In vitro fertilization

ANATOMY OR SYSTEM AFFECTED: Cells, reproductive system, uterus

DEFINITION: A procedure whereby eggs and sperm are combined in the laboratory to achieve fertilization, usually followed by the introduction of the resulting embryos into the uterus.

Indications and Procedures

The purpose of fertilization is to create a new organism or individual that has the same number of chromosomes as the parent individuals, but that has a unique mixing of genetic traits from both the mother and the father. In animals, this is accomplished by the fusion of egg and sperm cells. Both egg and sperm contain half the number of chromosomes needed to produce a healthy individual. The fusion of egg and sperm results in a zygote, or fertilized egg, which can develop into an individual organism.

Eggs and sperm are both gametes, cells that are specialized to carry out reproductive functions. The sperm cells are produced in the testicles of the male. Sperm production is continuous in the male, and millions of sperm are made within the testicles each day. Sperm cells contain genetic material within their head and are equipped with a flagellum, or whiplike tail, to enable them to swim within a liquid medium. The egg, or ovum, is about .01 millimeter in size and hundreds of times larger than the sperm. It is produced in the ovaries of females and contains cytoplasm, the cellular substance, and specialized cell structures that are needed for the zygote to form and grow. In women, a single mature egg is usually made with each menstrual cycle and is released from the follicle contained in one of the ovaries. As women age, their ovaries become depleted of follicles, and eventually, at the menopause, ovulation no longer occurs. Therefore, a woman’s age can contribute significantly to her ability to conceive. Other causes of ovarian failure that may lead to infertility include the use of chemotherapeutic agents and premature ovarian failure syndrome.

In natural, or in vivo, fertilization, sperm from the male are deposited in the vaginal canal of the female during sexual intercourse. The sperm are contained in nutritive fluid, called semen. The sperm can swim up the cervical canal (the lower part of the uterus) only during and around the time of female ovulation, as the cervical mucus becomes permeable to sperm at this time. Once within the uterine cavity, the sperm make their way up into the Fallopian tubes, where they can meet the egg and proceed with fertilization.

Several steps lead to fertilization. The egg is surrounded by a layer of cells called the corona radiata. This layer is loose and easily penetrated by sperm. The next layer is the zona pellucida, which is a critical barrier in fertilization. One of the sugarcoated proteins in the zona pellucida, ZP3, captures a sperm cell by binding to its head. This causes a structure on the head of the sperm, called an acrosome, to release enzymes. This process is called the acrosomal reaction. These enzymes then digest the coat on the head of the sperm cell and digest a path for the sperm through the zona pellucida. After this, the sperm reaches the membrane of the egg, and the sperm and egg cells fuse. The chromosomes of the sperm and egg join, thus completing the process of fertilization. Subsequently, the fertilized egg travels back into the uterus and implants into the lining of the uterus, where it continues to develop as an embryo and then as a fetus.

When the natural anatomy or physiology of the reproductive system is abnormal, infertility can result. For instance, endometriosis in women can cause severe scarring of the pelvic cavity, leading to occluded Fallopian tubes or ovaries that are completely encased in scar tissue. In these cases, the egg may have difficulty reaching the Fallopian tube canal and hence is unable to meet sperm to achieve fertilization. Another cause of pelvic scarring is pelvic inflammatory disease (PID), which can be caused by sexually transmitted diseases (STDs) or ruptures in the gastrointestinal tract.

In vitro fertilization (IVF) may be indicated when a couple experiences infertility. Infertility is defined as the lack of conception after one to two years of unprotected intercourse. There are many causes of infertility, which may be attributable to either the male or the female partner. Usually, when an infertile couple seeks medical attention, they are asked to give a detailed history and receive physical examinations by the physician. Depending on the findings, the couple will be asked to undergo testing to better identify the cause of the infertility. Men will be asked to give a semen sample. The sample will be analyzed in the laboratory to ensure that adequate numbers of sperm are present and that they are able to move appropriately, a procedure called semen analysis. Women may be assessed for anatomic defects, such as whether the Fallopian tubes are blocked, or large fibroid tumors in the uterus may prevent sperm from entering the Fallopian tubes. This assessment may be accomplished using a technique called a hysterosalpingogram, in which dye is introduced into the uterine cavity, and an X-ray picture is taken. If a woman’s Fallopian tubes are blocked, then no dye will spill into the pelvic cavity. If a woman’s tubes are open, then dye will be seen spilling into the pelvic cavity. In addition, women may also undergo assessments regarding their ovarian function and ability to produce eggs. Blood tests may be drawn to assess hormone levels.

If the cause of infertility is found to be blocked Fallopian tubes, then IVF may be indicated. Sometimes, women with irregular menstrual cycles who do not ovulate at predictable intervals may be treated with a medication called clomiphene, to induce ovulation. If a woman fails to achieve spontaneous conception after several months of clomiphene therapy, then the physician may proceed with in vitro fertilization as the next step in the attempt to achieve conception.

Another example of when IVF may be indicated is in cases where the sperm are defective. For instance, some men may have sperm that have difficulty swimming appropriately or penetrating the egg. In such cases, the sperm may need to be injected artificially into the egg to achieve fertilization, a procedure called intracytoplasmic sperm injection (ICSI). To perform this procedure, eggs must be harvested from the woman. The eggs are then placed in a petri dish, where they are injected with the sperm. Because fertilization is occurring outside the body in this situation, this procedure is also a type of in vitro fertilization. After the eggs have matured for a few days in the laboratory, the healthiest-looking zygotes are placed into the woman’s uterus, a procedure called embryo transfer.

Another example in which intracytoplasmic sperm injection might be used is when the couple’s infertility is caused by the man’s inability to ejaculate sperm. This might occur, for instance, with a lack or occlusion of the vas deferens, the tubes that carry sperm from the testicles to the urethra, where the sperm can exit the body. To obtain sperm for IVF in these cases, the male partner may undergo testicular sperm extraction, in which sperm are removed from the testicles. The sperm are then injected into the ova to achieve fertilization in vitro.

The procedures for IVF involve the induction of ovulation in the woman using hormones that stimulate the ovaries. These are usually hormones that are similar to endogenous follicle-stimulating hormone (FSH), which is responsible for follicle growth within the ovary. These exogenous hormones lead to the development of multiple follicles within both ovaries. The size and number of these follicles are observed by ultrasound, and when the appropriate number and size are achieved, the ovum harvest is performed. This procedure involves taking the woman to the operating room, where she is given anesthesia or consciously sedated and given analgesia and placed on her back with her legs in stirrups and knees apart. A needle attached to a vacuum device is carefully introduced into the vaginal canal with ultrasound guidance. With the ultrasound helping to locate the ovaries and follicles precisely, the needle is inserted into the follicle through the posterior vagina. (Alternatively, the needle may be inserted through the abdomen during a laparoscopic procedure.) The fluid within the follicle is aspirated, and the egg usually is suctioned out of the follicle along with the follicular fluid and placed into a test tube. The same procedure is repeated until a sufficient number of eggs have been harvested, or the follicles have been depleted. The eggs are then taken to the laboratory, where they are examined under a microscope.

A sperm sample is then collected from the male partner, and the sample is washed and analyzed to ensure that the sperm appear healthy and able to fertilize the eggs. The sperm are then introduced to the eggs within a petri dish containing tissue culture fluid. If intracytoplasmic sperm injection is to be performed, then single sperm are taken up into a glass needle and injected into individual eggs at this time. The petri dish is placed in an incubator for about three to six days. Once the embryos have developed sufficiently, a few healthy ones are chosen to be introduced into the woman’s uterus through embryo transfer. This involves picking up the embryos into a semiflexible tube. The tube is then inserted carefully through the cervical canal into the uterine cavity, where one or more embryos are released. Ultrasound may be used to guide the placement of the tube. Embryos that are not transferred into the woman’s uterus can be frozen using cryopreservation for future use.

Uses and Complications

IVF enables couples who suffer from infertility to conceive and bear children. Specifically, IVF is most helpful for couples whose infertility is caused by blocked Fallopian tubes or the inability of sperm to reach and penetrate the egg. In couples where the woman is unable to produce her own eggs, donor eggs from another woman may be used in IVF. If a man is unable to produce sperm, then sperm donors may be used in IVF.

Recent technology has enabled early prenatal diagnosis for inheritable conditions using cells taken from the early embryo during the six-to-eight-cell stage, called blastomere biopsy. Inheritable diseases caused by single gene defects, such as cystic fibrosis, Duchenne muscular dystrophy, sickle cell disease, hemophilia, and Tay-Sachs disease, have been detected using preimplantation diagnosis. This type of prenatal diagnosis is possible only through the IVF process, as the early embryo would not be accessible to the physician in cases of spontaneous conception. Procedures such as blastomere biopsy are far from common, however, given the technical difficulty and economic costs of such procedures. Other, standard types of genetic testing, such as chorionic villus sampling and amniocentesis, are conducted during the first or second trimester of pregnancy, respectively.

The complications associated with the IVF process include a condition called ovarian hyperstimulation syndrome. This situation can occur when a woman receives hormones to stimulate ovulation. In these cases, the follicles within the ovary become excessively stimulated and grossly enlarge the ovary. When this condition is severe, the woman can suffer abdominal pain, fluid imbalances, electrolyte imbalances, abnormal kidney function, and an accumulation of fluid in the abdominal cavity or lungs. Her blood may have an abnormal tendency to form clots, and her blood pressure may become dangerously low. These patients are monitored carefully and require hospitalization, as severe ovarian hyperstimulation syndrome can be fatal.

Other complications of the IVF process can occur during the ovum harvest procedure. These include the risks of anesthesia and infection (because the needle is a foreign body introduced through the vagina, a nonsterile field). Another risk involves bleeding. Although the needle for harvesting the eggs is under ultrasound guidance, the risk of the needle inadvertently puncturing neighboring blood vessels still exists. In addition, the ovaries themselves may bleed when punctured, as they are highly vascular organs. Bleeding that is severe and life-threatening may require abdominal or pelvic surgery to identify the location of the bleeding and to stop the bleeding with sutures. If the patient becomes significantly anemic from the bleeding, she may require a blood transfusion.

Other risks of IVF are incurred during the embryo culture process. During this process, the petri dishes containing the embryos may become contaminated with microorganisms. In addition, problems with the tissue culture medium or with the incubation process may lead to poor embryo development and the lack of any viable embryos to transfer into the woman. Another risk is that embryos transferred into the uterus may not implant themselves in the lining.

The rate of achieving pregnancy after IVF is directly related to the number of embryos transferred into the uterus. When multiple embryos are transferred back into the uterus, however, the woman is at risk for a multiple gestation pregnancy. Multiple gestation pregnancies lead to an increased risk of spontaneous abortion (miscarriage) and preterm birth, as well as other pregnancy complications such as low birth weight, growth restriction in utero, increased risk of congenital anomalies, placental abnormalities, preeclampsia (a hypertensive disease of pregnancy), umbilical cord accidents, and malpresentations (when the fetus is not lying in the uterus with the head down, making vaginal birth difficult). More long-term risks of in vitro fertilization are the increased risk for complications during pregnancy. For instance, women whose pregnancies were a result of assisted reproductive technologies such as IVF are at increased risk for preterm birth, when compared to age-matched women whose pregnancies were a result of spontaneous conception. Additionally, long-term outcomes of children conceived using IVF requires further research. In the early twenty-first century, scientists lacked consensus but speculated that individuals conceived using IVF were at a greater risk of congenital malformations and possible epigenetic changes in their DNA.

Perspective and Prospects

The first baby conceived through in vitro fertilization was Louise Brown, who was born in 1978. The English team responsible for this important breakthrough consisted of Patrick Steptoe, a surgeon from Oldham Hospital, and Robert Edwards, a reproductive physiologist from Cambridge University. In the 1960s, animal breeding programs had successfully utilized in vitro fertilization. In 1965, Edwards reported that he had successfully induced maturation of a human egg in vitro. Edwards teamed up with Steptoe and another colleague, Jean Purdy. In 1970, they reported that they had achieved in vitro fertilization and cleavage (cell division) in human eggs. The first successful birth of an IVF baby in the United States occurred in 1981 in Norfolk, Virginia. The first successful use of a previously frozen human embryo occurred in Australia in 1984; two years later, a similar procedure was employed successfully in the United States.

A couple can undergo multiple cycles of IVF. A 1996 study reported data from large centers in three countries that showed that the cumulative pregnancy rate after six cycles of IVF is approximately 60 percent. A 2008 French study estimated that 66 percent of patients starting IVF ultimately succeed in having a child, although this statistic included those who had a child after discontinuing IVF treatment. However, if a couple fails to achieve pregnancy after six cycles, then the chances of achieving pregnancy through IVF fall significantly. At that time, the infertile couple may be counseled to seek alternative means of becoming parents, such as adoption.

In vitro fertilization and its related procedures have provided opportunities to conceive for couples who would otherwise be childless. These opportunities have led to many ethical controversies as well. What should be done with frozen embryos that are not used? What are the rights of egg or sperm donors once the child is born? What are the rights of the child to know his or her parentage and family history of medical problems? What are the rights of surrogate mothers? How many embryos should be transferred back into the woman, given that multiple gestations are at increased risk for poor outcomes such as premature delivery? Is there a certain age at which women should not attempt pregnancy? Some countries, such as Australia, Norway, Spain, and the United Kingdom, have responded to some of these questions by passing legislation regulating IVF. Other countries have been slower to respond, leaving decisions related to IVF to physicians, the patients themselves, and the court system. In addition, some countries have placed restrictions on IVF and related technologies for moral or religious reasons: China has banned IVF and egg freezing for unmarried women, many Muslim nations allow IVF between married couples using their own sperm and eggs but do not allow the use of donor sperm or eggs, and Costa Rica initially banned all IVF due to objections to the practice by the Catholic Church, though the ban was later overturned. Other countries, like Canada, have sought to expand access to IVF and other assisted reproductive technologies (ART) regardless of class, marital status, or sexual orientation.

In February 2024, the Alabama Supreme Court ruled that frozen embryos, or "extrauterine children" had the same rights as children or gestating fetuses under the state's 1872 Wrongful Death of a Minor Act. The ruling allowed three couples to sue a Mobile, Alabama, fertility clinic, the Center for Reproductive Medicine at Mobile Infirmary, after their frozen embryos had been accidentally destroyed in a storage facility accident in 2020. The ruling also prompted three of the state's fertility clinics, including the Center for Reproductive Medicine, to suspend IVF treatments, however, out of fear that clinicians and patients could be criminally prosecuted for discarding extra embryos. The Republican-dominated legislature passed a state law in March 2024 that shielded IVF patients and providers from prosecution, but Democratic legislators, doctors, scientists, and other critics argued that the law still left open the question of whether embryos should be considered children. Two of the three IVF clinics resumed IVF treatments, but the Mobile clinic did not, citing the need for "legal clarification on the extent of immunity provided by the new Alabama law," according to the clinic's statement. The law did not apply retroactively to the suit against the Center for Reproductive Medicine, however, which was allowed to proceed, along with a second lawsuit filed against the clinic and the Infirmary Health hospital system after the law took effect. In April 2024, Infirmary Health announced it would no longer provide IVF lab services after December 31, 2024, while the Center for Reproductive Medicine stated that it had resumed IVF treatments but was relocating to other facilities in Mobile and Daphne, Alabama.

As more couples delay childbearing—the average age of a first-time mother in 1980 was 22.7, while in 2022 it was 27.4—the prevalence of infertility and the desire for IVF and other ART is likely to increase. Human reproduction is not an efficient process, and the older the female partner becomes, the less likely it is that natural conception will occur. The fertility rate of the average woman in her twenties, or likelihood that she will get pregnant in any given month of trying to conceive, is 20 to 25 percent; for the average woman in her early thirties, this declines to 15 percent, then to 10 percent at the age of thirty-five, then to 5 percent at forty. These statistics are partly attributable to the fact that the total length of time during which conception is possible is less in older women, as older women ovulate less frequently than do younger women. The average woman over forty-five has less than a 1 percent chance of getting pregnant naturally.

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