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In-Vitro Fertilization, or IVF, is a process designed to
help women achieve pregnancy. There may be many reasons why a
couple are unable to become pregnant, and a thorough investigation
of both partners is appropriate before making any decisions about
treatment.
The first baby born through IVF was Louise Brown, through the
pioneering efforts of Drs Steptoe and Edwards, in 1978. Originally,
IVF was designed to help women with tubal disease, but today IVF
is able to help couples with many different problems achieve a
healthy pregnancy.
Before explaining IVF it is important to have a basic understanding
of the female menstrual cycle.
The
Normal Menstrual Cycle
Women are born with a finite number of eggs. The ovaries
are not like the testes in men. The testes are like sperm factories
that continue to make fresh sperm all the time. The ovaries are
more like “banks” of eggs. The ovaries are not autonomous (self-regulating),
and need to be stimulated to function.
The ovaries are controlled by a hormone called FSH (follicle stimulating
hormone) produced in the brain. At the start of each menstrual
cycle the brain releases FSH and, in response, a number of eggs
are “recruited” or withdrawn from the “bank”. These eggs start
maturing and each egg grows in a capsule of fluid called a follicle.
A follicle is, in fact, a small cyst. Although many many eggs
start on this journey, within a couple of days most will die and
disappear, and only one or two will continue to grow and mature.
As the follicles grow they release a hormone called estradiol
(estrogen). When the egg is almost mature, the rising estrogen
level signals the brain to release a hormone called luteinizing
hormone (LH). This hormone triggers ovulation, and it can be detected
in a woman’s urine the day before she will ovulate. LH is the
hormone that is detected by ovulation predictor kits.
Around the time of ovulation, the rising estrogen levels act on
the mucus at the cervix, making it stringy – like the white of
an egg. Normally the cervical mucus is thick, and is designed
to prevent any bacteria from getting in to the uterus from the
vagina. The estrogen makes the mucus sperm-friendly so that the
sperm are able to penetrate through the mucus and get into the
uterus and then on to the fallopian tubes.
After ovulation the egg is picked up by the many tiny finger-like
structures at the end of the fallopian tube called fimbria. A
sperm will then fertilize the egg in the upper part of the tube.
A fertilized egg is called a zygote and then, once it starts to
divide, an embryo. The early embryo spends 3–5 days in the tube
before it reaching the uterus where it will then implant in the
uterine lining (the endometrium) and begins to grow.
What
Happens in an IVF Cycle
During
IVF you are given medications which manipulate your ovaries and
the eggs being produced. The idea is to try and get several eggs
to mature, not just one or two. The follicles where the eggs are
developing can be monitored by ultrasound and by measuring your
estrogen levels.
ULTRASOUND IMAGE OF OVARY CONTAINING FOLLICLES
When the eggs are mature, they are taken from the ovaries (using
a fine needle which is passed through the vagina under ultrasound
guidance) and handed to the embryologist. The eggs are then fertilized
with your partner's sperm (or, in some instances, donor sperm).
The fertilized eggs (embryos) are then cultured under very strict
conditions and examined each day by the embryologist to assess
their progress. On the third day the embryos are assessed by the
embryologist and a meeting is then held to discuss them. At this
meeting we decide how many to replace inside the uterus (by a
second procedure called an embryo transfer).
Sometimes more than one embryo will be transferred, and sometimes
the other good quality embryos will be suitable for freezing for
your later use. Our aim is to enhance the chances of pregnancy
but limit the risk of multiple pregnancies.
Multiple
Pregnancies
Although most couples are happy to accept a risk of twins,
it is important to know that even twins carry significant risks
(e.g. premature delivery, developmental abnormalities, toxaemia,
gestational diabetes, etc, etc). So although in most cases the
outcome with twins is good there are significantly increased risks
of problems over “singletons”.
Higher order multiple pregnancies such as triplets and quads carry
extremely high risks – and we do everything we can to avoid these.
If a pregnancy does occur with triplets or more we would encourage
you to consider a selective reduction. This is a procedure done
at 10–11 weeks’ gestation, whereby the number of fetuses is reduced
to twins. It is like an amniocentesis, and does carry a risk –
about 5 % – that the whole pregnancy could be miscarried. Ideally
we try and avoid this scenario, which is upsetting to everyone.
Preparation
for an IVF Cycle
In order to optimize results we recommend that you pay particular
attention to both your physical and mental health both before
and during the treatment phases. Both men and women are advised
to stop smoking and drinking alcohol prior to treatment. We also
recommend that women stop all caffeine as soon as they start medication
and stay off it until the first pregnancy test. If pregnancy occurs
we recommend no caffeine until 12 weeks’ gestation.
Optimal weight is very important, and being underweight or overweight
can adversely influence the success of a cycle. The ideal body
mass index (BMI) is between 20 and 25, and a BMI over 30 will
both significantly reduce the chances of conception and increase
the chance of miscarriage.
It is recommended that all women considering pregnancy take a
prenatal supplement containing folic acid for at least a month
or more before pregnancy, and then throughout the pregnancy. Materna
is a popular prenatal vitamin. Folic acid has been shown to reduce
the incidence of spina bifida and the ideal amount of folic that
should be taken daily is 1 mg. Women in certain high-risk groups
may need a higher dose to achieve the same protection. These include:
- Women who are overweight
- Diabetics
- Women who have had a child with spinal bifida, or who have a relative
with spinal bifida
- Certain racial groups including Sikhs and women from some European
countries such as Wales
- Women who take anti-epileptic drugs
These groups of women are recommended to take 4 mg of folic
acid daily.
You might be taking prescription drugs. Please make sure that
you have discussed these with VFC before starting IVF treatment.
It is important to keep physically fit, although we would
recommend that you moderate your exercise before an IVF cycle.
The
Treatment Cycle - What to Expect
Although
what follows is a "typical" approach – every treatment
is individualized and this is therefore just an example.
Step 1
- History, physical examination, blood tests, sperm functional assessment,
pelvic ultrasound
- Possibly hysteroscopy/laparoscopy
- Consultation with our reproductive psychologist
- Setting an individually-designed treatment plan
- Clinical orientation at VFC (with one of our Clinical Co-coordinators)
to explain your treatment plan and make sure that you understand
how to give injections and take medications
Step
2
- You maybe asked to take the birth control pill (the “Pill”) for
approximately 3 weeks. This suppresses the ovaries and the uterine
lining (puts them to sleep). It also suppresses other hormones
which in certain circumstances has a positive effect on outcome
- While on the Pill you will be asked to come to VFC for a Mock Embryo
Transfer. You will be given an instruction sheet about this
process. The reason for the Mock Embryo Transfer is to check
that there will not be any problems transferring the very delicate
embryos into your uterus.
Step
3
- After being on the Pill for 2 weeks, you will be started on a drug
called a GnRH analogue. The commonly-used ones, Suprefact and
Lupron, are given by injection once a day, preferably in the
morning. This drug suppresses the pituitary gland in the brain,
which prevents it releasing FSH and LH. This means that we can
take complete control of the ovaries and uterus without any
interference from the brain
- After being on the GnRH analogue for 7–10 days, you will be asked
to stop the Pill – but you will continue to take the GnRH analogue.
After stopping the Pill you will have a bleed (this is the lining
of the uterus shedding).
- You will then have an ultrasound to check that the ovaries are “suppressed”,
i.e. that there are no follicular cysts on them. You will also
have a blood test to check your estradiol level
- If everything looks good you will be ready to start the stimulation
phase of your cycle
Step
4: Stimulation Phase (ovulation induction)
- You will continue with your GnRH analogue, aspirin and prenatal
supplement
- You will be started on injections of gonadotrophins, FSH and LH,
to stimulate your ovaries. The names of the commonly used drugs
are: Gonal F, Puregon and Repronex (although there are others).
During your orientation session you will have been taught how
to mix and inject these hormones
- After approximately 7 days of stimulation you will have an estradiol
(blood test) and ultrasound. The dosage of your gonadotrophin
drugs might be adjusted at this stage
Step
5: The Follicles Are Ready
- When the follicles reach a certain size and your estradiol levels
are right you will be ready for “triggering”. At this stage
you will be asked to stop the GnRH analogue and FSH/LH (gonadotrophin)
injections. You will be told then when to have an injection
of another drug called hCG (trade names are Profasi or Pregnyl).
The hCG “matures” the eggs and makes them ready for retrieval
- You will also be asked to start taking an antibiotic called Doxycyline.
You will take this twice a day until the day of your embryo
transfer taking the last dose of Doxycycline that evening.
- Your egg retrieval will be scheduled for exactly 36 hours after
this injection
Step
6: Egg Retrieval
- You will be asked to do the following the day before your egg retrieval:
-
Have
a normal supper the night before retrieval, but nothing
to eat after midnight
-
Continue
to take the antibiotics as directed.
-
On
arrival, you will be asked to empty your bladder and change
into a nightgown
-
You
will then be given acupuncture for half an hour. This helps
you relax, and also helps control the discomfort during
the egg retrieval
-
After
the acupuncture you will be introduced to the RN (Registered
Nurse) who will assist with your procedure. The RN will
take you through to the Procedure Room, an intravenous line
will be started, and you will be hooked up to an ECG and
Oxygen Saturation Monitor
-
Your
legs will then be positioned in stirrups – just like when
you have a Pap smear
-
A
speculum will be introduced in to the vagina so that it
can be cleaned thoroughly with sterile saline. Local anesthetic
is then injected in to the vagina wall
-
During
this time you will be given some medications called Fentanyl
and Midazolam to control discomfort. These drugs will make
you feel drowsy and relaxed. You will also be given an intravenous
antibiotic to reduce the risk of infection
-
A
vaginal ultrasound probe is then inserted into the vagina.
A needle is passed alongside the probe, through the vagina
wall into the ovaries, and the follicles are aspirated and
their fluid collected in test tubes. The fluid is immediately
examined by our embryologist. The eggs are identified, placed
in culture medium and stored in an incubator. This whole
procedure takes about 15 minutes
-
At
the end of the procedure the probe is removed and you will
rest until you are ready to go through to the Recovery Room.
There you will rest until you feel ready to go home. During
this time you will be offered a drink and some cookies
-
You
will need to be escorted home by your partner or a friend.
You must not drive for 24 hours after egg retrieval
-
After
your egg retrieval, unless you are using frozen/donor sperm,
your partner will be asked to produce a fresh semen sample
at VFC
-
The
sperm are then washed and prepared in the laboratory by
our embryologist
-
The
eggs are then inseminated either by mixing the sperm and
eggs together (standard IVF) or by ICSI (ICSI stands for
Intracytoplasmic sperm injection and involves injecting
a single sperm into each egg). ICSI is performed only if
we have concerns about the sperm and their ability to fertilize
an egg. In either case, fertilization actually occurs several
hours later
-
After
egg retrieval you will be asked to start your progesterone
to prepare the uterine lining for the embryo transfer which
will take place on the third day after the egg retrieval.
Progesterone is usually given in one of two ways:
a. Prometrium: This comes in 100mg tablets
which are inserted in to the vagina. The usual dose is 200
mg (2 tablets) 3 times daily
b. Progesterone in oil: This is given by intra-muscular
(“IM”) injection, the usual dose is 50 mg per
day. These injections might need to be given at VFC –
or by your family doctor – daily
Step
7: The Short Wait....
This
is the 3-day period between egg retrieval and embryo transfer.
- The day after egg retrieval you will be telephoned to tell you how
many eggs have fertilized. The fertilized eggs (zygotes) are
cultured under carefully controlled conditions for 3 days. Zygotes
should divide into 2 cells later on the first day and are then
called embryos. On the morning of the second day the embryos
should have 4 cells each, and 8 cells by the morning of the
third day
- During these three days you may do everyday activities – but you
will be asked to refrain from
- Intercourse
- Swimming or hot tubs
- Coffee and alcohol
- You should continue with your prenatal vitamins. You should continue
with the progesterone preparation until told otherwise
Step
8: Day 3 – The Embryo Transfer
- On the day of embryo transfer you will be asked to come to VFC at
the specified time
- You should drink 2 glasses of water an hour before your transfer
– ideally we would like your bladder to be half full but not
uncomfortable
- We will discuss the embryos, their quality and confirm how many
to transfer and freeze
- You will be shown to the Procedure Room, and given acupuncture for
30 minutes
- An ultrasound will then be done to check how full your bladder is
- When ready, your legs will again be placed in some stirrups, a speculum
introduced into the vagina and the cervix cleaned with saline
- With an ultrasound probe on your tummy a fine catheter will then
be passed through your cervix and the embryo(s) injected in
to the uterus
- You will then be asked to lie quietly for at least 20 to 30 minutes
- After this you will be allowed to go home. You should rest quietly
for the rest of the day – but don’t worry, the embryos won’t
fall out
Step
9: The Long Wait....
This is the 12-day wait between your embryo transfer and
the expected date of your next period (which hopefully won’t come
for many months!).
- You will be instructed to continue with the progesterone and prenatal
vitamins – and any other medications that might be necessary
- You will be given a requisition to have a pregnancy test on a specified
date.
During this time we would encourage you to:
- Avoid intercourse
- Restrict exercise to everyday activities only
- Get lots of rest
- Think positively!!!
Expectations
It
is important to be well-informed and have realistic expectations.
Some important points are:
- Not every follicle contains an egg. So, if for example 10 follicles
were identified by ultrasound prior to retrieval, it would be
realistic to hope for 5 – 7 eggs
- The number and quality of eggs can also be predicted to some extent
by the levels of estradiol
- Not every egg is good quality – so not every egg fertilizes. We
expect a fertilization rate of about 80%
- Not every fertilized egg develops into a perfect embryo
- On Day 3 our embryologist assesses the embryos according to very
strict criteria to help us decide which embryos to choose for
transfer
- Not every embryo that is not transferred is suitable for freezing.
Poorer quality embryos are unlikely to survive freezing and
thawing – and may be discarded
- The table below gives some idea of IVF/ICSI cycles
for average patients
Schematic
Summary of an IVF Cycle
Birth control pill for 2 weeks
–
Add Suprefact – and
continue the Pill – for 1 week
–
Stop the Pill – continue
Suprefact
Expect vaginal bleed
– continue Suprefact only
–
Ultrasound and estradiol
(blood test)
If satisfactory, start
HMG (Gonal F, Puregon, Repronex)
–
After 7 days of HMG,
repeat ultrasound and estradiol
Further monitoring until
follicles are “ready”
Trigger with hCG (Profasi
or Pregnyl)
–
Egg retrieval – Fertilization
– Embryo culture
–
Embryo transfer
–
Pregnancy test
Risks and Possible Complications Related to Superovulation and IVF/ICSI
1.) Cancelled Cycles
A cycle might be cancelled for a variety of reasons, the most
common of which are either an under- or over-response to the fertility
drugs. We do our best to predict the ovaries’ likely responses
to the fertility drugs, and choose a dosage that is most appropriate
to your individual characteristics. The ovaries are assessed pre-IVF
by doing a Day 3 FSH level, and by examining them using ultrasound.
Your weight and age are also important considerations.
Older women, elevated FSH levels, and previous poor response
to stimulation are all factors that may predict a poor response
to these medications. In these situations, a protocol will be
selected to try and get the most from your ovaries. However, sometimes
there is such a poor response that the cycle has to be abandoned.
On the other hand, sometimes the ovaries over-respond. Women
at risk for this are those with polycystic ovarian syndrome (PCOS),
and women who are overweight and not menstruating regularly.
One of the potential complications from over-responding is
a condition called ovarian hyper-stimulation syndrome (OHSS).
This is a potentially dangerous condition that results from the
estrogen levels being too high. This causes the membranes between
fluid compartments in your body to become too permeable, resulting
in fluid leaking into body cavities such as the peritoneal cavity
(abdomen) and the pleural spaces (chest, around the lungs). OHSS
also tends to result in the fluid volume in your blood vessels
(the “intravascular volume”) falling, leading to a hypercoagulable
state – in other words, you may be more prone to blood clots and
stroke.
There are several ways to identify
this condition (OHSS), and precautions that can be taken to prevent
serious complications. If, during the stimulation phase of the
cycle, too many follicles start growing, and the estrogen levels
get too high, different options become available. This situation
usually only becomes dangerous if the hCG is given, or if pregnancy
occurs. The different options include:
-
Coasting – stopping the FSH drugs and waiting for the estrogen
levels to come down before giving hCG.
-
Retrieving and fertilizing the eggs, but then freezing all the
embryos for later use; so that pregnancy will not occur until
the ovaries and estrogen levels have had a chance to settle
down.
-
Cancelling the cycle completely.
Common symptoms associated with OHSS include bloating, nausea,
abdominal pain, shortness of breath, vomiting and low urine
output. Many cases are mild and respond to simple measures
such as fluid manipulations.
2.) Surgical Complications from the Egg Retrieval
Potential
complications from this procedure include the following:
These are all very uncommon.
3.) Ovarian Complications
After
IVF the ovaries become swollen and tender. They can be very uncomfortable
and can occasionally twist or bleed. Very rarely it might be necessary
to do a surgical procedure to untwist them or stop them bleeding.
4.) Multiple Pregnancy
It is our duty to do the very best to achieve pregnancy while
also reducing the risk of multiple pregnancy. Even twins carry
significant risks, some of which are listed below:
-
Increased social or domestic stress with child raising.
-
Increased chance of premature delivery, with all the associated
risks such as cerebral palsy, learning disorders, low birth
weight, congenital anomalies, etc.
-
Increased pregnancy risks, such
as toxaemia (high blood pressure), gestational diabetes, anaemia,
operative delivery, miscarriage, post-partum bleeding, etc.
Some of the ways to reduce the risks of a multiple pregnancy
include:
5.) Long-term Risks of Cancer
There have been concerns raised over the years that there might
be long-term cancer risks associated with the use of fertility
drugs.
One study in Washington State revealed that an unusual number
of women with cancer had used a fertility drug called Clomiphene.
However, subsequent studies that have been done are more, reassuring.
There are many other factors that might be associated with an
increased risk of ovarian cancer, one of which is infertility
itself.
Recently, some studies have suggested a possible increase in the
risk of breast cancer associated with the use of FSH (e.g. Gonal
F, Puregon, Repronex), although once again the findings across
all relevant studies are inconclusive.
At this present time the Cochrane review does not support an association
between IVF, Fertility drugs and breast or ovarian cancer.
The bottom line is that there may be a risk, and these drugs should
be used responsibly, on each occasion maximizing the chance of
a pregnancy so as to reduce long-term (repeated) exposure.
6.) Risks of IVF and ICSI to Children
So far, the studies done looking at children born after IVF and
ICSI have been very reassuring. There is some evidence that children
born after IVF/ICSI might have a slightly lower birth weight than
children conceived naturally.
Recent evidence suggests that there might be a slightly higher
risk of congenital abnormalities in children born after ICSI,
but not IVF. It should be remembered that all babies born (i.e.naturally
conceived babies) have a 4–6% risk of some form of congenital
abnormality. These should not be confused with the genetic problems
that increase with maternal age. Common congenital abnormalities
include such things as club foot, cleft palate, extra digits,
hernias, etc, which are not related to maternal age. However,
it must also be remembered that babies born after IVF and ICSI
are far more carefully scrutinized than babies conceived naturally.
Nonetheless, it is important that you are aware that there is
a likelihood that a male sperm problem, if it is something you
were born with, will probably be transmitted to your sons via
the Y chromosome.
Having said all this, for the most part, the information available
is reassuring.
7.) Miscarriage
Miscarriage can occur in up to 10–20% of pregnancies, depending
on maternal age. The rate of miscarriage may be higher with IVF/ICSI
than in natural conception cycles, although this could be influenced
by personal history and health. There may also be an increased
risk of ectopic pregnancy, especially if there is a history of
damaged fallopian tubes.
Dealing With Bad News – A Failed Cycle or Obtaining Fewer Than Expected
Eggs or Embryos
Unfortunately, one has to be realistic about IVF success rates. It
is recommended that dealing with a failed cycle be discussed beforehand,
and that plans are made for receiving the pregnancy test result
on the appointed day. A failed cycle often leave women with feelings
of frustration, sadness and even despair. This is why we encourage
all our patients at VFC to meet with our reproductive psychologist
at the start of a treatment cycle.
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