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Genome wide fetal aneuploidy detection by sequencing of maternal plasma DNA: diagnostic accuracy in a prospective, blinded, multicenter study

OBJECTIVE: The ability to detect fetal aneuploidies across the genome must be demonstrated if massively parallel sequencing (MPS) of maternal plasma DNA is to be widely incorporated into prenatal care.We prospectively determined the diagnostic accuracy of MPS to detect whole chromosome fetal aneuploidy.
STUDY DESIGN: Blood samples were collected in a prospective, blinded study from 2,882 women undergoing prenatal diagnostic procedures at 60 United States sites. All singleton pregnancies with any abnormal karyotype and a balance of subjects with euploid karyotypes (<1:4 ratio) were randomly selected by an independent biostatistician. Sample lists were submitted to the laboratory for sequencing. Six independent classifications for chromosomes 21, 18, 13, male, female and monosomy X were made for each sample and compared to fetal karyotype.
RESULTS: Within an analysis cohort of 532 samples, 89/89 trisomy 21 cases, (sensitivity 100% (95% CI 95.9-100)), 35/36 trisomy 18 cases (sensitivity 97.2%, (95% CI 85.5-99.9)), 11/14 trisomy 13 cases (sensitivity 78.6%, (95% CI 49.2-99.9)), 232/233 females (sensitivity 99.6%, (95% CI 97.6-99.9)), 184/184 males (sensitivity 100%, (95% CI 98.0-100)), and 15/16 monosomy X cases (sensitivity 93.8%, (95% CI 69.8-99.8)) were classified (Table 1, Figure 1). There were no false positives for autosomal aneuploidies in unaffected subjects (100% specificity). In addition, fetuses with mosaicism for trisomy 21 (3/3), trisomy 18 (1/1), and monosomy X (2/7), as well as three cases of translocation trisomy, two cases of other autosomal trisomy (T20 and T16) and other sex chromosome aneuploidies (XXX, XXY and XYY) were correctly classified.
CONCLUSION: This is the first prospective study to demonstrate the efficacy of MPS of maternal plasma DNA with optimized normalization to detect aneuploidy across the genome. MPS provides superior sensitivity and specificity to diagnose trisomies 21 and 18, compared to screening by serum analytes and ultrasound, and is capable of detecting trisomy 13 and monosomy X. This approach would require far fewer invasive procedures to diagnose fetal aneuploidy

Randomized controlled trial of progesterone treatment for preterm birth prevention in nulliparous women with cervical length less than 30 mm

For the Eunice Kennedy Shriver National Institute of Health and Human Development, Maternal-Fetal Units Network, Bethesda, MD
OBJECTIVE: To determine whether 17 alpha hydroxyprogesterone caproate (17-OHPc) reduces preterm birth in nulliparous women with a short cervical length (CL).
STUDY DESIGN: In this multicenter randomized controlled trial, nulliparous women with a singleton gestation between 16 and 22 3/7 weeks underwent transvaginal ultrasound CL measurement by centrally certified sonographers. Consenting women with a CL 30 mm (10th percentile in this gestational age range) were randomly assigned to either 17-OHPc (250 mg IM weekly through 36 weeks) or an identically appearing placebo. The primary outcome was preterm birth before 37 weeks (PTB).
RESULTS: Of 15,436 screened women, 1,588 (10.3%) had a CL 30 mm. The DSMB halted the study after 657 women had been randomized (N327 17-OHPc and 330 placebo) due to a planned interim analysis that revealed further enrollment was statistically very unlikely to demonstrate a significant difference between the groups. The frequency of PTB did not differ between the 17-OHPc and placebo groups (25.1% vs. 24.2%, P < 0.80). There also was no difference in delivery 35 weeks (13.5% v 16.1%, P  0.35) or 32 weeks (8.6% vs. 9.7%, P  0.61). While the power to show a difference was limited, subgroup analyses failed to demonstrate benefit from 17-OHPc in women with a CL 15mm or at 10-20 mm.
CONCLUSION: Weekly IM 17-OHPc does not reduce the frequency of PTB in nulliparous women with a short cervix 30 mm and should not be used for this indication.

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