Presentation: Pregnant woman experiencing recurrent miscarriage

A couple attend clinic having had three first-trimester miscarriages. The woman has had one previous spontaneous vaginal delivery with a previous partner and has no live children with her current partner.

• Genomic testing of the products of conception is typically indicated after a couple have had three pregnancy losses.
• After three pregnancy losses, genomic testing may be offered for all subsequent pregnancy losses, unless a genomic cause is identified.
• If genomic testing of the pregnancy loss has not been possible, after five untested pregnancy losses a couple may, in some instances, be offered genomic testing themselves.

• 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 guidance on recurrent early pregnancy loss. Referral to a recurrent pregnancy loss clinic is advised.
• Referral to clinical genetics is not routinely indicated for recurrent early pregnancy loss, but may be advisable where testing identifies a genomic cause or there is a known family history of a genetic condition.
• Genomic testing options may include the following.
  • R318 Recurrent miscarriage with products of conception available for testing. Patient are eligible for this testing for the third, and each subsequent, miscarriage where products of conception are available. It includes:
    • R318.1 Genomewide common aneuploidy testing, which includes trisomy 21, trisomy 18, trisomy 13 and certain sex chromosomal anomalies; and/or
    • R318.2 Genomewide microarray testing to look for any duplicated or deleted chromosomal segments.
  • R464 Recurrent miscarriage where products of conception are not available for testing (parental karyotype). This should be offered for:
    • recurrent miscarriage (defined as three or more miscarriages) where testing of the pregnancy loss has not been possible due to an unsuitable or failed sample, and where no previous losses have been successfully tested and reported (note that although parental karyotype analysis is available following a failed test, its usefulness is limited and the most informative pathway is to test any subsequent pregnancy loss); and
    • recurrent miscarriage (five or more pregnancy losses) where none of the previous losses have been successfully tested and reported (for example, biochemical pregnancies) and no products are available for testing.
• Note: Targeted chromosomal analysis should be offered to both parents where product-of-conception testing has shown an unbalanced chromosomal anomaly
  • R465 Familial cytogenic rearrangement – karyotype or targeted chromosomal analysis.
• Where there are fewer than three early pregnancy losses but other features suggestive of a chromosomal anomaly or genetic cause are present, alternative testing pathways can be considered. Discussion with clinical genetics services may be required. Testing may include:
  • R22 Fetus with a likely chromosomal abnormality: This is for cases of isolated miscarriage with additional features suggestive of chromosome anomaly.
  • R27 Paediatric disorders: This is for cases of isolated miscarriage with multiple major structural anomalies where a monogenic condition is highly likely. Testing is via whole genome sequencing (WGS).
  • R412 Fetal anomalies with a likely genetic cause – non urgent: This can be used in cases of fetal anomaly with a likely genetic cause, where testing with R27 is not possible (for example, when there is insufficient DNA for WGS).
• For tests that do not include WGS, including R318, R464, R465, R22 and R412:
  • you can use your local Genomic Laboratory Hub test order form and consent (record of discussion, or RoD) form.
• For tests that are undertaken using WGS, including R27, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents where available, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support in completing WGS-specific forms); and
  • complete an NHS GMS RoD form for each person being tested – for example, if you are undertaking trio testing of an affected child and their parents, you will need three RoD forms (see How to complete a record of discussion form for support).
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (typically a green-topped tube). For more information, 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

• NHS England: National Genomic Test Directory

References:

• Regan L, Rai R, Saravelos S and others. ‘Recurrent miscarriage Green-top Guideline no. 17‘. British Journal of Obstetrics and Gynaecology 2023: volume 130, issue 12, pages e9–e39. DOI: 10.1111/1471-0528.17515

For patients

• Royal College of Obstetricians & Gynaecologists: Recurrent miscarriage