Talk:Fetal Cells in Maternal Blood

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Cite this page: Hill, M.A. (2021, May 14) Embryology Fetal Cells in Maternal Blood. Retrieved from


Van De Looij A, Singh R, Hatt L, Ravn K, Jeppesen LD, Nicolaisen BH, Kølvraa M, Vogel I, Schelde P & Uldbjerg N. (2020). Do fetal extravillous trophoblasts circulate in maternal blood postpartum?. Acta Obstet Gynecol Scand , , . PMID: 32323316 DOI.

Do fetal extravillous trophoblasts circulate in maternal blood postpartum?

INTRODUCTION: Circulating fetal extravillous trophoblasts may offer a superior alternative to cell-free fetal DNA for noninvasive prenatal testing. Cells of fetal origin are a pure source of fetal genome, hence, unlike cell-free noninvasive prenatal test, fetal cell-based noninvasive prenatal test is not expected to be affected by maternal DNA. However, circulating fetal cells from previous pregnancies may lead to confounding results. MATERIAL AND METHODS: In order to study whether fetal trophoblast cells persist in maternal circulation postpartum, blood samples were collected from 11 women who had given birth to a boy, with blood sampling at 1-3 days (W0), 4-5 weeks (W4-5), around 8 weeks (W8), and around 12 weeks (W12) postpartum. The existence of fetal extravillous trophoblasts was verified either by X and Y chromosome fluorescence in-situ hybridization analysis, or by short tandem repeat analysis. In order to exclude technological bias in isolating fetal cells, blood samples were also collected from 10 pregnant women in gestational age of 10-14 weeks, the optimal time frame for cell-based noninvasive prenatal test sampling. All the samples were processed according to protocols established by ARCEDI Biotech (Vejle, Denmark) for fetal extravillous trophoblasts enrichment and isolation. RESULTS: Fetal extravillous trophoblasts were found in all the 10 samples from pregnant women in gestational age of 10-14 weeks. However, only four out of 11 blood samples taken from women, one to three days postpartum rendered fetal extravillous trophoblasts. And only two out of 11 samples rendered fetal extravillous trophoblasts at four weeks postpartum. CONCLUSIONS: In this preliminary dataset on few pregnancies, none of the samples rendered any fetal cells at or after eight weeks postpartum, showing that cell-based noninvasive prenatal testing based on fetal extravillous trophoblasts is unlikely to be influenced by circulating cells from previous pregnancies. This article is protected by copyright. All rights reserved. KEYWORDS: Noninvasive prenatal testing; chorionic villi sampling; fetal cells; fetal extravillous trophoblasts; prenatal diagnosis PMID: 32323316 DOI: 10.1111/aogs.13880


Fetal aneuploidy screening with cell-free DNA in late gestation

J Matern Fetal Neonatal Med. 2016 Apr 28:1-5. [Epub ahead of print]

Taneja PA1, Prosen TL2, de Feo E1, Kruglyak KM1, Halks-Miller M1, Curnow KJ1, Bhatt S1.


OBJECTIVE: The aim of this study was to evaluate clinical use of NIPT at gestational ages of 23 weeks and above. METHODS: A cohort of 5579 clinical patients with singleton gestations of 23 weeks or greater submitting a blood sample for NIPT in an 18-month period were selected for this study. Clinical outcomes were requested for samples with NIPT results indicating fetal aneuploidy and compared with NIPT findings to confirm concordance or discordance. RESULTS: A review of clinical indications revealed that a significantly (p < 0.0001) larger proportion of late-gestation samples indicated abnormal ultrasound findings with or without other indications, 6.2% and 42.1%, compared with early-gestation samples, 1.8% and 6.0%, respectively. Of 5372 reported late-gestation samples, 151 (2.8%) were reported as aneuploidy detected or suspected. In late-gestation samples, the overall observed positive predictive value (PPV) for NIPT was 64.7%, with an observed PPV of 100% in the subset of cases with multiple clinical indications including abnormal ultrasound findings. CONCLUSIONS: NIPT is a highly accurate prenatal screening option for women after 23 weeks of gestation. Women who presented for NIPT in the latter stages of pregnancy more frequently specified clinical indications of abnormal ultrasound findings than women who entered screening earlier in pregnancy. KEYWORDS: Chromosomal abnormalities; NIPT; positive predictive value; prenatal screening; third trimester PMID 27124739


Fetal Sex Chromosome Testing by Maternal Plasma DNA Sequencing: Clinical Laboratory Experience and Biology

Obstet Gynecol. 2015 Jan 7. [Epub ahead of print]

Bianchi DW1, Parsa S, Bhatt S, Halks-Miller M, Kurtzman K, Sehnert AJ, Swanson A.


OBJECTIVE:: To describe the clinical experience with noninvasive prenatal testing for fetal sex chromosomes using sequencing of maternal plasma cell-free DNA in a commercial laboratory. METHODS:: A noninvasive prenatal testing laboratory data set was examined for samples in which fetal sex chromosomes were reported. Available clinical outcomes were reviewed. RESULTS:: Of 18,161 samples with sex chromosome results, no sex chromosome aneuploidy was detected in 98.9% and the fetal sex was reported as XY (9,236) or XX (8,721). In 4 of 32 cases in which the fetal sex was reportedly discordant between noninvasive prenatal testing and karyotype or ultrasonogram, a potential biological reason for the discordance exists, including two cases of documented co-twin demise, one case of a maternal kidney transplant from a male donor, and one case of fetal ambiguous genitalia. In the remaining 204 samples (1.1%), one of four sex chromosome aneuploidies (monosomy X, XXX, XXY, or XYY) was detected. The frequency of false positive results for sex chromosome aneuploidies is a minimum of 0.26% and a maximum of 1.05%. All but one of the discordant sex chromosome aneuploidy results involved the X chromosome. In two putative false-positive XXX cases, maternal XXX was confirmed by karyotype. For the false-positive cases, mean maternal age was significantly higher in monosomy X (P<.001) and lower in XXX (P=.008). CONCLUSION:: Noninvasive prenatal testing results for sex chromosome aneuploidy can be confounded by maternal or fetal biological phenomena. When a discordant noninvasive prenatal testing result is encountered, resolution requires additional maternal history, detailed fetal ultrasonography, and determination of fetal and possibly maternal karyotypes. LEVEL OF EVIDENCE:: II.

PMID 25568992


Fetal gender and several cytokines are associated with the number of fetal cells in maternal blood - an observational study

PLoS One. 2014 Sep 4;9(9):e106934. doi: 10.1371/journal.pone.0106934. eCollection 2014.

Schlütter JM1, Kirkegaard I1, Petersen OB1, Larsen N2, Christensen B3, Hougaard DM2, Kølvraa S4, Uldbjerg N1.


OBJECTIVE: To identify factors influencing the number of fetal cells in maternal blood. METHODS: A total of 57 pregnant women at a gestational age of weeks 11-14 were included. The number of fetal cells in maternal blood was assessed in 30 ml of blood using specific markers for both enrichment and subsequent identification. RESULTS: Participants carrying male fetuses had a higher median number of fetal cells in maternal blood than those carrying female fetuses (5 vs. 3, p = 0.04). Certain cytokines (RANTES, IL-2 and IL-5) were significantly associated with the number of fetal cells in maternal blood. CONCLUSION: The number of fetal cells in maternal blood is associated with certain cytokines and fetal gender.

PMID 25188498

Noninvasive prenatal screening for fetal trisomies 21, 18, 13 and the common sex chromosome aneuploidies from maternal blood using massively parallel genomic sequencing of DNA

Am J Obstet Gynecol. 2014 Mar 19. pii: S0002-9378(14)00270-1. doi: 10.1016/j.ajog.2014.03.042. [Epub ahead of print]

Porreco RP1, Garite TJ2, Maurel K3, Marusiak B3, Ehrich M4, van den Boom D4, Deciu C4, Bombard A4.


OBJECTIVE: The objective of this study was to validate the clinical performance of massively parallel genomic sequencing of cell-free deoxyribonucleic acid contained in specimens from pregnant women at high risk for fetal aneuploidy to test fetuses for trisomies 21, 18, and 13; fetal sex; and the common sex chromosome aneuploidies (45, X; 47, XXX; 47, XXY; 47, XYY). STUDY DESIGN: This was a prospective multicenter observational study of pregnant women at high risk for fetal aneuploidy who had made the decision to pursue invasive testing for prenatal diagnosis. Massively parallel single-read multiplexed sequencing of cell-free deoxyribonucleic acid was performed in maternal blood for aneuploidy detection. Data analysis was completed using sequence reads unique to the chromosomes of interest. RESULTS: A total of 3430 patients were analyzed for demographic characteristics and medical history. There were 137 fetuses with trisomy 21, 39 with trisomy 18, and 16 with trisomy 13 for a prevalence rate of the common autosomal trisomies of 5.8%. There were no false-negative results for trisomy 21, 3 for trisomy 18, and 2 for trisomy 13; all 3 false-positive results were for trisomy 21. The positive predictive values for trisomies 18 and 13 were 100% and 97.9% for trisomy 21. A total of 8.6% of the pregnancies were 21 weeks or beyond; there were no aneuploid fetuses in this group. All 15 of the common sex chromosome aneuploidies in this population were identified, although there were 11 false-positive results for 45,X. Taken together, the positive predictive value for the sex chromosome aneuploidies was 48.4% and the negative predictive value was 100%. CONCLUSION: Our prospective study demonstrates that noninvasive prenatal analysis of cell-free deoxyribonucleic acid from maternal plasma is an accurate advanced screening test with extremely high sensitivity and specificity for trisomy 21 (>99%) but with less sensitivity for trisomies 18 and 13. Despite high sensitivity, there was modest positive predictive value for the small number of common sex chromosome aneuploidies because of their very low prevalence rate. Copyright © 2014 Mosby, Inc. All rights reserved. KEYWORDS: cell-free deoxyribonucleic acid, massively parallel genomic sequencing, noninvasive prenatal screening

PMID 24657131


Non-invasive prenatal testing for aneuploidy: current status and future prospects

Ultrasound Obstet Gynecol. 2013 Jul;42(1):15-33. doi: 10.1002/uog.12513.

Benn P1, Cuckle H, Pergament E.


Non-invasive prenatal testing (NIPT) for aneuploidy using cell-free DNA in maternal plasma is revolutionizing prenatal screening and diagnosis. We review NIPT in the context of established screening and invasive technologies, the range of cytogenetic abnormalities detectable, cost, counseling and ethical issues. Current NIPT approaches involve whole-genome sequencing, targeted sequencing and assessment of single nucleotide polymorphism (SNP) differences between mother and fetus. Clinical trials have demonstrated the efficacy of NIPT for Down and Edwards syndromes, and possibly Patau syndrome, in high-risk women. Universal NIPT is not cost-effective, but using NIPT contingently in women found at moderate or high risk by conventional screening is cost-effective. Positive NIPT results must be confirmed using invasive techniques. Established screening, fetal ultrasound and invasive procedures with microarray testing allow the detection of a broad range of additional abnormalities not yet detectable by NIPT. NIPT approaches that take advantage of SNP information potentially allow the identification of parent of origin for imbalances, triploidy, uniparental disomy and consanguinity, and separate evaluation of dizygotic twins. Fetal fraction enrichment, improved sequencing and selected analysis of the most informative sequences should result in tests for additional chromosomal abnormalities. Providing adequate prenatal counseling poses a substantial challenge given the broad range of prenatal testing options now available. Copyright © 2013 ISUOG. Published by John Wiley & Sons, Ltd. KEYWORDS: Down syndrome, amniocentesis, aneuploidy, chorionic villus sampling, fetal DNA, maternal plasma, screening, sequencing, trisomy

PMID 23765643


Pregnancy, microchimerism, and the maternal grandmother

PLoS One. 2011;6(8):e24101. doi: 10.1371/journal.pone.0024101. Epub 2011 Aug 30.

Gammill HS1, Adams Waldorf KM, Aydelotte TM, Lucas J, Leisenring WM, Lambert NC, Nelson JL.


BACKGROUND: A WOMAN OF REPRODUCTIVE AGE OFTEN HARBORS A SMALL NUMBER OF FOREIGN CELLS, REFERRED TO AS MICROCHIMERISM: a preexisting population of cells acquired during fetal life from her own mother, and newly acquired populations from her pregnancies. An intriguing question is whether the population of cells from her own mother can influence either maternal health during pregnancy and/or the next generation (grandchildren). METHODOLOGY/PRINCIPAL FINDINGS: Microchimerism from a woman's (i.e. proband's) own mother (mother-of-the-proband, MP) was studied in peripheral blood samples from women followed longitudinally during pregnancy who were confirmed to have uncomplicated obstetric outcomes. Women with preeclampsia were studied at the time of diagnosis and comparison made to women with healthy pregnancies matched for parity and gestational age. Participants and family members were HLA-genotyped for DRB1, DQA1, and DQB1 loci. An HLA polymorphism unique to the woman's mother was identified, and a panel of HLA-specific quantitative PCR assays was employed to identify and quantify microchimerism. Microchimerism from the MP was identified during normal, uncomplicated pregnancy, with a peak concentration in the third trimester. The likelihood of detection increased with advancing gestational age. For each advancing trimester, there was a 12.7-fold increase in the probability of detecting microchimerism relative to the prior trimester, 95% confidence intervals 3.2, 50.3, p<0.001. None of the women with preeclampsia, compared with 30% of matched healthy women, had microchimerism (p = 0.03). CONCLUSIONS/SIGNIFICANCE: These results show that microchimerism from a woman's own mother is detectable in normal pregnancy and diminished in preeclampsia, supporting the previously unexplored hypothesis that MP microchimerism may be a marker reflecting healthy maternal adaptation to pregnancy.

PMID 21912617


Presence of fetal DNA in maternal plasma and serum

Lancet. 1997 Aug 16;350(9076):485-7.

Lo YM1, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW, Wainscoat JS.


BACKGROUND: The potential use of plasma and serum for molecular diagnosis has generated interest. Tumour DNA has been found in 'the plasma and serum of cancer patients, and molecular analysis has been done on this material. We investigated the equivalent condition in pregnancy-that is, whether fetal DNA is present in maternal plasma and serum. METHODS: We used a rapid-boiling method to extract DNA from plasma and serum. DNA from plasma, serum, and nucleated blood cells from 43 pregnant women underwent a sensitive Y-PCR assay to detect circulating male fetal DNA from women bearing male fetuses. FINDINGS: Fetus-derived Y sequences were detected in 24 (80%) of the 30 maternal plasma samples, and in 21 (70%) of the 30 maternal serum samples, from women bearing male fetuses. These results were obtained with only 10 microL of the samples. When DNA from nucleated blood cells extracted from a similar volume of blood was used, only five (17%) of the 30 samples gave a positive Y signal. None of the 13 women bearing female fetuses, and none of the ten non-pregnant control women, had positive results for plasma, serum or nucleated blood cells. INTERPRETATION: Our finding of circulating fetal DNA in maternal plasma may have implications for non-invasive prenatal diagnosis, and for improving our understanding of the fetomaternal relationship. Comment in Non-invasive prenatal diagnosis of fetal aneuploidies. [Lancet. 2007]

PMID 9274585