In vitro fertilisation

In vitro fertilisation
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In vitro fertilisation[1] (IVF) is a technique in which egg cells are fertilised by sperm outside the woman's womb, in vitro. IVF is a major treatment in infertility when other methods of assisted reproductive technology have failed. The process involves hormonally controlling the ovulatory process, removing ova (eggs) from the woman's ovaries and letting sperm fertilise them in a fluid medium. The fertilised egg (zygote) is then transferred to the patient's uterus with the intent to establish a successful pregnancy.

Oocyte with surrounding granulosa cells

"In vitro"
Main article: In vitro
The term in vitro, from the Latin root meaning in glass, is used, because early biological experiments involving cultivation of tissues outside the living organism from which they came, were carried out in glass containers such as beakers, test tubes, or petri dishes. Today, the term in vitro is used to refer to any biological procedure that is performed outside the organism it would normally be occurring in, to distinguish it from an in vivo procedure, where the tissue remains inside the living organism within which it is normally found. A colloquial term for babies conceived as the result of IVF, test tube babies, refers to the tube-shaped containers of glass or plastic resin, called test tubes, that are commonly used in chemistry labs and biology labs. However in vitro fertilisation is usually performed in the shallower containers called petri dishes. (Petri-dishes may also be made of plastic resins.) However, the IVF method of Autologous Endometrial Coculture is actually performed on organic material, but is yet called in vitro.

History
On the basis of the findings of Min Chueh Chang's application of in vitro fertilization to animals, the technique was developed for humans in the United Kingdom by Patrick Steptoe and Robert Edwards. The first "test-tube baby", Louise Brown, was born in Oldham, Greater Manchester, England, as a result on July 25, 1978 amid intense controversy over the safety and morality of the procedure.[2]
Subhash Mukhopadhyay became the first physician in India, and the second in the world after Steptoe and Edwards, to perform the procedure and produce the test tube baby "Durga" (alias Kanupriya Agarwal) on October 3, 1978. Facing social ostracism, 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, Mukhopadhyay committed suicide in his Calcutta residence in 1981.
Major pioneering developments in IVF also occurred in Australia under the leadership of Carl Wood, Alan Trounson and Ian Johnston.[3][4] 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 (including with intracytoplasmic sperm injection (ICSI)) has been up to 4% of all babies born in Denmark.
Jane Mohr of Manhattan Beach California, gave birth to the nation's first set of triplets born 21 months apart due to in vitro fertilisation (IVF) and long-term embryo storage. Jane gave birth November 29, 1988 to two daughters, Mollie McKenna and Hannah Christina Mohr, nearly two years after the birth of her son, Cooper Patrick Mohr.

Indications
Initially IVF was developed to overcome infertility due to problems of the fallopian tube, but it turned out that it was successful in many other infertility situations as well. The introduction of intracytoplasmic sperm injection (ICSI) 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 fertilise, 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 who have already gone through pregnancy. The donated oocyte can be fertilised in a crucible. If the fertilisation is successful, the fertilised egg will be transferred 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 gynecologic ultrasonography, follicular growth. Typically approximately 10 days of injections will be necessary. Spontanenous ovulation during the cycle is prevented by the use of GnRH agonists or GnRH antagonists, which block the natural surge of luteinizing hormone (LH).

Oocyte retrieval
Main article: Transvaginal 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 luteinizing hormone, would cause ovulation about 36 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 anesthesia.

Oocyte is injected during ICSI

Fertilisation
In the laboratory , the identified eggs are stripped of surrounding cells and prepared for fertilisation. In the meantime, semen is prepared for fertilisation by removing inactive cells and seminal fluid. If semen is being provided by a sperm donor, it will usually have been prepared for treatment before being frozen and quarantined, and it will be thawed ready for use. 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 fertilisation should have taken place and the fertilised 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 fertilised egg is passed to a special growth medium and left for about 48 hours until the egg has reached the 6-8 cell stage.

8-cell embryo for transfer

Selection
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 American and Australian programmes[citation needed], 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. Blastocyst stage transfers have been shown to result in higher pregnancy rates.[5]. In Europe, day-2 transfers are common.[citation needed]

Embryo transfer
Main article: Embryo transfer
Embryos are graded by the embryologist based on the number of cells, evenness of growth and degree of fragmentation. The number to be transferred depends on the number available, the age of the woman and other health and diagnostic factors. In countries such as the UK, Australia and New Zealand, a maximum of two embryos are transferred except in unusual circumstances. For instance, a woman over 35 may have up to three embryos transferred. This is to limit the number of multiple pregnancies. 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. Several embryos may be passed into the uterus to improve chances of implantation and pregnancy.

Blastocyst for transfer

Success rates
While the overall live birth rate via IVF in the U.S. is about 27% per cycle (33% pregnancy rate), the chances of a successful pregnancy via IVF vary widely based on the age of the woman (or, more precisely, on the age of the eggs involved). [2] Where the woman's own eggs are used as opposed to those of a donor, for women under 35, the pregnancy rate is commonly approximately 43% per cycle (36.5% live birth), while for women over 40, the rate falls drastically - to only 4% for women over 42. [3] Other factors that determine success rates include 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.
A recent technique is to bathe an embryo in a culture of nutrients for five days until it reaches a developmental landmark known as the blastocyst stage. The doctors then determine which embryos are most likely to thrive long term. The best quality of these are transferred into a woman's uterus. In this way it is possible to enable pregnancy without the risk of multiple pregnancy. This technique is relatively new and has yet to be well tested.
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.
There are many reasons why pregnancy may not occur following IVF and embryo transfer, including
The timing of ovulation may be misjudged, or ovulation may not be able to be predicted or may not occur
Attempts to obtain eggs that develop during the monitored cycle may be unsuccessful
The eggs obtained may be abnormal or may have been damaged during the retrieval process
A semen specimen may not be able to be provided
Fertilisation of eggs to form embryos may not occur
Cleavage or cell division of the fertilised eggs may not take place
The embryo may not develop normally
Implantation may not occur
Equipment failure, infection and/or human error or other unforeseen and uncontrollable factors, which may result in the loss of or damage to the eggs, the semen sample and/or the embryos[6]
According to a 2005 Swedish study published in the Oxford Journal 'Human Reproduction' 166 women were monitored starting one month before their IVF cycles and the results showed no significant correlation between psychological stress and their IVF outcomes. The study concluded with the recommendation to clinics that it might be possible to reduce the stress experienced by IVF patients during the treatment procedure by informing them of those findings. While psychological stress experienced during a cycle might not influence an IVF outcome, it is possible that the experience of IVF can result in stress that leads to depression. The financial consequences alone of IVF can influence anxiety and become overwhelming. However, for many couples, the alternative is infertility, and the experience of infertility itself can also cause extreme stress and depression.

Complications
The major complication of IVF is the risk of multiple births.[4] 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 can occur, but this is rare and would lead to identical twins. A double blind, randomised study followed IVF pregnancies that resulted in 73 infants (33 boys and 40 girls) and reported that 8.7% of singeton infants and 54.2% of twins had a birth weight of < title="" href="http://en.wikipedia.org/w/index.php?title=In_vitro_fertilisation&printable=yes#cite_note-6">[7]. However 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.[8] 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.[9] 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. Some believe that in vitro fertilization lacks the theory of "survival of the fittest" between contending sperm that occurs inside the uterus which may lead to the possibility of birth defects.

Cryopreservation
Main article: 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.[5] 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. Spare embryos resulting from fertility treatments may be donated to another woman or couple, and embryos may be created, frozen and stored specifically for transfer and donation by using donor eggs and sperm.

Oocyte cryopreservation
Cryopreservation of unfertilised mature oocytes has been successfully accomplished, e.g. in women who are likely to lose their ovarian reserve due to undergoing chemotherapy.[10]

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.

Adjunctive interventions
There are several variations or improvements of IVF, such as ICSI, ZIFT, GIFT and PGD. An increasing number of fertility specialists and centers offer acupuncture as a part of their IVF protocol, or maintain a list of acupuncturists specialising in infertility.

ICSI
Main article: Intracytoplasmic sperm injection
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 where sperm have difficulty penetrating the egg and in these cases the partner's or a donor's sperm may be used. ICSI is also used when sperm numbers are very low. ICSI results in success rates equal to IVF fertilisation.

ZIFT
Main article: Zygote intrafallopian transfer
In Zygote intrafallopian transfer (ZIFT) eggs are removed from the woman, fertilised and then placed in the woman's fallopian tubes rather than the uterus.

GIFT
Main article: Gamete intrafallopian transfer
In gamete intrafallopian transfer (GIFT) eggs are removed from the woman, and placed in one of the fallopian tubes, along with the man's sperm. This allows fertilisation to take place inside the woman's body. Therefore, this variation is actually an in vivo fertilisation, and not an in vitro fertilisation.

PGD
Main article: 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).

Acupuncture
An increasing number of fertility specialists and centers recognise the benefits of acupuncture and offer acupuncture as a part of their IVF protocol. Limited but supportive[11] evidence from clinical trials and case series suggests that acupuncture may improve the success rate of IVF and the quality of life[11] of patients undergoing IVF and that it is a safe[11] adjunct therapy.

Mechanism of acupuncture
Scientific literature lists four[11] mechanisms of how acupuncture can improve IVF outcomes ; these include
Neuroendicrinological modulations
Increased blood flow to uterus and ovaries
Modulation in cytokines
Reducing stress, anxiety and depression

[edit] Studies
Summarizing four acupuncture trials published in peer reviewed scientific journal Fertility and sterility, involving a total of just under 800 women, the results clearly showed a pregnancy was twice as likely to occur in the acupuncture group compared to the control group[6]. Many fertility specialists recognise the positive role of acupuncture, although there are some methodological issues to be taken into account when assessing non-pharmacological studies, furthermore there are issues when assessing effectiveness of acupuncture, as the treatment is performed in person and is very difficult to fake acupuncture. Even the fake needles used in acupuncture trials as a placebo are considered to be able to produce a therapeutic effect through acupressure, making the research even more difficult.
Following are examples of individual studies. According to a report published in Fertility and Sterility, if done correctly, Acupuncture significantly improves IVF success rate[7].
Researchers in Adelaide has evaluated the effect of acupuncture on women undergoing IVF, and couldn't exclude a smaller treatment effect. However, there was no (statistically) significant difference compared to a control group of women not getting acupuncture[12]
A randomised, prospective study [13]showed that acupuncture significantly (p<0.01) title="" href="http://en.wikipedia.org/w/index.php?title=In_vitro_fertilisation&printable=yes#cite_note-13">[14], and by another scientist that positive impact of acupuncture on IVF success rates is not definitive. [15]. However, assessments of nonpharmacological treatments must take into consideration additional methodological issues. This criticism is possibly arising from lack of understanding of methodological differences in clinical trials evaluating nonpharmacological and pharmacological treatments[16] and in particular methodological issues in trials of acupuncture [17].

[edit] Electro-acupuncture in oocyte retrieval for IVF
Electro-acupuncture has a proven analgesic effect in oocyte retrieval for IVF[citation needed].

[edit] Complementary medicines
Infertility patients commonly use complementary medicines. Health-care practitioners and fertility specialists need to be proactive in acquiring and documenting the use of these practices. There is a need to provide further information to patients on the use of CMs and therapies. Further research examining the reasons for use of CMs and therapies is needed.[8]

[edit] Hypnosis
A study of hypnotherapy suggests a higher success rate when integrated with treatment [9]. However, this study is not without criticism. Experts say the study failed to take into account key differences between the groups compared in the study. These differences would have had a major influence on their chances of conceiving [18].

[edit] Ethics

[edit] Issues
See also: Beginning of pregnancy controversy

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The IVF process requires sperm, eggs and a uterus. To achieve a pregnancy any of these requirements can be provided by a third person: third party reproduction. This has created additional ethical and legal concerns.[citation needed]
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.[19]

[edit] 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. Women whose uteruses have been appropriately prepared receive embryos that originated from an egg of an egg donor. Therefore, although these women do not have a genetic link with the child, they have an emotional link through pregnancy and childbirth. In many cases the genetic father of the child is the woman's partner. Even after menopause the uterus is fully capable to carry out its function.[20]

[edit] Religious objections
The Roman Catholic Church is opposed to most kinds of in vitro fertilisation (although GIFT is accepted at certain conditions because fertilisation takes place inside the body and not inside a Petri dish [10]) and advocates that infertility is a call from God to adopt children. According to the Catholic Church, 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."[21] Also, embryos are sometimes discarded in the process, resulting in their demise. Catholics and many people of other faiths or none see embryos as human lives with the same rights as all others and, therefore, view the destruction of embryos as unacceptable.

[edit] Coping with IVF
Due to the emotional and financial aspects of infertility treatment, many feel isolated and sometimes become depressed. Online support forums and message boards have become a popular way for sufferers to exchange both information and support. Popular forums include Fertiliy Friends, IVFConnections, IVF.ca, Ivf-Infertility.com, INCIID, and IVF World.

[edit] See also