Test Tube Babies - IVF & GIFT
from the book How to Have a Baby:
by Dr. Aniruddha Malpani, MD and Dr. Anjali Malpani, MD.
table of contents
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Success Rates - Making Sense of the Figures
The most important question most patients have about IVF and GIFT is : What
are my chances of getting pregnant ?
This is a difficult question to answer, since there are so many variables
involved. Chances of success depend upon:
- the wife's age - chances decline with increasing age - precipitously so
over the age of 40
- the reason for the IVF / GIFT - chances of pregnancy decline when IVF is
done for male factor infertility
- the quality of the IVF Clinic and its services
- the number of embryos/eggs transferred
- the superovulation regime used
Of course, there are some variables about which nothing can be done - such as
the wife's age. But other variables can be controlled to try to maximize chances
of a pregnancy ! The good news is that with improving IVF technology, pregnancy
rates with IVF have increased dramatically.
Pregnancy rates are related directly to how many embryos are transferred. For
example, when 3 good quality embryos are transferred, the chance of pregnancy is
about 40% in that cycle. The number of embryos transferred needs also to be
balanced against the risk of multiple pregnancy, which naturally increases with
more embryos. With this in mind, the Fertility society of Australia recommends
that no more than 3 embryos be transferred during any treatment cycle. Studies
done the world over show that the average pregnancy rate per cycle for IVF is
about 30 % for most patients; and about 30% for GIFT. How can a patient
interpret this figure ? For example, let us consider a 30 year old patient with
irreparable tubal damage who goes through one IVF cycle. She can look at the
pregnancy rate figure of 30 %. in two ways . A success rate of 30 % means there
is an 70 % chance she will not get pregnant. On the other hand, if she takes no
treatment, her chance of getting pregnant is zero . The IVF cycle has increased
this to 30 % - no one can do any better than this today ! Of course, for the
couple who gets a baby, it's a 100% baby - and for the one who fails, it's 0% -
so for the individual patient, it's really not a question of statistics ! Each
IVF treatment cycle is a bit like taking a gamble - and you need to hope for the
best and prepare for the worst !
IVF and GIFT treatment should not be considered to be a single shot affair.
Patients should plan ( mentally at least !) to go through at least 3 to 4 cycles
to give themselves a fair chance of getting pregnant. With 4 treatment cycles,
the chance of getting pregnant ( the cumulative conception rate ) is about 70 %.
What this means, is that even though the chance of getting pregnant in a single
cycle may never be more than 40%, over 4 cycles, the chances increase to 70%
because the success rate is cumulative. Thus, let us assume the pregnancy rate
for IVF at a clinic is 30%. If 10 patients start an IVF cycle, 3 will get
pregnant, leaving 7 patients. If these 7 do another IVF cycle, another 30% ( 2.1
patients - so let's say another 2) will conceive. If the remaining 5 do another
cycle, 1 more will get pregnant; and at the end of the 4th cycle, 1 more will
conceive; so that of the 10 patients who started, 7 will have got pregnant in 4
attempts. This is because the chances of getting pregnant in the next IVF cycle
do not decrease just because a pregnancy has not occurred in the previous cycle
- so the best bet would be to keep on trying. Theoretically, we could reassure
every couple taking IVF treatment that they would get pregnant - provided they
were willing to go through as many cycles as were required, till they hit the
jackpot ! Of course, one has to set a limit somewhere, and the decision when to
stop is something which only the couple can make for themselves . After more
than 6 failed IVF cycles, the chance for a pregnancy with IVF does decline.
Games IVF Clinics Play with Pregnancy Rates
Of course, some clinics have much better pregnancy rates - and others much
worse. Nevertheless, many clinics will quote inflated rates - and this can
mislead patients ! Unfortunately, in India there is no central registry or
monitoring of IVF clinics, so that you pretty much have to trust what the doctor
tells you. In many countries in the West, the law mandates that IVF clinics
provide their pregnancy rates to a central authority - thus ensuring that IVF
clinics maintain high standards and quality control. This is very helpful for
Different programmes define success in various ways. To most couples, success
is a baby, not a pregnancy - so that what needs to be determined is the
"take home baby rate" . Some clinics quote pregnancy rates when
describing their success rates - and these can be considerably higher than the
live birth rate , depending upon how a pregnancy is defined. Thus, some programs
define pregnancy when the pregnancy test is positive; others define pregnancy as
a fetus seen on ultrasound.
So called biochemical pregnancies are also fairly common after IVF. These are
pregnancies confirmed by blood and urine tests but in which the embryo does not
develop beyond the earliest stage. No gestational sac and no fetus is seen on
ultrasound examination. Counting biochemical pregnancies will, of course,
inflate the pregnancy rate.
Other ways of juggling with pregnancy rates include: accepting only patients
who have a good chance of getting pregnant, or selectively reporting pregnancy
rates achieved in younger women ( and excluding other patients from data
Most good programs today express their pregnancy rate as the number of babies
born per treatment cycle, and this is the figure you should be looking at.
IVF technology is improving by leaps and bounds and many exciting advances
have taken place recently. Many of these are now available in India, and these include the following.
One of the major problems with IVF today is the low pregnancy rate after
successful embryo transfer. The reason why such few embryos implant successfully
(only 1 of 10 embryos will become a baby) is one of the things we really do
not understand today. Dr. Cohen from New York believes this is because the
surrounding shell of the embryo (called the zona pellucida) hardens when it is
cultured in the laboratory. They therefore use "embryo surgery" called
zona drilling or assisted hatching to "soften" the shell of the
embryo, and they believe this helps to increase pregnancy rates by improving
implantation rates, since embryo hatching is facilitated. This can be done using
an acid (acid Tyrode’s) or with a laser.
Fig 8. Assisted hatching. The embryo is held securely, and a carefully
controlled stream of acid is blown through a fine pipette in order to drill a
hole in the zona (shell).
Embryo surgery has also been used for embryo biopsy, for preimplantation
genetic diagnosis, in which single cells are removed from the developing embryo,
to make sure the embryos are healthy and have no genetic disease. This is
described in more detail in Chapter 26.
Embryo multiplication, by removing some of the cells from the embryo and
allowing them to divide, can allow doctors to "multiply" the number
of embryos formed in vitro. The new embryos can then be coated with a new shell
( zona) and then transferred into the uterus. This could help to increase the
chances of pregnancy is women who can produce only a small number of embryos.
Other scientists feel that the reason for the poor implantation is the poor
quality of the embryo cultured in vitro. They have therefore tried to improve
embryo quality in the laboratory by trying to provide it with more natural (
"physiological") culture conditions. This is done by a method called
co-culture in which the embryo is cultured along with "feeder cells"
in the culture dish . These cells provide the embryo with the extra nourishment
they need for better growth. Better pregnancy rates are claimed with co-cultured
embryos as compared to embryos grown under traditional IVF conditions.
Some patients going through IVF grow lots of eggs, but persistently form poor
embryos which fail to implant. In some of them, this may be because they have a
problem in their cytoplasm ( the area within the shell of the egg that lies
outside of the nucleus ) - either in their mitochondria or the cell-division
apparatus . Dr Cohen hypothesised that it should be possible to correct this
problem by replacing just the cytoplasm of the egg, instead of the whole egg,
thus keeping the mother's own genetic contribution ( the DNA contained in the
nucleus) to the baby intact. This high-tech method is called cytoplasmic
transfer, and uses cytoplasm donated from the healthy eggs of another woman.
The formulation of new laboratory culture media - the liquid in which the
embryo is grown in vitro - has made it possible to "grow" embryos in
vitro beyond the typical 2 to 3 day state of development , till they become
blastocysts. A blastocyst is the final stage of the embryo’s development
before it hatches out of its shell (zona pellucida) and implants in the uterine
wall.. Initial studies suggest that transfer of the embryo on day 5, at the
blastocyst stage, may yield higher pregnancy rates. There may be two possible
reasons for this. Firstly, transfer of the blastocyst to the uterus may be more
physiologically appropriate , since this mimics nature more closely, so that the
implantation rate may be higher. Also, waiting till the blastocyst stage allows
the doctor to select the "best " embryos, since unhealthy embryos are
likely to die ( arrest) before they reach this stage. Blastocyst transfer also
significantly reduces the possibility of potentially dangerous high-order
multiple births, such as triplets. Higher implantation rates allows doctors to
transfer fewer blastocysts - perhaps only one - reducing or avoiding multiple
births and their associated problems. Supernumerary blastocysts can also be
successfully cryopreserved with resulting pregnancies after thawing.
While blastocyst transfer is a very promising advance for patients who grow
lots of eggs ( good ovarian responders), its utility for the difficult patient -
the poor ovarian responder - is still debatable. This is because if there are
few eggs, there is a very real risk that none of them may develop to the
blastocyst stage. All of them may "arrest", so that there are no
embryos available for transfer. Every patient needs to balance these risks and
benefits , depending upon the clinic’s experience and success rate.
Fig 5. A beautiful blastocyst on Day 5.
Some people might ask whether all this is relevant to Indian conditions.
While these technologic refinements are very exciting, IVF clinics in India
should also focus on simplifying IVF technology - so that it can be made more
affordable for the average Indian couple. Advances which have occurred which
have helped to simplify IVF and make it more easily available include the
Intravaginal culture: This is a technique for IVF , which provides the same
rate of fertilization which conventional IVF does, at a fraction of the cost. In
this method, which was first described by Dr. Ranoux of France in 1984, the eggs
and sperm are placed in a sterile vial which is then sealed and placed in the
woman's vagina. Thus, the woman acts like her own incubator, since she keeps her
eggs and embryos at body temperature. Since expensive laboratory equipment is
not needed, this is much cheaper - and as effective as conventional IVF !
Natural cycle IVF: Natural cycle IVF is much less expensive because it does
away with the high expense of gonadotropin injections used for superovulation.
In this method, the single egg which the woman grows in her unstimulated
ovulatory cycle is used for IVF. While the pregnancy rate is lower, the expense
(and the stress of IVF) is much less ! Interestingly, "gentler" IVF is
becoming increasingly popular in the West as well. Many doctors are very
critical of the large amounts of hormones which are being used in traditional
IVF in order to produce large quantities of eggs. Gentler ovarian stimulation (
using only clomiphene or smaller doses of HMG) has also become popular once
again, since it reduces the risks of complications, such as ovarian
hyperstimulation and multiple pregnancy.
Transport IVF: Transport IVF is a recent innovation pioneered in the
Netherlands; and by Dr. Kingsland of UK. In this, the egg retrieval is performed
by the gynecologist in his own clinic or hospital; and the eggs ( in the
follicular fluid) are then transported to a central IVF laboratory by the
husband in a portable incubator . Insemination, fertilization and embryo
transfer take place in the central laboratory. This method allows gynecologists
to take an active part in their patients' treatment; ensures high quality, since
all laboratory procedures are performed in a central laboratory; and also
minimizes patient inconvenience ( since superovulation and egg retrieval are
done by the local gynecologist, the number of visits the patient has to make to
the IVF Center are minimized.)
Donor Sperms, Donor Eggs and Donor Embryos
[continued on next page]
by Dr. Aniruddha Malpani, MD and Dr. Anjali Malpani, MD.
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