
A new test may help more couples understand why they experience multiple miscarriages, a phenomenon known as recurrent pregnancy loss (RPL). The assay, developed by researchers in China, identifies the most common chromosomal abnormalities present during conception, and is a cost effective method compared to similar tests on the market.
RPL is defined as when women experience two or more miscarriages, and occurs in approximately 5% of clinically identified pregnancies. Genetic testing, along with other testing, is a clinical standard for identifying and evaluating RPL, but current assays have revealed shortcomings in clinical practice. A new report in The Journal of Molecular Diagnostics, published by Elsevier, describes a new, high-resolution melting analysis-based test (HRM), and whose developers claim is accurate, rapid, cheap, and easy to perform. When used prior to other tests, it has been shown to improved cost-effectiveness by 30 percent, an important consideration in populations with limited healthcare resources.
The vast majority of early pregnancy losses (50%–60%) are the consequence of chromosomal abnormalities, which can be of parental origin, or arise de novo in the embryo from parents with normal chromosomes, according to a review by Hady El Hachem, et al. Almost half of RPL cases remain unexplained and are empirically treated.
Several studies have reported a genetic predisposition to unexplained RPL (URPL), with an increased risk in siblings of patients with URPL. In response to this, various genetic association studies have been performed, and many candidate genes identified. A recent meta-analysis that included 428 case–control studies found an association for 21 variants in 13 genes. Most of the genes were involved in immune response, followed by coagulation, metabolism, and angiogenesis.
Much of this research is ongoing, but many patients who are trying to conceive are unable to access much needed genetic screening tools that can clearly aid them.
“We speculated that the cost of genetic tests such as chromosomal microarray (CMA) or next-generation sequencing (NGS) will remain high enough to hinder their acceptance as affordable detection methods for RPL evaluation in underdeveloped regions,” explained lead investigator Prof. Qiwei Guo, at Xiamen University in China. “Inspired by the success of prenatal screening and diagnosis for Down syndrome, we hypothesized that a well-accepted screening method like HRM combined with a diagnostic method (CMA or NGS) would advance the clinical practice of genetic testing for products of conception (POCs).”
The use of genetic tests for POCs has been limited in underdeveloped regions with large populations due to low test capacity and high cost. Prof. Guo and his co-investigators observed that although most patients with RPL wanted genetic testing, less than 5 percent had the testing performed, primarily because the cost (about US $440) was prohibitive.
HRM is recognized as one of the best screening methods for detecting point mutations and aneuploidy (the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46) or other medical conditions.
Investigators examined 765 miscarriage tissue samples that had undergone karyotyping, the conventional gold standard genetic test for RPL evaluation. Karyotyping shows the number, size, and appearance of the chromosomes, but the process can be labor intensive, time consuming, and susceptible to human error.
Of those 765 samples, approximately 60% showed the presence of numerical chromosomal abnormalities (NCAs). Almost two thirds of those with NCAs had the type of abnormalities that could be detected with HRM testing. Samples analyzed with HRM showed a high technical sensitivity (96.1%) and specificity (96.3%) as well as a high positive predictive value (95.9%) for the screening of chromosomal abnormalities.
Results determined that the costs of diagnosing an explained RPL using karyotyping or the HRM test alone were similar. Performing HRM screening before CMA/NGS testing, however, improved cost-effectiveness by approximately 30%. The data also suggested that the test was even more cost effective in women 35 years or older because of increased screening sensitivity.
“We suggest that the HRM test could be used as an initial screening tool followed by other diagnostic methods to improve the cost-effectiveness of RPL evaluation or as an alternative genetic test when other methods are unavailable or unaffordable,” stated Prof. Guo. He added that another advantage of HRM testing is its high capacity, which is especially important in underdeveloped countries with large populations.
“We believe that identifying the causes of miscarriages not only assists clinicians in genetic counseling and therapeutic management, but also reduces the emotional distress and psychological burden on affected couples,” noted Guo.