In Vitro Fertilization - Term Paper Example

In Vitro Fertilization Outline Definitions 2. Normal reproduction 3. Causes of infertility 3 Causes of infertility in men 3.2.Causes of infertility in women 4. Etiology of infertility 5. History of IVF 6. Indications for IVF 7. Procedure of IVF 7.1. Ovarian stimulation 7.2. Follicular aspiration 7.3. Classification of oocyte 7.4. Sperm preparation 7.5. Oocyte insemination 7.6. Culture of the embryo 7.7. Transfer of embryo 7.8. Managing the luteal phase 8. Other reproductive techniques 9. What are the chances of getting pregnant after IVF? 10. Is IVF safe for the baby? 11. Chances of multiple births and ectopic pregnancy in IVF 12. Artificial Sex Selection in Fertility Clinics 13. Cost of IVF 14. Ethical, social and legal issues in IVF 15. Conclusion Definitions Retrieval of preovulatory oocyte from the ovary and fertilizing it with a sperm in vitro in the laboratory and then transferring the embryo into the endometrial cavity of the woman in known as in vitro fertilization or IVF. IVF is one of the several artificial reproduction techniques that modern science had developed for infertility. Lack of pregnancy after one year of unprotected intercourse is known as infertility. 15% of the couples in the reproductive age have infertility (Garcia and Nelson, 2006). Normal reproduction Normal reproduction requires integrity and interaction between the female and male reproductive tracts. There must be normal release of preovulatory oocyte, adequate spermatozoa in the male must be present, the gametes must be transported normally to the place of fertilization, the ampullary portion of the fallopian tube and, after fertilization the cleaving embryo must be transported to the endometrial cavity where the embryo implants and develops further. Causes of infertility Multiple factors contribute to fertility. 32% of infertility cases are due to female factors while 18.8% of the cases can be accounted to male factors. Combined cause of infertility is seen in 18.8% cases. In about 11.1%, the etiology is unknown and causes other than male or female factors are seen in 5.6% (Garcia and Nelson, 2006). Causes of infertility in men: Impaired production of sperm or impaired function due to asthenopermia, oligospermia and azoospermia contribute to infertility. Impaired production of sperms can occur in varicocele, undescended testis, male hypogonadism, certain genetic defects like Klinefelters syndrome. Repeated bouts of sexually transmitted diseases can also cause infertility. In many cases, there may be no cause for reduced sperm production. Impaired delivery of sperms as in sexual issues like erectile dysfunction, premature ejaculation, dyspareunia and psychological conflict can lead to infertility. Retrograde ejaculation, blockage of epididymis or ejaculatory ducts, hypospadias and cystic fibrosis can affect delivery of sperms and thus cause infertility. Emotional stress, malnutrition, severe illness, obesity, increased age, consumption of illicit drugs and other health-related conditions can contribute to infertility (Mayoclinic, 2007). Causes of infertility in women: In women, blockage of fallopian tubes, endometriosis, hyperprolactinemia, polycystic ovarian disease, premature ovarian failure, ovulation disorders, benign uterine fibroids and pelvic adhesions lead to infertility. Another important factor contributing to infertility in women is thyroid disorders. Etiology of infertility 1. Pelvic inflammatory disease or PID: Chalmydia and gonorrhea are important causative factors for PID and tubal obstruction. The damage to the fallopian tubes after the first episode is 34% and after the subsequent episodes is 54% (Garcia and Nelson, 2006). 2. Endometriosis: Endometriosis is seen in 26% of cases of infertility (Garcia and Nelson, 2006). Severe endometriosis causes adhesions and damage the fallopian tubes and the ovaries. Mild-to-moderate endometriosis also contributes to infertility because of increased phagocytosis of sperm, decreased binding of the sperm to zona pellucida, increased proliferation of the peritoneal lymphocytes, increased levels of cytokinin, increased production of immunoglobulin, production of embryonic toxic serum and defective activity of natural killer cells. Certain ovulatory disorders like luteinized unruptured follicle, oligo-ovulation and luteal phase deficiency are associated with endometriosis. 3. Occupational and environmental factors: Excessive exposure to heat can contribute to infertility. Also, excessive exposure to microwave radiation, lead and other heavy metals and pesticides is associated with male infertility. 4. Smoking: This factor is associated with infertility in both males and females. Nicotine and certain polycyclic aromatic hydrocarbons block spermatogenesis and decrease the size of testicles. In women, nicotine alters the quality of cervical mucus and the cilial epithelium, thus affecting gamete transport. 5. Substance abuse: In women, marijuana and its metabolite delta-9-tetrahydrocannabinol cause infertility by inhibiting the secretion of leutinizing hormone and follicle- stimulating hormone. In men, marijuana decreases the count and quality of sperms. Consumption of alcohol in men delays sexual response and decreases the synthesis of testesterone, affecting sperm concentration. In females, chronic alcoholism predisposes to certain ovulatory disorders (Garcia and Nelson, 2006). 6. Exercise: Jogging stimulates endorphin production and excessive endorphin production is detrimental to the normal production of follicle stimulating hormone and leutinizing hormone. 7. Obesity: Excessive weight gain in women does affect fertility to some extent. 8. Anorexia nervosa: In this condition, hypothalamic amenorrhea is induced which affects fertility. 9. Advanced age: As the age increases, infertility chances also increase in both men and women. 10. Too much caffeine intake (Mayoclinic, 2007) increases the chances of infertility. History of IVF In vitro fertilization or IVF was first achieved in animals in the 1950s. Since then, for several decades, scientists have been using IVF in the field of animal husbandry and cattle breeding (Dukelow, 1984). However, deficient understanding of the development of human embryo and special metabolic needs of the human embryo delayed the use of IVF in humans (Garcia and Nelson, 2006). The first successful IVF human birth occurred in 1978 and since then many IVF clinics have come up world wide. Pioneers in the field of human IVF are Edwards and Steptoe (Garcia and Nelson, 2006). The first scientist to extract an intact fertilized egg was John Rock (The New Yorker Archive, 2000). The first test tube baby was born in 1978. His name is Louise Brown. The Monash team reported the first IVF pregnancy in humans. This was reported in The Lancet in the year 1973. This pregnancy lasted only a few days. Louis Brown was born after successful IVF by Steptoe and Edwards. In the earlier days, clomiphene and hCG were used to control and time oocyte maturation. Later, FSH was incorporated to improve stimulated cycles. The next step forward was the use of gonadotrophin-releasing hormone agonists and antagonists. These drugs prevent premature ovulation and thus increase the need for monitoring. Currently embryos can be freezed and then thawed, improving the effectiveness of IVF. In 1992, Andre van Steirtegham achieved intracytoplasmic injection of single sperms, a hope for those with severe oligospermia. Indications for IVF Absolute indications for IVF are absence of fallopian tubes and presence of severe pelvic adhesions. Other indications include unsuccessfully treated endometriosis, malformation of the uterus due to DES exposure, husbands with oligospermia or obstructive azoospermia and infertility of unknown cause. Procedure of IVF The following are the steps in IVF: 1. Ovarian stimulation: It is important to stimulate ovaries to increase the number of oocytes so that increased number of embryos can be developed. Ovarian stimulation can be done either by drugs, hormones or a combination of both as described below. Clomiphene citrate or CC: CC-only protocol consists of 5 to 7 days of taking 50- 150 mg of the drug starting on the 2nd day of menstrual cycle. Pelvic sonography and serum E2 and LH levels are used to monitor the ovarian response. Once the follicle diameter reaches 18mm, serum LH levels are measured every 3-4 hours to detect preovulation LH surge. Retrieval of the oocyte must be planned 24 to 26 hours after the LH surge. Though CC protocol involves low cost and absent risk of ovarian hyperstimulation syndrome, it is now not preferred for IVF because of low oocyte yield, frequent LH surges, high cancellation rate and low pregnancy rate (Garcia and Nelson, 2006). Combination of CC and human menopausal gonadotropins: In this protocol, along with CC, 150 IU of hMG is administered 4 times a day for 2- 7 days after CC. Pelvic sonography and daily assessment of E2 levels are done. Once the follicular size reaches 15mm, frequent assessment of LH levels are done and once the follicle reaches 17- 18mm, 10,000 IU of hCG is administered intramuscularly to complete oocyte maturation. Aspiration of the oocyte must be done about 35 hours after administration of hCG. In this protocol, the number of follicles recruited is increased. However, it has some disadvantages like premature luteinization, high rate of cancellation and in 25% to 50% of cases; spontaneous LH surge is also seen (Garcia and Nelson, 2006). Human menopausal gonadotrophins: In hMG -only protocol, either pure FSH or a combination of LH and FSH can be used. The dosage of these hormones varies between 150- 452 IU per day depending on the age of the woman and previous history of ovulatory response. Response is monitored like for any other protocol with pelvic ultrasound, E2 levels and LH surge detection. Once the follicles reach 17- 18 mm in diameter, hMG is stopped and the patient is given 10,000IU of hCG that day evening. 35 hours later oocyte is retrieved. This protocol has a cancellation rate of 25%. Some patients may respond poorly due to poor ovarian reserve (Garcia and Nelson, 2006). GnRHa agonists: These are used as per 2 protocols: Modified Flare- up protocol: Birth control pills are given between 4 to 21 days during the menstrual cycle preceding the scheduled IVF. Then, starting on day 1 of menstrual cycle, leuprolide acetate, a GnRHa agonist is given subcutaneously twice a day. From the fourth day onwards, recombinant FSH is given (Garcia et al, 1990). Luteal-phase protocol: Leuprolide is started on the 17th or 21st day of previous menstrual cycle. Administration of gonadotrophins can then be started on the second day of menstruation (Marci, 2001). Both these protocols lead to improvement in the IVF because of increased quality, number and synchronization of the oocytes that are recovered in each cycle (Garcia, 1990). Also, since there is more number of embryos, they can be cryopreserved and used for future embryo transfers. However, there are some disadvantages like increased expenditure, increased requirements of gonadotrophins, ovarian hyperstimulation syndrome and high risk for multiple pregnancies. GnRHa antagonists : These are drugs like cetrorelix and ganirelix which block the secretion of LH without flare up effect (North American Ganirelix Study Group, 1999). They can be administered in many ways. These drugs can either be given as a single dose on the 8th day of menstruation, or can be given in small amounts over 4 days from the seventh day of menstrual cycle. They can also be given when the follicle size reaches 14mm or when LH levels in the serum touches more than 10mIU/ml.The advantages with these drugs are absence of spontaneous LH, requirement of smaller doses of gonadotrophins or ovarian stimulation and prevention of ovarian hyperstimulation syndrome. Also, since the half-life of these drugs is short, leuprolide can be used to elicit preovulatory surge, thus avoiding the long-term side effects of hCG injection. 2. Follicular aspiration This procedure is undertaken 35- 36 hours after the administration of hCG. Currently follicular aspiration is done transvaginally under ultrasound guidance. The patient is placed in the dorsal lithotomy position after catherizing the bladder and preparing the vaginal wall. Then the ovaries and follicles are localized using a 5- to 7-MHz ultrasonographic probe that is inserted into the vagina. A 17-guage needle is then passed into the ovaries through the vaginal fornix and fluid is aspirated. This fluid is then sent to the IVF in a sterile way. This type of follicular aspiration does not require general anesthesia and can be under heavy sedation. There is no need for creating a carbon-monoxide pneumoperitoneum. There is no risk of bowel injury. Also, oocyte retrieval is possible even in those with frozen pelvis. Rarely, damage to pelvic vessels may occur (Howe et al, 1988). 3. Classification of oocyte This is the most crucial step for the success of IVF. The follicular fluid is examined under a microscope and the oocytes retrieved are studied based on the appearance of corona- cumulus complex. Presence of polar body indicates metaphase second stage and presence of germinal vesicle indicates prophase, both of which are indicators for preincubation time prior to contact with sperms. Only such oocytes are selected and presented. 4. Sperm preparation Just prior to the retrieval of the oocyte, semen sample is obtained from the male after abstinence for about 3 to 5 days. From this sample, unnecessary biological substances like cellular debris, leukocytes, seminal fluid and abnormal sperms are removed and motile fraction of the sperm is retained. This can be done by either running the semen through gradient system or by successive media washes. After this, sperms are incubated in 5% carbondioxide atmosphere and the supernatant containing motile fraction of sperm is extracted and concentrated to 50,000 motile sperms per ml. 5. Oocyte insemination The concentrated sperm sample is added to the oocytes which have been retrieved. 6. Culture of the embryo The inseminated oocytes are now incubated in a 5% carbondioxide atmosphere with 98% humidity. Fertilization is determined by presence of 2 pronuclei and extrusion of a second polar body. Whether fertilization has occurred or not can be determined about 18 hours after insemination. The fertilized oocytes are called embryos. These are transferred into growth media and then placed into incubator. After 36 to 48 hours after insemination, a 4 to 8 cell stage may be observed. After 48-72 hours, a 10 to 16 cell stage may be seen. Morula or blastocyst is seen after 96- 120 hours (Garcia and Nelson, 2006). 7. Transfer of embryo The most common method used to transfer the embryo into the uterus of the mother is transabdominal ultrasonography- guided transcervical transfer. This is done 42- 72 hours after oocyte insemination. While transferring, the embryo should be loaded with 30 microliter of culture media. After embrotransfer, the patient must take bed rest for 30- 60 minutes. 8. Managing the luteal phase Luteal phase is managed with exogenous progesterone supplementation to the mother. This is started 72 hours after oocyte retrieval. Supplementation is essential because aspiration of granulosa cells at the time of oocyte retrieval may cause and abnormal hormone environment. Progesterone is given for 2 weeks and if pregnancy test in the woman is positive, the hormone is continued until 8 weeks of gestation, after which placental progesterone takes over. Other artificial reproduction technique Zygote intrafallopian transfer, gamete intra fallopian transfer, embryo cryopreservation and assisted fertilization techniques like assisted hatching, partial zona dissection, subzonal sperm injection and intracytoplasmic sperm injection. What are the chances of getting pregnant after IVF? Each clinic has its own success rates. According to the CDC (2003), the overall pregnancy rate per intiated cycle is 34.3%. Also, live births per initiated cycle is 28.3% and live births per oocyte retrieval is 32.6%. Is IVF safe for the baby? According to the CDC (2003), the incidence of abortions, stillbirths, congenital malformations and chromosomal abnormalities in the babies born through IVF is similar to the general population. However, the National Birth Defects Prevention Study- 2008 has a different opinion. This study was conducted by Reefhuis et al (2009) who reported that children born out of IVF had increased risk of some birth defects like cleft lip, cleft palate, septal heart defects, esophageal atresia and anorectal atresia. Chances of multiple births and ectopic pregnancy in IVF It has been estimated that the chances of ectopic pregnancy after IVF is slightly higher than the general population at 0.7% (CDC, 2003). In some cases, the ectopic pregnancy was heterotopic. The incidence of multiple births is 35.4% and mainly twins. This is very high when compared to the incidence in general population which is 3%. Artificial Sex Selection in Fertility Clinics Since sperms are brought out in IVF and the sex of the embryo is based on the chromosomes in the sperms, it is possible to select the sex of the baby in IVF. Currently, there are 3 methods of sex selection: 1. Gradient method. The sperms are spinned in a centrifuge at high speeds. Since X-chromosome sperms are heavier, they fall into the lower portion of the centrifuge tube. Thus X and Y chromosome sperms can be separated. 2. Flow cytometry: This method employs a fluorescent dye which adheres to the genetic material in the sperm. X-bearing sperms contain more genetic material and hence pick up more dye. 3. Preimplantation Genetic Diagnosis: This is the most successful method of gender selection. In this method, the embryos are analyzed for cell structure and DNA and only the embryo with the desired sex will be implanted into the uterus of the mother (Harper, Delhanty, and Handyside, 2001). Cost of IVF The costs of IVF vary from country to country and clinic to clinic. For example, in Chicago, the Advanced fertility Center of Chicago charges $9500 per cycle of IVF which includes ovarian stimulation monitoring, anesthesia for egg retrieval, the actual procedure of egg retrieval, fertilization and culture of the eggs, embryo transfer, physician charges, IVF lab charges and facility fees. However, medications, prescreening tests, cryopreserrvation of embryo and sperms, pregnancy testing, pregnancy monitoring and consultation charges are not included in this package. The preIVF tests would approximately cost $600 and medications can cost anywhere between $1500- $ 4000. (Advanced Fertility Center of Chicago, 2009). Ethical, social and legal issues in IVF In the early days of development of this technique, on one side there was hope to those who feared would never have children, and on the other side, there were many doubts about the normalness of the baby born through the procedure. However, now, as it is established that the baby is likely to be as normal as any other baby born by natural conception, more and more infertile couples are opting for this procedure. Now the concerns have shifted to legal, ethical and religious issues. While many couples undergo IVF with their sperm and oocyte, some of them may have to adopt outside sperm or oocyte. The latter situation arouses many issues, especially religiously and socially. Some religions do not accept reproductive technology because it separates conjugal act from procreative act. This form of birth is seen as unnatural and a form of threat to the integrity of the family. Some argue that when the whole world is highly populated, those who cannot beget children through natural means should adopt rather than struggle to have their own children. Also, considering the cost of IVF, some societies wonder if it is worth all the trouble. On the ethical side, there are issues if it is proper to retrieve oocytes and treat those (Coutts, 1988). Doctors also face many ethical and legal issues when they produce multiple embryos and cause multiple pregnancy and its consequences. Also when there are many good embryos produced from a single couple, what to do with the unused ones is a major ethical problem: whether to donate them to someone else, whether to freeze them for future use in case this pregnancy does not happen or whether to discard them (Coutts, 1988). Such and other major issues entangle the procedure of IVF. Conclusion IVF is an artificial reproductive technique that is used to treat infertility of certain causes. It is a costly procedure and involves lot of effort both from the baby-desiring couple and the team of reproductive specialists. The success rate varies from clinic to clinic. Many couple may have to go through more than one cycle. Most of the research oriented literature has regarded this procedure as safe to both the baby and the mother with no rise in congenital abnormalities. This technique has many cultural, ethical, legal and social issues entangling it. Whatever may be the disparities, IVF has given hope to those who lost hope of having a biological child. References Advanced Fertility Center of Chicago. (2009). IVF costs. Retrieved Feb 25, 2009 from http://www.advancedfertility.com/ivfprice.htm Centers for Disease Control and Prevention (CDC), National Center for Chronic Disease Prevention and Health Promotion. (2003). Assisted Reproductive Technology Reports. 2001 Assissted Reproductive Technology Success Rates. Atlanta, Ga; Centers for Disease Control and Prevention. Coutts, M. C. (1988). Ethical Issues in In Vitro Fertilisation. National Reference Center for Bioethics Literature. Retrieved Feb 25, 2009 from http://72.14.235.132/search?q=cache:l9jziU_tCikJ:bioethics.georgetown.edu/publications/scopenotes/sn10.pdf+economic,+legal,+religious,+ethical+social+health+issues+IVF&hl=en&ct=clnk&cd=3&gl=in Dukelow, W.R. (1984). Invitro fertilization and preimplantation devlopment in the primate. J. Biosci., 6(2), 83- 91. Garcia, J.E. and Nelson, L.M. (2006). Infertility. Emedicine from WebMD. Retrieved Feb 25, 2009 from http://emedicine.medscape.com/article/274143-overview Garcia, J.E, Padilla, S.L., Bayati, J., Baramki, T.A. (1990). Follicular phase gonadotropin-releasing hormone agonist and human gonadotropins: a better alternative for ovulation induction in in vitro fertilization. Fertil Steril., 6, 22-28. Harper, J.C., Delhanty, J.D.A., and Handyside, A.H. (2001). Preimplantation Genetic Diagnosis. London: Wiley Interscience Howe, R.S., Wheeler, C., Mastroianni, L. Jr., et al. (1988). Pelvic infection after transvaginal ultrasound-guided ovum retrieval. Fertil Steril., 49(4), 726-8. North American Ganirelix Study Group. (1999). Results of a prospective, randomized, multicenter study to assess the efficacy and safety of a gonadotropin releasing hormone (GnRH) antagonist- Org 37462 (Ganirelex Acetate) treatment in women undergoing controlled ovarian hyperstimulation (COH). Fertil Steril, 6, 22- 28. Marci, R., Senn, A., Dessole, S., et al. (2001). A low-dose stimulation protocol using highly purified follicle- stimulating hormone can lead to high pregnancy rates in in vitro fertilization patients with polycystic ovaries who are at risk of a high ovarian response to gonadotropins. Fertil Steril., 75(6), 1131-5. Mayoclinic. (2007). Infertility. Retrieved Feb 25, 2009 from http://www.mayoclinic.com/health/infertility/DS00310/DSECTION=causes Reefhuis, J., Honein, M.A., Schieve, L.A., Correa, A., Hobbs, C.A., Rasmussen, S.A.; National Birth Defects Prevention Study. (2009). Assisted reproductive technology and major structural birth defects in the United States. Hum Reprod., 24(2), 360-6. The New Yorker Archive (2000). John Rocks Error. Annals of Medicine. Retrieved Feb 25, 2009 from http://www.gladwell.com/2000/2000_03_10_a_rock.htm Read More