In-vitro
fertilization (IVF) the process where by ova (eggs)
are fertilized by sperm
outside the body, and returned back into the uterus as embryos,
is an extremely successful form of therapy for many infertile
couples. The following information will take you step by
step through an IVF cycle that results in the highest take
home baby rate of any infertility
therapy available. All our IVF procedures are performed
at an off-site facility.
INITIAL SCREENING
Before
you actually begin a cycle of in-vitro fertilization, you
will be screened to ensure that everything is ideal for
you to succeed in establishing a pregnancy though IVF. At
your initial visit, you will meet with Dr. Freedman or Dr.
Castelbaum, who will take a complete history and perform
a physical exam. The process of in-vitro fertilization and
embryo
transfer will be explained in great detail. Arrangements
to meet the IVF nurse coordinator and financial counselor
will be made at this time.
Female
evaluation
Measurement of follicle
stimulating hormone (FSH)
levels on the second, third, or fourth day of a woman's
menstrual period is highly predictive of future fertility.
The FSH assay at Northern Fertility and Reproductive Associates
has been correlated with the largest known database. Women
in their late thirties and forties with an elevated FSH
level have a very poor prognosis for establishing a pregnancy
without the use of donor
eggs. We have an extremely successful donor egg program
has a very high pregnancy rate. Younger women with elevated
FSH levels may still be able to achieve pregnancy with IVF,
without resorting to donor eggs.
There are some women with a normal day three FSH level who
still have diminished ovarian
reserve. Such women, typically in their late thirties
and early forties, or with prior ovarian surgery, can be
identified with the use of a clomiphene
citrate challenge test (CCCT). Clomiphene citrate (100
mg) is given daily, starting on cycle day five for a total
of five days. On cycle day ten, an FSH level is again drawn.
FSH levels > 14 IU/L on day ten are also indicative of
diminished reserve. Though few studies exist, it appears
that a single elevated FSH level represents severely diminished
ovarian reserve and a poor prognosis for pregnancy, even
if FSH testing in subsequent months is normal.
Infectious
Disease Testing-Blood will be drawn on the initial visit
for Syphilis, Hepatitis B and C, and HIV.
Cervical Cultures-
At the time of the initial physical exam the cervix will be cultured for chlamydia,
gonorrhea, ureaplasma, and
mycoplasma.
Hysterosalpingogram
- and Office Hysteroscopy-
It is critical to be certain that a woman's uterine cavity
is normal prior to proceeding with IVF. A hysterosalpingogram
is performed in the radiology department of the hospital.
Dye is instilled to outline the uterus and fallopian
tubes. This allows us to determine that the fallopian
tubes are open. Blocked dilated fallopian tubes (hydrosalpinges)
make it more difficult for an embryo to implant. Many couples
choose to electively remove hydrosalpinges prior to starting
their IVF cycle. Hysteroscopy is performed on all patients
going through our program to evaluate the inside of the
uterus. This thirty second office procedure involves placing
a tiny fiber optic telescope through the cervix and into
the uterus to ensure that the cavity is normal and does
not contain any polyps, adhesions, or fibroids.
At the completion of the hysteroscopy, a small catheter
can be inserted into the uterus to determine the exact depth
of the uterine cavity. This data will be utilized at the
time of embryo transfer to ensure that the embryos are placed
into the ideal uterine location.
Male
evaluation
Infectious Disease
Testing - Blood will be drawn on the initial visit for Syphilis, Hepatitis B and
C, and HIV. A urine specimen is tested for Chlamydia and Gonorrhea.
Semen
Analysis - At the time of the initial visit a semen sample will be brought
into the office. This will be cultured for Mycoplasma and Ureaplasma. At a later
time, a test of sperm function, the Sperm Penetration Assay (SPA), will be performed.
Abnormal SPA testing is an indication for intracytoplasmic
sperm injection (ICSI).
OVULATION
INDUCTION
Ovulation
induction is the stimulation of the ovary to produce multiple
follicles, each containing an egg. In the month prior to
ovulation
induction, you will be asked to monitor with a urine
kit for your spontaneous ovulation. If this is not clearly
seen, you might be asked to come into the office to have
a tube of blood drawn for progesterone.
For those patients that do not ovulate, the birth control
pill may be used instead.
One
week after ovulation is documented, you will begin a medication
called Lupron,
which turns off the portion of the brain that stimulates
the ovary. Lupron is administered by subcutaneous
injection (small needle), two times a day for approximately
ten days. Minor side effects may include hot flashes, mild
headaches or vaginal spotting.
The
nurse coordinator will assign you a date to come to our
office for blood work and vaginal ultrasound (baseline monitoring)
at the beginning of your period on Lupron. Using vaginal
ultrasound,
the ovaries are examined for cysts. Blood is drawn to measure
your estrogen level, which should be very low. Most women
are ready to start stimulation immediately. If the estrogen
level is elevated or a cyst is present on the ovaries, you
may need to stay on the Lupron twice a day, for an additional
several days to weeks.
If
baseline evaluation is normal, you will decrease the Lupron
to once daily, and start injectable FSH/LH medication to
stimulate the development of many eggs. Daily or twice daily
injections of the human
menopausal gonadotropins (HMG), Repronex or Menopur
are used. Occasionally drugs containing only FSH, such as
Follistim Bravelle or Gonal-F are utilized. In general,
the number of follicles recruited decreases with advancing
maternal age and rising day
3 FSH levels. The dose of medication your doctor chooses
is based on your prior experience with the medications,
your age, or both. Some women require only one or two ampules
of medication daily, while others may need up to eight.
Most patients take four to six amps daily (300 to 450 IU
daily).
In
selected patients, we use a simpler and shorter ovulation
induction protocol. The drugs Cetrotide or Antagon are used
instead of Lupron. We start Repronex or Menopure on the
third day of a normal menstrual cycle. After five or six
days, a once daily injection of Cetrotide or Antagon is
added. This approach requires fewer days of injections.
In general, we use this protocol for women who are poor
responders.
One
risk of injectable FSH/LH medication is ovarian hyperstimulation
syndrome (OHSS). OHSS occurs when too many follicles develop
in the ovary. The ovary may then grow to a large size and
leak fluid into the abdominal cavity. The vast majority
of OHSS cases are mild. Patients complain of nausea and
bloating. Decreased activities and increased oral fluid
intake is all that is needed.
Fortunately,
serious cases of ovarian hyperstimulation are rare in our
in-vitro fertilization program. Severe OHSS is characterized
by massive accumulation of fluid in the abdomen. Dehydration,
decreased urine production, and blood clots may occur. Drainage
of the abdominal fluid by transvaginal needle aspiration
often leads to resolution. The ovaries can enlarge, twist,
or leak - requiring laparoscopic surgical intervention.
OHSS is most commonly seen in young women with estradiol
levels >4000 pg/ml and a large number of follicles. Your
retrieval may be postponed if your physician is concerned
about your risk of OHSS. If a cycle proceeds to egg
retrieval, embryos may be frozen and saved to a later
cycle when the ovaries are not as stimulated. Historically,
our practice has had fewer than one case of significant
OHSS annually.
Blood
testing for estrogen and progesterone, and serial ultrasound
monitoring will require approximately five to six visits
to the office during an IVF cycle. When the ultrasound measurements
and estrogen levels suggest that the eggs are mature, the
Lupron (or Cetritide/Antagon) and HMG will be stopped, and
one dose of human
chorionic gonadotropin (hCG) given. HCG ripens the egg
so that it can be fertilized after retrieval. Egg retrieval
is performed thirty-six and one half hours after hCG injection.
The timing of hCG is very critical. It must be taken at
the exact time that you are instructed. The usual dose of
hCG is 10,000IU. This may be lowered if your estrogen level
is very high.
From midnight before the egg retrieval you should not have
anything to eat or drink, including coffee or water. If
you are taking medications other than fertility drugs talk
with your doctor or nurse about taking the medication on
the day of the egg retrieval. Antibiotics, usually doxycycline
will be started the night before the egg retrieval.
OOCYTE
RETRIEVAL
The
egg retrieval is performed thirty-six and one-half hours
after the hCG injection at our off-site IVF center. An intravenous
line will be started upon your arrival at the procedure
facility. You will be lightly sleeping and feel no discomfort
as the egg retrieval is performed. After you are sedated,
the vaginal area will be cleansed with sterile water. The
egg retrieval will be performed with a needle placed through
the vaginal wall and into the ovary under ultrasound guidance.
The egg containing fluid from each follicle will be collected
into a test tube, which is handed to the embryologist for
analysis. After all the follicles are aspirated on one ovary
the procedure is repeated on the other ovary. The retrieval
will last anywhere from ten to thirty minutes.
After
the retrieval, discomfort is generally minimal. The recovery
is rapid with some minimal symptoms including pelvic heaviness,
soreness or cramping. Spotting may occur but this should
be minimal. Most women will go home one to two hours after
the completion of the procedure. Make sure someone is available
to drive you home since you cannot drive a car after receiving
anesthesia.
Your
partner will collect a semen sample by masturbation while
you are undergoing egg retrieval. He should abstain from
ejaculation for 2 days prior to your egg retrieval. On very
rare occasions, a second sample on the day of the egg retrieval
may be required. Occasionally, sperm is extracted surgically
from the epididymis or testicle. Arrangements with a urologist
will have already been made though our office.
At
the time of the egg retrieval, cells in the follicles which
produce progesterone are removed along with the eggs. Therefore,
progesterone (by injections or vaginal gel) is taken daily,
starting the day after egg retrieval. Progesterone supplementation
will be continued through ten weeks of pregnancy.
Don't
plan on doing any work on the day of the egg retrieval.
Avoid heavy lifting and vigorous exertion. Don't use douches
or vaginal creams.
We
will contact you daily after the egg retrieval for updates
on your embryos. Both male and female partners should be
available every day for telephone calls and consultations.
In the rare event that an additional sperm sample is needed,
or a change in plans occurs we need to be able to reach
you immediately.
INSEMINATION
AND FERTILIZATION
The
focus of your care now shifts to the embryology
laboratory. The eggs mature for several hours before
sperm are added. If this is conventional in
vitro fertilization, approximately 50 thousand sperm
are added to each egg. In cases of abnormally low sperm
count, motility, or morphology, one individual sperm will
be injected into each egg in a process called Intracytoplasmic
Sperm Injection (ICSI).
The
day after your egg retrieval the embryologists will look
to see if fertilization has occurred. After fertilization
the sperm loses its tail and its head enlarges. Two discrete
round pro-nuclei are noted in the fertilized egg. Each pro-nuclei
contains 23 parental chromosomes. If your two pro-nuclei
(2PN) embryos look good, six are typically left out for
continued observation and eventual embryo transfer. The
remaining embryos can be frozen for use in a later cycle.
Two
days after egg retrieval, the 2PN embryos start to divide.
They can reach 2 to 4 cells. Three days after egg retrieval,
your embryos ideally have reached the 8 cell stage. At a
minimum, we like to see 4 cell embryos.
Problems
can occur with fertilization and cleavage. Approximately
70% of eggs fertilize. Rarely, sperm are unable to penetrate
the egg in the first 24 hours and fertilization failure
occurs. When multiple sperm penetrate an egg, polyspermy
occurs. Polyspermic embryos are abnormal and cannot be transferred.
Sometimes embryos do not divide or stop dividing at an early
stage. This is referred to as a cleavage arrest. Many of
these embryos are chromosomally abnormal. Fragmentation
or or cellular debris within the embryo may also develop.
Severe fragmentation can reduce pregnancy rates.
EMBRYO
TRANSFER
Embryo
transfer occurs at about 72 hours from egg retrieval. You
will be asked to arrive at the procedure center with a full
bladder. The embryo transfer will be performed under abdominal
ultrasound guidance. A speculum
is placed into the vagina and excess mucus is wiped away
from the opening to the cervix. Dr. Freedman or Dr. Castelbaum
willknow exactly where to place your embryos, because you
already had a mock transfer in the office prior to your
IVF cycle.
The
embryos are loaded up into a very soft flexible catheter
by the embryologist. Dr. Freedman or Dr. Castelbaum will
then insert the catheter through the cervix and follow its
path up into the uterus while watching on the ultrasound
monitor screen. Embryo transfer does not hurt and no anesthesia
is required. After injecting the embryos a small white area
is seen on the screen signifying the air that surrounded
the embryos in the catheter. The catheter is removed and
handed back to the embryologist to insure that it is clean
and free of embryos. The speculum will be removed and you
will rest for an additional 15 minutes. At that point you
may empty your bladder, get dressed and drive home.
We
recommend you limit your activity for the next 48 hours.
Relax at home and don't exert yourself. If you have small
children you should not pick them up and should have help
caring for them for the first 48 hours. After 48 hours you
may increase your activity, but continue not to lift any
heavy objects.
THE
LUTEAL PHASE
You
will continue to take injectable or vaginal progesterone
over the next two weeks. This helps improve the lining of
the uterus and aids with embryo implantation. Depending
on your estradiol level at the time you received your triggering
shot of hCG, you may be asked to take supplemental injections
of hCG on the day of embryo transfer, as well as three days
and six days later. An office visit to check you hormone
response as well as an ultrasound to evaluate your ovarian
size will be performed one week after embryo transfer.
It
is not uncommon to have a small amount of bleeding during
the post transfer luteal
phase. As the embryo implants into the endometrium,
blood vessels may leak. If you have bleeding more than spotting,
a temperature over 100 degrees, significant increase in
pain, weight gain more than five pounds, or shortness of
breath, please call us immediately. It is not unusual to
have symptoms of pregnancy that come and go during this
two week period. Don't stop your progesterone if symptoms
go away. All your medication should be taken until your
pregnancy test is completed.
Two
weeks after the embryo transfer, you will return to the
office for a blood test for pregnancy, the beta hCG level.
If this is positive, you are pregnant. You will then return
two days later for a follow up beta hCG test to determine
if it is rising properly. One week later, an ultrasound
will be performed to determine the status of your early
pregnancy. If your test is negative, you can stop the progesterone
and your period will usually start in 2 to 5 days later.
SUCCESS
RATE AND OUTCOME OF IVF
Tabulated
below is our most recent data from Jan 1, 2004 through December
31, 2004.
*Comparison
of clinic success rates may not be meaningful because patient
medical characteristics and treatment approaches may vary
from clinic to clinic.
Choosing
the right infertility practice is the single most important
decision for a couple considering In Vitro Fertilization.
The most recent nationwide report of IVF success rates,
co-ordinated by the Centers for Disease Control, has just
been released. Northern Fertility continues to be one of
the best IVF practices in the Delaware Valley. The complete
SART database can be found at http://www.cdc.gov/reproductivehealth/art.htm.
We
have achieved extremely high pregnancy rates without transferring
large numbers of embryos. Most women under the age of 35
have only two embryos transferred. Our embryologists give
us valuable information about your embryos on the day of
transfer. If the embryos have not cleaved well, or have
significant fragmentation, we may suggest replacing more
than two embryos. Among women younger than 35 receiving
three embryos, five percent went on to have a triplet pregnancy
or chose to undergo selective reduction. In cases or advanced
maternal reproductive age, high FSH levels, and recurrent
IVF failures assisted hatching is indicated. The embryologist
will dissolve away part of the zona pellucida egg shell
surrounding the embryo, to make the embryo more likely to
implant.
Major congenital anomalies occur in 3% of pregnancies, established
with intercourse at home. That rate may be as high as 5%
in IVF cycles. There may be a slightly higher rate of chromosomal
abnormalities with ICSI compared to natural conceptions.
Pregnancies resulting from IVF may result in a miscarriage,
tubal pregnancy or stillbirth, as with spontaneous conceptions.
Tubal pregnancies occur in less than 3% of IVF pregnancies.
FREEZING
OF EMBRYOS ( EMBRYO CRYOPRESERVATION)
Earlier
reference was made to freezing 2PN embryos on the day after
egg retrieval. They can be subsequently thawed, and transferred.
It is critically important that your uterus be receptive
at the time your frozen embryos are transferred. We have
had consistently outstanding frozen (and donor egg) pregnancy
rates by using medications that mimic a normal menstrual
cycle. You will be placed on Lupron, followed by estrogen
patches, and subsequently progesterone injections. The estrogen
and progesterone supplements are tapered and then stopped
by the time you are 10 weeks pregnant.
Human
pregnancies have been established following transfer of
embryos cryopreserved at all stages from pre-cleavage through
expanded blastocyst. Since 1981, many normal infants have
been delivered worldwide as the result of embryo transfer
following embryo cryopreservation. Dr. Freedman was responsible
for the first pregnancy from a frozen embryo in the Mid-Atlantic
region. The chance of achieving pregnancy and delivering
following transfer of cryopreserved embryos is approximately
30% to 40% per transfer.
