Forming families for over 20 years IN VITRO fertilization www.ctfertility.com
Forming families for over 20 years Michael B. Doyle, M.D. Medical Director Introduction to IN VITRO fertilization Contents 1 Introduction 2 Getting started 3 Genetics and Pre-Conception Counseling 4 Medications 5 Monitoring 6-7 The egg retrieval: before, during & after 8 Fertilization, embryo development & embryo biopsy (PGD) 9 Embryo transfer and freezing 10 Bloodwork and Follow-up 11 Frequently asked questions 12 Cost Considerations www.ctfertility.com
Introduction In Vitro Fertilization In vitro fertilization (IVF) involves a series of steps and procedures, which include: the administration and monitoring of medications to stimulate the ovaries to produce eggs; the retrieval, fertilization and culture of those eggs in the laboratory; and the evaluation and transfer of some of those embryos into the uterus. IVF creates an environment which allows for maximal interaction between as many eggs and sperm as possible. Multiple embryos are usually formed, which can then be introduced directly into the uterus under highly optimized conditions. This booklet is designed to give you information about each of these steps in the IVF process; and to review with you the answers to many of the questions that our IVF patients have asked us in the past. Is IVF the right choice for you? IVF is an appropriate choice for many patients. Women with blocked or damaged fallopian tubes, severe endometriosis, ovulation disorders, severe cervical or uterine factors, or diminishing ovarian function are among the more obvious candidates to conceive with IVF, because in these conditions, the interaction between sperm and egg can be limited. When there is not enough sperm to achieve a pregnancy by intercourse or insemination because of a male factor, IVF can also help achieve a pregnancy by ensuring that the sperm and egg meet. When the number of sperm available is low, or fertilization is not clearly able to occur, the sperm can be directly inserted in the egg during IVF by a procedure called intracytoplasmic sperm injection (ICSI). In many other less clear-cut cases, patients may choose to pursue IVF when their evaluation fails to reveal any factors associated with infertility (unexplained infertility). It is also very common for couples who have not conceived with other fertility treatments to move on to IVF as their next step. Still other couples simply choose to proceed with IVF because it yields the highest pregnancy rates available, and it allows for the selection of the healthiest embryos for implantation, either by means of microscopic examination, or through embryo biopsy, using pre-implantation genetic diagnosis (PGD). 1
Getting Started your Checklist Once you decide to proceed with IVF you should schedule an orientation class with one of CFA s IVF Coordinators. Details of each phase of the process will be discussed, including administration of medication, ultrasound and blood testing, the procedures of egg retrieval and embryo transfer, and post transfer strategies. An injection lesson will also be given. Specific individualized dosing instructions about your medication will be reviewed. If you have questions after attending the class or reading this information, please do not hesitate to call us. You will also need to undergo testing to maximize the likelihood of a successful cycle. Please refer to this checklist to assist you in scheduling these important tests. Pre-IVF Screening Test Date Results Physical Exam HIV Hepatitis B & C Type & Screen Rubella/ RPR CBC TSH/ Prolactin CF Screen/ Genetic testing Pap Smear Cultures Baseline FSH & ultrasound Male Testing Test Date Results HIV Hep B sag Hep C Ab RPR Semen Analysis Date Results Date Results Count Motility Uterine / Tubal Evaluations Sonohysterogram Hysterosalpingogram Office hysteroscopy Cervical Mapping Required Consultations & Counseling Date IVF Class Financial Counseling Medication Instruction IVF Consent Forms Genetic Counseling PGD Consent Forms Notes 2
Genetic and Pre-Conception Counseling Genetic Counseling at Connecticut Fertility Associates To maximize the chance of delivering a healthy baby, Connecticut Fertility Associates offers and recommends genetic counseling and genetic screening for many patients. What is genetic counseling? Genetic counseling is the process of providing individuals and families with information and support on the nature, inheritance and implications of genetic and related conditions. A genetic counselor is a health professional with a specialized graduate degree in the areas of medical genetics and counseling. Genetic counseling involves taking a detailed family history, interpreting possible risks based on this family history as well as age and ethnicity, discussing appropriate options for the family and facilitating informed decision-making. To whom is genetic counseling offered? The following patients are required to consult with our genetic counselor prior to beginning treatment: Women who are age 42 or older; Patients undergoing IVF with pre-implantation genetic diagnosis (PGD); Patients and/or partners who have tested positive as carriers for specific diseases, especially cystic fibrosis; All patients intending to use an egg donor; All prospective egg donors and directed semen donors. Other patients could greatly benefit from a consultation with our genetic counselor including: Women who are age 35 or older; or men who are age 50 or over; Men with severe male factor infertility; or women with premature ovarian failure. Individuals with family histories of birth defects and/or genetic conditions; Patients considering advanced treatments, especially IVF and pre-implantation genetic diagnosis (PGD); Newly pregnant patients who are over age 35 or who have questions regarding prenatal testing options. Patients with questions regarding genetic screening or gender selection. How do I schedule a genetic counseling appointment? Jamie Speer, MS, CGC, received his Master s degree in Human Genetics and Genetic Counseling from Sarah Lawrence College in 1993. He is a member of the National Society of Genetic Counselors and was certified by the American Board of Genetic Counseling. He is available for consultations on Tuesdays and Fridays in our Bridgeport office. Some Saturday appointments will also be available. There will be a charge of $200 for this service. To schedule an appointment with Jamie, please call 373-1200. Jamie Speer, MS Genetic Counseling 3
MEDICATIONS for your IVF cycle Several types of medication generally set the stage for the development and harvesting of eggs. Birth control pills may be used for 2-4 weeks to rest the ovary prior to actual stimulation. Lupron (which is used in some patients) may also play a role in suppressing the hormones before the start of the stimulation medications. And gonadotropins such as Gonal F, Follistim, Bravelle Menopur, and Repronex (each of which may be used in differing combinations, depending on your specific needs) are used to stimulate the ovaries to grow a group of follicles, from which multiple eggs are removed. Lupron or Antagon Lupron is sometimes used to suppress the pituitary gland s secretions of luteinizing hormone (LH). Normally LH is secreted in high amounts by the pituitary gland just before ovulation. In fact, it is this rapid release of LH (the LH surge ) that triggers egg release. Lupron suppresses the LH surge and prevents ovulation so that you do not release the eggs prior to the retrieval. Another medication, Antagon, can also be used instead, to achieve the same goal. Lupron is usually prescribed for 2-4 weeks prior to the initiation of the gonadotropins and then is continued (usually at half-dose) once the gonadotropins are started. Once the ovary is adequately suppressed you may get your period. The ovary can then be maintained in this rested state for days or for even an additional few weeks, until conditions are optimal for you to begin gonadotropins. Alternatively, birth control pills, followed by microdose (diluted) Lupron may be also used. When Antagon is used instead of Lupron, it is only administered for approximately 5-7 days before the egg retrieval, beginning when the follicles reach mid-development. Lupron or Antagon are always given by subcutaneous injection into the front of the thigh or abdomen. The usual starting dose of Lupron is 0.1cc (10 units.) but may be lowered to 0.05cc (5 units) once the Lupron has taken effect, or with the start of gonadotropins. Again, Lupron is continued on a daily basis until the eggs are mature, and you take your HCG injection. Side effects associated with Lupron are rare. Gonadotropins Gonadotropins are injectable medications which stimulate the ovaries to produce multiple follicles, most of which usually contain eggs. These medications all contain Follicle Stimulating Hormone (FSH), but differ from each other in some ways (e.g., Gonal F, Follistim and Bravelle contain only FSH; Luveris contains only pure LH; and Menopur and Repronex contain both FSH and LH). Your physician will decide which medication and dosage is optimal for you, and your exact protocol will be outlined to you in detail during your individualized injection class. All gonadotropins may be administered by subcutaneous injection, though Repronex may be more comfortable when administered by intramuscular (IM) injection. Only someone who has received instruction on intramuscular injections may give the medication in that manner. During the ultrasound and hormone monitoring we will assess the number of follicles produced by your ovaries, as well as the rate of their growth. Your medication will then be adjusted accordingly (i.e., increased or decreased) depending on your response. When the largest follicles reach a critical size (approximately 20 millimeters) the eggs within them should be mature. Human chorionic gonadotropin (hcg) is then given, which causes the egg to undergo a final stage of maturation. The retrieval then follows precisely 34-36 hours later. 4 The potential risks of gonadotropins include multiple pregnancy and ovarian hyperstimulation, and these issues will be discussed in detail with you. Potential side effects of gonadotropins are generally minor but may include discomfort at the injection site, mild fatigue, bloating and cramping, fluid retention, mood swings, and headaches.
MONITORING your IVF cycle Blood Work Estradiol (E2): Estradiol is secreted by the follicles within the ovary. The measurement of estradiol provides an estimation of ovarian function and the health and quality of the follicles. Therefore, an estradiol blood test is obtained frequently throughout the stimulation cycle to monitor the response of the ovaries to the gonadotropins. Testing usually begins 4-5 days after gonadotropin injections. You will receive specific instructions regarding the timing of your monitoring and the timing of your visits. Luteinizing Hormone Test (LH): This hormone is secreted by the pituitary gland and causes ovulation which would be undesirable in an IVF cycle. Possible premature rises in LH will, therefore be monitored throughout the cycle, particularly when your protocol does not include Lupron. Progesterone: Measurement of progesterone levels is also monitored to determine the rate of maturation of the eggs within the follicles. If the progesterone level starts to raise prematurely, it may be a sign that the cycle is slowing down or declining, or that the eggs are maturing out of synchrony with the follicles. Progesterone is also important since it can affect the development of your uterine lining. Michael B. Doyle, M.D. Ultrasound Serial vaginal ultrasounds are required to track follicular growth stimulated by the gonadotropins. No preparation is needed before an ultrasound. The examination takes 5-10 minutes to perform. When the largest follicles approach the 20 mm range (and the estrogen level is adequate), it is likely that the follicles contain mature, fertilizable eggs. However, since not all follicles contain eggs, we can only estimate the actual numbers of eggs you will have. When we determine that your follicles are large enough, and your hormone levels are in the proper range, you are ready to receive your injection of human chorionic gonadotropin (hcg, Pregnyl, Ovidrel, or Profasi ). The hcg matures the eggs to their final stage and is the last medication you will take prior to egg retrieval. You will be scheduled for egg retrieval precisely 34-36 hours following hcg administration. Cycle Cancellation Cycle Cancellation / Modification About 20% of patients who begin taking medication may be canceled prior to the retrieval procedure. This may occur because the follicles have not developed optimally; blood hormone levels have not risen normally; or because less than four follicles matured simultaneously. In rare cases, your estradiol level may be too high. In this instance, the risk of hyperstimulation may be aggravated if the cycle continues and especially if pregnancy does occur. In such cases, we may recommend that all of the embryos be frozen, and transferred in a non-medicated cycle a month or two later. Lastly, fluid may accumulate in the uterus prior to the egg retrieval, creating an environment which is unfavorable for embryo attachment. In these cases, the eggs may still be retrieved and fertilized, but then prepared directly for freezing, with the transfer not occurring until the uterine environment has been corrected, usually weeks later. 5
The egg retrieval Before, During & After All egg retrievals and embryo transfers occur in our IVF suite at 4920 Main Street in Bridgeport, CT, Suite 307. The egg retrieval technique is a transvaginal ultrasound-guided needle aspiration. A vaginal probe (similar to the one used for your office ultrasounds) is placed into the vagina. A fine needle is then guided toward the ovary, while the follicles are visualized on ultrasound. Fluid from the follicles is collected through a suction needle, which is connected to a test tube. The embryologist examines the follicular fluid, identifies the eggs under the microscope, and places them in a special culture fluid. Later that day, sperm (which has been washed and treated to remove seminal fluid, and to isolate the most healthy and active sperm) are mixed with the eggs and put into an incubator overnight. In some cases, sperm may be directly injected into the egg using Intracytoplasmic Sperm Injection (ICSI). Egg retrieval is performed under light anesthesia (twilight sleep). It takes less than 30 minutes and requires a recovery period of about one hour. Your husband or partner may accompany you in the recovery room during this post-procedure period. Prior to the egg retrieval: Please read and complete all consent forms, indicating your plans and preferences regarding options such as sperm injection (ICSI), pre-implantation genetic diagnosis (PGD), embryo freezing, and assisted hatching. The lab requests that you complete all consent forms prior to beginning your gonadotropin medication. We recommend a 2-3 day period of abstinence from sexual intercourse or ejaculation prior to the day of the egg retrieval, to optimize sperm counts. If you or your partner have concerns about producing a semen sample, please discuss this with us well in advance of your retrieval date. Occasionally, we freeze semen samples prior to egg retrieval to alleviate any problems of production on the day of egg harvesting. Have nothing to eat or drink after midnight the night before the egg retrieval. This is essential for the safe administration of anesthesia. On the day of the egg retrieval: Arrive 30 minutes before the actual procedure time. A nurse will call for you and assist you in preparing for the procedure. At that time, you may place your personal belongings into a locker. You will meet with the anesthesiologist prior to the procedure, and then be escorted into the procedure room where an intravenous (IV) line will be started. 6 Unless otherwise arranged, semen production should occur on the day of egg retrieval preferably on-site in one of our comfortable collection rooms. Arrangements can also be made in advance to accomodate sperm production at home.
After the egg retrieval Following the egg retrieval, you will spend about an hour in the recovery room before being discharged. Prior arrangements for a ride home are mandatory, as you must be accompanied by a responsible adult upon discharge. Plain or Extra Strength Tylenol is allowed for any discomfort. Refrain from non-steroidals (such as Motrin, Advil, Anaprox ). Heating pads or warm compresses can also alleviate ovarian pressure. Call us if any of the following symptoms occur: Severe pain Fever > 101 Unusually heavy bleeding Fainting, shortness of breath, or chest pain Medications following the egg retrieval In the evening of the day of the egg retrieval, you must begin medications which are designed to enhance implantation. These include progesterone, prednisone, doxycycline, and baby aspirin. Progesterone You will begin taking injections of progesterone in oil (50 mg = 1 cc) once daily, unless otherwise specified, beginning on the evening of the egg retrieval. You will continue progesterone daily, every day thereafter, until the day of your blood pregnancy test. You may also be instructed to take vaginal or oral progesterone (Prometrium ). This natural form of progesterone is prescribed to supplement the natural progesterone already present in the body and to cause the uterine lining to be more receptive to embryo implantation. Side effects of progesterone include bloating; weight gain; mood swings; and discomfort at injection site. It is possible that progesterone may delay your menstrual cycle even if you are not pregnant. Also, please remember that some pharmacies do not carry this medication. Please also note that some pharmacies include a package insert warning of potential risks of progesterone in pregnancy. However there are absolutely no scientific studies that show that the natural progesterone (which we prescribe) increases the chances of any fetal abnormality. Progesterone use will be continued for approximately 8 weeks if you are pregnant. Prednisone 10 mg, 1 tablet once a day, for five days, is also begun on the evening of the egg retrieval. Prednisone is used to prevent an immune reaction against the embryo, which might hamper implantation. Doxycycline 100 mg, 1 tablet twice a day, for five days. Doxycyline is a tetracycline-like antibiotic used to prevent an infectious reaction against the embryo, which might also hamper implantation. Like prednisone, Doxycyline is begun the evening of the egg retrieval, and continued for 5 days. If you have an allergy to tetracyclines, please notify the office and do not take this medicine. Baby aspirin 1 tablet once a day, (81 mg) may be administered until well into the pregnancy. Baby aspirin has a proposed role in preventing blood clots and increasing embryo attachment. It is begun early on in your treatment cycle, but continued until the pregnancy test, and often, beyond that. 7
Fertilization, Embryo development & PGD Fertilization and Embryo Culture The sperm is always added to the eggs on the day of the retrieval. If a problem with fertilization is anticipated, or if poor fertilization has occurred in a previous treatment cycle, intracytoplasmic sperm injection (ICSI) is recommended. With ICSI a single sperm is chosen and injected directly into each egg. Once the eggs have fertilized, they are then cultured for another 2-4 days before the resulting embryos are considered ideal for transfer. At this time, the embryos are often hatched, a process which our embryologist performs to assist implantation. We generally transfer embryos on either the third or fifth day after harvesting. The pros and cons of each strategy will be discussed with you in detail once we have observed the way your embryos have developed, and the embryologist has graded their quality. Embryos can be graded based on their appearance alone, or actually biopsied for chromosomal testing using pre-implantation genetic diagnosis (PGD). You should discuss with your physician whether you are a candidate for PGD based on your history or needs. Pre-Implantation Genetic Diagnosis (PGD) Pre-implantation genetic diagnosis (PGD) utilizes embryo biopsy to evaluate the genetic composition of your growing embryos. To do this, our embryologists routinely separate one of the cells from each embryo, which is analyzed for chromosomal testing. We can then determine the true genetics of each embryo before any pregnancy is initiated. By using this more precise information, we can distinguish those embryos that are truly perfect from others which may look good but have a chromosomal disorder that could lead to cycle failure, miscarriage or birth defects. There are two types of tests that can be performed on an embryo: chromosomal testing (also known as aneuploidy screening) and genetic testing for a specific disease. Aneuploidy testing ensures that the embryo does not contain an abnormal number of chromosomes, which may lead to a failure of embryo growth, miscarriage, or birth abnormalities such as Down Syndrome, a form of mental retardation. Women who may benefit from chromosomal testing include older women, women in whom embryo quality is a concern, and women who have experienced multiple miscarriages or prior births with genetic disorders. Genetic testing can also be used to detect a specific gene defect that can be inherited from one or both parents. These defects can lead to conditions such as cystic fibrosis, sickle-cell anemia, hemophilia, Duchenne muscular dystrophy, and Tay-Sach s disease. There are many other genetic disorders for which PGD can be used, each one specific for a particular couple. Our on-site genetic counselor can review any questions you may have regarding PGD and its potential benefit to you. PGD may not be right for everyone, so please discuss with your physician or genetic counselor whether PGD makes sense for you. 8
embryo transfer & freezing Embryo Transfer Three to five days after the your egg retrieval (depending on your specific case), the embryos are ready for their transfer into the uterus. Which day is best for you will be determined after the laboratory team has evaluated the number and quality of your embryos. Embryo transfer is a minor procedure requiring no anesthesia. The number of embryos to transfer is a critical decision, and this will be discussed in detail with you on the day of transfer. By this time, we can carefully look at all the embryos, and estimate the chances of pregnancy (and multiple pregnancy) based on the embryo quality. Whether it makes sense to freeze extra embryos is also discussed at this time. Transfer of embryos usually takes about five minutes. First, a speculum is placed into the vagina and the cervix is cleaned. Then a soft plastic catheter is guided into the uterus, where the embryos are placed. Ultrasound is used to guide the catheter, and to confirm that the embryos have been placed in the ideal uterine location. After the embryo transfer Remain off your feet as much as possible, for 36 hours after the transfer. Keep optional activities to a minimum; but getting up for meals and bathroom visits is certainly allowed. Strict bed rest has never been proven to improve pregnancy rates. Resume normal diet and fluids. You may shower. Continue to take your progesterone, prednisone, doxycycline, and baby aspirin as previously directed. Abstain from vaginal intercourse until your pregnancy status is known. Embryo Freezing (Cryopreservation) If excess embryos of very good quality exist, they can be frozen (cryopreserved), stored, and thawed at a later date, when they can be used for transfer into the uterus. Although some embryos do not survive the freezing and thawing process, those that do are returned to the uterus. Only very high quality embryos are frozen. In other words, it is quite common to choose the very best embryos for transfer, and then evaluate the remaining extras to see if any are suitable for freezing. No evidence of abnormal development has been found with these embryos that survive the freezing and thawing process. Their transfer involves the same technique performed in a fresh IVF cycle, with embryos inserted through the cervix into the uterus. Egg Freezing If for whatever reason you wish to have your eggs harvested at this time but are not prepared to use them until later, CFA now offers oocyte (egg) freezing. This option allows future pregnancies to occur using eggs that we collect now and store for many years. If you are interested in this option, ask your physician for more details. 9
Bloodwork & Follow-up Bloodwork and Follow-up: Estrogen and progesterone levels are drawn 7 days after the egg retrieval to ensure that your hormone levels are optimal to allow for implantation. If they are not, dosage adjustments will be made. Even if the levels are good, however, it is too early to tell if pregnancy has occurred. An initial blood pregnancy test is performed 14 days after the egg retrieval. Even if bleeding has occurred, pregnancy testing still is necessary, as implantation bleeding is often mistaken for menses. It is normal to feel premenstrual and have cramping even if pregnancy has occurred. If your pregnancy test is negative, please schedule a consultation with your CFA physician. This appointment can be a critical part of the cycle. It gives you an opportunity to review the cycle and discuss possible recommendations for future cycles. At the post-cycle visit, we will have all of your cycle data available, so that your questions can be fully addressed at that time. If your pregnancy test is positive, you must continue your progesterone and aspirin. We will then follow you closely for approximately eight more weeks. This is to ensure that your hormone levels increase adequately, to determine that the pregnancy develops normally, and to monitor you for multiple pregnancies. While IVF pregnancies are no more likely to miscarry than other pregnancies, it is still a possibility, and the first two weeks are therefore approached with particularly cautious optimism. If everything proceeds normally for the two months after the egg retrieval, most of the hurdles have been passed, and you will be referred back to your obstetrician a few weeks later. Pregnancy Rates Pregnancy rates at Connecticut Fertility Associates for a single IVF cycle vary from patient to patient, depending on various individual factors, such as woman s age, type of cycle, cause of infertility, number and quality of the eggs and embryos, sperm factors, and uterine conditions. Therefore, chances for success with each patient will be discussed on an individual basis. Success rates for frozen cycles also depend on the number and quality of thawed embryos. 10
Frequently asked questions Q: Will the IVF technique damage my ovaries? A: There is no evidence to suggest that ultrasound or egg retrieval damages the ovaries. Q: If an egg is not retrieved or if the technique does not produce a pregnancy on the first attempt, how soon can the procedure be repeated? A: This depends on the individual. The primary reason for delay is to allow the patient's normal menstrual cycle to resume, which may take up to 3 months. Q: How many times will IVF be repeated per couple? A: There is no specific number. This is determined by the couple and the physician. Q: After the IVF procedure, how long must we wait to have intercourse? A: Although a definite time of abstinence to avoid damage to the embryo has not been determined, most experts recommend abstinence for two weeks. However, intercourse the night before embryo transfer is acceptable. Q: What about other activities? How soon can I resume my normal routine? A: The IVF team recommends that the patient be sedentary for 36 hours following embryo placement in the uterus. Strenuous exercises such as jogging, horseback riding, swimming, etc. should be avoided until pregnancy is confirmed. Otherwise, the patient is free to return to her regular activities. Q: How soon will I know if I'm pregnant? A: Pregnancy can be confirmed using blood tests about 14 days after egg aspiration. Pregnancy can be confirmed by ultrasound within two weeks after that. Q: Will I have an egg in every follicle? A: It varies from patient to patient. As many as half of the follicles may not contain an egg in some patients. Q: How much time does the entire procedure require? A: Approximately three weeks (all as an outpatient). Fertility drugs are administered to stimulate the ovaries. Then during the four to six days prior to ovulation, the patient is monitored by ultrasound as well as by hormone levels. Q: What happens to any extra embryos? A: Patients will have several options regarding the disposition of the remaining embryos. One option is to freeze embryos for your later use. Other options are to donate or simply dispose of them. Excess embryos belong to you, and only you will determine what is to be done with them. 11
Cost considerations All patients considering IVF treatment should have a Financial Consultation with a CFA Benefits Specialist to determine which, if any, services are covered by their plan; and which are not. It is essential that you fully understand your benefits and responsibilities before beginning your treatment cycle. CFA hails the passage of landmark legislation in Connecticut that would require most insurance companies to provide coverage of infertility diagnosis and treatment. Bill highlights Lifetime maximum benefit of 4 cycles of ovulation induction Lifetime maximum benefit of 3 cycles of intrauterine insemination (IUIs). Lifetime maximum benefit of 2 cycles of In Vitro fertilization (IVF). Age Requirement - under 40 years old. Our Insurance Plans CFA participates in the following plans: Blue Cross Blue Shield, Anthem BCBS, Bluecare Connecticare Healthnet Oxford Aetna Cigna PHCS 12
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...miracles happen Miracles happen at Connecticut Fertility Associates. Since 1991 we have helped more than 4,000 families achieve their dreams. Forming families for over 20 years Michael Doyle, MD To learn more visit our website: www.ctfertility.com