SHOULD WE TEST THE FIRST POLAR BODY OR THE EMBRYO?
L. Gianaroli, M.C. Magli, A.P. Ferraretti
SISMER, Reproductive Medicine Unit, Bologna, Italy
Human in vivo and in vitro fecundity is not as efficient as in most animal species. In natural
conceptions, the mean chances of conceiving at each ovulatory cycle is 20-25% even in
young, healthy couples. In ART cycles, where the number of embryos reaching the uterine
cavity is under control, these figures are confirmed in a way that is strictly dependent on
female age. Among the several reasons contributing to establish this situation, the tendency
to generate chromosomally abnormal embryos in humans might give reason of the high
degree of implantation failure. Although it is unknown to what extent the results obtained from
IVF patients are representative of the general population, the data from preimplantation
genetic diagnosis of aneuploidy have greatly contributed to the knowledge of meiotic and
mitotic errors in gametes and early embryos.
Aneuploidy in gametes. As the majority of chromosomal abnormalities in embryos are
maternal in origin, the study of chromosomes in the oocyte could represent an additional tool
for the identification of potentially viable oocytes. The removal of the first polar body (PB1) in
a group of 463 infertile patients performing 577 cycles with a mean age of 38 years, and the
analysis of its chromosomes has permitted to establish that approximately 52% of the oocytes
are aneuploid due to errors in the first meiotic division. According to the data in the literature,
the second meiotic division contributes 31% more abnormalities, while in 28% of cases errors
originate at both meiotic divisions. This means that the analysis of PB1 permits to detect
approximately 70% of total oocyte abnormalities. If the procedure of PB1 biopsy is performed
one hour after oocyte retrieval, the selection of oocyte to be inseminated can be based on the
results obtained. A expected, the incidence of chromosomal abnormalities in PB1 was directly
proportional to maternal age, being 48% in women younger than 36 and 61% in women older
than 42 years. Chromosomes 22, 21, and 16 showed the highest tendency to aneuploid
errors in meiosis I in a manner that was strictly dependent on age. This approach might be
especially valuable in patients with a poor prognosis for term pregnancy having the tendency
to generate high proportions of aneuploid oocytes. The advantages of the technique reside in
the fact that the biopsy removes a by-product of the meiotic process without affecting the
oocyte mass. In addition, it permits to select for insemination only the chromosomally normal
oocytes, avoiding generating embryos with no potential of normal implantation. In this way,
the need of spare embryo cryopreservation is kept to a minimum. The major limitation of PB1
biopsy consists in the impossibility of identifying abnormalities derived from the second
meiotic division, and those contributed by the sperm and by the following mitotic divisions.
Nevertheless, the clinical results obtained at SISMER refer a significant reduction in the
abortion rate, being the chromosomes tested in PB1 those more frequently implicated in
spontaneous abortions.
Conversely to what happens in female gametes, the incidence of aneuploidy in spermatozoa
is low, being estimated in 6.67% in normal samples. This figure increases significantly in
patients having a severe male factor of infertility, but still remains below 10% even in
testicular spermatozoa, in which the highest values of aneuploidy are detected.
Aneuploidy in embryos. The investigation of the chromosomal constitution of in vitro
generated embryos has demonstrated that the real incidence of aneuploidy is much higher of
what is observed in clinical pregnancies, up to a value of 67% in couples with a poor
prognosis of pregnancies.
These observations motivated the proposal of PGD for aneuploidy as a tool aimed at
increasing IVF efficiency based on the assumption that such a high proportion of aneuploid
embryos could be responsible for the poor reproductive performance in couples at risk of
aneuploidy. Their removal from transfer and the replacement of chromosomally normal
embryos only, could significantly increase the implantation rate and, concomitantly, decrease
the incidence of abortion and trisomic pregnancies. Several studies have reported an
increase in implantation and pregnancy rate after PGD for aneuploidy in concomitance with a
decrease in spontaneous abortions and trisomic pregnancies. On the other hand, other
groups did not find any significant advantage from the application of PGD for aneuploidy,
although they also identified categories of patients for which this technique is greatly
advantageous.
The SISMER experience on more than 1000 cycles, in which embryo transfer was possible in
68% of them, reported a clinical pregnancy rate of 30% with a take-home baby rate per
patient of 24%. Considering the poor prognosis indications and reproductive history of the
treated couples, the application of PGD for aneuploidy was significantly advantageous in
terms of take-home baby rate.
The analysis of a blastomere from cleavage-stage embryos is an invasive technique for which
great skill and experience are required. It implies the reduction in the embryonic mass, that it
is well known to represent a critical factor for implantation. On the other hand, the
chromosomal analysis on embryos permits to detect the abnormalities contributed by the
male gamete and those generated at fertilization and during the first cleavage events. The
interpretation of the results is not always easy due to the frequent occurrence of mosaicism
that represents the main cause of misdiagnosis, quantified in 5.6%.
Numerous strategies have been designed to minimize the negative effects due to the biopsy
procedure and the errors inherent to the diagnosis itself. When performed with all the
necessary precautions, the application of the technique in selected categories of patients is
associated with a significant improvement in the chances of giving birth to a healthy baby.
Conclusions. There are significant advantages derived from the testing of aneuploidy both in
PB1 and in embryos. The decision on what technique to apply should only depend on the
patients’ characteristics and indications, and on the type of information that is requested.
Nevertheless, in some countries this decision is limited by national regulations.