Guideline No. 456: Prenatal Screening for Fetal Chromosomal Anomalies

Objective

To review the available prenatal aneuploidy screening options and to provide updated clinical guidelines for reproductive care providers.

Target Population

All pregnant persons receiving counselling and providing informed consent for prenatal screening.

Benefits, Harms, and Costs

Implementation of the recommendations in this guideline should increase clinician competency to offer counselling for prenatal screening options and provide appropriate interventions. Given the variety of available options for prenatal screening with different performance, cost, and availability across Canada, appropriate counselling is of paramount importance to offer the best individual choice to Canadian pregnant persons. Prenatal screening may cause anxiety, and the decisions about prenatal diagnostic procedures are complex given the potential risk of fetal loss.

Evidence

Published literature was retrieved through searches of Medline, PubMed, and the Cochrane Library in and prior to July 2023, using an appropriate controlled vocabulary (prenatal diagnosis, amniocentesis, chorionic villi sampling, non-invasive prenatal screening) and key words (prenatal screening, prenatal genetic counselling). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies written in English and published from January 1995 to July 2023.

Validation Methods

The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations).

Intended Audience

Health care providers involved in prenatal screening, including general practitioners, obstetricians, midwives, maternal–fetal medicine specialists, geneticists, and radiologists.

Social Media Abstract

Non-invasive prenatal screening is the most accurate method for detecting major aneuploidies. It is not universally available in the public health system and has some limitations.

SUMMARY STATEMENTS

• 1.
  First-trimester ultrasound (at 11–14 weeks gestation) offers many advantages for prenatal screening and pregnancy management, including accurate dating, determination of twin chorionicity, and early detection of some major structural abnormalities, regardless of the aneuploidy screening options (high).
• 2.
  The risk of fetal loss after prenatal invasive testing is lower than the rates currently cited and appears to be negligible when these interventions are compared with control groups of patients with the same risk profiles. Second-trimester amniocentesis may increase the risk of pregnancy loss, but it is not possible to quantify this increase precisely. Transcervical chorionic villous sampling may be associated with a higher risk of pregnancy loss than transabdominal chorionic villous sampling and second-trimester amniocentesis (low).
• 3.
  Maternal circulating cell-free DNA is the most accurate method of early prenatal screening for common trisomies (21, 18, 13). Due to its superior performance, circulating cell-free DNA screening for common trisomies should be discussed as an option with all pregnant persons (high).
• 4.
  In most provinces in Canada, first-tier cell-free DNA screening is not currently offered to all pregnant persons by the public health care system owing to cost and resource issues. Some provinces offer public cell-free DNA screening for some indications. Offering cell-free DNA in a contingent model (after conventional screening) is a less costly option that has the potential to achieve a detection rate above 90% with an invasive testing rate below 3%. First-tier screening by cell-free DNA could become the first-line option in the future if costs decrease and if technical resources are made available (moderate).
• 5.
  In twin pregnancies, the most accurate screening for aneuploidy is achieved with cell-free DNA screening, although with weaker evidence and a higher rate of test failure due to lower fetal /placental fraction. First-trimester serum screening combined with nuchal translucency may also be considered in twin pregnancies (moderate).
• 6.
  The presence of specific ultrasound soft markers associated with fetal trisomy 21 (echogenic intracardiac focus) or trisomy 18 (choroid plexus cysts) at the time of the second-trimester ultrasound is not clinically relevant because of its poor predictive value, and such findings do not warrant further testing. The value of other soft markers, including mild ventriculomegaly, absent nasal bone, renal pyelectasis, thickened nuchal fold, and echogenic bowel, is weak in pregnancies at low risk for aneuploidy based on previous screening (moderate).

RECOMMENDATIONS

• 1.
  All pregnant persons in Canada, regardless of age, should be offered, through an informed counselling process with shared decision-making, the option of a prenatal screening test for the most common fetal aneuploidies and for major fetal anomalies (strong, high).
• 2.
  Health care providers should be aware of the screening modalities available in their province or territory. A reliable provincial system should ensure timely reporting of screening results. Prenatal screening programs should be implemented with resources that support audited screening and laboratory services, ultrasound services, genetic counselling, and patient and health care provider education. In addition, there must be flexibility and funding to adjust the program based on new technology and protocols (strong, high).
• 3.
  A discussion of the risks, benefits, expectations, and alternatives of the various prenatal screening and diagnostic options should be undertaken with all patients prior to prenatal aneuploidy screening. Following this, patients should be offered the choice of a) no aneuploidy screening; b) standard aneuploidy prenatal screening based on locally offered programs, with various combinations of serum screening and nuchal translucency; c) maternal plasma cell-free DNA screening, where available, with the understanding that it may not be publicly funded; or d) invasive diagnostic testing using chorionic villus sampling or amniocentesis with the understanding that it may not be publicly funded or even offered as a first-tier test (strong, high).
• 4.
  Regardless of aneuploidy screening choice, all pregnant persons should be offered a first-trimester fetal ultrasound, (optimally between 11- and 14-weeks gestation), to assess viability, gestational age, number of fetuses, chorionicity in multiples, early fetal anatomy, and nuchal translucency. Maternal serum screening (with or without nuchal translucency measurement for aneuploidy risk estimation) should not be performed if cell-free DNA screening is performed or planned (strong, high).
• 5.
  A high nuchal translucency measurement (above 3.5 mm) is a marker for fetal cardiac and other structural anomalies, as well as genetic conditions such as RASopathies (including Noonan syndrome). Genetic counselling and invasive testing are strongly recommended for diagnosis, followed by advanced genetic testing and ultrasound follow-up (strong, high).
• 6.
  Training of ultrasound providers, including maternal–fetal medicine specialists, radiologists, and sonographers, should be promoted to improve access to high-quality first-trimester ultrasound services for all Canadians. (strong, moderate).
• 7.
  Persons considering maternal plasma cell-free DNA screening should be informed that a) it is a highly effective screening test for the common fetal trisomies (21, 18, 13), when performed after 10 weeks gestation; b) there is a possibility of a failed (‘no-call’) test, false-negative or false-positive fetal aneuploidy result, or unexpected fetal or maternal result; c) all positive maternal cell-free DNA screening results should be confirmed with diagnostic fetal testing; d) routine cell-free DNA screening for fetal microdeletions is not currently recommended; e) routine cell-free DNA screening for sex chromosome abnormalities is debated and not currently recommended (strong, high).
• 8.
  If a fetal structural abnormality (not a soft marker) is identified during the first- or second-trimester ultrasound, regardless of previous screening test results, genetic counselling and invasive diagnostic testing should be offered, with rapid aneuploidy detection and reflex microarray analysis or exome/genome sequencing, if rapid aneuploidy detection is normal or inconclusive. The diagnostic role of fetal exome/genome sequencing is a rapidly evolving area, and maternity care providers should be aware of this technology (strong, high).
• 9.
  The presence of an isolated fetal soft marker in the second trimester should not be used to adjust the a priori risk for aneuploidy in persons at low risk based on previous screening (strong, high).