Our step-by-step overview of the IVF Process not meant to replace ongoing communication during your treatment with the team at Chelsea Fertility NYC. We pride ourselves on providing the highest level of customer service to our patients. The IVF process is a multi-step one. A Chelsea Fertility NYC doctor will work with you to prepare and choose the right treatment protocol. Once this is determined, the actual stimulation cycle with fertility drugs to develop multiple follicles/eggs is preceded by a deprogramming step in order to optimize the efficacy of the fertility drugs.
Prior to the IVF Cycle
A prep work-up involves several, if not all of the following:
- Ovarian reserve testing to decide on dose of fertility drugs and match the correct protocol for your cycle
- HSG, sonohsg, hysteroscopy to assess uterine cavity
- Trial or mock embryo transfer to document architecture and logistics for embryo replacement
- Endometrial scratch to improve implantation
Occasionally, an IVF cycle starts with a cycle day of the menstrual period without other medications.
Step 1 – Pre-stimulation Treatment: Deprogramming (Previously called Down-regulation)
In order for the stimulation with fertility drugs to work optimally, first the normal menstrual cycle and its control mechanisms must be unhinged or deprogrammed by one of the following agents.
Initiation of Oral Contraceptives
Some patients will receive oral contraceptives in the cycle prior to the IVF cycle. This ensures that GnRH analog therapy will start at the proper time if you have irregular cycles. There is also evidence that oral contraceptives can help prevent ovarian cysts, which sometimes develop during GnRH analog therapy. Provera® or progesterone may be prescribed for patients who ovulate irregularly or not at all. If you have regular cycles, oral contraceptives can be used to program cycle initiation to customize your cycle.
Suppression of Ovulation
There are two principle ways that physicians ensure ovulation does not occur before egg retrieval. One involves pre-treatment of a patient with a GnRH agonist. The other involves treatment after five days of stimulation with a GnRH antagonist. In either case, pre-treatment or deprogramming with oral contraceptives is standard practice.
GnRH Agonist Administration
GnRH agonist (Lupron®): This medication is taken by injection and is a short acting medication requiring daily injections. The primary role of this medication is to de-program and to prevent a premature LH surge, which could result in the release of eggs before they are ready to be retrieved. A GnRH agonist might be prescribed sometime after taking oral contraceptive pills. This dose may be reduced when ovarian stimulation is begun. Agonist is often discontinued on the day of hCG (human chorionic gonadotropin) administration. Some protocols also might begin GnRH agonist sometime after ovulation in the cycle preceding stimulation in the “mid-luteal” protocol, after the start of menses in the “flare” or “micro-flare” protocol. In these protocols, oral contraceptives are usually not used especially in patients with diminished ovarian reserve.
GnRH-antagonists (ganirelix acetate or cetrorelix acetate)
(Antagon®, Cetrotide®, Ganirelix): These are other classes of medications used to prevent premature ovulation. They are typically administered several days after stimulation and require fewer injections. Some novel protocols also use these agents in deprogramming.
Baseline Pelvic Ultrasound
Around the time of your expected period, your physician will perform an ultrasound scan to examine the ovaries and pelvic organs. If your physician detects a cyst, they may withhold further therapy until the cysts resolve spontaneously (usually in about a week).Rarely, cyst aspiration (drainage) is recommended. They may also perform a blood test (serum estradiol measurement) to confirm that the ovaries are properly suppressed. Baseline ovarian reserve testing can be repeated as indicated before proceeding with a treatment cycle. Once deprogramming is begun, these blood tests will not be relevant.
Step 2 – Ovarian Stimulation
Historically, this is the stage that most people think of when they consider their IVF cycle program. Obviously a critical stage, response to fertility drugs is critically influenced by the deprogramming pre-treatment stage. In general, ovarian stimulation begins after menstrual bleeding starts either spontaneously or after deprogramming. It is expected to have another menstruation after the deprogramming phase. Several similar medications may be used to stimulate follicle development: Bravelle®, Repronex®,Gonal-F®, Follistim® Follistim AQ pen and Gonal-F RFF Pen. GnRH-antagonists (ganirelix acetate or cetrorelix acetate) (Antagon®, Cetrotide®) are another class of medications used to prevent premature ovulation and, in combination with a Lupron trigger, they may offer protection from severe ovarian hyperstimulation syndrome. They tend to be used for short periods of time in the late stages of ovarian stimulation. There are several different types of stimulation protocols. All protocols employ the same types of medications, though specific protocols may help certain types of patients to have a better response than other types particularly by changing the deprogramming protocol and the dosage of the ovarian stimulation. Your physicians at Chelsea Fertility NYC are experts in this subspecialty at selecting the right protocol for you from the get-go.
Step 3 – Monitoring of Follicle Development
Follicuar development is monitored with a combination of vaginal ultrasound and hormone measurements (blood tests). These tests are performed frequently during the ART cycle, and the dose of medication might be adjusted in an effort to improve follicular development. The amount of medication prescribed also depends upon the results of the blood tests and ultrasound exams (5-7 visits on average).
Step 4 – Final Oocyte Maturation and hCG Administration
Human chorionic gonadotropin (hCG) (Profasi®, Novarel®, Pregnyl®, Ovidrel®) is a hormonal drug that stimulates the final maturation of the oocytes (mature follicles are 16-20 mm in size). Determining the proper day for hCG administration is critical. The time of the injection determines when the egg retrieval will be scheduled. Some protocols use GnRH agonists (Lupron) to trigger the final maturation of oocytes.
Step 5 – Transvaginal Oocyte Retrieval
Oocyte retrieval is performed about 35-36 hours after hCG has been administered. An anesthesiologist will administer (MAC anesthesia) intravenous medications (sedatives and pain relievers) in order to minimize the discomfort that may occur during the procedure. Most patients sleep through the procedure. A trans-vaginal ultrasound probe is used to visualize the ovaries and the egg-containing follicles within the ovaries. A needle, which can be seen on ultrasound, is guided into the follicles and the fluid contents aspirated. The aspirated material includes follicular fluid, oocytes (eggs) and granulosa (egg-supporting) cells. The physician will collect the oocytes and follicular fluid into a test tube and the laboratory embryologist will search the follicular fluid and locate the oocytes using a microscope. After the retrieval, patients recover from anesthesia where they will be observed while the intravenous medications wear off. It is not uncommon to have some vaginal spotting and lower abdominal discomfort for 24 hours following this procedure. Generally, patients feel completely recovered within 1 to 2 days. The number of oocytes retrieved is related to the ovarian response to medications, their accessibility, and the number of follicles that develop in response to stimulation. Ultrasound provides only an approximation of the number of oocytes that one can expect to recover. On the average, 8 to 15 oocytes are retrieved per patient while egg yield is lower in older patients.
Step 6 – Semen
In order to obtain sperm of optimal quality, it is important that patients follow clinic instructions for semen collection on the day of retrieval. Back up sperm can be frozen at any time prior.
Step 7- Embryology Lab Procedures
After eggs are retrieved, they are transferred to the embryology laboratory where they are kept in conditions that support their needs and growth. The embryos are placed in small dishes or tubes. Advanced technology has standardized and optimized embryo culture and sustainability. Chelsea Fertility NYC has a state-of –the –art embryology lab furnished with all the latest equipment on-site (2014).. A few hours after eggs are retrieved, sperm are placed in the culture medium with the eggs, or individual sperm are injected into each mature egg in a technique called intracytoplasmic sperm injection (ICSI) to achieve optimal fertilization. The eggs are then returned to the incubator, where they remain to develop. Periodically, over the next few days, the dishes are inspected so the development of the embryos can be assessed and tracked. The following day after eggs have been inseminated or injected with a single sperm (ICSI), they are examined for signs that the process of fertilization is underway. At this stage, normal development is evident by the still single cell having two nuclei; this stage is called a zygote (diploid, 2PN). Two days after insemination or ICSI, normal embryos have divided into about four cells. Three days after insemination or ICSI, normally developing embryos contain about eight cells. Five days after insemination or ICSI, normally developing embryos have developed to the blastocyst stage, which is typified by an embryo that now has 100 or more cells, an inner fluid-filled cavity, and a small cluster of cells called the inner cell mass (differentiation). It is important to note that since many eggs and embryos are abnormal, it is expected that not all eggs will fertilize and not all embryos will divide at a normal rate. The chance that a developing embryo will produce a pregnancy is related to whether its development in the lab is normal, but this correlation is not perfect. This means that not all embryos developing at the normal rate are in fact also genetically normal, and not all poorly developing embryos are genetically abnormal. Nonetheless, their visual appearance is the most common and useful guide in the selection of the best embryo(s) for transfer unless PGD/PGS is performed. Embryos are often transferred to the uterus three to six days after retrieval. Sometimes assisted hatching is used on day 3 embryos, which may consist of six to eight cells. After transfer of a day 3 embryo, the embryo must continue to develop to the blastocyst stage (a hollow ball of about 100 cells) before implantation can occur. This development takes several days. Immediately before implantation, the blastocyst must “‘hatch” from the zona coating which originally enveloped the egg. To assist the hatching process, a hole is made through the protein coat (zona pellucida) that surrounds the developing embryos just prior to embryo transfer. This involves dissolving part of the zona coating with an acid solution or cutting it with a fine needle or laser
Step 8 – Embryo Transfer
The embryo transfer is the critical last step in the IVF process whereby the embryo is gently placed in the uterine cavity suspended in one tenth of a drop of culture media. This procedure is done under speculum examination and the embryo transfer catheter (akin to linguini spaghetti in size and consistency) can be visualized by doing a simultaneous abdominal sonogram. This requires a semi-full urinary bladder to see clearly. Once the embryo is injected a bubble appears on the sonogram seen so the exact location of the embryo can be verified. Ideal location is approximately 2 cm from the top of the uterine fundus. At Chelsea Fertility NYC, before any embryo transfer we will do a trial transfer or mock transfer. This is simply recreating the steps of the actual transfer without the embryo in the catheter. This will ensure that we have a logistical roadmap for the technical aspects of the embryo transfer to optimize its efficacy.
Algorithm for embryo transfer:
Other than making sure that the transfer will go smoothly technically, the most interesting aspects of this process is when to do it and how many to transfer? The physicians at Chelsea Fertility NYC have done tens of thousands of transfers over 25 years experience working together and in separate clinics and have trained dozens of reproductive endocrinologists in this technique. Your physicians at Chelsea Fertility NYC have also published on landmark scientific papers in deciding on embryo number for patients and stage of transfer (cellular day2-3 vs. blastocyst). Contemporary management favors transferring at the Day 5-6 stage after fertilization or blastocyst stage. This works best in women under 40 with several embryos to choose from. The strategy is to transfer one blastocyst (SET BET, single embryo transfer, blastocyst embryo transfer). Poor responders or repeated failed cycles and older women will benefit from more than one embryo transferred as the genetic composition of any given embryo has a higher probability of abnormality (complex aneuploidy) which will disallow implantation. Without doing genetic screening (see PGD/PGS), one cannot know if the genetic integrity of any given embryo is intact. Abnormal (complex aneuploidy) embryos will disintegrate in-utero and not implant, so placing higher order numbers of embryos in these cases is safe and will not lead to multiple implantations. If it is decided with your physician that you will replace multiple embryos, an early transfer on day 2-3 may be advised. Scientific research published by your physicians at Chelsea Fertility NYC has shown no difference in the success between day 2 vs. day 3 (see Bibliography References). In general, if there is an over abundance of viable embryos, day 5 is preferred. Therefore, the algorithm is complex for this decision and consultation and guidance with your physician at Chelsea Fertility NYC will allow you the ability to make the right decision. First cycle decisions are simpler in that one need only consider age and number available; with favoring to replace the minimum number of embryos to reduce the risk of multiple gestation. Repeat cycles, failed cycles, or poor prognosis, and older patients bring in confounding variables to the discussion and requires customization and personalization of care. The physicians at Chelsea Fertility NYC are distinguished in this area and pride themselves on tailoring the embryo transfer to each specific case to optimize care.
Step 9 – Cryopreservation of Embryos
Embryo freezing is an important part of the IVF process. Patients who have additional good quality embryos can freeze them for future use. These embryos provide a second or even third opportunity for pregnancy without undergoing another ovarian stimulation and retrieval. Embryos that meet developmental criteria for appearance and rate of growth can be frozen at any of several stages of development. The technique for freezing embryos is called vitrification. In this ultra-rapid freezing method, embryos are placed into special solutions and then placed immediately into liquid nitrogen. The method used to freeze embryos dictates how the embryos must be warmed or thawed. Not all embryos survive the freezing/thawing. Embryos can be transferred into patients whose cycle has been synchronized by hormone replacement with that of the stage of the frozen embryo. Alternatively, embryos can also be transferred during a “natural” cycle. Embryos can be stored indefinitely without a compromise in their quality. Chelsea Fertility provides all these options.
Step 10 – Hormonal Support of the Uterine Lining (Progesterone Supplements)
Progesterone and estrogen supplementation can occur using vaginal, oral or injectable progestreone, and in some cases, a combination of methods. Supplementation usually begins on the day of or the day after oocyte retrieval. Usually, cells in the follicle will produce progesterone following aspiration. During oocyte retrieval, some of these cells may be removed along with the oocyte. Supplemental hormones helps prepare the uterine lining for implantation. This daily supplementation medication will continue until your pregnancy test. If the test is positive, you may be advised to continue to take progesterone for several more weeks.
Step 11 – Pregnancy Test
A pregnancy test is necessary regardless of vaginal spotting or bleeding. It determines if pregnancy has occurred and is done 9-12 days after the embryo transfer. This test is usually repeated 2 days later if positive. If the test is negative, the doctor may instruct you to stop the hormone supplementation.
Step 12 – Early Pregnancy Follow-up
Close scrutiny of a pregnancy is necessary to try to identify miscarriages or ectopic pregnancies and to help counsel regarding the status and treatment of multiple gestations. Patients are generally released to their obstetrician at 7-9 weeks gestation.
Assisted Hatching (AH)
Pioneered over 20 years ago, this technique allows for a small aperture (10 micrometers) to be made in the protein coat of the embryo (zona). As the embryo divides it eventually gets to a size that physically exceeds its protein coat or shell and literally hatches out. This occurs by day 6 after fertilization. Hatching is done right before the embryos are transferred by the embryologist using a laser to create the aperture. It is done to actually weaken the zona but not destroy the zona, so the embryo is still encased albeit with a nick in its coat. So that when the embryo reaches its critical mass size the busting out or hatching process is made more easily. AH is helpful for repeat failed implantation or for patients who have thicker zona. Older patients usually have thicker zona so AH is recommended for patients over 38 years of age. Your physicians at Chelsea Fertility NYC have much experience with AH and have published scientific papers on its efficacy and will help you customize your care to optimize your outcome.