Presentation: Pregnant woman with a previous history of stillbirth

A woman books her pregnancy at eight weeks’ gestation. She had a previous intrauterine death (IUD) at 35 weeks’ gestation. All appropriate fetal loss tests were completed following the birth, and the autopsy identified some structural malformations. She and her partner of worried that there may be a genetic cause for their loss, and they want to better understand the risks for future pregnancies.

• Many stillbirths cannot be attributed to any cause. The most common identifiable cause of stillbirth is disorders of placental function, often manifesting as poor fetal growth.
• Up to 1 in 4 (25%) of all stillbirths have a genetic cause. This is more likely when fetal structural anomalies are identified.
• Genomic testing should be considered where:
  • fetal structural anomalies are identified prenatally and/or postnatally;
  • tissues or samples from the previous pregnancy are available; and/or
  • there is a family history of a genetic condition that could be relevant to the previous pregnancy.
• Testing should be primarily targeted at cases in which it may influence future pregnancies.

• 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 the pregnant woman for consultant-led care via local pathways.
• If there is no clear cause for the previous pregnancy loss and a monogenic cause is felt to be likely, refer the case to clinical genetics services for review. Genomic testing in this situation is determined by multidisciplinary team review.
• Genomic testing of previous pregnancies may be considered if the multidisciplinary team deems it appropriate, and tissues or samples are available.
• • Testing of fetuses with identified congenital anomalies with a likely genetic cause is ideally via R27 Paediatric disorders, or via R412 Fetal anomalies with a likely genetic cause (non urgent) where there is insufficient DNA for whole genome sequencing (WGS).
• • If the management of a current pregnancy would be altered by a genomic diagnosis, these processes can often be expedited. In this situation, testing via R14 (Acutely unwell children with a likely monogenic disorder) would be considered.
• • In the absence of identified congenital anomalies and other likely causes of death or stillbirth from 24 weeks’ gestation, more limited genomic testing is available. In this case, testing is via R22 Fetus with a likely chromosomal abnormality (see below).
• Where there is a family history of a genetic condition relevant to the affected pregnancy, it may be possible to clarify the recurrence risk without testing the previous affected pregnancy – for example, by clarifying the carrier status of the parents.
• • If there is also evidence of fetal anomaly in a current pregnancy, the following testing may be considered for the current pregnancy:
• • • R22 Fetus with a likely chromosomal abnormality. This will process both:
• • • • R22.1 Genome-wide common aneuploidy testing; and
• • • • R22.2 Chromosomal microarray.
• • • Where there are multiple or complex anomalies, fetal exome sequencing may be considered via R21 Fetal anomalies with a likely genetic cause.
• • • • Referral to clinical genetics and/or multidisciplinary discussion is required.
• • In this situation, it is important to alert the laboratory to the previous stillbirth and provide detailed information, especially if DNA from the previous pregnancy loss is available.
• For tests that are undertaken using WGS, including R27 and R14, 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);
• • complete an NHS GMS record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected individual and their parents, you will need three RoD forms (see How to complete an RoD form for support); and
• • submit parental samples alongside the child’s sample (this is trio testing) to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• For tests that do not include WGS, including R22 and R412:
• • you can use your local Genomic Laboratory Hub test order and consent (RoD) forms; and
• • 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 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

• 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 & Gynaecologists: Care of late intrauterine fetal death and stillbirth (Green-top Guidelines No.55)

For patients

• Antenatal Results & Choices: Another pregnancy
• NHS North Thames and NHS West Midlands, Oxford and Wessex Genomic Laboratory Hubs: Information on prenatal exome sequencing for parents (PDF, two pages)
• Royal College of Obstetricians & Gynaecologists: When your baby dies before birth: Patient information
• Sands
• Tommy’s: Pregnant after a stillbirth