| In Vitro Fertilization(IVF)
IVF is an elective medical treatment usually undertaken when other fertility therapies have been unsuccessful or are not possible. It is a complex, multi step process, resulting in the creation of embryos in the laboratory. The embryos are then placed into the uterus for potential implantation. IVF treatment enables many patients to achieve their dream of parenthood.
Once the decision is made to proceed with IVF, several test results on both partners are usually required to be reviewed prior to the initiation of the IVF cycle. These include tests such as hormonal profile, ovarian reserve screening, semen analysis, tests for infectious screening (HIV, Hepatitis B, Syphilis etc…), genetic testing when indicated and uterine cavity assessment.
When all of the tests are completed, the treatment cycle begins. Each patient's treatment plan is unique. In general, the steps are as follows: The patient is placed on oral contraceptives (birth control pills)for approximately 14-35 days. During this time a trial transfer/ mock transfer may be performed. The patient will then take Lupron for approximately 12-14 days. These drugs prepare the body for the stimulation that will follow. A baseline ultrasound is performed. Ovarian stimulation with fertility medications is begun and continues for approximately 10-12 days. Close monitoring with blood tests and ultrasound examination occurs during this time. At the appropriate time, a trigger shot of hCG is given and is followed 36-38 hours later by egg retrieval. Progesterone supplementation is also usually started around this time. Fertilization of retrieved eggs with the sperm sample then occurs in the laboratory under the supervision and monitoring of an embryologist. Embryo transfer occurs 3-5 days after the egg retrieval. A pregnancy test is performed approximately 14 days later, followed by subsequent ultrasounds to detect a fetal heart beat.
Medication and their dosages can confuse patients. Detailed explanations to familiarize patients with the types of drugs and methods of administration help eliminate confusion. Every patient's response to the medications is unique and a patient's response from one cycle to the next may also be different. A treatment calendar which usually outlines the following is often helpful:
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Type of medications to be taken -
Dates when these medications are to be taken -
The patient's visits for blood tests and ultrasound examination, to monitor the response to medications. -
Other pertinent instructions - It is crucial that patients follow these directions carefully, as there is no room for error. Any mistake could jeopardize the success of the treatment.
- Oral contraceptives / Birth control pills (BCP)
Most patients start the treatment cycle with birth control pills (oral contraceptives). By putting the patient on BCPs, the menstrual cycle can be manipulated. This allows for flexible scheduling, the ability to plan ahead and to provide the patient with specific treatment dates that can be set well in advance. The patient usually takes these pills for a period of 2-5 weeks. This will in no way harm the patient's chances of conceiving.
- Lupron
Lupron is an analog of gonadotropin releasing hormone (GnRH). It suppresses the ovaries, improves the recruitment of multiple follicles and prevents premature ovulation. In short, it permits a better response with the fertility medications. Lupron is administered as a subcutaneous injection (under the skin) with a small needle. The patient will take daily Lupron injections until otherwise indicated, usually for 12- 14 days.
- Fertility Medications (super ovulating drugs)
These include one or a combination of the following: Gonal-f, Follistim, Menopur, Bravelle, Ovidrel or Repronex (all given subcutaneously). These medications are gonadotropins which directly stimulate the ovaries to produce multiple eggs. The response to these drugs varies according to the patient's age, her FSH hormone levels and the amount of drugs given. The dose to be taken will be clearly indicated on the treatment calendar. These drugs are given once (usually in the evening) or twice daily (morning and evening). Patients may need to make arrangements with someone (partner or friend) to give these injections. Mixing and injection instructions will be given prior to treatment. The response to these drugs is closely monitored by vaginal ultrasound examination and blood hormonal tests. These results are then used to individualize subsequent medication treatment and adjust the drug dosage, as patients move through a cycle. At every visit, the patient is informed about the changes in drug dosage based on the monitoring results Monitoring
First Visit:
At the first appointment, which is 3-4 days after the start of the fertility stimulation drugs the following will be performed: -
A blood test for the hormone Estradiol (E2): As the follicles (containing the eggs) mature, the eggs secrete the Estradiol hormone. Therefore, the level of this hormone in the blood is a good indicator of how the ovaries are responding to the drugs. The E2 level increases over the next several days as the eggs are maturing and the follicles growing. The more eggs or follicles a patient has, the higher the Estradiol level will be. -
A vaginal ultrasound examination: The purpose of this examination is to visualize the ovaries and count the number of follicles present. A follicle is the fluid-filled sac that contains the egg. Each follicle usually contains one egg. By counting the number of follicles, it is possible to determine how well the patient has responded to the fertility drugs. The follicles are also measured. The size of the follicle gives a good idea about the maturity of the egg. As the patient continues to take the fertility drugs, these follicles will grow (about 3 mm growth in 2 days); and at a certain point in time they will be ready to be harvested. A mature follicle measures around 16 mm. After evaluating the number and size of the follicles, the thickness and pattern of the uterine lining will also be evaluated. During this same visit, the patient's partner will be asked to produce a semen sample that will be frozen for back-up. The purpose of this back-up specimen is to have sperm available on the day of the egg retrieval. This will prevent compromising the success of the cycle, in the event the partner has difficulty producing a fresh semen sample at the time of egg retrieval, or if there are issues with quality of the sperm sample produced or if there is evidence of infection in the sample produced.
Based on the testing results, the patient will be given specific instructions on how to proceed with drug dosages. She will be told what medications to continue taking and when to come back for another blood test and ultrasound. Follow-up Visits During this follow-up visit, a blood test for Estradiol and an ultrasound examination to evaluate the growth of the follicles will again be performed. The patient will again be given further instructions on what to do based on the test results. Sometimes, yet another visit for another ultrasound examination and blood estradiol level will be required. The number of visits required prior to egg retrieval, varies from patient to patient and from cycle to cycle. hCG Injection
When the physician decides that the follicles are ready to be aspirated (to remove the eggs), the patient will be given instructions to take an hCG injection 36 to 38 hours prior to the Egg Retrieval. It is crucial that the dose and the time of administration of this medication be adhered to strictly. It provides the trigger that will "push" the eggs through their final stages of maturation and will release them from their attachments to the walls of the follicles to float inside the follicular fluid. If HCG is not taken correctly and at the exact time specified, the eggs will not be mature and will not be able to be aspirated.
The patient will be given written instructions on how and when to administer this medication. She will also be given a new calendar, the hCG Calendar, which will contain new instructions about additional medications (such as Progesterone) the patient should begin taking.
The patient will be contacted with the day and time to take the hCG injection as well as the time that the patient has to report for Egg Retrieval 34-36 hours later. hCG injections are usually given at night (usually between 8 PM and 11 PM) and the Egg Retrieval is scheduled 34-36 hours after the injection.
Progesterone
Progesterone is a hormone produced by the remainder of the follicle after its rupture (corpus luteum). Progesterone helps the lining of the uterus to become thick and is necessary for the implantation of the pre-embryo. Since the estrogen levels are higher than normal in stimulated ovarian cycles, it is necessary to administer natural progesterone supplements to establish a normal estrogen/progesterone ratio. These supplements will improve the uterine lining and facilitate pre-embryo implantation. Instructions as to the exact route and administration of natural progesterone are provided to patients. The progesterone can be administered through a vaginal suppository or an IM injection.
Egg Retrieval
When the size of the leading follicles reaches 16 mm in average diameter and the estradiol hormone level is appropriately elevated, then it is time for the eggs to be "harvested". The hCG injection (described in the previous section) will be administered in the evening usually between 8 PM and 11 PM. The egg retrieval will be scheduled 36 hours after the hCG injection. The couple needs to be at the IVF center at least 30 minutes prior to the scheduled time of Egg Retrieval (ER). The patient is instructed not eat or drink anything after midnight, the night before the ER day. Detailed Pre-Retrieval Instructions are provided to the patient prior to scheduling the procedure.
The egg retrieval (ER) is performed under "general anesthesia" but without intubation. The patient will not feel any discomfort during the procedure and will wake up within 10 to 15 minutes after the procedure. Depending on the number of follicles present, the ER usually lasts 10 to 30 minutes. 
The ER is performed under ultrasound guidance similar to the vaginal ultrasound examination that the patient has during monitoring of follicle growth. A needle guide is attached to the ultrasound probe, a long needle is introduced through the guide, and under direct visualization each follicle is punctured and the fluid (along with the egg floating in it) is aspirated. The fluid is then immediately sent to the laboratory where the embryologists search for the eggs, and isolate them. The prepared sperm will be added to each egg and they will be allowed to incubate overnight under controlled laboratory conditions. At the completion of the ER, the patient is taken to the recovery area where she will stay for about an hour. Pain medications might be administered at this time as needed. Some discomfort is expected for a few hours following ER and Tylenol can be taken by the patient at home as needed every 4 hours. Occasionally, some nausea might also occur which usually dissipates within a few hours.
After about an hour when the patient is fully awake and relatively pain-free, instructions are given by the recovery nurse and the patient is discharged home. The patient must be accompanied by someone who can drive her home and should not be left alone for the rest of the day. Post-Retrieval Instructions are provided to the patient. While the patient is undergoing ER, the partner is asked to provide a semen sample. Abstinence from ejaculation for two to five days prior to providing this semen specimen is recommended. The semen is washed and prepared to fertilize the eggs 3-4 hours later. The partner might be asked to give another semen sample, if the first sample does not have an adequate number of viable sperm.
Embryo Transfer
Three to five days following the Egg Retrieval, the patient will have the Embryo Transfer (ET). During this time the fertilized eggs (embryos) have been allowed to grow and divide in the incubator. The patient would have also been started on Progesterone injections and suppositories the day of hCG injection to prepare the uterine lining for implantation. Pre-transfer instructions are provided to the patient in advance. The physician will have a discussion about the number and quality of the embryos at hand. A decision will be made by the couple and their physician as to the number of embryos that will be transferred and the number to be frozen or discarded. The patient will then take a sedative pill. The embryos will be separated into a separate dish and then transferred to the transfer catheter. Meanwhile the physician will prepare the patient for the ET.
The procedure is very similar to an artificial insemination procedure except that embryos are transferred into the uterus instead of sperm. A speculum is inserted in the vagina and the cervix is washed and cleansed. The embryologist will then deliver the catheter to the physician who introduces it through the cervical canal into the uterine cavity where the embryos are released. The embryologist will then check the catheter to make sure none of the embryos are left behind in the catheter. The whole procedure takes approximately 15 minutes. The patient will remain in bed for about an hour. She will then be discharged home and will need a ride back home. Post-transfer instructions are provided to the patient. It is recommended that the patient rests at home for 4 days following the transfer.
Pregnancy Testing
Quantitative hCG pregnancy testing is usually done fourteen days after egg retrieval. The test is usually reported as either positive or negative; however, a test may be reported as "weakly positive." This could be due to one of several reasons as follows: -
Late but normal implantation of the embryo -
Discontinued pregnancy -
Ectopic pregnancy -
4. Lab error In such a situation, further hCG monitoring is indicated and a second pregnancy test will be performed 2 days later. During a normal pregnancy course, the hCG levels are expected to double every two to three days. An ultrasound examination will be performed approximately three to four weeks after the egg retrieval. This early ultrasound can help detect a miscarriage, ectopic pregnancy, and multiple pregnancies. An ectopic (tubal) pregnancy is known to occur in 2-4% of IVF pregnancies. If diagnosed early, this unfortunate complication may be treated as an outpatient with medication. Once a fetal heartbeat is detected on ultrasound examination, the patient is referred back to their obstetrician for prenatal care. Risks and Complications Associated with IVF
Every medical procedure has its share of risks and complication. This holds good for the IVF procedure as well, although every effort is made to keep complications to a minimum. Each step of the IVF process is associated with specific risks, some of which are described below. -
Side effects with Lupron therapy are short term and include hot flashes and occasionally patients experience headaches. -
Risks associated with the fertility medications include tenderness, infection, hematoma, and swelling or bruising at the injection site, allergic reactions, hyperstimulation of the ovaries, and failure of the ovaries to respond and cancellation of the treatment cycle. -
Since more than one follicle is produced during ovarian stimulation, hormone levels of estrogen and progesterone increase to levels much higher than normal. When the estrogen level becomes mildly to moderately elevated, side effects include fluid retention with slight transient weight gain, nausea, and diarrhea, pelvic discomfort due to enlarged cystic ovaries, breast tenderness, mood swings, headache and fatigue. -
Ovarian Hyperstimulation Syndrome (OHSS): This occurs if the estrogen level rises excessively and hCG is administered to trigger final maturation of the eggs. The signs and symptoms include excessive fluid retention with fluid in the abdomen and/or chest cavity; thrombosis of arteries and/or veins (formation of blood clots) which may lead to stroke, embolus, or potentially fatal complications and abnormally enlarged ovaries, which have the possibility of rupturing or twisting (a surgical emergency). Treatment involves hospitalization. Most often, close monitoring of estrogen levels can help prevent this complication from occurring. -
Risks of egg retrieval include reactions to the drugs used to administer anesthesia as well as risks associated with the passage of the needle through the vagina into the ovaries (including infection, bleeding, inadvertent damage to adjacent structures including the bowel, bladder, blood vessels, ureter, uterus or ovary and adhesion formation (internal scarring) following the procedure. -
Side effects of progesterone include vaginal dryness, bloating, breast tenderness, depression and mood swings. -
Embryo transfer can cause mild cramping. There is a small risk of bleeding or infection as a result of the transfer procedure. -
IVF is associated with the risk of a multiple pregnancy. Women with multiple pregnancies have a much higher risk of complicated pregnancies, which may include the following: toxemia, pre-eclampsia, miscarriage, premature labor and delivery, stillbirth, birth defects, and other complications. -
IVF is also associated with the risk of ectopic pregnancies within the tube. A combination of normal pregnancy and ectopic pregnancy is also possible. A tubal ectopic pregnancy if detected early may be treated with medication, but may require laparoscopy or major surgery for treatment. -
Pregnancies that occur with IVF may result in miscarriage. This is not unique to IVF pregnancies and can occur after spontaneous conception as well. Sometimes, a dilatation and curettage (D&C) may be necessary after a miscarriage. -
Congenital abnormalities, genetic abnormalities, mental retardation or other birth defects which occur in about 3% of spontaneously-conceived pregnancies may still occur in children born following assisted reproductive techniques. There is no evidence to indicate that babies born with IVF have a higher incidence of developmental anomalies. Prodedural Terminology Trial Embryo Transfer / Mock Transfer
This procedure is performed early on, when the patient is on birth control pills before the start of fertility medications. It consists of a pelvic examination and placement of a tiny empty catheter (similar to that used to transfer embryos) inside the uterus. Since each person's birth canal is unique, this procedure helps to determine the direction and length of the uterine cavity prior to the actual treatment cycle. It can be likened to the creation of a road map for the physician to follow at the time of the actual embryo transfer. This helps minimize trauma to the uterine lining during the actual IVF treatment cycle embryo transfer process. It helps keep the time period between embryo removal from the incubator to transfer into the uterine cavity to the minimum and may enhance pregnancy rates. Sometimes, it may detect a narrowing of the cervical canal which may require dilatation prior to embryo transfer. Cryopreservation Cryopreservation is the procedure of freezing sperm or fertilized eggs in liquid nitrogen for future reproductive use.
Cryopreservation of sperm is a routine procedure during an IVF cycle where it serves as a backup sample at the time of egg retrieval. Healthy sperm can be obtained from ejaculates or from liquid extracted during a surgical procedure. The sperm is preserved by freezing in liquid nitrogen at 320 degrees below 0 degrees Fahrenheit. There is no evidence to indicate an increase in birth defects between sperm that have been through the freeze-thaw procedure and freshly ejaculated sperm.
The purpose of cryopreservation of extra embryos is to preserve the unused embryos for future use. If the IVF fresh embryo procedure does not result in pregnancy, the frozen embryos can be thawed and transferred to the uterus. This frozen cycle allows for a second or third attempt at pregnancy without exposure to all the fertility stimulating drugs. Alternatively, if the first fresh cycle resulted in a pregnancy, the frozen embryo's can be used to attempt another pregnancy years later. The embryo can be frozen in liquid nitrogen indefinitely. Cryopreservation of human embryos has been successfully conducted worldwide for a number of years. To date, there are no reports of increased birth defects in pregnancies achieved through this process. Frozen Embryo Transfer At egg retrieval, when more eggs are retrieved than needed, majority are inseminated with sperm resulting in excessive embryos than are needed for the first embryo transfer. These embryos can be frozen at any stage between day one and day six after egg retrieval and can be stored for years. Frozen embryo transfer can be performed after a failed IVF cycle or after a successful IVF cycle for a second or third pregnancy. The frozen embryo transfer process is less invasive and may be done during a natural cycle. However, sometimes the cycle may need to be manipulated with medication to monitor and control occurrence of natural ovulation. Before the frozen embryo transfer can be performed, the embryos need to be thawed. Not all embryos survive the cryopreservation process. Before the frozen embryo transfer, the embryos are evaluated to make sure they are ready for transfer. The embryos are placed into the uterus at the time of ovulation and when the thickness of the endometrium (lining of the uterus) is right. During the procedure a catheter is inserted through the cervix and the embryos are placed into the uterus. The frozen embryo transfer usually takes about 15 minutes. The success rate of frozen embryo transfer is almost as successful as standard IVF. Success depends on several factors, including the number and quality of embryos, the patient's age, and the cause of infertility. Blastocyst Transfer Blastocyst Transfer refers to the placement of the embryo in the uterus five days after egg retrieval, rather than the traditional three days. A blastocyst is an embryo that has developed for five days after fertilization  and has divided into two different cell types. The embryos that survive to day five of development are thought to be strong and healthy, offer a greater chance of implantation into the uterine wall and possibly more likely to result in a pregnancy. Usually only two such blastocyst stage embryos are transferred into the uterus, resulting in a reduction of the risk of multiple gestation higher than twins. Blastocyst transfers can improve pregnancy rates in specific cases while transferring fewer embryos to reduce the risk of multiple gestations However, the primary disadvantage of blastocyst transfer is the overall reduction in the number of embryos that develop. Since some of the embryos will stop developing between day 3 and day 5 in the laboratory, it results in fewer overall embryos, fewer or no embryos to freeze (cryopreserve), and occasionally the need to cancel the transfer if all the embryos arrest. Therefore, blastocyst transfer is planned only after careful consideration and discussion. Preimplatation Genetic Diagnosis (PGD) Preimplantation genetic diagnosis (PGD), also termed embryo biopsy, is a procedure that can identify some genetic defects within an embryo before it is transferred into the uterus. The patient undergoes the normal IVF process until egg retrieval. These eggs are fertilized by a procedure called Intracytoplasmic Sperm Injection (ICSI) where one sperm fertilizes each egg. All embryos are biopsied on Day 3, by removing a single cell from each embryo. Each cell is then treated with probes for genetic abnormalities and the DNA is evaluated to determine if the inheritance of the gene is present. Those embryos without the genetic defect are transferred into the uterus. Preimplantation genetic diagnosis enables couples that carry genetic disorders to try for a biological normal child of their own. PGD minimizes the risk of passing genetic defects on to future generations. Assisted Hatching Assisted Hatching refers to the procedure wherein, a small hole is made in the outer membrane (shell) or zona pellucida of the embryo. The embryologist usually accomplishes this mechanically with a microscope needle (micromanipulation), although it can also be done chemically, or with a laser. This artificial "hatching" is performed on embryos that may be at higher risk of having hardened or thickened "shells", as is speculated to occur in women with more advanced reproductive age. The opening is said to help improve the chances of implantation of the embryo into the uterus, because it overcomes the age related changes in the covering of the embryo that probably interfere with the normal hatching process. Miscellaneous
The psychological stress associated with infertility and undergoing Assisted Reproduction procedures should not be underestimated. Patient may experience significant anxiety and disappointment. All patients are encouraged to consider short-term supportive counseling during this time. Dr. Pinto will be happy to assist patients with obtaining psychological support to help you them through this difficult time.
Patients should be aware that IVF therapy requires substantial time commitment by both partners. Couples will need to adjust their schedules to undergo the required testing and therapies associated with IVF.
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