Test Tube Babies - IVF & GIFT
from the book How to Have a Baby:
by Dr. Aniruddha Malpani, MD and Dr. Anjali Malpani, MD.
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The birth of Louise Brown through in vitro fertilization (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 !
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
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, 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 !
Tests prior to IVF
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
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
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
- 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
- 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
The Basic Steps of IVF
Superovulation or Ovulation Enhancement
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 using GnRH analogs in combination with gonadotropins
during ovulation enhancement. Treatment with the analogs prevents the release of
FSH and LH from the pituitary gland during treatment ( "downregulation")
and thereby prevents premature ovulation. This therefore gives the doctor much
more control over the superovulation phase. 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, which can
selectively suppress the LH surge, and it is hoped that these may provide better
An ultrasound scan is done on Day 3, to confirm that there are no cysts in
the ovary. 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. Our standard dose
is 225 IU for patients less than 35; 300 IU for patients more than 35; and 150
IU 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 off ovulation. The use of HCG allows us to control
when ovulation will take place – and this is 36 – 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.
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.
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
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
[continued on next page]
by Dr. Aniruddha Malpani, MD and Dr. Anjali Malpani, MD.
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