Association between low fetal fraction in cell-free DNA screening and fetal chromosomal aberrations: A systematic review and meta-analysis

Objective

To perform a systematic review and meta-analysis of the available literature on low fetal fraction (LFF) in cell-free DNA (cfDNA) screening and the risk of fetal chromosomal aberrations.

Method

We searched articles published between January 2010 and May 2021 in PubMed and EMBASE databases. Risk of bias was assessed using QUADAS-2.

Results

Twenty-seven studies met the inclusion criteria, comprising data of 243,700 singleton pregnancies. Compared to normal fetal fraction, LFF was associated with a higher risk of trisomy 13 (OR 5.99 [3.61–9.95], I ² of heterogeneity = 0%, n = 22 studies), trisomy 18 (OR 4.46 [3.07–6.47], I ² = 0%, n = 22 studies), monosomy X (OR 5.88 [2.34–14.78], I ² = 18%, n = 10 studies), and triploidy (OR 36.39 [9.83–134.68], I ² = 61%, n = 6 studies), but not trisomy 21 (OR 1.25 [0.76–2.03], I ² = 36%, n = 23 studies). LFF was also associated with a higher risk of various other types of fetal chromosomal aberrations (OR 4.00 [1.78–9.00], I ² = 2%, n = 11 studies). Meta-analysis of proportions showed that absolute rates of fetal chromosomal aberrations ranged between 1% and 2% in women with LFF. A limitation of this review is the potential risk of ascertainment bias because of differences in outcome assessment between pregnancies with LFF and those with normal fetal fraction. Heterogeneity in population characteristics or applied technologies across included studies may not have been fully addressed.

Conclusion

An LFF test result in cfDNA screening is associated with an increased risk of fetal trisomy 13, trisomy 18, monosomy X, and triploidy, but not trisomy 21. Further research is needed to assess the association between LFF and other specific types of fetal chromosomal aberrations.     

A rare case of cytogenetic discrepancy between extraembryonic and fetal tissue

We present a case of false-negative discrepancy between extraembryonic and fetal tissue sampled at 14 weeks of amenorrhoea when ultrasound examination showed morphological anomalies of the fetus. The same cytogenetic characteristic was confirmed on tissue samples after abortion.     

Complete discrepancy between abnormal fetal karyotypes predicted by QF-PCR rapid testing and karyotyped cultured cells in a first-trimester CVS

A chorion villus sample (CVS) biopsied at 11 weeks' gestation for raised nuchal translucency, revealed monosomy X (presumptive 45,X karyotype) by QF-PCR for rapid aneuploidy testing for chromosomes 13, 18, 21, X and Y. Long-term culture gave the karyotype: 47,XY,+ 21[66]/49,XYY,+ 21,+ 21 [22]. This discrepancy prompted redigestion of the combined residual villus fragments from the original QF-PCR assay. The repeat QF-PCR assay identified the presence of trisomy 21 and a Y chromosome consistent with a 47,XY,+ 21 karyotype. A double non-disjunction event early in embryogenesis in a 47,XY,+ 21 conceptus with subsequent cell lineage compartmentalisation of the three observed cell lines (45,X; 47,XY,+ 21 and 49,XYY,+ 21,+ 21) would account for these results. This is the first reported case to describe complete discrepancy at diagnosis between abnormal karyotypes detected by QF-PCR rapid aneuploidy testing and a cultured karyotype in the same CVS. Copyright © 2006 John Wiley & Sons, Ltd.     

Complete karyotype discrepancy between placental and fetal cells in a case of ring chromosome 18

A case of complete karyotype discrepancy between cultured chorionic villi and amniotic in addition to fetal cells is reported. Ring chromosome 18 and monosomy 18 mosaicism was detected after amniocentesis. The pregnancy was terminated in the 23rd gestational week. Cytogenetic analysis of cultured umbilical cord tissue after termination confirmed the finding of ring chromosome 18/monosomy 18 mosaicism. In cultured umbilical blood lymphocytes monosomic cells 45,-18 were not detected and the karyotype was 46,XY,r(18). In contrast, short-term and long-term cultured chorionic villi showed a normal male karyotype of 46,XY. Ultrasonographic examination revealed amniotic band syndrome and scoliosis in the caudal region of the spine. Copyright © 2001 John Wiley & Sons, Ltd.     

The use of amniotic FSH levels in resolving a discrepancy between fetal chromosomal and phenotypic sex

We report a case in which a discrepancy emerged between the prenatal diagnosis of female chromosomal sex and male sex at ultrasound examination. The FSH dosage performed on an amniotic fluid sample previously stored confirmed the male phenotype of the fetus. The effectiveness of the AF-FSH level dosage in prenatal diagnosis was taken into consideration.     

Detecting neural tube defects by amniocentesis between 11 and 15 weeks' gestation

Forty-two open neural tube defects (NTDs) were identified in our series of 7440 amniocenteses tested between 11 and 15 weeks of gestation. Using a cut-off of ≥2.0 MOM, the detection rate for open NTDs was 95 per cent; 100 per cent each for anencephaly and spina bifida; and 78 per cent for encephalocele. Two encephaloceles had AFP levels less than 2.0 MOM and negative AChEs. Thirty-four (81 per cent) of these NTDs were tested between 13 and 15 weeks and 8 (19 per cent) before 13 weeks. There were 0.6 per cent false positives by AFP (excluding serious abnormalities and fetal death) and 0.1 per cent after AChE. The likelihood of an open NTD after an elevated AFP (≥2.0 MOM) was 24 and 77 per cent for any serious abnormality. These results, when combined with an earlier study, indicate that amniotic fluid AFP appears to be as sensitive a test for open NTDs between 13 and 15 weeks as between 16 and 20 weeks. Additional experience is necessary to determine this before 13 weeks.     

First-trimester fetal heart block and increased nuchal translucency: an indication for early fetal echocardiography

Prevalence of congenital heart disease increases with nuchal translucency (NT) thickness. First-trimester fetal bradycardia may result from heart block associated with complex congenital heart disease. We report two cases detected in the first trimester of pregnancy, in which both fetuses showed an increased nuchal translucency and bradycardia. Fetal karyotype was normal in both fetuses. First-trimester fetal echocardiography was performed and, in both cases, complex congenital heart disease was diagnosed. We discuss the added role of fetal heart rate in first-trimester ultrasound screening, in fetuses with increased nuchal translucency and normal karyotype. We stress, as well, the importance of echocardiography performed in the first trimester as a potential tool for early diagnosis in selected cases. Copyright © 2005 John Wiley & Sons, Ltd.