Study Objective: To compare the rates of fetal chromosomal abnormalities (CA) detected during initial non-invasive prenatal DNA testing (NIPT) with the rates of CA found through repeat NIPT in patients with low fetal fraction or low quality of cell-free embryonic DNA.
Study Design: This was a retrospective cohort study.
Materials and Methods: Twenty-one thousand forty-two women who underwent NIPT in Russia between 2013 and 2018 were included in the study. The main group comprised 1,025 of the 1,044 patients with uninformative results (low fetal fraction result, making it impossible to assess the risk of CA), who consented to repeat NIPT. The control group was made up of 19,998 women who had informative results of initial NIPT. The exclusion group comprised women with low fetal fraction who declined repeat screening. The study method was targeted NIPT. Blood samples were taken from a vein and centrifuged to obtain plasma. Fetal cell-free DNA was analyzed by next-generation sequencing (NGS), a method patented by Natera for sequencing single nucleotide polymorphisms.
Study Results: Initial NIPT was uninformative in 1,044 (5%) of the patients and repeat procedure yielded informative results in 821 (80.1%) out of 1,025 patients. Among the patients with informative results from the initial study, the rate of chromosomal aneuploidies was 2.4%. In the group of women with informative results from the repeat procedure, fetal CA were detected in 27 (3.3%) cases. In the subgroup of women with informative results only after a third NIPT, the prevalence of CA was 9.3% (seven out of 75 cases). The study showed that in women carrying fetuses with trisomy 18 or 13 or monosomy X, mean fetal fraction in the first trimester was significantly lower than normal. In the second trimester, significantly lower than normal fetal fraction was observed in women carrying fetuses with trisomy 18 or monosomy X. There was a statistically significant difference in fetal fraction levels between patients with body weight <50 kg and those with body weight 80-89 kg or above (р<0.05).
Conclusion: The probability of detecting CA by repeat NIPT is significantly higher than in an initial procedure. If initial testing is not informative, it should be repeated. If the second procedure also fails to yield informative results, invasive prenatal diagnosis should be considered. Fetal fraction levels are lower in heavier women. Thus, other methods of prenatal diagnosis should be recommended for overweight and obese women.
Contributions: Dr. E.V. Kudryavtseva collected clinical material, reviewed relevant publications, did statistical analysis of the study data, and wrote the manuscript. Dr. V.V. Kovalev developed the design of the study. Dr. I.I. Baranov checked critically important content and approved the final version of the manuscript submitted for publication. Dr. I.V. Kanivets collected clinical material. Dr. Yu.K. Kievskaya collected clinical material and reviewed relevant publications. Dr. S.A. Korostelev collected clinical material and checked critically important content.
Conflict of interest:
The authors declare that they do not have any conflict of interests.
E.V. Kudryavtseva (Corresponding author) — Ural State Medical University (a Federal Government-funded Educational Institution of Higher Education), Russian Federation Ministry of Health; 3 Repin Str., Ekaterinburg, Russian Federation 620028. eLIBRARY.RU SPIN: 7232-3743. https://orcid.org/0000-0003-2797-1926. E-mail: firstname.lastname@example.org
V.V. Kovalev — Ural State Medical University (a Federal Government-funded Educational Institution of Higher Education), Russian Federation Ministry of Health; 3 Repin Str., Ekaterinburg, Russian Federation 620028. eLIBRARY.RU SPIN: 2061-0704. E-mail: email@example.com
I.I. Baranov — V.I. Kulakov National Medical Scientific Centre of Obstetrics, Gynecology and Perinatal Medicine of the Ministry of Health of the Russian Federation; 4 Academician Oparin Str., Moscow, Russian Federation 117997. eLIBRARY.RU SPIN: 4224-0437. https://orcid.org/0000-0002-9813-2823. E-mail: firstname.lastname@example.org
I.V. Kanivets — OOO Genomed; 8 Podolskoye Shosse, Bldg. 5, Moscow, Russian Federation 115093. eLIBRARY.RU SPIN: 4204-3575. https://orcid.org/0000-0001-5821-9783. E-mail: email@example.com
Yu.K. Kievskaya — OOO Genomed; 8 Podolskoye Shosse, Bldg. 5, Moscow, Russian Federation 115093. E-mail: firstname.lastname@example.org
S.A. Korostelev — I.M. Sechenov First Moscow State Medical University (Sechenov University) (a Federal Government Autonomous Educational Institution of Higher Education), Russian Federation Ministry of Health; 8 Trubetskaya St., Bldg. 2, Moscow, Russian Federation 119991. eLIBRARY.RU SPIN: 7252-1508. https://orcid.org/0000-0002-3816-8031. E-mail: email@example.com