from
the book How to Have a Baby: Overcoming Infertility
by Dr. Aniruddha Malpani, MD and Dr. Anjali Malpani,
MD.
Previous page:
Intrauterine Insemination (IUI)
Next page: Test
Tube Babies - IVF & GIFT (Page 2)
Table of Contents
What
are the assisted reproductive technologies ( ARTs )
?
What
tests need to be done prior to doing IVF treatment ?
How
is superovulation performed ?
How
is superovulation monitored ?
When
may an IVF cycle be cancelled ?
The birth of Louise Brown through in
vitro fertilization ( Fertilisation
Video ) (IVF) in 1978 was a major milestone in infertility
treatment. It dramatically changed the treatment options
for infertile couples, and techniques for assisted reproduction
have evolved rapidly since then. In a short span of
20 years, IVF has become the cornerstone of reproductive
medicine, and IVF clinics today routinely perform techniques
which were thought to belong to the realm of science
fiction a generation ago !
What
are the assisted reproductive technologies ( ARTs )
?
This chapter will help you understand
assisted reproductive technologies (ART) such as IVF
and Gamete Intra-fallopian Transfer (GIFT) that are
now standard medical treatments for infertility. A few
years ago, these techniques were used as methods of
last resort, when everything else which had been tried
had failed. Today, specialists will often resort to
these techniques first, since they offer such excellent
results, rather than waste the patient’s time and money
with the traditional ineffective options. Today, thanks
to IVF technology, there is practically no infertile
couple who cannot be offered treatment. However, as
with all technology, you need to understand exactly
how it works, and when it should be used.
IVF is the basic assisted reproduction technique , in
which fertilization ( Fertilisation
Video ) occurs in vitro ( literally, in glass) .
The man's sperm and the woman's egg are combined in
a laboratory dish, and after fertilization, the resulting
embryo is then transferred to the woman's uterus. The
five basic steps in an IVF treatment cycle are superovulation
(stimulating the development of more than one egg in
a cycle), egg retrieval, fertilization ( Fertilisation
Video ) , embryo culture, and embryo transfer.
IVF is a treatment option for couples
with various types of infertility, since it allows the
doctor to perform in the laboratory what is not happening
in the bedroom – we no longer have to leave everything
up to chance! Initially, IVF was only used when the
woman had blocked, damaged, or absent fallopian tubes
(tubal factor infertility). Today, IVF is used to circumvent
infertility caused by practically any problem, including
endometriosis; immunological problems; unexplained infertility;
and male factor infertility. It is a final common pathway,
since it allows the doctor to bypass nature’s hurdles,
and overcome its inefficiency, so that we can give Nature
a helping
hand !
What
tests need to be done prior to doing IVF treatment ?
In order to perform IVF, only 3 things are required
– eggs, sperms and a uterus, and before starting the
IVF cycle, the doctor will check these.
First, a sperm survival test is carried
out . This is a "trial" sperm wash, using exactly the
same method as will be actually used in IVF, to assess
whether an adequate numbers of sperms can be recovered
in order to do IVF. This test will also help the laboratory
to decide which method of sperm processing should be
used during IVF.
A blood FSH level will provide an idea
of the "ovarian reserve", and provide information on
whether or not the woman will produce enough eggs after
superovulation . For older women, some clinics do a
clomiphene citrate challenge test . If the level is
very high, this suggests early ovarian failure , and
it may be a better idea to consider donor eggs.
Many clinics may do a hysteroscopy,
in order to assess that the uterine cavity is totally
normal. They may also do a "dummy" embryo transfer to
make sure there are no technical problems with this
procedure. Some clinics also do a cervical swab test,
to rule out the presence of infection in the cervix.
If a woman has blocked fallopian tubes
with large hydrosalpinges, some clinics will remove
these prior to the IVF cycle, because they feel that
the presence of a hydrosalpinx decreases pregnancy rates
after IVF.
For men who have difficulty in producing
a semen sample " on demand", the clinic may also freeze
and store the sample prior to treatment, as a backup.
This can help to prevent the tragedy of having to abort
an entire treatment cycle because the man could not
produce a semen sample when needed.
Blood tests which may be done include
tests for immunity to rubella ; and tests for Hepatitis
B, and AIDS. Most doctors will also advise patients
to start taking folic acid, as part of prepregnancy
care, as this helps to reduce the risk of certain birth
defects.
Patients who stand a very poor chance
of success with IVF include the following :
- Older women, whose ovaries are failing.
However, there is no upper age limit at which IVF
should not be done,- and in fact, for older women,
it might represent their only chance of success. It's
not really the age of the woman which is the limiting
factor - it's the quality of her eggs.
- Men whose sperm count is very low.
Most clinics will consider doing IVF only for men
with at least 3 million motile sperm in the ejaculate.
If the sperm counts are lower than this, then ICSI
( or microinjection ) is a better option.
- Women with a damaged uterus ( for
example, because of healed tuberculosis ) because
the chance of successful implantation of the embryo
in the uterus becomes very poor.
- It is also not advisable to go in
for IVF treatment without trying simpler treatment
options first. IVF is a complex procedure involving
considerable personal and financial commitment, so
other treatments are usually recommended first.
How is superovulation performed
?
During superovulation , drugs are used to induce the
patient's ovaries to grow several mature eggs rather
than the single egg that normally develops each month.
This is done because the chances for pregnancy are better
if more than one egg is fertilized and transferred to
the uterus in a treatment cycle. Depending on the program
and the patient, drug type and dosage varies. Most often,
the drugs are given over a period of nine to twelve
days. Drugs currently in use include : Human Menopausal
Gonadotropin (HMG) , Follicle Stimulating Hormone (FSH)
, Human Chorionic Gonadotropin (HCG ) and gonodotropin
releasing hormone (GnRH) analog .
Today, most IVF programs use GnRH analogs
( such as Lupron or Buserelin) in combination with gonadotropins
during ovulation enhancement. Treatment with the analogs
prevents the release of FSH and LH from the pituitary
gland during treatment
( "pituitary downregulation") and thereby prevents premature
ovulation. This therefore gives the doctor much more
control over the superovulation phase, because we can
then grow eggs to suit our convenience, as we have taken
over control of the cycle. Patients are often confused
as to why we need to suppress the pituitary hormones
when we are trying to grow lots of eggs. Remember that
the GnRH analogs suppress the pituitary, and have no
direct effect on the ovary, so that they do not suppress
egg production. GnRH analogs can be used either
in the form of a long protocol ( when they are started
from Day 21 of the previous cycle) ; or as a short protocol
( when they are started from Day 1 of the cycle). Another
option is to use the newer GnRH antagonists ( such as
Antagon or Cetroride), which can selectively suppress
the LH surge, and it is hoped that these may provide
better control. However, the pregnancy rates with these
are no better.
How is superovulation monitored
?
An ultrasound scan is done on Day 3,
to confirm that there are no cysts in the ovary, and
that downregulation has been achieved. A blood test
for estradiol can also be done, to ensure that the ovaries
are quiescent and downregulated, and the result should
be less than 50 pg/ml. The HMG injections for superovulation
are then started from Day 3. The dose of HMG used needs
to be individualized for each patient., and depends
upon the antral follicle count and ovarian morphology.
Our standard dose is 225 IU daily for patients less
than 35; 300 IU daily for patients more than 35; 450
IU daily for poor responders; and 150 IU daily for patients
with PCOD.
Timing is crucial in an IVF treatment
cycle, in order that the doctor recover mature eggs.
To monitor egg production, the ovaries are scanned frequently
with vaginal ultrasound, usually on a daily or alternate
day basis from Day 10 onwards. Blood samples are also
drawn in some clinics, to measure the serum levels of
estrogen , and sometimes luteinizing hormone (LH). While
some clinics do this on a daily basis, we feel this
is very unkind to the patient, who often ends up feeling
like a pincushion ! For most patients, the ultrasound
scan provides enough information, and it is very rarely
that we need to do blood tests for our patients – we
try to be kind ! The dose of the HMG is adjusted, depending
upon the ovarian response.
By interpreting the results of the ultrasound,
we can determine the best time to harvest or remove
the eggs. Follicles usually grow at a rate of 1-2 mm/day,
and a mature follicle has a diameter of about 16-20
mm in size . Thus, if a patient has about 10 follicles
on ultrasound, of which the largest is more than 18
mm, we know that the follicles are mature and the eggs
are ready for retrieval. The endometrium should also
be examined carefully on the vaginal scan, and this
should be thick ( more than 7 mm, and have a triple
texture). Some clinics also measure the blood estradiol
level, to provide additional information, and each mature
follicle produces about 200-300 pg/ml of estrogen .
When the follicles are mature, we prescribe an injection
of human chorionic gonadotropin (HCG) to trigger ovulation.
The use of HCG allows us to control when ovulation will
take place – and this is 36 to 39 hours after the HCG
injection. This precise control allows the IVF team
to be prepared to harvest eggs just before that time.
The HCG simulates the woman's natural LH surge, which
normally triggers ovulation.
This is what a typical IVF treatment
protocol in our clinic looks like. Treatment starts
from Day 1 ( the day the bleeding starts) of the cycle.
At this time, we downregulate by starting Inj Buserelin
( Suprefact, GnRH analog mfr by Hoechst), 0.5 ml sc
daily . On Day 3, we do an ultrasound scan to confirm
there is no ovarian cyst, after which we start superovulation
with 3 ampoules ( 225 IU) of HMG (Menogon) daily. The
dose of HMG will
depend upon the ovarian morphology and the antral follicle
count.
We do the next scan on Day 10, after which we do scans
every alternate day, to monitor follicular growth.
This is what the daily schedule would look like.
Day 1. Inj Buserelin, 0.5 ml sc. ( Downregulation starts)
Day 2. Inj Buserelin, 0.5 ml sc.
Day 3. Inj Buserelin, 0.5 ml sc. Vaginal ultrasound
scan to confirm there is no ovarian cyst. If there is
no cyst, we can commence superovulation. If there is
a cyst larger than 30 mm, we can aspirate it and continue
with treatment.
Day 4 Inj Buserelin, 0.5 ml sc. Inj Menogon ( 75 IU),
3 amp IM. Superovulation starts.
Day 5 Inj Buserelin, 0.5 ml sc. Inj Menogon ( 75 IU),
3 amp IM
Day 6 Inj Buserelin, 0.5 ml sc. Inj Menogon ( 75 IU),
3 amp IM
Day 7 Inj Buserelin, 0.5 ml sc. Inj Menogon ( 75 IU),
3 amp IM
Day 8 Inj Buserelin, 0.5 ml sc. Inj Menogon ( 75 IU),
3 amp IM
Day 9 Inj Buserelin, 0.5 ml sc. Inj Menogon ( 75 IU),
3 amp IM
Day 10. Inj Buserelin, 0.5 ml sc. Inj Menogon ( 75 IU),3
amp IM.
Vaginal ultrasound scan to monitor follicular growth
The Buserelin and Menogon injections will continue on
a daily basis; and scans will be performed every alternate
day, until the follicles are mature. This is usually
Day 14- Day 16 for most patients. At this time, an HCG
injection will be given, and eggs retrieved 36 hours
after this.
With older forms of superovulation regimes using clomiphene
and HMG, the treatment cycle was cancelled in roughly
one quarter of the IVF cycles. One of the reasons for
this was that some of these women had a premature ,
spontaneously occurring LH surge with resulting premature
spontaneous ovulation . When this happened, the follicles
ruptured prior to egg collection, and the eggs were
lost in the pelvic cavity, as a result of which they
could not be retrieved. While spontaneous LH surges
are very rare with the use of GnRH analogs, we still
need to cancel cycles in about 10 % of patients.
When may an IVF cycle be
cancelled ?
The commonest reason for canceling a
cycle today is a poor ovarian response. If patients
grow less than three follicles, and if the estradiol
level is low, the chances of a pregnancy are poor, and
patients may decide to abandon the cycle. The problem
of a poor ovarian response is commoner in older women
and in women with elevated FSH levels, and these can
be difficult patients to treat ! Patients who have a
poor ovarian response during IVF treatment are often
very upset, because this is not something they ( especially
if they are young) are mentally prepared for. Most young
women expect to grow a lot of eggs, and are shattered
when they don’t do so. However, remember that this is
not the end of the road – it simply means that the superovulation
regime will need to be modified for the next treatment
cycle. The doctor may need to increase the dose of HMG
in order to grow more follicles, and this is often helpful
for young women.
The other reason to cancel a cycle is
when patients grow too many follicles ! These are usually
patients with PCOD; and if there are more than 25 follicles,
or if the level of the estradiol is more than 6000 pg/ml,
many clinics will cancel the cycle, because the risk
of ovarian hyperstimulation syndrome ( OHSS) is very
high. An alternative option is to go ahead with egg
collection, and freeze all the embryos. This allows
the doctor to salvage the cycle; and if the embryos
are not transferred, the risk of OHSS is reduced. The
frozen embryos can then be transferred later, giving
the patient a good chance of achieving a pregnancy.
In our clinic, however, we do not need to cancel these
cycles. This is because we use a special technique during
egg collection with a double lumen needle, which allows
us to remove all the granulosa cells from each follicle
at the time of egg retrieval, by flushing each follicle
meticulously. Since these cells are the ones responsible
for producing the chemicals which cause OHSS, by removing
them we reduce the risk of our patients getting OHSS
dramatically !
continued
. . .
Next page: Test
Tube Babies - IVF & GIFT (Page 2)
Previous page:
Intrauterine Insemination (IUI)
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