View source for Fetal Cells in Maternal Blood

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==Introduction==
[[File:Chromosome-_trisomy.jpg|thumb|Trisomy 21 karyotype cartoon]]
This current page is a general starting point for the topic of fetal cells and DNA in maternal blood as a new potential source for prenatal diagnosis. It turns out that the fetal cells in maternal blood are extremely difficult to isolate and analyse, so [[Non-Invasive Prenatal Testing]] (NIPT) of cffDNA is the more common method being employed.

As far back as 1997 fetal DNA was identified in maternal blood.<ref name=PMID9274585 ><pubmed>9274585 </pubmed></ref>it has taken some time for technologies to develop to a point where now just the fetal genetic material can be analysed as a [[Non-Invasive Prenatal Testing|noninvasive prenatal test]] (NIPT).

The links below are to resources that give more specific information about some diagnostic techniques available at different stages of pregnancy. When abnormal development is identified this can be due to genetic, environmental, unknown causes or a combination of these effects. (More? [[Human_Abnormal_Development|Abnormal Development]]) These tests currently being developed allow detection of some genetic abnormalities. A trend in developed countries of an increasing maternal age, long associated with increased genetic abnormalities, has emphasised the need for good diagnostic low risk tests that allow informed decisions early in a pregnancy. (More? [[Abnormal_Development_-_Genetic|Genetic]]).


The topic of [[Preimplantation_Genetic_Screening|Preimplantation Genetic Screening]] (PGS) of blastocysts, associated with [[Assisted Reproductive Technology|Assisted Reproductive Technologies]] (ART), is not discussed here.


:''This Embryology site is a developmental educational resource, it does not provide specific clinical details, you should always refer to a health professional.''


{{Prenatal diagnosis}} | [[Assisted Reproductive Technology]] | [[In Vitro Fertilization]] | [http://www3.interscience.wiley.com/journal/2252/home Journal - Prenatal diagnosis]

==Some Recent Findings==
[[File:Fetal cells maternal blood graph.jpg|thumb|alt=Fetal cells maternal blood graph|Fetal cells maternal blood graph<ref name=PMID25188498><pubmed>25188498</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0106934 PLoS One.]</ref>]]
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* '''Fetal aneuploidy screening with cell-free DNA in late gestation'''<ref name=PMID27124739><pubmed>27124739</pubmed></ref>"The aim of this study was to evaluate clinical use of NIPT at gestational ages of 23 weeks and above. 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. ...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. 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."
* '''Fetal Sex Chromosome Testing by Maternal Plasma DNA Sequencing: Clinical Laboratory Experience and Biology'''<ref name=PMID25568992><pubmed>25568992</pubmed></ref> "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). 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."
* '''Fetal gender and several cytokines are associated with the number of fetal cells in maternal blood - an observational study'''<ref name=PMID25188498><pubmed>25188498</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0106934 PLoS One.]</ref> "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. 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."
* '''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'''<ref name=PMID24657131><pubmed>24657131</pubmed></ref> "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). ...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."
* '''Noninvasive Prenatal Testing: The Future Is Now'''<ref name=PMID24466384><pubmed>24466384</pubmed></ref> "Prenatal detection of chromosome abnormalities has been offered for more than 40 years, first by amniocentesis in the early 1970s and additionally by chorionic villus sampling (CVS) in the early 1980s. ...The ability to isolate fetal cells and fetal DNA from maternal blood during pregnancy has opened up exciting opportunities for improved noninvasive prenatal testing (NIPT). Direct analysis of fetal cells from maternal circulation has been challenging given the scarcity of fetal cells in maternal blood (1:10,000-1:1,000,000) and the focus has shifted to the analysis of cell-free fetal DNA, which is found at a concentration almost 25 times higher than that available from nucleated blood cells extracted from a similar volume of whole maternal blood. There have now been numerous reports on the use of cell-free DNA (cfDNA) for NIPT for chromosomal aneuploidies-especially trisomy (an extra copy of a chromosome) or monosomy (a missing chromosome)-and a number of commercial products are already being marketed for this indication. This article reviews the various techniques being used to analyze cell-free DNA in the maternal circulation for the prenatal detection of chromosome abnormalities and the evidence in support of each."
* '''Noninvasive whole-genome sequencing of a human fetus'''<ref name=PMID22674554><pubmed>22674554</pubmed></ref> "Analysis of cell-free fetal DNA in maternal plasma holds promise for the development of noninvasive prenatal genetic diagnostics. Previous studies have been restricted to detection of fetal trisomies, to specific paternally inherited mutations, or to genotyping common polymorphisms using material obtained invasively, for example, through chorionic villus sampling. Here, we combine genome sequencing of two parents, genome-wide maternal haplotyping, and deep sequencing of maternal plasma DNA to noninvasively determine the genome sequence of a human fetus at 18.5 weeks of gestation. "
* '''A noninvasive test to determine paternity in pregnancy'''<ref><pubmed>22551147</pubmed></ref> "Our approach shows that noninvasive prenatal paternity testing can be performed within the first trimester with the use of a maternal blood sample." 
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| [[File:Mark_Hill.jpg|90px|left]] {{Most_Recent_Refs}}

Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=Fetal+Cells+in+Maternal+Blood ''Fetal Cells in Maternal Blood'']

<pubmed limit=5>Fetal Cells in Maternal Blood</pubmed>
Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=Fetal+DNA+in+Maternal+Blood ''Fetal DNA in Maternal Blood'']

<pubmed limit=5>Fetal DNA in Maternal Blood</pubmed>
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==Microchimerism== 

Microchimerism (Mc)  is a term used to describe when a usually small population of foreign cells or DNA harboured by one individual that derive from a genetically distinct individual. May occur in pregnancy when cells exchange between the fetus and mother or mother and fetus. Microchimerism may also be seen in twinning and transplants. Maternally acquired cells in the fetus may also persist postnatally.<ref><pubmed>24762743</pubmed></ref>



:'''Links:''' [[Abnormal Development - Twinning|Twinning]]
==Genetic Testing==

There are clinically more and more tests becoming available as we learn more about the genetic basis of some diseases. The most common diagnostic test relates to the current trend in an increasing maternal age, which has long been associated with an increase in genetic abnormalities, the most frequent of these is trisomy 21 or Down syndrome.

===Inheritance Genetics===
[[File:Pedigree_chart.jpg|thumb|Pedigree chart]]

<gallery>
File:Autosomal_dominant_inheritance.jpg|Autosomal dominant inheritance
File:Autosomal recessive inheritance.jpg|Autosomal recessive inheritance
File:X-Linked_dominant_(affected_father).jpg|X-Linked dominant (affected father)
File:X-Linked_dominant_(affected_mother).jpg|X-Linked dominant (affected mother)
File:X-Linked_recessive_(affected_father).jpg|X-Linked recessive (affected father)
File:X-Linked recessive (carrier mother).jpg|X-Linked recessive (carrier mother)
File:Mitochondrial_inheritance.jpg|Mitochondrial genome inheritance
File:Codominant inheritance.jpg|Codominant inheritance
</gallery>


:'''Links:''' [[Genetic risk maternal age]] | [[Trisomy 21]]
===Australia===

A recent publication from NHMRC [http://www.nhmrc.gov.au/publications/synopses/e99syn.htm Medical Genetic Testing: information for health professionals] (2010). This paper covers background information on all types of genetic tests, not just those associated with prenatal diagnosis.

====Types of genetic tests====
* '''Somatic cell genetic testing''' involves testing tissue (usually cancer) for non-heritable mutations. This may be for diagnostic purposes, or to assist in selecting treatment for a known cancer.
* '''Diagnostic testing''' for heritable mutations involves testing an affected person to identify the underlying mutation(s) responsible for the disease. This typically involves testing one or more genes for a heritable mutation.
* '''Predictive testing''' for heritable mutations involves testing an unaffected person for a germline mutation identified in genetic relatives. The risk of disease will vary according to the gene, the mutation and the family history.
* '''Carrier testing for heritable mutations''' involves testing for the presence of a mutation that does not place the person at increased risk of developing the disease, but does increase the risk of having an affected child developing the disease.
* '''Pharmacogenetic testing''' for a genetic variant that alters the way a drug is metabolised. These variants can involve somatic cells or germline changes. Even if these variants are heritable (that is germline changes), the tests are usually of relevance to genetic relatives only if they are being treated with the same type of medication.


:'''Links:''' [http://www.nhmrc.gov.au/publications/synopses/e99syn.htm NHMRC - Medical Genetic Testing: information for health professionals]

===USA===

A new site developed by NIH "GeneTests" provides medical genetics information resources available at no cost to all interested persons. It contains educational information, a directory of genetic testing laboratories and links to other databases such as OMIM.


:'''Links:''' [http://www.genetests.org/ GeneTests] | [http://www.nlm.nih.gov/medlineplus/genetictesting.html Medline Plus - Genetic Testing]

===Comparative Genomic Hybridization===
This new test under development is based upon microarray-based comparative genomic hybridization (array CGH).

All fetal cells should have complete copies of maternal and paternal genomes. The test compares regions of fetal DNA that deviate from this "pattern" due to either too much or too little DNA, alterations reflect regions of the genome that are either copied or deleted. These genetic changes may therefore cause disease. 

:'''Links:''' [[Comparative Genomic Hybridization]]

==Ethics of Testing==
Major developmental abnormalities detected early enough can be resolved far more easily than those discovered late in a pregnancy.

What are the ethical questions that are raised by prenatal testing? Future individual rights or parents rights? But what about diseases, like Huntington's, where a diagnostic test can be made but there are no current treatments for the postnatal (95% of cases adult onset) disease?

Huntington's disease

Guidelines for the molecular genetics predictive test

: Recommendation 2.1 "the test is available only to individuals who have reached the age of majority."

: Recommendation 7.2 "the couple requesting antenatal testing must be clearly informed that if they intend to complete the pregnancy if the fetus is a carrier of the gene defect, there is no valid reason for performing the test."

(excerpt from: [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=7966192&dopt=Abstract IHA and the World Federation of Neurology Research Group on Huntington's Chorea. Guidelines for the molecular genetics predictive test in Huntington's disease.])

==References==

<references />


===Articles===

<pubmed>17845745</pubmed>

===Search Pubmed===

'''Search Pubmed:''' [http://www.ncbi.nlm.nih.gov/pubmed/?term=Fetal+Cells+in+Maternal+Blood ''Fetal Cells in Maternal Blood''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Fetal+DNA+in+Maternal+Blood ''Fetal DNA in Maternal Blood'']



{{Prenatal Diagnosis terms}}


==External Links==
{{External Links}}

* '''Australian and New Zealand''' - College of Obstetricians and Gynaecologists [http://www.ranzcog.edu.au/publication/womens-health-publications/intrapartum-fetal-surveillance-clinical-guidelines.html Intrapartum Fetal Surveillance Clinical Guidelines - Second Edition] (June 2011)
* '''Canada''' - Society of Obstetricians and Gynaecologists of Canada
** [http://www.sogc.org/guidelines/index_e.asp Clinical Practice Guidelines]
** [http://www.sogc.org/guidelines/documents/gui197CPG0709.pdf Fetal health Surveillance: antepartum and intrapartum Consensus Guideline PDF] (Sept 2007)



{{Glossary}}



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[[Category:Abnormal Development]] [[Category:Genetic Abnormalities]] [[Category:Human Embryo]] [[Category:Human Fetus]]