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Accurate and Robust Quantification of Circulating Fetal and Total DNA in Maternal Plasma from 5 to 41 Weeks of Gestation

¹ BioAnalytical Innovation Team, LGC Ltd., Teddington, United Kingdom.
² Experimental Fetal Medicine Group, Institute of Reproductive & Developmental Biology, Imperial College London, and Centre for Fetal Care, Queen Charlotte’s & Chelsea Hospital, Hammersmith Campus, London, United Kingdom.

^aAddress correspondence to this author at: BioAnalytical Innovation Team, LGC Ltd., Queens Road, Teddington TW11 0LY, United Kingdom. Fax 44-20-8943-2767; e-mail jacquie.keer{at}lgc.co.uk.

Background: Detection of fetal DNA in maternal plasma is achievable at 5 weeks of gestation, but few large-scale studies have reported circulating fetal and maternal DNA across all trimesters.

Methods: Blood samples were collected from 201 women between 5 and 41 weeks of pregnancy. Quantitative PCR was used to assess total and fetal DNA concentrations, and allelic discrimination analysis was investigated as a route to detecting specifically fetal DNA.

Results: Male fetuses were detectable from 5 weeks amenorrhea with increasing fetal DNA concentrations across gestation. The sensitivity of fetal male gender determination in pregnancies with live birth confirmation was 99%, with 100% specificity. Total DNA concentrations did not correlate with gestational age, but appeared slightly higher in the first and third trimesters than in mid-pregnancy. Analysis of short tandem repeats demonstrated that significant improvements in the detection limit are required for specific detection of fetal DNA.

Conclusions: The high sensitivity of PCR-based detection, together with quantification provided by real-time DNA analysis, has clear potential for clinical application in noninvasive prenatal diagnosis. However, accurate quantification using best-fit data analysis, standardization of methods, and performance control indicators are necessary for robust routine noninvasive diagnostics.

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