In Vitro Fertilization: Process Definition

Introduction

Assisted reproductive technology has been introduced as a solution to various problems including infertility, alleviation of disease and improvement in the quality of life. Infertility is known to affect about 10% of all couples in the world, leading to psychological stress disorders like depression, social isolation and reduced quality of life. Infertile people had little medical assistance in the past, which led to high levels of risk of their health and lives, by taking part in ambiguous infertility treatment practises (Bavister & Andrews, 1988).

Female infertility is due to a variety of factors including: tuboperitoneal factors, which refers to destruction of the fallopian tubes or scarring of the intraperitoneal due to pelvic infection or surgery which leads to blocking of the oviduct; uvulatory factors originating from the hypothalamic pituitary axis that can be fixed by adjusting one’s behaviour or through hormone therapy; uterine factors such as congenital irregularities; and cervical factors caused by irregularities in the cervical mucus, which can be treated using antibiotics (Bavister & Andrews, 1988).

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Male infertility on the other hand involves irregularities with the semen, such as: azoospermia, caused by testicular failure or blocking of seminal pathways; hypogonadotropic hypogonadism, which is treated via therapy; and prostatitis, which can be treated using anti-inflammatory agents and antibiotics. According to studies, most of the sperm irregularities are untreatable by either medical or surgical means, which necessitate the physician, to identify how many spermatozoa are normal, in the ejaculate of an individual. Such knowledge is vital in finding out the possibilities of pregnancy via artificial insemination. Studies indicated that a number of motile sperms below 1 million resulted in lower chances of pregnancy (Bavister & Andrews, 1988).

According to Ashwood-Smith, Hollands, & Edwards (1989) successful assisted reproduction requires the “harmonization of medical and scientific approach to every couple undertaking a treatment cycle, with close association with doctors, scientists, nurses and counsellors”. Close monitoring is required in every step of the mother’s treatment, in order to ensure that the baby delivered is healthy. “The in vitro fertilization (IVF) laboratory should be provided with viable gametes that are capable of producing healthy embryos, by ensuring appropriate patient section, ovarian stimulation, monitoring and timing of oocyte retrieval” (Ashwood-Smith, Hollands, & Edwards, 1989). The IVF laboratory has the obligation to provide a steady, non-hazardous, pathogen-free setting, with most favourable considerations for oocyte fertilization and embryo development (Ashwood-Smith, Hollands, & Edwards, 1989).

Research on Human in vitro fertilization

Examination of the possibilities of significant situations that provide for fertilization of human oocytes in vitro began a few decades ago. The process showed challenges, due to the complication of its procedures, regardless of the progress on animal reproductive research, that had began much earlier. According to Angell, Templeton, & Aitken (1986) there was still some technological research being required, to provide for the ability to control the oocyte maturation process. Further research was also required to investigate “the ability to retrieve oocytes at a developmental stage appropriate for IVF, the ability to activate sperm in vitro, as well as to define conditions that would provide for fertilization and early embryo development, and lastly a method to allow for the transfer of early embryos back to the uterus of the mother” (Angell, Templeton, & Aitken, 1986).

Studies on animal reproductive physiology were very beneficial in providing the required broad knowledge to alleviate human infertility. Robert G. Edwards, worked at the National Institute for Medical Research in London, in the 1950’s, was very experienced in this field. One of the problems that he encountered was obtaining a method that would provide access to mature oocytes suitable for IVF. He later observed that human oocytes required a whole day of incubation in vitro, before the maturation process could initiate. The next discovery was made in the 1970’s when the researchers observed that the “hormone treatments given to women to induce oocyte maturation disturbed implantation of the embryo in the uterus, causing spontaneous abortions” (Bancsi, Broekmans, Nol, Habbema, & te Velde, 2003). A change of the hormones resulted in a successful pregnancy in 1976, though it had to be terminated since the implantation had occurred in the fallopian tubes (Bancsi, Broekmans, Nol, Habbema, & te Velde, 2003).

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This led them to do away with the ovarian stimulation procedure, and depend on the normal menstrual sequence of the patients, a process that would allow them access to only one egg, in every cycle. The researchers were able to retrieve the egg by laparoscopy before ovulation occurred, leading to the firs normal, fit and healthy baby, in 1978 (Elliot & Elder, 1997).

Further developments of IVF

After the first birth, of a child called Louise Brown, an infertility clinic was founded in Bourn Hall, by Edwards and Steptoe, in Cambridge, UK. Here, successful alterations of the experimental protocols used for hormonal ovarian stimulation and embryo cultivation were made, leading to 1,000 births, by 1986. At this time, other research stations had been started, and there were an equivalent number of births, from the other stations. Studies have indicated that IVF process has resulted in the birth of over four million babies, all over the world (Kurinczuk, Hansen, & C., 2004).

Ivf Procedure

There are many advanced infertility therapies including IVF (In Vitro Fertilization), GIFT (Gamete Intrafallopian Transfer), ZIFT (Zygote Intrafallopian Transfer) and FET (Frozen Embryo Transfer). IVF, GIFT, ZIFT and FET involve the “extraction of a woman’s eggs from her ovaries, processing them with sperm before returning them to the woman, in order to attain pregnancy” (Edwards & Brody, 1995). When returning the eggs, they may either be fertilized or waiting fertilization. “The differences in the techniques involve where the eggs become fertilized, and the duration during the fertilization process before they are returned to the woman’s uterus” (Edwards & Brody, 1995).

The evaluation before IVF for couples includes a semen analysis, assessment of the female reproductive tract and detection of ovulation. There is a wide variation in ovarian responsiveness and fertility at any particular chronologic age, which calls for further tests of ovarian reserve. When there is a reduced ovarian reserve observed when there is reduced ovarian response to medications for ovulation stimulation, there are fewer eggs retrieved, fewer embryos, and a lower pregnancy rate. Most women with unexplained infertility are observed to reduce the ovarian reserve (Edwards & Brody, 1995).

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In the process of IVF, “fertilization of the egg is done via intracytoplasmic sperm injection (ICSI), and then they are allowed to incubate together for a few days in the ivf laboratory” (Jackson, Gibson, Wu, & Croughan, 2004). The fertilized eggs are then returned to the woman’s womb via the cervix, once the physician has ascertained that the woman’s medical history is unlikely to cause any problems for the pregnancy. The IVF process takes about one and a half months, from the beginning of medication to the retrieval of the egg. The response of the woman to medication is monitored before the procedure (Jackson, Gibson, Wu, & Croughan, 2004).

Medication is issued to manipulate the ovaries and the eggs being produced, with a view to getting a few eggs to mature. “The follicles where the eggs are developing are monitored by ultrasound and by measuring the oestrogen levels” (Jackson, Gibson, Wu, & Croughan, 2004). At times, several embryos are transferred, though some are frozen for later use, to increase the probability of pregnancy, while minimizing the threat of multiple pregnancies (Jackson, Gibson, Wu, & Croughan, 2004).

According to Edwards & Brody (1995) most couples readily accept the risk of twins in order to increase the probabilities of pregnancy, irrespective of the risks that this poses. These risks include ‘premature delivery, developmental abnormalities, toxaemia and gestational diabetes among others” (Edwards & Brody, 1995). When there are multiple pregnancies, the couples are encouraged to exercise selective reduction at the age of about ten weeks, where the foetuses are reduced to either two or one. The procedure is dangerous, as it could lead to a miscarriage (Edwards & Brody, 1995).

In preparation for the IVF cycle, the couples are encouraged to watch closely their physical and mental health, both before and during the treatment. Both parties are advised to stay away from smoking and drinking. Women are required to stop caffeine, prior to, and during the tests. The success of a cycle can also be affected by weight, and women should neither be underweight, nor overweight. Women considering pregnancy are advised to take prenatal supplement for several weeks before pregnancy. These contain folic acid, which reduces the incidence of spina bifida (Jackson, Gibson, Wu, & Croughan, 2004).

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Health of the offspring conceived through in vitro fertilization

Follow up studies on children born after IVF showed that these children were as healthy as those born after natural conception. Another discovery was the high frequency of multiple births associated with IVF treatment, as opposed to normal pregnancies, owed to the practise at some infertility clinics of transferring two or more embryos back into the mother. Multiple births led to an increase in the risk for preterm birth, low birth weight, and caesarean sections, aspects that caused both prenatal and post natal health problems. Multiple births incidences have been reduced through regulatory procedures that have encouraged single embryo transfers (Bavister & Andrews, 1988).

Women undergoing IVF treatment have increased risk for preterm, due to the older age of these women. Another reason for the increased risk of preterm was the root cause of their infertility. Research revealed that the use of IVF increased the frequency of two imprinting disorders, namely Beckwith-Wiedemann Syndrome (BWS) and Angel man Syndrome (AS), slightly, though the risk is minimal since the diseases are rare. Other studies reported an increase in the risk of major malformations, causing functional impairment or requiring surgical correction, in children conceived through IVF, though the studies are unreliable due to their numerous limitations, as well as their inappropriate control groups (Strömberg, Dahlquist, Ericson, Finnström, Köster, & Stjernqust, 2002).

Birth Defects

Studies conducted on IVF pregnancies indicated high risk of adverse outcomes as compared to spontaneous pregnancies after adjustment for maternal age and other variables. The risk of these outcomes includes perinatal death, preterm delivery, low or very low birth weight, and delivery of small-for-gestational-age infants. These are about twice that associated with spontaneously conceived singletons. Additional risks include gestational diabetes, placenta previa, preeclampsia, and stillbirth. Inadequate research has been conducted on the causes of these adverse perinatal outcomes, leading to insufficient material on the subject. According to Matson (1998) birth defects are uncommon for most of the babies conceived through IVF, though there are studies indicating that assisted reproductive technology is connected with an high threat of birth imperfections (Matson, 1998).

“In the largest U.S. study, which used data from a state-wide registry of birth defects,28 6.2% of IVF conceived children had major defects, as compared with 4.4% of naturally conceived children matched for maternal age and other factors” (Matson, 1998). According to Matson, there were some birth defects that were increased in the IVF population, such as cardiovascular and musculoskeletal defects, as well as certain birth-defect syndromes (Matson, 1998). An observation of intracytoplasmic sperm injection showed no risk of birth defects over and above that associated with IVF. An increase in the rate of birth defects after IVF was observed, irrespective of the intracytoplasmic sperm injection, though the cause was not identified, though it was found to reflect on ascertainment bias, or problems inherent in the infertile couple, or even the IVF process, itself. Such a case was observed when several syndromes caused by imprinting defects (including the Beckwith–Wiedemann syndrome and Angelman’s syndrome) were reported to be more prevalent among children born after IVF (Matson, 1998).

There were speculations that over-exposure of the embryo to culture medium could present a tendency to imprinting defects, although the number of infants affected would be small. Exact figures could not be attained, leading to the need for further research, on this, as well as to identify the presence of adverse effects of IVF on neurodevelopment outcomes and the long-term health of children, including their reproductive health in adulthood. The ovarian hyper stimulation syndrome was observed to be a short-term consequence of gonadotropin stimulation and early pregnancy. This syndrome, which occurred in less than 5% of IVF cycles, comprised ovarian swelling, pelvic pain, and hemodynamic fluid shifts, often accompanied by ascites. The disorder was observed to resolve after several weeks, although it was fatal in few cases, due to thromboembolism (Venn, Watson, Bruinsma, & Giles, 1999).

Research indicated that there were no definite, long-term adverse effects of IVF on a woman’s health. The high estradiol and progesterone levels caused by ovarian stimulation raised concern about the possible increased risks of breast and gynaecologic cancers. Epidemiologic studies to date have been limited in many cases by small samples and by the fact that most women who have undergone IVF have not yet reached the age of peak cancer incidence; nevertheless, these studies have generally been reassuring. For example, in an Australian study involving more than 20,000 women exposed to fertility drugs, the overall incidence of ovarian, breast, and uterine cancer was no greater than that expected on the basis of age standardized population rates. Although the rates of breast and uterine cancer were higher than expected in the first 12 months after exposure, this increase might have been due to ascertainment bias (Venn, Watson, Bruinsma, & Giles, 1999).

Benefits of IVF

All IVF clinics in the US are required by law to report their outcomes to the Centres for Disease Control and Prevention (CDC), and national and clinic-specific outcomes. A study in the clinical pregnancy rate per cycle for IVF cycles with fresh, non donor eggs was found to be 34%. This implies that in spite of the high rate of efficiency of the procedure in relation to other treatments, a majority of the IVF cycles do not lead to pregnancies. The records show that the rate of live births per embryo transfer in women younger than 34 years ranges from 40-50%, and this rate reduce to 5% when the woman gets to 43 years, with 50% chances of a miscarriage at this age (Purdy, 1982).

IVF with the use of donor eggs from young women is however observed to be quite successful, with little effect based on the age of the recipient. The mean live-birth rate per embryo transfer for donor-egg cycles is approximately 50%, indicating that the reduced rate of pregnancy associated with aging is a direct result of diminished ovarian function and egg quality and is not due to a reduction in endometrial receptivity. The use of cryopreserved embryos may be cost-effective, since ovarian stimulation is not needed. The rate of live births per embryo transfer is lower with cryopreserved embryos than with fresh embryos, indicating some detrimental effect of the cryopreservation and thawing process. In addition to their highly publicized use as a source of stem cells, residual cryopreserved embryos can be donated to other infertile couples (Purdy, 1982).

Risks Of In Vitro Fertilization (Ivf)

The process of in vitro fertilization involves various medications and procedures, and like other medical treatments, there are potential problems. Medication risks could arise from the use of ovarian stimulation medications. The use of injectable gonadotropins could cause ovarian hyper stimulation syndrome, which is quite rare, occurring in less than 1% of women who have egg retrieval with IVF. “Severe hyper stimulation has resulted in dehydration, with large amounts of fluid accumulation in the abdominal and lung cavities, as well as blood clotting disorders. IVF cycles may be cancelled or embryo transfers postponed preventing ovarian hyper stimulation syndrome” (Jackson, Gibson, Wu, & Croughan, 2004).

“Transvaginal egg retrieval is made possible by ultrasound guidance, whereby a long thin needle is passed through the vagina, into the ovary, while the woman is under sedation” (Jackson, Gibson, Wu, & Croughan, 2004). Slight discomfort is experienced, though the injuries such as the bladder, bowel or blood vessels, which could need further surgery, are uncommon. The procedure may also result in some bleeding from the ovary, but not to the extent requiring blood transfusion, as well as infections, though both are extremely rare (Jain, Harlow, & Hornstein, 2002).

The risk of birth defects for children conceived through IVF is not greater than that for normal conception, neither is the rate of pregnancy loss, or miscarriage, which is about 19%. The latter is dependent on the age of the female partner. The risk for tubal pregnancy is about 2%, while that for multiple gestations is more common in women who conceive through IVF, at 25% for twins, and about 5% for triplets and more. An increased risk of premature labour could result in complications of multiple pregnancies. This could also be affected by premature delivery, maternal haemorrhage, caesarean delivery, pregnancy-induced high blood pressure and gestational diabetes (Jain, Harlow, & Hornstein, 2002).

“Stress leads to increased activity of many body organs, offset by hormones that are secreted by the adrenal glands and through the nervous system” (Jain, Harlow, & Hornstein, 2002). It could also lead to sweaty palms and cool clammy skin. It is uncommon for stress to result in infertility, though too much stress in women can alter hormone levels and cause unbalanced ovulation. “Studies conducted on the relationship between stress and infertility have indicated that high stress levels can result in fallopian tube spasm in women and reduced sperm production in men” (Jain, Harlow, & Hornstein, 2002).

According to Jain, Harlow, & Hornstein (2002), studies conducted on the stress levels induced on women by infertility revealed that women under treatment for infertility had high levels of stress, similar to those of other women with fatal illnesses like cancer. Couples that are infertile also showed chronic stress due to their hope for conception, and later due to the disappointment for their inability to do so. Infertility causes stress for most couples since one of their combined goals is parenthood. Most people also work hard to get things, though fertility cannot be attained this way. This causes a reduction in the intimacy between couples, in addition to the stress caused by infertility testing and treatments, physically, financially and even emotionally (Jain, Harlow, & Hornstein, 2002).

Studies conducted on the effects and causes of stress in couples with infertility also revealed some remedies for the stress, including: maintaining open lines of communication between partners; seeking emotional support to avoid the feeling of isolation, as from counselling, support groups or specific books; learning stress reduction techniques like yoga or meditation; regular exercises to release physical and emotional tension; having a comfortable medical treatment plan for the partners; and learning the most that the couple can, on infertility and available treatment options (Jackson, Gibson, Wu, & Croughan, 2004).

Alternatives to IVF

Although the optimal strategy for treating infertile couples may not always clear, the annual rate of spontaneous conception among infertile couples referred for IVF is between 3 and 13%. According to Strömberg, Dahlquist, Ericson, Finnström, Köster, & Stjernqust (2002) aappropriate treatments for a couple with unexplained infertility include intrauterine insemination and ovulation induction, either alone or in combination. An example is intrauterine insemination, which is a treatment timed to coincide with ovulation, whereby freshly ejaculated semen is processed and concentrated in the laboratory and then injected through the cervix into the uterus. These treatments are less costly and more cost-effective than IVF; however, the pregnancy rates associated with these methods (typically between 5 and 15% per cycle) are much below those attained with IVF (Strömberg, Dahlquist, Ericson, Finnström, Köster, & Stjernqust, 2002).

Couples who seek treatment for infertility are focused on having a child of their own, without having to adopt one. The first step for the physician approached by such a couple is to identify the root of the problem before proposing a remedy. Alternatives to IVF include artificial insemination, ovarian stimulation and timed intercourse, with studies conducted by the World Health Organization indicating that spontaneous pregnancies account for about 15% of the pregnancies during an infertility work up. The rate was observed to increase to 20%, which was an indication of the vital role of investigations before diagnosis of infertility cases (Elliot & Elder, 1997).

Further investigations were conducted on the spontaneous pregnancies as an alternative to IVF, which occurs during investigation of infertility in the couples. The success of these pregnancies was attributed firstly to variability of the monthly fecundability of the women due to age. The fecundability of women was observed to decrease with age, whereby women in their late thirties or older may become pregnant after continuous unprotected intercourse for a period of several months. The investigations for infertility in couples are usually conducted for a period of one year, after which unsuccessful conception would imply infertility. The success of the pregnancies was also observed to be dependent on the variability of an individual couple’s fertility. Men for instance were observed to have temporary irregularities in sperm quality due to stress, illness or medical treatment, while the women had irregular ovulation. Other factors influencing spontaneous pregnancies are sub fertility in one or both partners, and counselling of the couple by a skilled physician (Jain, Harlow, & Hornstein, 2002).

Ethical concerns

Edwards realized the ethical issues that would be raised by IVF research, and he therefore, wrote a paper were he presented his views that research on human germ cells and embryos should be carried out under stern ethical directives. This led to the creation of an ethics committee for IVF, to deal with the strong opposition from religious leaders, who argued that it was morally wrong. Government officials on the other hand were opposed to IVF, since they believed that fertility should be limited, instead of treating it, while scientists criticized the safety of the procedure. In spite of all the opposition, Edward was steadfast in fulfilling his scientific vision (Thurin, Hausken, & Hillensjö, 2004).

Conclusion

Research on the prevalence of unexplained infertility found an average of 10% of the cases, which can be treated using medication such as clomiphene and placebo. The former treatment was observed to result in pregnancy after several treatments, complemented by insemination combined it ovarian stimulation. For couples seeking pregnancy using means that are not natural, the choice for medical treatment or IVF depends on a variety of factors, with cost being a significant factor. The IVF procedure, for instance is very expensive, and its chances of yielding pregnancy or complications arising from the procedure are similar to those of other treatments (Strömberg, Dahlquist, Ericson, Finnström, Köster, & Stjernqust, 2002).

The research and documentation of all cases involving IVF, which is a requirement by the CDC, provides confidence to couples since the statistics can show their chances of attaining pregnancy, once the tests have been conducted. On the positive side, in Vitro Fertilization has been observed to work where other treatments have failed, making the risk of trying the treatment worthwhile.

References

Angell, R. R., Templeton, A. A., & Aitken, R. J. (1986). Chromosome studies in human in vitro fertilisation. Human Genetics , 72: 333- 339.

Ashwood-Smith, M. J., Hollands, P., & Edwards, R. G. (1989). The use of Albuminar (TM) as a medium supplement in clinical IVF. Human Reproduction , 4: 702-705.

Bancsi, L. F., Broekmans, F. J., Nol, B. W., Habbema, J. D., & te Velde, E. R. (2003). Performance ofbasal follicle-stimulating hormone in theprediction of poor ovarian response andfailure to become pregnant after in vitrofertilization: a meta-analysis. Fertil Steril , 79, 1091-1100.

Bavister, B. D., & Andrews, J. C. (1988). A raid sperm motility bioassay procedure for quality control testing of water and culture media. Journal of In Vitro Fertilization and Embryo Transfer , 5: 67-68.

Davidson, A., Vermesh, M., Lobo, R. A., & Paulsen, R. J. (1988). Mouse embryo culture as quality control for human in vitro fertilization: the one-cell versus two-cell model. Fertility and Sterility , 49: 516-521.

Edwards, R. G., & Brody, S. A. (1995). Human fertilization in the laboratory. Philadelphia: W. B. Saunders & Co.

Elliot, G. T., & Elder, K. (1997). Blastocyst culture, transfer, and freezing. Australia: Ladybrook Publishing.

Jackson, R. A., Gibson, K. A., Wu, Y. W., & Croughan, M. S. (2004). Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol , 103, 551-563.

Jain, T., Harlow, B., & Hornstein, M. (2002). Insurancecoverage and outcomes of in vitrofertilization. N Engl J Med , 347, 661-665.

Kurinczuk, J. J., Hansen, M., & C., B. (2004). The risk of birth defects in children born after assisted reproductive technologies. Curr Opin Obstet Gynecol , 16:201-209.

Matson, P. L. (1998). Internal and external quality assurance in the IVF laboratory. Human Reproduction Supplement 13 , 4, 156-165.

Purdy, J. (1982). Methods for fertilization and embryo culture in vitro. London: Academic press.

Strömberg, B., Dahlquist, G., Ericson, A., Finnström, O., Köster, M., & Stjernqust, K. (2002). Neurological sequelae in children born after in-vitro fertilisation: a population based study. Lancet , 359, 461-465.

Thurin, A., Hausken, J., & Hillensjö, T. (2004). Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med , 351, 2392-2402.

Venn, A., Watson, L., Bruinsma, F., & Giles, G. H. (1999). Risk of cancer after use of fertility drugs with in-vitro fertilisation. Lancet , 354, 1586-1590.

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