear to confer increased adverse perinatal or maternal risk over standard in vitro fertilization, and (2) the use of donor oocytes increases successful pregnancy rates in selected women, but even when accounting for maternal age, can increase the risks of low birth weight and preeclampsia. (II-2B) 9. Any assisted reproductive technology procedure should be prefaced by a discussion of fetal outcomes and the slight increase in the risk of congenital structural abnormalities, with emphasis on known confounding factors such as infertility and body mass index. (II-2B) 10. In pregnancies achieved by artificial reproductive technology, routine anatomic ultrasound for congenital structural abnormalities is recommended between 18 and 22 weeks. (II-2A) 11. Pregnancies conceived by intracytoplasmic sperm injection may be at increased risk of chromosomal aberrations, including sex chromosome abnormalities. Diagnostic testing should be offered after appropriate counselling. (II-2A) 12. The possible increased risk for late onset cancer due to gene dysregulation for tumour suppression requires more long-term follow-up before the true risk can be determined. (III-A) 13. The clinical application of preimplantation genetic testing in fertile couples must balance the benefits of avoiding disease transmission with the medical risks and financial burden of in vitro fertilization. (III-B) 14. Preimplantation screening for aneuploidy is associated with inconsistent findings for improving pregnancy outcomes. Any discussion of preimplantation genetic screening with patients should clarify that there is no adequate information on the long-term effect of embryo single cell biopsy. (I-C).

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).

Investigation and Management of Non-immune Fetal Hydrops

OBJECTIVE To describe the current investigation and management of non-immune fetal hydrops, with a focus on treatable or recurring etiologies. OUTCOMES To provide better counselling and management in cases of prenatally diagnosed non-immune hydrops. EVIDENCE Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in 2011 using key words (non-immune hydrops fetalis, fetal hydrops, fetal therapy, fetal metabolism). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, observational studies, and significant case reports. Additional publications were identified from the bibliographies of these articles. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to May 2012. 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. BENEFITS, HARMS, AND COSTS These guidelines educate readers about the causes of non-immune fetal hydrops and its prenatal counselling and management. It also provides a standardized approach to non-immune fetal hydrops, emphasizing the search for prenatally treatable conditions and recurrent genetic etiologies. VALUES The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). RECOMMENDATIONS 1. All patients with fetal hydrops should be referred promptly to a tertiary care centre for evaluation. Some conditions amenable to prenatal treatment represent a therapeutic emergency after 18 weeks. (II-2A) 2. Fetal chromosome analysis and genetic microarray molecular testing should be offered where available in all cases of non-immune fetal hydrops. (II-2A) 3. Imaging studies should include comprehensive obstetrical ultrasound (including arterial and venous fetal Doppler) and fetal echocardiography. (II-2A) 4. Investigation for maternal-fetal infections, and alpha-thalassemia in women at risk because of their ethnicity, should be performed in all cases of unexplained fetal hydrops. (II-2A) 5. To evaluate the risk of fetal anemia, Doppler measurement of the middle cerebral artery peak systolic velocity should be performed in all hydropic fetuses after 16 weeks of gestation. In case of suspected fetal anemia, fetal blood sampling and intrauterine transfusion should be offered rapidly. (II-2A) 6. All cases of unexplained fetal hydrops should be referred to a medical genetics service where available. Detailed postnatal evaluation by a medical geneticist should be performed on all cases of newborns with unexplained non-immune hydrops. (II-2A) 7. Autopsy should be recommended in all cases of fetal or neonatal death or pregnancy termination. (II-2A) Amniotic fluid and/or fetal cells should be stored for future genetic testing. (II-2B).

Fetal and perinatal autopsy in prenatally diagnosed fetal abnormalities with normal karyotype.

OBJECTIVE To review the information on fetal and perinatal autopsies, the process of obtaining consent, and the alternative information-gathering options following a prenatal diagnosis of non-chromosomal malformations, and to assist clinicians in providing postnatal counselling regarding fetal diagnosis and recurrence risks. OUTCOMES To provide better counselling about fetal and perinatal autopsies for women and families who are dealing with a prenatally diagnosed non-chromosomal fetal anomaly. EVIDENCE Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in 2009 and 2010, using appropriate key words (fetal autopsy, postmortem, autopsy, perinatal postmortem examination, autopsy protocol, postmortem magnetic resonance imaging, autopsy consent, tissue retention, autopsy evaluation). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. Additional publications were identified from the bibliographies of these articles. There were no date or language restrictions. 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. BENEFITS, HARMS, AND COSTS This update educates readers about (1) the benefits of a fetal perinatal autopsy, (2) the consent process, and (3) the alternatives when the family declines autopsy. It also provides a standardized approach to fetal and perinatal autopsies, emphasizing pertinent additional sampling when indicated. 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). Recommendations 1. Standard autopsy should ideally be an essential part of fully investigating fetal loss, stillbirths, and neonatal deaths associated with non-chromosomal fetal malformations. (II-3A) 2. Clinicians and health care providers approaching parents for autopsy consent should discuss the options for a full, limited, or step-wise postmortem examination; the issue of retained fetal tissues; and the value of autopsy and the possibility that the information gained may not benefit them but may be of benefit to others. This information should be provided while respecting the personal and cultural values of the families. (III-A) 3. If parents are unwilling to give consent for a full autopsy, alternatives to full autopsy that provide additional clinical information must be presented in a manner that includes disclosure of limitations. (III-A) 4. External physical examination, medical photographs, and standard radiographic or computed tomography should be offered in all cases of fetal anomaly(ies) of non-chromosomal etiology. (II-2A) 5. Well-designed, large prospective studies are needed to evaluate the accuracy of postmortem magnetic resonance imaging. It cannot function as a substitute for standard full autopsy. (III-A) 6. The fetal and perinatal autopsies should be performed by trained perinatal or pediatric pathologists. (II-2A) 7. The need for additional sampling is guided by the results of previous prenatal and/or genetic investigations, as well as the type of anomalies identified in the fetus. Fibroblast cultures may allow future laboratory studies, particularly in the absence of previous karyotyping or if a biochemical disorder is suspected, and DNA analysis. (II-3A) 8. In cases requiring special evaluation, the most responsible health care provider should have direct communication with the fetopathologist to ensure that all necessary sampling is performed in a timely manner. (II-3A) 9. The most responsible health care providers must see the families in follow-up to share autopsy findings, plan for the management of future pregnancies, obtain consent for additional testing, and offer genetic counselling to other family members when appropriate. (III-A).

Prenatal Screening, Diagnosis, and Pregnancy Management of Fetal Neural Tube Defects

OBJECTIVE To provide obstetrical and genetic health care practitioners with guidelines and recommendations for prenatal screening, diagnosis, and obstetrical management of fetal open and closed neural tube defects (OCNTD). OPTIONS This review includes prenatal screening and diagnostic techniques currently being used for the detection of OCNTD including maternal serum alpha fetoprotein screening, ultrasound, fetal magnetic resonance imaging, and amniocentesis. OUTCOMES To improve prenatal screening, diagnosis, and obstetrical management of OCNTD while taking into consideration patient care, efficacy, cost, and care procedures. EVIDENCE Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in November, 2013, using appropriate controlled vocabulary and key words (e.g., prenatal screening, congenital anomalies, neural tube defects, alpha fetoprotein, ultrasound scan, magnetic resonance imaging). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from 1977 to 2012. Searches were updated on a regular basis and incorporated in the guideline to November 30, 2013. 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. An online survey of health care practitioners was also reviewed. VALUES The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). BENEFITS, HARMS, AND COSTS This review will provide health care practitioners with a better understanding of the available prenatal screening methods for OCNTD and the benefits and risks associated with each technique to allow evidenced-based decisions on OCNTD screening, diagnosis, and obstetrical management.

Counselling Considerations for Prenatal Genetic Screening

This document has been developed to aid clinicians in counselling patients about prenatal screening and to provide assistance in counselling about both positive and negative screening results.