IVF Overview

Overview of In Vitro Fertilization (IVF)

In vitro fertilization (IVF) refers to the process of retrieving eggs from the ovaries of the female partner or a donor, fertilizing the eggs in the laboratory with sperm obtained from the male partner or a donor and transferring the resulting embryos into the uterine cavity of the female partner or a surrogate. I perform IVF in collaboration with the embryology laboratory at the George Washington University Medical Center (GWUMC). I personally conduct all preliminary testing and monitoring of drug treatment in my Rockville office and perform the egg retrieval and embryo transfer at the GWUMC.

A basic IVF cycle involves several steps: (1) temporary suppression of the woman's own hormone production,(2) ovarian stimulation with medications designed to increase egg production, (3) retrieval of the eggs, (4) fertilization of the eggs, (5) culture of the resulting embryos for several days in the laboratory, and (6) transfer of the embryos into the uterine cavity. In addition, several more specialized procedures such as blastocyst culture, intracytoplasmic sperm injection (ICSI), assisted hatching, embryo cryopreservation (freezing), testicular/epididymal sperm extraction (TESE) and preimplantation genetic screening (PGS) or diagnosis (PGD) may be utilized in selected cases, as discussed in more detail below.

Ovarian Stimulation

Lupron (Leuprolide)vs Ganirelix

A cycle of IVF generally begins with the use of several medications to stimulate the production of multiple eggs within the ovaries in order to increase the likelihood that there will be healthy embryos to transfer into the uterus. Lupron (leuprolide), which may be the first drug to be administered, is a modification of gonadotropin releasing hormone, a hormone that is normally produced by a part of the brain called the hypothalamus. Lupron is used to prevent a spontaneous surge of luteinizing hormone (LH) from the pituitary gland that could cause the eggs to release from the ovaries before the egg retrieval is performed.

In a "suppression" protocol, Lupron is started one week before the menstrual period that begins the IVF cycle because it takes about 7 to 10 days of treatment to fully suppress LH production. When there is concern that the ovaries may not be fully responsive to the stimulation drugs described in the next section, Lupron may, instead, be started on the third day of the menstrual period that begins the actual IVF cycle, in what is called a "flare" protocol. In this case, the initial stimulatory effect of Lupron on the ovaries is used in an attempt to boost the response to the drugs used to stimulate egg production. Lupron is given as a daily subcutaneous injection, using an insulin syringe with a short, thin needle, for a total of about three weeks.

Ganirelix may be used instead of Lupron in selected cases to suppress the natural LH surge and potential premature egg release. Ganirelix, also given by daily subcutaneous injection, has a more rapid onset of action and thus can be started later in the cycle, after several days of ovarian stimulation.


Several drugs are available to use either alone or in combination to promote extra egg production by the ovaries. All of these medications are made up of the same hormones that are produced by the pituitary gland in the brain that normally act to stimulate egg development and estrogen secretion by the ovary.

Gonal-F and Follistim are similar drugs containing so-called recombinant follicle stimulating hormone (FSH) that is produced by inserting the human FSH gene into cells grown in a laboratory. Menopur contains a mixture of FSH and luteinizing hormone (LH) that is purified from menopausal women's urine. Menopur may be used along with Follistim or Gonal-F to add LH to the stimulation treatment. These medications are also given by daily subcutaneous injections that usually begins on the third day of the menstrual period and continues for an average of 7 to 10 days, along with the Lupron injections that were started previously.

Monitoring the Cycle

After about five days of FSH and LH stimulation of the ovaries, it is necessary to begin monitoring the response to the medications to determine the need for any adjustment in dose and to decide when to discontinue the medications in anticipation of the egg retrieval. A blood sample is drawn for the measurement of the estrogen level, which provides an indication of the ovarian response and also helps to predict the potential for ovarian hyperstimulation syndrome (OHSS), a possible complication of the use of these medications.

An ultrasound (sonogram) is also performed, using a special probe that is inserted into the vagina, to visualize the ovarian follicles, the fluid-filled cysts that contain the eggs. This provides an indication of the number of mature eggs that are potentially available for retrieval. Monitoring is continued every one to two days until several follicles reach a size that is known to be consistent with the presence of a mature egg and the estrogen level is in the proper range.

Novarel/Pregnyl (hCG)

Once the follicles have grown to the proper size, Lupron, Ganirelix and the stimulation drugs are discontinued. An intramuscular injection of human chorionic gonadotropin (hCG) is used to mimic the surge of LH that is necessary to begin the final steps of egg maturation because the natural LH surge has been suppressed by the Lupron or Ganirelix taken previously. Novarel and Pregnyl are brands of hCG, the same hormone that is normally produced during pregnancy and measured during a pregnancy test. Since hCG is rapidly eliminated from the body, it does not affect the pregnancy test that will be performed in about two weeks.

The hCG injection would normally cause the eggs to release from the ovaries about 40 hours later if the egg retrieval were not performed. Thus, the egg retrieval is scheduled for about 36½ hours after the hCG injection. Pregnyl or Novarel is given as a single intramuscular injection, often referred as the "trigger shot," when several ovarian follicles reach a size of 18 to 20 mm. The injection must be given at a specific time, based on the schedule for egg retrieval.

Egg Retrieval

I will perform your egg retrieval at George Washington University on the second day after the hCG injection. The procedure is usually done under general anesthesia and takes about 10 to 20 minutes. Spinal anesthesia may occasionally be utilized if the anesthesiologist feels that this will be a safer alternative for your medical circumstance. An ultrasound is performed to image the ovaries and guide a needle through the wall of the vagina into each follicle. Suction is applied to aspirate as many eggs as possible. You will be able to go home within one to two hours after the egg retrieval.

Several days of antibiotics are given, beginning on the day before the procedure. A progesterone supplement is also started on the second day after egg retrieval, usually in form of a gel that is placed in the vagina on a daily basis. Progesterone is continued for at least two weeks until a pregnancy test can be performed. If pregnancy occurs, the progesterone supplement is continued for another six weeks, until the tenth week of pregnancy.

Fertilization of the Eggs

Following the egg retrieval, each egg is checked for maturity and placed in an incubator. Any eggs that are not mature at the time of retrieval will be observed for several hours in the hope that the maturation process will occur. If the sperm count, motility (movement) and morphology (shape) were previously judged to be normal, all mature eggs are then mixed with the sperm that were collected earlier that day to allow the eggs to fertilize.

Intracytoplasmic Sperm Injection (ICSI)

If prior testing has shown a significant problem with the number or quality of the sperm, individual sperm obtained from an ejaculated sample can be injected into each egg to increase the chance that the eggs will fertilize, a procedure known as intracytoplasmic sperm injection (ICSI). ICSI is also used when preimplantation genetic screening and/or diagnosis (PGS/PGD) is performed in order to avoid contamination from the genetic material of any sperm that may remain adherent to the outside of the embryo following natural fertilization.

Percutaneous Sperm Aspiration (PESA)/Testicular Sperm Extraction (TESE)

In selected cases when there are no sperm present in the ejaculate, it may be possible to obtain sperm directly from portions of the sperm duct known as the vas deferens and epididymis or from the testes. This is most likely to be successful in cases where sperm production by the testes is normal but the sperm ducts are blocked, either from prior infection or vasectomy. In a procedure known as percutaneous sperm aspiration (PESA), a urologist will attempt to insert a small needle into the duct to withdraw sperm that can be used for an egg retrieval scheduled for later that day or frozen for use at a later time.

In some cases when the sperm production from the testes is very low, a urologist may be able to find small amounts of sperm by performing a biopsy of several areas of the testes. Because the number of sperm that can be obtained from the sperm duct or directly from the testes is quite low, ICSI must be performed in this situation to improve the chance of fertilizing the eggs.

Embryo Culture

The growth of the embryos that result from the eggs that have fertilized normally is evaluated on a daily basis. The embryos should continue to split into increasing numbers of cells each day. By the second day after egg retrieval, the embryos should contain about four cells and by the third day after retrieval the embryos should contain approximately eight cells. If only a small number of growing embryos are available, they will generally be transferred into the uterus either two or three days after retrieval, at the four- to eight-cell stage of development.

Blastocyst Culture

If at least four to five eggs have fertilized, continued culture of the embryos for a total of five days after egg retrieval will be considered. By day five, the embryos should reach a stage of development called the blastocyst. A blastocyst contains about 100 cells that are arranged around a cystic cavity called a blastocele.

While not all embryos will progress to the blastocyst stage, those that develop to this point are considered to be of the highest quality. This allows us to select the best one, two or three embryos for transfer (depending on the age of the woman), which maintains good pregnancy rates while limiting the risk of multiple pregnancy that can occur with the transfer of more embryos. Apart from the embryo selection advantage, the transfer of blastocysts also appears to result in a higher pregnancy rate when compared with embryos transferred at an earlier stage of development, possibly because embryos normally implant in the uterus as blastocysts during natural cycles. Even if the embryos have not progressed to the blastocyst stage by day five, we have also seen successful pregnancies result from the transfer of embryos at the morula stage, which is the point of embryo development that is just before the blastocyst.

Embryo Transfer

The embryo transfer, which I will also perform at George Washington University, is accomplished by inserting a thin flexible tube through the opening of your cervix and into the uterine cavity to inject the embryos. Anesthesia is not required.

The number of embryos to be transferred into the uterus is a balance between increasing the success rate for the cycle and controlling the risk of developing a multiple pregnancy. If embryo transfer is performed two or three days after egg retrieval, usually up to three to four embryos will be transferred into the uterus depending on your age, the condition of your embryos, and the number of previous IVF attempts. For day five transfers, usually no more than two to three blastocysts are transferred, again, dependent on age and embryo quality. Women who are 35 or younger are encouraged to consider elective single embryo transfer (eSET), which still results in excellent pregnancy rates and significantly reduces the risk of multiple pregnancy with its attendant risk of complications such as premature delivery.

Following the embryo transfer you may resume your normal activities. As mentioned previously, you will be taking supplemental progesterone in the form of a vaginal gel for the next two weeks until a pregnancy test can be performed. If you become pregnant, an ultrasound is scheduled about six weeks from your last period to determine the number of pregnancy sacs and heartbeats that are present. Progesterone supplements are then continued until the tenth week of pregnancy.

Assisted Hatching

In selected cases, assisted hatching of the embryos may be recommended on the day of the embryo transfer. In order to implant in the uterus, the cells of the embryo must hatch out of their surrounding membrane, called the zona pellucida. While this occurs naturally in most cases, sometimes the zona pellucida may be thicker or harder than normal. This may be a concern for women in their late thirties or forties, women who have failed to get pregnant with several prior IVF cycles and embryos that have been previously frozen. With assisted hatching, a special laser is used under microscopic control to weaken a portion of the zona pellucida to assist the hatching process.

Embryo Cryopreservation (Freezing)

Embryos that fail to fertilize or that stop dividing are discarded. Any healthy embryos that are not used may be frozen and stored for transfer in a later cycle. The advantage of freezing embryos is the relative ease and lower cost of thawing and transferring these embryos at a later time. The disadvantages of cryopreservation are the possibility that the embryos may not survive the freezing process and the generally lower pregnancy rate seen with previously frozen embryos compared with fresh embryos.

Preimplantation Genetic Screening/Diagnosis (PGS/PGD)

Embryo Biopsy

Preimplantation screening for aneuploidy (PGS) or diagnosis (PGD) for specific single gene disorders can provide some indication of the genetic health of each of the embryos that result from the IVF procedure in those cases in which this issue may be of concern. Multiple cells are removed from each blastocyst on the fifth day after the egg retrieval. The resulting embryo biopsies are sent to a specialized laboratory to be analyzed for either a specific gene disorder (PGD) or to ensure that the correct number of chromosomes and/or the correct amount of genetic material is present within each embryo (PGS). The results of the analysis are received on the following day and used to select the healthy embryos for transfer to the uterus. While similar information can be obtained during a pregnancy by chorionic villus sampling or amniocentesis, PSG and/or PGD provides the opportunity to reduce the risk of the emotional hardship of a genetically abnormal pregnancy.

Single Gene Disorders

PGD can be used to check for the presence of numerous inherited disorders such as cystic fibrosis, hemophilia, sickle cell disease, and Tay-Sachs, to name a few, that are caused by a specific and known gene mutation. Here, a small segment of DNA that matches the affected gene mutation is constructed and used as a probe to determine whether there is a normal or abnormal gene present in the cells of the embryo. Couples in which one or both partners are carriers of an abnormal gene or who have had an affected child may benefit from PGD to improve the chances of having a healthy infant. Unlike PGS, PGD is often covered by insurance, even if the insurance policy does not cover the IVF procedure itself. A complete list of diseases that can currently be diagnosed by PGD may be found at the Web site of Genesis Genetics www.genesisgenetics.org. Note that PGD only provides information on the presence, or lack thereof, of a specific gene mutation. It does not evaluate for aneuploidy or balanced translocation as described below. For this reason, many patients will choose to do PGD in combination with PGS.

Aneuploidy/Balanced Translocation

The human genetic information is contained in 22 unique chromosomes that each exist in pairs, plus the X and Y chromosomes, totaling 46 chromosomes in all. The presence of extra or missing chromosomes is called aneuploidy. Although most cases of aneuploidy are lethal to the embryo, resulting in failed conception or miscarriage, some babies can be born with aneuploidy. For example, a child with Down's syndrome has three copies of chromosome number 21 and a girl with Turner's syndrome has only a single X chromosome.

Aneuploidy is common in human embryos and occurs with increasing frequency as women age into their late thirties and forties. This is thought to be a major reason for the relative inefficiency of human reproduction both naturally and with the use of IVF. Since aneuploidy does not occur until an egg is fertilized with sperm and the embryo begins to divide, there is no test for aneuploidy other than the analysis of the actual embryos derived from an IVF procedure. It has been suggested that this may be an appropriate analysis for couples that have had multiple miscarriages without any other identifiable cause or who have failed to conceive after several attempts at IVF.

In a balanced translocation, one of the paired chromosomes transfers a segment of genetic material to a different chromosome, resulting in one chromosome that is too long and another different chromosome that is too short resulting in an imbalance in the amount of genetic material for those specific chromosomes. Each of these chromosomes also has a corresponding paired chromosome that is normal. Thus, although the total amount of genetic material is correct (balanced) and the individual suffers no ill effects, there is the potential to transmit either the abnormally long or short chromosome to the pregnancy resulting in an imbalance in the amount of genetic material in the embryo. If the parent provides both of the the normal chromosomes to the embryo, the resulting pregnancy ends up with the right amount of genetic material. However, if the parent provides one of the chromosomes that contains either too much or too little genetic information to an embryo, miscarriage may occur. A balanced translocation in either partner can be detected by a blood test that is part of the evaluation for recurrent miscarriage.

The analysis for aneuploidy or balanced translocation is called preimplantation genetic screening (PGS). A relatively new testing procedure, known as Next Generation Sequencing (NGS), is performed on the embryo cell biopsies to determine whether the proper number of chromosome pairs and genetic material are present in the embryo. NGS is much more accurate and sensitive than previous genetic analysis techniques because it can detect multiple or missing copies of all 22 chromosome pairs in addition to the presence or absence of the X and Y chromosomes. PGS is generally not covered by insurance.

As with any procedure, couples should meet with me to obtain a complete understanding of the limitations of the PGS and/or PGD analysis. This includes the possibility that there may not be sufficient blastocysts available for biopsy and the possibility that the PGS analysis may not reflect additional genetic changes that occur as the pregnancy continues to develop. Thus, there is a small chance of a false positive result, where PGS shows a problem in the biopsied cells that does not exist in the remainder of the embryo, or a false negative result, where the biopsied cells are normal but the baby does, in fact, have a genetic abnormality, a situation known as mosaicism. Because of the small possibility of incorrect results from PGS or PGD, it is strongly recommended that couples confirm the results with genetic testing of the infant in early pregnancy.

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