European Journal of Obstetrics & Gynecology and Reproductive Biology
ReviewNon-invasive fetal RHD genotyping tests: A systematic review of the quality of reporting of diagnostic accuracy in published studies
Introduction
Fetal RHD genotyping from maternal whole blood [1], fetal cells [2] or cell free fetal DNA [3] in maternal blood has been feasible for over a decade. Following the first papers, research interest in this form of non-invasive prenatal diagnosis (NIPD) has become global. Publications in Europe, America and Australia aim to improve the management of pregnancies of women who are rhesus negative [2], [4], [5], [6], [7], [8], [9]. In white Caucasian populations about 10% of all pregnancies involve an RhD-negative mother and an RhD-positive fetus, potentially placing the mother at risk of sensitisation and future babies at risk of haemolytic disease of the fetus and newborn (HDFN).
Anti-D immunoglobulin can be given to prevent a woman producing antibodies against fetal RhD-positive blood cells. Introduction of postnatal anti-D prophylaxis (within 72 h of delivery) in the late 1960s reduced sensitisation and HDFN rates considerably internationally. Combined with antenatal prophylaxis for high-risk events, such as amniocentesis, this form of targeted prophylaxis has proved highly effective and cost-effective [10]. Consequently, the number of sensitised RhD-negative women who give birth every year is lower than 1% of total births.
For non-sensitised women, routine antenatal anti-D prophylaxis (RAADP) at 28–30 weeks gestation was introduced in the mid-1990s, and is now available in most European countries. However, 40% of RhD-negative women receive this blood product unnecessarily because the fetus is not RhD-positive. Fetal RHD genotyping has the potential to enable targeted antenatal prophylaxis only for women whose pregnancy is at risk. This might address any issues of limited anti-D supplies and perceived risk associated with unnecessary administration of a blood product.
The NIPD RHD genotyping test has already started to have an impact on the management of sensitised women, in countries where this technology is available, by replacing invasive procedures like amniocentesis for the determination of fetal RhD status. Replacement of amniocentesis is desirable since the procedure can promote feto–maternal blood exchange as well as being associated with a small increased risk of miscarriage [11], [12].
The current state of development of the RhD NIPD test is promising. Several studies have reported high accuracy rates [13], [14], [15], [16] and these have prompted the initiation of larger scale trials in the Netherlands, Germany and the UK [17], [18]. Reports in the literature have already led to initial use of the test for management of sensitised women. An increasing focus of debate is now on widespread implementation of the test in non-sensitised pregnancies [19]. Discussion of markers (exons and/or introns) to be used for RHD genotyping, and the applicability of NIPD tests for routine clinical use in diverse populations form part of this debate [13], [17].
A recent meta-analysis undertaken by Geifman-Holtzman et al. has reported sensitivity and specificity values of 0.986 and 0.954 respectively, and an overall positive predictive value of 0.990 and negative predictive value of 0.921 [20]. Some studies were excluded from this meta-analysis on the basis of sample numbers, but aspects such as study quality were not considered. Because assessment of the quality of reporting of diagnostic accuracy can be problematic, a world-wide Delphi panel has identified agreed international quality criteria for assessing the reporting of such studies [21]. The resulting checklist (STARD -standards for reporting studies of diagnostic accuracy) is now required from all authors of health technology assessment reports of diagnostic technologies in the UK, and increasingly requested by editors of international journals. We have undertaken an independent systematic literature search and assessed the quality of reporting of all identified articles using the STARD checklist. We further investigated the implications of any shortcomings on the generalisability of NIPD study results, in order to identify key aspects influencing test reliability and any underlying reporting biases. An NIPD assessment proforma has been produced as well as recommendations that are specific and relevant for reporting diagnostic accuracy of RhD NIPD tests.
Section snippets
Literature search strategy
Published articles were identified by systematic searches of electronic databases from 1966 until January 2007; these included PubMed, Ovid Medline, Ovid Embase, the Cochrane Library, the National Library for Health (UK), Online Computer Library Center (OCLC) and the Conference Papers Index. Text words and MeSH headings used separately and in combination included: prenatal diagnosis, Rh, fetal cells, fetal DNA, maternal blood, serum, plasma, Rh alloimmunis(z)ation. Bibliographies of all papers
Results
The literature search resulted in the identification of 51 publications. The selection procedure described above excluded 24 papers (Fig. 1) leaving 27 studies for final quality assessment (Table 2). Of these, 25 were in English, 1 in French and 1 in Polish. Publication dates ranged from 1996 to the end of 2006. Findings were published in a wide range of journals and originated from 15 countries.
Discussion
Articles which report the diagnostic accuracy of new non-invasive prenatal diagnostic tests for RHD genotyping are difficult to identify through systematic searches of the literature. Indexing of the articles identified was found to be poor, as has been reported by other diagnostic test reviews [40]. Of those finally identified, less than one-third were found to have included the correct MeSH headings for diagnostic accuracy.
A detailed appraisal of all retrieved articles has identified a
Acknowledgement
This work is supported by the European Commission funds allocated to the SAFE Network of Excellence under the 6th Framework. Project Number: LSHB-CT-2004-503243.
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