In vitro fertilization and embryo transfer

SIGNIFICANCE: The term “in vitro” designates a living process removed from an organism and isolated “in glass” for laboratory study. In vitro fertilization (IVF) is a process in which harvested eggs and sperm can be brought together artificially to form a zygote. The resulting zygote can be grown for a time in vivo, where it can be tested biochemically and genetically, if desired, after which it can be implanted in the uterus of the egg donor or a surrogate.

Natural Fertilization

Fertilization, the union of a male (sperm) with a female gamete (ovum), is fundamentally a genetic process. Each of the gametes is haploid, containing half of the genetic information needed for a living organism. Fertilization brings together these two sets, thereby producing a that will develop into an embryo.

Gametes are produced in the gonads (ovaries in females, testes in males) by a special type of cell division called meiosis. Instead of producing diploid daughter cells, as in mitosis, meiosis results in cells. In humans, the natural place for fertilization is in a Fallopian tube of a woman, the channel through which an ovum travels to the uterus. A normal adult woman ovulates each month, releasing a single haploid ovum from one of her two ovaries. Ovulation is under hormonal control.

Sperm from the male’s testis are deposited in the woman’s vagina during sexual intercourse. Typically, men release hundreds of millions of sperm into the vagina when they ejaculate. From the vagina, these sperm travel through the uterus and into each Fallopian tube in search of an ovum. During this trip, the sperm undergo changes called capacitation. To fuse with the ovum, a sperm must penetrate several surrounding barriers. After fusion of sperm and egg, the nuclear membranes of the two cells break down so that the paternal and maternal chromosomes can congregate in a single nucleus. The resulting zygote divides into two new diploid cells, the first cells of a genetically unique new being.

In Vitro Fertilization and Embryo Transfer

Fertilization can also take place artificially in laboratory culture dishes. Gametes are collected, brought together, and fertilized in a laboratory. After the zygote develops into an embryo, it can then be transferred to a uterus for continued development and eventual birth. This procedure can be done for many species, including humans. The first human conceived by (IVF), Louise Brown, was born on July 25, 1978, in England.

In humans IVF is usually used to overcome infertility caused by problems such as blocked Fallopian tubes or low sperm count. IVF is also done in veterinary medicine and for scientific research. IVF also makes genetic diagnoses easier and could eventually lead to more effective gene therapy. Mature sperm for IVF are easily obtained by masturbation. Mature ova are more difficult to obtain. The female is given gonadotropin hormones to stimulate her to superovulate (that is, to produce ten or more mature eggs rather than just one). Ova are later collected by inserting a small suction needle into her pelvic cavity. The ova are inseminated with laboratory-capacitated sperm. Two to four embryos are transferred into the uterus through a catheter. Excess embryos can be saved by a freezing procedure called cryopreservation. These may be thawed for later attempts at implantation should the first attempt fail or a second pregnancy be desired.

A study published in the journal Human Reproduction and presented the 2024 meeting of the European Society of Human Reproduction and Embroyology (ESHRE), researchers announced the results of a promising Phase II clinical trial. The OXOART2 trial showed a clinically significant increase in the successful pregnancy rates from embryo implantation. The trial used a drug called OXO-001, the first in a new class of non-hormonal drugs that helps the inner lining of a woman's uterus be more suitable for impregnation and maintaining a pregnancy.

Impact and Applications

Technology such as the polymerase chain reaction (PCR) permits assessment of genetic information in the nucleus of a single cell, whether diploid or haploid. IVF gives physicians access to sperm, ova, and very early embryos. One or two cells can be removed from an eight-cell embryo without damaging the ability of the remaining cells to develop normally following embryo transfer. Thus IVF permits genetic diagnosis at the earliest stages of human development and even allows the possibility of gene therapy.

Preimplantation genetic diagnosis (PGD) is used clinically to help people with significant genetic risks to avoid giving birth to an abnormal child that might die in infancy or early childhood. If tests show that the embryo is free of genetic defects, it can be transferred to the uterus for implantation; if found defective, it can be destroyed. PGD is successful in avoiding pregnancies with embryos that will develop cystic fibrosis, Huntington’s disease, Lesch-Nyhan disease, Tay-Sachs disease, and other genetic abnormalities. Prior to the development of PGD, detection of genetic defects was possible only by prenatal diagnosis during pregnancy. If a defect was detected, the pregnancy could be terminated through elective abortion, which not only represented a higher risk to the mother, but was also an unacceptable choice for many people because of ethical and moral concerns. As the use of PGD has increased in the United States, where it is unregulated, ethical concerns have arisen about whether it perpetuates ableism.

Access to gametes prior to fertilization and to embryos prior to implantation also opens the possibility of gene therapy. Gene therapy in human embryos presents insurmountable ethical issues, at present, and has been banned pending more study. Genetic modification of the embryos of other species, especially those of commercial interest, carries no such ethical concerns and is routinely practiced.

IVF also opens the possibility of genetic cloning. Cloning is the process of creating multiple individuals with identical genetic characteristics. This can be accomplished by dividing an early embryo, allowing each group of cells to develop into a separate embryo. A few of these embryos can then be implanted, saving the others for future attempts, or all can be implanted, using several different females as surrogate mothers. Through the use of cryopreservation, these pregnancies could occur years apart. It is even possible to remove the nucleus from an isolated cell and replace it with a nucleus taken from an adult. The cell with the transplanted nucleus is able, using special procedures, to develop into an embryo that can be implanted. The offspring will be genetically identical to the adult source of the transplanted nucleus. Most people recognize cloning technology as inappropriate in human medicine, but it has acceptable applications in agriculture and veterinary medicine.

In the United States, IVF has been part of the debate over abortion and fetal personhood, especially after the Supreme Court overturned Roe v. Wade and ruled in Dobbsv. Jackson Women's Health Organization (2022) that the right to abortion was not protected under the Constitution. By February 2024, more than a third of US states considered fetuses to be people at some point before birth. That same month, the Alabama Supreme Court ruled that frozen embryos had the same rights as children or gestating fetuses under the state's 1872 Wrongful Death of a Minor Act. The ruling prompted three of the state's fertility clinics to suspend IVF treatments, however, out of fear that clinicians and patients could be criminally prosecuted for discarding extra embryos. Though Alabama's Republican-dominated legislature passed a state law in March 2024 that shielded IVF patients and providers from prosecution, Democratic legislators, doctors, scientists, and other critics argued that the law still left open the question of whether embryos should be considered children. During the 2024 general election cycle, the debate over fetal personhood laws and their threats to IVF access intensified.

Key terms

• diploidpossessing a full complement of chromosome pairs, as in humans, who have 23 pairs of chromosomes for a total of 46
• gametea germ cell; an egg (ovum or oocyte) or a sperm (spermatozoan)
• haploidpossessing a full complement of one of each type of chromosome; mature human gametes are haploid, with 23 chromosomes
• surrogatea female that carries an embryo derived from an egg from another female
• zygotethe earliest stage in the development of an organism, just after fertilization

Bibliography

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