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What is IVF-ET?
Why attempt IVF-ET?
Who is a candidate?
What are the chances of pregnancy?
The five steps of the IVF-ET process
Associated therapies
What about the GIFT procedure and other types of assisted
reproduction?
Treatment of severe male infertility (ICSI)
Are IVF/ET pregnancies different?
Risks and complications of IVF and fertility therapies
Comparing
success rates
Readers are welcome to view the
details of the C.A.R.S.
IVF program.
In vitro, literally meaning “in
glass,” refers to a natural process that is performed
outside the body. It is from this literal translation that
the term “test tube baby” arises. IVF-ET represents
the flagship of assisted reproduction. It is from IVF-ET that
other technologies draw their impetus and scientific foundation.
In vitro fertilization, or IVF, involves obtaining an egg
(oocyte) from the female partner and placing it in a culture
dish (test-tube) with sperm from the male partner. Fertilization
occurs in the same manner as in a woman's fallopian tube but
instead takes place in a controlled laboratory environment.
After fertilization, the conceptus or "pre"-embryo
(usually called an embryo) that forms is allowed to grow for
1-3 days. The fertilized egg is a single cell that has a mixture
of genes from both the sperm and egg. This single cell divides
to form 2 cells, 2 cells form 4, 4 form 8, and so on. At 2-3
days the embryo is usually at the 2-12 cell stage and at this
point the growing conceptus is transferred (embryo transfer
-ET) into the uterus. An IVF-ET "cycle" translates
into one attempt at pregnancy, although this may span either
one or two menstrual cycles
IVF offers several distinct advantages
that make it more cost-effective than it might seem initially.
Perhaps the largest benefit, a desire shared by both clinician
and patient, is to evaluate the capacity of the oocyte to
be fertilized. An additional advantage is that a more aggressive
approach can be taken toward ovarian stimulation. With PCOS,
hyperstimulation is somewhat less of an issue because the
preovulatory size follicles are aspirated and a limited number
of embryos are replaced. Not only does this decrease the chance
of multiple pregnancies, it reduces the risk of more pronounced
cystic change. Many patients either over or under stimulate
with gonadotropin therapy alone. The use of GnRH analogs and
gonadotropins in conjunction with IVF may maximize control
and ensure the greatest chance of pregnancy in any one cycle.
- Diagnostic and prognostic procedure for egg assessment
- Less chance of multiple pregnancy than with gonadotropin
injection
- Ensure egg accessibility, by-pass need for ovulation
- Treatment of male and tubal factors
- Superior success rates over all other methods
- High financial, time, and emotional cost
- Pain of the aspiration procedure
- Ethical issues regarding freezing embryos
- Success is not guaranteed
Louise Brown, the first "test
tube baby," celebrated her twenty first birthday in July
1999. Her sister, also a IVF-ET pregnancy, established a pregnancy
without therapy and has a healthy child. The IVF-ET technique
enabled her mother's damaged uterine tubes to be by-passed
and for the first time a fallopian tube was not needed as
a site of fertilization and transport pathway to the uterus.
With this birth, IVF-ET became a totally new treatment for
patients with irreparable tubal damage. Despite the technological
explosion in the new reproductive technologies, tubal damage/blockage,
still represents the most common and undeniable reason for
IVF-ET. IVF/ET may even be preferable to surgery to "reconnect"
the tubes after previous sterilization in some cases. This
avoids major surgery with its prolonged recovery period and
the increased risk of ectopic (tubal) pregnancy. The option
of IVF/ET over tubal surgery may be especially important in
women over age 35.
The indications for IVF-ET have expanded
past tubal infertility to include many types of male and female
infertility such as endometriosis, cervical factor, immunologic,
male factors with abnormal semen, and unexplained infertility.
Besides its utilization as therapy, reasons for IVF-ET now
may include its application as a useful, albeit costly, diagnostic
and prognostic tool. There are many reasons for, and probably
no absolute contraindications against, IVF-ET. The American
Society for Reproductive Medicine states, “in vitro
fertilization for infertility, not solvable by other means,
is considered ethical.” For some, assisted reproduction
may represent the last hope at the end of a long path of infertility
therapy. For others, it may be the best place to start, depending
on age and cause of infertility. The major factor limiting
its greater use is its high cost.
Sometimes couples apply for an IVF-ET
program after an accelerated evaluation that has omitted basic
diagnostic and therapeutic steps. In other cases, insufficient
time may have been given for proper trial of less aggressive
techniques. In the final analysis, who should undergo IVF-ET
is a personal decision of the well informed couple that should
take into account age, cause and length of infertility, previous
treatment, willingness, and financial capacity to undergo
therapy and prognosis for success.
The success rate by a specific
clinic, age group, and cause of infertility can be quoted
and supported by written information. For the individual couple
embarking on an IVF cycle, the chance of success is a hard,
if not impossible, question to answer. According to the CDC
report, the live birth rate for women under age 35 was about
40%. This decreased to about 20 % by age 40 and 10% for age
41-42. In reality, the chances of a pregnancy are either 0
or 100% per cycle.
Although many of the pregnancies established
are in the first cycle, chances of pregnancy appear to be
equal with each try through the first 4 attempts. It is not
unreasonable to expect a pregnancy on the first attempt, but
it is better to anticipate that it may take a second or third
attempt as more is learned about individual response to therapy
and sheer chance alone.
Couples should expect a frank open discussion
of success rates and a copy of their center’s success
rates in the past several years. Beware if it sounds too good.
In theory, the IVF-ET procedure is simple.
An egg is taken from the ovary and healthy sperm are selected
from a sample produced by the male. Egg and sperm are placed
together in a culture dish where fertilization takes place.
The resulting embryo is transferred into the uterus at about
the time it would take to arrive there in a natural conception.
Does it sound easy? It isn’t!
In practice, IVF-ET demands a high level
of attention to detail and requires a precisely coordinated
effort among all involved. IVF-ET is a very emotional and
encompassing experience. It seems to focus all hopes and fears
about fertility and pregnancy into a “procedure.”
- Controlled ovarian stimulation
- Follicle aspiration
- In vitro fertilization and culture
- Embryo transfer
- Luteal implantation and support
Step 1: Controlled Ovarian
Stimulation.
Each month, a woman usually releases
(ovulates) a single egg (oocyte) from a
single small ovarian cyst, about half-dollar size, called
a follicle. One follicle usually equals one egg.
For IVF, we know that the more eggs there are (to a point)
the more embryos there are, and the better the chance of a
pregnancy. To obtain more than one oocyte, fertility drugs
are given to stimulate the ovary so that more than one “preovulatory”
follicle develops. Most often injectable fertility agents,
gonadotropins, are used to enable a larger number of follicles
to develop.
The first well known injectable fertility
drug was human menopausal gonadotropin (HMG) ( Pergonal).
More recently other brands of HMG, such as Repronex, have
been made available at slightly lower costs. All HMG preparations
consist of equal quantities of FSH and LH and should be identical
in action.
A major change in the way gonadotropins
were obtained was made possible by genetic engineering and
recombinant DNA technology. Here, specific cells that produce
massive amounts of absolutely pure hormone are cultured in
the laboratory. This type of production has obvious advantages,
but at present, the disadvantage is a higher cost. Presently,
the FSH preparations available in the U.S. are Gonal F
and Follistim.
Different centers use different stimualtion
regimens. Some use only a single agent,some use a mixture
of HMG and FSH. Although there are many claims, to date, no
specific formulation or product has emerged as superior for
controlled ovarian stimulation. Similar patients often respond
better to one drug, but it has been impossible to predict
this in advance.
The amount of gonadotropin given is
determined by expected and previous response. This may be
difficult to predict in advance. Often a higher dose is given
in the early stages of stimulation then lowered (step down)
when a good response is achieved. Usually these are the injectable
drugs, but some centers use clomiphene for selected patients.
There is some degree of disorder in
the normal follicular development of every woman’s ovary.
Several different medication regimens, including birth control
pills and progestins, may be used to synchronize the ovary
in hopes of obtaining the best quality eggs. Many IVF programs
use luprolide (one brand name is Lupron) starting about one
week before your period is due to help synchronize the cycle
and later block the LH surge and ovulation. This medication
is administered by a daily small subcutaneous (just under
the skin) injection. This therapy temporarily reduces natural
hormone production by the ovary and may provide a better starting
point for stimulation. If used for an extended time, these
medications would create a reversible medical menopause. It
is used only for a short time, several days to several weeks,
and generally has few, if any side effects. An alternative
to Lupron is the use of a GnRH “antagonist” (Antagon™
or Cetrotide™). This medication is begun AFTER gonadotropin
stimulation is underway for several days. They also block
ovulation and reduce the number of injections necessary, but
may not be as good in synchronizing.
When the menses occurs, a baseline
scan and estradiol level is drawn to make sure the ovary
is suppressed, no cysts have formed, and the uterine lining
is thin. After a normal baseline scan, stimulation is begun
with gonadotropin injections.
Ultrasound scan and estradiol levels
are used to monitor follicle growth and response to stimulation.
When a sufficient number of follicle(s) are judged to be mature,
both by size (16-22 mm) and estradiol level (above 200 pg
/ ml for each large follicle,) an injection of human chorionic
gonadotropin (hCG) is given to allow the follicles to complete
their last stages of maturation. Some centers place limits
on the number follicles required before progressing to follicle
aspiration. The IVF attempt may be cancelled or converted
to an insemination cycle if there are a small number of follicles.
The cycle may also be cancelled if there appears to be an
undue risk of ovarian hyperstimulation.
The follicle aspiration (the procedure
where the eggs are removed from the ovary) is scheduled about
thirty-six hours after the hCG injection. By that time, the
egg is floating in the follicle.
Step 2: Follicle Aspiration
In the past, aspiration of follicles
required laparoscopy. Now virtually all centers use a transvaginal
ultrasound guided approach that is often performed as an office
procedure. In the procedure of follicle aspiration, a needle
is passed through the upper vaginal wall, and, with the use
of vaginal ultrasound, fluid is removed from the follicles
by a gentle suction. The procedure is not painless, but it
is generally well tolerated. The procedure may last from five
to about twenty minutes with few exceptions. Centers vary
in their sedation; anything from a oral medications to general
anesthesia is used.
Immediately after aspiration of a follicle,
the oocyte is isolated from the follicular fluid and placed
in a culture dish that contains nutrient media. It is then
transferred to the incubator.
Shortly before or after the aspiration
procedure, the sperm are isolated from the semen that was
obtained earlier. During this procedure, the most active sperm
are selected and transferred to a culture dish for completion
of the changes necessary for fertilization.
Step 3: In Vitro Fertilization
Oocytes and sperm are placed together
in a culture dish, which is placed inside an incubator, thus
providing a controlled environment. There, they are left undisturbed
until the next day, at which time they are examined for fertilization.
Over the next day, the 1 cell embryo will divide (cleave)
into a 2-cell embryo, 2 cells into 4, 4 cells into 8 and so
on. In some cases sperm may be injected directly into the
egg (ICSI see below) as an additional step to ensure fertilization.
Step 4: Transfer of Embryos
Traditionally, on the second or third
day following follicular aspiration, when the embryos have
reached the four to ten cell stage, the embryo(s) is transferred
into the uterus. With the development of new types of media,
embryos can be cultured for longer periods of time in the
laboratory. The term blastocyst refers to the stage
of embryo development just prior to implantation and is reached
after about five days in culture. By extending the culture
period, blastocyst stage culture, the best embryos
can be selected and, theoretically, pregnancy rates improved.
This technique may be of greater importance in PCOS patients
who produce more embryos, rather than good quality embryos.
Fewer embryos transferred translates into a reduced risk of
multiple pregnancy and the serious consequences that can result.
The transfer takes only a few minutes
and involves placing a small plastic tube through the cervix
into the uterine cavity. The procedure usually is no more
uncomfortable than a Pap smear and no anesthesia or sedation
is required. Some centers use ultrasound guidance for the
transfer, others believe this is unnecessary.
Step 5: Implantation Support
and Monitoring
It is unknown when implantation takes
place or what can be done to ensure the best chance of implantation.
Because of the manipulation of the ovaries that has taken
place, additional supplements of hCG and/or progesterone are
given to help ensure the optimum environment for implantation.
Cryopreservation -
Cryopreservation, or freezing
of embryos is routinely performed when there is a greater
number of viable embryos available than are thought needed
to successfully establish a pregnancy. The embryos are allowed
to remain in culture long enough to determine the best quality
embryos for transfer. Embryos can be frozen at any time after
fertilization, but a general rule is the longer the embryo
remains in culture the less likely a subsequent pregnancy
from the frozen embryo will occur. That is embryos frozen
at the 2-pronuclear stage, the first day after aspiration
may be better than those frozen on day 3. Those frozen on
day 3 may be better than those frozen on day 5. Freezing allows
the possibility of an additional attempt at pregnancy without
the necessity of the fertility injections or aspiration procedure.
It is not known for how long an embryo can remain frozen,
but successful pregnancies have occurred ten years after the
initial transfer of embryos. As few as 50% of the embryos
survive the thaw process, but there is no evidence that cryopreservation
is harmful to children born from the technique.
Blastocyst culture
is an important scientific advance, but the practical advance
in terms of IVF success is much less clear. Unfortunately,
the technique has been the subject of some major media attention.
In some cases the uterus may still be a better incubator than
the laboratory. Extending the culture period and delaying
transfer may lose some pregnancies. There will be fewer embryos
for cryopreservation because of the need to keep more embryos
in culture to see which will continue to develop. An additional
attempt at success using frozen and thawed embryos may be
lost. Also, an extended culture can mean an extended cost.
Assisted Hatching The
zona pellucida (ZP) is a protein halo surrounding
the egg and later the embryo. The ZP prevents attachment of
the embryo to the wall of the tube as it travels down to the
uterus. Once in the uterus, the ZP dissolves and the embryo
“hatches.” There are several studies suggesting
the ZP abnormally thickens or “hardens,” thereby
causing a reduced success with IVF. Theoretically, older women
and those with PCOS are at a higher risk for this hardening.
In assisted hatching, the ZP is thinned either mechanically
by physically puncturing it, or chemically by using an acid
solution to partially dissolve it. Some excellent centers
swear by the technique. Others with equally good success rates
condemn the procedure as unnecessary. While the procedure
may improve the chances for pregnancy, it is more costly and
could destroy the embryo.
There are many variations on the
IVF/ET theme. In the GIFT procedure, follicles are aspirated
during laparoscopy and the unfertilized oocytes placed in
the fallopian tube with a sample of prepared sperm. This is
a single and simple procedure, but requires laparoscopy. The
GIFT procedure would seem to offer advantages of a more "natural
approach" by avoiding IVF and embryo culture. However,
the advantages of IVF-ET procedure are the avoidance of laparoscopy
with its required general anesthesia, postoperative recovery,
and higher cost. Knowing that fertilization has occurred and
that transport through a possibly abnormal tube is not necessary
are additional advantages. IVF-ET may have important diagnostic,
prognostic, and therapeutic consequences. The reasons to use
GIFT are very limited and the procedure has been largely abandoned
in favor of IVF-ET.
Other procedures such as PROST, ZIFT,
and TET are modifications of GIFT/IVF protocols where fertilization
is determined before transfer into the Fallopian tube. The
disadvantage of this group of therapies is that two surgical
procedures are required--the follicle aspiration and laparoscopy
for transfer. There are more variations than can be listed
here.
There has been a major breakthrough
over the last 3 years in treatment of severe forms of male
infertility. It is now possible to inject a single sperm directly
into the egg, a procedure called intracytoplasmic
sperm injection (ICSI). ICSI
bypasses the outer coverings of the egg and thus some of the
barriers to fertilization. Since a very small number of sperm
are needed for this procedure, it has a very important advantage
for men with extremely low sperm numbers, or sperm motility.
ICSI can be used together with
aspiration of sperm directly from the testis or the epididymis
(TESA) and can restore fertility after vasectomy, or failed
reversal of vasectomy. With these two techniques, many men,
previously believed sterile can father children. Because of
the low sperm number and motility, TESA must be performed
in conjunction with ICSI. (See
info sheet on ICSI)
Spontaneous abortion (miscarriage)
may occur following an IVF pregnancy, just as in any pregnancy.
A pregnancy achieved without any form of fertility therapy
has about an 8- 15% chance of aborting. Most of these miscarriages
occur in the first 8 weeks after conception. The abortion
rate may be slightly higher after IVF-ET where rates vary
from 10 to 20%. This increase probably is more related to
egg, sperm, and uterine factors --infertility itself-- rather
than from the IVF/ET procedure. Pregnancy loss after the first
12 weeks is equally uncommon in both IVF-ET and non-IVF-ET
pregnancies.
Ectopic pregnancy occurs in about 1%
of all pregnancies in the USA. Patients with abnormalities
of the Fallopian tubes may have a 10-40% risk of an ectopic
pregnancy with a pregnancy achieved without IVF-ET and a small
increase in chance of ectopic pregnancy with IVF compared
with individuals with no tubal disease. After IVF-ET, the
risk for ectopic pregnancy is about 1% of all patients.
There is a higher incidence of twins
and multiple pregnancies following the transfer of multiple
embryos. Occasionally, when multiple pregnancies are noted
on an early ultrasound, one or more pregnancies are later
absorbed, leaving a single pregnancy. Therefore, if multiple
pregnancies are diagnosed by ultrasound scan, close follow-up
is indicated. A repeat ultrasound by you obstetrician at 16
to 20 weeks to reevaluate the progress of your pregnancy is
suggested.
Genetic counseling and amniocentesis
are not a necessity just because a pregnancy is achieved by
IVF-ET. However, if there is any family history of genetic
diseases or congenital anomalies, if you are over age 35,
or if there are any other indications for amniocentesis and/or
genetic counseling, then this should be performed. Congenital
anomalies and/or genetic disease have been reported in IVF-ET
children. The incidence of these problems after IVF-ET has
not been found to be higher than in non-IVF-ET pregnancies.
Although the studies are relatively limited, it appears that
children born after IVF-ET have no greater risk of developmental
or learning defects.
It is not necessary to have a Cesarean-section
delivery for an IVF-ET pregnancy. However, a Cesarean section
may be necessary for obstetrical indications, just as in any
other pregnancy.
Now that you know the basics read
about IVF-ET at
C.A.R.S.
Ovarian Hyperstimulation Syndrome
(OHSS) - It is difficult
to determine in advance whether an individual will over- or
under-stimulate with gonadotropin injections. The threshold
level between too much and too little can sometimes be very
narrow. An objective of the use of fertility agents is to
affect some degree of hyperstimulation of the ovaries. Residual
cystic change of the ovaries and mild discomfort are quite
common. This is of short duration and little risk.
Ovarian hyperstimulation is very different
from ovarian hyperstimulation syndrome (OHSS). The risk factors
for OHSS include younger age and polycystic ovary syndrome.
While the cause of OHSS is unknown it seems to be a discrete
disease process associated with altered permeability and leakage
of protein-rich fluid from the small vessels of the ovary
into the pelvis, abdomen, and possibly even around the lungs.
OHSS is said to be mild when there is
abdominal swelling, ovarian enlargement with cysts up to 5
cm and discomfort. Mild OHSS is relatively common after gonadotropin
injections and may be indistinguishable from the natural effects
of the ovaries to gonadotropin injections.
In severe OHSS there is marked fluid
accumulation and moderate to severe pelvic pain. Sometimes,
the amount of fluid is enough to warrant removal. This is
usually accomplished with vaginal ultrasound as an office
procedure with generally good pain relief.
The greatest concern is that there is
so much loss of fluid from the blood vessels that there is
a possibility of blood clot development. In some cases hospitalization
and intravenous fluid is needed. Although rare and now much
less common than in the past, deaths have been reported from
severe OHSS.
The primary strategy for OHSS should
be its prevention. Since risk is related to amount of gonadotropin
used for stimulation, use of less gonadotropin therapy translates
into less risk. Consideration should be given to withholding
the hCG injection when estradiol levels are very high. Each
center sets its own guidelines. It is reasonable to ask how
many patients develop OHSS each year; how many are hospitalized.
Withholding therapy for several days once gonadotropin therapy
is started (coasting), which allow the smaller follicles to
regress and larger follicles to continue to grow before the
hCG injection, is another option. The success with coasting
is usually decreased. In cases of IVF, it is sometimes reasonable
to proceed with aspiration, but freeze all embryos for later
transfer rather than transfer in the stimulation cycle.
As a precaution all patients should
weigh at the start of stimulation cycle and after hCG. It
is common to have some water retention during gonadotropin
stimulation. If there is the feeling of excessive abdominal
fullness or weight gain, daily weight should be taken. Your
physician should be contacted if the weight gain is over 5
pounds, there is difficulty breathing, or severe abdominal
pain, vomiting, fever, or reduced output of urine. Strenuous
exercise and sexual intercourse should be avoided. There should
be adequate intake of fluids containing salt (electrolytes).
Juices are better than water or soft drinks.
Multiple Pregnancies
- You must be fully informed about
the considerable dangers and the emotional risks and problems
in a multi-fetal pregnancy. Many infertility patients initially
think of the possibility of twins, or even triplets as exciting.
Twins and greater are just not an issue of having one’s
hands full and one’s pocketbook emptying after the babies
are born! Multi-fetal pregnancies carry significantly higher
physical risks for both mothers and babies.
Most of the complications that arise
from pregnancy after IVF are related to multiple pregnancy
and premature birth. Multiple pregnancies are often born prematurely.
Prematurely born infants may experience serious, or life threatening
complications, or permanent medical disability.
As the IVF technology has improved so
has the chance of multiple gestations. It is a simplistic
approach but a reasonable exercise to consider the following
model. If one embryo is transferred and the implantation rate
is 20%, there is a 20 % chance of a pregnancy and no chance
of fraternal (non-identical) twins or triplets. When 2 embryos
are replaced the pregnancy chances increase to 40%with 20%
chance of twins and 0% chance of triplets. With 3 embryos
the chances of a single pregnancy increase to 60%, twins 40%
and triplets 20%. We have limited capacity to select an embryo
that will result in a pregnancy. The best way to avoid triplets
is to limit transfer to 2 embryos, Additional embryos can
be frozen for use in other cycles with good success. It is
strongly suggested for women under age 35 that no more than
2 embryos are transferred. In women over age 35, each patient
should be assessed individually.
Pregnancy Complications
- Tubal pregnancy may occur after
IVF-ET. Tubal pregnancy often requires surgery. Such surgery
may result in the loss of the tube, which, in turn, can further
impair fertility. In rare instances, a tubal pregnancy may
present a medical/surgical emergency due to shock from blood
loss and require transfusion and/or other treatment.
The risk of congenital malformation
in spontaneous pregnancies is about 1-3%. Congenital abnormalities
and/or genetic disease have been reported in IVF-ET children.
Overall there is increased evidence that a pregnancy after
IVF-ET may carry a slightly higher risk of obstetric complications
and birth defects. It is thought that therapy itself poses
no risk to the pregnancy but the risk may be due to the same
factors that cause infertility. These risks have not been
judged high enough to alter decision-making about IVF. The
risk that a child will be born with major birth defects increases
as its parents' ages increase.
Amniocentesis and/or chorionic villous
sampling, each of which can aid in the recognition of genetic
defects, should be discussed with your obstetrician. These
and other defects can often be detected by ultrasound screening.
For this reason, we recommend ultrasound screening of the
pregnancy, especially in its early stages. However, not all
defects will necessarily be detected by ultrasound or other
examination.
Even an apparently normal ongoing pregnancy
presents risks to both the mother and the baby, and does not
guarantee a normal delivery at term of a normal infant. In
pregnancies resulting from intercourse, the rate of serious
obstetrical complications is approximately 10-15%. This is
no different after IVF-ET.
Long-term risks of infertility
therapies. - Several reports
have linked ovarian cancer with use of "fertility drugs".
These reports are unconfirmed and have been subjected to much
criticism. The issue is under investigation, but it has not
altered recommendations or indications for usage. It is the
sincere belief of the vast majority who work with either the
clinical or scientific aspects of human reproduction that
the techniques in themselves pose no long-term health risk.
Dr. Thatcher has written an editorial
on comparing
success rates published by the
American Infertility Association (AIA).
Visit IVF-ET
at C.A.R.S.
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