Tales from the first trimester
The history of IVF
35 years of human-assisted reproduction from 1973 to 2008
The first pregnancy achieved following invitro human fertilisation of a human oocyte was reported in The Lancet from the Monash team in 19731, although it only lasted a few days and would today be called a biochemical pregnancy.
This was followed by a tubal ectopic pregnancy from Steptoe and Edwards in 1976, resulting from the successful partnership with Bob Edwards which resulted in the birth of Louise Brown in 19782 and another unnamed birth from Oldham, the world’s first IVF babies. This was followed by the birth of Candice Reed in Melbourne in 3 Prof Gab Kovacs AM 1980. It was the subsequent use of stimulated cycles with clomiphene FRANZCOG citrate and the use of human chorionic gonadotrophin (hCG) to control and time oocyte maturation, thus controlling the time of collection, that converted IVF from a research tool to a clinical treatment.4 This was followed by a total of 14 pregnancies resulting in nine births in 1981 with the Monash university team.5 The Jones team in Norfolk, Virginia, further improved stimulated cycles by incorporating the use of a follicle stimulating hormone (uHMG).6 This then became known as controlled ovarian hyperstimulation (COH). Another step forwards was the use of gonadotrophin releasing hormone agonists (GnRHA), thus decreasing the requirement for monitoring by preventing premature ovulation, and more recently gonadotrophin releasing hormone antagonists (GnRH Ant), which have a similar function. The additional use of the oral contraceptive pill has allowed the scheduling of IVF cycles, which has made the treatment far more user-friendly both for staff and patients. The ability to freeze and subsequently thaw and transfer embryos has also significantly improved the effectiveness of IVF. The other very significant milestone in IVF was the development of the intra cytoplasmic sperm injection of single sperms by Andre van Steirtegham in Brussels,1992. This has enabled men with minimal sperm production to achieve pregnancies, sometimes in conjunction with sperm recovery, using a testicular fine needle or open testicular biopsy, with some men even with kleinfelter’s syndrome occasionally achieving pregnancy. Thus, IVF has become the final solution for most fertility problems, moving from tubal disease to male factor, idiopathic subfertility, endometriosis, advancing maternal age, and anovulation not responding to ovulation induction. How do we improve IVF treatment further? During the last 25 years we have seen a steady increase in pregnancy rates as result of IVF from ‘across the board’, with pregnancy rates of 15 per cent
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Tales from the first trimester
per embryo transfer in the 1990s to 35 per cent today, despite a steady reduction in the number of embryos transferred. Much better pregnancy rates can be produced for certain subgroups. There has been a very steady move to reduce the number of embryos transferred and thus avoid multiple pregnancies. Triplets have virtually disappeared as it is now the recommendation of the Fertility Society of Australia that no more than two embryos should be transferred. There is now a very strong move to replace only one embryo at a time, especially for women under 40, thus avoiding twins. This will become virtually universal with the ability to select the embryo with the best potential to implant. One of the strategies to improve selection, albeit still on morphological appearance, is the technique of extended culture to the blastocyst stage. This enables the best growing embryo to be transferred, improving the chance of conception. There are two exciting techniques being researched further at Monash IVF to improve selection of the embryo most likely to implant. The first is the study of a number of candidate genes which determine implantation. Embryos are biopsied and the genes analysed retrospectively by a micro-array technique to determine which are associated with successful outcome. Another project to try and select viable embryos is to spectroscopically study the culture medium in which they grow, again identifying patterns associated with subsequent successful outcome. Identifying such markers would also aid in selection of the embryo most likely to implant. As the final barrier is that the endometrium should be receptive, much effort is also being placed into the analysis of the endometrium, to again identify which patterns are associated with likelihood of success. Histological and morphometric assessment has not been very helpful and techniques of proteomic analysis are now being developed. With these developments, it will be possible to select the embryo with the highest potential for implantation to be transferred, possibly raising pregnancy rates well above 50 per cent per single embryo transfer. The other exciting development is the new technique for blastocyst freezing. A recent modification of the vitrification technique for freezing blastocysts at Monash IVF, in Melbourne, has resulted in pregnancy rates of 50 per cent per embryo transfer in the first 200 cycles. This means that a woman will have an excellent chance of becoming pregnant from one stimulated cycle and its associated frozen embryo transfer(s). The final change we have to make in Assisted Reproductive Technology (ART) treatment is to make it more user-friendly. Gone are the days from the early 1980s where a woman had to be hospitalised for ten days to have treatment. using the pill down regulation regimen, most women can be managed with two blood tests and one ultrasound. With recent modification of the ultra-short pill down regulation protocol which we have trialled at Monash IVF, the stimulation phase can be shortened to three weeks, therefore decreasing the inconvenience. using the flex-short modification of the stimulation, the woman can even be involved in the approximate timing of her oocyte collection. Finally, thanks has to be expressed to our government for supporting the funding of ART. With the introduction of appropriate item numbers for IVF and recently ICSI, the provision of the World’s Best Hormones for COH, IVF has never been more affordable or more successful. Three percent of Australian babies born are now conceived by ART. Thus, every class in primary school will have an IVF baby in it. We have come a long way in the last 30 years since Louise Brown was conceived in November, 1977. IVF has also had some spin-offs for patients who do not have subfertility. The most important has been the development of pre-implantation genetic diagnosis (PGD). By 2003 and follow-up of the pregnancies and babies born up until October 2004, for which the latest data is available7, 50 centres participated, reporting on 2984 cycles, 501 pregnancies and 373 babies born. 529 cycles were reported for chromosomal abnormalities, 516 cycles were reported for monogenic diseases, 137 cycles for sexing for X-linked diseases, 1722 cycles for pre-implantation genetic screening (PGS) and 80 cycles were reported for social sexing. Another rare but very useful possible use of PGD is HLA testing in combination with PGD to produce immunologically similar siblings, in conjunction with avoiding a genetic disease, and thus enabling. The umbilical cord blood from the ‘saviour’ sibling can then be used to treat the effected sibling.
References 1. De kretzer D, Dennis P Hudson B, Leeton J, Lopata A, Outch k, Talbot J, , Wood C. Transfer of a Human Zygote. Lancet. 1973; ii: 728-729. 2. Edwards RG, Steptoe PC, Purdy JM. Establishing full-term human pregnancies using cleaving embryos grown in vitro. Br J Obstet Gynaecol. 1980;87:737-56. 3. Lopata A, Johnston IW, Hoult IJ, Speirs AI . Pregnancy following intrauterine implantation of an embryo obtained by in vitro fertilization of a preovulatory egg. Fertil Steril. 1980;33:117-20. 4. Trounson AO, Leeton JF, Wood C, Webb J, Wood J. Pregnancies in humans by fertilization in vitro and embryo transfer in the controlled ovulatory cycle. Science. 1981;212:681-2. 5. Wood C, Trounson A, Leeton J, Renou P Walyerts W AW et al, Clinical , features of eight pregnancies resulting from in vitro fertilization and embryo transfer. Fertil Steril. 1982;38:22-29. 6. Jones HW Jr, Jones GS, Andrews MC, Acosta A, Bundren C, Garcia J, Sandow B, Veeck L, Wilkes C, Witmyer J, Wortham JE, Wright G. The program for in vitro fertilization at Norfolk Fertil Steril.1982;38:14-21. 7. Sermon kD, Michiels A, Harton G, Moutou C, Repping S, Scriven PN, Sen Gupta S, Traeger-Synodinos J, Vesela k, Viville S, Wilton L, Harper JC. ESHRE PGD Consortium data collection VI: cycles from January to December 2003 with pregnancy follow-up to October 2004. Hum Reprod. 2007 Feb;22(2):323-36. Epub 2006 Nov 28.
Magazine Autumn
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Vol 9 No 4 Summer 2007