Robert F.
Casper
Professor and Head
Division of Reproductive Sciences
The University of Toronto
Recently, concerns
have been raised that there may be risks to the offspring born from
ICSI, as a result of the procedure itself. This summary is a review
of the recent literature, which will serve to address these concerns
and put the potential risks into perspective. The bottom line is
that ICSI appears to be remarkably safe, but further follow up of
babies born from this procedure is required. There are several reasons
for concern regarding the safety of ICSI. First of all, the natural
selection process by which sperm normally fertilizes the egg is
bypassed and a single sperm is selected for mechanical injection
into the oocyte. In addition, it is known that chromosomal abnormalities
in infertile males are more common and these abnormalities maybe
transmitted to the offspring. Finally, insertion of sperm by injection
into the cytoplasm could damage the egg with resulting problems
in cell division later on.
Genetic
Evaluation of Sub fertile Males
Genetic abnormalities
may cause low sperm counts and male infertility. These genetic abnormalities
are potentially transmissible to a baby born through assisted reproductive
procedures. The three most common known genetic factors related
to male infertility are:
- Cystic fibrosis
gene mutations leading to congenital absence of the vas deferens
(the tube that carries sperm from the testicle to the penis).
- Deletions
of one or more genes present on the Y chromosome, which are necessary
for normal sperm development.
- Chromosomal
abnormalities, most frequently extra X or Y-chromosomes, which
may be associated with severely reduced sperm counts, or no sperm
at all, in the semen.
A recent paper
from Holland (Tuerlings et al, 1998) reported results of chromosomal
analysis on almost 1800 men with severe low sperm counts or no sperm
in the ejaculate. Seventy-two of the men or 4% had a chromosomal
abnormality, most of which were numerical sex chromosomal (X or
Y chromosomes) abnormalities. It is very likely, in view of the
large number of men studied, that the figure of 4% is an accurate
prevalence of chromosomal abnormalities in men with severe male
factor infertility. This is, therefore, the baseline rate that could
be expected for sex chromosomal abnormalities in the offspring produced
by ICSI. However, it appears that the actual rate is lower, based
on a large prospective study performed by Bonduelle et al, 1996.
This group in Belgium studied 904 pregnancies obtained after ICSI
with chromosomal analysis in about two-thirds of the children. The
incidence of sex chromosomal abnormalities was 1% or about one-quarter
of what would be anticipated based on the previous study of the
incidence of sex chromosomal abnormalities in the fathers. It is
possible that embryos with a sex chromosomal abnormality may not
survive as well as normal embryos and this may account for the much
lower incidence seen in this prospective study.
Implications
of Sex Chromosome Abnormalities
Major abnormalities
of the cardiovascular system and the kidneys can occur in individuals
with Turner's Syndrome (females missing one X chromosome), but are
not seen in Klinefelter (XXY), the triple X, and the XYY syndromes.
Importantly, mental retardation does not occur more often in individuals
with sex chromosomal abnormalities than in normal controls. However,
there is some evidence that academic achievement may be somewhat
reduced compared with peers. Meshede and Horst (1997) concluded
that the long term developmental prognosis is fairly good for individuals
carrying a sex chromosomal abnormality and, if such an abnormality
is diagnosed by amniocentesis following an ICSI pregnancy, a detailed
discussion with a geneticist is warranted. The option of continuing
such a pregnancy should be considered seriously.
Y Chromosome
Microdeletions
Recent studies
by Roberts and his colleagues from Minnesota (Pryor et al, 1997),
studying a large group of men with severe male factor infertility,
have demonstrated that about 10% of these men are missing one or
more genes on the Y chromosome which are responsible for normal
sperm production. These genes appear to be related only to sperm
production and not to any other physical or mental characteristic.
In other words, these men are entirely normal but have infertility
because of severely reduced sperm counts. These abnormalities are
called Y chromosome microdeletions, since they involve a very small
area of the Y chromosome, and cannot be determined by the usual
method of chromosomal analysis (karyotype). Therefore, at the present
time, apart from DNA sequencing to look for these gene defects,
there is no routine test available to detect these abnormalities.
Gene sequencing is available at a few centers in Canada and in the
United States but is not covered by medical health plans. In most
cases, men who harbor a Y chromosome microdeletion will pass on
this deletion to their male offspring through ICSI. As a result,
the male offspring of these men should be normal with the exception
of having low sperm counts and infertility similar to their fathers.
Major
Congenital Abnormalities
A number of
studies have compared ICSI pregnancies with in vitro fertilization
pregnancies to determine if there is an increased risk of congenital
abnormalities in the ICSI group. One of the first studies was done
by Bonduelle et al (1995) in Belgium where 130 ICSI pregnancies
were compared with 130 IVF pregnancies, in which the mothers were
matched for age at the time of conception. Pregnancies were also
matched for multiple pregnancy. These authors found that there was
no difference in birth weights, lengths, or head circumference in
the ICSI babies versus the IVF babies. They observed four major
malformations in the ICSI group and six major malformations the
IVF group. They concluded that there was no difference in the pediatric
follow up of children born after ICSI compared with conventional
IVF in age matched patients. In addition, the major malformation
rate in both groups was within the normal range for the general
population.
A follow up
prospective study of 904 pregnancies obtained after ICSI by the
same group was published in 1996 (Bonduelle et al). This study revealed
a major malformation rate of 2.6%, which again is consistent with
the major malformation rate seen in the general population.
A more recent
study by Bowen et al (1998) from Australia compared children born
by ICSI with those born after IVF or conceived naturally, and found
no difference in major malformations between the three groups. All
these studies are reassuring that ICSI does not increase the congenital
malformation rate in offspring produced by this technique.
Chromosomal
Analysis in Couples Undergoing ICSI
Two studies
have examined the chromosomal make-up of both the male and female
partner of couples referred for ICSI. One study from Holland by
Van der Ven (1998) obtained karyotypes on both partners of 305 couples
referred to the ICSI program. Ten of the men (3.3%) were found to
have a chromosomal abnormality, which is in keeping with the previous
finding by Tuerlings et al (1998) of a 4% incidence of chromosomal
aberration in men with severe male factor infertility. A surprising
finding, however, was that there was also a 3.3% incidence of abnormal
karyotypes in the female partners who were thought to be normal
at the time of referral. A second study by Mau et al (1997) looked
at karyotypes in 150 couples referred for ICSI and found again that
about 2% of the women had a chromosomal abnormality. The conclusion
from these two studies is that karyotyping should be done on both
partners prior to proceeding through the ICSI procedure, since a
hidden female chromosomal factor may be present in some cases of
suspected severe male factor infertility. The female chromosomal
abnormality could also be transmitted to the offspring.
Developmental
Outcome
Because of the
short time most clinics have been performing ICSI, very limited
information is available regarding motor or mental development in
children conceived by this procedure. However, one study by Bowen
et al (1998) compared a small number of children conceived by ICSI
with children conceived by routine IVF and those conceived naturally.
The study measured the Bayley mental development index (MDI) which
has a mean of 100 and a normal range of 85-114 in the general population.
Those children born as a result of ICSI had a mean MDI of 96 while
those conceived by IVF or by natural conception had a mean of 102.
When the data was further subdivided, there was no difference in
the female babies born by the three methods, whereas boys born by
ICSI had a significantly lower MDI compared to the other two groups.
The authors concluded that most children conceived by ICSI are healthy
and develop normally but there may be an increased risk of mild
delays in development at one year. There was no increased incidence
of mental retardation. However, since testing was performed at one
year of age, precise assessment of mental development is difficult.
In addition, karyotypes were not done on these children so it is
unknown whether there was an increased incidence of sex chromosomal
abnormalities in the males, which is known to lead to some developmental
delay. There is a need for ongoing developmental follow up to see
if increased risk of learning difficulties or intellectual impairment
occurs at school age in these ICSI children.
Mechanical
Damage to the Eggs from the Injection
Apart from gross
oocyte damage rates, which are detectable immediately following
ICSI, there are no data at present regarding potential damage to
the chromosomes of the oocyte from insertion of the sperm injection
needle. There is some concern that rough handling of the oocytes
during cumulus cell stripping may displace the internal apparatus
for chromosomal division (meiotic spindle) from its normal position
near the polar body, so that the spindle could be damaged by injection
of the sperm (Hewitson et al, 1999). However, no studies have been
done to determine whether this hypothetical concern is realistic
or not.
Conclusion
It would appear
that men with severe male factor infertility have an increased incidence
of chromosomal abnormalities, most likely sex chromosome abnormalities
and Y chromosome microdeletions, which could be transmitted to the
offspring by the ICSI procedure. However, it appears ICSI is remarkably
safe despite these potential risks. The incidence of sex chromosomal
abnormalities in ICSI offspring is likely in the range of 1%, while
the percent of offspring with Y-chromosomal microdeletions is unknown
at present in the absence of a routine test for this abnormality.
Y-chromosome microdeletions, however, do not appear to cause any
physical or mental abnormalities, and are related only to low sperm
counts. The present review of the literature results in four recommendations
regarding ICSI:
- ICSI should
not replace routine IVF. IVF should be standard treatment if it
is anticipated that the sperm can fertilize the eggs spontaneously.
- Chromosomal
analysis or karyotyping should be done on both partners of couples
referred for the ICSI procedure, and karyotyping should be done
prior to the couple going through an ICSI cycle.
- The presence
of cystic fibrosis gene mutations should be tested in both partners
of couples in whom the male has congenital absence of the vas
deferens or unexplained severe low sperm counts.
- Testing for
Y-chromosome microdeletions should be offered to men with unexplained
very low sperm counts.
References
Tuerlings et
al, Eur J Hum Genet 6:194-200, 1998
Bonduelle et al, Hum Reprod 10:3327-31, 1995
Bonduelle et al, Hum Reprod 11(suppl 4):131-55, 1996
Meshede and Horst, Hum Reprod 12:1125-7, 1997
Bowen et al, Lancet 351:1529-34, 1998
Van der Ven et al, Hum Reprod 13:48-54, 1998
Mau et al (1997)
Hewitson et al, Nat Med 5:431, 1999 |
