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In vitro fertilisation

In vitro fertilisation
In vitro fertilization (IVF) is a technique in which egg cells are fertilized outside the woman's body. IVF is a major treatment in infertility where other methods of achieving conception have failed.

The process involves hormonally controlling the ovulatory process, removing ova (eggs) from the woman's ovaries and letting sperm fertilize them in a fluid medium. The fertilized egg (zygote) is then transferred to the patient's uterus with the intent to establish a successful pregnancy. "In vitro" is Latin for "in glass", referring to the test tubes; however neither glass nor test tubes are used, and the term is used generically for laboratory procedures. Babies that are the result of IVF have been called "test tube babies".

History

The technique was developed in the United Kingdom by Doctors Patrick Steptoe and Robert Edwards. The first so-called "test-tube baby", Louise Brown, was born in Oldham, England, as a result on July 25, 1978 amid intense controversy over the safety and morality of the procedure.
Major pioneering developments in IVF also occurred in Australia under the leadership of Carl Wood, Alan Trounson and Ian Johnston. The world's third IVF baby, Candice Reed was born on June 23, 1980 in Melbourne, Australia.

The first successful IVF treatment in the USA (producing Elizabeth Jordan Carr) took place in 1981 under the direction of Doctors Howard Jones and Georgeanna Seegar-Jones in Norfolk, Virginia. Since then IVF has exploded in popularity, with as many as 1% of all births now being conceived in-vitro, with over 115,000 born in the USA to date. At present, the percentage of children born after IVF or ICSI has been up to 4% of all babies born in Denmark.

Subhash Mukhopadhyay (physician) created history when he became the first physician in India (and second in the world after British physicians Patrick Steptoe and Robert Edwards) to perform the first In vitro fertilization resulting in a test tube baby "Durga" (alias Kanupriya Agarwal) on October 3, 1978. Facing social ostracization, bureaucratic negligence, reprimand and insult instead of recognition from the Marxist West Bengal government and refusal of the Government of India to allow him to attend international conferences, he committed suicide in his Calcutta residence in 1980.

Indications

Initially IVF was developed to overcome infertility due to problems of the fallopian tube, but it turned out that it was successful in most other infertility situations as well. The introduction of intracytoplasmic sperm injection addresses the problem of male infertility to a large extent.

Thus, for IVF to be successful it may be easier to say that it requires healthy ova, sperm that can fertilize, and a uterus that can maintain a pregnancy. Cost considerations generally place IVF as a treatment when other less expensive options have failed.

This means that IVF can be used for females already gone through pregnancy. The donated oocyte can be fertilized in a crucible. If the fertilization is sucessful, the fertilized egg will be implanted into the uterus, within which it will develop into an embryo.

METHOD

Ovarian stimulation

Treatment cycles are typically started on the third day of menstruation and consist of a regimen of fertility medications to stimulate the development of multiple follicles of the ovaries. In most patients injectable gonadotropins (usually FSH analogues) are used under close monitoring. Such monitoring frequently checks the estradiol level and, by means of gynaecologic ultrasonography, follicular growth. Typically approximately 10 days of injections will be necessary. Endogenous ovulation is blocked by the use of GnRH agonists or GnRH antagonists.

Oocyte retrieval

When follicular maturation is judged to be adequate, human chorionic gonadotropin (β-hCG) is given. This agent, which acts as an analogue of luteinising hormone, would cause ovulation about 42 hours after injection, but a retrieval procedure takes place just prior to that, in order to recover the egg cells from the ovary. The eggs are retrieved from the patient using a transvaginal technique involving an ultrasound-guided needle piercing the vaginal wall to reach the ovaries. Through this needle follicles can be aspirated, and the follicular fluid is handed to the IVF laboratory to identify ova. The retrieval procedure takes about 20 minutes and is usually done under conscious sedation or general anaesthesia.

IVF laboratory

In the laboratory, the identified eggs are stripped of surrounding cells and prepared for fertilization. In the meantime, semen provided by the male partner is prepared for fertilization by removing inactive cells and seminal fluid. The sperm and the egg are incubated together (at a ratio of about 75,000:1) in the culture media for about 18 hours. By that time fertilization should have taken place and the fertilized egg would show two pronuclei. In situations where the sperm count is low a single sperm is injected directly into the egg using intracytoplasmic sperm injection (ICSI). The fertilized egg is passed to a special growth medium and left for about 48 hours until the egg has reached the 6-8 cell stage.

Laboratories have developed grading methods to judge oocyte and embryo quality. Typically, embryos that have reached the 6-8 cell stage are transferred three days after retrieval. In many programmes, however, embryos are placed into an extended culture system with a transfer done at the blastocyst stage, especially if many good-quality day-3 embryos are available. Blastocysts may give higher pregnancy rates if embryo quality is in doubt. However, many studies have shown no difference in pregnancy rates between day-3 and day-5 transfers.

Embryo transfer

The embryos judged to be the "best" are transferred to the patient's uterus through a thin, plastic catheter, which goes through her vagina and cervix. Often, several embryos are passed into the uterus to improve chances of implantation and pregnancy.

Post-transfer

The patient has to wait two weeks before she returns to the clinic for the pregnancy test. During this time she may receive progesterone-a hormone that keeps the uterus lining thickened and suitable for implantation. Many IVF programmes provide additional medications as part of their protocol.

Acupuncture

According to the latest reports published in Fertility and Sterility, if done correctly, Acupuncture significantly improves IVF success rate. Acupuncture is integrated into the treatment protocols by many progressive fertility clinics in the United States.

Pregnancy

The chance of a successful pregnancy is approximately 20-30% for each IVF cycle, although selected clinics are now able to quote rates up to 50% per cycle. There are many factors that determine success rates including the age of the patient, the quality of the eggs and sperm, the duration of the infertility, the health of the uterus, and the medical expertise. It is a common practice for IVF programmes to boost the pregnancy rate by placing multiple embryos during embryo transfer. A flip side of this practice is a higher risk of multiple pregnancy, itself associated with obstetric complications.
IVF programmes generally publish their pregnancy rates, however comparisons between clinics are difficult as many variables determine outcome. Furthermore, these statistics depend strongly on the type of patients selected.

Complications

The major complication of IVF is the risk of multiple births. This is directly related to the practice of transferring multiple embryos at 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. Strict limits on the number of embryos that may be transferred have been enacted in some countries (e.g., England) to reduce the risk of high-order multiples (triplets or more), but are not universally followed or accepted. Spontaneous splitting of embryos in the womb after transfer does occur, but is rare (<1%) and would lead to identical twins. Recent evidence suggest that singleton offspring after IVF is at higher risk for lower birth weight for unknown reasons.

Another risk of ovarian stimulation is the development of ovarian hyperstimulation syndrome.
If the underlying infertility is related to abnormalities in spermatogenesis, it is plausible, but too early to examine that male offspring is at higher risk for sperm abnormalities.

Birth defects

The issue of birth defects remains a controversial topic in IVF. A majority of studies do not show a significant increase after use of IVF. Some studies suggest higher rates for ICSI , while others do not support this finding. Major birth defect include chromosomal abnormalities, genetic imprinting defects, and multiple organ abnormalities. Hansen et al conducted a systematic review of published studies (including ICSI) and found a 30-40% increase risk of birth defects associated with assisted reproductive technology when compared to children born after spontaneous conception. Possible explanations offered were the underlying cause of the infertility, factors associated with IVF/ICSI, culture conditions, and medications, however, the actual cause is not known.

Cryopreservation

Embryo cryopreservation

If multiple embryos are generated, patients may choose to freeze embryos that are not transferred. Those embryos are placed in liquid nitrogen and can be preserved for a long time. There are currently 500,000 frozen embryos in the United States. The advantage is that patients who fail to conceive may become pregnant using such embryos without having to go through a full IVF cycle. Or, if pregnancy occurred, they could return later for another pregnancy.

Oocyte cryopreservation

Cryopreservation of unfertilized mature oocytes has been successfully accomplished, e.g. in women who are likely to lose their ovarian reserve due to undergoing chemotherapy.

Ovarian tissue cryopreservation

Cryopreservation of ovarian tissue is of interest to women who want to preserve their reproductive function beyond the natural limit, or whose reproductive potential is threatened by cancer therapy. Research on this issue is promising.

Development

Intracytoplasmic sperm injection (ICSI) is a more recent development associated with IVF which allows the sperm to be directly injected in to the egg using micromanipulation. This is used for sperm that have difficulty penetrating the egg and when sperm numbers are very low. ICSI results in success rates equal to IVF fertilization.

Preimplantation genetic diagnosis (PGD) can be performed on embryos prior to the embryo transfer. A similar, but more general test has been developed called Preimplantation genetic haplotyping (PGH).

ETHICS

Issues

Certain ethical issues have been raised from the beginning when IVF was introduced. These concerns include:
  • Bypassing the natural method of conception.

  • Creating life in the laboratory.

  • Fertilizing more embryos than will be needed.

  • Discarding excess embryos.

  • Unnatural environment for embryos.

  • Using untested technology.

  • Not affordable for many.

  • Misallocation of medical resources.

  • Creating embryos, freezing them, and keeping them "in limbo".

  • Exposing embryos to unnatural substances.

  • Destroying embryos in research.

  • Potential to create embryos for medical purposes.

  • Potential to select embryos (PGD).

  • Potential to modify embryos.

  • Facilitates idea that embryos are commodities.

  • Financial rewards for IVF doctors dissuade them from recommending other methods to couples.

  • Infertility is treated as a disease and not as a symptom of underlying medical problems.
Separating the traditional mother-father model

The IVF process requires sperm, eggs, and a uterus, of course. To achieve a pregnancy any of these requirements can be provided by a third party (or more parties): third party reproduction. This has created additional ethical and legal concerns. The use of IVF provides also greater range of options for single people and same-sex couples wishing to have children. Although both groups already raise children, IVF facilitates this process. Some people object that this could give psychological problems to the child if they grow up without a mother/father role-model.

A number of cases have achieved notoriety:

In 2001, a French woman received worldwide publicity when she posed as the wife of her brother in order to give birth to a donor egg fertilized by his sperm. Some saw this as a form of incest; others thought it would prove psychologically unhealthy for the child when he learned how he was delivered; whereas other people simply couldn't see anything wrong with the situation.

In a few cases laboratory mix-ups (misidentified gametes, transfer of wrong embryos) have occurred leading to legal action against the IVF provider and complex paternity suits. An example is the case of a woman in California who received the embryo of another couple and was notified of this mistake after the birth of her son.

Pregnancy past menopause

While menopause has set a natural barrier to further conception, IVF has allowed women to be pregnant in their fifties and sixties. These are women whose uterus has been appropriately prepared receive embryos that originated from an egg of an egg donor. Therefore, their children are not genetically linked to them. Even after menopause the uterus is fully capable to carry out its function. Currently, the oldest woman to give birth is Adriana Iliescu, age 66, from Romania.

Religious objections

The Roman Catholic Church is opposed to in vitro fertilization in all instances and advocates that infertility is a call from God to adopt children. It "infringe[s] the child's right to be born of a father and mother known to him and bound to each other by marriage." Also, embryos are discarded in the process causing them, according to the Church, to die. Some estimates of the numbers of embryos involved reach 6 million. Catholics and those of other faiths see embryos as human lives with the same rights as all others and, therefore, view this procedure as always unacceptable. However, the Church allows the use of more natural techniques which seek to treat the underlying causes of infertility.

Regulatory events

While in the United States IVF programmes operate under voluntary guidelines, programmes in many other countries are subject to regulations that regulate many aspects of IVF practice. In such settings regulations may dictate:

  • The number of oocytes that can be fertilized.

  • The number of embryos that can be transferred.

  • The use of cryopreservation.

  • The use of third party reproduction.

  • The ability to perform tests or interventions on the embryo.
In 2004, the government of Italy made it a crime to freeze human embryos or to perform preimplantation diagnosis.



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