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The diagnostic accuracy of non-invasive fetal RhD genotyping by using cell-free fetal DNA in maternal plasma

Year 2019, Volume: 4 Issue: 1, 1 - 6, 18.03.2019

Cisem Akurut Fatma Silan , Sinem Yalcintepe Ozturk Ozdemir

https://doi.org/10.22391/fppc.418647

Abstract

Introduction: The non-invasive prenatal
diagnosis of the fetus RhD genotype in RhD incompatibility has a crucial role
in the prevention of increased anti-D immunoglobulin therapy for haemolytic
diseases in pregnant women carrying RhD negative fetus. It was aimed to detect
fetal RhD genotyping by using maternal circulating cell-free DNA in the current
study.

Methods: Maternal blood samples were
collected in different trimester of pregnancies (12-40 weeks) in 12 D-negative
mothers. Cell-free fetal DNA was extracted from 2 ml of maternal plasma by an
conventional DNA isolation technique (Qiagen, Hilden, Germany) and real-time
PCR was performed for genotyping target RhD exons 7 and 10 and GLO genes.
Postnatal serological evaluations were performed and the results were
confirmed.

Results: 6 cases (50 %)
were determined D positive and 6 cases (50 %) were determined D negative. All
results were also confirmed after birth serologically.







Conclusions: In conclusion,
the current results showed us the non-invasive target RhD genotyping from cell
free fetal DNA from maternal plasma samples have a diagnostic accuracy in RhD
incompatibility pregnancies.

Keywords

maternal plasma Cell free fetal DNA prenatal screening real-time PCR

References

  • 1. Moise KJ. Management of rhesus alloimmunization in pregnancy. Obstet Gynecol 2008;112:164–176. https://doi.org/10.1097/AOG.0b013e31817d453c
  • 2. Aykut A, Onay H, Sagol S, Gunduz C, Ozkinay F, Cogulu O. Determination of fetal rhesus D status by maternal plasma DNA analysis. Balk J Med Gen 2013; 16(2):33-38. https://doi.org/10.2478/bjmg-2013-0029
  • 3. Cetinkaya M, Ozkan H, Koksal N, Akkus H, Kimya Y. [Influence of intrauterine transfusion on neonatal outcome in Rh hemolytic disease] (in Turkish). J Curr Pediatr 2010; 8:1-6.
  • 4. Wright CF, Burton H. The use of cell-free fetal nucleic acids in maternal blood for non-invasive prenatal diagnosis. Hum Reprod Update 2009; 15(1):139–151. https://doi.org/10.1093/humupd/dmn047
  • 5. NICE. Routine antenatal anti-D prophylaxis for women who are rhesus D negative: review of NICE technology appraisal guidance 2011; 41 London.
  • 6. Gunel T, Kalelioglu I, Ermis H, Aydinli K. Detection of fetal RhD gene from maternal blood. J Turkish-German Gynecol Assoc 2010; 11:82-85. https://doi.org/10.5152/jtgga.2010.04
  • 7. Mujezinovic F, Alfirevic Z. Procedure-related complications of amniocentesis and chorionic villous sampling: a systematic review. Obstet Gynecol 2007; 110:687–694. https://doi.org/10.1097/01.AOG.0000278820.54029.e3
  • 8. Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW et al. Presence of fetal DNA in maternal plasma and serum. Lancet. 1997; 350:485–487. https://doi.org/10.1016/S0140-6736(97)02174-0
  • 9. Guibert J, Benachi A, Grebille AG, Ernault P, Zorn JR, Costa JM. Kinetics of SRY gene appearance in maternal serum: detection by real time PCR in early pregnancy after assisted reproductive technique. Hum Reprod 2003; 18:1733–1736. https://doi.org/10.1093/humrep/deg320
  • 10. Liao GJW, Gronowski AM, Zhaol Z. Non-invasive prenatal testing using cell-free fetal DNA in maternal circulation. Clinica Chimica Acta 2014; 428:44–50. https://doi.org/10.1016/j.cca.2013.10.007
  • 11. Lo YM, Tein MS, Lau TK, Haines CJ, Leung TN, Poon PM et al. Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet. 1998; 62:768–775. https://doi.org/10.1086/301800
  • 12. Lo YM, Chan KC, Sun H, Chen EZ, Jiang P, Lun FM et al. Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci Transl Med 2010; 8:2(61):61ra91.
  • 13. Chan KC, Zhang J, Hui AB, Wong N, Lau TK, Leung TN et al. Size distributions of maternal and fetal DNA in maternal plasma. Clin Chem 2004; 50:88–92. https://doi.org/10.1373/clinchem.2003.024893
  • 14. Kent J, Farrell AM, Soothill P. Routine administration of Anti-D: the ethical case for offering pregnant women fetal RHD genotyping and a review of policy and practice. BMC Pregnancy Childb 2014; 14:87. https://doi.org/10.1186/1471-2393-14-87
  • 15. Clausen FB, Christiansen M, Steffensen R, Jørgensen S, Nielsen C, Jakobsen MA, et al. Report of the first nationally implemented clinical routine screening for fetal RHD in D- pregnant women to ascertain the requirement for antenatal RhD prophylaxis. Transfusion 2012; 52:752–758. https://doi.org/10.1111/j.1537-2995.2011.03362.x
  • 16. Wikman AT, Tiblad E, Karlsson A, Olsson ML, Westgren M, Reilly M. Noninvasive single-exon fetal RHD determination in a routine screening program in early pregnancy. Obstet Gynecol 2012; 120:227–234. https://doi.org/10.1097/AOG.0b013e31825d33d9
  • 17. Finning KM, Martin PG, Soothill PW, Avent ND. Prediction of fetal D status from maternal plasma: introduction of a new noninvasive fetal RHD genotyping service. Transfusion 2002; 42(8):1079–1085. https://doi.org/10.1046/j.15372995.2002.00165.x
  • 18. Minon JM, Gerard C, Senterre JM, Schaaps JP, Foidart JM. Routine fetal RHD genotyping with maternal plasma: a fouryear experience in Belgium. Transfusion 2008; 48(2):373-381. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.15372995.2007.01533.x
  • 19. Rouillac-Le Sciellour C, Puillandre P, Gillot R, Baulard C, Metral S, Van Le Kim C, et al. Large-scale pre-diagnosis study of fetal RHD genotyping by PCR on plasma DNA from RhD-negative pregnant women. Mol Diagn 2004; 8(1):23–31. https://doi.org/10.2165/00066982-200408010-00004
  • 20. Chitty LS, Finning K, Wade A, Soothill P, Martin B, Oxenford K, et al. Diagnostic accuracy of routine antenatal determination of fetal RHD status across gestation: population based cohort study. BMJ 2014; 349:g5243. https://doi.org/10.1136/bmj.g5243
  • 21. Clausen FB, Christiansen M, Steffensen R, Jorgensen S, Nielsen C, Jakobsen MA, et al. Report of the first nationally implemented clinical routine screening for fetal RHD in D-pregnant women to ascertain the requirement for antenatal RhD prophylaxis. Transfusion 2012; 52(4):752–758. https://doi.org/10.1111/j.1537-2995.2011.03362.x
  • 22. Hromadnikova I, Vechetova L, Vesela K, Benesova B, Doucha J, Kulovany E, Vlk R. Non-Invasive Fetal RHD Exon 7 and Exon 10 Genotyping Using Real-Time PCR Testing of Fetal DNA in Maternal Plasma. Fetal Diagn Ther 2005; 20:275–280. https://doi.org/10.1159/000085085
  • 23. Vivanti A, Benachi A, Huchet F, Ville Y, Cohen H, Costa J, PharmD. Diagnostic accuracy of fetal rhesus D genotyping using cell-free fetal DNA during the first trimester of pregnancy. Am J Obstet Gynecol 2016; 215:606.e1-5. https://doi.org/10.1016/j.ajog.2016.06.054
  • 24. Zhou L, Thorson JA, Nugent C, Davenport RD, Butch SH, Judd WJ. Noninvasive prenatal RHD genotyping by real-time polymerase chain reaction using plasma from D-negative pregnant women. Am J Obstet Gynecol 2005; 193:1966–1971. https://doi.org/10.1016/j.ajog.2005.04.052
  • 25. Müller S, Bartels I, Stein W, Emons G, Gutensohn K ve Legler TJ. Cell-free fetal DNA in specimen from pregnant women is stable up to 5 days. Prenat Diagn 2011; 31:1300-1304. https://doi.org/10.1002/pd.2889
  • 26. Macher HC, Noguerol P, Medrano-Campillo P, Garrido-Márquez MR, Rubio-Calvo A, Carmona-GonzálezM, et al. Standardization noninvasive fetal RHD and SRY determination into clinical routine using a new multiplex RT-PCR assay for fetal cell free fetal DNA in pregnant women plasma: Results in clinical benefits and cost saving. Clinica Chimica Acta 2012; 413:490-494. https://doi.org/10.1016/j.cca.2011.11.004
  • 27. Hromadnikova I, Vechetova L, Vesela K, Benesova B, Doucha J, Kulovany E, et al. Non-invasive fetal RHD exon 7 and exon 10 genotyping using real-time PCR testin gof fetal DNA inmaternal plasma. Fetal Diagn Ther 2005; 20(4):275-280. https://doi.org/10.1159/000085085
  • 28. Kimura M, Sato C, Hara M, Ishihara O, Ikebuchi K. Noninvasive fetal RHD genotyping by maternal plasma with capillary electrophoresis. Transfusion 2008; 48(6):1156-1163. https://doi.org/10.1111/j.1537-2995.2008.01681.x
  • 29. Papasavva T, Martin P, Legler TJ, Liasides M, Christofides GAA, Christodoulou T et al. Prevalence of RhD status and clinical application of non‑invasive prenatal determination of fetal RHD in maternal plasma: a 5 year experience in Cyprus. BMC Res Notes 2016; 9:198. https://doi.org/10.1186/s13104-016-2002-x
  • 30. Kenneth J. Moise Jr, Manisha Gandhi, Noemi H. Boring, Richard O’Shaughnessy, Lynn L, et al. Circulating Cell-Free DNA to Determine the Fetal RHD Status in All Three Trimesters of Pregnancy. Obstet Gynecol. 2016; 128:1340–6. https://doi.org/10.1097/AOG.0000000000001741
  • 31. Finning K, Martin P, Geoff Daniels. Prediction of Fetal RHD Genotype Using Real‐Time Polymerase Chain Reaction. Ann N Y Acad Sci 2004; 1022:119-23. https://doi.org/10.1196/annals.1318.019

Maternal plazmadaki hücre dışı serbest fetal DNA kullanılarak girişimsel olmayan fetal RhD genotiplemesinin tanısal doğruluğu

Year 2019, Volume: 4 Issue: 1, 1 - 6, 18.03.2019

Cisem Akurut Fatma Silan , Sinem Yalcintepe Ozturk Ozdemir

https://doi.org/10.22391/fppc.418647

Abstract



Giriş: Rh uyuşmazlığında fetusun
RhD genotipinin girişimsel olmayan prenatal tanısı, RhD negatif fetus taşıyan
gebelerin hemolitik hastalıklar için artmış anti-D immünoglobulin tedavisinin
önlenmesinde önemli bir role sahiptir. Bu çalışmada maternal plazmadaki hücre
dışı DNA kullanılarak fetal RhD genotiplemesinin saptanmasının tanısal
doğruluğunu tespit etmek amaçlandı.



Yöntem: Rh uyuşmazlığı bulunan
farklı gebelik haftalarında (12-40 hafta), D negatif 12 gebeden periferik kan
örnekleri toplandı. 2 ml maternal plazma kullanılarak konvansiyonel bir DNA
izolasyon tekniği (Qiagen, Hilden, Almanya) ile hücre dışı DNA izole edildi.
Real Time PCR tekniği kullanılarak fetal RhD geni ekzon 7, ekzon 10 ve GLO
geninin genotiplemesi yapıldı. Postnatal serolojik değerlendirmeler yapılmış ve
sonuçlar doğrulanmıştır.



Bulgular:  6 olgu (% 50) D pozitif, 6 olgu (% 50) D
negatif olarak belirlendi. Tüm sonuçlar ayrıca serolojik olarak doğumdan sonra
doğrulandı.



Sonuç: Sonuç olarak RhD uyuşmazlığı görülen gebelerde girişimsel olmayan bir
yöntem olarak maternal plazmadan elde edilen hücre dışı fetal DNA kullanılarak
yapılan RhD genotiplemesinin tanısal doğruluğa sahip olduğu gösterildi.



Keywords

Hücre dışı fetal DNA maternal plazma prenatal tarama real time PCR

References

  • 1. Moise KJ. Management of rhesus alloimmunization in pregnancy. Obstet Gynecol 2008;112:164–176. https://doi.org/10.1097/AOG.0b013e31817d453c
  • 2. Aykut A, Onay H, Sagol S, Gunduz C, Ozkinay F, Cogulu O. Determination of fetal rhesus D status by maternal plasma DNA analysis. Balk J Med Gen 2013; 16(2):33-38. https://doi.org/10.2478/bjmg-2013-0029
  • 3. Cetinkaya M, Ozkan H, Koksal N, Akkus H, Kimya Y. [Influence of intrauterine transfusion on neonatal outcome in Rh hemolytic disease] (in Turkish). J Curr Pediatr 2010; 8:1-6.
  • 4. Wright CF, Burton H. The use of cell-free fetal nucleic acids in maternal blood for non-invasive prenatal diagnosis. Hum Reprod Update 2009; 15(1):139–151. https://doi.org/10.1093/humupd/dmn047
  • 5. NICE. Routine antenatal anti-D prophylaxis for women who are rhesus D negative: review of NICE technology appraisal guidance 2011; 41 London.
  • 6. Gunel T, Kalelioglu I, Ermis H, Aydinli K. Detection of fetal RhD gene from maternal blood. J Turkish-German Gynecol Assoc 2010; 11:82-85. https://doi.org/10.5152/jtgga.2010.04
  • 7. Mujezinovic F, Alfirevic Z. Procedure-related complications of amniocentesis and chorionic villous sampling: a systematic review. Obstet Gynecol 2007; 110:687–694. https://doi.org/10.1097/01.AOG.0000278820.54029.e3
  • 8. Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW et al. Presence of fetal DNA in maternal plasma and serum. Lancet. 1997; 350:485–487. https://doi.org/10.1016/S0140-6736(97)02174-0
  • 9. Guibert J, Benachi A, Grebille AG, Ernault P, Zorn JR, Costa JM. Kinetics of SRY gene appearance in maternal serum: detection by real time PCR in early pregnancy after assisted reproductive technique. Hum Reprod 2003; 18:1733–1736. https://doi.org/10.1093/humrep/deg320
  • 10. Liao GJW, Gronowski AM, Zhaol Z. Non-invasive prenatal testing using cell-free fetal DNA in maternal circulation. Clinica Chimica Acta 2014; 428:44–50. https://doi.org/10.1016/j.cca.2013.10.007
  • 11. Lo YM, Tein MS, Lau TK, Haines CJ, Leung TN, Poon PM et al. Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet. 1998; 62:768–775. https://doi.org/10.1086/301800
  • 12. Lo YM, Chan KC, Sun H, Chen EZ, Jiang P, Lun FM et al. Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci Transl Med 2010; 8:2(61):61ra91.
  • 13. Chan KC, Zhang J, Hui AB, Wong N, Lau TK, Leung TN et al. Size distributions of maternal and fetal DNA in maternal plasma. Clin Chem 2004; 50:88–92. https://doi.org/10.1373/clinchem.2003.024893
  • 14. Kent J, Farrell AM, Soothill P. Routine administration of Anti-D: the ethical case for offering pregnant women fetal RHD genotyping and a review of policy and practice. BMC Pregnancy Childb 2014; 14:87. https://doi.org/10.1186/1471-2393-14-87
  • 15. Clausen FB, Christiansen M, Steffensen R, Jørgensen S, Nielsen C, Jakobsen MA, et al. Report of the first nationally implemented clinical routine screening for fetal RHD in D- pregnant women to ascertain the requirement for antenatal RhD prophylaxis. Transfusion 2012; 52:752–758. https://doi.org/10.1111/j.1537-2995.2011.03362.x
  • 16. Wikman AT, Tiblad E, Karlsson A, Olsson ML, Westgren M, Reilly M. Noninvasive single-exon fetal RHD determination in a routine screening program in early pregnancy. Obstet Gynecol 2012; 120:227–234. https://doi.org/10.1097/AOG.0b013e31825d33d9
  • 17. Finning KM, Martin PG, Soothill PW, Avent ND. Prediction of fetal D status from maternal plasma: introduction of a new noninvasive fetal RHD genotyping service. Transfusion 2002; 42(8):1079–1085. https://doi.org/10.1046/j.15372995.2002.00165.x
  • 18. Minon JM, Gerard C, Senterre JM, Schaaps JP, Foidart JM. Routine fetal RHD genotyping with maternal plasma: a fouryear experience in Belgium. Transfusion 2008; 48(2):373-381. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.15372995.2007.01533.x
  • 19. Rouillac-Le Sciellour C, Puillandre P, Gillot R, Baulard C, Metral S, Van Le Kim C, et al. Large-scale pre-diagnosis study of fetal RHD genotyping by PCR on plasma DNA from RhD-negative pregnant women. Mol Diagn 2004; 8(1):23–31. https://doi.org/10.2165/00066982-200408010-00004
  • 20. Chitty LS, Finning K, Wade A, Soothill P, Martin B, Oxenford K, et al. Diagnostic accuracy of routine antenatal determination of fetal RHD status across gestation: population based cohort study. BMJ 2014; 349:g5243. https://doi.org/10.1136/bmj.g5243
  • 21. Clausen FB, Christiansen M, Steffensen R, Jorgensen S, Nielsen C, Jakobsen MA, et al. Report of the first nationally implemented clinical routine screening for fetal RHD in D-pregnant women to ascertain the requirement for antenatal RhD prophylaxis. Transfusion 2012; 52(4):752–758. https://doi.org/10.1111/j.1537-2995.2011.03362.x
  • 22. Hromadnikova I, Vechetova L, Vesela K, Benesova B, Doucha J, Kulovany E, Vlk R. Non-Invasive Fetal RHD Exon 7 and Exon 10 Genotyping Using Real-Time PCR Testing of Fetal DNA in Maternal Plasma. Fetal Diagn Ther 2005; 20:275–280. https://doi.org/10.1159/000085085
  • 23. Vivanti A, Benachi A, Huchet F, Ville Y, Cohen H, Costa J, PharmD. Diagnostic accuracy of fetal rhesus D genotyping using cell-free fetal DNA during the first trimester of pregnancy. Am J Obstet Gynecol 2016; 215:606.e1-5. https://doi.org/10.1016/j.ajog.2016.06.054
  • 24. Zhou L, Thorson JA, Nugent C, Davenport RD, Butch SH, Judd WJ. Noninvasive prenatal RHD genotyping by real-time polymerase chain reaction using plasma from D-negative pregnant women. Am J Obstet Gynecol 2005; 193:1966–1971. https://doi.org/10.1016/j.ajog.2005.04.052
  • 25. Müller S, Bartels I, Stein W, Emons G, Gutensohn K ve Legler TJ. Cell-free fetal DNA in specimen from pregnant women is stable up to 5 days. Prenat Diagn 2011; 31:1300-1304. https://doi.org/10.1002/pd.2889
  • 26. Macher HC, Noguerol P, Medrano-Campillo P, Garrido-Márquez MR, Rubio-Calvo A, Carmona-GonzálezM, et al. Standardization noninvasive fetal RHD and SRY determination into clinical routine using a new multiplex RT-PCR assay for fetal cell free fetal DNA in pregnant women plasma: Results in clinical benefits and cost saving. Clinica Chimica Acta 2012; 413:490-494. https://doi.org/10.1016/j.cca.2011.11.004
  • 27. Hromadnikova I, Vechetova L, Vesela K, Benesova B, Doucha J, Kulovany E, et al. Non-invasive fetal RHD exon 7 and exon 10 genotyping using real-time PCR testin gof fetal DNA inmaternal plasma. Fetal Diagn Ther 2005; 20(4):275-280. https://doi.org/10.1159/000085085
  • 28. Kimura M, Sato C, Hara M, Ishihara O, Ikebuchi K. Noninvasive fetal RHD genotyping by maternal plasma with capillary electrophoresis. Transfusion 2008; 48(6):1156-1163. https://doi.org/10.1111/j.1537-2995.2008.01681.x
  • 29. Papasavva T, Martin P, Legler TJ, Liasides M, Christofides GAA, Christodoulou T et al. Prevalence of RhD status and clinical application of non‑invasive prenatal determination of fetal RHD in maternal plasma: a 5 year experience in Cyprus. BMC Res Notes 2016; 9:198. https://doi.org/10.1186/s13104-016-2002-x
  • 30. Kenneth J. Moise Jr, Manisha Gandhi, Noemi H. Boring, Richard O’Shaughnessy, Lynn L, et al. Circulating Cell-Free DNA to Determine the Fetal RHD Status in All Three Trimesters of Pregnancy. Obstet Gynecol. 2016; 128:1340–6. https://doi.org/10.1097/AOG.0000000000001741
  • 31. Finning K, Martin P, Geoff Daniels. Prediction of Fetal RHD Genotype Using Real‐Time Polymerase Chain Reaction. Ann N Y Acad Sci 2004; 1022:119-23. https://doi.org/10.1196/annals.1318.019
There are 31 citations in total.

Details

Primary Language English
Subjects Health Care Administration
Journal Section Original Research
Authors

Cisem Akurut 0000-0003-3559-5860

Fatma Silan 0000-0001-7191-2240

Sinem Yalcintepe 0000-0002-8557-8885

Ozturk Ozdemir 0000-0003-1057-3235

Publication Date March 18, 2019
Submission Date April 26, 2018
Acceptance Date December 12, 2018
Published in Issue Year 2019 Volume: 4 Issue: 1

Cite

APA Akurut, C., Silan, F., Yalcintepe, S., Ozdemir, O. (2019). The diagnostic accuracy of non-invasive fetal RhD genotyping by using cell-free fetal DNA in maternal plasma. Family Practice and Palliative Care, 4(1), 1-6. https://doi.org/10.22391/fppc.418647
AMA Akurut C, Silan F, Yalcintepe S, Ozdemir O. The diagnostic accuracy of non-invasive fetal RhD genotyping by using cell-free fetal DNA in maternal plasma. Fam Pract Palliat Care. March 2019;4(1):1-6. doi:10.22391/fppc.418647
Chicago Akurut, Cisem, Fatma Silan, Sinem Yalcintepe, and Ozturk Ozdemir. “The Diagnostic Accuracy of Non-Invasive Fetal RhD Genotyping by Using Cell-Free Fetal DNA in Maternal Plasma”. Family Practice and Palliative Care 4, no. 1 (March 2019): 1-6. https://doi.org/10.22391/fppc.418647.
EndNote Akurut C, Silan F, Yalcintepe S, Ozdemir O (March 1, 2019) The diagnostic accuracy of non-invasive fetal RhD genotyping by using cell-free fetal DNA in maternal plasma. Family Practice and Palliative Care 4 1 1–6.
IEEE C. Akurut, F. Silan, S. Yalcintepe, and O. Ozdemir, “The diagnostic accuracy of non-invasive fetal RhD genotyping by using cell-free fetal DNA in maternal plasma”, Fam Pract Palliat Care, vol. 4, no. 1, pp. 1–6, 2019, doi: 10.22391/fppc.418647.
ISNAD Akurut, Cisem et al. “The Diagnostic Accuracy of Non-Invasive Fetal RhD Genotyping by Using Cell-Free Fetal DNA in Maternal Plasma”. Family Practice and Palliative Care 4/1 (March2019), 1-6. https://doi.org/10.22391/fppc.418647.
JAMA Akurut C, Silan F, Yalcintepe S, Ozdemir O. The diagnostic accuracy of non-invasive fetal RhD genotyping by using cell-free fetal DNA in maternal plasma. Fam Pract Palliat Care. 2019;4:1–6.
MLA Akurut, Cisem et al. “The Diagnostic Accuracy of Non-Invasive Fetal RhD Genotyping by Using Cell-Free Fetal DNA in Maternal Plasma”. Family Practice and Palliative Care, vol. 4, no. 1, 2019, pp. 1-6, doi:10.22391/fppc.418647.
Vancouver Akurut C, Silan F, Yalcintepe S, Ozdemir O. The diagnostic accuracy of non-invasive fetal RhD genotyping by using cell-free fetal DNA in maternal plasma. Fam Pract Palliat Care. 2019;4(1):1-6.
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Family Practice and Palliative Care       ISSN 2458-8865       E-ISSN 2459-1505