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Indications for PGD
Indications for PGD
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Recurrent Miscarriage
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Unsuccessful IVF Cycles (>2)
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Unexplained Infertility
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Advanced Maternal Age
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Male Factor Infertility
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History of Chromosomally Abnormal Child or Pregnancy
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Family history of structural chromosomal condition
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Family history of X-linked disease
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Inherited genetic disorders
Currently, there are mainly two groups of patients for which
PGD is indicated.
• The first group consists of couples with a high risk of
transmitting an inherited condition. This can be a
 monogenic
disorder (autosomal recessive, autosomal dominant or
X-linked disorders) or a chromosomal structural aberration
(such as a balanced translocation). Generally, these couples
oppose to prenatal diagnosis followed by selective
termination of pregnancy, either for moral or religious
reasons or because they have undergone already several
abortions. In addition, there are infertile couples that
carry an inherited condition, which opt for PGD as it can be
easily combined with their IVF treatment.
• The second group consists of couples that undergo IVF
treatment and whose embryos are screened for chromosome
aneuploidies (PGS) to increase the chances of an ongoing
pregnancy. The main indications for PGS are an advanced
maternal age, a history of recurrent miscarriages or
repeated unsuccessful implantation. It has also been
proposed for patients with obstructive and non-obstructive
azoospermia.
Nowadays, PGD is available for a large number of monogenic
disorders. The most frequently diagnosed autosomal recessive
disorders are cystic fibrosis, Beta-thalassemia, sickle cell
disease and spinal muscular atrophy type 1. The commonest
dominant diseases are myotonic dystrophy,Huntington's
disease and Charcot-Marie-Tooth disease type 1A; and in the
case of the X-linked diseases, most of the cycles are
performed for fragile X syndrome, haemophilia A and Duchenne
muscular dystrophy. Though it is quite infrequent, some
centers report PGD for mitochondrial disorders or two
indications simultaneously.
In the case of chromosomal abnormalities, PGD is mainly
carried out for reciprocal and Robertsonian translocations,
and few cases for other abnormalities such as chromosomal
inversions or deletions.
 Aneuploidy
screening is probably the most frequent indication for PGD,
mainly suggested to couples undergoing IVF with an advanced
maternal age and for patients with repetitive IVF failure.
The principle behind it is that, since it is known that
numerical chromosomal abnormalities explain most of the
cases of pregnancy loss, and a large proportion of the human
embryos are aneuploid, the selective replacement of euploid
embryos should increase the chances of a successful IVF
treatment. Different studies provide indications that PGS
increases the implantation rate (Gianaroli et al., 1999;
Munne et al., 1999; Munne et al., 2002; Rubio et al., 2003)
and lowers the spontaneous abortion rate (Munne et al.,
2005), though other studies indicate that there are no
significant differences for patients with an advanced
maternal age (Kahraman et al., 2000; Staessen et al., 2004),
with a poor implantation rate (Kahraman et al., 2000) or
with recurrent idiopathic miscarriages (Platteau et al.,
2005). It is thus clear that large randomised-controlled
studies are still necessary to measure the real impact of
this technique for the different indications. A recent
systematic review on PGS can be found in the Cochrane
database (Twisk et al., 2006)
 A
fourth group of indications can be defined that includes all
the ethically difficult cases. These include situations such
as HLA typing of the embryo, so that the child born out of
this treatment could be a cord-blood stem cell donor for a
sick sibling. Verlinsky and collaborators described the
first case in 2001. HLA typing has meanwhile become an
important PGD indication in five countries, USA (Verlinsky
2001), Italy (Fiorentino et al., 2004, 2005), Turkey (Kharaman
2004), Belgium (Van de Velde 2004), Australia (Marshall
2004). The HLA matching can be combined with the diagnosis
for monogenic diseases such as Fanconi anaemia or Beta-thalassemia
in those cases where the ill sibling is affected with this
disease, or be performed on its own for cases such as
children with leukaemia. The main ethical argument against
is the possible instrumentalization of the child, although
some authors maintain that the Kantian imperative is not
breached since the future donor child will not only be a
donor but also become a loved individual within the family.
 Another
difficult case is the non-disclosure PGD for Huntington's
disease. It is applied in those cases in which the patients
do not wish to know their carrier status but want to have
offspring free of the disease. This procedure can bring
practitioners in difficult situations, e.g. when no embryos
are available for transfer and a mock transfer has to be
carried out to avoid the patient to suspect that he/she is a
carrier and the lack of embryos is due to the fact that they
are all affected. The ESHRE ethics task force currently
recommends using exclusion testing instead. Exclusion
testing is based on a linkage analysis with polymorphic
markers, in which the parental and grandparental origin of
the chromosomes can be established. This way, only embryos
are replaced that do not contain the chromosome derived from
the affected grandparent, avoiding the need to detect the
mutation itself.
A more recent application of PGD is to diagnose late-onset
diseases and (cancer) predisposition syndromes. It can be
argued that PGD for late-onset diseases is unethical since
the individuals remain healthy until the onset of the
disease, usually in the fourth decade of life. On the other
hand, the high probability or certainty of developing some
disorders, and their incurable nature, can lead to a
stressful life, waiting for the first symptoms to occur and
to an early death. In the case of predisposition syndromes,
such as BRCA1 mutations predisposing to breast cancer, it
can be argued that there is no certainty of getting the
disease and that the disease can usually be treated. It is a
fact that although PGD is often regarded as an early form of
prenatal diagnosis, the nature of the requests for PGD often
differs from the prenatal diagnosis requests. Some of the
widely accepted indications for PGD, such as the previously
mentioned, would not be acceptable for prenatal diagnosis.
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Recurrent Miscarriage
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