To understand in vitro fertilization, it is necessary to understand the natural conception process. In the middle of a normal menstrual cycle, an egg is released from the ovary into the fallopian tube. Fertilization occurs in the fallopian tube, where the fertilized egg remains for several days while dividing and becoming an early embryo. A few days later, the embryo enters the uterus and implants in the uterine wall.
In vitro fertilization can be thought of as a fallopian tube bypass. The ovaries are stimulated with injectable fertility drugs to make multiple eggs. Transvaginal ultrasounds and blood tests done during this time help determine when the eggs are mature. At this point, they are retrieved through the vagina with a minor procedure that requires only a mild anesthetic. The eggs are put in a petri dish and exposed to the husband’s sperm.
The next day, the eggs are examined to see if fertilization has been successful. If so, they are left in the petri dish to divide and become early embryos. After several days, one or more embryos are placed in the woman’s uterus in a simple procedure that is generally no more uncomfortable than a Pap test. Extra embryos are assessed by the IVF laboratory personnel. If they are viable they may be frozen for future use by the couple.
In vitro fertilization (IVF) is an advanced reproductive technology that was first successful in England in 1978. Initially IVF was used to treat only infertility caused by blocked fallopian tubes. Today, IVF has evolved to become an effective treatment for all causes of infertility when simpler treatments have not been successful or are not an option. The chance for success with IVF has also come a long way over the last several decades. In fact, many clinics are now attaining IVF success rates of 50 percent or more for patients with a favorable prognosis.
The IVF procedure
In natural conception, an egg is released from the ovary into the fallopian tube in the middle of a menstrual cycle. The egg is fertilized in the fallopian tube. The fertilized egg then begins to divide in the fallopian tube, thus becoming an early embryo. After being in the fallopian tube for several days the embryo enters the uterus where it will implant.
IVF can be thought of as a bypass of the fallopian tubes. The IVF process involves stimulating the ovaries with "fertility shots" to mature multiple eggs. Development of the eggs is monitored with blood tests and vaginal ultrasounds. Once the eggs are "mature," they are removed from the ovary with a very minor surgical procedure and mild anesthesia. After the eggs are retrieved, they are put into a petri dish and exposed to the partner's sperm. The eggs are examined the following morning to see if they have been successfully fertilized by the sperm. The fertilized eggs are left in the petri dish for several days during which time they begin to divide and become early embryos (as occurs in the fallopian tubes during natural conception). The embryos are then placed in the woman's uterus with a small catheter through the cervix that is generally no more uncomfortable than a Pap test. If there are extra embryos that are viable, they may be cryopreserved (frozen) for future use.
IVF laboratory procedures
The full spectrum of IVF laboratory procedures are performed at Cleveland Clinic, including:
- Fertilization with intracytoplasmic sperm injection (ICSI): ICSI is an effective method of fertilizing eggs in situations when insufficient sperm is available, sperm parameters are compromised, or when previous fertilization methods have failed. Through ICSI, even the most severe cases of male infertility – very low numbers of sperm or even no sperm in the ejaculate – can be successfully treated with IVF. In these cases, sperm often can be obtained from the testes or epididymis by a minor outpatient procedure.
- Assisted hatching: In order for an embryo to implant in the uterus it must break through the zona pellucida, a thin "shell" surrounding the embryo. The process of the embryo breaking through the zona pellucida is called "hatching." Hatching can be aided by making a tiny opening in the zona pellucida just prior to transferring the embryo to the uterus. In Cleveland Clinic's IVF program, assisted hatching is routinely performed on all embryos before they are transferred to the uterus.
- Embryo freezing: Surplus embryos that are not transferred to the patient's uterus may be able to be frozen ("cryopreserved") for future use by the couple. In Cleveland Clinic's IVF program, cryopreservation of embryos is carried out either on the third day after egg retrieval when the embryo is between 6 and 8 cells in size or on the fifth or sixth day after egg retrieval (the "blastocyst" stage). Embryos that have potential to become successful pregnancies in the future are cryopreserved.
- Preimplantation genetic diagnosis (PGD): In 2002, Cleveland Clinic's IVF program was the first in the region to launch a PGD program. PGD involves removing a single cell from a developing embryo at the eight-cell stage. The cell is then analyzed for chromosomal and/or specific genetic disorders. For patients with sex-linked diseases or single gene disorders such as cystic fibrosis, genetic screening of embryos is a powerful technique. In these patients, IVF coupled with embryo screening can greatly reduce the risk of offspring being affected by the disease.
- Oocyte/ovarian tissue cryopreservation: Cleveland Clinic's IVF laboratory is becoming increasingly active in the area of freezing eggs and ovarian tissue. There have been very few births resulting from ovarian tissue cryopreservation and it is clearly still very experimental. In contrast, egg freezing has become much more successful in the past decade and is no longer considered experimental. Egg freezing may be considered for:
- Women with cancer who are about to undergo chemotherapy that can cause their ovaries to be unable to make eggs in the futureW
- Women who are undergoing In Vitro Fertilization who do not feel comfortable freezing all or any embryos
- Women in their 30's who are delaying child bearing
- Genetic Screening for Chromosome Anomalies: Cleveland Clinic is offering a new technique for screening patient embryos and selecting those most likely to result in a pregnancy. This powerful new technique know as Trophectoderm Biopsy allows the removal of multiple cells at the blastocyst stage. Embryos can be examined for inherited genetic disorders as well as chromosomal abnormalities. Patients with recurrent losses or at risk for chromosomal abnormalities can have their embryos analyzed using the new Genesis-24 screen. By testing a patient’s embryos for chromosomal abnormalities and selecting only normal embryos for transfer, the patient's opportunity for a pregnancy with a healthy baby is increased. The Genesis-24 technique is quite powerful and allows transfer of embryos in the same IVF cycle.
What does Cleveland Clinic offer in the way of emotional support?
The emotional stress of infertility can be overwhelming. Our physicians and infertility nurses are all very experienced in providing ongoing emotional and educational support as well as guidance for couples going through infertility evaluation and treatment. Acupuncture and guided imagery are available as techniques for stress reduction. In addition, we work closely with psychiatrists and mental health nurses for patients who may benefit from their services.
The nursing staff in the IVF Operating Room area, where retrievals and embryo transfers are done, include:
- Lori Myerhoff, RN
- Mary Alice Rigden, CLPN
- Doreen Peskin CRNA, Nurse Anesthetist
Nurses at the Main Campus IVF office include:
- Debbi Breeden, RN
- Cindy McCrork, LPN
- Brenda Nikolaisen, RN
All of our very experienced nurses can provide emotional and educational support and guidance for couples going through infertility treatment and IVF.
In addition, the Beachwood Fertility Center includes a psychiatrist, Jennifer Rosenberg, MD, who specializes in women's mental health and a nurse, Lynne Norrie, RN, who has extensive experience in teaching relaxation techniques and guided imagery. At Cleveland Clinic's main campus, Dana Everson, PhD, is available to provide counseling and psychological support for patients as they experience the stress of infertility and IVF.
When should a couple seek an infertility evaluation?
Infertility is generally defined as not conceiving after one year of unprotected intercourse. At this point, couples may benefit from an infertility evaluation.
Some couples should seek help earlier. Couples in whom the woman is over age 35 are advised to have an evaluation after six months of trying to conceive. Women with irregular periods and or pelvic pain, men with a history of urologic problems, and couples who are stressed from their inability to conceive are also among those who should seek evaluation earlier.
What diagnostic tests are done for infertility?
Standard testing done by our fertility specialists includes a semen analysis to assess the number and quality of the sperm and a hysterosalpingogram (HSG) to evaluate the uterine cavity and document that the fallopian tubes are open. The HSG is performed in the X-ray department by injecting X-ray dye through the cervix while observing on a TV monitor.
Additional tests may be recommended by fertility specialists based on the individual patients’ history, physical examination and the results of previous testing. These may include blood work for hormone levels, ultrasound of the uterus and ovaries or laparoscopy. Laparoscopy is an outpatient procedure which involves placing a thin scope through the navel to diagnose and treat conditions such as endometriosis, pelvic adhesions (scar tissue), fibroid tumors and tubal disease.
What infertility treatments other than in vitro fertilization are available?
The majority of couples can conceive with simpler, less expensive treatments than in vitro fertilization. Common treatments include:
- Oral medications to restore regular menstrual cycles such as clomiphene, letrozole or metformin.
- Injectable fertility drugs to stimulate several eggs to ovulate, which include Repronex, Gonal-F, Follistim, Bravelle and Menopur.
- Intrauterine insemination, a process in which the husband’s sperm is “washed” and inserted into the uterus. Intrauterine insemination is often used in combination with clomiphene citrate or gonadotropins injections.
- Donor insemination, a process in which sperm from an anonymous donor is used to inseminate a woman. This can be done for single women or married couples in whom the husband has severely compromised sperm (although most of these couples choose in vitro fertilization).
- Medical and surgical treatment for the man.
- Reproductive surgery.
Is egg donation or surrogacy an option?
Cleveland Clinic offers both services. Egg donation may be considered by couples who are unlikely to have success with in vitro because the woman does not produce enough healthy eggs. We will work with couples utilizing all options for obtaining donor eggs including known donors, anonymous donors, donor egg agencies and egg sharing.
Surrogacy is available for women who produce an adequate number of healthy eggs but have no uterus, a damaged uterus or a medical condition that precludes carrying a pregnancy safely. While the technology for both of these programs is readily available, it is essential that couples be comfortable with the use of “third party reproduction” before proceeding with these programs.
What is the risk of multiple pregnancies with in vitro fertilization?
The risk of higher order multiple births (triplets or more) has decreased significantly over the last decade. As technology has improved, we are able to transfer fewer embryos without compromising the chance of success. Ten years ago, three or four embryos needed to be transferred to achieve a pregnancy rate of 25-30 percent, even when the woman was under age 35. This resulted in an unacceptably high number of triplets and quadruplets.
Today, we achieve approximately twice the success rate in women under 35 despite transferring only two embryos. This high success rate with transferring fewer embryos has decreased the incidence of higher order multiple pregnancies in our in vitro fertilization program and around the world.
Step By Step
- Patients are scheduled for surgery.
- Physicians use a long needle to puncture ovarian follicles and collect fluid.
- Embryologist looks at the fluid under the microscope and finds the egg from each follicle.
- Eggs are washed and placed in a dish.
Finding the best lookers and swimmers
- Husbands are asked to give a sperm sample. To get good fertilization the lab tries to isolate fast swimming sperm with good morphology.
- The sperm sample is placed on a column of silica beads and centrifuged.
- The “best” sperm reach the bottom fastest and are collected.
- Motile sperm and eggs are combined to create an embryo. This step is called “Insemination.”
Intracytoplasmic Sperm Injection (ICSI)
Sometimes nature needs a hand
- When sperm counts or motility are too low ICSI is used for the insemination step.
- A single motile sperm is visualized under the microscope.
- The embryologist picks it up with a glass needle.
- The sperm is then injected into the egg.
Testicular/Epididymal for ICSI
All you need is one sperm per egg
- Sometimes with severe male factor infertility, sperm needs to be surgically isolated from the testis or epididymis by a urologist.
- Sperm isolated from the testis or epididymis are injected into oocytes (ICSI).
- IVF lab personnel often search for hours just to find a dozen sperm for injection.
- Pregnancy rates of 35% to 60% have been achieved depending on patient age and sperm quality from the testis or epididymis.
Male and female genetic material combine
- Eggs are examined the day after retrieval for fertilization.
- The presence of two nuclei in the center of the egg is a sign that normal fertilization occurred.
- The fertilized eggs are moved to a new dish and watched every day for cell division.
Embryo divides each day
- The embryo should divide each day going from a single cell to over 100 cells by the time it attaches to the uterine wall at the blastocyst stage.
Steps towards implantation
- During early blastocyst development, fluid starts to fill embryo. The embryo starts to expand like a balloon. To implant, the embryo must escape from the shell surrounding it. This is called "hatching."
No place like home
- Embryos are transferred to the patient’s uterus on Day 3 or Day 5.
- Most patients have Day 3 transfers.
- Transferring later on Day 5 can help in embryo selection.
- The deciding factor for a Day 3 vs. Day 5 transfer is overall embryo number and cell division.
- Extra non-transferred embryos of good quality are frozen.
Planning for the future
- Extra embryos not used for the fresh transfer can be frozen between Day 3 and Day 6.
- Only high quality embryos are frozen.
- Vitrification, a recent advance in cryobiology, is currently used for all embryo freezing.
- Introduction of this technique to our IVF lab has increased post-thaw survival and clinical pregnancy outcomes.
Storing fertility potential
- Patients may now freeze their unfertilized eggs for a future IVF cycle.
- Egg freezing offers cancer patients an opportunity to bank oocytes before starting radiation or chemotherapy.
- Ovarian tissue cryopreservation is also available for cancer patients.
Preimplantation Genetic Diagnosis (PGD)
Chromosomes tell all
- Screening embryos for genetic diseases is a powerful new tool to enhance opportunity for a healthy baby.
- CCF Fertility Center was the first program in northeast Ohio to offer PGD.
- A single cell is removed on Day 3 at the six-eight cell stage and its chromosomal status is assessed.
- Only normal embryos are transferred.
- Embryos can be screened for many diseases such as cystic fibrosis, muscular dystrophy, Down’s syndrome, etc.
Co-culture for Implantation Failure
Helper cells to jumpstart the embryo
- Cleveland Clinic IVF program is one of the few centers offering co-culture to enhance embryo development.
- Co-culture may benefit patients with previous failed IVF attempts or poor embryo quality.
- Embryos are cultured in a unique chamber with uterine cells.
- Growth factors from uterine cells may help struggling embryos to divide.
In Vitro Maturation
Growing eggs in a culture dish
- New frontier in assisted reproduction.
- Immature oocytes recovered with minimal or no hormonal stimulation.
- Immature oocytes cultured in the laboratory.
- Benefits patients who don't respond well to conventional stimulations.
- Reduce cost of IVF by minimizing use of medications.
Harboring Hope Fund
Giving couples a second chance
Cleveland Clinic’s Harboring Hope® fund is available to childless couples who have failed one cycle of IVF at Cleveland Clinic.