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Illustration depicting intracytoplasmic sperm injection (ICSI), an example of assisted reproductive technology.
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Assisted reproductive technology (ART) are medical procedures used primarily to address infertility. It includes procedures such as in vitro fertilization. It may include intracytoplasmic sperm injection (ICSI), cryopreservation of gametes or embryos, and/or may involve the use of fertility medication. When used to address infertility, it may also be referred to as fertility treatment. ART mainly belongs to the field of reproductive endocrinology and infertility. Some forms of ART are also used with regard to fertile couples for genetic reasons (preimplantation genetic diagnosis). ART may also be used in surrogacy arrangements, although not all surrogacy arrangements involve ART.
Procedures
General
With ART, the process of sexual intercourse is bypassed and fertilization of the oocytes occurs in the laboratory environment (i.e., in vitro fertilization).In the US, the Centers for Disease Control and Prevention (CDC)—which is required as a result of the 1992 Fertility Clinic Success Rate and Certification Act to publish the annual ART success rates at U.S. fertility clinics—defines ART to include "all fertility treatments in which both eggs and sperm are handled. In general, ART procedures involve surgically removing eggs from a woman's ovaries, combining them with sperm in the laboratory, and returning them to the woman's body or donating them to another woman." According to CDC, "they do not include treatments in which only sperm are handled (i.e., intrauterine—or artificial—insemination) or procedures in which a woman takes medicine only to stimulate egg production without the intention of having eggs retrieved."[1]
In Europe, ART also excludes artificial insemination and includes only procedures where oocytes are handled.
The WHO also defines ART this way.
Fertility medication
Most fertility medications are agents that stimulate the development of follicles in the ovary. Examples are gonadotropins and gonadotropin releasing hormone.In vitro fertilization
In vitro fertilization is the technique of letting fertilization of the male and female gametes (sperm and egg) occur outside the female body.Techniques usually used in in vitro fertilization include:
- Transvaginal ovum retrieval (OVR) is the process whereby a small needle is inserted through the back of the vagina and guided via ultrasound into the ovarian follicles to collect the fluid that contains the eggs;
- Embryo transfer is the step in the process whereby one or several embryos are placed into the uterus of the female with the intent to establish a pregnancy.
- Assisted zona hatching
(AZH) is performed shortly before the embryo is transferred to the
uterus. A small opening is made in the outer layer surrounding the egg
in order to help the embryo hatch out and aid in the implantation
process of the growing embryo;
- Intracytoplasmic sperm injection (ICSI) is beneficial in the case of male factor infertility where sperm counts are very low or failed fertilization occurred with previous IVF attempt(s). The ICSI procedure involves a single sperm carefully injected into the center of an egg using a microneedle. With ICSI, only one sperm per egg is needed. Without ICSI, you need between 50,000 and 100,000. This method is also sometimes employed when donor sperm is used;Intracytoplasmic sperm injection (ICSI);
- Autologous endometrial coculture is a possible treatment for patients who have failed previous IVF attempts or who have poor embryo quality. The patient's fertilized eggs are placed on top of a layer of cells from the patient's own uterine lining, creating a more natural environment for embryo development;
- In zygote intrafallopian transfer (ZIFT), egg cells are removed from the woman's ovaries and fertilized in the laboratory; the resulting zygote is then placed into the fallopian tube.
- Cytoplasmic transfer is the technique in which the contents of a fertile egg from a donor are injected into the infertile egg of the patient along with the sperm;
- Egg donors are resources for women with no eggs due to surgery, chemotherapy, or genetic causes; or with poor egg quality, previously unsuccessful IVF cycles or advanced maternal age. In the egg donor process, eggs are retrieved from a donor's ovaries, fertilized in the laboratory with the sperm from the recipient's partner, and the resulting healthy embryos are returned to the recipient's uterus;
- Sperm donation may provide the source for the sperm used in IVF procedures where the male partner produces no sperm or has an inheritable disease, or where the woman being treated has no male partner;
- Preimplantation genetic diagnosis (PGD) involves the use of genetic screening mechanisms such as fluorescent in-situ hybridization (FISH) or comparative genomic hybridization (CGH) to help identify genetically abnormal embryos and improve healthy outcomes;
- Embryo splitting can be used for twinning to increase the number of available embryos.
Pre-implantation genetic diagnosis
A pre-implantation genetic diagnosis procedure may be conducted on embryos prior to implantation (as a form of embryo profiling), and sometimes even of oocytes prior to fertilization. PGD is considered in a similar fashion to prenatal diagnosis. When used to screen for a specific genetic disease, its main advantage is that it avoids selective pregnancy termination as the method makes it highly likely that the baby will be free of the disease under consideration. PGD thus is an adjunct to ART procedures, and requires [in vitro fertilization to obtain oocytes or embryos for evaluation. Embryos are generally obtained through blastomere or blastocyst biopsy. The latter technique has proved to be less deleterious for the embryo, therefore it is advisable to perform the biopsy around day 5 or 6 of development.Others
Other assisted reproduction techniques include:- In gamete intrafallopian transfer (GIFT) a mixture of sperm and eggs is placed directly into a woman's fallopian tubes using laparoscopy following a transvaginal ovum retrieval.
- Sex selection is the attempt to control the sex of offspring to achieve a desired sex. It can be accomplished in several ways, both pre- and post-implantation of an embryo, as well as at birth. Pre-implantation techniques include PGD, but also sperm sorting;
- Reproductive surgery, treating e.g. fallopian tube obstruction and vas deferens obstruction, or reversing a vasectomy by a reverse vasectomy:
- In surgical sperm retrieval (SSR) the reproductive urologist obtains sperm from the vas deferens, epididymis or directly from the testis in a short outpatient procedure;
- By cryopreservation, eggs, sperm and reproductive tissue can be preserved for later IVF.
Risks
The majority of IVF-conceived infants do not have birth defects. However, some studies have suggested that assisted reproductive technology is associated with an increased risk of birth defects. Artificial reproductive technology is becoming more available. Early studies suggest that there could be an increased risk for medical complications with both the mother and baby. Some of these include low birth weight, placental insufficiency, chromosomal disorders, preterm deliveries, gestational diabetes, and pre-eclampsia(Aiken and Brockelsby).In the largest U.S. study, which used data from a statewide registry of birth defects, 6.2% of IVF-conceived children had major defects, as compared with 4.4% of naturally conceived children matched for maternal age and other factors (odds ratio, 1.3; 95% confidence interval, 1.00 to 1.67). ART carries with it a risk for heterotopic pregnancy (simultaneous intrauterine and extrauterine pregnancy). The main risks are:
- Genetic disorders;
- Low birth weight. In IVF and ICSI, a risk factor is the decreased expression of proteins in energy metabolism; Ferritin light chain and ATP5A1;
- Preterm birth. Low birth weight and preterm birth are strongly associated with many health problems, such as visual impairment and cerebral palsy, and children born after IVF are roughly twice as likely to have cerebral palsy.
- Membrane damage, which may be reflected by increased expression of the membrane fusion proteins NAPA and Annexin A3.
Current data indicate little or no increased risk for postpartum depression among women who use ART.
Usage of assisted reproductive technology including ovarian stimulation and in vitro fertilization have been associated with an increased overall risk of childhood cancer in the offspring, which may be caused by the same original disease or condition that caused the infertility or subfertility in the mother or father.
That said, In a landmark paper by Jacques Balayla et al. it was determined that infants born after ART have similar neurodevelopment than infants born after natural conception.
Usage
Assisted reproductive technology procedures performed in the U.S. has more than doubled over the last 10 years, with 140,000 procedures in 2006, resulting in 55,000 births.In Australia, 3.1% of births are a result of ART.
In case of discontinuation of fertility treatment, the most common reasons have been estimated to be: postponement of treatment (39%), physical and psychological burden (19%, psychological burden 14%, physical burden 6.32%), relational and personal problems (17%, personal reasons 9%, relational problems 9%), treatment rejection (13%) and organizational (12%) and clinic (8%) problems.
Society and culture
Ethics
Some couples find it difficult to stop treatment despite very bad prognosis, resulting in futile therapies. This may give ART providers a difficult decision of whether to continue or refuse treatment.For treatment-specific ethical considerations, see entries in individual subarticles, e.g. In vitro fertilisation, Surrogacy and Sperm donation
Some assisted reproductive technologies can in fact be harmful to both the mother and child. Posing a psychological and a physical health risk, which may impact the ongoing use of these treatments. The adverse effects may cause for alarm, and they should be tightly regulated to ensure candidates are not only mentally, but physically prepared.
Costs
United States
Many Americans do not have insurance coverage for fertility investigations and treatments. Many states are starting to mandate coverage, and the rate of use is 278% higher in states with complete coverage.There are some health insurance companies that cover diagnosis of infertility but frequently once diagnosed will not cover any treatment costs.
2005 approximate treatment/diagnosis costs (United States, costs in US$):
- Initial workup: hysteroscopy, hysterosalpingogram, blood tests ~$2,000;
- Sonohysterogram (SHG) ~ $600–$1,000;
- Clomiphene citrate cycle ~ $200–$500;
- IVF cycle ~ $10,000–$30,000;
- Use of a surrogate mother to carry the child – dependent on arrangements.
For the community as a whole, the cost of IVF on average pays back by 700% by tax from future employment by the conceived human being.
United Kingdom
In the United Kingdom, all patients have the right to preliminary testing, provided free of charge by the National Health Service. However, treatment is not widely available on the NHS and there can be long waiting lists. Many patients therefore pay for immediate treatment within the NHS or seek help from private clinics.In 2013, the National Institute for Health and Care Excellence published new guidelines about who should have access to IVF treatment on the NHS in England and Wales.
The guidelines also say women aged between 40 and 42 should be offered one cycle of IVF on the NHS if all of the following additional criteria are also met: They have never had IVF treatment before, have no evidence of low ovarian reserve (this is when eggs in the ovary are low in number or low in quality) and have been informed of the additional implications of IVF and pregnancy at this age. However, if tests show IVF is the only treatment likely to help them get pregnant, women should be referred for IVF straight away.
This policy is often modified by local Clinical Commissioning Groups, in a fairly blatant breach of the NHS Constitution for England which provides that patients have the right to drugs and treatments that have been recommended by NICE for use in the NHS. For example, the Cheshire, Merseyside and West Lancashire Clinical Commissioning Group insists on additional conditions:
- The person undergoing treatment must have commenced treatment before her 40th birthday;
- The person undergoing treatment must have a BMI of between 19 and 29;
- Neither partner must have any living children, from either the current or previous relationships. This includes adopted as well as biological children;
- Sub-fertility must not be the direct result of a sterilisation procedure in either partner (this does not include conditions where sterilisation occurs as a result of another medical problem). Couples who have undertaken a reversal of their sterilisation procedure are not eligible for treatment.
Canada
Some treatments are covered by OHIP (public health insurance) in Ontario and others are not. Those with bilaterally blocked fallopian tubes and under 40 have treatment is covered but are still required to pay lab fees (around $3,000–4,000). Coverage varies in other provinces. Most other patients are required to pay for treatments themselves.Israel
Israel's national health insurance, which is mandatory for all Israeli citizens, covers nearly all fertility treatments. IVF costs are fully subsidized up to the birth of two children for all Israeli women, including single women and lesbian couples. Embryo transfers for purposes of gestational surrogacy are also covered.Germany
On 27 January 2009, the Federal Constitutional Court ruled that it is unconstitutional, that the health insurance companies have to bear only 50% of the cost for IVF. On 2 March 2012, the Federal Council has approved a draft law of some federal states, which provides that the federal government provides a subsidy of 25% to the cost. Thus, the share of costs borne for the pair would drop to just 25%.Fictional representation
Films and other fiction depicting emotional struggles of assisted reproductive technology have had an upswing in the latter part of the 2000s decade, although the techniques have been available for decades. Yet, the number of people that can relate to it by personal experience in one way or another is ever growing, and the variety of trials and struggles are huge.For specific examples, refer to the fiction sections in individual subarticles, e.g. surrogacy, sperm donation and fertility clinic.
In addition, reproduction and pregnancy in speculative fiction has been present for many decades.
Research and speculative uses
The idea of using future ART techniques, including direct human germline engineering technologies, to select and genetically modify embryos for the purpose of human enhancement has been referred to as designer babies, reprogenetics, and liberal eugenics.The term "liberal eugenics" was coined by bioethicist Nicholas Agar. Liberal eugenics is aimed at "improving" the genotypes of future generations through screening and genetic modification to eliminate "undesirable" traits. The term "reprogenetics" was coined by Lee M. Silver, a professor of molecular biology at Princeton University, in his 1997 book Remaking Eden.
The philosophical movement associated with these speculative uses is transhumanism. When eugenics is discussed in this context it usually in context of allowing parents to select desirable traits in an unborn child and not in the use of genetics to destroy embryos or to prevent the formation of undesirable embryos.
Safety is a major concern when it comes to the gene editing and mitochondrial transfer. Since the effects of germline modification can be passed down to multiple generations, experimentation of this treatment brings forth many questions and concerns about the ethics of completing this research. If a patient has undergone germline modification treatment, the coming generations, one or two after the initial treatment, will be used as trials to see if the changes in the germline have been successful. This extended waiting time could possess harmful implications since the effect of the treatment is not known until it has been passed down to a few generations. Problems with the gene editing may not appear until after the child with edited genes is born. If the patient assumes the risk alone, consent may be given for the treatment, but it is less justified when it comes to giving consent for future generations. On a larger scale, germline modification has the potential to impact the gene pool of the entire human race in a negative or positive way. Germline modification is considered a more ethically and morally acceptable treatment when a patient is a carrier for a harmful trait and is treated to improve the genotype and safety of the future generations. When the treatment is used for this purpose, it can fill the gaps that other technologies may not be able to accomplish.
The main ethical issue with pure germline modification is that these types of treatments will produce a change that can be passed down to future generations and therefore any error, known or unknown, will also be passed down and will affect the offspring. New diseases may be introduced accidentally. Since experimentation of the germline occurs directly on embryos, there is a major ethical deliberation on experimenting with fertilized eggs and embryos and killing the flawed ones. The embryo cannot give consent and some of the treatments have long-lasting and harmful implications. In many countries, editing embryos and germline modification for reproductive use is illegal. As of 2017, the United States of America restricts the use of germline modification and the procedure is under heavy regulation by the FDA and NIH. The American National Academy of Sciences and National Academy of Medicine gave qualified support to human genome editing in 2017 once answers have been found to safety and efficiency problems "but only for serious conditions under stringent oversight." Germline modification would be more practical if sampling methods were less destructive and used the polar bodies rather than embryos.
Lee Silver has projected a dystopia in which a race of superior humans look down on those without genetic enhancements, though others have counseled against accepting this vision of the future. It has also been suggested that if designer babies were created through genetic engineering, that this could have deleterious effects on the human gene pool. Some futurists claim that it would put the human species on a path to participant evolution. It has also been argued that designer babies may have an important role as counter-acting an argued dysgenic trend.
In 2018, the Nuffield Council on Bioethics issued a report which concluded that under certain circumstances, editing of the DNA of human embryos could be acceptable. The Nuffield Council is a British independent organisation that evaluates ethical questions in medicine and biology.
In November 2018, He Jiankui announced that he had edited the genomes of two human embryos, to attempt to disable the gene for CCR5, which codes for a receptor that HIV uses to enter cells. He said that twin girls, Lulu and Nana, had been born a few weeks earlier. He said that the girls still carried functional copies of CCR5 along with disabled CCR5 (mosaicism) and were still vulnerable to HIV. The work was widely condemned as unethical, dangerous, and premature.
