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Fertility Drugs and Selective Reduction

Joni Payne, Cindy Crissman, Jeri Crenshaw, Kelly Hagan

According to the National Center for Health Statistics there are 2.3 million childless couples in the United States due to infertility. Infertility is defined as 12 months of unprotected intercourse without pregnancy. There are two types of infertility. Primary, which indicates that the woman has never been able to get pregnant and secondary, which indicates that the woman has had at least one other child previously.

Approximately one third of the infertile couples in the United States are appropriate candidates for the Assisted Reproductive Technologies (ART). These are procedures which involve high technology and the combination of sperm and eggs to treat infertility. There are 5 types of ART, Intrauterine Insemination (IUI), In Vitro Fertilization (IVF), Gamete Intrafallopian Transfer (GIFT), Zygote Intrafallopian Transfer (ZIFT), and Intracytoplasmic Sperm Injection (ICSI).

Intrauterine insemination is the most common form of artificial insemination. A syringe is used to inject the sperm into the cervical canal right before or on the day of ovulation. Used for men with low sperm count, poor sperm quality, overly dense semen or any other problem that prevents the male from having intercourse.

For the process of in vitro fertilization a women's ovaries are first stimulated with fertility drugs to produce several usable eggs. Then the eggs are retrieved from the ovaries using an ultrasound guided needle. The eggs are fertilized in a petri dish and then the embryo is placed in the mother's uterus. IVF is useful for women who have absent or diseased fallopian tubes, which is where normal fertilization occurs, women who have uncurable endometriosis, and unexplained infertility that has not responded to other treatments, also possibly a male contributing factor.

Gamete intrafallopian transfer which is similar to IVF but the women must have at least one functioning fallopian tube and no suggestion of a male factor involved. The procedure is the same up to egg retrieval, 3-5 eggs are taken from the ovaries and then are placed in the fallopian tube with the husband's sperm, and allowed to fertilize naturally. GIFT was developed to more closely simulate the natural process of fertilization. GIFT is recommended for couples with unexplained infertility, or when infertility is due to cervical or immunological factors.

Zygote intrafallopian transfer again is similar to IVF again but this time a fertilized egg is place in the fallopian tube. ZIFT is performed in cases where the woman has normal fallopian tubes but there is a sever male factor of infertility. ZIFT became available in 1993.

Intracytoplasmic sperm injection is the newest treatment for severe cases of male infertility. This treatment was first used in 1994 at Univ. Cal at San Fran., the baby was born in Feb 1995. Again the woman must use fertility drugs to stimulate egg production. The eggs are then aspirated through the vagina using vaginal ultrasound. Then the male provides a semen sample, which is prepared by centrifuge to separate the live sperm from any debris or dead sperm. One single live sperm is picked up by a glass needle and injected directly into an egg. Fertilization rates are 70-80% of all eggs injected according to UCSF. They also say that worldwide the rate of birth defects in pregnancies using ICSI are no higher than those seen in the general population. (Genesis)

There are several drugs used to treat infertility. First is Lupron which is a gonadotropin releasing hormone (GnRH) agonist. GnRH is produced by the hypothalamus. GnRH stimulates the pituitary to produce Luteinizing hormone (LH) and Follicle stimulating hormone (FSH). FSH in females is responsible for the development and maturation of ovarian follicles. In males FSH is responsible for the development and maturation of sperm. In females a surge of LH will initiate ovulation. LH in males initiates and maintains testicular production of testosterone.

Lupron is a subcutaneous injection given in the thigh at approximately the same time each day. The purpose of Lupron is to prevent premature LH surge and ovulation. Lupron is used in conjunction with other fertility drugs mainly Pergonal which will be discussed later. Lupron is usually given 7-10 days prior to initiating another fertility drug.

Some women experience temporary fluctuations in mood, hot flashes, nausea, and symptoms not vastly dissimilar form PMS. No serious long lasting side effects have been reported. (Pacific)

Next is Serophene also know as Clomid. This drug is often referred to as the "fertility pill". It is used to treat infertile women who have an ovulation problem. It works by helping your pituitary gland improve the stimulation of developing eggs in the ovaries. These drugs may not help a woman become more fertile if she is already ovulating normally. 60-80% of women treated with Serophene or Clomid will ovulate normally. Only half of those patients who ovulate will become pregnant. 10-20% of women taking Serophene or Clomid will experience side effects, which include hot flashes, blurred vision, nausea, bloating sensation and headache. (Atlanta) Due to the visual problems patients should be advised that driving or operating machinery may be dangerous especially in conditions of variable lighting. Serious side effects are rarely seen with these drugs, but there are two that warrant discussion. First there is a possibility of multiple pregnancy. With 10% of women taking the drug having twins, 1 in 400 having triplets and 1 in 800 having quadruplets. (Atlanta) Also these drugs may cause ovarian cysts and usually will resolve without treatment. But on occasion the women's ovary has been removed due to complications. Studies have shown that if pregnancy does occur due to the use of these drugs there is not an increased risk of miscarriage or congenital birth defects when compared to other infertile couple who conceived without Clomid or Serophene.

Clomid or Serophene should not be given to patients with liver disease. In cases of abnormal or irregular uterine bleeding, abnormalities of the endometrium or cervix should first be ruled out. If the patient already has ovarian cysts these drugs should not be given. 4 to 6 cycles of treatment are necessary before one has given Clomid or Serophene an adequate trial. (Atlanta)

Next are Pergonal and Metrodin these two are naturally occurring hormones excreted in the urine of post-menopausal women. When given to pre-menopausal women these hormones stimulate ovarian follicle formation and maturation with associated egg production. For actual ovulation to occur a separate injection of HCG (human chorionic gonadotropin) is needed to provide the surge of LH, which will release the egg. Pergonal or Metrodin are usually given for 7-12 days, per cycle.

Complications and side effects are hyperstimulation of the ovary, possible increased ovulation with multiple gestations and possible premature delivery or pregnancy loss. Hyperstimulation of the ovaries consists of low abdominal pain, pressure, weight gain and swelling. With avoidance of activities and pelvis rest, meaning no intercourse these symptoms usually resolve spontaneously. Although an occasional patient has needed to be hospitalized for observation and fluid hydration. (Bay)

The incidence of multiple gestations appears to be 20-40%, most of these are twins 75%, triplets or more account for 25%. 60-80% of the pregnancies are one fetus. (Bay)

Medical studies indicate that 70-100% of women ovulate following Pergonal or Metrodin. The conception rate is reported to be 15-50% with 25% incidence of miscarriage. Somewhat higher than the 15% miscarriage rate seen in the general population. (Bay)

Lastly Gonal F/ Follistim Gonadotropins are drugs used for ovulation induction for women who don't ovulate on their own, or who need multiple eggs for an insemination process. These drugs are a more pure form of FSH. These are obtained from recombinant technology not from the urine of menopausal women. Another plus is that these injections are with a much smaller needle so it would be easier for the pt. to give the shot to themselves.

Once again when given to pre-menopausal women the hormone stimulates ovarian follicle formation and maturation, with assoc. egg production. An injection of HCG is needed for the LH surge so actual ovulation can occur. Again 7-12 days of injections is the typical regimen.

Complications and side effects resulting in the use of these drugs are related to hyperstimulation of the ovary, possible increased ovulation with multiple gestations and possible premature delivery. Again with avoidance of activities and pelvic rest these symptoms usually resolve spontaneously. (Bay)

Studies indicate that 70-100% of women ovulate with these drugs and the conception rate is 15-20% with 25% having miscarriages. again the normal rate of miscarriages for the general pop is 15%. (Bay)

These next two drugs are not specifically for fertility but as supplemental drugs that would aid in the fertility process. Birth control pills are sometimes used for suppression of the ovaries prior to a stimulated cycle. Common side effects include headaches, weight gain, light periods, mid-cycle spotting and elevated blood pressure. A drug named Provera is used to induce a period when there is no natural cycle. side effects are bloating, headaches, mood swings, swelling of face and extremities, increase blood pressure and weight gain.

There is much cost associated with fertility drugs, both physical and financial. The goal of fertility medicine is to produce a single healthy baby. The injectable drugs increase the number of eggs a woman produces, the chance of multiple fetuses also increases. Doctors cannot precisely control how many fetuses will result. In cases involving injectable fertility, about 15 percent of the pregnancies result in multiple births compared to 1 percent without the drugs. (Smith) Fertility drugs are given to stimulate the ovaries to produce 5 or 6 eggs. These drugs can also cause overstimulation where 34 eggs can ripen at once. This stress on a woman's system can lead to kidney failure. In 1993 alone, 171 women were hospitalized with this potentially life threatening condition. (Kong)

A reproductive endocrinologist (RE) completes the same training and residency as an OB/GYN, but spends and addition 2 years in a fertility fellowship. Doctors listed as "infertility specialists" in HMO directories or in the phone book are not necessarily reproductive endocrinologists.

Lupron is a member of a class of drugs known as gonadotropin releasing hormone. It is FDA approved to alleviate bone pain and some urinary problems that are associated with metastatic prostate cancer. Many women are given Lupron during fertility treatment without being told that the drug does not have FDA approval for that use. (Kong) This drug can also cause birth defects, if present during pregnancy.

Ovulation inducing agents have been available for clinical use for approximately 30 years. With the advent of modern assisted reproductive technologies, their use has escalated dramatically in recent years. A major risk that has received much publicity recently is that these ovulation-inducing drugs may increase the risk of developing ovarian cancers. There is still no definite answer to this question because there is data in support of an association between fertility drugs and ovarian cancer, but there is also equally convincing data that there is no such association. One study suggests that women who use fertility drugs are 3 times more likely to develop ovarian cancer. (Benjamin) Another more recent study suggests that it is infertility not the infertility drugs that cause in increase in the risk of ovarian cancer. "While ovarian cancer accounts for only 4% of all cancers in women, it is a particularly dangerous form of cancer. Less than half of all women with ovarian cancer survive beyond 5 years of being diagnosed." (La Voie) The FDA has begun to request that drug firms add the potential risk of ovarian cancer to the adverse drug reaction section of fertility drug labels. the possibility that the use of fertility may increase the risk of ovarian cancer has prompted researchers to conduct studies to determine the long-term effect of such drugs.

According to the National Center of Health Statistics, the number of triplets has more than tripled since the 1970's and the use of fertility drugs accounts for most of the increase. Multiple pregnancies virtually always end with premature delivery. this increases the chance of losing all the babies or delivering ones that are permanently damaged, blindness or death. On the average, triplets stay in intensive care for four to six weeks. Accommodating multiple births, as well as other high-risk births can be a challenge to any hospital. Caring for infants once home can be a struggle for new parents, especially if the need for special medical attention exists. (Rosenthal)

Other than physical costs, there are also financial costs to consider. Fertility treatments are very expensive. Some couples do not have insurance and must pay for the cost entirely on their own. Overall, about 25% of traditional insurance plans and 37% of HMO's offer coverage for infertility treatments. (Kiplinger) It is now mandatory in 11 states that health insurance coverage includes infertility. Kentucky is not one of them. Some insurance policies cover only certain costs, so it may dictate what types of treatment you receive.

One frequently used drug in Metrodin. Metrodin is given by daily injection, over the course of 9 to 12 days. A $200 per dose, the cost can reach $1900 per cycle. (Minch) The cost of these drugs has caused some to seek out pharmacies in Mexico. Internet postings brag about the savings to be had by purchasing the drugs overseas. It is legal to bring medication across the border, as long as you have a prescription and bring back no more than the amount prescribed. Many patients mail order Perganol from other countries where they are far cheaper than the US. For three cycles of Perganol, the cost in the US is $4,000. In Mexico, the cost is $780. (Kiplinger)

One couple, whose attempts were unsuccessful, was quoted as saying, "With an adoption, when you pay $10,000 you are sure to get a child, but with infertility treatments, you pay your $10,000 but you are not sure of any thing." (Kiplinger) Many couples would agree that the cost is worth it, that they are willing to forgo a new home or car or expensive vacation.

Fertility treatments can also bring about other controversial issues, such as is the case with selective reduction. Selective reduction is a process used to reduce the number of developing fetuses in the case of a multiple pregnancy. It is performed to improve the chances for survival of the remaining fetuses. Though, selective reduction has been performed on women with naturally occurring multiple pregnancies, the majority are used to reduce the number resulting from fertility drugs, in-vitro fertilization, and other reproductive techniques.

There are many procedures used to go about selective reduction but the most common technique involves injecting potassium chloride into the heart of each fetus to be eliminated (MacIsaac, 3). Other techniques are transcervical suction, transabdominal and vaginal needling of the heart, exsanquinating, which means the forcible expulsion of blood from a part of the body usually the heart, and air injection. Except for transcervical suction, these techniques target the developing heart of the fetus because once the heart is destroyed the fetus immediately dies.

Selective reduction is usually performed as soon as possible because the longer the mother carries the multiple fetuses the greater the negative consequences on the remaining fetuses. Most reductions occur between the ninth and thirteenth weeks of pregnancy (MacIsaac, 3). These usually involve elimination of the fetuses that are most easily accessible to the needle or other device rather than which ones are the most viable (Streeter, 1). Reductions occurring in the eighteenth to twenty-fourth week are based more on the elimination of weak or abnormal fetuses. At all times, though, doctors try to eliminate the weak or abnormal fetuses but since it sometimes takes awhile for abnormalities to show, many fetuses may appear equally viable well into the pregnancy.

Statistically speaking, selective reduction does not appear to be simply a matter of convenience but of necessity. Thirteen percent of multiple pregnancies result in no live births if selective reduction is not performed and 15.5 % result in premature births (MacIsaac, 4). The remaining 71.5% represents either pregnancies where selective reduction was used or full term births. However, in the full term births as well as the premature births, the majority did not result in the survival of all babies. Also, many of the surviving children of full term multiple pregnancies suffered various problems such as cerebral palsy, mental retardation and blindness.

The obvious controversy surrounding selective reduction is that some feel it is a form of abortion. Many pro-lifers feel that the termination of "life" is unjustifiable even if the process will increase the chances of survival of the remaining fetuses. One pro-life supporter, Shelley Lembke, stated in an article of Totally Catholic E-Zine that the correct term for selective reductions should be selective "abortions". She felt that the one fetus was being deemed more important than the other. Stacy, a women who with the aid of fertility drugs conceived 10 children and had to undergo selective reduction to ensure her own survival as well as that of the fetuses, disagrees. She says, "This is not abortion. When a woman gets an abortion, she does not want to have a child. Someone goes through this because they desperately want to have a child" (Peyser, 2). Another pro-life supporter cited an incident that occurred in England where a woman who could not afford twins opted to have one fetus removed as evidence of the wrongs of selective reduction. This account, however, is unusual for two reasons: 1) selective reductions are usually performed either to ensure the health of the mother or fetuses not due to expected financial hardships and 2) twins develop within the same sac in the womb and the attempt to eliminate one will most likely harm the other. This is not a problem in multiple pregnancies resulting from artificial means because the fetuses develop in separate sacs so it's easier to eliminate some without harming the others. Another controversial issue with selective reduction is that it's viewed as a way of correcting the mistakes of reproductive technology after the fact rather than correcting the technology itself. As food for thought, a New York Post article asked the question: If technology creates a multiple pregnancy -an event Mother Nature usually rejects-does it then make sense, medically or morally, to let nature decide the outcome?" (Peyser, 1)

Clinics are ever increasing the incidences for selective reductions. The chance for successful implantation by transferring two embryos is 15-20%, with three it rises to 20-25%, and so on until the percentages top out with the transfer of six embyos giving successful implantation rates of nearly 40 percent. As clinics compete to boost success rates, some have been transferring more and more embryos in a cycle--not the usual two or three, but as many as eight--to increase the odds of pregnancy. There's no limit to the number of embryos a clinic can transfer into a woman's uterus.

Multiple births are risky for mothers and babies. Twins are seven times more likely to be born smaller than single infants. More than half of all twins weigh less than five and a half pounds, compared to six percent of single babies, and four out of every 100 twins die. The risk of low birth weight and death only increases with multiple births. For example, more than 90 percent of triplets born each year weigh less than five and a half pounds and ten out of every 100 die.

Despite these risks, the rate of multiple births increased twenty-four percent between 1983 and 1993 with 2.5 percent of all 1993 babies born as twins, triplets, quadruplets, or quintuplets. The arate of premature births climbed nearly 15 percent. In 1993, the most recent year tabulated, babies born weighing 5.5 pounds or less accounted for 7.2 percent of all births--the highest low birthweight rate since 1976. Thus, the rise in multiple births show a direct correlation with the rise in low birhtweight babies.

While newnatal intensive care continues to save many of these tiny babies, some public health specialists worry that if the trend continues, their numbers could drive up pre- and post-natalmedical costs and perhaps the infant mortality rate.

Because of these risks, some clinics (nearly 300 in the U.S.) perform selective reductions on unborn fetuses. While there are many advantages to performing these selective reductions, the main one being to increase the birth weight and chance of survival of existing fetuses, there are also risks associated. These risks of selective reduction, termed by some of its opponents as selective feticide, include: the accidental loss of pregnancy, the performance of the procedure on the wrong 'healthy' fetuses, chorioamnionitis (inflammation of the tissues surrounding the fetus), premature dilivery, and permanent damage of the surviving fetuses. There is also some question of the psychological effects of selective reduction on the mother, and it has been proven that severe depression can persist after the procedure. Many consider the selective reduction procedure to be an abortive process and deem it morally and ethically wrong for the same reasons.

Selective reduction procedures, as well as the many Assisted Reproductive Technologies aforementioned, are not currently under governmental regulation. To date, there is no significant legislation regulating the action of fertility clinics or the use of fertility drugs. Many organizations including the Ethics Advisory Board of the U.S. Department of Health Education and Welfare, the American Society for Reproductive Medicine, the American College of Obstetricians and Gynecologists, and the Judicial Council of the American Medical Association are convening in an attempt to establish guidelines that clarify the responsibilities of participants and set professional standards. However, agreements have yet to be made upon such restriction.

The technology associated with fertility treatments has moved at such a rapid pace that legislation has not been able to keep up. It is growing more and more important to seriously examine the moral and ethical issues involved in such manipulations in order to have the tools to approach situations such as the following:

A plane crash cuts short the lives of an infertile couple, leaving two frozen embryos orphaned. Do the embryos have a right to be born? If so, do they inherit the couple's estate? Who would have decision-making powers over the fate of the embryos?
 


Infertility

Defined as 12 months of unprotected intercourse without pregnancy.

Two types: Primary Infertility - meaning pregnancy has never occurred.

Secondary Infertility - meaning there has been one or more pregnancies previously.
 

Assisted Reproductive Technologies (ART)

Procedures that involve high technology and the combination of sperm and eggs to treat infertility
 

5 Types of Assisted Reproductive Technologies
 

Fertility Drugs
 


The basic question is: To what extent should technology be allowed to alter the normal course of nature? In other words, where does it all end?

The following three examples illustrate the kinds of moral and ethical questions the laboratory director of a major IVF program encounters:

A 28-year-old female medical student asked:

Is it possible for you to freeze two or three stimulated cycles of my eggs now? I'll be over 35 by the time I get out of medical school, and I'd like to begin my family about age 40 but with age-28 eggs.

When a graduate student received widespread publicity after the birth of identical twin calves from a cow embryo he had split, a couple inquired of the laboratory director:

Would you please split one of our embryos so we can have identical twins?

And a terminally ill man asked:
 

 

Professor Arthur Caplan, medical ethicist:
 



 

Evaluation

Two words kept reappearing in the evaluations made by the class--informative and interesting. The class as a whole felt the presentation was well-prepared and organized. It was commented that the presentation "hit all the major points" and that it "tied into medical ethical issues." Most were impressed with the use of the overheads. Many commented that the presentation was well-researched and very thorough. A few expressed their liking of the frequently asked questions and were impressed with the way that it focused on regulations.

Many said that they would have liked to have asked questions. A couple of people did not like presenters reading directly from the notes, but one admitted that it would be "difficult not to with the extent of the info presented."
 


Works Cited

Atlanta Reproductive Health Center: Online.Internet Available: http://www.ivf.com//clom.html

Bay Area Fertility and Gynecology Medical Group: Online.Internet Available: http://www.ihr.com/bafertil/articles/pergmetr.html

Benjamin, Ivor, M.D. "Fertility Drugs and Ovarian Cancer: What are the risks when used for surrogacy" Online.Internet. Available: http://www.surrogacy.com/medes/article/fertdrug.html

Genesis Fertility Centre: Online.Internet. Available: http://www.iatronet.net

Kiplinger Features "The Agonizing Price of Infertility" Online.Internet. 1996 May
Available: http://www.kiplinger.com/magazine/may96/inferti.html

La Voie, Angela "Infetility, not its treatment poses Ovarian Cancer Risk." Online.
Internet. 1996 Oct. 14. Available: http://www.thriveonline.com/newsstand/today/times1.10-14-96.html

MacIsaac, Ian "Selective Termination and Multi-Fetal Pregnancy Reduction-A Procedure With No Clinical Place" <http://www.sehlat.com/lifelink/med/ausmed.html> (March 27,1998).

Minch, Linda ...Lexington Herald-Leader Online. Internet. 1996 Aug. 26 Available:
http://www.kentuckyconnect.com/hearaldleader/newsd/0826/fcenter.html

Peyser, Andrea "How Can You Say It's Wrong When It Turned Out So Right?" New York Post, 1997. <http://www.nypostonline.com/news/1036.htm> (April 1,1998).

Rosenthal, E. "Cost of high-tech fertility: too many tiny babies." New York Times 1992 May 26:141(48,978):B5,B7

Smith, Rick "Clients not scared of fertility drugs." Iowa City Gazette 1997 Nov. 20

Streeter, Tom "Bobbi" Jan.1998 <http://www.users.delnet.com/~streeter> (March 31, 1998)