Pregnancy loss should not stop urgent genomic investigation of fetal malformations

In the National Health Service in England, if a pregnancy approved for rapid prenatal-exome sequencing (“R21”) ends with miscarriage, stillbirth, termination or neonatal death, the testing moves to a non-urgent pathway. The longer turnaround time means women awaiting results may become pregnant. This study examines this occurrence in a small cohort and the impact on clinical care. Subgroup analysis of data from the first 22 months of R21 testing in the West Midlands, UK. R21 cases which did not proceed to the reporting stage because of pregnancy loss were identified. A case note review selected cases where a subsequent pregnancy occurred before a monogenic etiology of the “index case” had been confirmed or excluded. Eighty-five pregnancies were registered for R21 between 01/10/20 and 18/08/22. In 18 cases, the urgent R21 pathway was halted because of pregnancy loss, and non-urgent testing was planned. Notification of 8 pregnancies in couples ‘at risk’ was received before reporting of the non-urgent genomic results. Testing was expedited in 6 cases (demonstrating 1 diagnosis, 1 uncertain finding and 4 cases with no pathogenic variant). Of these, 1 fetus had a recurrent major brain anomaly leading to re-analysis of the trio by whole-genome sequencing, which identified a pathogenic variant. Four of the new pregnancies had healthy livebirths. Some 44% of parents after a pregnancy with fetal malformation and bereavement, conceived soon after their loss without knowing the cause. Deprioritising genomic analysis saves limited resources for urgent cases (ongoing pregnancies/acutely unwell neonates) and allows time for perinatal pathology input. However, delays can cause anxiety for parents who want answers. Reporting timescales and contraception advice must be emphasised. Although this is a small cohort study, these data suggest that all perinatal genomic results should be considered urgent due to the high chance of new pregnancy, to enable pre-conceptual counselling and informed decision-making.