In Vitro Fertilization The First Three Decades

Pregnancy Miracle

The Pregnancy Miracle Book

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Jean Cohen

International Federation of Fertility Societies, European Society of Human Reproduction and Embryology, Paris, France

Howard W. Jones, Jr.

Eastern Virginia Medical School, Norfolk, Virginia and Johns Hopkins University Hospital, Baltimore, Maryland, U.S.A.

The birth of the world's first baby born as a result of in vitro fertilization (IVF) in July 1978 was by no means a chance event. Indeed, in the long evolution of reproduction, conception by IVF represents the end of a continuum which originated with childbirth wholly dependent on chance but which today is almost exclusively under human control. Today, nearly all forms of infertility can be treated by the various techniques of assisted reproduction, which are now responsible for the birth of around two million children worldwide.

THE HISTORY OF THE PAST

Although the origins of our medical knowledge of human reproduction are usually attributed to Hippocrates, so often described as the ''father of medicine," we do know that in the fifth century b.c. it was believed that both males and females each produced two seminal liquors, one stronger than the other; a blend predominantly with the former would produce a male offspring, with the latter a female. In the following century, Aristotle proposed that the first stage of a human being was indeed the egg found in females. Sperm had the power to give that egg its shape; the male would bring immaterial strength, the female material substance. For centuries, people lived with this concept of pre-formation, even after De Graaf described the follicle in 1672 and, at the same time, Leuwenhoek the spermatozoa. Only in 1875 would Hertwig demonstrate in the sea urchin that only one sperm cell would penetrate the egg to achieve fertilization.

In 1786, Hunter performed the first artificial insemination in humans, and in 1866 Sims the first donor insemination. In 1833, the cytologist Van Beneden demonstrated that gametes had only two chromosomes in the ascaria. The two chromosomes of the male nucleus would join with the two chromosomes of the female to form the nucleus of a new zygote, thereby laying the foundations for the discovery of the hereditary principle. In 1903, a Danish pharmacist, Johannsen, coined the term "gene," from which Bateson 3 years later defined the new science of "genetics." Almost 50 years later, in 1953, Watson, Crick, and Wilkins discovered the double helic structure of DNA and in 1956 Tijo and Levan identified 46 chromosomes in the human.

Equally important were the advances made by gynecologists in their understanding of the physiology of reproduction. By observing the effects of ovariectomy, they were able to explain the function of the ovary and in particular the menstrual cycle; the first treatments were developed as a result of injecting extracts of ovarian tissue. The concept of "hormone" activity was proposed by Baylin in 1904, and the subsequent discovery of the different hormones persisted throughout the rest of the 20th century.

1950-1978

Studies of animal and then human fertilization began in the second half of the 20th century. In 1954, Thibault achieved the first fertilization in vitro in the mammal (in the rabbit); the following year, Chang (1,2) succeeded in growing rabbit embryos derived from oocytes fertilized in vitro, and in 1959 achieved a live birth by transfer of an in-vitro-fertilized oocyte. In 1965, Edwards (3) determined that human oocytes removed from ovarian biopsies required 37 hr to complete their maturation in vitro.

This time was also the beginning of the gynecologist's interest in infertility. It was in 1959 that the first Congress on Infertility was held in New York. Five years earlier, in 1954, the first human pregnancy derived from frozen sperm was achieved, and the following year Pincus (4), who at the time was best known for his (unsuccessful) attempts to fertilize human oocytes in vitro, published the first results on hormonal contraception (for Enovid®, Searle Pharmaceuticals). In 1958 and 1960, Gemzell and Lunen-feld obtained the first pregnancies following treatment with human pituitary gonadotrophin (hPG) and human menopausal gonadotrophin (hMG), respectively (5,6). In 1961, Klein and Palmer (7) described the first aspiration of a human oocyte during laparoscopy.

However, throughout this time there was also a man working to achieve in humans what had seemed possible from work in animal models, much of it his own work in mice: IVF and embryo transfer. Eventually, in his scientific rigor and disciplined success, this man would change the face of human reproduction, demonstrating throughout persistence, self-denial, and exceptional confidence. This man was Edwards.

Edwards had completed his Ph.D. in 1958 on developmental genetics in mice. His studies, using diakinesis and metaphase-2 as markers, had shown that mice needed around 12 hr to achieve oocyte maturation, but now, as his work progressed from mouse models to the human, it was clear that human eggs required much longer. However, at the same time he and colleagues in Glasgow had produced the world's first embryonic stem cells from rabbit embryos. Intrigued by the therapeutic potential of these stem cells, Edwards turned to the maturation and fertilization of human oocytes in vitro—as a source of stem cells and for other research purposes. And it was from this work with human embryos—during an intense 6-wk period at Johns Hopkins Hospital in Baltimore—that Edwards found that human oocytes required 37 hr to reach full maturity, and thus 35-40 hr after ovulation before insemination could be carried out. By 1969, working with Ph.D. student Barry Bavister, Edwards was able to fertilize human eggs without any obvious need for sperm capacitation.

It was at this time—in 1967—that one of us (Cohen) first met Edwards. Both (Cohen and Edwards) were attending a conference on immunology in reproduction in Bulgaria. We met again in 1972 at an IFFS Congress in Tokyo, and here we talked of the possibilities of IVF in humans. At least, I listened, as he explained his vision of the future of human repro-duction—IVF, cryopreservation, preimplantation, and genetic diagnosis. I asked myself if he was serious, but I quickly understood that his was the vision of a true prophet.

Edwards had tried unsuccessfully to collaborate with clinicians in Cambridge and London to supply him with human oocytes. Frustrated in these efforts, he thus turned to the United States and in 1965 had joined Georgeanna and Howard Jones at Johns Hopkins where ovarian tissue (from wedge biopsies) was more readily available. And it was here, during this 6-wk working visit, that he obtained human oocytes, confirmed the precise timing of human oocyte maturation. Back in the United Kingdom, his clinical collaborations continued to prove fruitless, until his chance meeting at a London conference with the gynecologist Steptoe. At the time Steptoe was working in the small northern town of Oldham and already had much experience in the surgical use of laparoscopy. Steptoe immediately agreed to collaborate with Edwards, and so began—in 1968—the partnership that would leave such a lasting legacy in reproductive medicine.

The story of Edwards and Steptoe is well known, but for them it was also a difficult one—the long drives of Edwards from Cambridge to Oldham (180 miles each way), the laparoscopic recovery of oocytes from the ovary, the start of embryo transfers in 1971, ovarian stimulation with hMG, clomi-phene, luteal support, and constant failure—until the first ectopic pregnancy in 1975. Finally, despite accusations of malpractice by some U.K. colleagues and after 32 embryo transfers, their first healthy pregnancy was achieved with the birth of Louise Brown on July 25, 1978 (8).

I was surprised that the announcement of the world's first IVF birth was received in such a variety of ways. Certainly, there were very few people in the world who immediately understood the huge importance of its scientific achievement. Many doubted it, or did not even pay it much attention. I remember that I made the trip to London in early 1979 to hear Edwards and Steptoe report their medical and scientific success to the Royal College of Obstetricians and Gynaecologists, and I remember, too, the discussions and doubts when I arrived. However, after their precise and somewhat unsettling lecture (both the biologist and the clinician presenting data), any doubts in the audience evaporated and the meeting ended to the tune of ''For he's a jolly good fellow____''

Immediately after the birth of Brown, the attention of Edwards and Steptoe turned to extending their clinical work, but their progress was halted by the retirement of Steptoe from Britain's nationalized health service. It took two more years before an alternative private service could be set up at Bourn Hall near Cambridge, which in time would become one of the most progressive and best known in the world.

However, while Edwards and Steptoe planned their move to Bourn Hall, other groups throughout the world were inspired by the U.K. success and set about their own efforts to repeat it. Like Edwards and Steptoe, they were contemplating a treatment for tubal infertility, with the idea that IVF would circumvent the tubal blockage if tubal surgery had failed.

1978-1982

The embryo that became Brown was derived from a natural—and not stimulated—cycle. Thus, with the success of Edwards and Steptoe showing the way, the predominant scenario of these first IVF attempts was the natural cycle, determination of the luteinizing hormone (LH) peak and follicle puncture during laparoscopy. There was also a new demand for the development of culture media.

In Australia at the time there was already a long history in reproductive medicine. By 1970, Prof. Wood had established a combined research team in Melbourne involving the Royal Women's Hospital and the University of Monash. Johnston was the Medical Director at the former, while Leeton and Talbot comprised the medical staff at the latter, with

Lopata and Trounson handling the biology. This joint group was working with hormonally stimulated IVF cycles throughout the mid-1970s, using hPG or clomiphene and hMG. However, following the birth of Brown, the Melbourne group also turned its attention to the natural cycle. Improvements in culture media were initiated by Trounson, while the development of Teflon-lined catheters by Buttery and Kerin improved the technique of embryo transfer. Australia achieved its first IVF birth— the third in the world—in June 1980 when Candice Reed was born at the Royal Women's Hospital.

In June 1978, Howard and Georgeanna Jones had retired from Johns Hopkins—where Edwards had joined them for his 6-wk working visit in 1965—and had been asked by Andrews to set up a division of reproductive medicine at the Eastern Virginia Medical School in Norfolk. They began their IVF program in 1980, but, following 41 laparoscopies to collect oocytes, they had achieved embryo cleavage in only 13 patients, and no pregnancies following transfer.

In 1981, Georgeanna Jones proposed a change to hMG and the stimulated cycle to obtain more oocytes, a move which yet again prompted intense debate on the relative merits of the natural or stimulated cycle in IVF. The Norfolk group had its first success in the 13th attempt in a stimulated cycle, the first American IVF baby born in December 1981.

In France, two groups were making progress in friendly competition. At the university hospital in Clamart, Frydman as clinician and Testart as biologist were focusing their research on the LH peak, and in 1981 developed an assay for the initial rise of LH in plasma (LHSIR) (9). This assay would allow the accurate prediction of the start of the LH surge, and thus more time for the organization of follicle puncture. In Sevres, a non-university hospital, the biologists Mandelbaum and Plachot and I found ourselves frustrated by the absence of a laboratory on site, and adopted a policy of transporting oocytes by thermos flask to the INSERM laboratory of the Hospital Necker, 30 minutes away by taxi. It was also at Sevres that Pez and I began tracking follicular growth by ultrasound.

Both French groups benefited from the help of veterinary researchers at INRA (Institut National de la Recherche Agronomique), one of whom, Menezo, had developed the B2 culture medium known as the ''French medium.''

France's first IVF babies were born at Clamart in February 1982 and at Sevres the following June. And there were now several other live births being reported from groups elsewhere—in Sweden, Finland, the Netherlands, and Germany, as well as in the United Kingdom, United States, and Australia. In Vienna, Feichtinger and Kemeter began with clo-miphene cycles in the summer of 1981 and, doing their own biology, had their first live births (twins) in August 1982.

One catalyst for the surge of activity in IVF at this time was a meeting at Bourn Hall in September 1981 organized by Edwards for those groups worldwide now actively involved and reporting results—from Bourn Hall itself, Basel, Gothenburg, Kiel, Manchester, Melbourne, Norfolk, Paris, and Vienna. It was here that many of us met for the first time, and the atmosphere was warm and friendly. Comparing experiences was reassuring for everyone, and one important conclusion did emerge—a preference for stimulated cycles, which would generate more oocytes and allow a better prediction of the timing of ovulation. Now, looking back through the proceedings of that 1981 meeting and the reported discussions, I can see the following:

1. ovarian stimulation was mainly with clomiphene,

2. ultrasound was already in use (with Feichtinger) for monitoring follicular growth,

3. a concern for the effect of gas on oocyte quality during laparoscopy,

4. a concern about quality control in culture media and during laboratory processes,

5. and the conviction of Edwards that his former use of Primolut® (norethisterone) during the luteal phase of his earlier stimulated cycles would explain the failure of his first attempts at IVF; most participants at the meeting seemed to agree that, if post-aspiration progesterone values were low, a progesterone supplement would be needed during the luteal phase. Primolut, Edwards concluded, was probably an abortifacient.

If my descriptions of this first clinical phase of IVF seems to focus on just a few groups, it is because there was so little reporting of scientific data from elsewhere and because only the announcement of a pregnancy allowed some form of recognition from the scientific and lay communities. A fuller review of these pioneering days of IVF can be found in a series of articles in Human Reproduction Update by, Trounson, Dawson, Jones, Hagekamp, Nygren, Hamberger, and myself (10).

This was also, let us not forget, a period of general doubt in the scientific integrity of IVF and in its wider clinical application. In 1982, there were only 11 reported IVF births in the world, but this does not mean that the "celebrity" groups were the only ones doing IVF successfully. In many cities, there were young groups making their first attempts, and many of them traveled to the United Kingdom, United States, and Australia for their training. In the years which followed, they too would achieve their first pregnancies and live births.

1982-1992

The next decade was a time of huge progress in IVF. There was an explosion in the number of centers performing IVF in many countries, and it was also at this time that the first discussions on the ethics of assisted reproduction began in earnest, many of which would pave the way for subsequent legislation and guidelines.

Each year saw important new clinical and scientific developments. Among the milestones were

1982: The recognition of poor and high responders to hMG, the first ultrasound-guided aspiration of follicles, and the first reports of GnRH agonist use for the downregulation of pituitary hormones in IVF (11-13)

1983: Human embryo freezing (14)

1984: The first pregnancy following gamete intrafallopian transfer (GIFT) (15)

1986: The first pregnancy following zygote intrafallopian transfer (ZIFT) (16)

1986: The first human pregnancy following oocyte freezing (17)

1988: The first report of a human pregnancy following sub-zonal insemination (18)

1989: Vitrification of human oocytes (19)

1990: The first live birth following preimplantation genetic diagnosis, the detection of aneuploidy following polar body testing, and the first description of assisted hatching (20-22)

1991: The first clinical use of GnRH antagonists for the suppression of pituitary hormones (23)

1992: Intracytoplasmic sperm injection (ICSI) (24)

ICSI would become the most successful technique introduced in the decade, thereafter applied throughout the world to overcome fertilization failure as a result of male factor or unexplained infertility. The success of ICSI would also be shown to be independent of the three basic sperm parameters, motility, morphology, and concentration.

Throughout the decade, there was a huge increase in the use of assisted reproduction and in its success. In 1986, approximately 2000 babies were born following IVF, with half of them conceived at Bourn Hall. However, by 1989, the first year of data presented in the initial world collaborative report at the Seventh World Congress of IVF in Paris in 1991, that total had increased to more than 18,000 (Table 1).

In January 1984, Seppala had sent a questionnaire to 65 individuals or groups then working in IVF which had produced data on 10,028 cycles. Success rates according to the type of ovarian stimulation is shown in Table 2, and according to the number of embryos transferred in Table 3. In 1988, I reported a similar collaborative study at the Sixth World Congress of IVF in Melbourne which showed that, of 2342 pregnancies in the database, 24.8% were spontaneously lost and 5.2% were ectopic (Tables 4 and 5).

Table 1 In Vitro Fertilization: 1989 General Data

FR

USA

UK

Aus/ NZ

DE

Scand

BE

JP

CA

ES

Clinics

115

180

24

40

33

14

124

14

reported Clinics

50

161

35

23

37

25

14

67

10

10

participating Studied

15,880

18,211

10,489

9345

8385

6245

4578

3726

3180

cycles OPU

15,725

15,392

8514

7356

5759

5379

3750

3438

2724

1247

cycles Transfer

10,531

13,523

6553

6261

4365

4581

3040

2571

2233

1158

cycles Clinical

(+999) 2526

2811

1354

1040

900

(+100) 997

741

(+93) 421

391

244

pregnancies Deliveries

(+142) 1893a

2146

982

755

646

(+21) 705a

(+5) 306a

264

194

Babies

2531a

2929

964

926a

391

286

232

including stillborn Total babies reported since start Abnormal babies

11,127 11,015

4595 3275 1864 2428

552 1337

aIncluding frozen-thawed transfers (numbers in parentheses).

FR; France, USA; United States of America, UK; United Kingdom, AU; Australia,

KR; Korea, CZ; Czechoslovakia, GR; Greece, Yug; Yugoslavia, NL; Netherlands,

Abbreviation: IVF, in vitro fertilization.

Source: From Ref. 35.

Table 2 Type of Ovarian Stimulation and Number of Pregnancies Achieved

No. of

reporting

No. of pregnancies/

Success (%)

Stimulation

teams

No. of cycles

per cycle

None; natural cycle

7

41/352

11.6

Clomiphene/hCG

44

256/3083

8.3

Clomiphene/hMG/hCG

50

377/3847

9.8

Clomiphenea

14

167/980

17.0

Clomiphene/hMGa

7

53/340

15.6

hMG/hCG

41

235/1591

14.8

aSpontaneous LH surge.

Abbreviations: hMG, human menopausal gonadotropin; hCG, human chorionic gonadotropin. Source: From Ref. 36.

KR

CZ

GR Yug NL

SG CN

BR

IN

PT

EG

TR

IE

Total %OPU

5

5

8 7

1

6 7

3

9

3

4

1

1

>649

3

5

62

1

64

3

4

2

1

1

1

469

1456

1456

1232

769

696 617

504

383

271

243

66

>87,732

1240

1234

1000 857

656

618 509

455

322

222

168

66

34

76,030 100

1019

524

835 655

531

483 358

383

267

178

139

65

29

60,282 79.3

(+41) 191

51

(+21) 156 89

(+49) (+60) 140 110 94

85

(+18) 51

51

27

8

2

12,480 16.4

(+2) 137a

32

(+1) 100 61

(+7) (+11) 112a 95a

68

33a

40

20

6

0

>8595 12.0

122a

34

98 72

162a

137a

90

50a

62

31

8

>9125

151

55

206 153

399

139 202

171

109

117

105

13

>38,013

3

0

4 1

15

0 2

2

3

0

0

>278 1.5

NZ;New Zealand, DE; Germany, Scand; Scandinavia, BE; Belgium, JP; Japan, CA; Canada, ES; Spain, SG; Singapore, CN; China, BR; Brazil, IN; India, PT; Portugal, EG; Egypt, TR; Turkey, IE; Ireland.

It seems worthwhile to pause here and reflect on our main concerns during this decade of such great progress in reproductive medicine. First, our main scientific efforts were concentrated on fertility itself, whether to prevent pregnancy with contraception or to facilitate it with assisted reproduction. In IVF, we were looking for ways to increase the number of oocytes available for fertilization but to decrease the number of sperm cells necessary to achieve it (as it was by now quite clear that the failure of fertilization was often the result of a low concentration of motile sperms). At the same time, we were also searching for ways—as reflected in the techniques of zona drilling or partial zona dissection, or indeed in GIFT or ZIFT—to bring gametes closer together in time and space, and break through the physiological barriers of the oocyte.

However, the indications for IVF were not yet changing in any major way—and would not until the introduction of ICSI opened a door to the treatment of male infertility. From the beginning, IVF had remained indicated mainly for the treatment of tubal infertility as a result of blocked or damaged Fallopian tubes. Thus, there was a lively debate in the early

Table 3 Clinical Pregnancies Relative to Number of Embryos Replaced

No. of embryos No. of pregnancies/ Success replaced No. of replacement cycles rate (%)

One embryo 317/3321 9.5

Two embryos 366/2514 14.6

Three embryos 259/1340 19.3

Four or more 197/818 24.1 embryos

Source: From Ref. 36.

1980s following developments in microsurgery on how tubal blockage might best be treated; the microsurgeons were insistent that their new surgical techniques were potentially more effective than IVF. However, IVF quickly won that debate by gradually extending its indications far beyond the range of surgery, first into tubal infertility with patent but diseased tubes, and then into polycystic ovary disease and other idiopathic conditions. By the time the indications had been stretched to male infertility following the introduction of ICSI in the early 1990s, the debate between assisted reproduction and surgery was long over. Today, ICSI accounts for around 40% of all the indications for assisted reproductive technology (ART).

Table 4 Features of the Population Under Study: 2342 Pregnancies in Women of Mean Age of 33 Yr

Indications Type of ovarian Oocyte

(%) for IVF stimulation collection

Tubal 67.9

Idiopathic 11.0

Male infertility 3.5

Other 16.7

Clomiphene 3.9

hMG 20.8

FSH 3.4

CC/hMG 62.7

hMG/FSH 7.4

Other 1.8

By ultrasound 22.6

By laparoscopy 77.4

Abbreviations: IVF, in vitro fertilization; hMG, human menopausal gonadotropin; FSH, follicle stimulating hormone. Source: From Ref. 37.

Table 5 Incidence of the Different Pregnancy Outcomes (2329 cases)

Early abortions Late abortions Ectopic pregnancies Births

Ongoing pregnancies

Source: From Ref. 37.

There was also another trend evident throughout this important decade. It was clear by the early 1980s that ovarian stimulation with gona-dotrophins would allow the collection of more oocytes for fertilization and more embryos for transfer. However, with no limit on the number of embryos transferred and clinics anxious to increase their success rates, the number (and proportion) of multiple pregnancies was seen to increase in parallel to the wider use of ovarian stimulation. Multiple pregnancies would become one of the real issues of ART, both in terms of health and cost.

There were also major changes introduced in the technicalities of IVF: egg collection via laparoscopy was almost totally replaced by the far less invasive, ultrasound-guided transvaginal route; and there were also at this time great improvements made in the composition of culture media and in the processes of laboratory quality control.

And for the patient, what was the benefit of these developments? There were still those who argued that IVF was an inefficient procedure, with success rates improving only marginally with each scientific advance. However, in the adoption of embryo freezing, patients had more opportunity for embryo transfer from a single stimulation, and with it a much greater chance of success. Even in 1991, when I presented results from the world collaborative report in Paris, I reported a 20.7% pregnancy rate from fresh embryo transfers, and 13.7% from frozen (25). And it is also worth noting that throughout the decade the application of gamete donation developed remarkably such that with the introduction of oocyte and embryo donation, even those women with premature ovarian failure now had the chance to have their own babies, even if from a donated egg.

There were other developments too, outside the laboratory and clinic. Even before the birth of Brown, both Edwards and Steptoe were in favor of ethical discussion about IVF. The British government was the first to appoint a commission of enquiry into all forms of assisted conception in 1982 (under the chairmanship of Warnock), which reported 2 years later with a list of recommendations, including a statutory licensing authority. The United Kingdom was the first country to introduce legislation and regulation to assisted reproduction.

What was, clear, however, with legislation or not, was that each successive discovery in IVF stimulated some ethical discussion, and the press, politicians, theologians, and medical groups all raised concerns about such rapid progress into new forms of human conception. These discussions are clearly set out in a chapter titled "The History and Ethics of Assisted Conception'' in a 1995 textbook on ART by Edwards and Brody (26).

There was a broad disparity in how different countries adopted different moral positions with respect to the new reproductive technologies. In some countries, politicians and representatives of society were the final arbiters, whereas in others clinicians and scientists were left to define their own codes of practice. In 1999, Jones and I, on behalf of the IFFS, published a review of the guidelines and legislation in place in 38 countries, and could not find even two of those countries sharing the same legal positions (27). Indeed, even in the same geographical group of countries, there were significant differences: in Australia, there were even different laws on the two sides of a state border; in France, patients were forced to go to Belgium for pre implantation diagnosis (PGD) or oocyte donation; in the Nordic countries, Iceland and Finland had no legislation in place, whereas Denmark, Norway, and Sweden each had contradictory legislation with respect to gamete freezing and donation.

These paradoxes were essentially created by politicians and healthcare regulators and resulted mainly in sizable traffic of infertile couples seeking treatment beyond their own legislative borders, thereby initiating the "import and export'' of ART. Even if the legislation has changed over the years, the problem of "reproductive tourism'' has not.

Thus, even from the pioneering days of IVF, clinicians and biologists have shared a concern for the moral responsibility of providing IVF that was not always the same as the legislators'. Both of the leading scientific societies in reproductive medicine have continued to encourage discussions on its ethics, with debate, taskforce review, and publications. However, 25 years after the birth of Brown, there remain different opinions adopted by ethicists on the status of the human embryo which find their way into the contradictory laws which still persist in many countries.

1992-THE PRESENT

Although the outcome of ART procedures appears to have shown a constant, if slow, improvement throughout the 1990s, it has always been difficult to record precise results and compare them from one year to the next or from one country to another. Many registries have been set up, but most submissions and results were not audited, and wide methodological discrepancies remain between one registry and the next. Nevertheless, most reports show that, although the mean delivery per embryo transfer increased from 22% in 1995 to 31% in 2000, some individual groups achieved published rates of 40% or more.

Any progress in these results appears to have been modest in recent years, but the problems emerging in the 1990s have remained: a high rate of pregnancy loss (25%) and a high incidence of multiple pregnancies (2540%) (28). The result is that today the avoidance of multiple pregnancies after ART has become one if its main goals, with legislation now in place in some countries to limit the number of embryos transferred to two or even one.

In recent years, there have also been several studies showing that even singleton children born after ICSI or IVF have an increased risk of malformation or some developmental abnormality. The possible source of these risks has been associated with ovarian stimulation, laboratory procedures, or infertility itself. Prospective studies designed to identify the etiology of these problems are needed, even though most studies so far suggest that the causes of the infertility itself are the main associations with risk.

Since the introduction of ICSI in the early 1990s, ART has continued to pass significant milestones:

1994: Pregnancy following fertilization with sperm cells retrieved from the testes or epidydimis, and in vitro maturation (29,30)

1997: Blastocyst transfer (31)

1998: Mitochondrial transfer between oocytes (32)

2001: Single embryo transfer (33)

2004: First pregnancy following implantation of an embryo obtained from frozen ovarian tissue (34)

In the 21st century, it is clear how much the new reproductive technologies have allowed and initiated advances in genetics. The ability to transfer embryos screened for chromosomal and single gene defects has reduced the risk of many inherited diseases, while immunoassay technology has provided detailed insight into the cellular processes involved in gene expression. However, such developments—as well as the publicly perceived ability to select embryos for their sex and genetic characteristics—have raised fears of "designer babies'' and a move towards some kind of eugenics under pressure of parents.

Since the birth of Dolly, the sheep in Scotland in 1996, the issue of reproductive or therapeutic cloning has been exposed. In therapeutics, the transplantation of human embryonic stem cells now holds great promise for the treatment of diseases such as Parkinson's or diabetes, whereas developments in stem cell biology will lead to a better understanding of infertility, implantation failure, genomic imprinting, and meiosis. The gynecologist could take part in that research, but for now the initiative lies with the scientists and the active work of the geneticist.

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