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The ABCs of IVF

By David Kreiner MD

May 9th, 2014 at 9:15 am

 

credit: digitalart/freedigitalphotos.net

If you’re not pregnant yet and you’re wondering what to do, this post may shed some light on infertility diagnoses and treatments. Yes, there’s a lot to learn. Yes, it can be overwhelming. But the good news is that you can go to the head of the class by the time you finish reading this post.

Dr. David Kreiner of Long Island IVF gives you the low-down and the lingo. It’s everything you need to know, from A to… well… P. And what better letter to stop at? “P” is for pregnant:

“Why me? My wife never had any infections, surgery or any other problem? I have no difficulty ejaculating and there’s plenty to work with so why can my friends and neighbors and coworkers get pregnant and we can’t?”

I hear these questions daily and understand the frustrations, anger and stress felt by my patients expressing these feelings through such questions. There are many reasons why couples do not conceive. An infertility workup will identify some of these. A semen analysis will pick up a male factor in 50-60% of cases. A hysterosalpingogram will locate tubal disease in about 20% of cases. Another 20-30% of women do not ovulate or ovulate dysfunctionally. A post coital test may identify that the problem is that the sperm is not reaching the egg. It may not be able to swim up the cervical canal into the womb and up the tubes where it should normally find an egg to fertilize. When these tests are normal a laparoscopy may be performed to identify the 20-25% of infertile women with endometriosis. However, even when this is normal and there is no test that logically explains the lack of success in achieving a pregnancy; an IVF procedure may both identify the cause and treat it successfully.

What is IVF?

In Vitro Fertilization, IVF, is the process of fertilizing a woman’s eggs outside the body in a Petri dish. Typically, a woman’s ovaries are stimulated to superovulate multiple eggs with gonadotropin hormones, the same hormones that normally make a woman ovulate every month. Injections of these hormones are usually performed by either the husband or wife subcutaneously in the skin of the lower belly with a very tiny needle. It takes 9-14 days for the eggs to mature. She will then take an HCG injection which triggers the final stage of maturation 35-36 hours prior to the egg retrieval. This is performed in an operating room, usually with some anesthetic. The eggs are inseminated in the lab and 3-5 days later, embryos are transferred into the uterus with a catheter placed transvaginally through the cervix into the womb.

What is ICSI?

Some times even in the presence of a normal semen analysis, and normal results on all the infertility tests, fertilization may not occur without microsurgically injecting the sperm directly into the egg. This procedure is called Intracytoplasmic Sperm Injection or ICSI and may achieve fertilization in almost all circumstances where there is otherwise a sperm cause for lack of fertilization.

If it looks like a sperm and swims like a sperm, why doesn’t it work like a sperm?

A South African gynecologist, Thinus Kruger, discovered that small differences in the appearance of sperm affected the sperm’s ability to fertilize an egg. In 1987, Thinus demonstrated that when we used the very strict Kruger criteria for identifying a normal sperm, we were able to identify most men who had normal semen analyses and were yet unable to fertilize their wife’s eggs. Most of these couples suffered from unexplained infertility except now utilizing the Kruger criteria for sperm morphology we were able to identify the problem. Today, these couples are successfully treated with the ICSI procedure.

Old eggs?

As women age, the percentage of genetically abnormal eggs increases. These older eggs are less likely to fertilize, divide normally into healthy embryos or result in a pregnancy. When older women do conceive they are more likely to miscarry then when they were younger. Aging of eggs begins in the 20’s but accelerates after age 35. This is why a woman’s fertility drops as she gets older. The age at which it becomes significant for a woman varies. Some women in their 30’s have significant aging of their egg. Others less so and may have a good number of healthy eggs into their 40’s.

ABC’s of IVF

Assisted Hatching is when the embryologist makes a hole in the shell around the embryo called the zona pellucidum. This is performed minutes prior to embryo transfer and may be performed chemically with acid tyrodes, mechanically with a micropipette or with a laser. It is commonly believed that older eggs may lead to embryos with a thicker or harder shell that may prevent the natural hatching of an embryo that must occur prior to the embryo implanting into a woman’s lining of her womb.

Blastocyt embryo transfers occur on day 5 or 6 after the egg retrieval. This is the embryonic stage when an embryo normally implants into the womb. These embryos have been selected to be healthier by virtue of the fact that they have made it to this stage. Statistically, the pregnancy rates for women who have had blastocysts transferred is higher than when the same number is transferred on day 3 using “cleaved” embryos of 4-10 cells. As the advantage of the blastocyst transfer may be only a matter of selection, it is thought that there may be no advantage if the embryologist is able to select just as well the best embryos to transfer on day 3 which is typically the case when there are not excess numbers of high quality embryos which will vary according to the patient and be dependent on the age of the patient.

Bravelle – Brand of FSH, follicle stimulating hormone which is a gonadotropin used to stimulate a woman’s ovaries to superovulate and make multiple eggs mature during the IVF cycle.

Cetrotide – Brand of Gonadotropin Releasing Hormone Antagonist that prevents a woman’s pituitary gland from producing LH, luteinizing hormone. LH increases can trigger premature ovulation and stimulate testosterone and progesterone production which can be harmful to a woman’s egg production and prematurely mature the lining of womb potentially affecting implantation.

Co-culture of a woman’s endometrial cells from the uterine lining or granulosa cells from aspirated ovarian follicles along with the embryos in the same culture dish is thought to provide growth factors for the embryos which may improve the health and growth of the embryos.

Cleavage Stage Embryos are 2-10 cell embryos transferred on day 2 or 3. They are often graded by their lack of fragmentation and granularity of the inside of the cell cytoplasm; A to D or 1to 5 with A or 1 being the best grade.

Cryopreservation or freezing can be performed on individual eggs where it may serve as a way to preserve a woman’s fertility either due to aging or in preparation for surgery, chemotherapy or radiation which may affect future access to a woman’s eggs.  It may be performed on cleaved embryos or blastocyst embryos that are already fertilized either because they are in excess of the desired number of embryos to be transferred fresh or to bank for a future PGS/PGD or to improve implantation by delaying transfer to a subsequent unstimulated cycle.

Embryo Glue is a protein supplement to the transfer media prepared minutes prior to transfer to make the embryo more likely to stick to the lining of the womb. It is believed that some embryos may not implant since they are not adhering to the lining and do not get an opportunity to burrow into the endometrium.

Estradiol is produced by the granulosa cells of the follicle which surround the egg in the ovary. As follicles are stimulated and grow they produce more estradiol. We measure estradiol to monitor development of the follicles. It also helps to prepare the lining of the womb for implantation.

Follistim – Brand of FSH, follicle stimulating hormone which is a gonadotropin used to stimulate a woman’s ovaries to superovulate and make multiple eggs mature during the IVF cycle.

Ganirelix – Brand of Gonadotropin Releasing Hormone Antagonist that prevents a woman’s pituitary gland from producing LH, luteinizing hormone. LH increases can trigger premature ovulation and stimulate testosterone and progesterone production which can be harmful to a woman’s egg production and prematurely mature the lining of womb potentially affecting implantation

Gonal F – Brand of FSH, follicle stimulating hormone which is a gonadotropin used to stimulate a woman’s ovaries to superovulate and make multiple eggs mature during the IVF cycle.

Gonadotropins – FSH, follicle stimulating hormone and LH, luteinizing hormone stimulate the follicles in the ovary to mature and produce ovarian hormones, estradiol, testosterone and progesterone. It also is used to stimulate a woman’s ovaries to superovulate and make multiple eggs mature during the IVF cycle. We adjust the ratio of FSH and LH to achieve goals of optimal follicular development and maturation while trying to minimize the risk of hyperstimulation. Typically we administer the gonadotropins to the woman for 8-14 days before giving her HCG 35-36 hours prior to the egg retrieval

HCG is human chorionic gonadotropin, the pregnancy hormone we measure to see if your wife is pregnant. We follow the numbers to monitor the growth and health of the pregnancy. HCG has the same biological effect as LH and therefore can be used to mature the egg in the same way as if it were getting ready to ovulate. We therefore administer HCG to women 35-36 hours prior to the egg retrieval. Brand names for HCG include Pregnyl and Ovidrel.  HCG is occasionally used in place of HMG (Menopur, see below) with similar effects.

HMG – Human Menopausal Gonadotropins are purified from the urine of menopausal women since they have high levels of FSH and LH. Menopur is the brand of HMG used in IVF stimulations containing a 1:1 ratio of FSH to LH. We adjust the ratio of FSH and LH to achieve goals of optimal follicular development and maturation while trying to minimize the risk of hyperstimulation. Adding pure FSH, i.e. Bravelle, Follistim or Gonal F will increase the ratio of FSH to LH which may be desirable especially early in a stimulation. Some patients may not need any supplemental LH and are stimulated with FSH only. HMG is sometimes added towards the end of a stimulation to minimize the risk of hyperstimulation syndrome.

Hyperstimulation syndrome is a condition which occurs approximately 3% of the time as a result of superovulation of a woman’s ovaries with gonadotropins. A woman’s ovaries become enlarged and cystic, fluid accumulates in her belly, and occasionally around her lungs. When it becomes excessive, it may make it uncomfortable to breathe. We remove this excess fluid with a needle. Women can also become dehydrated and put them at risk of developing blood clots. We therefore recommend fluids high in salt content like V 8 and Campbell’s chicken soup. We give patients baby aspirin to prevent clot formation and a medication called cabergoline which helps prevent the development of Hyperstimulation.  It may also be recommended to freeze all the embryos and postpone the transfer to a later cycle as pregnancy can significantly exacerbate Hyperstimulation syndrome as well as potentially be more likely to implant in a subsequent cycle.

ICSI – Some times even in the presence of a normal semen analysis, and normal results on all the infertility tests, fertilization may not occur without microsurgically injecting the sperm directly into the egg. This procedure is called Intracytoplasmic Sperm Injection or ICSI and may achieve fertilization in almost all circumstances where there is otherwise a sperm cause for lack of fertilization

Lupron is a Gonadotropin Releasing Hormone Agonist that must be administered after a woman ovulates or concurrent with progesterone or oral contraceptive pills to effectively suppress gonadotropins. Lupron prevents a woman’s pituitary gland from producing LH, luteinizing hormone. LH increases can trigger premature ovulation and stimulate testosterone and progesterone production which can be harmful to a woman’s egg production and prematurely mature the lining of womb potentially affecting implantation

Monitoring of a woman’s stimulation with gonadotropins is performed by transvaginal ultrasound examination of her ovarian follicles and blood hormone levels. The gonadotropin doses can be adjusted according to the results of the monitoring. The timing of the HCG and subsequent egg retrieval are likewise based on the monitoring. Typically, a woman need not be monitored more frequent than every 3 days initially but may need daily monitoring as she approaches follicular maturation to determine timing of the HCG injection and retrieval.

Morula is the stage between the cleavage stage embryo and blastocyst. It is when the embryo is a ball of cells and is usually achieved by the 4th day after insemination.

Oral contraceptive pills are often given prior to the stimulation to help time stimulation starts and bring a woman’s reproductive system to a baseline state from which the stimulation may be initiated.

PGD/PGS is preembryo genetic diagnosis and screening.  PGD refers to diagnosing the presence of a single gene disorder in the embryo.  Typically, patients with a prior history of producing a child with this disorder or where both partners are known carriers for a genetic disease are candidates for PGD.  Alternatively, patients could make the diagnosis in pregnancy by chorionic villus sampling or amnioscentesis.  PGS is screening for chromosomal abnormalities and has been used to improve success after embryo banking, to prevent chromosomally caused recurrent miscarriages, to improve success with older patients’ IVF cycles and for family balancing/gender selection.  Embryos are biopsied 3 days after retrieval in the cleaved state or 5 or 6 days after retrieval in the blastocyst state. 

Progesterone is an ovarian hormone that prepares the lining of the womb for implantation. We measure it during stimulation to check if the lining is getting prematurely stimulated. We add it to the woman after the retrieval to better prepare the lining and continue it as needed to help sustain the implanted embryo until the placenta takes over production of its own progesterone.  It may be administered as an intramuscular injection in which it is placed in various oil media to facilitate absorption.  It may also be administered as vaginal suppositories or tablets either as compounded micronized progesterone or in the commercially prepared brands; Endometrin and Crinone.

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