Presentation: Pregnant woman with a higher-chance first-trimester combined screening test result

A pregnant woman presented for her combined first-trimester screening. During ultrasound, measurements of the fetal crown-rump length and fetal nuchal translucency were taken, while maternal serum PAPP-A and free beta-HCG measurements were obtained via laboratory tests. A statistical chance calculation was performed by clinical scientists to estimate the chance of Down syndrome (trisomy 21) and a joint chance for Edwards (trisomy 18) and Patau (trisomy 13) syndromes. Screening test results show that the woman is a ‘higher-chance’ (1-in-2 to 1-in-150 chance ratio) for the conditions. She asks if there are any other tests that can be carried out.

Consider genomic testing when:

• there is a higher-chance (1-in-2 to 1-in-150 chance ratio) first-trimester combined screening result; or
• findings characteristic of a genetic condition in the fetus are made during an ultrasound scan.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• For information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Refer to local and national NHS Fetal Anomaly Screening Programme (FASP) guidance regarding first-trimester screening.
• A further discussion with the screening co-ordinator or a fetal medicine midwife is usually warranted to discuss options around non-invasive prenatal testing (NIPT) or diagnostic tests, as this technology can provide a more sensitive screening test for information and reproductive choice.
• If anomalies are noted on the ultrasound scan, a referral to a fetal medicine unit is usually recommended for a detailed scan and a review to determine which genomic tests are appropriate.
• Referral to clinical genetics services is not routinely indicated for higher-chance first-trimester screening results. In the case of suspected anomalies, a referral may be considered.
• Depending on the clinical scenario, a range of different genomic tests may be considered, as outlined below.
• • Where there is an isolated higher-chance screening result:
• • • R401 Common aneuploidy screening: This will process only a QF-PCR and should be requested in cases in which the pregnant woman might have a diagnosis of aneuploidy (trisomy 21, 18 or 13).
• • Where there are concerns regarding an atypical phenotype, the following may be considered:
• • • R22 Fetus with a likely chromosomal abnormality: This will process both genome-wide common aneuploidy testing and genome-wide microarray.
• • Where there are multiple or complex anomalies and/or the above testing is non-diagnostic, (rapid) fetal exome sequencing may be considered:
• • • R21 Fetal anomalies with a likely genetic cause: This is a large panel fetal exome sequence. Referral to clinical genetics and multidisciplinary team discussion is required.
• NIPT is available via the National Genomic Test Directory for women with a previous pregnancy with full trisomy 21, 18 or 13 (R445 Common aneuploidy testing – NIPT). NIPT is also offered as part of an evaluative roll-out, which is not currently part of the test directory. Contact your local screening midwife or fetal medicine team for information and support.
• None of the tests outlined above use whole genome sequencing, so you should use your local Genomic Laboratory Hub test order form and consent (record of discussion, or RoD) form.
• Parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
• For R21 Fetal anomalies with a likely genetic cause, you will need to:
• • ensure that the required multidisciplinary discussions have taken place, including fetal medicine, clinical genetics and the regional specialist R21 laboratory, and that there is an agreement that R21 can be offered;
• • inform your local laboratory of the plan for R21 testing, so that they can arrange the necessary exports to the specialist R21 laboratories in a timely fashion;
• • fill in the R21-specific test order form;
• • take informed consent for both parents, documented on R21-specific RoD discussion forms;
• • send blood samples for both parents to the local laboratory (if only one parent is available, let the lab know – testing can still proceed, but there will be a small reduction in diagnostic yield); and
• • arrange and send a chorionic villus sample or amniocentesis sample for the fetus.
• Note that, in Scotland, referral to clinical genetics is required for consideration of rapid prenatal exome testing.
• All of the above tests are DNA based and require an amniocentesis or chorionic villus sample, or a fetal blood sample in an EDTA (typically purple-topped) tube. For more information about different sample types, see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• Gov.uk Guidance: NHS Fetal Anomaly Screening Programme (FASP): Programme overview
• Gov.uk Guidance: Screening for Down’s syndrome, Edwards’ syndrome and Patau’s syndrome
• NHS England: National Genomic Test Directory
• NHS North Thames and NHS West Midlands, Oxford and Wessex Genomic Laboratory Hubs: National Genomic Test Directory Clinical Indication R21 Rapid prenatal exome sequencing test request (PDF, two pages)
• NHS North Thames and NHS West Midlands, Oxford and Wessex Genomic Laboratory Hubs: Record of discussion regarding prenatal exome sequencing (PDF, two pages)
• Royal College of Obstetricians and Gynaecologists: Amniocentesis and chorionic villus sampling (Green-top Guideline no. 8)

References:

• International Society of Ultrasound in Obstetrics and Gynecology, Bilardo CM, Chaoui R and others. ‘ISUOG Practice Guidelines (updated): Performance of 11–14-week ultrasound scan‘. Ultrasound in Obstetrics and Gynecology 2023: volume 61, issue 1, pages 127–143. DOI: 10.1002/uog.26106

For patients

• Antenatal Results & Choices
• Down’s Syndrome Association
• Gov.uk Guidance: Your choices after a higher-chance screening result
• NHS England: Screening tests in pregnancy
• Positive about Down syndrome
• SOFT UK
• NHS North Thames and NHS West Midlands, Oxford and Wessex Genomic Laboratory Hubs: Information on prenatal exome sequencing for parents