Techniques to enable non-invasive prenatal testing (NIPT) of the foetus were developed during the middle to late 1990s and are now available clinically for a limited range of conditions, including some monogenic disorders, and for foetal sexing for sex-specific disorders. Using the technique to identify a foetus affected by a specific monogenic disorder has been referred to as non-invasive prenatal diagnosis; however, for applications such as foetal sexing and screening for Rhesus D status, it is appropriate to use the term testing, rather than diagnosis. For brevity, in this paper, we will use the inclusive term ‘non-invasive prenatal testing’ (NIPT) throughout (except when referring to the original papers in Table 1).
|Authors, title and country||Aims||Method||Sample||Analysis||Findings/results||Quality issues|
|Hill et al. ‘Incremental cost of non-invasive prenatal diagnosis versus invasive prenatal diagnosis of fetal sex in England’, UK||‘To evaluate the incremental cost of NIPD compared with IPD for fetal sex determination in the English NHS’ (p. 268)||Cost analysis||Comparison of NIPD and IPD in two conditions: congenital adrenal hyperplasia and Duchenne muscular dystrophy||Mean costs of pregnancy||No significant difference in cost between IPD and NIPD. Costs of fetal sexing with NIPD were offset by the smaller proportion of women who required CVS.||88%; Limitations: care pathways derived from a study that was primarily concerned with diagnostic accuracy. Costs were calculated to end of pregnancy and did not consider lifetime costs of a diagnosis.|
|Care pathways derived from empiric data. Costs established from NHS data. Perspective NHS costs||Univariate and probabilistic sensitivity analysis to determine limits of uncertainty|
|Monte Carlo simulation model|
|Hill et al. ‘Determination of foetal sex in pregnancies at risk of haemophilia: a qualitative study exploring the clinical practices and attitudes of health professionals in the United Kingdom’, UK||‘To determine the current practices of health professionals in offering prenatal care for women who are carriers of haemophilia and explore the introduction and use of NIPD for foetal sex determination’ (p. 576)||Qualitative cross-sectional study based on grounded theory||32 health professionals who were involved in management of women who were carriers of haemophilia during pregnancy. Of these, 12 worked in haemophilia centres, six in genetics units and six in foetal medicine units.||Grounded theory method||Offering NIPD for foetal sexing was felt to enhance prenatal care of carrier women. Use of NIPD was not felt to increase workload for staff. Although respondents reported that most women were relaxed about use of NIPD, the main questions asked by carriers focussed on the accuracy and timing of the test. Respondents felt it was important the test was not seen as routine.||90%; No evidence given of researcher reflexivity, otherwise an excellent paper|
|Kelly and Farrimond ‘Non-invasive prenatal genetic testing: a study of public attitudes’, UK||‘To identify the range of viewpoints on NIPD amongst a sample of the UK public with a diversity of experiences and demographic characteristics’ (p. 75)||Q-methodology. Qualitative data were collected via postal self-completion questionnaires.||Purposive sample of 71 UK individuals aged between 18 and 60 years (73% RR). Sample recruited via media sources.||Thematic analysis of participants' first responses to brief factual information about NIPD.||Although 63% of first responses were positive, many of those respondents had concerns. Ambivalence about testing focussed on increased safety and utility by individual parents, contrasting with more ethical concerns about increase ease leading to more casual use, changes in attitudes to disabled children and increased termination rates.||80%; Good theoretical underpinning for study but lacked sufficient information on sampling procedure and data analysis.|
|Kooij et al. ‘The attitude of women toward current and future possibilities of diagnostic testing in maternal blood using fetal DNA’, The Netherlands||To determine ‘women's attitudes toward current and future testing possibilities’ (p. 165) concerning NIPD.||Cross-sectional survey. Questions were derived from a questionnaire used in a previous study. Participants used Likert scales to indicate level of agreement with statements on use of NIPD.||Women recruited from two groups: (1) pregnant women and (2) female Master's level students. A power calculation indicated 100 women needed in each group, recruitment continued until sample obtained.||Descriptive statistics calculated. Chi-square distribution to determine differences in responses between the two groups.||Pregnant women were more likely than students to state that NIPD for Down syndrome should be offered to all pregnant women. The majority in both groups supported use of NIPD for prenatal diagnosis of gender-specific condition, but not for family balancing.||75%; Study questionnaire is well described. Rationalisation for using only female Master's students rather than broadening recruitment to other young women not given. Does not state if the students had children.|
|Lewis et al. ‘Non-invasive prenatal diagnosis for fetal sex determination: benefits and disadvantages from the service users' perspective’||Authors aimed to explore ‘the benefits and disadvantages of NIPD from the service users' perspective’ (p. 1127).||Qualitative cross-sectional descriptive study. Data were collected using semi-structured interviews.||45 participants who had experience of using NIPD for foetal sex determination were recruited from appropriate health service clinics in the UK.||Thematic analysis of transcribed interview data.||Participants were overwhelmingly positive about their use of NIPD. Positive attributes cited included safety for foetus and timing of the procedure, whereas increased anxiety and potential misuse of the technology were cited as negative aspects.||80%; The sampling strategy and data analysis are well described; however, there is a lack of reflexivity in the account.|
|Lewis et al. ‘Fetal sex determination using cell-free fetal DNA: service users' experiences of and preferences for service delivery’||‘To determine service users' experiences and preferences for service delivery' regarding fetal sex determination using NIPD’ (p. 735)||Qualitative cross-sectional descriptive study. Data were collected using semi-structured interviews.||38 women who had used NIPD for foetal sex determination because the foetus was at high risk of a specific condition affecting one sex and six of their partners. All recruited via relevant clinics in England.||Thematic analysis of transcribed interview data.||Participants believed use of NIPD enhanced reproductive choice. They preferred receiving pre-test information and results from a specialist who understood the procedure and the condition. Accuracy of results considered most important feature.||80%; Sampling strategy clear. There is no reflexive account given in the report.|
|Sayres et al. ‘Cell-free fetal DNA testing: a pilot study of obstetric healthcare provider attitudes toward clinical implementation’||To assess the opinions of healthcare providers on introduction of NIPD||Questionnaire distributed at a conference||62 of approximately 180 surveys completed. 34% response rate Majority of respondents had MD degree and majority were practising in the United States||Descriptive||85% did not have a high level of knowledge about cell-free foetal DNA testing. 55% thought it would encourage testing for more people and 45% more conditions. Clinical utility ranked first out of six aspects of prenatal testing followed by risk to mother or foetus and sensitivity. Majority would follow guidelines if issued, felt test should be covered and a minority would support direct-to-consumer testing||65%; Small sample|
|Low response rate and potential sample bias limit generalisability|
|Szczepura et al. ‘A new fetal RHD genotyping test: Costs and benefits of mass testing to target antenatal anti-D prophylaxis in England and Wales’||Cost-effectiveness of NIPD targeted prophylaxis in pregnancies of rhesus negative mothers compared with normal practice||Cost analysis||Two scenarios compared with normal practice: (1) NIPD used to target antenatal prophylaxis with serology tests directing post-delivery prophylaxis, and (2) in addition to antenatal prophylaxis, NIPD also replaces serology testing postnatally if RhD negative foetus was identified.||Financial modelling. Univariate sensitivity analysis||Net financial benefit of implementing mass NIPD testing in the antenatal setting while maintaining current strategies for postnatal testing is negligible. NIPD is unlikely to produce any clinical benefit in these scenarios as the number of sensitisations may not fall. Depending on test sensitivity, they may in fact rise||88%; Many assumptions in modelling as limited data. Predominantly from a laboratory perspective. Main uncertainty concerns potential royalty fees for tests.|
|Costs established from NHS data together with a threshold royalty fee per test.|
|Care pathways derived from literature review and expert opinion|
|Perspective NHS England and Wales|
|Tischler et al. ‘Noninvasive prenatal diagnosis: pregnant women's interest and expected uptake’||To assess whether pregnant women are interested in NIPD and what factors would influence their interest and expected uptake’ (p. 1293).||Experimental study. Women were allocated to two groups before completing a questionnaire on NIPD. In one group, the women were given brief information on NIPD prior to reading the questionnaire; in the other, more detailed information was given.||114 pregnant women (80.9% RR) more than 24 weeks of gestation. Women were recruited in the waiting room of the local antenatal clinic.||Descriptive statistics used. Chi-square analysis used to compare responses between those who read the brief and those who read the detailed description of NIPD.||The majority of women expressed interest in using NIPD if available. Safety of the foetus and accuracy of the results were most important factors in deciding to use NIPD. Women who read the brief description of NIPD were more likely to use the test.||68%; Although randomisation appears to have been possible, it is not mentioned.|
|Van den Heuvel et al. ‘Will the introduction of non-invasive prenatal diagnostic testing erode informed choices? An experimental study of health professionals’||To assess the extent to which the introduction of NIPD of Down's syndrome may undermine the process of making informed choices (p. 25)||A vignette study, between-subjects design. Each participant randomly presented with one vignette: IPD, NIPD and DSS. Outcome variables: topics considered important to communicate, timing of the test and the perceived need for written consent assessed by questionnaire.||231 obstetricians and midwives working in the UK. Invitations given to attendees at three conferences on updates in prenatal diagnosis and three maternity units. Majority of respondents were obstetricians (59.3%), female (79.7%) with a mean age of 39.7 years. Age, gender, profession and data source (i.e. the conference or maternity unit) were distributed evenly across intervention groups.||Descriptive statistics for responses across the groups. Univariate analyses across test types to compare the three characteristics of prenatal counselling. Logistic regression to identify independent predictors of beliefs about the timing of the test and the perceived need to sign a consent form.||Five of the seven topics were considered equally important to communicate across the three vignettes. Procedure itself and miscarriage risk more important for IPD vignette. Respondents receiving IPD vignette more likely to indicate presentation and uptake of tests should occur on different days and that signed consent was necessary as compared with those receiving NIPD and DSS.||88%; Randomisation method not clear and sample possibly not representative. However, no significant differences in the characteristics of participants between experimental groups. As discussed in the paper, the main limitation is that the outcome measure may not be a true measure of informed decision-making.|
|Yotsumoto et al. ‘Attitudes toward non-invasive prenatal diagnosis among pregnant women and health professionals in Japan’ Japan||To assess attitudes towards non-invasive diagnosis in Japan||Self-completed questionnaire mailed to clinical staff and pregnant women in two hospitals||252 respondents 185 health professionals: RR 58% obstetricians, 39% paediatricians, 45% genetic counsellors 67 pregnant women RR unknown||Descriptive statistics||79% health professionals 97% women agreed with application of PGD p < 0.01||75%; Sample selection may be biased. Small number of pregnant women responders may limit generalisability|
|Comparison between responses of pregnant women and health professionals|
|Women expected the test to be safer earlier and easier to understand than health professionals who were more concerned about diagnostic accuracy and reliability Health professionals had more concerns about implementation than pregnant women. Suggestion that individuals who had less knowledge were more supportive of NIPD.|
Although there have been numerous papers focussed on the development and quality of laboratory techniques to determine foetal status using cell-free foetal DNA extracted from maternal plasma, these must be placed into a health services context through consideration of the clinical, ethical, legal, social and economic issues related to the introduction of any new technology. The use of NIPT will result in a reduction in the number of invasive tests performed. The major clinical advantages of using NIPT compared with invasive testing have been cited as eliminating the risk of miscarriage due to testing and enabling confirmation of foetal status earlier in the pregnancy.[6, 7] At present, NIPT for aneuploidy is not fully diagnostic, and confirmatory invasive testing should be offered; however, there is anticipation that this will change. Offering one diagnostic test for aneuploidy, as opposed to stepwise screening and invasive testing, has been cited as a factor in simplifying the counselling process, enabling parents to focus on one decision. However, there have been serious ethical concerns aired about the use of NIPT. For example, the potential for the test to be viewed as ‘routine’[9, 10] and the ease with which a blood sample can be taken may reduce the consideration given by parents as to the outcome and implications of the test, placing in jeopardy the need for informed consent[9, 11] to the procedure. Greely makes the point that in other areas of reproductive healthcare, there are demonstrable disparities in access to services between individuals from different ethnic or socio-economic groups, and the use of NIPT might exacerbate these. He, amongst others, also raises the issue that the ease with which NIPT can be used will inevitably result in increases in the number of prenatal tests and subsequent abortions. Concerns that use of NIPT will result in sex selection for social reasons and the fear that pressure to increase the range of conditions for which testing is offered (due to specification creep) will result in eugenic practices have also been voiced.
Although it is evident that both advantages and disadvantages regarding the clinical use of NIPT have been expressed, the evidence base for offering NIPT and the impact on prospective parents and health professionals has not been reviewed. We therefore conducted a systematic review on this topic.