Assisted reproductive technologies

Anatomy or system affected: Endocrine system, genitals, glands, reproductive system, uterus

Definition: A range of medical procedures that are used to assist couples in conception and prenatal care, with special focus on infertility and its cure. Assisted reproductive technologies include techniques, such as in vitro fertilization, artificial insemination, and surgical procedures, to repair or diagnose reproductive problems and, in the future, may include cloning or gene therapy.

Indications and Procedures

Although most couples experience little or no difficulty conceiving and carrying a child to term, between 12 and 15 percent experience infertility. Infertility is defined as an inability to conceive after a year of having regular, unprotected intercourse. Not all couples can be helped, but an increasing number of reproductive technologies are available, from in vitro fertilization (IVF) and artificial insemination to drug therapies and surgical repair.

Typically, the first step is to determine whether the man’s sperm is fertile by performing a simple sperm count. If sperm counts are low or the sperm are abnormal, the primary treatment is artificial insemination, also called intrauterine insemination (IUI). Cryopreserved sperm are obtained from a sperm bank, which collects ejaculate from healthy, fertile men. Sperm donors remain anonymous, and the samples are usually a mixture of sperm from two or more men. This method maintains even greater anonymity and increases the amount of sperm available, thus, increasing the chances of conception.

To ensure the highest probability of success, IUI should be performed when the woman is ovulating and most fertile. Most women experience a slight rise in their basal body temperature when they ovulate, and monitoring daily body temperature upon waking can be used in some cases. A more reliable method is detection of a surge in luteinizing hormone (LH) in the urine. LH usually stimulates ovulation within thirty-six to forty hours after the surge. A home urine LH analysis kit can be used, and when the LH surge is detected, insemination can be scheduled for the following day. Self-observation of cervical mucus changes can also be used to detect ovulation. Insemination is a simple office procedure in which the physician uses a special catheter to transfer the semen sample into the uterus.

If adequate numbers of sperm are present, and they appear normal and active, then the diagnostic focus shifts to the woman. Because the female reproductive system is primarily internal, diagnosis is often more complicated and expensive and, in some cases, can pose risks to the woman. The primary cause of infertility in women is the inability to ovulate. Factors that may prevent ovulation include lifestyle factors (drug abuse, obesity, weight loss, prolonged acute stress), hormone imbalance, ovarian tumors or cysts, previous infection, an unusually short menstrual cycle, previous surgery, or birth defects. Sorting out the specific cause or causes can be a daunting task, and the causes remain unknown in some cases.

The initial diagnosis involves extensive consultation on health status and lifestyle, a complete physical examination, urine and blood tests to check for infection or hormone imbalance, and often tests on samples of cervical mucus and a portion of the endometrium (lining of the uterus). The primary goal of these initial tests is to determine whether ovulation is occurring. If ovulation is occurring, the problem likely involves an abnormal uterine condition or an endocrine imbalance that is interfering with implantation. Other problems may include some fault with the eggs that are released or with the ability of sperm to penetrate or fuse with the nucleus of the egg.

If the ova (eggs) are abnormal, donor ova can be collected from another woman, followed by IVF with the male partner’s sperm. Often, the fault with abnormal ova is with the cytoplasm, so another possible treatment is to remove the nucleus from an abnormal ovum and place it into a donor ovum from which the nucleus has been removed. The resulting ovum would then have a nucleus derived from the mother and a cytoplasm derived from the donor. Although this approach is technically feasible, it has ignited ethical concerns similar to those raised about cloning.

If ovulation is not occurring, which is true in most cases, then additional tests are required. Continued monitoring of hormone levels may identify an imbalance or timing problem that can be corrected with hormone treatments. Sometimes hormone treatments alone can normalize ovulation and restore fertility. In other cases, the problem involves a blockage or abnormal shape of the Fallopian tubes or uterus. Diagnostic procedures at this stage typically involve some form of imaging technology so that the condition of the reproductive organs can be assessed.

Hysteroscopy is a procedure for viewing the interior of the uterus. It can be done either in a doctor’s office or in an outpatient setting at a hospital. In preparation for the procedure, the woman is usually given a mild analgesic, such as acetaminophen or ibuprofen, as minor cramping is common. The doctor then washes the vagina and cervix. A local anesthetic is administered to the cervix. The cervix is carefully dilated, and the hysteroscope is inserted through the cervix into the uterus. The hysteroscope contains a small light for illuminating the interior of the uterus and a small camera for viewing. Some conditions that can be detected using hysteroscopy include a septum that divides the uterus, fibroid growths or polyps, and cancerous or precancerous lesions. Often, the location where the Fallopian tubes enter the uterus can also be viewed. Many of these conditions can be asymptomatic. Surgical removal of a septum or other growths may restore fertility. If a woman can produce an egg to fertilize but is unable to carry the child herself, another option is surrogacy, which involves legal procedures to establish parentage.

Hysterosalpingography can be used to view the uterus and Fallopian tubes. This X-ray procedure uses a contrast dye to visualize internal structures. Placing the dye into the uterus involves insertion of a special flexible catheter through the cervix. A balloon at the end of the catheter is inflated to hold the catheter in place as the contrast dye is pumped into the uterus. X-rays are taken every few seconds as the dye travels through the uterus. Eventually, the dye travels the length of the Fallopian tubes. The images obtained can be used to identify many of the anomalies also detectable using hysteroscopy and can identify problems with the Fallopian tubes. If the Fallopian tubes are blocked, the dye will not travel their length, which will be visible in the X-rays.

In some cases, none of these minimally invasive diagnostic procedures identifies a problem. In such cases, diagnostic laparoscopy can be used. Using a laparoscope, a flexible tube with a light and special lens at the end, a doctor can view internal organs directly. After administering regional or general anesthesia, an incision is made near the region of the peritoneal cavity to be imaged. Carbon dioxide is used to fill the peritoneal cavity to improve viewing conditions. The laparoscope is then inserted through the incision. If an abnormality is detected, the doctor may insert another instrument to collect tissue for a biopsy. After laparoscopic examination is completed, the incision is closed. Laparoscopy is usually done in a hospital as an outpatient procedure, and the patient can go home the same day. Even after diagnostic laparoscopy, the cause of infertility may remain unknown.

Uses and Complications

Assisted reproductive technologies are best suited to couples in which one partner is infertile but otherwise in good health. Age may also be an important factor for the woman, as fertility, implantation, and normal development of the fetus are all affected as a woman ages, especially beyond thirty-five. Although these technologies can be successful in older women, the risks involved need to be assessed carefully with a doctor. They can also be more costly in older women because more attempts using IUI and IVF are often required.

Hysteroscopy and hysterosalpingography are the most used procedures for diagnosing infertility, once the more obvious causes have been ruled out. Although both can cause mild to moderate discomfort, they have very few associated risks and can be performed in most obstetrics/gynecology (OB/GYN) offices. If a clear diagnosis is obtained, several problems may require surgery. Blockage, abnormalities of the Fallopian tubes or other reproductive organs, ectopic pregnancies, and abnormal growths (cysts or tumors) can be treated or repaired surgically. In most cases, laparoscopic surgery is used, as it is less invasive than traditional abdominal surgery. Laparoscopic surgery is performed in the same way as diagnostic laparoscopy and may be done at the same time if a problem is discovered in the process.

Diagnostic laparoscopy is typically the method of last resort, as some potentially life-threatening risks are involved, such as damage to abdominal organs, inflammation or infection of the peritoneum or other organs, hemorrhaging, and formation of embolisms that may block an important artery. The procedure can also be more painful in cases where anesthesia is only partially effective. Research suggests that the benefits may outweigh the risks, but some women choose not to have diagnostic laparoscopy, and not all doctors consider the risks appropriate.

When surgical intervention is unable to restore fertility, the most common option is in vitro fertilization (IVF). If the woman’s uterus is anatomically and physiologically normal, IVF can be an effective, although expensive, option. It is the method of choice for women who have blocked Fallopian tubes or an abnormal pelvic anatomy or who have had tubal ligation and are considering reversal. It also tends to increase the chances of pregnancy in older women and women with endometriosis. Low sperm count or vasectomy reversal in the male partner may also require IVF, as the sperm may require concentration for effective fertilization. IVF can also be an effective solution for women who cannot ovulate or who have very few or faulty eggs, in which case donated eggs can be used. Gamete intrafallopian transfer (GIFT) collects multiple eggs and places them into a catheter along with sperm. Ovum and sperm are then together injected surgically into the Fallopian tubes, where conception may take place. In zygote intrafallopian transfer (ZIFT), ovum are mixed with sperm in the laboratory, and the resulting zygotes are surgically placed into the Fallopian tubes.

IVF is not without its risks and potential failings. Carefully designed hormone injection protocols are used to stimulate multiple follicle formation and prevent premature ovulation. Progress is typically monitored using ultrasound. If the number of follicles is too small, then the cycle may be canceled, as the cost of retrieval, given the number of eggs that could be available, is too high. Overstimulation can also occur, which can lead to abnormal levels of estrogen that may pose a health threat. If an appropriate number of follicles are produced, then eggs are retrieved using a needle inserted through the top of the vagina. The placement of the needle is guided using ultrasound, and once the ovaries are reached, the eggs are aspirated into it.

A final concern with IVF is the increased incidence of multiple pregnancies. To increase the chance of a pregnancy, multiple fertilized eggs are placed in the uterus. As IVF procedures have steadily improved, the incidence of multiple pregnancies increased. Based on data from 2019, the Centers for Disease Control and Prevention (CDC) reported that 10.6 percent of all multiples born in the US were the product of assisted reproductive technologies. Because of the number of premature births resulting from in vitro fertilization, most reproductive endocrinologists limit the number of embryos transferred to limit the number of multiple births. In fact, the CDC is careful to note that the chances for success based on two single-embryo transfers are about the same as those for one double-embryo transfer. These physicians further restricted practices which were more likely to result in twins or multiples in early 2020 because of the COVID-19 pandemic. The birth of multiples poses much more risk to the mother and children. Eliminating the chance of this occurring ensured a lower strain on the delicate healthcare system, but was disappointing to some hopeful couples.

IVF is a solution only when sperm quantity is adequate, or donor sperm is acceptable to the couple. In some cases, the male's sperm count may be so low that even concentrating the sperm would be insufficient to achieve fertilization. Sperm can still be obtained from the male in some cases. If no sperm are found in the ejaculate, there may be an obstruction, and sperm may still be obtained by using a needle inserted near the obstruction. In some cases, the male’s sperm may lack the ability to penetrate the egg. If a couple insists that they do not want to use donor sperm, then the last option available is typically intracytoplasmic sperm injection (ICSI), in which a single sperm is injected directly into the cytoplasm of an egg. This technique has been so successful that even males with only a few sperm have been able to father a child. If sperm count is low or motility is poor, sperm from the male may be mixed with donor sperm, so that if pregnancy occurs, the identity of the father can remain uncertain if so desired by the parents.

Perspective and Prospects

Assisted reproductive technologies arose during the latter half of the twentieth century. Prior to this period, infertility was poorly understood, and treatments were essentially nonexistent. The first attempt at treating infertility involved artificial insemination in 1785 by the Scottish surgeon John Hunter. A child was born that same year, apparently because of his attempts. The next documented attempt at IUI was by Robert Dickinson in 1890. His attempts were highly secretive because the Anglican Church condemned such procedures. The first comprehensive guidelines for determining male infertility based on sperm count and quality were published in 1934.

In 1945, a report of early IUI experiments was published in the British Medical Journal. As a result, in 1948 the archbishop of Canterbury proposed making IUI a criminal offense. Although the British government did not follow his advice, it did discourage the use of IUI. During the 1950s, the public demand for solutions to infertility far exceeded medical solutions. By 1955, there had been four successful pregnancies using frozen donor sperm. Despite these successes, IUI was not to become an acceptable and widely used procedure until the 1970s.

The first fertility drug was developed in 1949, but it took until 1962 for this discovery to be applied successfully, resulting in ovulation and a successful birth. Throughout the 1960s and beyond, the use of fertility hormones was further refined, allowing more infertile women to ovulate and bear children. Use of fertility hormones has become a key part of IVF as well, allowing the harvesting of viable eggs.

The first step toward IVF occurred in 1944, when the first in vitro fertilization took place. It took another thirty-one years for the first IVF pregnancy, and unfortunately, it was an ectopic pregnancy. Three years later, in 1978, Louise Brown became the first “test tube” baby born as a result of IVF. In 1981, Elizabeth Jordan Carr became the first IVF baby in the United States. Use of IVF is now routine, and success rates continue to rise.

The 1980s and 1990s saw even greater improvements. Surgical procedures using laparoscopy continued to improve, and diagnostic procedures became ever more sensitive. In the 1980s, donor eggs became widely available. One of the difficulties in using donor eggs had always been preserving them until use, because they seemed much more sensitive than sperm. The first baby derived from a frozen egg occurred in 1983, and methods of preservation are now even better. In 1986, the first baby derived from a frozen donor egg was born in Australia.

In 1992, researchers in Belgium reported the first pregnancies resulting from ICSI, and a year later, the first successful birth from ICSI was reported in the United States. IVF was so routine by this time that in 1994 a sixty-two-year-old woman gave birth, and a year later, a sixty-three-year-old woman who lied to her doctor about her age also gave birth.

To work around the use of defective eggs, in 1997, the first cytoplasmic transfer birth occurred and ignited controversy over the continued use of the technique. Some ethicists saw it as being too much like human cloning and germline genetic manipulation, and they advocated banning the technique. In the United States, the Food and Drug Administration (FDA) quickly stepped in and claimed jurisdiction over use of the technique, and eventually, the technique became much more common.

The cloning of the first mammal from adult cells, Dolly, the sheep, brought the possibility of reproductive cloning in humans to the forefront. In response to the many concerns about the potential for cloning humans, President Bill Clinton issued a moratorium on funding to those performing research on human cloning. Human cloning remains a very controversial issue and has been banned by most countries.

The future of assisted reproductive technologies will include ever more improved techniques and may include germline gene modification. Embryos can be screened for many genetic defects so that parents can be given the opportunity to use only healthy embryos using genome editing. The potential for screening for a variety of genetic defects or traits means that parents, in the future, could choose embryos that meet certain criteria, such as sex, intelligence, or personality, or even engineer improvements in embryos. Somatic human genome editing is used in the twenty-first century to address HIV and sickle-diseases, but the ethics of using these techniques to alter heritable human genomes continues to be debated and considered questionable by many.

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