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Maternal and fetal factors influencing fetal fraction: A retrospective analysis of 153,306 pregnant women undergoing noninvasive prenatal screening.

Author(s): Deng C, Liu J, Liu S, Liu H, Bai T, Jing X, Xia T, Liu Y, Cheng J, Wei X, Xing L, Luo Y, Zhou Q, Zhu Q, Liu S.

Publication: Front Pediatr, 2023, Vol. 11, Page 1066178

PubMed ID: 37114008 PubMed Review Paper? No

Purpose of Paper

Conclusion of Paper

Studies

1. Study Purpose

   This study retrospectively analyzed NIPS data from 153,306 singleton pregnancies to identify a possible relationship between fetal fraction or z-score of chromosomes 21, 18, and 13 and gestational age, maternal BMI, and maternal age. A potential relationship between fetal fraction and z-score of chromosomes 21, 18, and 13 was also investigated.  NIPS was conducted using 8-10 mL blood collected in Streck Cell-free blood collection tubes (BCT); plasma was obtained by dual centrifugation (speed not specified) within 3 days. cfDNA was extracted using a kit from Hangzhou Berry Gene Diagnostic Technology Co and libraries were constructed by Reversile Terminator Sequencing. Libraries were sequenced on a NextSeq CN500 instrument.  Cases were stratified based on gestational age at the time of maternal blood collection (39,417 were 12-16 weeks of pregnancy, 83,892 were 17-20 weeks of pregnancy, 21,632 were 21-24 weeks of pregnancy, and 8,365 were ≥25 weeks pregnancy), maternal age (28,870 were < 25 years, 57,520 were 25-29 years, 45,039 were 30-34 years, 19,576 were 35-39 years, and 2,298 were ≥40 years), and maternal BMI (10,079 were <18.5, 114,495 were 18.5 to <25, 25,719 were 25 to <30, and 3,013 were ≥30 kg/m²).  DNA was extracted and sequenced (details not provided). Fetal fraction of male and female fetuses was determined using the Y chromosome and fragment length, respectively. Results were only considered accurate if the fetal fraction was ≥4%. A z-score ≥3 was considered high risk for trisomy. Of the 492 women with a z-score ≥3, 405 opted for invasive prenatal testing (villus sampling or amniocentesis).

   Summary of Findings:

   The median fetal fraction fetal increased with gestational age (11.25%, 11.37%, 12.32%, and 15.15% for specimens from women 12-16 weeks, 17-20 weeks, 21-25 weeks and ≥25 weeks pregnant, respectively, P<0.001). The median fetal fraction was significantly lower in specimens from women that were 12-16 weeks pregnant than those that were ≥17 weeks pregnant (P<0.05), from women 17-20 weeks pregnant than ≥21 weeks pregnant (P<0.05), and from women 21-24 weeks pregnant than those that were ≥25 weeks pregnant (P<0.05).   The median fetal fraction was higher in younger women than older women (12.04%, 11.81%, 11.51%, 10.85% and 10.65% for specimens from women <25, 25-29, 30-34, 35-39 and ≥40 years of age, respectively, P<0.001), with significant differences found between each group (P<0.05). The median fetal fraction was higher in specimens from patients with a BMI <18.5 kg/m² than those from patients with a BMI 18.5 to <25, 25 to <30 kg/m² or ≥30 kg/m² (13.28% versus 11.87%, 10.16%, and 8.81%, respectively; P<0.05, both), in specimens from patients with a BMI of 18.5-<25 kg/m² than ≥25 kg/m² (P<0.05), and in specimens from patients with a BMI of 25-<30 kg/m² than ≥30 kg/m² (P<0.05). Of the 405 cases in which the patients chose to have an invasive test based on a noninvasive prenatal test (NIPT) z-score >3, trisomy was confirmed in 282 cases (243, 31 and 8 cases of trisomy of chromosomes 21, 18 and 13, respectively). Seven additional cases of trisomy (3 cases of trisomy chromosome 21 and cases of trisomy chromosome 18) were later diagnosed in patients classified as low risk (z-score <3) based on NIPT. While the median fetal fraction was higher in specimens from women carrying a fetus with trisomy 21 than those screened as negative (12.49% versus 11.62%, P<0.05), the median fetal fraction was lower in specimens from women carrying a fetus with trisomy 18 or 13 than those that screened negative (9.28% and 10.86%, respectively, versus 11.62%; P<0.05 both). Further analysis found that the z-scores for true positives in chromosomes 21 and 18 trisomy were strongly correlated with fetal fraction (r=0.8097, P<0.0001 and r=0.8246, P<0.0001, respectively), but z-scores and fetal fraction were not correlated for true positives of trisomy chromosome 13. Very weak negative correlations were observed between the z-scores and fetal fraction in trisomy 18 and 13 negative specimens (r=-0.0276, P<0.0001 and r=-0.09256, P<0.0001, respectively).

   Biospecimens

   • Bodily Fluid - Plasma
   • Bodily Fluid - Blood

   Preservative Types

   • Streck/BCT

   Diagnoses:

   • Pregnant

   Platform:

   Analyte	Technology Platform
   DNA	Next generation sequencing

   Pre-analytical Factors:

   Classification	Pre-analytical Factor	Value(s)
   Preaquisition	Patient age	< 25 years 25-29 years 30-34 years 35-39 years ≥40 years
   Preaquisition	Patient body mass index	<18.5 kg/m2 18.5-<25 kg/m2 25-<30 kg/m2 ≥30 kg/m2
   Preaquisition	Diagnosis/ patient condition	12-16 weeks of pregnant 17-20 weeks of pregnant 21-24 weeks of pregnant ≥25 weeks pregnant

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