I. Introduction
In vitro fertilization (IVF) and the related procedures of intra-cytoplasmic
sperm injection (ICSI) and
assisted hatching are collectively known as assisted reproductive
technologies
(ARTs). Each ART treatment is complex and may consist of many different
steps. You will feel much more comfortable with them if you take the
time to read the
following information carefully. When you are fully aware of the many
aspects of ART, you will know better what to expect at each step and
will have realistic
expectations. We no longer routinely offer gamete intrafallopian
transfer (GIFT) although in special cases it may be made available.
Even though many patients achieve pregnancy in their
first attempt, think of ART as an ongoing series of
treatments which, we
hope, will eventually allow you to conceive and deliver a healthy baby.
Depending on your age and diagnosis, it may take more than one attempt for you to conceive and
deliver a healthy baby.
In the course of your treatment you may meet other couples with similar
problems. We realize that infertility can be a very stressful and
frustrating
experience. It often helps to know that you are not alone and to share
your feelings.
II. Patient Selection
Couples are selected for ART on the basis of numerous causes of
infertility. Conditions requiring ART include:
- Absence, damage, scarring or blockage of fallopian tubes due to previous
inflammation or surgery
- Endometriosis
- Age-related infertility
- Unknown factors with an apparently normal evaluation
- Poor cervical mucus or cervical stricture (for example after
previous "cone"-type biopsy procedures)
- Male factor infertility (for example, low count, low motility, abnormal sperm
shape, no sperm in the semen, from obstruction of the male ducts)
One of the universal findings in reproductive medicine is the adverse
effect of ageing. For that
reason, with rare exceptions, we generally do not recommend initiating ART treatments in women
beyond their 43rd birthday if they use their own eggs. Older women are
sometimes excellent candidates for pregnancy using donated eggs.
The presence of a uterus and at least one functioning ovary is a
prerequisite for IVF.
With severe decreases in the sperm count, traditional IVF may be difficult if not
impossible. In most cases of severe male factor, however, excellent
fertilization rate can generally be achieved through ICSI.
III. Pre-Treatment Preparation
A. Initial Visit and Screening Tests
At the time of the initial consultation, the physician typically reviews
your history and medical records, performs a physical examination, and formulates a treatment
plan. Past
medical records, especially operative reports, results of semen analyses
and tests of ovulation (such as LH, FSH and progesterone tests) should
be sent to
our office well in advance of the initial visit.
If you have previously undergone ART at another program, please forward
detailed records for our review. A form for
release of medical information needs to be sent to each doctor who
tested or treated you for infertility in the past.
Screening blood and tissue tests are frequently ordered at the initial
visit. We sometimes test women for evidence of past exposure to
Chlamydia, the
microorganism most frequently responsible for tubal damage. If she shows
evidence of antibodies to Chlamydia, antibiotics may be prescribed
before treatment.
A hormonal profile of the thyroid, ovary, and adrenal glands is also
frequently obtained to tailor the stimulation regimen to the individual
patient.
Both partners will be tested for carrier status for hepatitis B
and C, the HIV viruses, and syphilis if they are likely to require ART.
Additional
tests may include rubella immunity, prolactin and thyroid hormone screening. As with all
tests, there are occasionally misleading results (false positive and
false negatives)
which may necessitate confirmatory testing. Repeat semen analysis is
frequently scheduled because most outside laboratories do not generally
test sperm as
broadly or strictly as we do. Patients usually receive a
vaginal ultrasound and frequently a hysterosalpingogram (HSG). We
frequently do in-office hysteroscopy in
order to evaluate the
pelvic anatomy as well. If one or both tubes are closed at the distal end (near
the ovaries, forming a stagnant fluid pocket called a hydrosalpinx)
removal of the
damaged tubes may be advisable, because closed, inflamed tubes may lower pregnancy
rates during IVF.
B. Injection Techniques
Shortly before the first treatment cycle the patient's partner or
designee needs to learn the technique of intramuscular and subcutaneous
injections. Materials demonstrating injection techniques are available
from the office and on the internet from some of the larger
pharmaceutical companies (www.fertilitylifelines.com
and www.fertilityjourney.com ). One of the
nurses may supervise
your first injection at which time additional questions can be answered.
Please make sure that you have medications well in advance of starting a
treatment cycle. We provide you with prescriptions and a list of
participating
pharmacies where the medications you will need can be obtained.
Comparative shopping can be worthwhile as the medication prices do vary.
Since many of these
medicines are injectable, they are generally not stocked by most
pharmacies and may need to be ordered. Most injectables can be express
shipped over night,
but over weekends and holidays this can take a few days...so plan ahead!
IV. Actual IVF and IVF/ICSI Treatment Cycle
A. Controlled Ovarian Hyperstimulation
The single most important factor to maximize success rates of ART is the
transfer of high-quality embryo(s) (the fertilized, dividing egg). We
maximize your
chances of producing a healthy embryo(s) by stimulating the development
of multiple ovarian follicles (the fluid-filled sacs containing the
oocytes (eggs)),
with injectable ovulatory medications (gonadotropins). The medications
currently available in the United States are human menopausal
gonadotropins hMG
(Humegon, Repronex, Menopur are some brand names) and highly purified
hFSH (Follistim, Gonal-F, and Bravelle).
hMG is a purified extract of two natural hormones, FSH and LH, which are
released by the pituitary gland to stimulate the development of
follicles in the
ovary. hMG has been used for many years to stimulate ovulation in women
who do not ovulate regularly. Since FSH and LH would be digested if
given orally, hMG
has to be administered by intramuscular injection. Recently "pure" FSH
has become available and may be used in conjunction with or in place of
hMG. FSH
hormone is the primary active ingredient in both preparations and their
effectiveness is similar. The modern FSH preparations are given
subcutaneously.
Both hMG and FSH can overstimulate the ovaries to produce cysts.
Massive overstimulation is a rare (<2%), but can be a serious complication. Most cysts resolve
spontaneously over a
period of a few weeks. More extreme degrees of ovarian enlargement and
tenderness represent the hyperstimulation syndrome which is usually
treated with
bedrest and the witholding of the ovulation injection or hCG. In rare
cases, ovarian hyperstimulation syndrome may be so pronounced that
intravenous fluids
or even hospitalization may be required. With close monitoring, the severe degree of ovarian hyperstimulation can usually be
avoided, however. Gonadotropins have been used for many years without any evidence of
increased birth defects or spontaneous miscarriage.
Other medications often used before and during stimulation with
gonadotropins are leuprolide (Lupron) and nafarelin (Synarel). They are
synthetic
modifications of the
hypothalamic hormone GnRH that controls the pituitary gland, which in turn
influences the ovaries. By using these medications we can eliminate the
influence of
the pituitary gland on ovarian stimulation and achieve recruitment of a
larger number of follicles (fluid-filled sacs containing the eggs).
Leuprolide and nafarelin are usually started before menses (long
protocol) but in women, whose ovaries are less sensitive to stimulation,
leuprolide may be
started at a lower dose after onset of the period (short protocol).
Leuprolide is given in the form of self-administered subcutaneous
injections in the
morning while nafarelin is given as twice-per-day nasal spray. When
leuprolide is to be begun before the onset of menses, we recommend that
a barrier method
of contraception (condoms, diaphragm or spermicidal jelly) be used
during that cycle. If your period is more than 2-3 days delayed, please
call the office to
schedule a sensitive blood pregnancy test. While there is little reason
to expect that leuprolide would cause any congenital anomalies, it might
interfere
with implantation of the fertilized egg in the uterus.
Whereas leuprolide and nafarelin are GnRH agonists, recently the GnRH
antagonists; ganirelix (Antagon) and cetrorelix (Cetrotide) have become
available in the
US for prevention of premature ovulation in women undergoing ovarian
stimulation with gonadotropins. These drugs have a more rapid onset of
action than the
agonists and are usually started 5-6 days after the start of gonadotropins. Thus the total number of injections with the antagonists
are less than with
leuprolide.. The antagonists are administered subcutaneously.
An individualized treatment plan will be discussed with you prior to
starting and again at baseline ultrasound so you will know what to
anticipate. It is of
utmost importance that we have your current telephone numbers so that we
can always reach you and/or your partner in case there is a change in
the treatment
plan.
B. Monitoring of Ovarian Response
Gonadotropins are usually started 2-5 days after the onset of menses.
Prior to beginning the gonadotropins, a baseline ultrasound is done to
detect any
preexisting ovarian cysts. A vaginal probe is used so a full bladder is
not necessary and the procedure is generally painless and not
uncomfortable. Simple ovarian cysts are common and they usually resolve
on their own.
However, if a large cyst is found, a cycle may be delayed. After three
to four days of gonadotropins, an ultrasound and a blood test is usually
done to assess your response.
The blood hormone estradiol (E2) is usually measured each time another
vaginal ultrasound is done to examine the number and size of the follicles. Most
patients have 5-6
ultrasounds. Ultrasound has not been shown to cause you or the
developing
eggs any harm.
Depending on the growth of the follicles and E2 levels, variable
doses of
gonadotropins are usuallygiven for a total of usually 8-12 days. We monitor
your response closely and frequently adjust the dose of medications in
the course of the hormonal
stimulation.
When the lead follicles are mature (generally about 18 mm diameter) on
the basis of ultrasound and blood tests, you receive a single injection
of human
chorionic gonadotropins (hCG; Pregnyl and Profasi are some brand names).
The hCG injection is in the evening (generally at 8 to 11 PM). hCG
provides for the
final phase of egg development. It is a natural hormone produced by the
placenta during pregnancy and is similar to the LH hormone which is
released by the
pituitary gland to trigger ovulation in spontaneous cycles. hCG has been
used for many years and has not been associated with any increase in
congenital
abnormalities.
C. Egg Retrieval
Oocyte retrieval (i.e., removal of the eggs from your ovaries) takes
place 34-35 hours after the injection of hCG just before ovulation would
otherwise occur. At that
time we collect as many eggs as possible. In the vast majority of cases the
aspiration is done transvaginally with ultrasound guidance.
Ultrasound-guided retrieval is performed with intravenous sedation (a
light, but general anesthesia; you are totally asleep during the procedure). A
thin needle is
introduced through the vagina into the ovaries and the follicles are
aspirated. Aspiration of ovarian follicles causes moderate
post-operative discomfort.
Following this procedure you may have a small amount of vaginal
spotting. Rarely there may be small amount of blood in your urine
immediately after the
aspiration which usually clears rapidly. Rare risks of ultrasound-guided
aspiration are injury to the bowel, a blood vessel or bladder, infection
and
excessive bleeding. In the highly unlikely event one of these
complications occurs, emergency major surgery might have to be performed
to repair the injury.
The risk of a major injury during an egg retrieval is probably less than
one-in-one thousand (<0.1%).
D. Semen Collection
We suggest that prior to the retrieval, your partner refrain from
ejaculation for at least one day. We will keep you informed as to the
progress of
follicular development to enable him to judge when abstinence should
begin. The morning of the egg retrieval, your partner provides a semen
specimen by
masturbation in a private area in our office. Prior to that, a frozen
specimen is reserved for emergency use if a fresh specimen is not
available.
E. In Vitro Fertilization and Embryo Development
Several hours after retrieval, the eggs are inseminated with sperm
prepared by washing in culture medium. If ICSI is to be done, then the
eggs will be
"stripped" of their surrounding cumulus cells and directly injected with
individual sperm using a procedure called micromanupulation. The day
after the
retrieval, the eggs are examined for evidence of fertilization. The
embryos are reexamined daily after retrieval to monitor their progress
so that we can
optimize treatment decisions in real time in response to evolving
conditions.
Day Three ("eight cell") Embryo Transfer
While transfer of multiple embryos increases the chance of pregnancy, it
also increases the risk of multiple pregnancy. The decision regarding
the number of
embryos to transfer can be difficult. In making a recommendation we take
into account the woman's age, the appearance of the embryos, the
couple's prior
history, the advisability of embryo freezing, and the couple's concern
about multiple pregnancy. In general, we transfer 1-2 embryos in women
under the age
of 35, 1-3 embryos in women aged 35-39, and 1-4 embryos in women over 40
years of age. Some couples may choose a lower number of embryos to have
transferred
because of concern about the risks of multiple pregnancy. The embryos
that are not transferred may be frozen for your future use. It is not uncommon
for a couple to
be able to have more than one child from a single IVF procedure. Having
children of different ages, yet with identical conception dates, is
always a great
topic for conversation!
Day Five (Blastocyst) Embryo Transfer
In some cases, if enough embryos are available, a couple has the option of allowing their embryos to grow
to a more advanced multicell state called a blastocyst. At this stage
some
embryos will have "declared" themselves by their
appearance if they are likely normal or abnormal. By delaying transfer
to day five, we may increase the chances of transferring the healthiest embryos that are
most likely to implant and grow in a healthy manner. For couples wishing
to transfer
only one embryo, this is an excellent option to both maximize IVF
success and minimize the risk of multiple gestation.
F. Embryo Transfer and Post-Transfer Care
The embryo transfer is done in a room adjacent to the laboratory. The
transfer requires no anesthesia and is virtually painless. If at all
possible, we would
like your partner to be present. In the usual position for a pelvic
examination, a tiny catheter is gently inserted into the upper uterus
and a small drop of
fluid containing the embryos is deposited.
You then rest horizontally for one hour before discharge. Following
transfer you might notice light spotting for a couple of days. For two
days after the
transfer we recommend that you refrain from vaginal intercourse and
orgasm which are associated with uterine contractions which in turn
could expel the
embryos from the uterus. Otherwise, we leave it up to your discretion to
what extent you may want to modify your usual activities.
Vaginal progesterone supplementation continues until a sensitive blood
test for pregnancy is done approximately 11 days later. It is important
to have the
test done even if you are spotting or bleeding. If the test is negative,
progesterone is stopped and a period usually follows within a few days.
If the test
is positive, it is repeated in two days to determine whether there is
a normal increase. In the presence of pregnancy, progesterone is continued
for six more
weeks.
In some instances the first hCG test is higher than the second or is
followed by a delayed heavy period despite the progesterone. These cases
are classified
as "biochemical" pregnancies, which do not progress and will
disintegrate spontaneously. If your pregnancy progresses normally, you
will be scheduled for an ultrasound examination about 3-4 weeks after
the retrieval in order to visualize the pregnancy and make sure it is
properly within the uterus. With
intrauterine pregnancies there is still the risk of eventual
miscarriage. We usually perform a few ultrasounds over the course of a
month or so to document
healthy progress of the gestation.
G. ICSI (Micro-injection fertilization)
Couples with male factor infertility can often use a technique called
intra-cytoplasmic sperm injection (ICSI) to realize their aim of
parenthood. The
ICSI procedure was initially developed for severe male factor cases when
the number and/or functional capacity of sperm is not sufficient for
standard IVF.
Recently the use of ICSI has been extended to couples with milder
forms of
male-factor as well as couples with unexplained or multi-factorial
infertility in order to avoid the low or absent fertilization which
occurs in some of
these cases. During ICSI, a single sperm cell is injected directly into
the egg. The procedure is carried out under a special microscope while the eggs
are kept on a warm platform. During these injection procedures,
micromanipulators are used to reduce hand movements to microscopic
movements. A sperm
injection
pipette is used to immobilize and then to inject the sperm into the egg
while it is kept stationary using a holding pipette. A small percentage
of the eggs
may be damaged by the ICSI procedure. Not all eggs will fertilize after
ICSI and some fertilized eggs may not divide into a cleavage stage
embryo. Overall,
however, the live birth rates with ICSI are almost equal to those
achieved by conventional IVF. For most couples with severe male factor
infertility, ICSI is
the only currently available option available to achieve parenthood with their own sperm and
eggs.
TESA and MESA Procedures
In cases where the ejaculate does not contain sperm, MESA (microsurgical
epididymal sperm aspiration) or TESA (testicular sperm aspiration or
biopsy) may be
performed by a urologist colleague specializing in infertility. If sperm are
recovered they are generally frozen for use in upcoming IVF-ICSI cycles.
Epididymal and
testicular sperm require ICSI for fertilization. The risk of genetic
abnormalities in children born form ICSI has been a concern to patients
and health
professionals since the procedure was developed. Studies carried out
world-wide have shown that some forms of congenital abnormalities have a
slightly higher
incidence in male babies born from ICSI but the most recent studies
showed no difference between IVF with and without ICSI. Men with marked
sperm
abnormalities have a high chance of carrying mild genetic abnormalities
which would then be transmitted to their offspring conceived through
ICSI but would
not be the result of the ICSI procedure itself. Specifically, men with
very low sperm counts often have deletions or mutations in the long arm
of the Y
chromosome which would be passed on to their sons born from ICSI.
Therefore, when the sons born form ICSI reach reproductive age, they may
also find that
they are sub-fertile or infertile due to the genes inherited from their
fathers.
H. Assisted Hatching
Assisted hatching (AH) is a laboratory procedure designed to facilitate
implantation or attachment of the dividing embryos to the wall of the
uterus. In
order for implantation and pregnancy to occur, the embryo must "hatch"
out of the zona pellucida (the egg's outermost membrane). In some
patients, failure to
establish a pregnancy after IVF may be related to the inability of the
embryos to get out of the zona. On the day of transfer, a small opening
is created in
the zona pellucida under microscopic control, thus aiding the hatching
process. We currently reserve AH for our older patients, those with
thick zonas, or
those who have failed previous IVF transfers.
I. Prenatal Care
If your pregnancy progresses normally to 10 to 12 weeks, you will select
your obstetrician for prenatal care and delivery. The the rates of
congenital anomalies in the general population, with standard ART and
with ICSI are at 2-6% (depending on the definition of abnormality used).
J. Pre-Implantation Genetic Diagnosis (PGD)
PGD is one of the most recent advancements in the field of Assisted
Reproductive Technologies (ART). PGD usually involves the removal
("biopsy") of a single cell from an embryo that has usually grown to at
least eight cells in number. In experienced hands this procedure has a
very low risk of significant damage to the growing embryonic cell group.
The removed material can then be tested with an ever-growing number of
probes, stains, or genetic amplification procedures that can provide
very detailed and specific information about the embryo in question.
PGD is not done without good reason. The cost of the process and risk to
the embryo must be outweighed by the potential benefits of obtaining the
genetic testing information. One typical example of PGD's benefits might
involve cases of severe genetic diseases where a couple has the
potential to pass on (or not to pass on) a particular disease. PGD in
these cases can allow a couple the option of selecting and implanting
embryos that would not suffer from the severe disease condition.
Current technology allows testing for diseases such as the following:
Alpha-thalassemia Anemia, Glycogen storage diseases, Beta-thalassemia
Anemia, Hemophilia, Canavan's Disease, Huntington's disease, Cystic
fibrosis, Marfan's Syndrome, Charcot-Marie-Tooth Disease, Myotonic
Dystrophy, Down's Syndrome, Neurofibromatosis, Duchenne Muscular
Dystrophy, Polycystic Kidney Disease, Fanconi anemia, Retinitis
Pigmentosa, Fragile X Syndrome, Spinal Muscular Atrophy, Gaucher
Disease, Tay Sachs Disease.
Probes for other severe diseases are being added to the list fairly
frequently as they are discovered. Other possible reasons to consider
PGD are problems with recurrent miscarriage, unexplained infertility,
advancing maternal age, and cases of severe male factor infertility. PGD
may offer the potential of an increased successful pregnancy rate with a
better chance of delivering a healthy baby.
Chromosomal abnormalities in growing pregnancies can be detected through amniocentesis or CVS (chorionic
villus sampling). We currently do not offer these services, but can
recommend a physician who does. Since amniocentesis and CVS are not risk free, we do
not
recommend them for all pregnancies established through IVF or GIFT. We
believe they should be performed for the usual indications such as
maternal age above
35 years or history of a previous anomaly. At this time, it may be
appropriate to consider genetic testing in some pregnancies established
through IVF.
In order to further our understanding of the IVF process, and to comply
with reporting requirements, it is most important that you keep us
informed of the
progress and outcome of your pregnancy, especially if there are any
problems. We count on you to ensure that your obstetrician will also
provide us with all
relevant medical information.
K. Reasons for Delay or Cancellation of a Treatment Cycle
Infection of the male reproductive tract (prostatitis) may be evident on
semen analysis or semen culture, even though the man may be entirely
without
symptoms. Since infection is associated with decreased fertilization
rate and can introduce contamination into the laboratory, we attempt to
first eradicate
the infection with antibiotics before proceeding with IVF. Sometimes
prolonged treatment is required.
If review of your past tests of tubal patency (HSG and/or laparoscopy)
indicates that you have dilated distally closed tube, which is known
as a
hydrosalpinx, removal of the tube(s) by laparoscopy will be discussed
with you and may be advisable before starting IVF. Hydrosalpinx fluid
interferes with
embryo implantation decreasing pregnancy rate by as much as 60%. The
presence of hydrosalpinges also increases the risks of severe pelvic
infection and
ectopic pregnancy.
About 10% of women fail to respond to the ovulatory medications
adequately. Some develop no follicles and some develop only a single
follicle. These cycles
are usually canceled before egg retrieval. Evaluation of the hormones
FSH and Estradiol on day 3 of the cycle permits identification of some
of the patients
who are likely not to respond to ovarian stimulation. It has been shown
that falling values of estradiol are seen in unsuccessful cycles.
Therefore, patients
exhibiting a large fall in serum estradiol before hCG do not usually
undergo retrieval. A small percentage of patients ovulate prematurely
before retrieval
because their pituitary gland initiates the process before we administer
hCG. Occasionally patients develop such a large number of follicles with
very high
levels of estradiol that hCG needs to be withheld lest they develop
severe hyperstimulation of the ovaries. Sometimes, if
hyperstimulation is becoming severe, we can institute a "freeze all"
cycle where all embryos are frozen for later use. The embryos can
be used at a later date when the woman is not in the dangerous,
hyperstimulated state.
The health and maturity of oocytes varies considerably and not all eggs
will fertilize. The
average fertilization rate is about 67%. In rare cases no eggs
fertilize. Sometimes
the sperm prove incapable of fertilization despite a normal semen
analysis. In such cases, ICSI can be done the day after retrieval
("rescue ICSI"). While fertilization can sometimes be established, the pregnancy rate with
"rescue ICSI" is much lower than in cycles with timely fertilization. At
other times the eggs
are not as ready to be fertilized as they appeared to be by ultrasound and
blood tests. Finally, cell division and embryo development may fail to
occur despite
apparently normal fertilization. In some cases embryo quality may not be
optimal or the embryos may stop developing.
Obviously the embryo transfer will have to be canceled if one of these
problems arise, but fortunately they are quite uncommon and almost all
patients in
our program undergo transfer of fresh embryos.
Handling of the minute eggs outside of the body is
inherently hazardous and requires great skill and care. On occasion, an
egg or an embryo,
fresh or frozen, may get stuck to the side of a culture dish and cannot
be found. These kinds of mishaps are rare but you need to be aware of
these "real world"
possibilities.
VI. Embryo Freezing
If more eggs are normally fertilized and divide to form healthy-looking
embryos than is advisable to replace during the treatment cycle, the
additional
embryos can be frozen and stored for replacement in the future. However,
the embryos may not survive the freezing process or may be incapable of
resuming
growth after thawing. Offspring born from frozen embryos have no higher
rate of congenital abnormalities than the general population. When damage
occurs during the freezing process, a pregnancy usually does not ensue. The
likelihood of establishing a pregnancy following transfer of
frozen-thawed embryos is about
15-20% per transfer. While the embryos remain in storage, you need to
pay a small, reasonable annual fee to cover the customary expenses of
maintenance and preservation.
