Implementation of high‐throughput non‐invasive prenatal testing for fetal RHD genotype testing in England: Results of a cross‐sectional survey of maternity units and expert interviews

Abstract Background Previously, routine antenatal anti‐D prophylaxis (RAADP) was administered to all RhD‐negative mothers to reduce the risk of sensitisation in the UK's National Health Service (NHS). If the baby is RhD‐negative, RAADP is not required. In 2016, the UK National Institute for Health and Care Excellence (NICE) recommended non‐invasive prenatal testing (NIPT) for fetal RHD genotype as a cost‐effective option to guide RAADP. Objectives To evaluate the implementation of high‐throughput NIPT for fetal RHD genotype in maternity units in England by addressing research recommendations from the NICE. These were to reduce uncertainty around the resource use and cost of staff training, management of samples and results and record‐keeping, as well as resultant changes to antenatal or post‐partum care and performance of NIPT. Methods A cross‐sectional survey was developed and sent to clinicians at 39 English NHS Trusts in May 2018. Qualitative interviews with seven individuals were conducted to explore missing or contraindicatory data. Qualitative findings were supplemented with NIPT test results (April 2017 to February 2019) from English hospitals. Results Staff reported that training took up to 30 minutes. There were no extra costs associated with sample management or additional appointments. Extra time required for record‐keeping and management of test results was balanced later in the patient pathway. The antenatal pathway was not changed in the Trusts surveyed. The survey revealed that four post‐partum scenarios were being used within English NHS Trusts. The frequency of inconclusive NIPT results was 4.3%. Conclusion NIPT for fetal RHD genotype can be implemented without consuming substantial extra resources through incorporation into an existing patient pathway.


| INTRODUCTION
Babies of a Rhesus D (RhD)-negative mother can inherit the RhDpositive blood type from their father. This type of pregnancy is at high risk of sensitisation where anti-D antibodies develop against RhD antigens. Sensitisation can lead to haemolytic disease of the fetus/ newborn or even stillbirth. 1,2

| Current antenatal pathway for RhD-negative women
In August 2008, the National Institute for Health and Care Excellence (NICE) recommended routine antenatal anti-D Prophylaxis (RAADP) for RhD-negative women who are not sensitised to the RhD antigen. 2 F I G U R E 1 Simplified schedule of appointments based on the current antenatal pathway in the United Kingdom for women known to be RhD-negative (according to results of blood test at booking appointment) with highlighted changes to the pathway following the implementation of non-invasive prenatal testing (NIPT) for fetal RHD genotype. Please note that each Trust can introduce changes to the schedule of appointments For uncomplicated pregnancies, RAADP is given to all RhDnegative women at or around 28 weeks' gestation (and at 34 weeks if given in two doses) as part of a standard schedule of appointments and following a sensitising event (eg, abdominal trauma, invasive intrauterine procedure etc). The blood type of a baby is determined with cord blood testing (CBT), and potential feto-maternal haemorrhage is estimated with the Kleihauer test. If a child is confirmed as RhD-positive, the RhD-negative mother will receive another dose of RAADP to prevent complications in future pregnancies.
Within the United Kingdom, approximately 40% of RhD-negative women carry RhD-negative fetuses; in such cases, there is no risk of haemolytic disease of the foetus/newborn. These women receive RAAPD (an injection of a blood-related product, which is associated with risk of blood-borne infections) unnecessarily. 2

| Introduction of non-invasive prenatal testing for fetal RHD genotype
In 2016, NICE recommended high-throughput non-invasive prenatal testing (NIPT) for fetal RHD genotype as a clinically effective and cost-effective option to guide RAADP in the United Kingdom 3 ( Figure 1). NIPT is offered during the early stages of pregnancy in a routine antenatal appointment and enables the assessment of fetal Rh status from a maternal peripheral blood sample. Based on the published literature evaluating the test performance at different time points, the false negative rate is much higher before 11 weeks and becomes stable after this time 4,5 ; thus, the test is more accurate after the first trimester of pregnancy. The results inform whether RAADP is required during pregnancy. The new testing strategy is used as an addition to current standard care, and it has the potential to remove the need for CBT in the future.
These recommendations from NICE are likely to impact staff by requiring additional training of midwives and laboratory staff in order to safely perform the test and manage the sample, extra blood sampling and an increase in administrative tasks (taking consent and checking results). However, the new service is expected to affect the total number of RAADP doses administered and improve patients experience through, for example, reduction in the anxiety associated with the injections. In NICE's guidance, 12 studies were identified in a review of implementation of NIPT for fetal RHD. 3 Most concluded that implementation of this new technology was feasible, but issues included anti-D prophylaxis adherence, the importance of short transport times for samples and effective management of sample transport, and a need for greater knowledge of NIPT among physicians and midwives.
NICE identified uncertainties in its guidance and recommended data collection and analysis by Trusts implementing the service associated with costs and resource use of providing the NIPT service in practice. The recommendations were focused on staff training, informing patients, sample management, record-keeping, management of results, changes to antenatal or postnatal pathways, test failures and adherence to new test and RAADP. 3 The aim of this study was to  confirmed that these activities were not researches, and as such, ethical approval was not sought.

| Phase 1: Survey
A questionnaire was developed based on addressing the research recommendations included in NICE's Diagnostics Guidance on NIPT for fetal RHD genotype (DG25). 3 The areas of uncertainty were formulated into questions that could be answered by clinicians. The draft questionnaire was sent to four experts, and their comments were incorporated into the next version of the document and sent for a second check before the development of the final version (see Table S1).

| Phase 2: Expert interviews
The results from the survey were used to identify missing or contradictory information requiring more in-depth discussion. Phase 2 of the study used semi-structured interviews with clinical experts. A guide sheet with the same structure as the survey was developed and sent to clinical experts prior to the interview to allow them to familiarise themselves with topics and consider their responses (see Table S2).
To ensure a good geographical spread, a range of interviewees from both the north and the southeast of England were invited.
Each interview lasted approximately 60 minutes, and it was recorded following participants' verbal consent. Transcripts were written verbatim by E.R. The transcripts were sent, verified and corrected by interviewees within 2 weeks of the interview. Analysis of the qualitative data was performed in Microsoft Word 2013 using the thematic techniques 6 -answers were categorised by relating to the same question asked, reviewed, each category given a title and summarised in the narrative.  questions; the number of responses received is stated in each subsection below. Questions with more than a 50% response rate, including data than can be categorised into emerging theme, are reported in this article. Uptake and adherence to either the NIPT or RAADP were estimates and/or clinicians' opinion, not actual data, and they are not included in the results.

| Additional data collection
At the time of survey completion, 21 of 25 survey responders (84%) indicated that their Trust had already implemented the NIPT for fetal RHD genotype testing. The remaining sites were preparing for implementation. The qualitative interviews were carried out with seven clinicians from three high-volume (>5000 deliveries per year) and three lower-volume (<5000 deliveries per year) NHS centres.
Results from the survey and interviews have been presented together under subsections that correspond to objectives of the study. Interviewees highlighted that a lack of compatibility between the electronic reporting system used by IBGRL and local laboratory IT system resulted in some staff requiring an extra training session to provide information on how to access the NIPT for fetal RHD genotype reports and record patient results. Interviews and survey results showed that samples mislabelled due to human error were rejected in the laboratory, and women were informed about the possibility of having another test sample taken. In most cases, inconclusive test results are treated as RhD-positive, and women will receive RAADP later in pregnancy.

| Aim 2: Costs and management of samples
The results of NIPT for fetal RHD genotype are recorded in the patient's electronic record with automatic comments for midwives as a sticker in the baby's notes or as a paper copy in their notes, sometimes including the patient pathway. Women eligible for NIPT for RHD genotype but presenting to hospital after the time when the test is offered ("late bookers") can access the service only if they did not receive it elsewhere. In most Trusts, the NIPT for RHD genotype is offered up to the 26th week of pregnancy, just before RAADP appointment.

| Aim 5: Changes to antenatal care
Of 18, 13 (71%) survey responders stated that some appointments are shorter or not required. Women with a predicted RhD-negative baby do not need RAADP; thus, fewer RAADP appointments at 28 weeks' gestation, and following any sensitising event, are needed. The simplified schedule of appointments for women known to be RHD-negative with incorporated findings in this study can be seen in  Interviewees highlighted that assistance of experienced healthcare professionals at early stages of implementation and engagement of employees were crucial factors contributing to successful implementation. Moreover, a routine audit of the clinical practice will enable the capture of any arising and ongoing issues, which can be resolved quickly.

| Aim 6: Changes to post-partum care
It is important to highlight the risks associated with a lack of uniform reporting system between the laboratory performing the test and local IT. The need to transfer the results between two different platforms carries the risk of transcription errors, which can have a significant impact on patients' health (due to, eg, missed RAADP dose) and contribute to an increase in resource use. The authors encourage discussion within Trusts to determine the best arrangements to transfer the results with the least risk of transcription errors. Moreover, the differences in the patient pathways (eg, schedule of visits) or RAADP management (eg, dosage and time of administration) between hospitals within the same Trust can contribute to delays in incorporating the new service in practice. Each Trust needs to routinely evaluate its current working system in order to incorporate changes without consuming additional resources.
This study has some limitations. The survey and interview methodology was a basic cross-sectional design, and the sample size was relatively small. Authors relied on clinicians' opinion and level of details provided; interpretation and the data collection was performed by only one researcher. The number of Trusts implementing the NIPT for fetal RHD genotype in the United Kingdom is currently increasing; thus, real-time mapping of the patient pathway and monitoring of the service are suggested as potential research recommendations.
The study was performed shortly after the publication of new recommendations included in DG25. Thus, Trusts were at different stages of implementation, and the new service was not yet embedded in practice, which affected the quality and inaccuracies of responses.
The study can be repeated when NIPT for fetal RHD genotype is widely used in clinical practice to compare the results and highlight its impact.
The uptake of NIPT for fetal RHD genotype, RAADP adherence and false-negative/-positive results are not routinely monitored; thus, this article does not report any analysis as responses received were not representative of the population. It is recommended that this type of data is collected in order to fully assess the impact of the new testing strategy. Monitoring of discrepancies between NIPT for fetal RHD genotype and CBT can inform future decisions regarding removing CBT from the current postnatal pathway. In addition, the results show that at least 34.5% of women will not require RAADP; thus, the cost implications of implementation of NIPT for fetal RHD genotype should be documented.
NICE guidance recommending NIPT for fetal RHD genotype in the NHS identified uncertainties regarding the costs associated with implementing the service. This article presents a "real-world" qualitative study of the implementation of the NIPT service in NHS maternity units in England. Trusts report that implementation of this service does not consume additional resources through management of samples or additional antenatal visits and that the new service fits well within the previous patient pathway. Extra resources may be required to manage and record results and for internal staff training of nurses, midwives, laboratory staff and doctors. NIPT for fetal RHD genotype is an important improvement in patient care, which enables targeted prophylactic administration of RAADP only to women who need it. The results of this study reduce much of the uncertainty associated with NICE's recommendation for the routine use of NIPT for fetal RHD genotype in the United Kingdom, giving support to the findings that the technology is a cost-effective option to guide the administration of RAADP.

ACKNOWLEDGMENTS
This work was commissioned by NICE and undertaken by Cedar. It was funded through Cedar's existing contract with NICE to undertake a range of evaluation activities. The authors acknowledge members of Cedar team, Dr James Evans, Ruth Louise Poole, Kathleen Withers, Dr Laura Knight and Dr Helen Morgan, for their contribution to the study design, management and/or revision of the paper; Erika Rutherford from IBGRL for initial information, help with designing the survey and providing the test results; and the National Institute for Health and Care Excellence for their support during the initial stages of the project. E.R. designed and performed the study, analysed the data and wrote the paper; J.W. designed the study and contributed to the manuscript preparation; and G.C.-R. helped to design the study and contributed to the manuscript preparation. All authors approved the submitted and final versions of the manuscript.

CONFLICT OF INTEREST
Cedar, a department within NHS, receives funding from the National Institute for Health and Care Excellence (NICE). NICE not involved in the data collection and analysis. No other conflicts of interest exist.