The History of In Vitro Fertlization and IVF Treatment Process
In vitro fertilization is arguably the most
significant advance in fertility treatment since the
field of reproductive medicine began. The first IVF
baby, Louise Brown, was conceived and born in
England in 1978. Since that time, an estimated one
million babies have been born as a result of this
technology. Initially, in vitro fertilization was
developed for the treatment of women with fallopian
tube disease, but now it is the treatment of choice
for fertility caused by many other conditions,
including significant male factor, unexplained
infertility, and endometriosis-associated
infertility. IVF is the most successful fertility
treatment available using a patient’s eggs and her
partner’s sperm.
The five steps of in vitro fertilization include
ovulation induction, the oocyte retrieval,
fertilization, the embryo transfer, and hormonal
support of the luteal phase with progesterone. In
most cases, ovulation induction initially involves
the use medications to suppress ovarian cysts and
prevent ovulation from a spontaneous LH surge. The
most common protocol utilized by IVF programs in the
United States includes administration of oral
contraceptives with an overlap of an injectable
medication called Lupron™. This medication is given
prior to ovarian stimulation and suppresses the
pituitary gland’s ability to produce the hormone LH
– which could trigger ovulation to occur, ruining
the stimulation cycle.
We ask patients to continue to take their birth
control pills for the first five days that they are
taking Lupron, and they then typically start a
period soon after stopping the pills. Once the
menses occurs, ovulation induction is begun using
subcutaneous daily injections of the gonadotropin
hormone FSH (FollistimTM, Gonal-FTM,
or BravelleTM.) Some centers add the
hormone LH or HCG in low doses to the stimulation
protocol, as some people believe that may produce a
better stimulation in some patients. During the
course of gonadotropin administration, the woman is
evaluated with blood tests to measure estradiol
(estrogen) production from the follicles as well as
transvaginal ultrasound examinations every 2-3 days
to monitor the development of the ovarian
follicles. This monitoring is performed every two
to three days during stimulation – which typically
takes 9 to 14 days. Once the follicles reach
maturity, as determined by their average diameter as
well as their estradiol production, the oocyte
retrieval is scheduled. In order to achieve optimal
egg maturity, we administer a single injection of
OvidrelTM approximately 36 hours before
the scheduled retrieval time.
The oocyte retrieval is performed in a surgical
suite where an anesthesiologist will give you
intravenous (IV) medication to keep you
comfortable. Oocyte retrieval is performed on a
outpatient basis – the entire procedure typically
lasts 20 minutes, following which time you will
remain in the recovery area for about an hour. You
are technically not put to sleep for the retrieval,
you do not have breathing tube placed in your
throat, and there are not any incisions in your
body. Rather, the eggs are removed transvaginally
under ultrasound guidance.
Your male partner provides a sperm sample on the
morning of the oocyte retrieval, and the sperm are
prepared by the embryologists for their addition to
the eggs. If your partner’s sperm are normal, then
approximately five hours after the eggs are removed,
15,000 moving sperm will be added to a drop of media
(the special liquid in which the eggs grow). If the
sperm are abnormal, then the embryologists inject a
single sperm into each mature egg – a procedure
called intracytoplasmic sperm injection (ICSI)
in order to facilitate fertilization. Following
either insemination or ICSI, dishes containing the
sperm and eggs are placed into an incubator where
the environmental conditions (temperature, humidity,
light, gas concentration, etc.) can be tightly
controlled in order to simulate the conditions
inside the woman’s fallopian tubes and uterus as
closely as possible.
The following morning, the embryologists evaluate
the eggs to determine whether or not fertilization
has taken place. All normally fertilized eggs are
placed back into the incubator and evaluated for the
next several days to determine if appropriate embryo
development is occurring. Embryos are transferred
into the uterus on either Day #3 or Day #5 after the
retrieval (which occurs on Day #0), depending on the
number of healthy embryos available for transfer.
The recommended number of embryos to transfer is
determined by the female’s age, the cause of
infertility, previous pregnancy history, and other
factors. If abnormal fertilization occurs, those
embryos have a chromosomal number incompatible with
life and, as such, they are discarded, as they can
never develop into a viable human being.
The embryo transfer is similar to a pelvic exam and
may be performed under abdominal ultrasound
guidance. A soft flexible catheter is introduced
into the cervix and positioned approximately 1-2 cm
from the top of the uterine cavity where the embryos
are released. Extra, viable embryos that are of
good quality can be cryopreserved and stored for
future use. A serum pregnancy test is performed
exactly two weeks after the oocyte retrieval.
Many studies over the years have demonstrated that
pregnancy and delivery rates are significantly
higher in women who receive luteal phase support
with progesterone following the embryo transfer.
Progesterone is a hormone that is produced by the
ovary following ovulation, and it results in
maturation and stabilization of the uterine lining
for implantation. Luteal phase support has
traditionally been accomplished with the
administration of intramuscular progesterone –
although recent studies, including one performed by
our physicians, suggest that a vaginal progesterone
product (Crinone™) may be even more effective. The
standard protocol for luteal phase support is to
administer progesterone from two days after oocyte
retrieval until the pregnancy test. If a pregnancy
occurs, the progesterone may be continued or stopped
depending on the serum progesterone level. Studies
have confirmed that there is no increased risk of
birth defects or other fetal abnormalities resulting
from the administration of progesterone during the
luteal phase and/or early pregnancy.
When IVF treatment was first developed, stimulation
medications were not used. Rather, patients were
monitored during their natural cycles. The timing
of egg retrieval was based on the occurrence of a
woman’s spontaneous LH surge, which had to be
measured several times per day. Natural cycle IVF
has been largely abandoned in modern day fertility
treatment, due to the extreme inefficiency and high
cancellation rate associated with this approach.
Some couples will occasionally inquire about a
natural IVF cycle because of medical or moral
objections to stimulated IVF or because of medical
contraindications to controlled ovarian
hyperstimulation. Couples who want to minimize the
risk of multiple pregnancy may also consider natural
cycle IVF. The goal of the natural cycle is the
retrieval of one egg and replacement of one embryo.
Historically, the success rate is less than 5%,
which is the major disadvantage of this procedure.
The
marked increase in the success of IVF over time has
been primarily due to significant advances in the
IVF laboratory. Specifically, improvements in
gamete and embryo culture conditions, embryo
handling, and the catheters that we use to place
embryos back into the uterus have enabled pregnancy
rates to rise significantly.
In the
mid 1980s, fertility programs around the world were
continuing to struggle with poor success rates for
IVF. It was universally accepted that the main
factor inhibiting higher pregnancy rates was the
length of time that embryos had to stay in the
laboratory prior to being transferred back into the
woman’s body. This was due to the fact that the
longer embryos stayed in the laboratory, the more
they were exposed to suboptimal environmental
conditions. After much deliberation and
experimentation in both humans and in animals,
investigators at the University of Texas Health
Science Center at San Antonio reported success with
a procedure they called GIFT. Although GIFT
technically stands for Gamete Intrafallopian
Transfer, most patients referred to it as
putting “Gametes Into the Fallopian
Tube”.
This new
procedure was offered to patients with at least one
normal fallopian tube as an alternative to IVF. The
majority of the basic steps of the GIFT procedure
were identical to those involved in IVF. Patients
were stimulated the same way, using the same
fertility medications. After superovulation,
however, the oocytes were collected laparoscopically
rather than through the vagina. The eggs were then
identified in the laboratory, and 2-4 oocytes with
washed sperm obtained from the patient’s partner
were then loaded into a transfer catheter. The
catheter was then placed into the fallopian tube
through its fimbriated end while the patient was
still under anesthesia. If both tubes were normal,
then half of the eggs and sperm were placed into one
tube and half into the other tube. Patients then
started progesterone supplementation and a pregnancy
test was performed two weeks later.
Early
studies demonstrated significantly higher pregnancy
rates with GIFT, and as a result, its popularity
spread rapidly. In addition, as fertilization
occurred inside the woman’s body – specifically
inside the fallopian tubes, just like in a naturally
occurring pregnancy – this became an acceptable
alternative to IVF for some Catholic patients.
Over
time, due to the tremendous advances in the IVF
laboratory, pregnancy rates for IVF have become much
higher than those that were achieved with GIFT. In
addition, IVF does not require either a laparoscopic
procedure, general anesthesia, or the extended use
of an operating room, making it safer, less
invasive, and less expensive than GIFT. As a
result, GIFT has become less popular and is now only
rarely performed in the United States.
Shortly after the GIFT procedure was developed, it
was suggested that success rates might improve even
more if the oocytes that were placed in the
fallopian tube were already fertilized. As a
result, ZIFT, or zygote intrafallopian transfer, was
developed. The procedure for ZIFT was identical to
that of the GIFT procedure with one significant
exception. Rather than obtain the eggs and sperm
and transfer them back into the woman’s fallopian
tube(s) on the same day (GIFT), with ZIFT the eggs
and sperm were cultured together in the laboratory
for 24 hours to allow fertilization to occur and the
fertilized eggs (zygotes) were then transferred into
the woman’s fallopian tube(s).
Specifically, oocytes were retrieved transvaginally
from the woman’s ovaries. Following the procedure
the patient was allowed to go home. Meanwhile, the
oocytes were combined with her partner’s sperm and
fertilization occurred in the laboratory. On the
following day, a laparoscopy was performed and two
zygotes were placed in each fallopian tube through
its fimbriated end. As with GIFT, patients could
only undergo ZIFT if the woman had at least one
normal fallopian tube. Pregnancy rates were higher
for ZIFT than GIFT because the oocytes placed in the
fallopian tubes were already fertilized. The
pregnancy rate for ZIFT was approximately 40-45%,
while the pregnancy rate for GIFT was approximately
20-25%.
Over
time, due to the tremendous advances in the IVF
laboratory, pregnancy rates for IVF have become much
higher than those that were achieved with ZIFT. In
addition, IVF does not require either a laparoscopic
procedure, general anesthesia, or the extended use
of an operating room, making it safer, less
invasive, and less expensive than ZIFT. As a
result, ZIFT has become less popular and is now only
rarely performed in the United States. One relatively rare exception to this
statement is the occasion where a woman’s cervix is
severely scarred and transcervical embryo transfer
cannot be accomplished. In this situation,
consideration for transfer of zygotes into the
fallopian tube through the laparoscope remains an
option.
It is often difficult for patients to understand
why, when we obtain eggs and sperm, combine them in
a successful laboratory to develop embryos and put
what appear to be healthy dividing embryos into the
uterus, IVF could possibly not succeed. As with
most biological events, pregnancy is a very complex
process. Even today, what we do not know about
pregnancy continues to exceed what we do know.
Nevertheless, there are some specific factors that
we have identified that can occasionally lead to IVF
failure.
The most important variables involved in a
successful IVF cycle are a healthy egg, normal,
functional sperm, and a uterus that is capable of
nurturing the growth of a baby. In addition to
these issues, there are many other factors that can
impact one’s chance for pregnancy with IVF. These
include the laboratory environment, the techniques
used in the lab, and the skill of the specialists
performing the egg retrieval and embryo transfer.
The human egg is a very complex structure. As such,
it is subject to damage that can render it
nonfunctional. As you may recall from high school
biology, when cells divide, chromosomes (the packets
of DNA that contain your genes and those of your
partner) duplicate and line up in the middle of the
cell. As the cell divides, half of the chromosomes
move in one direction and the other half move in the
exact opposite direction, resulting in two identical
cells. These chromosomes move because they are
attached to a structure called the spindle apparatus
that is responsible for chromosome separation, which
is necessary for cell division. As the oocyte ages,
the spindle apparatus becomes prone to breakage –
such breakage can result in an abnormal distribution
of chromosomes, leading to a chromosomally abnormal
and therefore, nonviable embryo. The oocyte is also
subject to damage due to the presence of free
radicals, reactive oxygen species and other products
of metabolism that occur within the ovary as a woman
ages. Many recent studies have demonstrated that
between 25% and 40% of all oocytes are chromosomally
abnormal. This number obviously increases as a
woman ages.
Although abnormal sperm appear to be a less common
factor affecting the success of an IVF cycle, they
nevertheless play an important supporting role.
Sperm do not merely bump into an egg and cause
fertilization. Rather, the process of fertilization
itself is very complex. In order for sperm to
migrate to the egg, they must be motile; in other
words, the tail of the sperm must be able to propel
the sperm through the female reproductive tract to
the egg. There are specific receptors on the
surface of a sperm head that bind to specific
receptors on the outer membrane of an egg allowing
for sperm/egg interaction. Once this happens,
enzymes are released from the sperm head that enable
digestion of a hole in the outer membranes of the
egg. The sperm eventually penetrates the egg where
the nucleus of the sperm opens, releasing the sperm
DNA. At that point, the chromosomes from the sperm
and the chromosomes from the egg combine, producing
a fertilized egg (which is actually a very early
embryo). Studies suggest that the incidence of
chromosomal abnormalities in sperm is far greater
than that seen in eggs. However, whereas a
chromosomally abnormal oocyte may lead to a
chromosomally abnormal pregnancy, chromosomally
abnormal sperm appear to not be able to successfully
fertilize an egg.
Intracytoplasmic sperm injection (ICSI) was
developed to enable men with very low sperm counts,
low motility, or very few normal sperm to be able to
achieve fertilization and pregnancy. Over the past
few years, ICSI has evolved to the point that it is
now routinely performed in cases of severe male
factor, resulting in fertilization rates comparable
to those achieved with normal sperm. In addition,
data from long term studies suggest that the
incidence of chromosomal abnormalities in the
offspring from IVF cycles in which ICSI was utilized
do not exceed those found in nature.
The embryos that are ultimately transferred into the
women’s uterus are selected by the embryologist.
Unfortunately, our ability to distinguish
chromosomally normal from chromosomally abnormal
embryos remains severely limited. Essentially, our
embryologists select embryos for transfer based on
three basic criteria: cell stage, embryo grade and
the rate of cell division. We know from studies
performed in our laboratory that on day three,
embryos that have developed to at least the 6 cell
stage have a much better prognosis for success than
embryos that have 5 or fewer cells. Similarly, we
believe that embryos that are of a better grade
(grade 1, 2 or even 2.5) are much more likely to
implant that those embryos with lower grades (3 or
4). In addition, as we observe the embryos on a
regular basis, our embryologists are able to
determine the rate of cell division. For example,
an embryo that gradually reaches the 8 cell stage by
day three is much more likely to do well than an
embryo that has delayed fertilization and rapid
growth towards the end of this time period.
The IVF laboratory is a very tightly controlled
environment, in which we attempt to simulate what
sperm, eggs and embryos experience inside the female
reproductive tract. Specifically, we tightly
control oxygen concentration, carbon dioxide
concentration, and other factors such as humidity,
PH, temperature and light. Even slight alterations
from what embryos normally experience can lead to
death of the embryos and therefore no chance for
pregnancy from the resulting cycle. Our
embryologists continuously keep up with the changing
literature and make alterations in our laboratory as
necessary, in order to continue to optimize the
environment to which gametes and embryos are
exposed. In addition, they perform daily quality
assessment and control procedures in order to
confirm that our equipment is always functioning
optimally. The construction of the laboratory
itself, which involved the placement of multiple
types of filters in the ceilings of the operating
room and the laboratory, was meticulously overseen
in order to guarantee an optimal laboratory
environment. In addition, such seemingly minor
details as using only incandescent light during
procedures can have profound effects on ultimate
outcome.
The surgical procedures themselves, the egg
retrieval and the embryo transfer, are very
important to the success of an IVF cycle.
Retrieving fewer eggs than expected, or even worse –
failing to retrieve any eggs, can lead to an adverse
outcome. In addition, during the embryo transfer
procedure – one of the most important steps of the
entire cycle – embryos must be placed in the correct
location. In our program, we perform a trial
transfer in order to determine, in advance, the
optimal location for embryo placement. In addition,
prior to transferring the embryos, your physician
will take great pains to remove any cervical mucus
or other cellular debris that may plug up the
transfer catheter. We also pre-treat all of our
patients with a smooth muscle relaxant in order to
prevent contractions of the uterus.
Despite all of the challenges noted above, in vitro
fertilization remains extraordinarily successful. A
large nationwide study lead by our physicians and
involving over 55,000 IVF cycles from 54 different
programs throughout the United States, revealed that
a couple’s chance of delivering a baby is the same
in their first three cycles of in vitro
fertilization. In other words, even if a couple
fails to conceive in their first two IVF cycles,
their chance for success in the third cycle is still
the same as it was in cycle one or two. If, however
a couple fails to conceive after three cycles of in
vitro fertilization, their chance for a successful
conception in another IVF cycle diminishes
drastically. At that point in time, they should
consider other options such as seeking treatment at
another facility, donor gametes or other
alternatives.
Many patients are referred to TFC following
unsuccessful treatment elsewhere. After reviewing
their medical records, we may suggest such things as
an alternative stimulation regimen, a different IVF
protocol, the use if ICSI or even pre-implantation
genetic screening, or proceeding to donor gametes.
It is important to realize that different IVF
centers may approach the same patient in a different
manner; therefore failure at one facility does not
have to mean that you should give up on your dream
of having a baby.
