The main durations of embryo culture are until  cleavage stage  (day two to four after  co-incubation ) or the  blastocyst  stage (day five or six after  co-incubation ). [ 59 ]  Embryo culture until the blastocyst stage confers a significant increase in  live birth rate  per  embryo transfer , but also confers a decreased number of embryos available for transfer and  embryo cryopreservation , so the cumulative clinical pregnancy rates are increased with cleavage stage transfer. [ 40 ]  Transfer day two instead of day three after fertilisation has no differences in  live birth rate . [ 40 ]  There are significantly higher odds of  preterm birth  ( odds ratio  1.3) and  congenital anomalies  ( odds ratio  1.3) among births having from embryos cultured until the blastocyst stage compared with cleavage stage. [ 59 ]


Laboratories have developed grading methods to judge ovocyte and  embryo  quality. In order to optimise  pregnancy rates , there is significant evidence that a morphological scoring system is the best strategy for the selection of embryos. [ 60 ]  Since 2009 where the first  time-lapse microscopy  system for IVF was approved for clinical use, morphokinetic scoring systems has shown to improve to  pregnancy rates  further. [ 61 ]  However, when all different types of  time-lapse embryo imaging  devices, with or without morphokinetic scoring systems, are compared against conventional embryo assessment for IVF, there is insufficient evidence of a difference in live-birth, pregnancy, stillbirth or miscarriage to choose between them. [ 62 ]  Active efforts to develop a more accurate embryo selection analysis based on Artificial Intelligence and Deep Learning are underway. Embryo Ranking Intelligent Classification Assistant ( ERICA ), [ 63 ]  is a clear example.  This Deep Learning software substitutes manual classifications with a ranking system based on an individual embryo's predicted genetic status in a non-invasive fashion. [ 64 ]  Studies on this area are still pending and current feasibility studies support its potential. [ 65 ]


The number to be transferred depends on the number available, the age of the patient and other health and diagnostic factors. In countries such as Canada, the UK, Australia and New Zealand, a maximum of two embryos are transferred except in unusual circumstances. In the UK and according to  HFEA  regulations, a woman over 40 may have up to three embryos transferred, whereas in the US, there is no legal limit on the number of embryos which may be transferred, although medical associations have provided practice guidelines. Most clinics and country regulatory bodies seek to minimise the risk of multiple pregnancy, as it is not uncommon for multiple embryos to implant if multiple embryos are transferred. Embryos are transferred to the patient's uterus through a thin, plastic  catheter , which goes through their  vagina  and cervix. Several embryos may be passed into the uterus to improve chances of  implantation  and pregnancy. [ 66 ] [ 67 ]


Luteal support  is the administration of medication, generally  progesterone ,  progestins , hCG, or  GnRH agonists , and often accompanied by estradiol, to increase the success rate of  implantation  and early  embryogenesis , thereby complementing and/or supporting the function of the  corpus luteum . A Cochrane review found that hCG or progesterone given during the luteal phase may be associated with higher rates of  live birth  or ongoing pregnancy, but that the evidence is not conclusive. [ 68 ]  Co-treatment with  GnRH agonists  appears to improve outcomes, [ 68 ]  by a live birth rate  RD  of +16% (95%  confidence interval  +10 to +22%). [ 69 ]  On the other hand,  growth hormone  or  aspirin  as adjunctive medication in IVF have no evidence of overall benefit. [ 40 ]


There are various expansions or additional techniques that can be applied in IVF, which are usually not necessary for the IVF procedure itself, but would be virtually impossible or technically difficult to perform without concomitantly performing methods of IVF.


Preimplantation genetic screening  (PGS) or preimplantation genetic diagnosis (PGD) has been suggested to be able to be used in IVF to select an embryo that appears to have the greatest chances for successful pregnancy. However, a systematic review and meta-analysis of existing  randomised controlled trials  came to the result that there is no evidence of a beneficial effect of PGS with cleavage-stage biopsy as measured by  live birth rate . [ 70 ]  On the contrary, for those of  advanced maternal age , PGS with cleavage-stage biopsy significantly lowers the live birth rate. [ 70 ]  Technical drawbacks, such as the invasiveness of the biopsy, and non-representative samples because of  mosaicism  are the major underlying factors for inefficacy of PGS. [ 70 ]


Still, as an expansion of IVF, patients who can benefit from PGS/PGD include:


PGS screens for numeral chromosomal abnormalities while PGD diagnosis the specific molecular defect of the inherited disease. In both PGS and PGD, individual cells from a  pre-embryo , or preferably trophectoderm cells biopsied from a  blastocyst , are analysed during the IVF process. Before the transfer of a pre-embryo back to a person's uterus, one or two cells are removed from the pre-embryos (8-cell stage), or preferably from a  blastocyst . These cells are then evaluated for normality. Typically within one to two days, following completion of the evaluation, only the normal pre-embryos are transferred back to the uterus.  Alternatively, a blastocyst can be cryopreserved via vitrification and transferred at a later date to the uterus. In addition, PGS can significantly reduce the risk of multiple pregnancies because fewer embryos, ideally just one, are needed for implantation.


Cryopreservation  can be performed as  oocyte cryopreservation  before fertilisation, or as  embryo cryopreservation  after fertilisation.


The Rand Consulting Group has estimated there to be 400,000 frozen embryos in the United States in 2006. [ 72 ]  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 oocytes or embryos resulting from fertility treatments may be used for  oocyte donation  or  embryo donation  to another aspiring parent, and embryos may be created, frozen and stored specifically for transfer and donation by using donor eggs and sperm. Also, oocyte cryopreservation can be used for those who are likely to lose their ovarian reserve due to undergoing  chemotherapy . [ 73 ]


By 2017, many centres have adopted embryo cryopreservation as their primary IVF therapy, and perform few or no fresh embryo transfers.  The two main reasons for this have been better endometrial receptivity when embryos are transferred in cycles without exposure to ovarian stimulation and also the ability to store the embryos while awaiting the results of  preimplantation genetic testing .


The outcome from using cryopreserved embryos has uniformly been positive with no increase in birth defects or development abnormalities. [ 74 ]


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. Britain, Belgium) to reduce the risk of high-order multiples (triplets or more), but are not universally followed or accepted. Spontaneous splitting of embryos in the uterus 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, and reported that 8.7% of singleton infants and 54.2% of twins had a birth weight of less than 2,500 grams (5.5 lb). [ 78 ]  There is some evidence that making a double embryo transfer during one cycle achieves a higher live birth rate than a single embryo transfer; but making two single embryo transfers in two cycles has the same live birth rate and would avoid multiple pregnancies. [ 79 ]


Certain kinds of IVF have been shown to lead to distortions in the  sex ratio  at birth.  Intracytoplasmic sperm injection  (ICSI), which was first applied in 1991, leads to slightly more female births (51.3% female).  Blastocyst transfer , which was first applied in 1984, leads to significantly more male births (56.1% male). Standard IVF done at the second or third day leads to a normal sex ratio. [ citation needed ]


Epigenetic modifications  caused by extended culture leading to the death of more female embryos has been theorised as the reason why blastocyst transfer leads to a higher male sex ratio; however, adding retinoic acid to the culture can bring this ratio back to normal. [ 80 ]  A second theory is that the male-biased sex ratio may due to a higher rate of selection of male embryos. Male embryos develop faster in vitro, and thus may appear more viable for transfer. [ 81 ]


By  sperm washing , the risk that a chronic disease in the individual providing the sperm would infect the birthing parent or offspring can be brought to negligible levels.


If the sperm donor has  hepatitis B , The Practice Committee of the American Society for Reproductive Medicine advises that sperm washing is not necessary in IVF to prevent transmission, unless the birthing partner has not been effectively vaccinated. [ 82 ] [ 83 ]  In birthing people with hepatitis B, the risk of  vertical transmission  during IVF is no different from the risk in spontaneous conception. [ 83 ]  However, there is not enough evidence to say that  ICSI  procedures are safe in birthing people with hepatitis B in regard to vertical transmission to the offspring. [ 83 ]


Regarding potential spread of  HIV/AIDS , Japan's government prohibited the use of IVF procedures in which both partners are infected with HIV. Despite the fact that the ethics committees previously allowed the  Ogikubo, Tokyo  Hospital, located in Tokyo, to use IVF for couples with HIV, the  Ministry of Health, Labour and Welfare  of Japan decided to block the practice. Hideji Hanabusa, the vice president of the Ogikubo Hospital, states that together with his colleagues, he managed to develop a method through which scientists are able to remove HIV from sperm. [ 84 ]


In the United States, people seeking to be an embryo recipient undergo infectious disease screening required by the  Food and Drug Administration  (FDA), and reproductive tests to determine the best placement location and cycle timing before the actual embryo transfer occurs. The amount of screening the embryo has already undergone is largely dependent on the genetic parents' own IVF clinic and process. The embryo recipient may elect to have their own  embryologist  conduct further testing.


A risk of ovarian stimulation is the development of  ovarian hyperstimulation syndrome , particularly if hCG is used for  inducing final oocyte maturation.  This results in swollen, painful ovaries. It occurs in 30% of patients. Mild cases can be treated with over the counter medications and cases can be resolved in the absence of pregnancy. In moderate cases, ovaries swell and fluid accumulated in the abdominal cavities and may have symptoms of heartburn, gas, nausea or loss of appetite. In severe cases, patients have sudden excess abdominal pain, nausea, vomiting and will result in hospitalisation.


During egg retrieval, there exists a small chance of bleeding, infection, and damage to surrounding structures such as bowel and bladder (transvaginal ultrasound aspiration) as well as difficulty in breathing, chest infection, allergic reactions to medication, or nerve damage (laparoscopy).


Ectopic pregnancy  may also occur if a fertilised egg develops outside the uterus, usually in the fallopian tubes and requires immediate destruction of the foetus.


IVF does not seem to be associated with an elevated risk of  cervical cancer , nor with  ovarian cancer  or  endometrial cancer  when neutralising the  confounder  of infertility itself. [ 85 ]  Nor does it seem to impart any increased risk for  breast cancer . [ 86 ]


Regardless of pregnancy result, IVF treatment is usually stressful for patients. [ 87 ]   Neuroticism  and the use of  escapist  coping strategies are associated with a higher degree of distress, while the presence of social support has a relieving effect. [ 87 ]  A negative pregnancy test after IVF is associated with an increased risk for  depression , but not with any increased risk of developing  anxiety disorders . [ 88 ]  Pregnancy test results do not seem to be a risk factor for depression or anxiety among men in the case of relationships between two cisgender, heterosexual people. [ 88 ]   Hormonal agents  such as  gonadotropin-releasing hormone agonist  (GnRH agonist) are associated with  depression . [ 89 ]


Studies show that there is an increased risk of  venous thrombosis  or  pulmonary embolism  during the first trimester of IVF. [ 90 ]   When looking at long-term studies comparing patients who received or did not receive IVF, there seems to be no correlation with increased risk of cardiac events. There are more ongoing studies to solidify this. [ 91 ]


Spontaneous pregnancy  has occurred after successful and unsuccessful IVF treatments. [ 92 ]  Within 2 years of delivering an infant conceived through IVF, subfertile patients had a conception rate of 18%. [ 93 ]


A review in 2013 came to the result that infants resulting from IVF (with or without ICSI) have a  relative risk  of birth defects of 1.32 (95%  confidence interval  1.24–1.42) compared to naturally conceived infants. [ 94 ]  In 2008, an analysis of the data of the National Birth Defects Study in the US found that certain birth defects were significantly more common in infants conceived through IVF, notably  septal heart defects ,  cleft lip  with or without  cleft palate ,  esophageal atresia , and  anorectal atresia ; the mechanism of causality is unclear. [ 95 ]  However, in a population-wide cohort study of 308,974 births (with 6,163 using assisted reproductive technology and following children from birth to age five) researchers found: "The increased risk of birth defects associated with IVF was no longer significant after adjustment for parental factors." [ 96 ]  Parental factors included known independent risks for birth defects such as maternal age, smoking status, etc. Multivariate correction did not remove the significance of the association of birth defects and ICSI (corrected odds ratio 1.57), although the authors speculate that underlying male infertility factors (which would be associated with the use of ICSI) may contribute to this observation and were not able to correct for these confounders. The authors also found that a history of infertility elevated risk itself in the absence of any treatment (odds ratio 1.29), consistent with a Danish national registry study [ 97 ]  and "implicates patient factors in this increased risk." [ 96 ]  The authors of the Danish national registry study speculate: "our results suggest that the reported increased prevalence of congenital malformations seen in singletons born after assisted reproductive technology is partly due to the underlying infertility or its determinants." [ 97 ]


If the underlying infertility is related to abnormalities in  spermatogenesis , male offspring will have a higher risk for sperm abnormalities. In some cases genetic testing may be recommended to help assess the risk of transmission of defects to progeny and to consider whether treatment is desirable. [ 99 ]


IVF does not seem to confer any risks regarding cognitive development, school performance, social functioning, and behaviour. [ 100 ]  Also, IVF infants are known to be as securely attached to their parents as those who were naturally conceived, and IVF adolescents are as well-adjusted as those who have been naturally conceived. [ 101 ]


Limited long-term follow-up data suggest that IVF may be associated with an increased incidence of  hypertension ,  impaired fasting glucose , increase in total  body fat  composition, advancement of  bone age , subclinical  thyroid disorder , early adulthood  clinical depression  and  binge drinking  in the offspring. [ 100 ] [ 102 ]  It is not known, however, whether these potential associations are caused by the IVF procedure in itself, by adverse obstetric outcomes associated with IVF, by the genetic origin of the children or by yet unknown IVF-associated causes. [ 100 ] [ 102 ]  Increases in embryo manipulation during IVF result in more deviant fetal growth curves, but birth weight does not seem to be a reliable marker of fetal stress. [ 103 ]


IVF, including  ICSI , is associated with an increased risk of  imprinting disorders  (including  Prader–Willi syndrome  and  Angelman syndrome ), with an  odds ratio  of 3.7 (95%  confidence interval  1.4 to 9.7). [ 104 ]


An IVF-associated incidence of  cerebral palsy  and  neurodevelopmental delay  are believed to be related to the  confounders  of prematurity and low birthweight. [ 100 ]  Similarly, an IVF-associated incidence of  autism  and  attention-deficit disorder  are believed to be related to confounders of maternal and obstetric factors. [ 100 ]


Overall, IVF does not cause an increased risk of  childhood cancer . [ 105 ]  Studies have shown a decrease in the risk of certain cancers and an increased risks of certain others including  retinoblastoma , [ 106 ]   hepatoblastoma [ 105 ]  and  rhabdomyosarcoma . [ 105 ]


In some 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. [ 107 ]  This has led to many authorities and individual clinics implementing procedures to minimise the risk of such mix-ups. The  HFEA , for example, requires clinics to use a double witnessing system, the identity of specimens is checked by two people at each point at which specimens are transferred. Alternatively, technological solutions are gaining favour, to reduce the manpower cost of manual double witnessing, and to further reduce risks with uniquely numbered  RFID  tags which can be identified by readers connected to a computer. The computer tracks specimens throughout the process and alerts the embryologist if non-matching specimens are identified. Although the use of RFID tracking has expanded in the US, [ 108 ]  it is still not widely adopted. [ 109 ]


Pre-implantation genetic diagnosis  (PGD) is criticised for giving select demographic groups disproportionate access to a means of creating a child possessing characteristics that they consider "ideal". Many fertile couples [ 110 ] [ 111 ]  now demand equal access to embryonic screening so that their child can be just as healthy as one created through IVF.  Mass use of PGD, especially as a means of  population control  or in the presence of legal measures related to population or demographic control, can lead to intentional or  unintentional  demographic effects such as the skewed live-birth sex ratios seen in China following implementation of its  one-child policy .


While PGD was originally designed to screen for embryos carrying hereditary genetic diseases, the method has been applied to select features that are unrelated to diseases, thus raising ethical questions. Examples of such cases include the selection of embryos based on  histocompatibility  (HLA) for the donation of tissues to a sick family member, the diagnosis of genetic susceptibility to disease, and  sex selection . [ 112 ]


These examples raise ethical issues because of the morality of  eugenics . It becomes frowned upon because of the advantage of being able to eliminate unwanted traits and selecting desired traits. By using PGD, individuals are given the opportunity to create a human life unethically and rely on science and not by  natural selection . [ 113 ]


For example, a deaf British couple, Tom and Paula Lichy, have petitioned to create a deaf baby using IVF. [ 114 ]  Some  medical ethicists  have been very critical of this approach.  Jacob M. Appel  wrote that "intentionally culling out blind or deaf embryos might prevent considerable future suffering, while a policy that allowed deaf or blind parents to select  for  such traits intentionally would be far more troublesome." [ 115 ]


Robert Winston, professor of fertility studies at Imperial College London, had called the industry "corrupt" and "greedy" stating that "one of the major problems facing us in healthcare is that IVF has become a massive commercial industry," and that "what has happened, of course, is that money is corrupting this whole technology", and accused authorities of failing to protect couples from exploitation: "The regulatory authority has done a consistently bad job. It's not prevented the exploitation of people, it's not put out very good information to couples, it's not limited the number of unscientific treatments people have access to". [ 116 ]  The IVF industry has been described as a market-driven construction of health, medicine and the human body. [ 117 ]


The industry has been accused of making unscientific claims, and distorting facts relating to infertility, in particular through widely exaggerated claims about how common infertility is in society, in an attempt to get as many couples as possible and as soon as possible to try treatments (rather than trying to conceive naturally for a longer time). [ citation needed ]  This risks removing infertility from its social context and reducing the experience to a simple biological malfunction, which not only  can  be treated through bio-medical procedures, but should be treated by them. [ 118 ] [ 119 ]


All pregnancies can be risky, but there are greater risk for mothers who are older and are over the age of 40. As people get older, they are more likely to develop conditions such as gestational diabetes and pre-eclampsia. If the mother does conceive over the age of 40, their offspring may be of lower birth weight, and more likely to requires intensive care. Because of this, the increased risk is a sufficient cause for concern. The high incidence of caesarean in older patients is commonly regarded as a risk. [ 120 ]


Those conceiving at 40 have a greater risk of gestational hypertension and premature birth. The offspring is at risk when being born from older mothers, and the risks associated with being conceived through IVF. [ 121 ]


Adriana Iliescu  held the record for a while as the oldest woman to give birth using IVF and a donor egg, when she gave birth in 2004 at the age of 66. [ citation needed ]  In September 2019, a  74-year-old woman became the oldest-ever to give birth after she delivered twins at a hospital in  Guntur ,  Andhra Pradesh . [ 122 ]


Although menopause is a natural barrier to further conception, IVF has allowed people to be pregnant in their fifties and sixties. People whose uteruses have been appropriately prepared receive embryos that originated from an egg donor. Therefore, although they do not have a genetic link with the child, they have a physical link through pregnancy and  childbirth . Even after menopause, the uterus is fully capable of carrying out a pregnancy. [ 123 ]


A 2009 statement from the  ASRM  found no persuasive evidence that children are harmed or disadvantaged solely by being raised by single parents, unmarried parents, or homosexual parents. It did not support restricting access to assisted reproductive technologies on the basis of a prospective parent's marital status or sexual orientation. [ 124 ]  A 2018 study found that children's psychological well-being did not differ when raised by either same-sex parents or heterosexual parents, even finding that psychological well-being was better amongst children raised by same-sex parents. [ 125 ]


Ethical concerns include reproductive rights, the welfare of offspring, nondiscrimination against unmarried individuals, homosexual, and professional autonomy. [ 124 ]


A controversy in California focused on the question of whether physicians opposed to same-sex relationships should be required to perform IVF for a lesbian couple. Guadalupe T. Benitez, a lesbian medical assistant from San Diego, sued doctors Christine Brody and Douglas Fenton of the North Coast Woman's Care Medical Group after Brody told her that she had "religious-based objections to treating her and homosexuals in general to help them conceive children by artificial insemination," and Fenton refused to authorise a refill of her prescription for the fertility drug Clomid on the same grounds. [ 126 ] [ 127 ]  The California Medical Association had initially sided with Brody and Fenton, but the case,  North Coast Women's Care Medical Group v. Superior Court , was decided unanimously by the California State Supreme Court in favour of Benitez on 19 August 2008. [ 128 ] [ 129 ]


Nadya Suleman  came to international attention after having twelve embryos implanted, eight of which survived, resulting in eight newborns being added to her existing six-child family. The Medical Board of California sought to have fertility doctor Michael Kamrava, who treated Suleman, stripped of his licence. State officials allege that performing Suleman's procedure is evidence of unreasonable judgment, substandard care, and a lack of concern for the eight children she would conceive and the six she was already struggling to raise. On 1 June 2011 the Medical Board issued a ruling that Kamrava's medical licence be revoked effective 1 July 2011. [ 130 ] [ 131 ] [ 132 ]


The research on  transgender  reproduction and family planning is limited. [ 133 ]  A 2020 comparative study of children born to a transgender father and cisgender mother via  donor sperm insemination  in France showed no significant differences to IVF and naturally conceived children of cisgender parents. [ 134 ]


Transgender men can experience challenges in pregnancy and birthing from the cis-normative structure within the medical system, [ 133 ]  as well as psychological challenges such as renewed gender dysphoria. [ 135 ]  The effect of continued testosterone therapy during pregnancy and breastfeeding is undetermined. [ 136 ]  Ethical concerns include reproductive rights, reproductive justice, physician autonomy, and transphobia within the health care setting. [ 133 ]


Alana Stewart, who was conceived using donor sperm, began an online forum for donor children called AnonymousUS in 2010. The forum welcomes the viewpoints of anyone involved in the IVF process. [ 137 ]  In May 2012, a court ruled making anonymous sperm and egg donation in British Columbia illegal. [ 138 ]


In the U.K., Sweden, Norway, Germany, Italy, New Zealand, and some Australian states, donors are not paid and cannot be anonymous.


In 2000, a website called  Donor Sibling Registry  was created to help biological children with a common donor connect with each other. [ 139 ] [ 140 ]


There may be leftover embryos or eggs from IVF procedures if the person for whom they were originally created has successfully carried one or more pregnancies to term, and no longer wishes to use them. With the patient's permission, these may be donated to help others conceive by means of  third party reproduction .


In  embryo donation , these extra embryos are given to others for  transfer , with the goal of producing a successful pregnancy. Embryo recipients have genetic issues or poor-quality embryos or eggs of their own. The resulting child is considered the child of whoever birthed them, and not the child of the donor, the same as occurs with  egg donation  or  sperm donation . As per The National Infertility Association, typically, genetic parents donate the eggs or embryos to a  fertility clinic  where they are preserved by  oocyte cryopreservation  or  embryo cryopreservation  until a carrier is found for them. The process of matching the donation with the prospective parents is conducted by the agency itself, at which time the clinic transfers ownership of the embryos to the prospective parent(s). [ 141 ]


Alternatives to donating unused embryos are destroying them (or having them  transferred  at a time when pregnancy is very unlikely), [ 142 ]  keeping them frozen indefinitely, or donating them for use in research (rendering them non-viable). [ 143 ]  Individual moral views on disposing of leftover embryos may depend on personal views on the  beginning of human personhood  and the definition and/or value of  potential future persons , and on the value that is given to fundamental research questions. Some people believe donation of leftover embryos for research is a good alternative to discarding the embryos when patients receive proper, honest and clear information about the research project, the procedures and the scientific values. [ 144 ]


During the  embryo selection  and transfer phases, many embryos may be discarded in favour of others. This selection may be based on criteria such as genetic disorders or the sex. One of the earliest cases of special gene selection through IVF was the case of the Collins family in the 1990s, who selected the sex of their child. [ 145 ]


The ethic issues remain unresolved as no worldwide consensus exists in science, religion, and philosophy on when a human embryo should be recognised as a person. For those who believe that this is at the moment of conception, IVF becomes a moral question when multiple eggs are fertilised, begin development, and only a few are chosen for uterus transfer. [ citation needed ]
If IVF were to involve the fertilisation of only a single egg, or at least only the number that will be  transferred , then this would not be an issue. However, this has the chance of increasing costs dramatically as only a few eggs can be attempted at a time.  As a result, the couple must decide what to do with these extra embryos. Depending on their view of the embryo's humanity or the chance the couple will want to try to have another child, the couple has multiple options for dealing with these extra embryos. Couples can choose to keep them frozen, donate them to other infertile couples, thaw them, or donate them to medical research. [ 142 ]  Keeping them frozen costs money, donating them does not ensure they will survive, thawing them renders them immediately unviable, and medical research results in their termination. In the realm of medical research, the couple is not necessarily told what the embryos will be used for, and as a result, some can be used in  stem cell  research.


In February 2024, the  Alabama Supreme Court  ruled in  LePage v. Center for Reproductive Medicine  that cryopreserved embryos were "persons" or "extrauterine children". After  Dobbs v. Jackson Women's Health Organization  (2022), some antiabortionists had hoped to get a judgement that fetuses and embryos were "person[s]". [ 146 ]


The  Catholic Church  opposes all kinds of  assisted reproductive technology  and artificial  contraception , on the grounds that they separate the procreative goal of  marital sex  from the goal of uniting married couples.
The Catholic Church permits the use of a small number of reproductive technologies and contraceptive methods such as  natural family planning , which involves charting ovulation times, and allows other forms of reproductive technologies that allow conception to take place from normative sexual intercourse, such as a fertility lubricant. Pope Benedict XVI had publicly re-emphasised the Catholic Church's opposition to in vitro fertilisation, saying that it replaces love between a husband and wife. [ 147 ]


The Catechism of the Catholic Church, in accordance with the Catholic understanding of  natural law , teaches that reproduction has an "inseparable connection" to the sexual union of married couples. [ 148 ]  In addition, the church opposes IVF because it might result in the disposal of embryos; in Catholicism, an embryo is viewed as an individual with a  soul  that must be treated as a person. [ 149 ]  The Catholic Church maintains that it is not objectively evil to be infertile, and advocates adoption as an option for such couples who still wish to have children. [ 150 ]


Hindus  welcome IVF as a gift for those who are unable to bear children and have declared doctors related to IVF to be conducting  punya  as there are several characters who were claimed to be born without intercourse, mainly  Kaurav  and five  Pandavas . [ 151 ]


Regarding the response to IVF by  Islam , a general consensus from the contemporary Sunni scholars concludes that IVF methods are immoral and prohibited. However, Gad El-Hak Ali Gad El-Hak's ART fatwa includes that: [ 152 ]


Within the  Orthodox Jewish  community the concept is debated as there is little precedent in traditional Jewish legal textual sources. Regarding  laws of sexuality , religious challenges include  masturbation  (which may be regarded as "seed wasting" [ 149 ] ), laws related to sexual activity and menstruation ( niddah ) and the specific laws regarding intercourse. An additional major issue is that of establishing paternity and lineage. For a baby conceived naturally, the father's identity is determined by a legal presumption ( chazakah ) of legitimacy:  rov bi'ot achar ha'baal  – a woman's  sexual relations  are assumed to be with her husband. Regarding an IVF child, this assumption does not exist and as such Rabbi  Eliezer Waldenberg  (among others) requires an outside supervisor to positively identify the father. [ 153 ]   Reform Judaism  has generally approved IVF. [ 149 ]


Many women of sub-Saharan Africa choose to foster their children to infertile women. IVF enables these infertile women to have their own children, which imposes new ideals to a culture in which fostering children is seen as both natural and culturally important. Many infertile women are able to earn more respect in their society by taking care of the children of other mothers, and this may be lost if they choose to use IVF instead. As IVF is seen as unnatural, it may even hinder their societal position as opposed to making them equal with fertile women. It is also economically advantageous for infertile women to raise foster children as it gives these children greater ability to access resources that are important for their development and also aids the development of their society at large. If IVF becomes more popular without the birth rate decreasing, there could be more large family homes with fewer options to send their newborn children. This could result in an increase of orphaned children and/or a decrease in resources for the children of large families. This would ultimately stifle the children's and the community's growth. [ 154 ]


In the US, the  pineapple  has emerged as a symbol of IVF users, possibly because some people thought, without scientific evidence, that eating pineapple might slightly increase the success rate for the procedure. [ 155 ]


Studies have indicated that IVF mothers show greater emotional involvement with their child, and they enjoy motherhood more than mothers by natural conception. Similarly, studies have indicated that IVF fathers express more warmth and emotional involvement than fathers by adoption and natural conception and enjoy fatherhood more. Some IVF parents become overly involved with their children. [ 156 ]


Research has shown that men largely view themselves as "passive contributors" [ 157 ] : 340   since they have "less physical involvement" [ 158 ]  in IVF treatment. Despite this, many men feel distressed after seeing the toll of hormonal injections and ongoing physical intervention on their female partner. [ 157 ] : 344   Fertility was found to be a significant factor in a man's perception of his masculinity, driving many to keep the treatment a secret. [ 157 ] : 344   In cases where the men did share that he and his partner were undergoing IVF, they reported to have been teased, mainly by other men, although some viewed this as an affirmation of support and friendship. For others, this led to feeling socially isolated. [ 157 ] : 336    In comparison with females, males showed less deterioration in mental health in the years following a failed treatment. [ 159 ]  However, many men did feel guilt, disappointment and inadequacy, stating that they were simply trying to provide an "emotional rock" for their partners. [ 157 ] : 336


In certain countries, including Austria, Italy, Estonia, Hungary, Spain and Israel, the male does not have the full ability to withdraw consent to storage or use of embryos once they are fertilised. In the United States, the matter has been left to the courts on a more or less ad hoc basis. If embryos are implanted and a child is born contrary to the wishes of the male, he still has legal and financial responsibilities of a father. [ 160 ]


Costs of IVF can be broken down into direct and indirect costs. Direct costs include the medical treatments themselves, including doctor consultations, medications, ultrasound scanning, laboratory tests, the actual IVF procedure, and any associated hospital charges and administrative costs. Indirect costs includes the cost of addressing any complications with treatments, compensation for the  gestational surrogate , patients' travel costs, and lost hours of productivity. [ 161 ]  These costs can be exaggerated by the increasing age of the woman undergoing IVF treatment (particularly those over the age of 40), and the increase costs associated with multiple births. For instance, a pregnancy with twins can cost up to three times that of a singleton pregnancy. [ 162 ]  While some insurances cover one cycle of IVF, it takes multiple cycles of IVF to have a successful outcome. [ 163 ]  A study completed in Northern California reveals that the IVF procedure alone that results in a successful outcome costs $61,377, and this can be more costly with the use of a donor egg. [ 163 ]


The cost of IVF rather reflects the costliness of the underlying healthcare system than the regulatory or funding environment, [ 164 ]  and ranges, on average for a standard IVF cycle and in 2006 United States dollars, between $12,500 in the United States to $4,000 in Japan. [ 164 ]  In Ireland, IVF costs around €4,000, with fertility drugs, if required, costing up to €3,000. [ 165 ]  The cost per live birth is highest in the United States ($41,000 [ 164 ] ) and United Kingdom ($40,000 [ 164 ] ) and lowest in Scandinavia and Japan (both around $24,500 [ 164 ] ).


The high cost of IVF is also a barrier to access for disabled individuals, who typically have lower incomes, face higher health care costs, and seek health care services more often than non-disabled individuals. [ 166 ]


Navigating insurance coverage for transgender expectant parents presents a unique challenge. Insurance plans are designed to cater towards a specific population, meaning that some plans can provide adequate coverage for gender-affirming care but fail to provide fertility services for transgender patients. [ 167 ]  Additionally, insurance coverage is constructed around a person's legally recognised sex and not their anatomy; thus, transgender people may not get coverage for the services they need, including transgender men for fertility services. [ 167 ]


In larger urban centres, studies have noted that lesbian, gay, bisexual, transgender and queer (LGBTQ+) populations are among the fastest-growing users of fertility care. [ 168 ]  IVF is increasingly being used to allow lesbian and other LGBT couples to share in the reproductive process through a technique called  reciprocal IVF . [ 169 ]  The eggs of one partner are used to create embryos which the other partner carries through pregnancy. For gay male couples, many elect to use IVF through gestational surrogacy, where one partner's sperm is used to fertilise a donor ovum, and the resulting embryo is transplanted into a surrogate carrier's womb. [ 170 ]  There are various IVF options available for same-sex couples including, but not limited to, IVF with donor sperm, IVF with a partner's oocytes, reciprocal IVF, IVF with donor eggs, and IVF with gestational surrogate. IVF with donor sperm can be considered traditional IVF for lesbian couples, but reciprocal IVF or using a partner's oocytes are other options for lesbian couples trying to conceive to include both partners in the biological process. Using a partner's oocytes is an option for partners who are unsuccessful in conceiving with their own, and reciprocal IVF involves undergoing reproduction with a donor egg and sperm that is then transferred to a partner who will gestate. Donor IVF involves conceiving with a third party's eggs. Typically, for gay male couples hoping to use IVF, the common techniques are using IVF with donor eggs and gestational surrogates. [ 171 ]


Many LGBT communities centre their support around cisgender gay, lesbian and bisexual people and neglect to include proper support for transgender people. [ 172 ]  The same 2020 literature review analyses the social, emotional and physical experiences of pregnant transgender men. [ 133 ]  A common obstacle faced by pregnant transgender men is the possibility of  gender dysphoria . Literature shows that transgender men report uncomfortable procedures and interactions during their pregnancies as well as feeling misgendered due to gendered terminology used by healthcare providers. Outside of the healthcare system, pregnant transgender men may experience gender dysphoria due to cultural assumptions that all pregnant people are cisgender women. [ 133 ]  These people use three common approaches to navigating their pregnancy: passing as a cisgender woman, hiding their pregnancy, or being out and visibly pregnant as a transgender man. [ 133 ]  Some transgender and gender diverse patients describe their experience in seeking gynaecological and reproductive health care as isolating and discriminatory, as the strictly binary healthcare system often leads to denial of healthcare coverage or unnecessary revelation of their transgender status to their employer. [ 173 ]


Many transgender people retain their original sex organs and choose to have children through biological reproduction. Advances in assisted reproductive technology and fertility preservation have broadened the options transgender people have to conceive a child using their own gametes or a donor's. Transgender men and women may opt for fertility preservation before any gender affirming surgery, but it is not required for future biological reproduction. [ 133 ] [ 174 ]  It is also recommended that fertility preservation is conducted before any hormone therapy. [ 171 ]  Additionally, while fertility specialists often suggest that transgender men discontinue their testosterone hormones prior to pregnancy, research on this topic is still inconclusive. [ 175 ] [ 133 ]  However, a 2019 study found that transgender male patients seeking oocyte retrieval via assisted reproductive technology (including IVF) were able to undergo treatment four months after stopping testosterone treatment, on average. [ 176 ]  All patients experienced menses and normal AMH, FSH and E 2  levels and antral follicle counts after coming off testosterone, which allowed for successful oocyte retrieval. [ 176 ]  Despite assumptions that the long-term androgen treatment negatively impacts fertility, oocyte retrieval, an integral part of the IVF process, does not appear to be affected.


Biological reproductive options available to transgender women include, but are not limited to, IVF and IUI with the trans woman's sperm and a donor or a partner's eggs and uterus. Fertility treatment options for transgender men include, but are not limited to, IUI or IVF using his own eggs with a donor's sperm and/or donor's eggs, his uterus, or a different uterus, whether that is a partner's or a surrogate's. [ 177 ]


People with disabilities who wish to have children are equally or more likely than the non-disabled population to experience infertility, [ 166 ]  yet disabled individuals are much less likely to have access to fertility treatment such as IVF. There are many extraneous factors that hinder disabled individuals access to IVF, such as assumptions about decision-making capacity, sexual interests and abilities, heritability of a disability, and beliefs about parenting ability. [ 178 ] [ 179 ]  These same misconceptions about people with disabilities that once led health care providers to sterilise thousands of women with disabilities now lead them to provide or deny reproductive care on the basis of stereotypes concerning people with disabilities and their sexuality. [ 166 ]


Not only do misconceptions about disabled individuals parenting ability, sexuality, and health restrict and hinder access to fertility treatment such as IVF, structural barriers such as providers uneducated in disability healthcare and inaccessible clinics severely hinder disabled individuals access to receiving IVF. [ 166 ]


In Australia, the average age of women undergoing ART treatment is 35.5 years among those using their own eggs (one in four being 40 or older) and 40.5 years among those using  donated eggs . [ 180 ]  While IVF is available in Australia, Australians using IVF are unable to choose their baby's gender. [ 181 ]


Ernestine Gwet Bell  supervised the first Cameroonian child born by IVF in 1998. [ 182 ]


In Canada, one cycle of IVF treatment can cost between $7,750 to $12,250 CAD, and medications alone can cost between $2,500 to over $7,000 CAD. [ 183 ]  The funding mechanisms that influence accessibility in Canada vary by province and territory, with some provinces providing full, partial or no coverage.


New Brunswick  provides partial funding through their Infertility Special Assistance Fund – a one time grant of up to $5,000. Patients may only claim up to 50% of treatment costs or $5,000 (whichever is less) occurred after April 2014. Eligible patients must be a full-time New Brunswick resident with a valid Medicare card [ 184 ]  and have an official medical infertility diagnosis by a physician. [ 185 ]


In December 2015, the  Ontario  provincial government enacted the Ontario Fertility Program for patients with medical and non-medical infertility, regardless of sexual orientation, gender or family composition. Eligible patients for IVF treatment must be Ontario residents under the age of 43 and have a valid  Ontario Health Insurance Plan  card and have not already undergone any IVF cycles. Coverage is extensive, but not universal. Coverage extends to certain blood and urine tests, physician/nurse counselling and consultations, certain ultrasounds, up to two cycle monitorings, embryo thawing, freezing and culture, fertilisation and embryology services, single transfers of all embryos, and one surgical sperm retrieval using certain techniques only if necessary. Drugs and medications are not covered under this Program, along with psychologist or social worker counselling, storage and shipping of eggs, sperm or embryos, and the purchase of donor sperm or eggs. [ 186 ]


IVF is expensive in China and not generally accessible to unmarried women. [ 187 ]  In August 2022, China's National Health Authority announced that it will take steps to make assisted reproductive technology more accessible, including by guiding local governments to include such technology in its national medical system. [ 187 ]


Croatia


No egg or sperm donations take place in Croatia, however using donated sperm or egg in  ART  and IUI is allowed. With donated eggs, sperm or embryo, a heterosexual couple and single women have legal access to IVF. Male or female couples do not have access to ART as a form of reproduction. The minimum age for males and females to access ART in Croatia is 18 there is no maximum age. Donor anonymity applies, but the born child can be given access to the donor's identity at a certain age [ 188 ]


The penetration of the IVF market in  India  is quite low, with only 2,800 cycles per million infertile people in the reproductive age group (20–44 years), as compared to China, which has 6,500 cycles. The key challenges are lack of awareness, affordability and accessibility. [ 189 ]  Since 2018, however, India has become a destination for fertility tourism, because of lower costs than in the Western world. In December 2021, the  Lok Sabha  passed the Assisted Reproductive Technology (Regulation) Bill 2020, to regulate ART services including IVF centres, sperm and egg banks. [ 190 ]


Israel has the highest rate of IVF in the world, with 1,657 procedures performed per million people per year. [ 191 ]  Couples without children can receive funding for IVF for up to two children. The same funding is available for people without children who will raise up to two children in a  single parent  home. IVF is available for people aged 18 to 45. [ 192 ]  The Israeli Health Ministry says it spends roughly $3450 per procedure. [ citation needed ]


One, two or three IVF treatments are government subsidised for people who are younger than 40 and have no children. The rules for how many treatments are subsidised, and the upper age limit for the people, vary between different  county councils . [ 193 ]  Single people are treated, and embryo adoption is allowed. There are also private clinics that offer the treatment for a fee. [ 194 ]


Availability of IVF in England is determined by  Clinical Commissioning Groups  (CCGs). The  National Institute for Health and Care Excellence  (NICE) recommends up to 3 cycles of treatment for people under 40 years old with minimal success conceiving after 2 years of unprotected sex. Cycles will not be continued for people who are older than 40 years. [ 195 ]  CCGs in  Essex ,  Bedfordshire  and  Somerset  have reduced funding to one cycle, or none, and it is expected that reductions will become more widespread. Funding may be available in "exceptional circumstances" – for example if a male partner has a transmittable infection or one partner is affected by cancer treatment.  According to the campaign group Fertility Fairness "at the end of 2014 every CCG in England was funding at least one cycle of IVF". [ 196 ]   Prices paid by the  NHS  in England varied between under £3,000 to more than £6,000 in 2014/5. [ 197 ]  In February 2013, the cost of implementing the NICE guidelines for IVF along with other treatments for infertility was projected to be £236,000 per year per 100,000 members of the population. [ 198 ]


IVF increasingly appears on  NHS treatments blacklists . [ 199 ]   In August 2017 five of the 208 CCGs had stopped funding IVF completely and others were considering doing so. [ 200 ]   By October 2017 only 25 CCGs were delivering the three recommended NHS IVF cycles to eligible people under 40. [ 201 ]   Policies could fall foul of  discrimination laws  if they treat same sex couples differently from heterosexual ones. [ 202 ]   In July 2019  Jackie Doyle-Price  said that women were registering with surgeries further away from their own home in order to get around CCG rationing policies. [ citation needed ]


The  Human Fertilisation and Embryology Authority  said in September 2018 that parents who are limited to one cycle of IVF, or have to fund it themselves, are more likely choose to implant multiple embryos in the hope it increases the chances of pregnancy.  This significantly increases the chance of multiple births and the associated poor outcomes, which would increase NHS costs.  The president of the  Royal College of Obstetricians and Gynaecologists  said that funding 3 cycles was  "the most important factor in maintaining low rates of multiple pregnancies and reduce(s) associated complications". [ 203 ]


In the United States, overall availability of IVF in 2005 was 2.5 IVF physicians per 100,000 population, and utilisation was 236 IVF cycles per 100,000. [ 204 ]  126 procedures are performed per million people per year. Utilisation highly increases with availability and IVF insurance coverage, and to a significant extent also with percentage of single persons and median income. [ 204 ]   In the US, an average cycle, from egg retrieval to embryo implantation, costs $12,400, and insurance companies that do cover treatment, even partially, usually cap the number of cycles they pay for. [ 205 ]  As of 2015, more than 1 million babies had been born utilising IVF technologies. [ 36 ]


In the US, as of September 2023, 21 states and the  District of Columbia  had passed laws for fertility insurance coverage. In 15 of those jurisdictions, some level of IVF coverage is included, and in 17, some fertility preservation services are included.  Eleven states require coverage for both fertility preservation and IVF: Colorado, Connecticut, Delaware, Maryland, Maine, New Hampshire, New Jersey, New York, Rhode Island, Utah, and Washington D.C. [ 206 ]  The states that have infertility coverage laws are Arkansas, California, Colorado, Connecticut, Delaware, Hawaii, Illinois, Louisiana, Maryland, Massachusetts, Montana, New Hampshire, New Jersey, New York, Ohio, Rhode Island, Texas, Utah, and West Virginia. [ 207 ]  As of July 2023, New York was reportedly the only state Medicaid program to cover IVF. [ 208 ]   These laws differ by state but many require an egg be fertilised with sperm from a spouse and that in order to be covered you must show you cannot become pregnant through penile-vaginal sex. [ 207 ]  These requirements are not possible for a same-sex couple to meet. [ 208 ]


Many fertility clinics in the United States limit the upper age at which people are eligible for IVF to 50 or 55 years. [ 209 ]  These cut-offs make it difficult for people older than fifty-five to utilise the procedure. [ 209 ]


Government agencies in China passed bans on the use of IVF in 2003 by unmarried people or by couples with certain infectious diseases. [ 210 ]


In India, the use of IVF as a means of sex selection ( preimplantation genetic diagnosis ) is banned under the  Pre-Conception and Pre-Natal Diagnostic Techniques Act, 1994 . [ 211 ] [ 212 ] [ 213 ]


Sunni Muslim nations generally allow IVF between married couples when conducted with their own respective sperm and eggs, but not with donor eggs from other couples. But Iran, which is Shi'a Muslim, has a more complex scheme. Iran bans sperm donation but allows donation of both fertilised and unfertilised eggs. Fertilised eggs are donated from married couples to other married couples, while unfertilised eggs are donated in the context of mut'ah or temporary marriage to the father. [ 214 ]


By 2012  Costa Rica  was the only country in the world with a complete ban on IVF technology, it having been ruled unconstitutional by the nation's Supreme Court because it "violated life." [ 215 ]  Costa Rica had been the only country in the western hemisphere that forbade IVF.  A law project sent reluctantly by the government of President  Laura Chinchilla  was rejected by parliament. President Chinchilla has not publicly stated her position on the question of IVF. However, given the massive influence of the Catholic Church in her government any change in the status quo seems very unlikely. [ 216 ] [ 217 ]  In spite of Costa Rican government and strong religious opposition, the IVF ban has been struck down by the Inter-American Court of Human Rights in a decision of 20 December 2012. [ 218 ]  The court said that a long-standing Costa Rican guarantee of protection for every human embryo violated the reproductive freedom of infertile couples because it prohibited them from using IVF, which often involves the disposal of embryos not implanted in a woman's uterus. [ 219 ]  On 10 September 2015, President Luis Guillermo Solís signed a decree legalising in-vitro fertilisation. The decree was added to the country's official gazette on 11 September. Opponents of the practice have since filed a lawsuit before the country's Constitutional Court. [ 220 ]


All major restrictions on single but infertile people using IVF were lifted in Australia in 2002 after a final appeal to the Australian High Court was rejected on procedural grounds in the Leesa Meldrum case. A  Victorian  federal court had ruled in 2000 that the existing ban on all single women and lesbians using IVF constituted sex discrimination. [ 221 ]  Victoria's government announced changes to its IVF law in 2007 eliminating remaining restrictions on fertile single women and lesbians, leaving South Australia as the only state maintaining them. [ 222 ]


Despite strong popular support (7 out of 10 adults consider IVF access a good thing [ 223 ]  and 67% believe that health insurance plans should cover IVF [ 224 ] ), IVF can involve complicated legal issues and has become a contentious issue in US politics. [ 225 ] [ 226 ]   Federal regulations include screening  requirements and restrictions  on donations, [ 227 ]  but these generally do not affect heterosexually intimate partners. [ 228 ]  Doctors may be required to provide treatments to unmarried or LGBTQ couples under non-discrimination laws, as for example in California. [ 129 ]  The state of  Tennessee  proposed a bill in 2009 that would have defined donor IVF as adoption. [ 229 ]  During the same session, another bill proposed barring adoption from any unmarried and cohabitating couple, and activist groups stated that passing the first bill would effectively stop unmarried women from using IVF. [ 230 ] [ 231 ]  Neither of these bills passed. [ 232 ]


In 2023, the Practice Committee of the  American Society for Reproductive Medicine  (ASRM) updated its guidelines for the definition of “infertility” to include those who need medical interventions “in order to achieve a successful pregnancy either as an individual or with a partner.” [ 233 ]  In many states, legal and financial decisions about provision of infertility treatments reference this “official” definition. [ 234 ]  On September 29, 2024, California Governor  Gavin Newsom  signed SB 729, legislation which aligns with the ASRM definition of “infertility”. [ 235 ] [ 236 ]


In the United States, much of the opposition to the use of IVF is associated with the  anti-abortion movement ,  evangelicals , and denominations such as the  Southern Baptists . [ 237 ]  Current legal opposition to IVF and other fertility treatment access has stemmed from recent court rulings regarding women's reproductive healthcare. In the 2022  Dobbs v. Jackson Women's Health Organization  decision, [ 238 ]  the U.S. Supreme Court overturned the 1973 Roe v. Wade [ 239 ]  decision which had federally protected the right to abortion. The 2024 Alabama Supreme Court decision regarding IVF has since threatened IVF access and legality in the U.S. Frozen embryos at an IVF clinic were accidentally destroyed  resulting in a lawsuit during which the attorneys for the plaintiff sought damages under the Wrongful Death of a Minor Act. The court ruled in favor of the plaintiffs, setting a state-level precedent that embryos and fetuses are given the same rights as minors/children, regardless of whether they are in utero or not. [ 240 ]  This has created confusion over the status of unused embryos and questions surrounding when life begins. After the court's decision, numerous IVF clinics in Alabama halted IVF treatment services [ 241 ]  for fears of civil and criminal liability associated with the new rights granted to embryos. Since, laws proposing embryonic personhood have been proposed in 13 other states, [ 242 ]  creating fear of further state restrictions. This ruling raised concerns from  The National Infertility Association  and the  American Society for Reproductive Medicine  that the decision would mean  Alabama 's bans on abortion prohibit IVF as well, [ 243 ]  while the  University of Alabama at Birmingham health system  paused IVF treatments. [ 244 ]  Eight days later the  Alabama legislature  voted to protect IVF providers and patients from criminal or civil liability. [ 245 ] [ 246 ]


The  Right to IVF Act , federal legislation that would have codified a right to fertility treatments and provided insurance coverage for in vitro fertilisation treatments, was twice brought to a vote in the Senate in 2024. Both times it was blocked by Senate Republicans, of whom only  Lisa Murkowski  and  Susan Collins  voted to move the bill forward. [ 247 ] [ 237 ] [ 248 ] [ 249 ]


Few American courts have addressed the issue of the "property" status of a frozen embryo.  This issue might arise in the context of a divorce case, in which a court would need to determine which spouse would be able to decide the disposition of the embryos.  It could also arise in the context of a dispute between a sperm donor and egg donor, even if they were unmarried.  In 2015, an Illinois court held that such disputes could be decided by reference to any contract between the parents-to-be.  In the absence of a contract, the court would weigh the relative interests of the parties. [ 250 ]


Some alternatives to IVF are:


52°27′11″N   1°56′20″W  /  52.4531°N 1.9389°W  /  52.4531; -1.9389


The Birmingham Women's Fertility Centre  at  Birmingham Women’s Hospital ,  Birmingham , England, formerly named the "Assisted Conception Unit", is one of the UK's leading medical centres for  infertility  treatment and care. It is the longest established fertility clinic in the Midlands, marking thirty years operations in the year 2010. The clinic is based in an NHS hospital and provides integrated care to both NHS and private patients; the staff is internationally recognised for their work in treating with infertility. The clinic runs active programmes of egg-sharing, sperm donation and egg-donation. [ citation needed ]


The Fertility Centre was one of five clinics selected around the UK to receive  Medical Research Council  funding to elevate the IVF laboratories to ‘ cleanroom ’ levels. This is fundamental for producing  human embryonic stem cells  that are suitable for human use, as all stages of development were in strictly controlled conditions. These opened in summer 2006 and the centre has maintained good clinical results at the new operating levels (see  HFEA ).
During 2010 the Centre developed and now offers Preimplantation Genetic Testing / Diagnosis services (PGD; PGT-M; PGT-SR; PGT-A). These are in alliance with the West Midlands Regional Genetics Service, which is also based at the hospital. The first PGD baby was born in November 2011. [ citation needed ]


2011 saw the centre launch Birmingham Spermbank, a separate organisation dedicated to dealing with sperm donors. The Spermbank aims to raise awareness of sperm donation across the communities in the Midlands and increase the availability of affordable donor sperm to those in the local community. [ 1 ]  One way it has done this is through engagement with programmes on local and national media for example a recent programme on BBC Asian Network. [ 2 ]


The centre has a recognised international research profile through its academic wing the  Centre for Human Reproductive Science (ChRS) . This has included notable high-profile achievements in translational medicine such as the invention of the male  Fertell  over-the-counter home fertility test. [ 3 ]


Bourn Hall Clinic  in  Bourn ,  Cambridgeshire , England, is a centre for the treatment of  infertility . The original building,  Bourn Hall , is about 400 years old. Since becoming a medical centre, it has been greatly extended.


Bourn Hall Clinic was founded in 1980 by  IVF  pioneers Mr  Patrick Steptoe , embryologist  Jean Purdy  and Professor  Robert Edwards , who were responsible for the conception of  Louise Brown , the world's first  IVF  or  test-tube baby  in 1977. [ 1 ]  Since its foundation the clinic has assisted in the conception of over 10,000 babies.


Following the death of Patrick Steptoe in 1988,  Peter Brinsden  was appointed Medical Director in March 1989.


Bourn Hall Clinic is one of five fertility centres selected by the  NHS  East of England Specialised Commissioning Group to provide treatment to patients in the region. As of 1 May 2009, childless couples in Cambridgeshire,  Norfolk ,  Suffolk ,  Essex ,  Bedfordshire  and  Hertfordshire  will be able to access up to three cycles of  IVF , plus a further three frozen embryo transfers. [ 2 ] [ 3 ]


A breakthrough that occurred in Bourn Hall’s early days was the application of  cryobiology  to IVF, allowed embryos to be frozen for transfer at a later date. The first "frozen babies" were born in 1984. Bourn Hall also led the way in offering in vitro fertilisation  surrogacy . They treated the first couple in the United Kingdom in 1988 and the first IVF surrogacy child was born in 1989. [ 4 ]


The world’s first baby born as a result of directly injecting a single sperm into the centre of an oocyte was conceived at Bourn Hall. Since this birth in 1992 "intracytoplasmic sperm injection" or  ICSI  has been adopted by IVF clinics around the world.


More recently, Bourn Hall pioneered the use of  blastocyst  culture, where the embryo is grown for up to five days prior to implantation. This increases the chances of IVF success. [ 5 ]


In 2009, Bourn Hall acquired the former ISIS Fertility Centre in Colchester, Essex which has enabled more convenient access to both NHS and self funded fertility treatments for patients from the Essex and Suffolk regions. [ 6 ]


In 2010 Bourn Hall Clinic celebrated the award of the  Nobel Prize for Physiology and Medicine  to co-founder Professor  Robert Edwards .


A plaque was unveiled at the Clinic in July 2013 by Louise Brown and Alastair MacDonald—the world's first IVF baby boy—commemorating Steptoe and Edwards. [ 7 ] [ 8 ]  The plaque missed out  Jean Purdy  who had been the person who chose Bourn Hall, was a co-founder of the clinic and an equal partner in developing IVF. In 2018, to mark the 40th anniversary of IVF, the clinic unveiled an additional memorial to Jean Purdy, the "world's first IVF nurse and embryologist. Co-founder of Bourn Hall Clinic". [ 9 ]


The current Science Director, appointed in January 2018, is Martyn Blayney MSc,  DIP RCPath . [ 10 ]


Peter Robert Brinsden   MBBS ,  MRCS ,  LRCP ,  FRCOG  (born 2 September 1940) is known for the treatment of infertility in couples. From 1989 to 2006 he was the medical director of  Bourn Hall Clinic  in the UK, a leading centre for the treatment of fertility problems, and where about 6,000 babies have been conceived using  IVF  and other assisted conception treatments. [ 1 ]


Brinsden was born in  Peking  in China in 1940. He lived in China, the United States, Canada and Hong Kong until 1950. Brinsden was educated at  Rugby School ,  King's College London  and  St George's Hospital Medical School . He qualified MBBS and MRCS, LRCP in 1966. [ 2 ]


Brinsden joined the  Royal Navy  in 1966, and served as ship's medical officer 1969–1970. He started training as a  gynaecologist  in 1970 in military and civilian  NHS  hospitals until 1978. He qualified  DObst RCOG  in 1981, MRCOG in 1976 and was elected FRCOG in 1989. [ 2 ]  Brinsden was made a Consultant Gynaecologist in 1978, with a principal interest in infertility treatment.


He retired from the  Royal Navy  in 1982 with the rank of surgeon commander. [ 2 ]  Brinsden served as a consultant at King Fahad Hospital,  Riyadh  in Saudi Arabia 1982–1985 and then at  Bourn Hall Clinic  under  Patrick Steptoe , the  IVF  pioneer who, with  Robert Edwards , was responsible for the birth of the world's first  IVF  baby  Louise Brown  in 1978.


Brinsden joined the Wellington Hospital IVF Unit, then the world's largest  IVF  and  GIFT  clinic, [ 3 ]  as deputy director. He was appointed medical director at  Bourn Hall Clinic ,  Cambridge , in the UK in March 1989 following the death of  Patrick Steptoe  in 1988. Since his retirement in 2006 he has been the consultant medical director.


He has been an affiliated lecturer at the  University of Cambridge 's Clinical School at  Addenbrookes Hospital  since 1992, and a visiting professor in gynaecology and fertility at the Capital Medical University in Beijing since 2001. Brinsden has also been an inspector for the  Human Fertilisation and Embryology Authority  since 1997.


Brinsden is in great demand internationally as a lecturer on fertility and assisted conception issues, and in recent years has lectured at, among others, the Fertility Society of Australia's 2006 Conference, [ 4 ]
the Serono Symposia International, [ 5 ]  the Chicago 2007 Midwest Reproductive Symposium, [ 6 ]  and the 2006 Barbados IVF Conference. [ 7 ]


Brinsden was elected president of the British Fertility Society in April 2009 [ 8 ]  and is the vice-chairman of The Nelson Society. [ 9 ]


Sir Robert Geoffrey Edwards  (27 September 1925 – 10 April 2013) was a British  physiologist  and pioneer in  reproductive medicine , and  in-vitro fertilisation  (IVF) in particular. Along with obstetrician and gynaecologist  Patrick Steptoe [ 7 ]  and nurse and embryologist  Jean Purdy , Edwards successfully pioneered conception through IVF, which led to the birth of  Louise Brown  on  25 July  1978. [ 8 ]  They founded the first IVF programme for infertile patients and trained other scientists in their techniques. Edwards was the founding editor-in-chief of  Human Reproduction  in 1986. [ 9 ]  In 2010, he was awarded the  Nobel Prize in Physiology or Medicine  "for the development of in vitro fertilization". [ 10 ] [ 11 ]


Edwards was born in  Batley , Yorkshire, and attended  Manchester Central High School [ 6 ]  on Whitworth Street in central Manchester, after which he served in the  British Army , and then completed his undergraduate studies in biology, graduating with an  ordinary degree  from  Bangor University . [ 12 ] [ 13 ]  He studied at the  Institute of Animal Genetics and Embryology  at the  University of Edinburgh , where he was awarded a PhD in 1955 under the supervision of R.A. Beatty and  C. H. Waddington . [ 4 ]


After a year as a  postdoctoral research  fellow at the  California Institute of Technology  he joined the scientific staff of the  National Institute for Medical Research  at Mill Hill. After a further year at the  University of Glasgow , in 1963 he moved to the  University of Cambridge  as Ford Foundation Research Fellow at the Department of Physiology, and a member of  Churchill College, Cambridge . He was appointed  Reader  in physiology in 1969. [ 14 ]


Circa 1960 Edwards started to study human  fertilisation , and he continued his work at Cambridge, laying the groundwork for his later success. In 1968 he was able to achieve fertilisation of a human egg in the laboratory and started to collaborate with  Patrick Steptoe , a  gynaecological  surgeon from  Oldham . Edwards developed human culture media to allow the fertilisation and early  embryo  culture, while Steptoe used  laparoscopy  to recover  ovocytes  from patients with tubal  infertility . Their attempts met significant hostility and opposition, [ 15 ]  including a refusal of the  Medical Research Council  to fund their research and several lawsuits. [ 16 ] [ 17 ]   Roger Gosden  was one of his first graduate students. [ 3 ]


The birth of  Louise Brown , the world's first 'test-tube baby', at  11:47 pm  on  25 July  1978 at the  Oldham General Hospital  made medical history: in vitro fertilisation meant a new way to help infertile couples who formerly had no possibility of having a baby.  Nurse  Jean Purdy  was the first to see Brown's embryo dividing. [ 18 ]


Refinements in technology have increased pregnancy rates and it is estimated that in 2010 about  4 million  children have been born by IVF, [ 10 ]  with approximately 170,000 coming from donated  oocyte  and embryos. [ 19 ] [ 20 ] [ 21 ]  Their breakthrough laid the groundwork for further innovations such as intracytoplasmatic sperm injection  ICSI , embryo biopsy ( PGD ), and  stem cell  research.


Edwards, Purdy, and Steptoe founded the  Bourn Hall Clinic  as a place to advance their work and train new specialists. Purdy died in 1985 and Steptoe in 1988. Edwards continued in his career as a scientist and an editor of medical journals.


Edwards received numerous honours and awards including:


Edwards was a supporter of the  Labour Party , and represented  Newnham  ward on  Cambridge City Council  for two terms, from 1973 to 1978. [ 33 ]  He enjoyed the experience enough to consider at one stage standing for parliament, but nothing came of it. [ 34 ]


Edwards married  Ruth Fowler Edwards  (1930–2013), also a scientist with significant work, granddaughter of 1908 Nobel laureate physicist  Ernest Rutherford  and daughter of physicist  Ralph Fowler , in 1956. [ 35 ]  The couple had five daughters and 12 grandchildren. [ 36 ]


Edwards died at home near Cambridge, England [ 36 ]  on 10 April 2013 after a long lung illness. [ 37 ]  A spokesperson for the  University of Cambridge  said "He will be greatly missed by family, friends and colleagues." [ 38 ]   The Guardian  reported that, as of Edwards' death, more than four million births had resulted from IVF. [ 38 ]  Louise Brown said "His work, along with Patrick Steptoe and Jean Purdy, has brought happiness and joy to millions of people all over the world by enabling them to have children." [ 39 ]  According to the BBC, his work was motivated by his belief that "the most important thing in life is having a child." [ 39 ]


A plaque was unveiled at the Bourn Hall Clinic in July 2013 by Louise Brown and Alastair MacDonald – the world's first IVF baby boy – commemorating Steptoe and Edwards. [ 40 ]


Embryo culture  is a component of  in vitro  fertilisation  where in resultant embryos are allowed to grow for some time in an artificial medium.


The duration of embryo culture can be varied, conferring different stages of  embryogenesis  at  embryo transfer . The main stages at which embryo transfer is performed are  cleavage stage  (day 2 to 4 after  co-incubation ) or the  blastocyst  stage (day 5 or 6 after  co-incubation ). [ 1 ]


Embryos which reach the day 3 cell stage can be tested for chromosomal or specific genetic defects prior to possible transfer by  preimplantation genetic diagnosis  (PGD). Embryo culture until the blastocyst stage confers a significant increase in  live birth rate  per  embryo transfer , and there is no evidence of a difference between the groups in cumulative pregnancy rates. [ 2 ]  Transfer day 2 instead of day 3 after fertilization has no differences in  live birth rate . [ 3 ]


Monozygotic twinning  is not increased after blastocyst transfer compared with  cleavage-stage embryo  transfer. [ 4 ]


There are significantly higher odds of  preterm birth  ( odds ratio  1.3) and  congenital anomalies  ( odds ratio  1.3) among births from embryos cultured until the blastocyst stage compared with cleavage stage. [ 1 ]


The first thing to take into account are the oxygen and carbon dioxide conditions because they must be as similar as the uterus ones as possible. It is for this reason that oxygen has to be at 5% and carbon dioxide at 6% (depending on altitude). On the other hand, temperature must be set at 37 degrees. In addition, the pH levels should be between 7.2 and 7.5.


Regarding the incubator, technicians should place one patient per incubator and avoid frequent door opening. Taking into account the number of embryos used in the culture, group embryo culture is recommended, so they can exchange growing factors while time is saved in the lab but embryo fusion is a drawback that has to be taken into account, in fact, after day five embryo fusion is more likely to happen.


Culture of embryos can either be performed in an artificial culture medium or in an  autologous endometrial coculture  (on top of a layer of cells from the woman's own uterine lining). With artificial culture medium, there can either be the same culture medium throughout the period ( monoculture medium ), or a  sequential system  can be used, in which the embryo is sequentially placed in different media, with different formulations based on the different concentration and composition of the tubal and uterine fluid in relation to change in the metabolic activity of the embryo during its development. [ 5 ]  For example, when culturing to the blastocyst stage, one medium may be used for culture to day 3, and a second medium is used for culture thereafter. [ 6 ]  Single or sequential medium are equally effective for the culture of human embryos to the blastocyst stage. [ 7 ]  Artificial embryo culture media basically contain glucose, pyruvate, and energy-providing components, but the addition of amino acids, nucleotides, vitamins, and cholesterol improve the performance of embryonic growth and development. Specifically, embryo culture media contain more pyruvate concentration than glucose in the cleavage phase and more glucose concentration than pyruvato in the blastocyst phase. This is because before day 3 the embryo uses the oocyte reserves, however, from day 3 to the blastocyst it starts to express different proteins to continue its development, so it starts to degrade glucose (it needs more glucose in this case).   [ 8 ]  Also substances like antioxidants, antibiotics, macromolecules, hormones and growth factors can be added. [ 5 ]  Methods to permit dynamic embryo culture with fluid flow and embryo movement are also available. [ 9 ]  A new method in development uses the uterus as an incubator and the naturally occurring intrauterine fluids as culture medium by encapsulating the embryos in a permeable intrauterine vessel. [ 10 ]


A review in 2013 meta-analysis of commercially available IVF culture media was unable to identify a specific media that was superior in terms of pregnancy outcome. [ 11 ]


Usage of low oxygen concentrations of 5% rather than about 20% in the atmosphere has been shown to increase live birth rate to a  relative probability  of 1.24, without any evidence of increased risk for multiple pregnancies, miscarriages or congenital abnormalities. [ 12 ]


Control and regulation of pH are mandatory for in vitro embryo culture. Culture media can be classified according to type of buffer used:


CO₂ / bicarbonate - buffered medium: uses the same physiological buffering system surrounding mammalian cells. Require the use of CO₂ incubators at 5-7%;


Phosphate-buffered medium: does not require CO₂ environment. Seems to have detrimental effects in embryo development in vitro;


HEPES-buffered medium: used as buffered medium for human oocyte collection and embryo handling;


MOPS-buffered medium: like HEPES, has the potential advantage that the buffering capacity is less temperature dependent. [ 13 ]


While it has been hypothesized that incubating at a temperature lower than 37 °C may be a more accurate recreation of the temperature in the female reproductive tract, the evidence is uncertain whether different temperatures for embryo culture have different effects on pregnancy or live birth rates. [ 14 ]


Animal studies have detected  epigenetic  abnormalities in embryos having undergone embryo culture, indicating a need to optimize the procedures. [ 15 ]


In addition to human embryo culture, the technique is employed extensively for non-human species, especially when exploring embryo development,  assisted reproductive technology , and the generation of  genetically modified animals . [ 16 ]   Mouse  embryos, in particular, are frequently cultured for these specific research purposes. The two often used cultural media are  potassium simplex optimized medium  (KSOM) and  human tubal fluid  (HTF). Because KSOM uses a  bicarbonate buffering  mechanism, it is dependent on a  CO 2  incubator  to maintain the right  pH . [ 16 ]  As with KSOM, HTF is only appropriate for a CO 2  incubator environment but is employed during the  fertilisation  process. [ 17 ]  Buffered by a  HEPES  system, M2 medium facilitates embryo handling in ambient conditions without the need for CO 2  regulation. [ 18 ]


Embryo transfer  refers to a step in the process of  assisted reproduction  in which  embryos  are placed into the  uterus  of a female with the intent to establish a  pregnancy . This technique - which is often used in connection with  in vitro fertilization  (IVF) - may be used in humans or in other animals, in which situations and goals may vary.


Embryo transfer can be done at day two or day three, or later in the  blastocyst  stage, which was first performed in 1984. [ 1 ]


Factors that can affect the success of embryo transfer include the endometrial receptivity, embryo quality, and embryo transfer technique.


Embryos can be either "fresh" from fertilized egg cells of the same  menstrual cycle , or "frozen", that is they have been generated in a preceding cycle and undergone  embryo cryopreservation , and are thawed just prior to the transfer, which is then termed "frozen embryo transfer" (FET). The outcome from using cryopreserved embryos has uniformly been positive with no increase in birth defects or development abnormalities, [ 2 ]  also between fresh versus frozen eggs used for  intracytoplasmic sperm injection  (ICSI). [ 3 ]  In fact,  pregnancy rates  are increased following FET, and perinatal outcomes are less affected, compared to embryo transfer in the same cycle as  ovarian hyperstimulation  was performed. [ 4 ]  The  endometrium  is believed to not be optimally prepared for  implantation  following ovarian hyperstimulation, and therefore frozen embryo transfer avails for a separate cycle to focus on optimizing the chances of successful implantation. [ 4 ]  Children born from  vitrified   blastocysts  have significantly higher  birthweight  than those born from non-frozen blastocysts. [ 5 ]  When transferring a frozen-thawed oocyte, the chance of pregnancy is essentially the same whether it is transferred in a natural cycle or one with  ovulation induction . [ 6 ]


There is probably little or no difference between FET and fresh embryo transfers in terms of live birth rate and ongoing pregnancy rate and the risk of  ovarian hyperstimulation syndrome  may be less using the "freeze all" strategy. [ 7 ]  The risk of having a large-for-gestational-age baby and higher birth rate, in addition to  maternal hypertensive disorders  of pregnancy may be increased using a "freeze all" strategy. [ 7 ]


In the human, the uterine lining ( endometrium ) needs to be appropriately prepared so that the embryo can implant. In a natural cycle the embryo transfer takes place in the  luteal phase  at a time where the lining is appropriately undeveloped in relation to the status of the present Luteinizing Hormone. In a stimulated or cycle where a "frozen" embryo is transferred, the recipient woman could be given first estrogen preparations (about 2 weeks), then a combination of  estrogen  and  progesterone  so that the lining becomes receptive for the embryo. The time of receptivity is the  implantation window . A  scientific review  in 2013 came to the conclusion that it is not possible to identify one method of endometrium preparation in frozen embryo transfer as being more effective than another. [ 8 ]


Limited evidence also supports removal of  cervical mucus  before transfer. [ 9 ]


Embryo transfer can be performed after various durations of  embryo culture , conferring different stages in  embryogenesis . The main stages at which embryo transfer is performed are  cleavage stage  (day 2 to 4 after  co-incubation ) or the  blastocyst  stage (day 5 or 6 after  co-incubation ). [ 10 ]


Because in vivo, a cleavage stage embryo still resides in the fallopian tube and it is known that the nutritional environment of the uterus is different from that of the tube, it is postulated that this may cause stress on the embryo if transferred on day 3 resulting in reduced implantation potential. A blastocyst stage embryo does not have this problem as it is best suited for the uterine environment   [1]


Embryos who reach the day 3 cell stage can be tested for chromosomal or specific genetic defects prior to possible transfer by  preimplantation genetic diagnosis  (PGD). Transferring at the blastocyst stage confers a significant increase in  live birth rate  per transfer, but also confers a decreased number of embryos available for transfer and  embryo cryopreservation , so the cumulative clinical pregnancy rates are increased with cleavage stage transfer. [ 6 ] [ needs update ]  It is uncertain whether there is any difference in  live birth rate  between transfer on day two or day three after fertilization. [ 11 ]


Monozygotic twinning  is not increased after blastocyst transfer compared with  cleavage-stage embryo  transfer. [ 12 ]


There is a significantly higher odds of  preterm birth  ( odds ratio  1.3) and  congenital anomalies  ( odds ratio  1.3) among births having reached the blastocyst stage compared with cleavage stage. [ 10 ]  Because of increased female embryo mortality due to epigenetic modifications induced by extended culture, [ 13 ]  blastocyst transfer leads to more male births (56.1% male) versus 2 or 3 day transfer (a normal sex ratio of 51.5% male).


Laboratories have developed grading methods to judge oocyte and  embryo  quality. In order to optimise  pregnancy rates , there is significant evidence that a morphological scoring system is the best strategy for the selection of embryos. [ 14 ]  Since 2009 where the first  time-lapse microscopy  system for IVF was approved for clinical use, morphokinetic scoring systems has shown to improve to  pregnancy rates  further. [ 15 ]  However, when all different types of  time-lapse embryo imaging  devices, with or without morphokinetic scoring systems, are compared against conventional embryo assessment for IVF, there is insufficient evidence of a difference in live-birth, pregnancy, stillbirth or miscarriage to choose between them. [ 16 ]  A small prospectively randomized study in 2016 reported poorer embryo quality and more staff time in an automated  time-lapse embryo imaging  device compared to conventional embryology. [ 17 ]  Active efforts to develop a more accurate embryo selection analysis based on Artificial Intelligence and Deep Learning are underway.  Embryo Ranking Intelligent Classification Algorithm  (ERICA), [ 18 ]  is a clear example.  This Deep Learning software substitutes manual classifications with a ranking system based on an individual embryo's predicted genetic status in a non-invasive fashion. [ 19 ]  Studies on this area are still pending and current feasibility studies support its potential. [ 20 ]


The embryo transfer procedure starts by placing a speculum in the vagina to visualize the cervix, which is cleansed with saline solution or culture media.  A transfer catheter is loaded with the embryos and handed to the clinician after confirmation of the patient's identity. The catheter is inserted through the cervical canal and advanced into the uterine cavity. [ 21 ]  Several types of catheters are used for this process, however, there is good evidence that using a soft vs a hard transfer catheter can increase the chances of clinical pregnancy. [ 22 ]


There is good and consistent evidence of benefit in  ultrasound guidance , [ 9 ]  that is, making an abdominal ultrasound to ensure correct placement, which is 1–2 cm from the uterine fundus. [ 23 ]  There is evidence of a significant increase in clinical pregnancy using ultrasound guidance compared with only "clinical touch", as well as performing the transfer with hyaluronic acid enriched transfer media. [ 24 ]  Anesthesia is generally not required. Single embryo transfers in particular require accuracy and precision in placement within the uterine cavity. The optimal target for embryo placement, known as the maximal implantation potential (MIP) point, is identified using 3D/4D ultrasound. [ 25 ]  However, there is limited evidence that supports deposition of embryos in the midportion of the uterus. [ 9 ] [ 24 ]


After insertion of the catheter, the contents are expelled and the embryos are deposited. Limited evidence supports making trial transfers before performing the procedure with embryos. [ 9 ]  After expulsion, the duration that the catheter remains inside the uterus has no effect on pregnancy rates. [ 26 ]  Limited evidence suggests avoiding negative pressure from the catheter after expulsion. [ 9 ]  After withdrawal, the catheter is handed to the embryologist, who inspects it for retained embryos.


In the process of  zygote intrafallopian transfer  (ZIFT), eggs are removed from the woman, fertilised, and then placed in the woman's fallopian tubes rather than the uterus.


A major issue is how many embryos should be transferred, since placement of multiple embryos carries a risk of multiple pregnancy. While the past physicians placed multiple embryos to increase the chance of pregnancy, this approach has fallen out of favor. Professional societies, and legislatures in many countries, have issued guidelines or laws to curtail the practice. [ 27 ]  There is low to moderate evidence that making a double embryo transfer during one cycle achieves a higher live birth rate than a single embryo transfer; but making two single embryo transfers in two cycles has the same live birth rate and would avoid multiple pregnancies. [ 28 ]


The appropriate number of embryos to be transferred depends on the age of the woman, whether it is the first, second or third full IVF cycle attempt and whether there are top-quality embryos available. According to a guideline from The  National Institute for Health and Care Excellence  (NICE) in 2013, the number of embryos transferred in a cycle should be chosen as in following table: [ 29 ]


The technique of selecting only one embryo to transfer to the woman is called  elective-single embryo transfer  ( e-SET ) or, when embryos are at the blastocyst stage, it can also be called  elective single blastocyst transfer (eSBT) . [ 30 ]  It significantly lowers the risk of multiple pregnancies, compared with e.g. Double Embryo Transfer (DET) or  double blastocyst transfer  (2BT), with a twinning rate of approximately 3.5% in sET compared with approximately 38% in DET, [ 31 ]  or 2% in eSBT compared with approximately 25% in 2BT. [ 30 ]  At the same time,  pregnancy rates  is not significantly less with eSBT than with 2BT. [ 30 ]  That is, the cumulative live birth rate associated with single fresh embryo transfer followed by a single frozen and thawed embryo transfer is comparable with that after one cycle of double fresh embryo transfer. [ 11 ]  Furthermore, SET has better outcomes in terms of mean gestational age at delivery, mode of delivery, birthweight, and risk of  neonatal intensive care unit  necessity than DET. [ 31 ]  e-SET of embryos at the cleavage stage reduces the likelihood of live birth by 38% and multiple birth by 94%. [ 32 ]  Evidence from randomized, controlled trials suggests that increasing the number of e-SET attempts (fresh and/or frozen) results in a cumulative live birth rate similar to that of DET. [ 32 ]


The usage of single embryo transfer is highest in Sweden (69.4%), but as low as 2.8% in the USA. Access to public funding for ART, availability of good  cryopreservation  facilities, effective education about the risks of multiple pregnancy, and legislation appear to be the most important factors for regional usage of single embryo transfer. [ 33 ]  Also, personal choice plays a significant role as many subfertile couples have a strong preference for twins. [ 33 ]


It is uncertain whether the use of mechanical closure of the cervical canal following embryo transfer has any effect. [ 34 ]


There is considerable evidence that prolonges bed rest (more than 20 minutes) after embryo transfer is associated with reduced chances of clinical pregnancy. [ 35 ]


Using  hyaluronic acid  as an adherence medium for the embryo may increase live birth rates. [ 34 ]  There may be little or no benefit in having a full bladder, removal of cervical mucus, or flushing of the endometrial or endocervical cavity at the time of embryo transfer. [ 34 ]  Adjunctive antibiotics in the form of  amoxicillin  plus  clavulanic acid  probably does not increase the clinical pregnancy rate compared with no antibiotics. [ 34 ]  The use of Atosiban, G-CSF and hCG around the time of embryo transfer showed a trend towards increased clinical pregnancy rate. [ 36 ]


For frozen-thawed embryo transfer or transfer of embryo from  egg donation , no previous  ovarian hyperstimulation  is required for the recipient before transfer, which can be performed in spontaneous ovulatory cycles. Still, various protocols exist for frozen-thawed embryo transfers as well, such as protocols with  ovarian hyperstimulation , protocols in which the endometrium is artificially prepared by  estrogen  and/or  progesterone . There is some evidence that in cycles where the endometrium is artificially prepared by estrogen or progesterone, it may be beneficial to administer an additional drug that suppresses hormone production by the ovaries such as continuous administration of a  gonadotropin releasing hormone agonist  (GnRHa). [ 37 ]  For  egg donation , there is evidence of a lower pregnancy rate and a higher cycle cancellation rate when the progesterone supplementation in the recipient is commenced  prior  to  oocyte retrieval  from the donor, as compared to commenced day of oocyte retrieval or the day after. [ 6 ]


Seminal fluid  contains several proteins that interact with epithelial cells of the  cervix  and  uterus , inducing active  gestational immune tolerance . There are significantly improved outcomes when women are exposed to seminal plasma around the time of embryo transfer, with statistical significance for  clinical pregnancy , but not for ongoing pregnancy or  live birth rates  with the limited data available. [ 38 ]


Patients usually start progesterone medication after egg (also called oocyte) retrieval. While daily intramuscular injections of progesterone-in-oil (PIO) have been the standard route of administration, PIO injections are not FDA-approved for use in pregnancy.  A recent meta-analysis showed that the intravaginal route with an appropriate dose and dosing frequency is equivalent to daily intramuscular injections. [ 39 ]  In addition, a recent case-matched study comparing vaginal progesterone with PIO injections showed that live birth rates were nearly identical with both methods. [ 40 ]  A duration of progesterone administration of 11 days results in almost the same  birth rates  as longer durations. [ 41 ]


Patients are also given estrogen medication in some cases after the embryo transfer. Pregnancy testing is done typically two weeks after egg retrieval.


It is not necessary that the embryo transfer be performed on the female who provided the eggs. Thus another female whose uterus is appropriately prepared can receive the embryo and become pregnant.
Embryo transfer may be used where a woman who has eggs but no uterus and wants to have a biological baby; she would require the help of a  gestational carrier  or surrogate to carry the pregnancy. Also, a woman who has no eggs but a uterus may utilize  egg donor  IVF, in which case another woman would provide eggs for fertilization and the resulting embryos are placed into the uterus of the patient. Fertilization may be performed using the woman's partner's sperm or by using donor sperm. 'Spare' embryos which are created for another couple undergoing IVF treatment but which are then surplus to that couple's needs may also be transferred (called  embryo donation ). Embryos may be specifically created by using eggs and sperm from donors and these can then be transferred into the uterus of another woman. A surrogate may carry a baby produced by embryo transfer for another couple, even though neither she nor the 'commissioning' couple is biologically related to the child. Third party reproduction is controversial and regulated in many countries. Persons entering gestational surrogacy arrangements must make sense of an entirely new type of relationship that does not fit any of the traditional scripts we use to categorize relations as kinship, friendship, romantic partnership or market relations. [ 42 ]  Surrogates have the experience of carrying a baby that they conceptualize as not of their own kin, while intended mothers have the experience of waiting through nine months of pregnancy and transitioning to motherhood from outside of the pregnant body. This can lead to new conceptualizations of body and self. [ 42 ]


The first transfer of an embryo from one human to another resulting in pregnancy was reported in July 1983 and subsequently led to the announcement of the first human birth 3 February 1984. [ 43 ]  This procedure was performed at the Harbor UCLA Medical Center  [ 44 ]  under the direction of Dr.  John Buster  and the University of California at Los Angeles School of Medicine.


In the procedure, an embryo that was just beginning to develop was transferred from one woman in whom it had been conceived by  artificial insemination  to another woman who gave birth to the infant 38 weeks later. The sperm used in the artificial insemination came from the husband of the woman who bore the baby. [ 45 ] [ 46 ]


This scientific breakthrough established standards and became an agent of change for women with infertility and for women who did not want to pass on genetic disorders to their children. Donor embryo transfer has given women a mechanism to become pregnant and give birth to a child that will contain their husband's genetic makeup. Although donor embryo transfer as practiced today has evolved from the original non-surgical method, it now accounts for approximately 5% of in vitro fertilization recorded births.


Prior to this, thousands of women who were  infertile , had adoption as the only path to parenthood. This set the stage to allow open and candid discussion of embryo donation and transfer. This breakthrough has given way to the donation of human embryos as a common practice similar to other donations such as blood and major organ donations. At the time of this announcement the event was captured by major news carriers and fueled healthy debate and discussion on this practice which impacted the future of reproductive medicine by creating a platform for further advancements in woman's health.


This work established the technical foundation and legal-ethical framework surrounding the clinical use of human  oocyte  and  embryo donation , a mainstream clinical practice, which has evolved over the past 25 years. [ 45 ] [ 46 ]