Preimplantation genetic testing.

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 Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice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

Diagnosing chromosomal abnormalities from "big" to "small" with molecular cytogenetic technology.

We reviewed the available molecular cytogenetic techniques and their potential use in prenatal diagnosis of fetuses with multiple congenital anomalies and a "normal" standard chromosomal karyotype. We searched Medline to identify reports published after 1995 that were related to molecular prenatal diagnosis. After review, we reached the following conclusions: 1. In fetuses with a normal standard karyotype result, common chromosomal microdeletion syndromes may be suspected based on the pattern of congenital anomalies seen on prenatal ultrasound. 2. When a microdeletion syndrome is suspected based on the pattern of fetal anomalies, FISH testing for the specific molecular locus should be undertaken. 3. Routine chromosome analysis, which has been the gold standard for prenatal cytogenetic diagnosis, may in the future be replaced by microarray technology with increased diagnostic capability for smaller, submicroscopic genetic alterations associated with postnatal morbidity. 4. Microarray technology has been shown to increase our ability to make a diagnosis of known or new chromosomal deletion syndromes in pediatric populations with developmental delay. The use of this technology for prenatal diagnosis is currently limited but is likely to expand.

New molecular techniques for the prenatal detection of chromosomal aneuploidy.

OBJECTIVE: To review the molecular genetic techniques currently available for rapid prenatal diagnosis of fetal aneuploidy, as well as those still under investigation. OPTIONS: Limited to introductory discussion of rapid aneuploidy detection methods. EVIDENCE: Medline was searched for articles related to the topic that were published after 1992. This document represents an abstraction of the information. VALUES: This update was prepared by the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. BENEFITS, HARMS, AND COSTS: This update provides information about methods of rapid aneuploidy detection using molecular techniques and the evidence supporting their use in prenatal diagnosis. These methods are reliable and cost-effective for detecting the targeted fetal aneuploidies, but are limited in their ability to detect non-aneuploid chromosome abnormalities, some of which are clinically significant.

Unexplained elevated maternal serum alpha-fetoprotein and/or human chorionic gonadotropin and the risk of adverse outcomes.

OBJECTIVE: The study was undertaken to determine the risks of adverse obstetric outcomes in pregnant women with unexplained elevations of maternal serum alpha-fetoprotein (MSAFP) and/or human chorionic gonadotropin (hCG) and to determine whether these risks vary by prepregnancy risk status. STUDY DESIGN: All women who underwent double-marker screening (MSAFP+hCG) between 1994 and 2000 and were delivered of an infant in Nova Scotia, Canada, during this period were identified from a hospital serum screening database and a provincial perinatal database. Patients with inaccurate dating, major structural anomalies, or chromosomal abnormalities were excluded. The primary outcomes studied were preeclampsia, abruptio placentae, fetal growth restriction, fetal death, and preterm birth. Women with medical or previous obstetric complications were designated high risk. Logistic regression, controlling for confounding factors, was used to estimate the relative risks (RRs) and 95% CI for elevated levels of MSAFP and/or hCG and each of the outcomes. RESULTS: Among the 14,374 women who met the study criteria, 5,789 were designated high risk. Except for abruptio placentae, unexplained elevated MSAFP or elevated hCG levels were independently associated with all the outcomes in both high- and low-risk women. Elevated screening values were associated with increased risk of abruptio placentae among low-risk women only. Particularly large RRs were seen for fetal death in both high- and low-risk women (RR=4.9, 95% CI 2.7-8.7 for elevated MSAFP or hCG in high- and low-risk women combined). CONCLUSION: Unexplained elevated levels of MSAFP and/or hCG are associated with an increased risk of most pregnancy complications. Increased antenatal surveillance of these patients is important regardless of prepregnancy risk status.