FINAL PAPER COVER PAGE

FINAL PAPER COVER PAGE Research Question: Most couples desire to have children at some point during the course of their relationship. However, infertility is an important problem that many couples face. Numerous medical developments have led to treatments that can combat infertility in both men and women, including Intrauterine Insemination, Assisted Reproductive Technologies, and Intracytoplasmic Sperm Injection. Each of these infertility treatments possesses risks and side effects. We intend to serve as an unbiased source to provide health professionals with detailed information regarding the pros and cons of each of these treatments, based on associated health risks for the mother and child, success rates, and cost-effectiveness. Even though reasons for infertility vary, we expect that intrauterine insemination will be useful for the widest population of infertile couples. In the end, we hope that these couples will then be able to make an educated decision regarding the type of infertility treatment that best suits their needs. 1

Aparna Ramaseshan and Christie Walsh November 30, 2006 English 395.1101 FEASIBILITY REPORT MODERN TREATMENTS AVAILABLE TO THE INFERTILE COUPLE INTRODUCTION Centuries ago, it was standard for men to hang their wives for not producing a child. Furthermore, in ancient India, the angry husband would take part in kitchen burnings, by tying his wife to a chair and lighting her on fire in the kitchen for her inability to conceive. Today, however, current developments in research and technology have greatly improved our knowledge on the science of infertility. Medical professionals declare a couple infertile if no successful live birth has taken place within one year of normal sexual activity without the use of contraception. Little did these men know that 40% of infertility cases result from the man, 40% result from the woman, 10% are shared, and 10% are undiagnosable (Kranz 17). For men, the most common causes of infertility include infection, hormone imbalance, injury, or anatomical abnormalities. Additionally, infertility arises in men when too few sperm are produced, called oligospermia, or when the sperm lack adequate motility, called asthenospermia. For women, infertility often stems from structural problems, ovulation variances, hormone imbalance, endometriosis, and stress. From 1988 to 1995, the incidence of infertility in women in the United States increased 25%, from 4.9 million to 6.1 million (Ryan 2). With this expansion of infertility problems comes a greater need for understanding the latest treatment options. The most widely used infertility treatments of the 21 st century include intrauterine insemination (IUI), Assisted Reproductive 2

Technologies (ART), and Intracytoplasmic Sperm Injection (ICSI). ART comprises all treatments where the egg and sperm are combined in the laboratory outside of the woman s body; this includes In-vitro fertilization (IVF) and several variations of IVF such as Gamete Intrafallopian Transfer (GIFT) and Zygote Intrafallopian Transfer (ZIFT). While these procedures have certain aspects in common, they vary by health risks for the mother and child, success rates, and cost-effectiveness. An unbiased critique of the treatment methods using these criteria is necessary in order to determine which method should be utilized. First we will discuss any health problems associated with each treatment. Next, we will look at recently reported success rates for each option. And finally, we will review the costs incurred with each procedure in order to successfully analyze the most well-known infertility treatments. After careful analysis of these factors, we predict that intrauterine insemination will be the preferred method because of its reduced health risks and cost-effectiveness. BACKGROUND Intrauterine Insemination The technique for Intrauterine Insemination (IUI), a type of artificial insemination, involves placing sperm into a woman s uterus by artificial means to achieve fertilization. First, physicians will measure levels of luteinizing hormone, take ultrasounds, and perform blood tests to determine when the woman is ovulating. To increase the likelihood of fertilization, the woman takes a fertility drug to induce ovulation and stimulate her ovaries to produce more ova and mature eggs. Similarly, physicians may choose to administer hormone therapy for this purpose. Following ovulation, the next step is to collect the male donor s semen in a sterile container. Finally, the sperm is inserted into the uterus via a catheter inside of a speculum placed in the woman s vagina. 3

Reports of the use of intrauterine insemination date back for centuries. Some historians suggest that it was attempted on the wife of King Henry IV of Castile in the early 1400s. Intrauterine insemination had its first recorded modern success in 1799, when the first child conceived using this treatment was born. It wasn t until 1899 that scientists in Russia began to develop practical methods for insemination, after studying the previous use of IUI in the cattle industry. Throughout the 1900s, researchers advanced the techniques of intrauterine insemination by adding antibiotics to sperm solutions and improving methods of collection, making IUI what it is today. Assisted Reproductive Technologies (ART) Our main focus when addressing ART is In-Vitro Fertilization because the other methods of ART are variations of IVF that share common characteristics and trends. Therefore when discussing IVF, it is implied that each aspect of IVF also applies to the variations unless otherwise noted. IVF consists of retrieving mature eggs from a woman, fertilizing them with a man's sperm in a dish in a laboratory, and implanting the embryos in the uterus three to five days after fertilization. In order to collect mature eggs, the woman is given hormones to induce ovulation. These ovulation drugs include clomiphene citrate, human menopausal gonadotropins (hmg), follicle stimulating hormone (FSH), recombinant FSH and LH, and human chorionic gonadotropin (hcg) (Assisted Reproductive Technologies 5) After ovulation, the mature eggs are removed from the ovarian mature eggs through transvaginal ultrasound aspiration. This technique is a minor surgical procedure performed under anesthesia where the eggs are removed with a needle aspirator guided into the vagina by an ultrasound probe. The mature eggs are then mixed with sperm that is prepared by separating it from the semen in the laboratory. If the sperm successfully fertilizes the egg, then the embryo is placed in the uterus through a non-surgical 4

process. This method has effectively delivered approximated 20,000 babies worldwide (In vitro Fertilization para.1). Developed in 1978, this infertility treatment is used when infertility is caused due to tubal damage in the woman, infertility in the male, endometriosis, problems with cervical mucous quality, presence of antisperm antibodies, or when the reason for infertility cannot be explained. Variations of IVF The two variations within IVF include Gamete Intrafallopian Transfer (GIFT) and Zygote Intrafallopian Transfer (ZIFT). GIFT is similar to IVF; however, the egg and the sperm are placed in the fallopian tubes, where fertilization takes place, instead of the uterus. Another difference between GIFT and IVF is that the transfer of eggs and sperm into the fallopian tubes requires laparoscopy, a surgical procedure. Furthermore, unlike IVF, fertilization cannot be confirmed in GIFT. In the United States, GIFT comprises less than 2% of infertility treatments performed (Assisted Reproductive Technologies 10) Zygote Intrafallopian Transfer (ZIFT) is another treatment variation within IVF. ZIFT differs from GIFT in that fertilization takes place in a laboratory as opposed to the fallopian tubes. However, the fertilized egg is placed in the tube and not the uterus. ZIFT comprises about 1.5% of the infertility treatments performed in the United States (Assisted Reproductive Technologies 10). Both of these treatments still require the women to take ovulation drugs. Intracytoplasmic Sperm Injection Intracytoplasmic Sperm Injection (ICSI), generally used in conjunction with IVF, is a relatively new procedure to increase the chance of fertilization. Belgian researchers pioneered ICSI in 1992, and the first birth from ICSI was reported in 1993 (Spar 62). This treatment requires micromanipulation, where scientists utilize a micropipette to inject a single sperm into 5

an egg. A holding pipette secures the mature oocyte on one side while a thin, sharp, and hollow needle carrying a single sperm penetrates the inner side of the oocyte, called the zona or the oolemma. The needle releases the sperm inside the cytoplasm of the egg before it is carefully removed. By the next day, the egg should show signs of normal fertilization. Embryologists now choose mature sperm based on their binding to hyaluronan, the main component of the gel layer surrounding the oocyte, ever since the U.S. Food and Drug Administration cleared the procedure in 2006 (Jakab 1665). HEALTH CONCERNS The first criterion involves the health and well-being of the mother and child, which are high priority for an infertile couple. Because these techniques are very involved, we must accept that complications will arise and may cause serious health problems. Therefore, in analyzing these treatment methods, we must evaluate the extent and incidence of the various types of health risks associated with each method. Furthermore, we must discover ways in which to minimize health problems while still taking effectiveness into account. Intrauterine Insemination The procedure in itself may cause pain and anxiety for the woman undergoing treatment. First of all, the chemicals in the semen may cause discomfort, but doctors perform sperm washing to try to minimize the irritation. While the insemination takes only a few minutes, most women are on fertility drugs for a week prior to the procedure. Additionally, discomfort from the procedure is similar to that of a pap smear and may cause minor stomach cramping. Infection is possible but not common. On the other hand, IUI does not affect the sexual activity of the woman. She may have sexual intercourse before or after the procedure without disturbing the chance of pregnancy. 6

Women who choose IUI may experience several types of health problems due to the effects of IUI on pregnancy. One study from 2003 studied various health effects in 510 cycles of the treatment. The researchers found that there was a 6% chance per cycle that the woman would give birth to one normal term child, a 20% chance that the woman would give birth to twins, and a less than one percent chance that the woman would give birth to triplets (Healy screen 3). Of the 234 patients, 22% had miscarriages and only 15% of the women receiving treatment gave birth (Healy screen 4). While none of the patients in this trial gave birth prematurely, a chance does exist for premature birth after IUI. However, a more recent and much larger study of 1010 cycles of IUI presented much lower rates of miscarriage: 3% pregnancy loss from ectopic and spontaneous fetal heart miscarriages (Lenton 254). These miscarriages occurred in the youngest and oldest women undergoing IUI. This procedure also may increase the risk for ovarian hyperstimulation syndrome (OHSS). Hyperstimulation is a condition when the ovaries become swollen and painful. This condition causes weight gain due to the accumulation of fluid in the abdomen, nausea, lack of appetite, low output of urine, and potential serious changes in the blood chemistry. In serious cases of hyperstimulation, the woman might have to go to the hospital in order to get some of the fluid drained if it starts to cause breathing problems. However, of the 30% that experience hyperstimulation, only one or two percent suffer from the serious form of it (Assisted Reproductive Technologies 13). Health effects for mother and child also depend on the use of ovulation inducing hormones. Taking hormones to increase the chance of fertilization also increases the chance of having twins or higher order multiple pregnancies (HOMPs), where three or more births occur. Intrauterine insemination is possible without the use of these drugs, but the treatment must be timed perfectly to take place just before ovulation. A study from 2004 reported the birth of 33 7

twins and 11 HOMPs out of 1010 cycles, which is about 4.3% multiple births per cycle and about 23.6% multiple births per pregnancy (Lenton 255). The number of HOMPs has declined significantly since 1997 because by today s criteria, one is only allowed to proceed with IUI when one or two pre-ovulatory mature eggs are present, since more than three mature eggs indicates an increased risk of multiple births (Lenton 255). The transmission of the genes from infertile parent to child may cause the child to be infertile. For example, this treatment may be used for a couple diagnosed with male factor infertility. If the donation of sperm comes from an infertile man who produces low amounts of sperm, the gene that is responsible for the father s infertility will most likely be passed on to the offspring, causing the offspring to be infertile as well. In addition, other diseases that may have caused the infertility will be passed on to offspring. This fact increases the need for further research in determining the causes of infertility prior to starting a treatment. Preliminary testing would help to ensure the birth of a healthy child. Assisted Reproductive Technologies (ART) A couple that undergoes IVF as a part of an ART procedure experiences many physical and mental challenges. The woman specifically is at a risk of suffering from different short and long term effects due to this procedure. The most common side effects from this procedure are caused by the heavy dosage of ovulation drugs. Pergonal, a common drug used as a human menopausal gonodotropin in IVF, has been linked with the incidence of ovarian cancer (Cooper 37). In a study that was published in 1993, the data suggested that women who used fertility drugs such as Pergonal and did not become pregnant have a significant chance of developing ovarian cancer. Even though this study was flawed in many ways, it raised questions regarding 8

the potential harmful effects of fertility drugs. Based off of this study, Venn et al. conducted a study in 1995 that further investigated the incidence of breast and ovarian cancer in women who had undergone in vitro fertilization. This study concludes that the incidence of breast cancer in women who have had IVF treatment with ovarian stimulation is no different from the incidence in women referred for IVF but not treated (with fertility drugs), or the incidence of the general population (Venn et al. 999). Additionally, this study further reports that ovarian stimulation by fertility drugs does not increase the risk of ovarian cancer (Venn et al 995). Based on the results of this study, IVF does not appear to increase the chance of acquiring breast or ovarian cancer; however, the study only used a small number of classes due to which more research is needed in this area. Similarly, Luporn is another ovulation drug that causes unpleasant side effects. Even though the side effects are not as serious as ovarian cancer, it physiologically puts women into (temporary) menopause (Cooper 38), where women frequently suffer from headaches and hot flashes. Additional risks caused by ovarian stimulation include Ovarian Hyperstimulation (OHSS), the same condition caused by Intrauterine Insemination. Apart from the potential risks caused by fertility drugs, the IVF procedure itself comes with many dangers. The egg retrieval process involves a laparoscopy, which is a surgical procedure. Even though it is a minor surgery, the procedure comes with all the risks that a surgery in general entails such as anesthesia, pain, and general discomfort. The most common problems with a laparoscopy are skin irritations and bladder infections, which are not life threatening conditions. Therefore, the incidences of death from laparoscopy are extremely low, only around 3 in 100,000 patients (Laparoscopy and Hysteroscopy 5). The use of an aspirator needle in order to remove the mature eggs can cause bleeding, infection, and damage to the 9

bowel, bladder or the blood vessel. Although there are risks associated with this procedure, less than 1 in 1000 patients experience serious complications from the egg retrieval process (Assisted Reproductive Technologies 13). Additionally, multiple pregnancies are another significant risk posed by IVF. Because more than one embryo is transferred, the chance of a multiple pregnancy is extremely high within all assisted reproductive technologies. In the report published by the CDC in 2006, 34.9% of the pregnancies resulted in multiple births, where 29% were twins and the other 5.9% were triplets or more (CDC Screen 6). By having a multiple pregnancy, a woman greatly increases her chance of having an extremely complicated pregnancy. Carrying a multiple pregnancy might require a woman to spend many days or even months in order to prevent the delivery of premature babies. Having a premature baby is a very precarious situation because premature babies require a lot of care and attention. Based on how prematurely a baby is born, it might have to spend numerous days, weeks or even months in the Neonatal Intensive Care Unit (NICU), receiving the care that is necessary for it to survive. Furthermore, premature babies are generally at a high risk for acquiring life long handicaps. Hence, a multiple pregnancy is a serious risk with reproductive technologies like IVF. Besides multiple pregnancies, miscarriages and ectopic pregnancies are other common problems that arise with assisted reproductive technology. Ectopic pregnancies are pregnancies in which the fertilized egg is found somewhere other than the uterus. It is generally found in the fallopian tubes, which can severely endanger the mother s life. About 5% of in vitro s result in ectopic pregnancies (Assisted Reproductive Technology 13). In terms of miscarriages, 15% of women younger than age 35, 25% at age 40, and 35% at age 42 experience a miscarriage after ultrasound confirmation of an ART procedure (Assisted Reproductive Technology 13). The 10

chances of having a miscarriage greatly increase as the woman gets older. It is as high as 56% in women over the age of 42 (CDC Screen 7) As well as causing long and short term problems in the mother, the child might suffer birth defects due to ART. However, more research is needed in this area because while some studies prove that IVF causes birth defects, other studies refute these results. Intracytoplasmic Sperm Injection The design of ICSI may lead to health problems for the mother. In terms of psychological issues, the process may be frustrating because the completion of one cycle takes about four to six weeks. Doctors must wait until the medication causes the woman s ovaries to produce mature eggs before continuing the procedure. Additionally, since the procedure involves inserting sperm inside of an egg, this micromanipulation may cause damage to the egg. As a result, the egg may fail to divide or it may arrest early in its development. Intracytoplasmic sperm injection also affects the child conceived. One study from 2006 reported that 35% of births from ICSI are multiples and about 3% of these are triplets. Moreover, a significant amount of these babies are premature and have a low birth weight (Spar 229). According to one study, the risk of substantial anomalies doubles with the use of ICSI from 4% to 8% (Blair 14). As one example, ICSI is associated with an increased risk of chromosomal aneuplodies and the proliferation of disorders caused by deletions in the Y-chromosome (Jakab 1665). Additionally, a study on congenital malformations in children born from ICSI reported an increased incidence (seven out of 1008 births) of hypospadias (Wennerholm 945). In hypospadias, the urethra opening is on the underside of the penis and it is most likely due to paternal subfertility. Many of the health problems among the children born from ICSI were 11

associated with multiple and premature birth, including 18% of the infants who had undescended testicles and patent ductus arteriosus, a condition that affects the cardiovascular and respiratory systems (Wennerholm 947). Chromosomal aneuplodies, that may cause Y-microdeletions, Kallman s syndrome, and cancer, can have serious consequences such has infertility, mental and physical disabilities, and even death in some instances. Since ICSI is a relatively new procedure, the long term effects of ICSI remain unknown because the oldest baby conceived through ICSI is only about thirteen years old. ANALYSIS: HEALTH CONCERNS All of these treatments come with significant health risks to both the mother and the child. Therefore, it is unreasonable for couples to expect an infertility treatment that bears no negative consequences. In terms of comparing these treatments based on health risks, IUI and IVF share many similarities. Both of these techniques cause OHSS and hormonal side effects from fertility drugs in the mother. However, the side effects caused by IVF are more severe than the ones caused by IUI. Even though more research is necessary in this area, it is important to note that some studies have linked incidences of breast and ovarian cancers with the use of ovulation drugs in conjunction with IVF. As far as the child is concerned, it can be born premature, which can cause numerous physical and mental disabilities. Additionally, both of these treatments can cause multiple pregnancies and miscarriages. However, the percentage of these two risks varies significantly across these two treatments. It is mentioned in the above section that IUI results in 6% singleton births and approximately 20%- 24% result in multiple births. On the other hand, 65.8% of IVF treatments result in singleton births and the remaining 34.2% consists of multiple births (CDC screen 6). By comparing the 12

percentages, it can be seen that IVF results in more singleton birth than IUI. Even though the percentage of multiple births is higher with IVF, it is safe to assume that couples undergoing fertility treatments would be happier with multiple children as opposed to none at all. Miscarriage is another safety concern that should be considered with these two treatments. Based on the percentages provided, it can be seen that miscarriages with IVF are lower when the woman is under 35 years of age (15%). However, if the woman is over 40 years old, then IUI s 22% is lower than IVF s 25%. In terms of miscarriages, it is hard to determine the superiority of one of these techniques since the percentages are so close. However, our data on IUI is limited compared to our data on IVF since our IVF data includes IVF procedures done all across the United States for the year 2003. Since ICSI is a relatively new procedure, the health risks arising from it are not as well known as they are for either IVF or IUI. However, there are potential risks such as damages to the egg and deleterious mutations to the chromosomes of the offspring. When comparing ICSI with the other two treatment methods, it is more invasive, which further decreases the desire to choose this technique. In light of all this information and keeping in mind the limitations of our data, we have decided that IUI poses the least number of risks. Even though both IUI and IVF cause many side effects to the fertility drugs, the effects of IUI are much lower because the dosage of these drugs is lower with this procedure. Furthermore, it has not been linked with the incidence of either breast or ovarian cancer. It is important to note that the number of live births from both singleton and multiple births with IVF is quite higher; however, the goal of this criterion is to evaluate the health risks and not the success of a particular procedure. Therefore, in spite of having a higher number of births, IVF is riskier since it has a higher percentage of multiple pregnancies. 13

SUCCESS RATES The success of a fertility treatment boils down to the number of live births from that treatment. Therefore, when comparing the effectiveness of different fertility treatments, we have chosen to evaluate them based on the percentage of live births delivered by women undergoing the various treatments. However, it is important to interpret success rates correctly. The word pregnancy does not always result in a live birth. A pregnancy can be confirmed through urine/blood tests and an ultrasound. A woman can be declared pregnant through a blood or urine test; however, it might not show up on an ultrasound if the pregnancy is miscarried before it can receive ultrasound verification. Furthermore, a pregnancy can still be miscarried even after ultrasound confirmation. Therefore, a success rate of an infertility treatment should be evaluated on the basis of the number of live births from that treatment. Live birth rates are highly influenced by the woman s age and whether there is male factor infertility. Furthermore, the use of hormones specifically influences live birth rates in women using Intrauterine Insemination. Hence, we will be evaluating the success rate of a treatment based on these factors. Intrauterine Insemination The success rates for intrauterine insemination vary depending on several different factors. First of all, the use of hormones directly affects the success of IUI. One study from 2000 found that there were 31% live births for unstimulated IUI but there were 37% live births for IUI involving hormones (Goverde screen 5). Also, the number of mature eggs affects the success of achieving a pregnancy. For the stimulated treatments of IUI, 10% of the cases where more than one mature egg was formed resulted in pregnancy, but 7% of the cases with only one mature egg resulted in pregnancy (Goverde screen 5). 14

Another study from 2000 found a much lower percent of pregnancies per cycle, which results in an even lower number of actual live births. In this case, out of 811 stimulated IUI cycles, 102 pregnancies occurred (12.6%); 70.6% of these were viable and the rest were spontaneously aborted or ectopic (Nuojua-Huttunen screen 5). This study also shows variations in success rates of pregnancy per cycle based on maternal age and sperm count. As seen in other trials, the success of IUI decreases as maternal age increases: for women under 40 years of age, 14.2% of their cycles resulted in pregnancy, while only 6.1% of the women over 40 became pregnant per cycle (Nuojua-Huttunen screen 6). In addition, the sperm count also affects the success of pregnancy rates. When less than 5 x 10 6 sperm per ml were used, the percentage of pregnancies per cycle was 7.1%, but this number rose to 13.2% for all numbers of sperm over 5 x 10 6 per ml (Nuojua-Huttunen screen 6). Moreover, the design of intrauterine insemination makes it successful for different types of infertility. Because this technique bypasses the woman s cervix and introduces sperm directly into the uterus, intrauterine insemination is especially useful in cases where the woman has a cervical problem, where the man produces sperm with low motility, or when the sperm has a negative interaction with the woman s cervical mucus. Additionally, intrauterine insemination is successful because it is designed to maximize the chance of fertilization through sperm washing, where all components of the semen are removed except for the sperm. However, physicians avoid this technique when the woman s fallopian tubes are damaged because fertilization will not be successful. 15

Assisted Reproductive Technologies Since 1997, the Center for Disease Control (CDC) has been compiling data related to Assisted Reproductive Technologies, including IVF, GIFT, ZIFT, and ICSI. The report published in 2006 evaluates the percentage of live births based on data collected in 2003. The number of live births for all Assisted Reproductive Technologies where the women used the embryo from her own eggs as opposed to donor eggs was 43.2% in women under 35 years of age (Wright et al. screen 14). The percentage is lower as the age of the woman increases. For instance, the live birth percentages in women between the ages 35-37, 38-40, 41-42, and over 42 years of age are 36.6, 26.1, 15.1 and 5.9 respectively (Wright et al. screen 14). The study by the CDC also published data on live births from women who only had IVF. In other words, the live births due to GIFT or ICSI were not included in this set of data. Of the women who attempted infertility treatments, 33.9% under 35 years of age, 35.2% between ages 35-37, 36.5% between ages 38-40, 39% between ages 41-42, and 39.1% over the age of 42 used IVF (Wright et al. screen 18). Of the 33.9% of women under 35 years of age who had IVF, 45.3% of them gave birth to live babies (Wright et al. screen 19). 38.7% of the women between the ages 35-37, 28.5% of the women between the ages of 38-40, and 17.3% of the women between the ages of 41-42 delivered live babies (Wright et al. screen 19). The lowest percentage of live births was seen in women over the age of 42, where only 7.1% of the women who had IVF gave birth to live babies (Wright et al. screen 19). Apart from IVF, the study by CDC also has information on the number of women who underwent GIFT and ZIFT. A very low percentage of women undergoing infertility treatments underwent either of these two procedures. For GIFT, the average percentage of women using this treatment across the different age groups is.16% (Wright et al. screen 14). Likewise, the average 16

percentage of women using ZIFT across the different age groups is.19% (Wright et al. screen 14). However, in a review conducted by Pandian et al., the authors compared the pregnancy and live birth rates for IVF and GIFT based on data accumulated from different studies. Even though there was no significant difference with live birth rates, IVF showed a higher pregnancy rate. Approximately, 48% of the couples who underwent IVF became pregnant. On the other hand, only 30% of the couples who underwent GIFT were able to actually conceive (Pandian et al. 25) Intracytoplasmic Sperm Injection Studies on ICSI suggest the influence of age and type of infertility diagnosis on success rates. For example, the CDC studied ICSI in couples diagnosed with male factor infertility and found that for women less than 35 years of age, 43.7% of the procedures produced a live birth (Wright et al. screen 19). For women ages 35-37, there were 36.7% live births per transfer procedure and for women ages 38-40 there were 25.7% live births per procedure (Wright et al. screen 19). The records reported that success rates continued to decrease with age because women ages 41-42 had 14.7% live births per procedure, and women over 42 years of age gave birth to live babies in 4.7% of the transfer procedures (Wright et al. screen 19). Success rates recorded by the CDC in 2003 were lower for couples not diagnosed with male factor infertility. This result occurs because ICSI cannot improve the quality of the woman s eggs, if the couple has female factor infertility. In these cases, success also decreased as maternal age increased. For women under 35, 40.0% of the procedures produced a live birth (Wright et al. screen 19). For women ages 35-37, a success rate of 34.2% live births per procedure was recorded (Wright et al. screen 19). For the next age bracket, ages 38-40, the success rate was 23.8% live births per transfer procedure (Wright et al. screen 19). Finally, the 17

rates were much lower for women ages 41-42 and women over 42, showing live birth rates of 12.7% and 5.4% respectively (Wright et al. screen 19). There have been other studies outside of the Center for Disease Control that look at different measures of success. For example, success of intracytoplasmic sperm injection can also be defined by the percent fertilization per transfer procedure. A higher success rate of fertilization ensures that the couple has to go through fewer hassles and cycles of procedure. This definition of success is less prevalent because fertilization cannot imply the actual birth of a child. Nevertheless, in 2001, the American Society for Reproductive Medicine reported 50% to 80% successful fertilization per intracytoplasmic injection (screen 1). ANALYSIS: SUCCESS RATES For obvious reasons, including psychological well-being, a couple will want the infertility treatment with the highest rates of success. The process of infertility treatment is exhausting in many respects, and thus the high success of a treatment appeals to the anxious couple. Therefore, it is important to have accurate research about the predicted outcome of a treatment to allow for a valid evaluation of success. Success rates are difficult to analyze because so many factors affect the outcome of a procedure. First of all, as shown, hormones, age, and sperm count will all alter the efficacy of the treatment. Type of infertility, as well, will determine the efficacy of the procedure because each treatment type works on a specific part of the reproductive system. Therefore, the man s sperm should be carefully screened prior to beginning treatment to determine the sperm s functional capability and to help identify candidates that will benefit most from ICSI, for example. One doctor reported that since starting to use sperm screening, his use of ICSI decreased significantly, but his failed fertilization rate also decreased from 6% to.6% (Blair 14). Hence, it is very 18

important to determine the type of infertility before choosing a treatment option. Issues like these will skew the reported success rates, so more data is necessary before ruling out ICSI completely. At this point, elaborate data combining all of these factors does not exist. Hopefully in the future, comprehensive information on the success of infertility treatments needs to be broken down by age and general health factors and combined with success rates for couples diagnosed with each type of infertility problem. This collaboration of data would aid couples in choosing treatment options according to their specific needs and circumstances. Evaluation is made more complex because many of these statistics do not include the actual number of live births per attempted cycle. This number is important because patients may want to know their odds for pregnancy after attempting one treatment. Some studies do not include cancelled cycles in their reported success rates, which inflates actual success rate values. Data is necessary for specific cycles because some trials show that effectiveness of a treatment decreases with each insemination cycles. More data is necessary to determine the effectiveness per cycle number, instead of just averaging all of the known data. However, this information comprises what is available today on infertility treatments, and we must use it to make an educated guess. While research is still proceeding and improving, we can look at past successes per infertility treatment to determine the more advantageous treatment option. Even at the highest recorded success for IUI, which happens to be supplemented by hormones, Intrauterine Insemination produced the lowest percent delivery of 37%. ICSI came in second place, with the highest average at 43.7% delivery for women under 35 years of age. The highest success rate for IVF also came from women under 35 years, at 45.3% delivery. Unfortunately, IVF also had the largest variation in success as maternal age increases, but this makes sense because it has the highest possible range since it has the highest success rate. In 19

addition, IVF has a higher percentage of failed fertilizations than ICSI. However, the difference was only 3%, so IVF still has a very high rate of success (Blair 14). As far as success rates for GIFT are concerned, IVF has a higher pregnancy rate than GIFT; however, there is no significant difference in the live birth percentage. The live birth percentage is the one that is most important because couples would rather have a pregnancy that results in a live baby as opposed to a pregnancy that yields no baby. However, the study from which we acquired the data for our GIFT versus IVF comparison is limited in that the sample sizes were fairly small. Therefore, more conclusive and large-scale research is needed in this area. Overall, based on all the information that we have on success rates, we have decided that IVF has the highest success rates amongst all infertility treatments. COSTS In the United States, laws concerning insurance coverage are regulated at the state level. In 1998, only 12 states currently had legislation concerning infertility treatment coverage (Van Voohis, et al. 995). And within those few states, several variations on restrictions to treatment coverage exist. Furthermore, some insurance plans are excused from covering some treatments or there are limits to reimbursement. Additionally, only 40% of large self-insured employers cover some form of advanced fertility service (Ryan 2). As a result, the patients themselves must pay the bulk of cost of infertility treatments. However, the extent of the cost of infertility treatments cannot be expressed simply in monetary terms. Costs of infertility treatments may be direct medical, direct non-medical, indirect morbidity and mortality, or intangible (Van Voorhis, et al. 996). Direct medical costs include the money spent for the services and medical products, such as medications, testing, and hospitalization. Direct non-medical costs are defined by the money spent on food, lodging, and 20

transportation while obtaining infertility treatments. We do not discuss these costs here because they will vary for each patient, depending on the accessibility of the infertility treatments and the duration of the treatment. Patients experience indirect costs because of any deaths or loss of livelihood and the costs of lost salary. Lastly, intangible costs arise due to the pain and suffering brought about by the medical care. Therefore, evaluating the cost-effectiveness of the infertility treatments is very complex. To simplify this task, in this paper we will discuss costs in terms of cost-effectiveness, by analyzing the expenses of the service as well as the beneficial outcome. Intrauterine Insemination The costs associated with IUI add up very quickly. One study from 2004 reported the costs of stimulation hormones such as clomiphene citrate and FSH to be about $180 (Lenton 260). The IUI treatment also requires additional costs for endocrine blood tests ($23 per sample), ultrasounds ($68 per scan), averaging about $370 for these monitoring techniques (Lenton 260). The actual insemination ($270), pregnancy detection ($54), and post treatment medical reviews ($135) also significantly raise the cost of IUI (Lenton 261). Furthermore, an additional $225 is needed when donor sperm is used and it even costs $684 extra to cancel a cycle after stimulation has begun (Lenton 261). Altogether, this becomes about $1170 per treatment cycle, or about $7103-7477 for one live birth, when assuming a 15% live birth success rate (Lenton 263). These values for cost per live birth will also vary by the use of hormones as well as other factors affecting the success of IUI. For instance, a study conducted in the Netherlands in 2000 found that one treatment cycle of spontaneous IUI costs about $299, but stimulated IUI costs about $446 per treatment cycle (Goverde screen 6). More recent information from 2006 confirms the average cost per cycle in the United States to be between $300 and $700 when the male partner s sperm is used, but those estimates do not include the price of ultrasounds and 21

medication (Pisarska screen 2). In the 2000 study, the costs can be translated into about $4035 per pregnancy for spontaneous IUI and $5108 for stimulated IUI (Goverde screen 6). Besides the variation due to hormone use, the study also compared costs based on maternal age and type of infertility. IUI for couples with idiopathic subfertility ($3019 per pregnancy) was less costeffective than IUI ($2815 per pregnancy) for couples with male factor infertility for women 28 years of age, as one example (Goverde screen 8). The same trend was true for when hormones were used: $4537 compared to $4121 per pregnancy for women 28 years of age (Goverde screen 8). As expected, costs were significantly higher as maternal age increased for both types of infertility. In one specific case, the costs incurred at 38 years of age were 175% of those incurred at 28 years of age (Goverde screen 10). Assisted Reproductive Technologies In Vitro Fertilization is one of the more expensive infertility treatments available. IVF costs are based on the number of cycles. The total cost of IVF varies significantly from one couple to another because it is dependent on the geographical location of the fertility clinic, the amount of medications the woman has to take, the number of cycles she has to undergo, and the amount of money the patient s insurance company will pay towards the procedure. Taking all of the above variables into consideration, in a comparative study conducted by Collins, the projected average cost for an IVF cycle for the year 2002 was $9547 (Collins 268). The study expected one cycle of IVF to cost anywhere between $8129 and $11,385 (Collins 268). These numbers were projected based on the costs of IVF in the preceding years and based on the trends in healthcare cost inflation. For instance, the cost in 1993 was $6233, whereas the cost in 1994 had increased to approximately $7620 per IVF cycle (Collins 268). Even though the most recent 22

costs date back to 2002, it can be seen that based on the trend the cost of one IVF cycle increases on a yearly basis. Since one In Vitro Fertilization cycle consists of different procedures, fertility clinics charge for each of these procedures separately. A full cycle consists of ovarian stimulation, egg retrieval, insemination, fertilization, embryo culture, and embryo transfer. Furthermore, additional costs are charged for initial evaluations, pregnancy tests, medications, and cyropreservation. In an article by the Director of Research at Harvard Business School published in 2006, the author compared the rates of different procedures within IVF for four different fertility clinics (See Table 1). Of the four fertility clinics, two are located in New York, where as the other two are located in Boston and Virginia. The prices for the different procedures vary significantly from one fertility clinic to another. For example, the cost of an initial evaluation ranges from $920-$1410 in the fertility clinic in Virginia, where as, it costs roughly $266 and $300 in the clinics in Boston and New York (Spar 59). Similarly, the cost for cycle stimulation shows discrepancies in the different fertility clinics. The cost for it in one of the fertility clinics in New York is $8900, whereas the cost for it in the second fertility clinic in New York ranges from $2000-$5000. Furthermore, the price for it in Virginia and Boston is $5720 and $2569 respectively; however, the latter includes the costs for pregnancy tests with it (Spar 59). Nevertheless, the total cost for IVF without ICSI approximately ranges from $11000-$15000. It is interesting to note that the total cost per cycle for IVF for the two fertility clinics located in New York vary significantly. While one clinic s total cost is approximately $11600, the other one costs almost $15000, despite being located in the same city. Therefore, in terms of evaluating IVF costs, it is important to compare the costs of the different procedures within IVF across various fertility clinics. 23

Apart from evaluating IVF based on the cost per cycle, the cost effectiveness ratio provides further insight into the cost aspect of IVF. Cost effectiveness ratio expresses the relationship between the outcome and the cost. Essentially, the cost effectiveness ratio, in this context, provides the cost per live birth. Collins projected the average cost per live birth for 2002 based on the same trends that he used to predict the cost per cycle. The anticipated mean average cost per live birth was $58,394 (Collins 270). He projected the cost to range anywhere from $39,688 to $87,788 (Collins 270). Similar to the cost per cycle, the yearly trends of the cost per live birth show that it increases on a yearly basis also. Intracytoplasmic Sperm Injection Little information exists on the variations in cost-effectiveness of intracytoplasmic sperm injection. However, we do know that indications of infertility diagnoses will affect the costeffectiveness of ISCI. For varicocele associated male factor infertility, IVF cost $89,091 per live birth, which includes the cost for initial evaluation, delivery costs, complication costs, and multiple gestation costs and assumes a 33% delivery rate (Honig screen 1). When only considering treatment costs, ICSI costs about $11,667 per delivery (Honig screen 3). This cost was verified by a study from 2006 that states the price of the treatment is between $10,000 and $17,000 per cycle (de Sutter 648). For other types of male infertility such as obstructive azoospermia, the cost per delivery was about $72,521 for ICSI assuming a 33% delivery rate, which further confirms the great variation in costs (Honig screen 4). Additionally, the age of the woman partner will affect cost-effectiveness because age affects success rates in general. As one specific example, for men with obstructive azoospermia with women partners over 37 years of age, the cost per delivery was about $103,940 when assuming an 8% success rate; however, the cost was about $85,061 per delivery for women under 37 years of age (Honig screen 4). 24

ANALYSIS: COSTS With fertility treatments, cost is a very important factor since these procedures are extremely expensive. Therefore, the cost of these treatments plays a significant role in the minds of couples who are deciding their best infertility treatment option. The treatments share many common trends. For instance, the cost per delivery increases as the number of cycles for a woman increases. Similarly, the cost of all of these treatments increases as the woman gets older. Deleted sentence Even though these treatments share commons trends, IVF is significantly more expensive than IUI. The average cost per delivery for IUI is between $7103-7477, which is expensive. However, it is nearly not as expensive as IVF where the cost per cycle ranges from $11000-$15000 and the average cost per delivery is more than $58,394. It is interesting to note here that just the cost per cycle for IVF is significant higher than the cost it takes to deliver a baby through IUI. In terms of ICSI, because of the lower success rates, this procedure is the most cost-ineffective of the three, with costs around $85,000 per live birth. These costs will vary because of the varying success rates for individual infertility problems. Therefore, based on the research currently available, we recommend IUI over IVF and ICSI. FINAL ANALYSIS Based on the analyses of the different treatments with respect to the three criteria, we can defend our claim that Intrauterine Insemination is the more effective infertility treatment. In order to make the above statement, we have to evaluate the importance of our three criteria. The most important criterion is the one that involves the health risks that both the mother and the child can face from a certain infertility treatment. This criterion is more important than either the cost or the success of the treatment because the end goal of all couples going though infertility treatments is to have a normal child and a healthy mother. The health of the mother or the child 25

should be compromised under no circumstances. Therefore, this criterion supercedes the other two criteria. The next important criterion is the success rate of a particular treatment. For obvious reasons, couples only wish to invest their time, money, and energy in treatments that provide results. Hence, there is no point in investing in a treatment that has very low success rates. For this reason, couples should look into success rates of treatment before they decide their course of treatment. Finally, we evaluated costs as our third criteria. Money is a chief concern for infertility treatments because they are so expensive. Hence, couples should consider the costs of these treatments and pick the one that best suits their affordability. Because we ranked health concerns as our top criteria, we chose Intrauterine Insemination as the most effective fertility treatment. Compared to IVF and the variations within IVF, it posed the less serious health risks. However, it has a lower success rate than IVF, but it is also significantly cheaper; hence, it is more accessible to people in terms of cost than IVF. It is important to note that the evidence on cost is slightly skewed since the data does not accommodate for inflation. Through this feasibility report, we have extensively explored this topic of infertility treatments. For infertility being such a common problem, I was extremely surprised by the cost of these treatments. Therefore, this raises the question of whether or not people can actually afford it. Many insurance companies refuse to cover infertility treatments. Hence, the price of the treatment makes it less accessible to the common man. Because fertility treatments are so expensive, it is important to thoroughly investigate the necessity of many of the different parts of the entire procedure, specifically for IVF. One reason why IVF is so costly is because it has so many different parts to it. Since it entails a very extensive procedure, one has to wonder if all of the steps are actually necessary in order to have a successful pregnancy. In a study conducted by Hurst et al., the researchers obtained satisfactory 26