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In Vitro Fertilisation

In Vitro Fertilisation is defined as the process of spontaneous fertilisation of an ovum with a male sperm outside the body in an authorised institution. Simply put, In Vitro Fertilisation is an assisted reproductive technology (ART) commonly referred to as ‘IVF’. IVF is the process of fertilisation by extracting eggs, retrieving a sperm sample, and then manually combining an egg and sperm in a laboratory dish.

A process called insemination is used, this process involves mixing the sperm and eggs together in a liquid in the laboratory, where after they are stored in a laboratory dish to encourage fertilisation. In some cases, where there is a lower probability of fertilisation, intracytoplasmic sperm injection (ICSI) may be used. Through this procedure, a single sperm is injected directly into the egg in an attempt to achieve fertilisation.

The fertilised eggs (zygote) undergoes embryo culture for 2 – 6 days, during this time they are monitored to confirm that fertilisation and cell division are taking place. Once this occurs, the fertilised eggs are considered embryos. The embryo(s) is then transferred to the uterus of the Recipient and any remaining surplus embryo(s) are cryopreserved.

What is Oocyte (egg) Retrieval (Oocyte (egg) Harvest, Follicle Aspiration) and how is it performed?

Oocyte (egg) retrieval is the removal of an oocyte (egg) from the ovary for the purpose of producing a pregnancy. Women take an ovary stimulating medication (some examples of such are – Gonadotropin, Gonal F, Menopur) used to produce several oocytes (eggs). These oocytes (eggs) are then collected from the ovaries using a minor surgical technique known as transvaginal oocyte removal. A transvaginal ultrasound probe is used to visualise the ovaries and the oocyte (egg) containing follicles within the ovaries. A long, hollow needle is threaded alongside of the ultrasound probe. The needle, which can be seen on ultrasound, can then be directed into the follicle and the contents aspirated (withdrawn). The aspirated material includes follicular fluid, oocytes (eggs), and granulosa (egg-supporting) cells. Rarely, the ovaries are not accessible by the transvaginal route and laparoscopy or transabdominal retrieval is necessary. Transvaginal oocyte removal is done under anaesthetic, where an intravenous anaesthesia is used during the procedure (adjunctively) to reduce discomfort. These procedures and risks will be discussed with you by your doctor if applicable.

Risks of oocyte (egg) retrieval

Infection:
Bacteria normally present in the vagina may be inadvertently transferred into the abdominal cavity by the needle used to retrieve the eggs. These bacteria may cause an infection of the uterus, fallopian tubes, ovaries or other intra-abdominal organs. The estimated incidence of infection after egg retrieval is less than 0.5%. Treatment of infections could require the use of oral or intravenous antibiotics. Severe infections occasionally require surgery to remove infected tissue. Infections can have a negative impact on future fertility. Prophylactic antibiotics are sometimes used before the egg retrieval procedure to reduce the risk of pelvic or abdominal infection in patients at higher risk of this complication. Despite the use of antibiotics, there is no way to eliminate this risk completely.

Bleeding:
The needle passes through the vaginal wall and into the ovary to obtain the eggs. Both of these structures contain blood vessels. In addition, there are other blood vessels nearby. Small amounts of blood loss are common during egg retrievals. The incidence of major bleeding problems has been estimated to be less than 0.1%. Major bleeding will frequently require surgical repair and possibly loss of the ovary. The need for blood transfusion is rare. (Although very rare, review of the world experience with IVF indicates that unrecognised bleeding has led to death).

Trauma:
Despite the use of ultrasound guidance, it is possible to damage other intra-abdominal organs during the egg retrieval. Previous reports in the medical literature have noted damage to the bowel, appendix, bladder, ureters, and ovary. Damage to internal organs may result in the need for additional treatment such as surgery for repair or removal of the damaged organ. However, the risk of such trauma is low.

Failure:
It is possible that the aspiration will fail to obtain any eggs, or the eggs may be abnormal or of poor quality and otherwise fail to produce a viable pregnancy.

Anaesthesia:
Usually medications administered by an anaesthesiologist are required for the egg retrieval surgery. You will have a consultation with the anaesthesiologist before the procedure to review the risks and benefits of the anaesthesia. In some cases, the use of anaesthesia on a specific patient may be associated with an increased risk. In such cases the physician may offer local anaesthesia without the assistance of an anaesthesiologist. It is mandatory that you do not drink or eat anything after midnight prior to day of the egg retrieval. After the procedure is completed, you will be discharged home in about an hour. Following any aesthetic, you must be accompanied home by a responsible adult. You are responsible for bringing a responsible adult with you on the day of the egg retrieval. Following the egg retrieval, vaginal spotting and lower abdominal cramping are normal.

During the remainder of the day following the surgery, activities should be limited. If significant bleeding, vomiting, abdominal pain or any other symptoms develop, you should contact your physician. If you should have any difficulty in contacting your physician, you should proceed to the emergency department of the nearest hospital.

Ovulation Induction Medication and/or Hormones

The oocytes (eggs) are present in the ovaries within fluid-filled cysts called follicles. During a woman’s menstrual cycle, usually one mature follicle develops, which results in the ovulation of a single egg. Several hormones including follicle stimulating hormone (FSH) and luteinizing hormone (LH) influence the growth of the ovarian follicle. These hormones are produced by the pituitary gland, which is located at the base of the brain. FSH is the main hormone that stimulates the growth of the follicle, which produces an oestrogen hormone called estradiol. When the follicle is mature, a large amount of LH is released by the pituitary gland. This surge of LH helps to mature the egg and leads to ovulation 36-40 hours after its initiation.

Medications are administered to increase the number of follicles that develop, which will increase the number of eggs that are obtained at the egg retrieval. The ‘main” medications that are used to cause many follicles to develop. In addition to the gonadotropins you will receive another medication to prevent ovulation: a gonadotropin-releasing hormone (GnRH) agonist or antagonist.

Gonadotropins
These are injectable medications commonly prescribed to stimulate the ovaries of women undergoing IVF treatment. Two types of gonadotropins can be prescribed and are discussed below and one or more of them may be prescribed.

  • FSH (Gonal-F, Follistim, Bravelle) – These medications contain only FSH and are administered on a daily basis by injection;
  • LH (Luveris) – This medication contains only LH and is administered by injection. It is used in combination with FSH containing medications;
  • Human Menopausal Gonadotropins (Menopur, Repronex) – These medications contain equal amounts of FSH and LH, and are administered on a daily basis by injection.

GnRH Agonist (Lupron)
This medication is taken by daily injection. The primary role of this medication is to prevent a premature release of the LH from the pituitary gland (the ‘LH surge’), which normally causes the release of eggs (ovulation). Premature ovulation would result in no eggs available to be retrieved and must be prevented by administration of the GnRH agonist or antagonist medication. GnRH agonist such as Lupron need to be taken for several days before they have their effect to prevent ovulation. Though leuprolide acetate is an FDA (Federal Drug Administration) approved medication, it has not been approved for use in IVF, although it has routinely been used in this way for more than 20 years. Potential side effects usually experienced with long-term use include but are not limited to hot flashes, vaginal dryness, bone loss, nausea, vomiting, reactions at the injection site, fluid retention, muscle aches, headaches, and depression. No long term or serious side effects are known. Since GnRH agonists are often times administered after ovulation in the menstrual prior to beginning treatment, it is possible that they could be taken early in pregnancy. The safest course of action is to use a barrier method of contraception (condoms) during the month that you will be starting the GnRH-a. Sometimes the oral contraceptive pill is used just before the GnRH agonist is started. GnRH agonists have not been associated with any foetal malformations however you should discontinue use of this medication if an inadvertent pregnancy is confirmed.

GnRH Antagonist (Cetrotide, Ganirelix)
GnRH antagonists are medications that reversibly bind to GnRH receptors in the pituitary gland and prevent release of FSH and LH. They perform the same role as GnRH agonists do, to prevent ovulation, but they are typically started on different days and administered for a shorter time since (unlike HnRH agonists) they instantly prevent ovulation when they are started. GnRH antagonists are administered in combination with gonadotropins. The major benefit of a GnRH antagonist is that it suppresses a LH surge thereby preventing ovulation.

Clomiphene Citrate (Clomid, Serophene) and letrozole (Famara)
These medications are rarely used in combination with or in lieu of gonadotropin medications to stimulate egg development. These medications are synthetic hormones that are taken orally for a period of five days and cause the release of FSH and LH, which stimulate the development of follicles.

Human Chorionic Gonadotropin [hCG] (Ovidrel, Profasi, Pregnyl, Novarel)
This medication contains the pregnancy hormone, hCG, which functions similarly to LH. It is administered by injection 36 hours before the egg retrieval to cause the eggs to become mature which will allow them to become fertilised. hCG also loses the microscopic egg from the wall of the follicle so it can be more easily be removed at the egg retrieval.

Oral contraceptive pills
Many treatment protocols include oral contraceptive pills to be taken for 2 to 4 weeks before gonadotropin injections are started in order to suppress hormone production or to schedule a cycle. Side effects include unscheduled.

Transfer of the embryo(s)

The embryos are usually transferred into the woman’s uterus three to five days following egg retrieval and fertilisation. A catheter or small tube is inserted into the uterus, along with a transvaginal ultrasound probe, used to visualise the transfer of the embryos. This procedure is painless for most women, although some may experience mild cramping. If the procedure is successful, implantation typically occurs around six to ten days following egg retrieval.

Medical Risks

As with all injectable medications, bruising, redness, swelling, or discomfort can occur at the injection site. Rarely, there can be an allergic reaction to these drugs. The use of the above listed medications can cause side effects such as nausea, vomiting, hot flashes, headaches, mood swings, visual symptoms, memory difficulties, joint problems, weight gain and weight loss, all of which are temporary. The intent of giving these medications is to mature multiple follicles, and many women experience some bloating and minor discomfort as the follicles grow and the ovaries become temporarily enlarged. Other possible side effects include the following:

Ovarian Hyper Stimulation
After the egg retrieval is performed, the ovarian follicles, which have been aspirated, can fill up with fluid and form cysts. The formation of cysts will result in ovarian enlargement and can lead to lower abdominal discomfort, bloating and distention. These symptoms generally occur within two weeks after the egg retrieval. The symptoms usually resolve within 1-2 weeks without intervention. If ovarian hyper stimulation occurs, your physician may recommend a period of reduced activity and bed rest. Pregnancy can worsen the symptoms of ovarian hyper stimulation. Severe ovarian hyper stimulation is characterised by the development of large ovarian cysts and fluid in the abdomen and sometimes, the chest. Symptoms of severe ovarian hyper stimulation include abdominal distention and bloating along with weight gain, shortness of breath, nausea, vomiting and decreased urine output. Approximately 2% of women will develop severe ovarian hyper stimulation and may need to be admitted to the hospital for observation and treatment. To help alleviate the symptoms of severe ovarian hyper stimulation an ultrasound-guided paracentesis can be performed which results in the removal of fluid from of the abdominal cavity. Rare, but serious consequences of severe ovarian hyper stimulation include formation of blood clots that can lead to a stroke, kidney damage and possibly death. Every woman who takes these medications can develop ovarian hyper stimulation

Ovarian Torsion (Twisting)
In less than 1% of cases, a fluid filled cyst(s) in the ovary can cause the ovary to twist on itself. This can decrease the blood supply to the ovary and result in significant lower abdominal pain. Surgery may be required to untwist or possibly remove the ovary.

Ovarian Cancer
Some research suggested that the risk of ovarian tumours may increase in women who take any fertility drugs over a long period of time. These studies had significant flaws which limited the strength of the conclusions. Some more recent studies have not confirmed this risk.

Breast and Uterine Cancer
More research is required to examine what the long-term impact of fertility drugs on the development of breast and ovarian cancer. For uterine cancer, the numbers are too small to achieve statistical significance, but it is at least possible that use of fertility drugs may indeed cause some increased risk of uterine cancer.

Multiple Births
The major complication of IVF is the risk of multiple births. This is directly related to the practice of transferring multiple embryos at the embryo transfer. Multiple births are related to increased risk of pregnancy loss, obstetrical complications, prematurity and neonatal morbidity with the potential for long term damage. The law in South Africa limits the number of embryos to 3 (three) that may be transferred so as to reduce the risk of high-order multiples (triplets or more). Spontaneous splitting of embryos in the womb after transfer can occur, but this is rare and would lead to identical twins.

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