Diagnostic accuracy
Eight studies12,17–23were included in the diagnostic review of high-throughput NIPT. There were three studies based in Bristol (UK).12,17,18The majority of included studies were judged as having a low risk of bias. Meta-analyses found that high-throughput NIPT had very good diagnostic accuracy. In the primary
analyses, in which women with inconclusive test results were treated as if positive, the summary FNR (women at risk of sensitisation) was 0.34% (95% CI 0.15% to 0.76%) and the FPR (women needlessly receiving anti-D) was 3.86% (95% CI 2.54% to 5.82%).
The three high-quality studies performed at Bristol,12,17,18which were most representative of UK practice, had a lower FNR of 0.21% (95% CI 0.09% to 0.48%), with a consequently higher FPR of 5.73% (95% CI 4.58% to 7.16%). This difference may be partly because the NIPT used in Bristol had a different test threshold to other countries to further reduce false-negative results.
The FPR found is mostly a consequence of treating women who have an inconclusive test result
(approximately 7% of non-invasive prenatal tests in the UK) as if they had a positive test. Excluding these women from analysis gave a lower FPR of 1.26% (95% CI 0.87% to 1.83%). It may therefore be possible to reduce the FPR by further targeted testing of women with an initially inconclusive result.
The diagnostic accuracy performance of high-throughput NIPT varied by gestational age. The data suggest that high-throughput NIPT is insufficiently accurate before around 11 weeks’ gestation (i.e. in first
the number of inconclusive results may decline over time. Hence, NIPT cannot be recommended before the second trimester and may be best performed later in the second trimester.
Clinical effectiveness
Seven studies18,20,22,24–27were included in the clinical effectiveness review. Only two studies had a control group. All studies were judged as having a high risk of bias. As all except one were conducted in non-UK countries, the generalisability of their findings to the UK setting is limited because of variations in national guidelines and health policies between countries (e.g. prescription of RAADP). One large prospective cohort study26reported that use of high-throughput NIPT for targeted antenatal anti-D prophylaxis was associated with a significant risk reduction in sensitisation (adjusted odds ratio 0.41, 95% CI 0.22 to 0.87) compared with historical controls (routine management, postpartum anti-D only).
Uptake rates of NIPT were reported in seven studies, ranging from 70% in a pilot study conducted in England to > 95% in an established national programme in Denmark. Uptake rates of RAADP in women who accepted NIPT and received a positive result were moderate to high, ranging from 86% to 96.1% (four studies). Uptake rates of routine postnatal anti-D prophylaxis in women who accepted NIPT and received a positive result were reported in three studies and were generally high, ranging from 92% to 99.7%.
Three non-comparative studies evaluated changes in anti-D use following the implementation of NIPT. All found that the use of NIPT reduced the total use of anti-D immunoglobulin doses, which fell by 29% in one UK study18, because around 35% of RhD-negative women avoided receiving anti-D unnecessarily. As the quality of the clinical effectiveness evidence was limited, we performed a simulation study, based on the findings of our reviews, to assess the probable clinical consequences of implementing NIPT. Its results were broadly consistent with the review evidence. It suggested that NIPT, when compared with offering anti-D to all RhD-negative women, would substantially reduce the use for anti-D from 99% of women to 65.9%. The number of women receiving anti-D unnecessarily would fall from 38.9% to 5.7%. The number missing out on potentially beneficial anti-D (because of a false-negative test result or
non-compliance) depends on the compliance rate but could increase from 0.6% to between 1.2% and 3.1%. The impact of NIPT on sensitisation rates (compared with universal anti-D use) also depends on compliance. Sensitisation rates may increase by 3–15 sensitisations per 100,000 women if postpartum cord blood testing is continued, or 13–28 per 100,000 women if cord blood testing is withdrawn and postpartum anti-D given on the basis of the NIPT result. Ensuring that women who do not receive NIPT are still offered, and receive, antenatal anti-D will minimise the number of additional sensitisations.
Implementation
Twelve studies were included in the review of implementation. Most of the included studies were large cohort studies reporting implementation data along with diagnostic accuracy data, although one study was a UK-based survey. As most studies were conducted in non-UK countries, the generalisability of their findings to the UK settings is limited because of variations in national guidelines and health policies between countries. All the large cohort studies suggested that high-throughput RhD genotyping of fetuses in all RhD-negative women was feasible and should be recommended. A number of studies reported issues of implementation such as those relating to programme anti-D prophylaxis compliance. Some studies emphasised the importance of short transport times of samples and the need for good management of transporting samples. Some studies also identified the need for greater knowledge of NIPT among physicians, midwives and pregnant women.
Conclusions
High-throughput NIPT for fetal RhD status is an accurate diagnostic test, if performed after 11 weeks’ gestation. It has a FNR (women remain at risk of sensitisation) of around 0.2% and a FPR (women receive unnecessary anti-D) of around 5.7%. The test gives an inconclusive result in around 7% of women in the
UK. Owing to limited evidence, the accuracy of NIPT in non-white women and multiple pregnancies is unclear. Treating inconclusive tests as if they were positive is the cause of most false-positive results. Giving antenatal anti-D immunoglobulin on the basis of NIPT, rather than to all RhD-negative women, will reduce the use of anti-D and largely eliminate unnecessary use of anti-D in women who do not need it because they have a RhD-negative fetus. Some women will, however, continue to receive anti-D unnecessarily because of an inconclusive test result.
Although the evidence was limited, it appears that using NIPT will lead, at worst, to only a small increase in the number of sensitisations compared with universal use of anti-D. The simulation suggested that achieving high compliance with both NIPT and antenatal anti-D (particularly in women who do not receive NIPT) is important in order to achieve good clinical effectiveness and to reduce the sensitisation rate. It may be clinically reasonable to withdraw postpartum cord blood testing and base postpartum anti-D administration on the results of NIPT. All large implementation studies suggested that high-throughput NIPT in all RhD-negative women was feasible and should be recommended. Key issues of implementation include ensuring anti-D prophylaxis compliance, effective management of transporting samples and greater knowledge of NIPT among physicians, midwives and pregnant women.