In vitro fertilisation
This image shows intracytoplasmic sperm injection, the most commonly used IVF technique.
Specialty	Reproductive Endocrinology & Infertility
ICD-10-PCS	8E0ZXY1
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In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating a patient's ovulatory process, removing an ovum or ova (egg or eggs) from their ovaries and letting sperm fertilise them in a culture medium in a laboratory. After the fertilised egg (zygote) undergoes embryo culture for 2–6 days, it is transferred by catheter into the uterus, with the intention of establishing a successful pregnancy.

IVF is a type of assisted reproductive technology used for infertility treatment, gestational surrogacy, and, in combination with pre-implantation genetic testing, avoiding transmission of genetic conditions. A fertilised egg from a donor may implant into a surrogate's uterus, and the resulting child is genetically unrelated to the surrogate. Some countries have banned or otherwise regulate the availability of IVF treatment, giving rise to fertility tourism. Restrictions on the availability of IVF include costs and age, in order for a person to carry a healthy pregnancy to term. Children born through IVF are colloquially called test tube babies.

In July 1978, Louise Brown was the first child successfully born after her mother received IVF treatment.^[1] Brown was born as a result of natural-cycle IVF, where no stimulation was made. The procedure took place at Dr Kershaw's Cottage Hospital (now Dr Kershaw's Hospice) in Royton, Oldham, England. Robert Edwards was awarded the Nobel Prize in Physiology or Medicine in 2010. The physiologist co-developed the treatment together with Patrick Steptoe and embryologist Jean Purdy but the latter two were not eligible for consideration as they had died and the Nobel Prize is not awarded posthumously.^[2][3]

Assisted by egg donation and IVF, there are many people with uteruses who may be past their reproductive years, have infertile partners, have idiopathic female-fertility issues, or have reached menopause, that can still become pregnant. After the IVF treatment, some couples get pregnant without any fertility treatments.^[4] In 2018, it was estimated that eight million children had been born worldwide using IVF and other assisted reproduction techniques.^[5] A 2019 study that explores 10 adjuncts with IVF (screening hysteroscopy, DHEA, testosterone, GH, aspirin, heparin, antioxidants, seminal plasma and PRP) suggests that until more evidence is done to show that these adjuncts are safe and effective, they should be avoided.^[6]

Terminology

The Latin term in vitro, meaning "in glass", is used because early biological experiments involving cultivation of tissues outside the living organism were carried out in glass containers, such as beakers, test tubes, or Petri dishes. Today, the scientific term "in vitro" is used to refer to any biological procedure that is performed outside the organism in which it would normally have occurred, to distinguish it from an in vivo procedure (such as in vivo fertilisation), where the tissue remains inside the living organism in 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 and biology labs. However, IVF is usually performed in Petri dishes, which are both wider and shallower and often used to cultivate cultures.

IVF is a form of assisted reproductive technology.

History

The first successful birth of a child after IVF treatment, Louise Brown, occurred in 1978. Louise Brown was born as a result of natural cycle IVF where no stimulation was made. The procedure took place at Dr Kershaw's Cottage Hospital (now Dr Kershaw's Hospice) in Royton, Oldham, England. Robert G. Edwards, the physiologist who co-developed the treatment, was awarded the Nobel Prize in Physiology or Medicine in 2010. His co-workers, Patrick Steptoe and Jean Purdy, were not eligible for consideration as the Nobel Prize is not awarded posthumously.^[2][3]

The second successful birth of a 'test tube baby' occurred in India just 67 days after Louise Brown was born. The girl, named Durga, was conceived in vitro using a method developed independently by Subhash Mukhopadhyay, a physician and researcher from Kolkata. Mukhopadhyay had been performing experiments on his own with primitive instruments and a household refrigerator.^[7] However, state authorities prevented him from presenting his work at scientific conferences,^[8] and it was many years before Mukhopadhyay's contribution was acknowledged in works dealing with the subject.^{[9][better source needed]}

Adriana Iliescu held the record as the oldest woman to give birth using IVF and a donor egg, when she gave birth in 2004 at the age of 66, a record passed in 2006. After the IVF treatment some couples are able to get pregnant without any fertility treatments.^[4] In 2018 it was estimated that eight million children had been born worldwide using IVF and other assisted reproduction techniques.^[5]

Medical uses

Indications

IVF may be used to overcome female infertility when it is due to problems with the fallopian tubes, making in vivo fertilisation difficult. It can also assist in male infertility, in those cases where there is a defect in sperm quality; in such situations intracytoplasmic sperm injection (ICSI) may be used, where a sperm cell is injected directly into the egg cell. This is used when sperm has difficulty penetrating the egg. ICSI is also used when sperm numbers are very low. When indicated, the use of ICSI has been found to increase the success rates of IVF.

According to UK's National Institute for Health and Care Excellence (NICE) guidelines, IVF treatment is appropriate in cases of unexplained infertility for people who have not conceived after 2 years of regular unprotected sexual intercourse.^[10]

In people with anovulation, it may be an alternative after 7–12 attempted cycles of ovulation induction, since the latter is expensive and more easy to control.^[11]

Success rates

IVF success rates are the percentage of all IVF procedures that result in favourable outcomes. Depending on the type of calculation used, this outcome may represent the number of confirmed pregnancies, called the pregnancy rate, or the number of live births, called the live birth rate. Due to advances in reproductive technology, live birth rates by cycle five of IVF have increased from 76% in 2005 to 80% in 2010, despite a reduction in the number of embryos being transferred (which decreased the multiple birth rate from 25% to 8%).^[12]

The success rate depends on variable factors such as age of the birthing person, cause of infertility, embryo status, reproductive history, and lifestyle factors. Younger candidates of IVF are more likely to get pregnant. People older than 41 are more likely to get pregnant with a donor egg.^[13] People who have been previously pregnant are in many cases more successful with IVF treatments than those who have never been pregnant.^[13]

Live birth rate

The live birth rate is the percentage of all IVF cycles that lead to a live birth. This rate does not include miscarriage or stillbirth; multiple-order births, such as twins and triplets, are counted as one pregnancy. A 2019 summary compiled by the Society for Assisted Reproductive Technology (SART) which reports the average IVF success rates in the United States per age group using non-donor eggs compiled the following data:^[14]

In 2006, Canadian clinics reported a live birth rate of 27%.^[15] Birth rates in younger patients were slightly higher, with a success rate of 35.3% for those 21 and younger, the youngest group evaluated. Success rates for older patients were also lower and decrease with age, with 37-year-olds at 27.4% and no live births for those older than 48, the oldest group evaluated.^[16] Some clinics exceeded these rates, but it is impossible to determine if that is due to superior technique or patient selection, since it is possible to artificially increase success rates by refusing to accept the most difficult patients or by steering them into oocyte donation cycles (which are compiled separately). Further, pregnancy rates can be increased by the placement of several embryos at the risk of increasing the chance for multiples.

Because not each IVF cycle that is started will lead to oocyte retrieval or embryo transfer, reports of live birth rates need to specify the denominator, namely IVF cycles started, IVF retrievals, or embryo transfers. The SART summarised 2008–9 success rates for US clinics for fresh embryo cycles that did not involve donor eggs and gave live birth rates by the age of the prospective mother, with a peak at 41.3% per cycle started and 47.3% per embryo transfer for patients under 35 years of age.

IVF attempts in multiple cycles result in increased cumulative live birth rates. Depending on the demographic group, one study reported 45% to 53% for three attempts, and 51% to 71% to 80% for six attempts.^[17]

Effective from 15 February 2021 the majority of Australian IVF clinics publish their individual success rate online via YourIVFSuccess.com.au. This site also contains a predictor tool.^[18]

Pregnancy rate

Pregnancy rate may be defined in various ways. In the United States, SART and the Centers for Disease Control (and appearing in the table in the Success Rates section above) include statistics on positive pregnancy test and clinical pregnancy rate.

The 2019 summary compiled by the SART the following data for non-donor eggs (first embryo transfer) in the United States:^[14]

In 2006, Canadian clinics reported an average pregnancy rate of 35%.^[15] A French study estimated that 66% of patients starting IVF treatment finally succeed in having a child (40% during the IVF treatment at the centre and 26% after IVF discontinuation). Achievement of having a child after IVF discontinuation was mainly due to adoption (46%) or spontaneous pregnancy (42%).^[19]

Miscarriage rate

According to a study done by the Mayo Clinic, miscarriage rates for IVF are somewhere between 15 and 25%.^[20]

Predictors of success

The main potential factors that influence pregnancy (and live birth) rates in IVF have been suggested to be maternal age, duration of infertility or subfertility, bFSH and number of oocytes, all reflecting ovarian function.^[21] Optimal age is 23–39 years at time of treatment.^[22]

Biomarkers that affect the pregnancy chances of IVF include:

• Antral follicle count, with higher count giving higher success rates.^[24]
• Anti-Müllerian hormone levels, with higher levels indicating higher chances of pregnancy,^[24] as well as of live birth after IVF, even after adjusting for age.^[25]
• Level of DNA fragmentation^[26] as measured, e.g. by Comet assay, advanced maternal age and semen quality.
• People with ovary-specific FMR1 genotypes including het-norm/low have significantly decreased pregnancy chances in IVF.^[27]
• Progesterone elevation on the day of induction of final maturation is associated with lower pregnancy rates in IVF cycles in women undergoing ovarian stimulation using GnRH analogues and gonadotrophins.^[28] At this time, compared to a progesterone level below 0.8 ng/ml, a level between 0.8 and 1.1 ng/ml confers an odds ratio of pregnancy of approximately 0.8, and a level between 1.2 and 3.0 ng/ml confers an odds ratio of pregnancy of between 0.6 and 0.7.^[28] On the other hand, progesterone elevation does not seem to confer a decreased chance of pregnancy in frozen–thawed cycles and cycles with egg donation.^[28]
• Characteristics of cells from the cumulus oophorus and the membrana granulosa, which are easily aspirated during oocyte retrieval. These cells are closely associated with the oocyte and share the same microenvironment, and the rate of expression of certain genes in such cells are associated with higher or lower pregnancy rate.^[29]
• An endometrial thickness (EMT) of less than 7 mm decreases the pregnancy rate by an odds ratio of approximately 0.4 compared to an EMT of over 7 mm. However, such low thickness rarely occurs, and any routine use of this parameter is regarded as not justified.^[30]

Other determinants of outcome of IVF include:

• As maternal age increases, the likelihood of conception decreases^[31] and the chance of miscarriage increases.^[32]
• With increasing paternal age, especially 50 years and older, the rate of blastocyst formation decreases.^[33]
• Tobacco smoking reduces the chances of IVF producing a live birth by 34% and increases the risk of an IVF pregnancy miscarrying by 30%.^[34]
• A body mass index (BMI) over 27 causes a 33% decrease in likelihood to have a live birth after the first cycle of IVF, compared to those with a BMI between 20 and 27.^[34] Also, pregnant people who are obese have higher rates of miscarriage, gestational diabetes, hypertension, thromboembolism and problems during delivery, as well as leading to an increased risk of fetal congenital abnormality.^[34] Ideal body mass index is 19–30.^[22]
• Salpingectomy or laparoscopic tubal occlusion before IVF treatment increases chances for people with hydrosalpinges.^[22][35]
• Success with previous pregnancy and/or live birth increases chances^[22]
• Low alcohol/caffeine intake increases success rate^[22]
• The number of embryos transferred in the treatment cycle^[36]
• Embryo quality
• Some studies also suggest that autoimmune disease may also play a role in decreasing IVF success rates by interfering with the proper implantation of the embryo after transfer.^[27]

Aspirin is sometimes prescribed to people for the purpose of increasing the chances of conception by IVF, but as of 2016^[update] there was no evidence to show that it is safe and effective.^[37][38]

A 2013 review and meta analysis of randomised controlled trials of acupuncture as an adjuvant therapy in IVF found no overall benefit, and concluded that an apparent benefit detected in a subset of published trials where the control group (those not using acupuncture) experienced a lower than average rate of pregnancy requires further study, due to the possibility of publication bias and other factors.^[39]

A Cochrane review came to the result that endometrial injury performed in the month prior to ovarian induction appeared to increase both the live birth rate and clinical pregnancy rate in IVF compared with no endometrial injury. There was no evidence of a difference between the groups in miscarriage, multiple pregnancy or bleeding rates. Evidence suggested that endometrial injury on the day of oocyte retrieval was associated with a lower live birth or ongoing pregnancy rate.^[35]

Intake of antioxidants (such as N-acetyl-cysteine, melatonin, vitamin A, vitamin C, vitamin E, folic acid, myo-inositol, zinc or selenium) has not been associated with a significantly increased live birth rate or clinical pregnancy rate in IVF according to Cochrane reviews.^[35] The review found that oral antioxidants given to the sperm donor with male factor or unexplained subfertility may improve live birth rates, but more evidence is needed.^[35]

A Cochrane review in 2015 came to the result that there is no evidence identified regarding the effect of preconception lifestyle advice on the chance of a live birth outcome.^[35]

Method

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Theoretically, IVF could be performed by collecting the contents from the fallopian tubes or uterus after natural ovulation, mixing it with sperm, and reinserting the fertilised ova into the uterus. However, without additional techniques, the chances of pregnancy would be extremely small. The additional techniques that are routinely used in IVF include ovarian hyperstimulation to generate multiple eggs, ultrasound-guided transvaginal oocyte retrieval directly from the ovaries, co-incubation of eggs and sperm, as well as culture and selection of resultant embryos before embryo transfer into a uterus.

Ovarian hyperstimulation

Ovarian hyperstimulation is the stimulation to induce development of multiple follicles of the ovaries. It should start with response prediction by e.g. age, antral follicle count and level of anti-Müllerian hormone.^[40] The resulting prediction of e.g. poor or hyper-response to ovarian hyperstimulation determines the protocol and dosage for ovarian hyperstimulation.^[40]

Ovarian hyperstimulation also includes suppression of spontaneous ovulation, for which two main methods are available: Using a (usually longer) GnRH agonist protocol or a (usually shorter) GnRH antagonist protocol.^[40] In a standard long GnRH agonist protocol the day when hyperstimulation treatment is started and the expected day of later oocyte retrieval can be chosen to conform to personal choice, while in a GnRH antagonist protocol it must be adapted to the spontaneous onset of the previous menstruation. On the other hand, the GnRH antagonist protocol has a lower risk of ovarian hyperstimulation syndrome (OHSS), which is a life-threatening complication.^[40]

For the ovarian hyperstimulation in itself, injectable gonadotropins (usually FSH analogues) are generally 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.

When stimulating ovulation after suppressing endogenous secretion, it is necessary to supply exogenous gonadotropines. The most common one is the human menopausal gonadotropin (hMG), which is obtained by donation of menopausal women. Other pharmacological preparations are FSH+LH or coripholitropine alpha.

Natural IVF

There are several methods termed natural cycle IVF:^[41]

• IVF using no drugs for ovarian hyperstimulation, while drugs for ovulation suppression may still be used.
• IVF using ovarian hyperstimulation, including gonadotropins, but with a GnRH antagonist protocol so that the cycle initiates from natural mechanisms.
• Frozen embryo transfer; IVF using ovarian hyperstimulation, followed by embryo cryopreservation, followed by embryo transfer in a later, natural, cycle.^[42]

IVF using no drugs for ovarian hyperstimulation was the method for the conception of Louise Brown. This method can be successfully used when people want to avoid taking ovarian stimulating drugs with its associated side-effects. HFEA has estimated the live birth rate to be approximately 1.3% per IVF cycle using no hyperstimulation drugs for women aged between 40 and 42.^[43]

Mild IVF^[44] is a method where a small dose of ovarian stimulating drugs are used for a short duration during a natural menstrual cycle aimed at producing 2–7 eggs and creating healthy embryos. This method appears to be an advance in the field to reduce complications and side-effects for women, and it is aimed at quality, and not quantity of eggs and embryos. One study comparing a mild treatment (mild ovarian stimulation with GnRH antagonist co-treatment combined with single embryo transfer) to a standard treatment (stimulation with a GnRH agonist long-protocol and transfer of two embryos) came to the result that the proportions of cumulative pregnancies that resulted in term live birth after 1 year were 43.4% with mild treatment and 44.7% with standard treatment.^[45] Mild IVF can be cheaper than conventional IVF and with a significantly reduced risk of multiple gestation and OHSS.^[46] Zdroj:https://en.wikipedia.org?pojem=In_vitro_fertilisation
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