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Ethical, legal, social issues in non-invasive prenatal diagnosis (NIPD)




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Ethical, legal, social issues in non-invasive
prenatal diagnosis (NIPD)

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1.0 - Introduction
Prenatal diagnosis is an essential part of obstetric practice. Genetic diagnosis prenatally is
currently offered to women at risk of carrying a fetus with an aneuploidy, either due to a high risk
Down’s syndrome screening result or due to fetal abnormalities seen on a scan (Nicolaides 2004),
or to couples who are carriers of a single gene disorder. Conventionally, fetal genetic material is
sampled by amniocentesis, chorionic villus sampling (CVS) and cordocentesis which provide
accurate prenatal diagnosis. However, these invasive procedures are associated with a 1% risk of
fetal loss (Mujezinovic and Alfirevic 2007), cannot be performed until after 11 weeks of gestation,
and making decisions about whether to risk the pregnancy cause much parental anxiety (Alfirevic,
Sundberg et al. 2003).
Because of the risk to the fetus, a major goal in prenatal diagnosis in the last few years has
been to develop methods to carry out the tests non-invasively using a maternal blood test. Initial
studies focused on diagnosis from fetal cells, but this proved to be technically challenging due to
the fact that these cells are very difficult to isolate (Bianchi, Simpson et al. 2002). Additionally,
many types of fetal cell persist in the mother’s body for years after the pregnancy, and so are not
pregnancy-specific (Rust and Bianchi 2009). The landmark discovery that circulating cell-free fetal
DNA (cffDNA) exists in maternal plasma has set the grounds for the development of non-invasive
methods for safer prenatal diagnosis (Lo, Corbetta et al. 1997).
Until recently it was believed that cffDNA is limited in amounts in the maternal circulation,
reaching 3.4% and 6.2% of the total plasma DNA concentration in early and late pregnancy,
respectively (Lo, Tein et al. 1998). However, with the use of microfluidics digital PCR it was found
that the median fractional circulating fetal DNA concentration is actually between 10% and 20%,
much higher in all three trimesters of pregnancy than previously reported (Lun, Chiu et al. 2008).
The main challenge with using cffDNA for non-invasive prenatal testing (NIPD) is caused by the
co-existence of maternal cell free DNA and fetal DNA; it is not possible to isolate pure fetal DNA
and therefore the analysis of maternally inherited fetal sequences is difficult (Wright and Chitty
1.1 - Cell-free fetal nucleic acids
Cell-free DNA (cfDNA) consists of short DNA fragments, with an average length of 146
base pair (bp) for the fetal DNA compared to the maternal derived ones which are longer (an
average of 166 bp) (Lo, Chan et al. 2010). Cell-free fetal DNA in maternal plasma originates from
apoptosis of syncytiotrophoblastic cells (Alberry, Maddocks et al. 2007) and is promptly cleared
from the maternal plasma within two hours of delivery (Lo, Zhang et al. 1999). It can be detected
from the fourth week of gestation (Illanes, Denbow et al. 2007) and the fact that is undetectable in
the maternal circulation after delivery makes it specific to that pregnancy (Rafi and Chitty 2009). A
disadvantage may be the potential for false positive results from a multiple pregnancy or fetal loss
in a discordant twin pregnancy (as it is uncertain which twin the DNA was obtained from). There
are also technical difficulties associated with the analysis of cffDNA, the most problematic is the
fact that cffDNA cannot yet be completely separated from the preponderance of cell free maternal
DNA (Lo, Lun et al. 2007).

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1.2 - Clinical Applications of NIPD
Until recently NIPD methods utilizing cffDNA were based on the identification of genes or
alleles that are present only in the fetal and not in the maternal genome, as they have been inherited
from the father or arisen as de novo germline mutations at conception. Clinical applications for
NIPD include determination of fetal sex (Finning and Chitty 2008), RHD gene typing in RhD
negative mothers (van der Schoot, Hahn et al. 2008), and diagnosis of some specific monogenic
disorders such as achondroplasia and thanatophoric dysplasia (Li, Page-Christiaens et al. 2007;
Chitty, Griffin et al. 2011). Non-invasive determination of fetal RhD genotype using cffDNA found
in maternal plasma has proven to be a useful tool in the management of pregnancies of RHD
negative women with RhD positive partners (Bombard, Akolekar et al. 2011). In these cases, early
determination of the fetal RHD genotype is critical as can determine the need for prenatal and
postnatal immunoprophylaxis with anti-D to prevent haemolytic disease of the newborn (Bombard,
Akolekar et al. 2011). Currently, NIPD is used routinely by some centers in the European Union for
the management of sensitized women (Bombard, Akolekar et al. 2011).
Also, it is expected that the development of NIPD using cffDNA for single gene disorders
will soon implemented as part of routine antenatal care. Initial research using NIPD for single gene
disorders were restricted to cases where the mutation was inherited paternally or had arisen de
novo. Early studies looking at prenatal diagnosis of autosomal recessive disorders were carried out
in cases where the father carries a different mutation from the mother, and were based on exclusion
of the affected status. Examples include exclusion of paternal inheritance in a case of CAH (Chiu,
Lau et al. 2002) and diagnosis of inheritance of paternal cystic fibrosis mutations (Gonzalez-
Gonzalez, Garcia-Hoyos et al. 2002; Bustamante-Aragones, Gallego-Merlo et al. 2008). In these
cases where the paternal mutation is detected, it is still possible that the fetus is only a carrier, and
so further invasive testing would be recommended. It is much more difficult to test for conditions
where both parents are carriers of the same mutation or where the condition is maternally inherited.
This is because it is difficult to discriminate between the maternal and fetal alleles.
1.3 - Advantages of NIPD
The non-invasive cffDNA technology, offers significant advantages over current clinical
protocols. It is expected that cffDNA analyses will allow a considerable reduction of invasive
genetic testing, regardless of the genetic status of the fetus, for example for sex determination in
pregnancies at high risk of X-linked conditions (Hill, Finning et al. 2011) and that cffDNA
technology will also allow for better targeting of interventions to pregnancies affected by certain
conditions, for example for RhD (Bombard, Akolekar et al. 2011).
In addition, NIPD not does not only offer clinical benefits but also provides psychological
benefits to the pregnant woman. These include normalization of pregnancy, control and peace of
mind. The absence of distress is a psychological benefit that sharply contrasts with women’s
experiences of invasive testing, which carries a risk of miscarriage.
Even if cffDNA technology is amenable for safer and earlier prenatal testing for the
mentioned abnormalities, the clinical utility of the test remains to be assessed. This includes
balancing the benefits to the harms also with regard to its psychological, ethical, legal, social and
economic implications. The possible ethical implications of NIPD as a new approach to prenatal
testing have so far been reviewed in a few publications (de Jong, Dondorp et al. 2010). We discuss

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