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The History of IVF -The Milestones
The history of In Vitro Fertilization (IVF) and embryo transfer (ET) dates back as early as the 1890s when Walter Heape a professor and physician at the University of Cambridge, England, who had been conducting research on reproduction in a number of animal species, reported the first known case of embryo transplantation in rabbits, long before the applications to human fertility were even suggested.
In 1932, ‘Brave New World’ was published by Aldous Huxley. In this science fiction novel, Huxley realistically described the technique of IVF as we know it. Five years later in 1937, an editorial appeared in the New England Journal of Medicine (NEJM 1937, 21 October) which is note worthy.
"Conception in a watch glass: The ‘Brave New World’ of Aldous Huxley may be nearer realization. Pincus and Enzmann have started one step earlier with the rabbit, isolating an ovum, fertilizing it in a watch glass and reimplanting it in a doe other than the one which furnished the oocyte and have thus successfully inaugurated pregnancy in the unmated animal. If such an accomplishment with rabbits were to be duplicated in the human being, we should in the words of ‘flaming youth’ be ‘going places.’"
In 1934 Pincus and Enzmann, from the Laboratory of General Physiology at Harvard University, published a paper in the Proceedings of the National Academy of Sciences of the USA, raising the possibility that mammalian eggs can undergo normal development in vitro. Fourteen years later, in 1948, Miriam Menken and John Rock retrieved more than 800 oocytes from women during operations for various conditions. One hundred and thirty-eight of these oocytes were exposed to spermatozoa in vitro. In 1948, they published their experiences in the American Journal of Obstetrics and Gynecology.
However, it was not until 1959 that indisputable evidence of IVF was obtained by Chang (Chang MC, Fertilization of rabbit ova in vitro. Nature, 1959 8:184 (suul 7) 466) who was the first to achieve births in a mammal (a rabbit) by IVF. The newly-ovulated eggs were fertilized, in vitro by incubation with capacitated sperm in a small Carrel flask for 4 hours, thus opening the way to assisted procreation.
Professionals in the fields of microscopy, embryology, and anatomy laid the foundations for future achievements. The recent rapid growth of IVF-ET and related techniques worldwide are further supported by the social and scientific climate which favours their continuation.
Through the years numerous modifications have been made in the development of IVF-ET in humans: refinement of fertilization and embryo culture media; earlier transfer of the embryo; improvements in equipment; use of a reduced number of spermatozoa in the fertilization dish, embryo biopsy among others.
The purpose of this introduction is to acknowledge those who initiated new steps in the development of the treatment protocols and techniques that we now use facilitating such simple and promising IVF-ET procedures.
1961
Palmer from France described the first retrieval of oocytes by laparoscopy.
1965
In 1965, Robert Edwards together with Georgeanna and Howard Jones at Johns Hopkins Hospital in the USA attempted to fertilize human oocytes in vitro (Edwards RG, Donahue RP, Baramki TA, Jones HW Jr. Preliminary attempts to fertilize human oocytes matured in vitro. Am J Obstet Gynecol. 1966; 15;96:192-200).
1973
The first IVF pregnancy was reported by the Monash research team of Professors Carl Wood and John Leeton in Melbourne, Australia. Unfortunately, this resulted in early miscarriage (dDe Kretzer D, Dennis P, Hudson B, Leeton J, Lopata A, Outch K, Talbot J, Wood C. Transfer of a human zygote. Lancet, 1973 29;2:728-9).
1976
Y. Menezo developed the world's first B2 culture medium, known as ‘the French medium’. This specific medium reflected the follicular, tubal and uterine environments of the sheep, rabbits and humans.
Steptoe and Edwards published a report on an ectopic pregnancy following transfer of a human embryo at the late morulae /early blastocyst stage. (Steptoe PC, Edwards RG. Reimplantation of a human embryo with subsequent tubal pregnancy. Lancet, 1976; 24:1:880-2).
1978
The first ever IVF birth occurred in Oldham, England on July 25, 1978. This birth was the result of the collaborative work of Patrick Steptoe and Robert Edwards (Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet, 1978 ; 12;2:366).
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Lopata in Melboure described the first cycles stimulated with clomiphene citrate (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).
1979
Pez et al, began tracking the growth of follicles by ultrasound. They showed an appreciable relationship between the echographic and laparoscopic observations (Pez JP, Cohen J et al. 1979 Recherche d’une concordance entre l’e´chographie et l’observation par coelioscopie des follicules stimule´s par les inducteurs de l’ovulation. 178 soire´e gyne´co-obstricale de St Maurice le 9.10.79. Milupa. Bagnolet).
The first published use of ultrasound to identify growing follicles (Hackeloer BJ, 1977, The ultrasonic demonstration of follicular development during the normal menstrual cycle and after hormone stimulation. In Kurjak A (ed) Recent Advances in Ultrasound Diagnosis. Excerpta Medica, Amsterdam-Oxford, pp 122 – 128).
1980
The first IVF birth in Australia to the joint Victorian Monash-Melbourne team occurred at RWH. (Lopata et al. 1980 Fertil Steril 33,117)
The introduction of culture medium (Mohr LR, Trounson AO. The use of fluorescein diacetate to assess embryo viability in the mouse. J Reprod Fertil 1980;58:189-96).
1981
Howard and Georgianna Seegar Jones announced the delivery of the first IVF baby in the United States. This first IVF birth in the USA was achieved with the use of hMG.
Wood and his colleague introduced a foot-controlled fixed aspiration pressure control (Wood C, Leeton J, Talbot JM, Trounson AO. Technique for collecting mature human oocytes for in vitro fertilization. Br J Obstet Gynaecol. 1981;88(7):756-60).
Introduction of Clomiphene Citrate and hMG in the IVF treatment protocol (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 8;212:681-2) .
The Clamart group in France developed an LH assay (LH-SIR0 which could detect the initial LH rise in plasma allowing accurate prediction of the ideal time for the retrieval of oocytes (Testart J, Frydman R, Feinstein MC, Thebault A, Roger M, Scholler R. Interpretation of plasma luteinizing hormone assay for the collection of mature oocytes from women: definition of a luteinizing hormone surge-initiating rise. Fertil Steril. 1981 Jul;36(1):50-4).
1982
The first French IVF birth occurred in Clamart, France by the group of Frydman and Testart.
The first IVF birth in Sweden (Hamberger L, Wikland M, Nilsson L, Janson PO, Sjo¨ gren A and Hillensjo¨ T (1982) Methods for aspiration of human oocytes by various techniques. Acta Med Rom 20,370 – 378).
Birth of first Austrian "Test tube baby" (Twin pregnancy) (Feichtinger W, Szalay S, Kemeter P, Beck A, Janisch H.Twin pregnancy after laparoscopic oocyte recovery, in-vitro fertilization and embryotransfer (author's transl)]Geburtshilfe Frauenheilkd. 1982;42(3):197-9).
The first demonstration that GnRH agonists can be used to eliminate premature luteinization and control ovarian stimulation
(Fleming R, Adam AH, Barlow DH, Black WP, MacNaughton MC, Coutts JR. A new systematic treatment for infertile women with abnormal hormone profiles. Br J Obstet Gynaecol. 1982 ;89:80-3).
The first report of the need for a delay between oocyte collection and insemination to allow oocytes collected to complete maturation (Trounson AO, Mohr LR, Wood C, Leeton JF. Effect of delayed insemination on in-vitro fertilization, culture and transfer of human embryos. J Reprod Fertil 1982;64:285-94).
Susan Lenz and Jurgen G Lauritsen demonstrated trans abdominal transvesical oocyte aspiration using an ultrasound-guided needle (Lenz S, Lauritsen JG. Ultrasonically guided percutaneous aspiration of human follicles under local anesthesia: a new method of collecting oocytes for in vitro fertilization. Fertil Steril 1982;38:673-7).
Bourn Hall worlds first IVF Conference
Front row, from left to right: Bob Edwards, Jean Purdy, Patrick Steptoe, John Webster and Simon Fishel
1983
Donor egg: The Monash IVF team achieved the first pregnancy in a woman without ovaries by using donor eggs creating of artificial menstrual cycles and a special hormonal formula for the first 10 weeks of pregnancy (Trounson A, Leeton J, Besanko M, Wood C, Conti A. Pregnancy established in an infertile patient after transfer of a donated embryo fertilised in vitro. Br Med J (Clin Res Ed). 1983 Mar 12;286(6368):835-8).
Monash IVF team reported on the birth of the first frozen embryo baby. (embryo freezing developed in Cambridge, England on cattle – minor adaptations to adjust to humans) (Trounson A and Mohr L. Human pregnancy following cryopreservation thawing and transfer of an eight-cell embryo. Nature 1983;305,707 – 709.) .
Maturation and fertilization of morphologically immature human oocytes in an IVF (Veeck LL, Wortham JW Jr, Witmyer J, Sandow BA, Acosta AA, Garcia JE, Jones GS, Jones HW Jr. Maturation and fertilization of morphologically immature human oocytes in a program of in vitro fertilization. Fertil Steril 1983;39:594-602).
First pregnancy after oocyte donation (Trounson A, Leeton J, Besanko M, Wood C and Conti A (1983) Pregnancy established in an infertile patient after transfer of a donated embryo fertilized in vitro. Br Med J (Clin Res Ed) 286,835 – 838).
First successful delivery following egg donation. (Buster JE, Bustillo M, Thorneycroft IH, Simon JA, Boyers SP, Marshall JR, Louw JA, Seed RW, Seed RG. Non-surgical transfer of in vivo fertilised donated ova to five infertile women: report of two pregnancies. Lancet. 1983;23;2:223-4).
Casper and his colleagues were the first to described the use of low dose hCG for support of the luteal phase in ART cycles. (Casper RF, Wilson E, Collins JA, Brown SF, Parker JA.. Enhancement of human implantation by exogenous chorionic gonadotropin. Lancet, 1983;19;2:1191).
Gleicher and his group reported the first vaginal egg retrieval using an abdominal ultrasound (Gleicher N, Friberg J, Fullan N, Giglia RV, Mayden K, Kesky T, Siegel I. EGG retrieval for in vitro fertilisation by sonographically controlled vaginal culdocentesis. Lancet, 1983 27;2:508-9).
First report on the Canadian IVF baby by the group of Victor Gomel at the University of British Columbia
World's first IVF triplets reported by Christopher Chen.
The first report on human pregnancy following cryopreservation, thawing and transfer of an eight-cell embryo (Trounson A, Mohr L. Human pregnancy following cryopreservation, thawing and transfer of an eight-cell embryo. Nature, 1983;20-26;305:707-9).
The first paper predicting follicular steroids as a prognosticator for successful IVF (Fishel SB, Edwards RG, Walters DE. Follicular steroids as a prognosticator of successful fertilization of human oocytes in vitro. J Endocrinol. 1983;99(2):335-44.)
1984
The Government of Victoria established a review of IVF research and practice which led to the proclamation of the Infertility (Medical Procedures) Act 1984, the first legislation to regulate IVF and its associated human embryo research.
First surrogacy embryo transfer baby born in California
First report on pregnancy following translaparoscopic GIFT procedure (Asch RH, Ellsworth LR, Balmaceda JP, Wong PC. Pregnancy after translaparoscopic gamete intrafallopian transfer. Lancet, 1984;3;2:1034-5).
The first report on pregnancy following IVF and egg donation in a woman with primary ovarian failure. (Lutjen P, Trounson A, Leeton J, Findlay J, Wood C and Renou P. The establishment and maintenance of pregnancy using in vitro fertilization and embryo donation in a patient with primary ovarian failure. Nature, 1984;307,174 – 175).
Introduction of GnRH agonists to the IVF treatment protocol (Porter RN, Smith W, Craft IL, Abdulwahid NA, Jacobs HS. Induction of ovulation for in-vitro fertilisation using buserelin and gonadotropins. Lancet, 1984;1;2:1284-5).
A report of pregnancy following transfer of intact frozen-thawed embryos (Zeilmaker GH, Alberda AT, van Gent I, Rijkmans CM, Drogendijk AC.Two pregnancies following transfer of intact frozen-thawed embryos. Fertil Steril. 1984;42(2):293-6).
An unusual report of the possibility that abnormal spermatozoa could be enriched and give rise to healthy babies. (Cohen J, Fehilly CB, Fishel SB, Edwards RG, Hewitt J, Rowland GF, Steptoe PC, Webster J. Male infertility successfully treated by in-vitro fertilisation.Lancet. 1984, 2;1(8388):1239-40).
The first publication demonstrating HCG secretion by the human embryo (Fishel SB, Edwards RG, Evans CJ. Human chorionic gonadotropin secreted by preimplantation embryos cultured in vitro.Science. 1984, 24;223(4638):816-8).
The world's first IVF quadruplets were born on January 6, 1984, in Melbourne.
1985
Human pregnancy by in vitro fertilization (IVF) using sperm aspirated from the epididymis. (Temple-Smith PD, Southwick GJ, Yates CA, Trounson AO, de Kretser DM. Human pregnancy by in vitro fertilization (IVF) using sperm aspirated from the epididymis. J In Vitro Fert Embryo Transf. 1985;2(3):119-22).
Lars Nilsson in Gothenburg, Sweden, described the possibility of using a vaginal sector scanner (transvaginal technique) for oocyte aspiration (Wikland M, Enk L, Hamberger L. Transvesical and transvaginal approaches for the aspiration of follicles by use of ultrasound. Ann N Y Acad Sci. 1985;442:182-94).
First report of the use of abdominal ultrasound guidance for embryo transfer. (Strickler RC, Christianson C, Crane JP, Curato A, Knight AB, Yang V. Ultrasound guidance for human embryo transfer. Fertil Steril 1985 ;43:54-61).
The first reported birth after replacement of hatching blastocyst cryopreserved at expanded blastocyst stage (Cohen J, Simons RF, Fehilly CB, Fishel SB, Edwards RG, Hewitt J, Rowlant GF, Steptoe PC, Webster JM. Birth after replacement of hatching blastocyst cryopreserved at expanded blastocyst stage. Lancet. 1985;16;1:647).
In 1985 Quinn and Warnes published a formula entitled Human Tubal Fluid (HTF) that mimics the in vivo environment to which the embryo is exposed (Quinn P, Kerin JF, Warnes GM. Improved pregnancy rate in human in vitro fertilization with the use of a medium based on the composition of human tubal fluid. Fertil Steril 1985;44:493-8).First ultrasound guidance for human embryo transfer. (Strickler RC, Christianson C, Crane JP, Curato A, Knight AB, Yang V.Ultrasound guidance for human embryo transfer. Fertil Steril. 1985;43(1):54-61).
First Delivery Resulting From Gestational Surrogacy. (Utian WH, Sheean L, Goldfarb JM, Kiwi R. Successful pregnancy after in vitro fertilization and embryo transfer from an infertile woman to a surrogate. N Engl J Med. 1985:21;313(21):1351-2).
First successful egg donation in Europe. (Feichtinger W, Kemeter P. Pregnancy after total ovariectomy achieved by ovum donation. ancet. 1985:28;2(8457):722-3).
Transabdominal ultrsound guided embryo transfer (Strickler RC, Christianson C, Crane JP, Curato A, Knight AB, Yang V. Ultrasound guidance for human embryo transfer. Fertil Steril. 1985;43(1):54-61).
Navot et al. reported the possibility of artificially induced endometrial cycles and establishment of pregnancies in the absence of ovaries. (Navot D, Laufer N, Kopolovic J, Rabinowitz R, Birkenfeld A, Lewin A, Granat M, Margalioth EJ, Schenker JG.Artificially induced endometrial cycles and establishment of pregnancies in the absence of ovaries. N Engl J Med. 1986 Mar 27;314(13):806-11). Although it was published in 1986 it was first reported in 1985.
1986
Monash IVF report on the world’s first pregnancy and birth from the sperm retrieval operation performed on a patient who had a blocked sperm duct.
First description of transvaginal sector scan sonography for needle-guided transvaginal follicle aspiration (Feichtinger W, Kemeter P. Transvaginal sector scan sonography for needle guided transvaginal follicle aspiration and other applications in gynecologic routine and research. Fertil Steril 1986 May;45(5):722-5).
First pregnancy, following IVF donated oocytes, in a non-ovarian failure patient. (Rosenwaks Z, Veeck LL, Liu HC.Pregnancy following transfer of in vitro fertilized donated oocytes. Fertil Steril. 1986;45(3):417-20).
First report on pregnancy after translaparoscopic zygote intrafallopian transfer (Devroey P, Braeckmans P, Smitz J, Van Waesberghe L, Wisanto A, Van Steirteghem A, Heytens L, Camu F. Pregnancy after translaparoscopic zygote intrafallopian transfer in a patient with sperm antibodies. Lancet, 1986 7;1:1329). In parallel the goup at the RWH was involved too in studies on gamete intra-Fallopian transfer (GIFT), (Molloy D, Speirs A, du Plessis Y, McBain J, Johnston I. A laparoscopic approach to a program of gamete intrafallopian transfer. Fertil Steril. 1987;47(2):289-94).
Delivery of twins from frozen human eggs (Chen C, Pregnancy after human oocyte cryopreservation. Lancet 1986, 1,884 – 886).
Jacqueline Mandelbaum with Dan Szollosi described the microstructures of the human oocyte, which becameknown as ‘oocyte dysmorphia’ (Szollosi D, Mandelbaum J, Plachot M, Salat-Baroux J, Cohen J. Ultrastructure of the human preovulatory oocyte. J In Vitro Fert Embryo Transf. 1986 ;3:232-42).
1987
Fertilization of human oocytes by microinjection of a single sperm under the zona pellucida (Laws-King A, Trounson A, Sathananthan H, Kola I. Fertilization of human oocytes by microinjection of a single spermatozoon under the zona pellucida. Fertil Steril. 1987;48:637-42).
1988
First two babies born after epididymal sperm aspiration for men with congenital absence of the vas deferens and naming of the technique MESA (Patrizio P, Silber S, Ord T, Balmaceda JP, Asch RH. Two births after microsurgical sperm aspiration in congenital absence of vas deferens. Lancet. 1988, 10;2(8624):1364).
Australia’s first IVF surrogate birth.
The first baby birth using subzonal sperm injection at National University of Singapore (Ng SC, Bongso A, Ratnam SS, Sathananthan H, Chan CL, Wong PC, Hagglund L, Anandakumar C, Wong YC, Goh VH. Pregnancy after transfer of sperm under zona. Lancet. 1988; 1;2:790).
Pregnancy was obtained from micromanipulation using zona drilling or mechanical partial zona dissection (Cohen J, Malter H, Fehilly C, Wright G, Elsner C, Kort H, Massey J. Implantation of embryos after partial opening of oocyte zona pellucida to facilitate sperm penetration. Lancet, 1988;16;2:162).
The death of Dr. Patrick Steptoe -March 21 1988. (The Washington Post ,Article: Dr. Patrick Steptoe, 74, Dies; Pioneered Test-Tube Baby Field, March 23, 1988).
The first preclinical evaluation of pronuclear formation by microinjection of human spermatozoa into human oocytes. (Lanzendorf SE, Maloney MK, Veeck LL, Slusser J, Hodgen GD, Rosenwaks Z. A preclinical evaluation of pronuclear formation by microinjection of human spermatozoa into human oocytes. Fertil Steril. 1988 May;49(5):835-42).
1989
First report on biopsy of human preimplantation embryos and sexing by DNA amplification. (Handyside AH, Pattinson JK, Penketh RJ, Delhanty JD, Winston RM, Tuddenham EG. Biopsy of human preimplantation embryos and sexing by DNA amplification. Lancet. 1989;18;1:347-9).First report on the use of laser techniques in the field of assisted reproduction for application in gametes or embryos (Tadir Y, Wright WH, Vafa O, Ord T, Asch RH, Berns MW. Micromanipulation of sperm by a laser generated optical trap. Fertil Steril. 1989 Nov;52(5):870-3).
Gonen and her colleagues in Toronto pioneered the use of ultrasound for endometrial quality (thickness and pattern) related to IVF pregnancy. (Gonen Y, Casper RF, Jacobson W, Blankier J. Endometrial thickness and growth during ovarian stimulation: a possible predictor of implantation in in vitro fertilization. Fertil Steril. 1989;52(3):446-50).
Embryo biopsy technique was developed in mice by Professor Alan Trounson and Leeanda Wilton. (Wilton LJ, Trounson AO. Biopsy of preimplantation mouse embryos: development of micromanipulated embryos and proliferation of single blastomeres in vitro. Biol Reprod. 1989;40(1):145-52).
1990
The first successful human cleavage-stage embryo vitrification followed by a successful delivery (Gordts S, Roziers P, Campo R, Noto V. Survival and pregnancy outcome after ultrarapid freezing of human embryos. Fertil Steril 1990;53:469-72).
Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification. (Handyside AH, Kontogianni EH, Hardy K, Winston RM. Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification. Nature. 1990;19;344:768-70).
First report of assisted hatching in human embryos. (Cohen J, Elsner C, Kort H, Malter H, Massey J, Mayer MP, Wiemer K. Impairment of the hatching process following IVF in the human and improvement of implantation by assisting hatching using micromanipulation. Hum Reprod. 1990;5(1):7-13).
The first report on polar body biopsy, transfer of the embryo and achieving pregnancy (Verlinsky Y, Ginsberg N, Lifchez A, Valle J, MoiseJ, Strom CM. Analysis of the first polar body: preconception genetic diagnosis. Hum. Reprod. 1990 5: 826-829).
Gonen et al proposed the use of GnRH agonist in place of hCG as a means to trigger the gonadotropic surge for IVF. (Gonen Y, Balakier H, Powell W, Casper RF. Use of gonadotropin-releasing hormone agonist to trigger follicular maturation for in vitro fertilization. J Clin Endocrinol Metab. 1990;71(4):918-22).
Gonen, Jacobson and Casper pioneered the use of combined oral contraceptives for follicle synchronization and cycle scheduling in IVF. (Gonen Y, Jacobson W, Casper RF. Gonadotropin suppression with oral contraceptives before in vitro fertilization. Fertil Steril 1990;53:282-7).
Fishel et all reported about twin birth after subzonal insemination (Fishel S, Antinori S, Jackson P, Johnson J, Lisi F, Chiariello F, Versaci C. Twin birth after subzonal insemination. Lancet. 1990 24;335(8691):722-3).
1991
In Vitro Maturation (IVM) in an unstimulated cycle resulted in pregnancy in a donor oocyte program (Cha KY, Koo JJ, Ko JJ, Choi DH, Han SY, Yoon TK. Pregnancy after in vitro fertilization of human follicular oocytes collected from nonstimulated cycles, their culture in vitro and their transfer in a donor oocyte program. Fertil Steril 1991 Jan;55(1):109-13).
The first report on the use of a laser for Zona Pelucida drilling (Palanker D, Ohad S, Lewis A, Simon A, Shenkar J, Penchas S, Laufer N. Technique for cellular microsurgery using the 193-nm excimer laser. Lasers Surg Med. 1991;11(6):580-6).
Navot et all. confirmed that the age-related decline in female fertility is attributable to oocyte quality (Navot D, Bergh PA, Williams MA, Garrisi GJ, Guzman I, Sandler B, Grunfeld L. Poor oocyte quality rather than implantation failure as a cause of age-related decline in female fertility. Lancet. 1991 Jun 8;337(8754):1375-7).
Introduction of GnRH antagonist (Nal-Glu) in IVF procedures (Frydman R, Cornel C, de Ziegler D, Taieb J, Spitz IM, Bouchard P. Prevention of premature luteinizing hormone and progesterone rise with a gonadotropin-releasing hormone antagonist, Nal-Glu, in controlled ovarian hyperstimulation. Fertil Steril. 1991;56(5):923-7).
Embryo transfer catheter is visualized by vaginal ultrasound (Hurley VA, Osborn JC, Leoni MA, Leeton J. Ultrasound-guided embryo transfer: a controlled trial.Fertil Steril. 1991;55(3):559-62).1992
Successful in-vitro fertilisation and embryo transfer after treatment with recombinant human FSH. Presented simultaneously by two groups: (Germond M, Dessole S, Senn A, Loumaye E, Howles C, Beltrami V. Successful in-vitro fertilisation and embryo transfer after treatment with recombinant human FSH. Lancet, 1992 9;339:1170) (Devroey P, van Steirteghem A, Mannaerts B, Bennink HC. Successful in-vitro fertilisation and embryo transfer after treatment with recombinant human FSH. Lancet. 1992;9;339:1170).
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Assisted zona hatching was introduced in IVF programs to breach the zona pellucida and promote the natural process of hatching. (Cohen J, Alikani M, Trowbridge J, Rosenwaks Z. Implantation enhancement by selective assisted hatching using zona drilling of human embryos with poor prognosis. Hum. Reprod. 1992 7: 685-691).
(Anguiano et al. 1992, JAMA 267(13)1794)(Patrizio and Asch 1992, Annals Acad Med Singapore 21:533)
Pregnancy after embryo biopsy and coamplification of DNA from X and Y chromosomes. (Grifo JA, Tang YX, Cohen J, Gilbert F, Sanyal MK, Rosenwaks Z. Pregnancy after embryo biopsy and coamplification of DNA from X and Y chromosomes. JAMA 1992, 12;268(6):727-9).
Ovulation induction by endogenous LH released by the administration of an LHRH agonist after follicular stimulation for in vitro fertilization (Emperaire JC, Ruffié A, Audebert AJ. Ovulation induction by endogenous LH released by the administration of an LHRH agonist after follicular stimulation for in vitro fertilization. J Gynecol Obstet Biol Reprod (Paris). 1992;21:489-94. French).
SL. Tan
First report on cumulative conception and live birth rates after IVF in relation to patient's age and cause of infertility (Tan SL, Royston P, Campbell S, Jacobs HS, Betts J, Mason B, Edwards RG. Cumulative conception and livebirth rates after in-vitro fertilisation. Lancet. 1992,6;339(8806):1390-4).
First two births from replacement of frozen embryos produced with epididymal sperm (Patrizio P, Silber S, Ord T, Marello E, Balmaceda JP, Asch RH. Replacement of frozen embryos generated from epididymal spermatozoa: the first two pregnancies. Hum Reprod 1992;7(5):652-3)
Report on using Erbium YAG laser for micromanipulation of oocytes and spermatozoa (Feichtinger W, Strohmer H, Radner KM. Erbium YAG laser for micromanipulation of oocytes and spermatozoa. Lancet. 1992, 11;340(8811):115-6).
Investigating the role of FSH in hypogonadotropic women usung the new recombinant FSH drug (Schoot DC, Coelingh Bennink HJ, Mannaerts BM, Lamberts SW, Bouchard P, Fauser BC. Human recombinant follicle-stimulating hormone induces growth of preovulatory follicles without concomitant increase in androgen and estrogen biosynthesis in a woman with isolated gonadotropin deficiency. J Clin Endocrinol Metab 1992; 74: 1471-3).
1993
The second term pregnancy after ICSI reported by a group in Sweden (Hamberger et al, 1993, In Gordts S (ed) Proceedings of European Symposium on Micromanipulation. Drukkerij Nauwelaerts, Leuven, Belgium, pp 85).
Confirmation that men with congenital absence of the vas defference, have cystic fibrosis mutations which can be transmitted to the offspring (Patrizio P, Asch RH, Handelin B, Silber SJ. Aetiology of congenital absence of vas deferens: genetic study of three generations. Hum Reprod. 1993;8(2):215-20).
First report on the use of TESE (testicular sperm extraction) and ICSI (Silber SJ, Nagy ZP, Liu J, Godoy H, Devroey P, Van Steirteghem AC. Conventional in-vitro fertilization versus intracytoplasmic sperm injection for patients requiring microsurgical sperm aspiration. Hum Reprod. 1994;9(9):1705-9).
First Preganancy and birth following treatment with Rec-FSH (Devroey P, Mannaerts B, Smith J, Coelingh Bennink H, Van Steirteghem A. First established pregnancy and birth after ovarian stimulation with recombinant human follicle stimulating hormone (Org 32489). Hum Reprod.1993 Jun;8(6):863-5).
1994
The first live birth as a result of IVM following transvaginal ultrasound–guided oocyte collection. (Trounson A, Wood C, Kausche A. In vitro maturation and the fertilization and developmental competence of oocytes recovered from untreated polycystic ovarian patients. Fertil Steril 1994;62(2):353-62).
Development of the first highly purified FSH preparation for use in IVF (Howles CM, Loumaye E, Giroud D, Luyet G. Multiple follicular development and
ovarian steroidogenesis following subcutaneous administration of a highly purified urinary FSH preparation in pituitary desensitized women undergoing IVF: a multicentre European phase III study. Hum Reprod. 1994;9(3):424-30). First pregnancy after use of r-hLH (Hull M, Corrigan E, Piazzi A, Loumaye E. Recombinant human luteinising hormone: an effective new gonadotropin preparation. Lancet 1994;30;344(8918):334-5). 1995
Pregnancies after Testicular Sperm Extraction (TESE) and ICSI in non-obstructive azoospermia. (Devroey P, Liu J, Nagy Z, Goossens A, Tournaye H, Camus M, Van Steirteghem A, Silber S. Pregnancies after testicular sperm extraction and intracytoplasmic sperm injection in non-obstructive azoospermia. Hum Reprod. 1995;10(6):1457-60).
Birth after blastocyst development from IVM oocyte plus ICSI plus Assisted Hatching (Barnes FL, Crombie A, Gardner DK, Kausche A, Lacham-Kaplan O, Suikkari AM, Tiglias J, Wood C, Trounson AO. Blastocyst development and birth after in-vitro maturation of human primary oocytes, intracytoplasmic sperm injection and assisted hatching. Hum Reprod. 1995;10(12):3243-7).
The first report of aneuploidy testing (Munné S, Sultan KM, Weier HU, Grifo JA, Cohen J, Rosenwaks Z. Assessment of numeric abnormalities of X, Y, 18, and 16 chromosomes in preimplantation human embryos before transfer. Am J Obstet Gynecol. 1995;172(4 Pt 1):1191-9; discussion
Zenzes from the group of Casper in Toronto demonstrated adverse effects of cigarette smoking on nuclear spindle. (Zenzes MT, Wang P, Casper RF. Cigarette smoking may affect meiotic maturation of human oocytes. Hum Reprod. 1995;10(12):3213-17).
The first report in which spermatids were used to achieve pregnancy. (Fishel S, Green S, Bishop M, Thornton S, Hunter A, Fleming S, al-Hassan S. Pregnancy after intracytoplasmic injection of spermatid. Lancet. 1995, 24;345(8965):1641-2).
Dmitri Dozortsev and coworkers have discovered that oocyte activation during ICSI is triggered by a water-soluble, heat-sensitive, non species specific cytosolic sperm factor. (Dozortsev D, Rybouchkin A, De Sutter P, Qian C, Dhont M. Human oocyte activation following intracytoplasmic injection: the role of the sperm cell. Hum Reprod. 1995;10(2):403-7).
The larget study done in the filed of IVF comparing urinary FSH with Rec-FSH (Out, H.J., Mannaerts, B.M., Driessen, S.G. and Coelingh Bennink, H.J. A prospective, randomized, assessor blind, multicenter study comparing recombinant and urinary follicle-stimulating hormone in in vitro fertilization. Hum. Reprod., 1995: 10, 2534 –2540).
1996
The Valencia group reported on the first pregnancy employing cryopreserved testicular sperm following IVF-ICSI. . (Gil-Salom M, Romero J, Minguez Y, Rubio C, De los Santos MJ, Remohí J, Pellicer A. Pregnancies after intracytoplasmic sperm injection with cryopreserved testicular spermatozoa. Hum Reprod. 1996;11(6):1309-13).
Discovery that some men with severe oligoasthenospermia have deletions in the Y-chromosome (Reijo R, Alagappan RK, Patrizio P, Page DC. Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y chromosome. Lancet, 1996, 11;347(9011):1290-3).
Jurisicova from the Casper group was the first to recognize that preimplantation of human embryo fragmentation involved programmed cell death. (Jurisicova A, Varmuza S, Casper RF. Programmed cell death and human embryo fragmentation. Mol Hum Reprod. 1996;2(2):93-8).
Casper and his colleagues were the first to demonstrate and introduce the use of the hypo-osmotic swelling test for selection of immotile sperm for ICSI. (Casper et al. 1996 Fertil Steril 65:972)
1997
First report on cytoplasmic transfer (Cohen J, Scott R, Schimmel T, Levron J, Willadsen S. Birth of infant after transfer of anucleate donor oocyte cytoplasm into recipient eggs. Lancet, 1997, 19;350(9072):186-7)
Sun, Jurisicova and Casper described the use of TUNEL for detection of DNA fragmentation in sperm and correlation with IVF outcome. They showed almost uniform presence of DNA fragmentation in round spermatids as the explanation for failure to achieve pregnancy with these immature gametes. (Sun JG, Jurisicova A, Caspe RF. Detection of deoxyribonucleic acid fragmentation in human sperm: correlation with fertilization in vitro. Biol Reprod. 1997 Mar;56(3):602-7).
First births of babies from frozen oocytes following use of ICSI: - Porcu et al, Birth of a healthy female after intracytoplasmic sperm injection of cryopreserved human oocytes. (Porcu E, Fabbri R, Seracchioli R, Ciotti PM, Magrini O, Flamigni C. Birth of a healthy female after intracytoplasmic sperm injection of cryopreserved human oocytes. Fertil Steril. 1997;68(4):724-6).
First report on cytoplasmic transfer (Cohen J, Scott R, Schimmel T, Levron J, Willadsen S. Birth of infant after transfer of anucleate donor oocyte cytoplasm into recipient eggs. Lancet, 1997;19;350:186-7).
Falloposcopic GIFT: Births after transcervical gamete intrafallopian transfer with a falloposcopic delivery system. (Porcu E, Dal Prato L, Seracchioli R, Petracchi S, Fabbri R, Flamigni C. Births after transcervical gamete intrafallopian transfer with a falloposcopic delivery system. Fertil Steril. 1997 Jun;67(6):1175-7).
Pregnancy after treatment with three recombinant gonadotropins (Agrawal R, West C, Conway GS, Page ML, Jacobs HS. Pregnancy after treatment with three recombinant gonadotropins. Lancet. 1997;4;349:29-30).
Eleonora Porcu
1998
First establish pregnancy using recombinant FSH and GnRH antagonist (Itskovitz-Eldor J, Kol S, Mannaerts B, Coelingh Bennink H. First established pregnancy after controlled ovarian hyperstimulation with recombinant follicle stimulating hormone and the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462). Hum Reprod. 1998;13:294-5).
Gardner introduced sequential media and blastocyst transfer which is now greatly assists in the move to single embryo transfer (Gardner DK, Schoolcraft WB, Wagley L, Schlenker T, Stevens J, Hesla J. A prospective randomized trial of blastocyst culture and transfer in in-vitro fertilization. Hum Reprod 1998;13:3434-40).
Births after intracytoplasmic injection of sperm obtained by testicular extraction from men with nonmosaic Klinefelter's syndrome (Palermo GD, Schlegel PN, Sills ES, Veeck LL, Zaninovic N, Menendez S, Rosenwaks Z. Births after intracytoplasmic injection of sperm obtained by testicular extraction from men with nonmosaic Klinefelter's syndrome. N Engl J Med. 1998, 26;338(9):588-90).
The first pregnancies following embryo culture in sequential media and transfer at the blastocyst stage of development (Jones GM, Trounson AO, Gardner DK, Kausche A, Lolatgis N, Wood C. Evolution of a culture protocol for successful blastocyst development and pregnancy. Hum Reprod. 1998 ;13:169-77).
First ovum pick-up under 3-D ultrasound vision (Feichtinger W. Follicle aspiration with interactive three-dimensional digital imaging (Voluson): a step toward real-time puncturing under three-dimensional ultrasound control. Fertil Steril. 1998;70(2):374-7).
In 1998 first reports on births from frozen GV eggs, and donor eggs: - Tucker et al. Birth after cryopreservation of immature oocytes with subsequent in vitro maturation. (Tucker MJ, Wright G, Morton PC, Massey JB. Birth after cryopreservation of immature oocytes with subsequent in vitro maturation. Fertil Steril. 1998;70(3):578-9); Tucker et al. Clinical application of human egg cryopreservation. (Tucker MJ, Morton PC, Wright G, Sweitzer CL, Massey JB. Clinical application of human egg cryopreservation. Hum Reprod. 1998;13(11):3156-9).
Michael Tucker
1999
First unaffected pregnancy using preimplantation genetic diagnosis for sickle cell anemia. (Xu K, Shi ZM, Veeck LL, Hughes MR, Rosenwaks Z. First unaffected pregnancy using preimplantation genetic diagnosis for sickle cell anemia. JAMA. 1999, 12;281(18):1701-6).
Birth following vitrification of human oocyte (Lilia Kuleshova, Luca Gianaroli, Cristina Magli, Anna Ferraretti, and Alan Trounson. Birth following vitrification of a small number of human oocytes: Case Report. Hum. Reprod. 1999 14: 3077-3079).
Chian et al. demonstrated that hCG priming prior to immature oocyte retrieval in women with PCO increases the maturation rate and produces high pregnancy rates of 40% per IVM started cycle (Chian, R.C., Gülekli, B., Buckett, W.M. and Tan, S.L. Priming with human chorionic gonadotrophin before retrieval of immature oocytes in women with infertility due to the polycystic ovary syndrome. N. Eng. J. Med., 1999;341, 1624–1626).
World’s first IVF/ICSI pregnancy and live-birth after successful air transport of oocytes reported by the McGill Reproductive Centre, enabling the creation of an air-transport IVF program in large countries with scattered populations or in areas remote from infertility centers (Buckett WM, Fisch P, Dean NL, Biljan MM, Tan SL. In vitro fertilization and intracytoplasmic sperm injection pregnancies after successful transport of oocytes by airplane. Fertil Steril. 1999;71(4):753-5).
Cryopreserved oocytes and testicular sperm: first ever birth. (Porcu E, Fabbri R, Petracchi S, Ciotti PM, Flamigni C. Ongoing pregnancy after intracytoplasmic injection of testicular spermatozoa into cryopreserved human oocytes. Am J Obstet Gynecol. 1999;180:1044-5).
Cryopreserved oocytes and epididimal sperm: first ever birth. (Porcu E, Fabbri R, Ciotti PM, Petracchi S, Seracchioli R, Flamigni C. Ongoing pregnancy after intracytoplasmic sperm injection of epididymal spermatozoa into cryopreserved human oocytes. J Assist Reprod Genet. 1999;16(5):283-5).
2000
Oktay and Karlikaya were the first to report on ovarian tissue transplants after frozen storage. (Oktay K, Karlikaya G. Ovarian function after transplantation of frozen, banked autologous ovarian tissue. N Engl J Med. 2000 Jun 22;342(25):1919).
The development of a completely chemically defined protein-free embryo culture medium and the births of the first batch of babies generated from the fertilization of eggs collected and inseminated in the said protein-free medium using spermatozoa also prepared in the same protein-free medium in both conventional IVF and ICSI. (Ali, Shahata MAM., Al-Natsha SD. Formulation of a protein-free medium for human assisted reproduction. Hum. Reprod. 2000 15: 145-156).
Cryopreserved oocytes and frozen sperm: first ever birth. (
Porcu E, Fabbri R, Damiano G, Giunchi S, Fratto R, Ciotti PM, Venturoli S, Flamigni C. Clinical experience and applications of oocyte cryopreservation. Mol Cell Endocrinol. 2000:27;169(1-2):33-7).
2001
Birth of an infant from cryopreserved embryos (zygotes) produced by IVM oocytes derived from an unstimulated patient with PCOS (Chian RC, Gülekli B, Buckett WM, Tan SL. Pregnancy and delivery after cryopreservation of zygotes produced by in-vitro matured oocytes retrieved from a woman with polycystic ovarian syndrome. Hum Reprod. 2001;16(8):1700-2).
Ongoing twin pregnancy after ICSI of PESA-retrieved spermatozoa into in-vitro matured oocytes reported by the McGill group. (Ahmad Kamal Abdul-Jalil, Tim J. Child, Simon Phillips, Nicola Dean, Serge Carrier, and Seang Lin Tan. Ongoing twin pregnancy after ICSI of PESA-retrieved spermatozoa into in-vitro matured oocytes: Case report, Hum. Reprod. 2001 16: 1424-1426).
Live birth after sperm retrieval from a moribund man (Belker AM, Swanson ML, Cook CL, Carrillo AJ, Yoffe SC. Live birth after sperm retrieval from a moribund man. Fertil Steril. 2001;76(4):841-3).
2002
First live birth following blastocyst biopsy and PGD analysis. (De Boer K, McArthur S, Murray C and Jansen R. First live birth following blastocyst biopsy and PGD analysis. Reprod Biomed Online 2002;4,35).
First clinical application of comparative genomic hybridization and polar body testing for preimplantation genetic diagnosis of aneuploidy. (Wells D, Escudero T, Levy B, Hirschhorn K, Delhanty JD, Munné S. First clinical application of comparative genomic hybridization and polar body testing for preimplantation genetic diagnosis of aneuploidy. Fertil Steril. 2002;78(3):543-9).
2003
Live births after vitrification of oocytes in a stimulated in vitro fertilization–embryo transfer program (Yoon TK, Kim TJ, Park SE, Hong SW, Ko JJ, Chung HM, Cha KY. Live births after vitrification of oocytes in a stimulated in vitro fertilization-embryo transfer program. Fertil Steril. 2003;79(6):1323-6) .
Implantation of the human embryo is the limiting factor in the success of IVF. Dr. Barash and Prof. Dekel showed an Increasing implantation rate following endometrial injury, performed by Pipelle curettage as a simple outpatient procedure. (Barash A, Dekel N, Fieldust S, Segal I, Schechtman E, Granot I. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization. Fertil Steril. 2003;79(6):1317-22).
Normal birth after microsurgical enucleation of tripronuclear human zygotes (Kattera S, Chen C. Normal birth after microsurgical enucleation of tripronuclear human zygotes: Case report. Hum. Reprod. 2003 18: 1319-1322).
2004
Jaques Donnez reporting on the first Live birth after orthotopic transplantation of cryopreserved ovarian tissue (Donnez J, Dolmans MM, Demylle D, Jadoul P, Pirard C, Squifflet J, Martinez-Madrid B, van Langendonckt A. vebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004:364(9443):1405-10).
Gardner and colleagues performed the world’s first prospective single blastocyst trial, which showed the feasibility of SBT and in keeping high pregnancy rates (Gardner DK, Surrey E, Minjarez D, Leitz A, Stevens J, Schoolcraft WB. Single blastocyst transfer: a prospective randomized trial. Fertil Steril. 2004;81(3):551-5).
The first preimplantation HLA matching for stem-cell transplantation to an affected sibling (Verlinsky Y, Rechitsky S, Sharapova T, Morris R, Taranissi M, Kuliev A. Preimplantation HLA testing. JAMA. 2004;291(17):2079-85).
First report of fertility preservation for cancer patients using IVM and oocyte vitrification (Rao GD, Chian RC, Son WS, Gilbert L, Tan SL. Fertility preservation in women undergoing cancer treatment. Lancet. 2004;363(9423):1829-30).
First report on oocyte cryopreservation to save fertility in cancer patients. (
Porcu E, Fabbri R, Damiano G, Fratto R, Giunchi S, Venturoli S. Oocyte cryopreservation in oncological patients. Eur J Obstet Gynecol Reprod Biol. 2004;113 Suppl 1:S14-6).
The first reported live born following preimplantation genetic diagnosis for Retinoblastoma (Xu K, Rosenwaks Z, Beaverson K, Cholst I, Veeck L, Abramson DH. Preimplantation genetic diagnosis for retinoblastoma: the first reported liveborn. Am J Ophthalmol. 2004;137(1):18-23).
First report on a natural cycle in IVF combined with IVM as a potential approach to infertility treatment (Chian RC, Buckett WM, Abdul Jalil AK, Son WY, Sylvestre C, Rao D, Tan SL. Natural-cycle in vitro fertilization combined with in vitro maturation of immature oocytes is a potential approach in infertility treatment. Fertil Steril. 2004;82(6):1675-8).
2005
Pregnancies and live births after trophectoderm biopsy and preimplantation genetic testing of human blastocysts. (McArthur SJ, Leigh D, Marshall JT, de Boer KA, Jansen RP. Pregnancies and live births after trophectoderm biopsy and preimplantation genetic testing of human blastocysts. Fertil Steril. 2005;84(6):1628-36).
The first live-birth after trophectoderm biopsy and preimplantation genetic testing of human blastocysts for beta-Thalassaemia (Kokkali G, Vrettou C, Traeger-Synodinos J, Jones GM, Cram DS, Stavrou D, Trounson AO, Kanavakis E, Pantos K. Birth of a healthy infant following trophectoderm biopsy from blastocysts for PGD of beta-thalassaemia major. Hum Reprod. 2005;20(7):1855-9).
2006
First successful pregnancy after preimplantation genetic diagnosis for aneuploidy screening in embryos generated from natural-cycle IVF combined with IVM, achieved at the McGill Reproductive Centre. (Ao A, Jin S, Rao D, Son WY, Chian RC, Tan SL. First successful pregnancy outcome after preimplantation genetic diagnosis for aneuploidy screening in embryos generated from natural-cycle in vitro fertilization combined with an in vitro maturation procedure. Fertil Steril. 2006;85(5):1510.e9-11).
Cryopreservation of intact human ovary with its vascular pedicle. (Mohamed A. Bedaiwy, Mahmoud R. Hussein, Charles Biscotti, and Tommaso Falcone. Cryopreservation of intact human ovary with its vascular pedicle. Hum. Reprod. 2006 21: 3258-3269).
Report from McGill Reproductive Center, Canada and Maria Infertility Hospital Seoul, Korea on deliveries after transfer of human blastocysts derived from oocytes matured by In Vitro Maturation (IVM) (Son WY, Lee SY, Yoon SH, Lim JH. Pregnancies and deliveries after transfer of human blastocysts derived from in vitro matured oocytes in in vitro maturation cycles. Fertil Steril. 2007;87(6):1491-3).
Introducing the concept of Mild Treatment Strategy for IVF (Heijnen EM, Eijkemans MJ, De Klerk C, Polinder S, Beckers NG, Klinkert ER, Broekmans FJ, Passchier J, Te Velde ER, Macklon NS, Fauser BC. A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial. Lancet. 2007;369(9563):743-9) .
A novel multi-gradient freezing technique for the cryopreswervation of the whole ovary. Thawing the ovary resulted in normal ovarian architecture and no damage to the vascular wall or intima. (Arav and Pasquale 2007 Yale Practice 12:2)
First IVM egg donation pregnancy in North America achieved by McGill Reproductive Centre (Holzer H, Scharf E, Chian RC, Demirtas E, Buckett W, Tan SL. In vitro maturation of oocytes collected from unstimulated ovaries for oocyte donation. Fertil Steril. 2007;88(1):62-7).
2008The first report of DNA fingerprinting to identify the blastocyst of origin for live-births and that gene expression profiles of biopsied trophectoderm can discriminate between viable and non-viable blastocysts. (Gayle M. Jones, David S. Cram, Bi Song, Georgia Kokkali, Kostas Pantos, and Alan O. Trounson. Novel strategy with potential to identify developmentally competent IVF blastocysts. Hum. Reprod. 2008; 23: 1748-1759).
Cryopreserved oocytes in cancer patients: first ever birth of healthy twins after oocyte cryopreservation and bilateral ovariectomy. (Porcu E, Venturoli S, Damiano G, Ciotti PM, Notarangelo L, Paradisi R, Moscarini M, Ambrosini G. Healthy twins delivered after oocyte cryopreservation and bilateral ovariectomy for ovarian cancer. Reprod Biomed Online. 2008;17:265-7).
2009
Simon Fishel and his group from CARE Fertility, Nottingham, reported about a Live birth after polar body array comparative genomic hybridization. (Fishel S, Gordon A, Lynch C, Dowell K, Ndukwe G, Kelada E, Thornton S, Jenner L, Cater E, Brown A, Garcia-Bernardo J. Live birth after polar body array comparative genomic hybridization prediction of embryo ploidy-the future of IVF? Fertil Steril. 2010;93(3):1006.e7-1006.e10).
Prof. Laufer at the Hadassah Medical Center in Jerusalem reported on a viable pregnancy achieved in a woman who carries the defective BRCA2 genes after In-Vitro Fertilized Embryos were tested and implanted. (Sagi M, Weinberg N, Eilat A, Aizenman E, Werner M, Girsh E, Siminovsky Y, Abeliovich D, Peretz T, Simon A, Laufer N. Preimplantation genetic diagnosis for BRCA1/2--a novel clinical experience. Prenat Diagn. 2009;29(5):508-13).
