Success, Safety, Single Sperm: Intracytoplasmic Sperm Injection Today

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'GYNAECOLOGY""'"

SUCCESS, SAFETY, SINGLE SPERM: INTRACYTOPLASMIC SPERM INJECTION TODAY I.S. Tummon, MD, FRCSC, K.A. Skinner, MSc, A. Sharma, MB BS, MS (Gynae. & Obst.) FR. Tekpetey, PhD, B.M. Bany, MSc, J.S.B. Martin, MD, FRCSC, Department of Gynaecology and Reproductive Medicine, London Health Sciences Centre, University Campus, Department of Obstetrics and Gynaecology, The University of Western Ontario

ABSTRACT

Objectives : To assess the indications arul merits of intracytoplnsmic sperm injection, To consider the affordability of intracytoplnsmic sperm injection, To consider the hazards of intracytoplnsmic sperm injection, Design: Silver Platter Review of English language citations for intracytoplnsrnic sperm injection from 1990 to 1996, harul searching abstracts arul journals , Conclusions: Intracytoplnsrnic sperm injection is a vital innovation for treating rrwle infertility. Intracytoplnsmic sperm injection is complex arul costly, Rational use of intracytoplnsmic sperm injection depends on accurate diagnostic arulrology , Data are inadequate to assess the risks of congenital malformations accurately. Even in young women there may be a one percent risk of sex chromatin abnormalities, RESUME

Objectifs: Evaluer les indications et les benefices de l'injection intracytoplasmique de spermatozoK1es. Considerer les couts-benefices d'injection intracytoplnsmique de spermatozoK1es. Considerer les risques de l'injection intracytoplnsmique de spermatozoK1es. Plan d'experience: Une analyse "Silver Platter" des citations de langue anglaise de l'injection intracytoplasmique de spermatozoK1es des annees 1990-1996, avec d'autres articles et abreges,

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, , , Conclusions:

L'injection intracytoplasmique de spermatozoWes est une methode superieure comparee a la fecondation in vitro. L'injection intracytoplasmique de sperrnatozoides est complexe et dispendieuse. L' usage rationelle de l'injection intracytoplasmique de sperrnatozoides depend d' adequate obtenu par l' androgie diagnostique. Les donees sont insuffisantes pour evaluer de fcu;on precise les risques de rrwlformations congeniwles. Meme chez les femmes plus jeunes il pourrait y voir un risque de 1% d' anomalies des cromatines sexuelles.

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KEY WORDS

Intracytoplasmic sperm injection, oocyte, fertilization, infertility. Received and accepted on June 15th, 1996.

INTRODUCTION

FIGURE 2 " ACCIDENTAL" INTRACYTOPLASMIC SPERM INJECTION, BRUSSELS, 1990

WHAT IS INTRACYTOPLASMIC SPERM INJECTION?

Intracytoplasmic sperm injection (ICSI) is the micro-injection of a single sperm into the ooplasm of an oocyte (Figure 1). It is a complex and costly laboratory technology which may be optimal treatment for male infertility. The development of ICSI occurred fortuitously in 1990 when an inadvertent puncture of the oolemma occurred during subzonal sperm injection. This unintended breach of the oolemma resulted in successful fertilization l (Figure 2). THE EVOLUTION OF MICROMANIPULATION

- subzonal insertion of sperm - intracytoplasmic sperm injection.

PROCEDURES FOR MALE INFERTILITY

Success using conventional in vitro fertilization (IYF) is lower for male infertility than other diagnostic categories. 1 The need for improved microfertilization techniques for male infertility has resulted in a rapid evolution of micromanipulation techniques. Assisted fertilization techniques have encompassed: - zona drilling - partial zona dissection

Injection of a single spermatozoon into the ooplasm was used as treatment of infertility caused by severely impaired sperm characteristics. In 1992, pregnancies resulting from direct injection of oocytes were reported. l RAPID ADOPTION OF THIS TECHNOLOGY IN

CANADA

In the four years since the first intracytoplasmic sperm injection pregnancy, the technology has been adopted rapidly in Canada. Most Canadian assisted reproductive technology programmes now offer intracytoplasmic sperm injection. 3

FIGURE 1 INTRACYTOPLASMIC SPERM INJECTION

WHAT IS MALE INFERTILITY?

Intracytoplasmic sperm injection is effective treatment for male infertility. In contrast, intracytoplasmic sperm injection is ineffective treatment for fertilization failure due to reduced oocyte quality and ovarian reserve. It is essential to determine why reproductive success is

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prFOSAMAX® increases bone mass in postmenopausal women

8.8% increase in BMO at the spine '·••·u

7.8%

3.1%

increase in BMO' at the hip l.U

increase in BMO at the wrist (ultradistal forearm)"u

20% of bone mass has been lost by the average postmenopausa l woman FOSAMAXIII is a bone metabolism regulator FOSAMAXIII is indicated for the treatment of osteoporosis in postmenopausal women .. Bone Mineral Density •• In clinical studies. over 96% of patients studied for up to three years had a measured increase in

spine BMD.I

t FOSAMAXoSI 10 mg daily produced statistically significant and clinically important increases in BMD at the hip, spine. and wrist (ultradistal forearm) relative to placebo at three years IpSO.OOt L 1,2 i Combined data from two large. identically designed, double-blind, placebo-controlled. three-year multicenter studies in 994 women with osteoporosis. defined as low bone mass, 397 of whom received placebo and 196 of whom received FQSAMAX- 10 mglday_ To ensure an adequate calcium intake. all patients were supplemented with 500 mg of calcium per day_I I. Liberman UA et al Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333(22) 1437-43 2. Data on file. Merck Frosst Canada Inc.: 'TWo double-blind. randomized. placebo-controlled . parallelgroup. multicenter studies to evaluate the safety and effect on bone density of daily oral MK-217 for two years in osteopenic postmenopausal women . with a one-year open treatment extension fProtocol No. 035 (US) and 037 (Internationaill-Three Year Data.

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, , , lacking prior to deciding on the appropriate treatment. Male infertility is a common problem but the majority of men with infertility have reduced semen quality which impairs fertility to a variable degree. Despite low sperm concentration, standard semen analysis is not predictive of fertility potential. Provided some motile sperm are present, successful fertilization is possible and there is no useful cut-off point to discriminate between fertility potential and lack of fertility potential. 4 Standard semen analysis, therefore, is unhelpful except at very low ranges of sperm density (1 or 2 million sperm per mL). Sperm function as opposed to sperm number is the critical factor for fertility potential. s The pertinent question in deciding whether male infertility exists is to know "do the sperm work; are they competent?" This information cannot be obtained by standard semen analysis.

FIGURE 3 RELATIVE RISK OF FERTILIZATION WITH ICSI

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6

--il et -..,I Aboulghar et al.

~ Palermo et al.'

IF INTRACYTOPLASMIC SPERM INJECTION IS

Comparison of rcsr to conventional IVF has been hampered by the scarcity of controlled studies. Studies have not relied on uniform inclusion criteria nor involved the most relevant outcome: pregnancy. Aboulghar and co-workers studied 24 IVF cycles involving men with borderline sperm characteristics. 6 Fertilization of sibling oocytes was higher (P=O.OOI) with ICSI (59%) compared with zona intact insemination (27% ).6The relative risk of fertilization following intracytoplasmic sperm injection was 2.2 with 95% confidence limits of 1.3 to 3.7. In 1993, Palermo and co-workers compared intracytoplasmic sperm injection to subzonal insertion and found intracytoplasmic sperm injection to be superior.) In 300 cycles, subzonal insertion and intracytoplasmic sperm injection were variously applied for previous fertilization failure or sperm defects. In 206 cycles, both intracytoplasmic sperm injection and subzonal insertion were performed on sibling oocytes in an unrandomized fashion.) Results pooled for all 300 cycles showed fertilization of 44 percent of oocytes after intracytoplasmic sperm injection versus 18 percent after subzonal insertion. The relative risk of fertilization after rCSI was 2.1 with 95% confidence limits of 1.8 to 2. In both studies, relative risks were significant, consistent, and in favour of intracytoplasmic sperm injection (Figure 3). Therefore, intracytoplasmic sperm injection is considered the optimal microfertilization technique for severe male infertility.8

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BEST, WHAT IS THE QUALITY OF THE EVIDENCE?

10.0

Re lative Risk (95% Cll TECHNICAL FACTORS

Technical factors critical for achieving high rates of fertilization and pregnancy are: - standardized ICSI pipettes9 - immobilization of sperm before injection lO - aspiration of a minimal amount of ooplasm to ensure breakage of the oolemma before reinjection with the sperm 9 - choice of a morphologically normal sperm DIAGNOSTIC ANDROLOGY: SPERM FUNCTION PROFILE

Interpretation of treatment results for male infertility is affected critically by accurate diagnosis of sperm function. 1I Standard semen analysis fails to screen for functional abnormalities or to predict the success of intracytoplasmic sperm injection. II A profile of sperm function tests is most helpful as it offers a clearer prognostic picture of fertility potential and identification of otherwise occult male infertility. Abnormal results of diagnostic tests for male infertility are often more useful than normal results. Sperm cannot be competent if they fail to perform an essential function. The goal is to sampLe as many critical functions of the sperm as possible. At London Health Sciences Centre, a profile of sperm function, not covered under provincial health

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FOSAMAX® reduces the risk of fractures There was a trend towards a reduction in the proportion of patients treated with FOSAMAX® experiencing one or more nonvertebral fractures relative to those receiving placebo in pooled analysis (5-20 mg) (p=NSj '·tt

48%

reduction in the proportion of patients treated with FOSAMAX® experiencing one or more vertebral fractures relative to th ose treated with pl acebo in pooled analysis (5 -20 mgj (p=0.03j '·'

Low b one mass is a maj or pred ictor of increased ri sk of osteoporoti c f ractures' 11 Vertebral fractures occurred in 6.2% (221355) of patients who received placebo and 32% (171526) of

patients who received FO$AMAX* (5 or 10 mg for 3 years or 20 mg for 2 years followed by 5 mg for I year),1

t t NQl1vertebral fractures occurred in 9.6% (381397) of patients who received placebo and 7.5% (451597) of

patients who re
FOSAMAX·_I 3. Consensus Development Conference Diagnosis, prophylaxis. and treatment of osteoporosis Am I Med 1993;94.646-9 FOSAMAXe, like other bisphosphonates. may cause local irritation of the upper gastrointestinal mucosa

Esophageal adverse experiences. such as esophagitis. esophageal ulcers and esophageal erosions have been reported in patients receiving treatment with FOSAMAXe, In some cases these have been severe and required hospitalization, Healthcare professionals should therefore be alert to any signs or symptoms Signaling a possible esophageal reaction and patients should be instructed to discontinue FOSAMAXimmediately and seek medical attention if they develop dysphagia. odynophagia or retrosternal pain FOSAMAX- is contraindicated in patients who have abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia. who are unable to stand or sit upright for at least 30 minutes. who are hypersensitive to any component of this product who are hypocalcemic or who suffer from renal insuffiCiency (creatinine clearance < 35 mUmin)

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MERCK SHARP & DOHME CANADA DIV. OF M ERCK FROSST CAN ADA I NC. KIR KLAND, QUEBEC

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, , , The decision to treat with intracytoplasmic sperm injection depends on the chances of pregnancy versus cost, complexity, and effectiveness oftreatment, as well as such factors as motivation, duration of infertility, and adequacy of ovarian reserve. In 1995, in 179 ICSI cycles started at London Health Sciences Centre, the live birth rate and ongoing pregnancy rate was 15 percent per cycle initiated. The multifetal pregnancy rate was 35 percent. Singletons accounted for 65 percent of births while twins and triplets were 27 percent and eight percent, respectively. In 1995 at London Health Sciences Centre, live birth and multifetal pregnancy rates were not different be tween intracytoplasmic sperm injection and zona intact in vitro fertilization. Intracytoplasmic sperm injection has not been associated with an increase in pregnancy losses.1 9

insurance, is offered when sperm function is in doubt. Given the acronym "AIM" for Acrosin, Immunobead, and Monash (Figure 4), the profile is used to: - measure potential oocyte binding and penetration using the total acrosin activity assayj lJ - assess the presence of sperm surface antibodies using immunobeadsj 14 - assess functional mobility with the Monash swim up test; 15 - measure sperm morphology according to Kruger strict criteria. 16 Intracytoplasmic sperm injection provides good fertilization results for specific male infertility conditions that otherwise have a poor prognosis: - low proportions of morphologically normal sperm using strict criteriajl) - positive antisperm antibodies; - subnormal acrosin activity. IS

IN THE REAL WORLD HOW SUCCESSFUL IS INTRACYTOPLASMIC SPERM INJECTION?

Success rates for ICSI are reported in an illusory fashion .lO What may be quoted as a 25 percent pregnancy rate (preclinical + clinical pregn ancies/cycles reaching embryo transfer) is more realistically a 15 percent rate of achieving a live birth.lI

AFFORDABILITY IS THE BIG PROBLEM

The principal drawbacks of intracytoplasmic sperm injection are complexity and cost. The decision to undergo ICSI requires that the female partner be subjected to the costs and rigours of in vitro fertilization: ovarian stimulation and oocyte retrieval. Although the problem may originate with the male partner, the female partner undertakes almost all of the burden of the medical risks. The cost of intracytoplasmic sperm injection at London Health Sciences Centre is $1,500. In addition, cycle fees are $3,500 for the first cycle and $3,000 for subsequent cycles, excluding medication costs which average $3,225. Lack of affordability is, thus, the single greatest problem with ICSI and no provincial health insurance covers the procedure.

VERSATILITY

Intracytoplasmic sperm injection permits the use of marginal sperm samples that are insufficient for zona intact insemination, and also is advised to achieve fertilization with micro-epididymal sperm aspirations or following retrieval of testicular sperm. n.ll Intracytoplasmic sperm injection may be beneficial in cases of assisted ej aculation. 14 In cases of assisted ej aculation for spinal cord injury, the need for ICSI will likely be affected by such factors as time since injury and history of recurrent urinary tract infections.

FIGURE 4

HAZARDS

SPERM FUNCTION PROFILE

There is intense concern about the potential adverse effects of intracytoplasmic sperm injection. Although ICSI involves careful selection of viable, morphologically normal sperm, the procedure bypasses natural selection. What are the short and long term effects o f uch s interference? Potentially hazardous effects include direct destruction of the oocyte by the micromanipulation process (15% at London Health Sciences Centre) and the general medical risks of assisted reproduction.

Monash Swim Up Surface Antibodies

Acrosin Activity

+Kruger Strict

Morphology

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, , , General risks include: - bleeding, infection, and trauma after oocyte retrieval - ovarian hyperstimulation syndrome - multifetal gestatiod l - potential remote effects of ovarian stimulation - an increase in ovarian cancer?

CONCLUSIONS

- Intracytoplasmic sperm injection is an expensive but effective treatment for male infertility. - Accurate determination of male infertility is a prerequisite for appropriate application of ICSI. It is inappropriate that ICSI be used to treat all infertile couples. I I - The chance of pregnancy with ICSI is limited by oocyte quality and ovarian reserve. - As intracytoplasmic sperm injection has been used for less than five years, there is inadequate knowledge oflong term risks. The use ofICSI may increase the risk of sex chromatin abnormalities.

Potential hazards for offspring include: - mortality and morbidity associated with multifetal gestation - increased risk of major congenital or sex-chromatin anomalies 26 Data are inadequate to assess the risks of congenital malformations. Three percent of the first 877 children born following ICSI in Brussels had major congenital malformations which may not differ from the rate seen in the general population. 26 There may be an increased risk of sex chromosomal abnormalities in children conceived after intracytoplasmic sperm injection. In the Brussels experience, one percent of pregnancies showed sex chromosome abnormalities, most in young women. 26 Many factors may affect congenital malformations after mictosurgical fertilization where oocytes are exposed to: - hyaluronidase - polyvinylpyrrolidone 27 - intense light - fluctuations in temperature - mechanical breach of the zona pellucida and oolemma

REFERENCES

1.

Pregnancies after intracytoplasmic injection of a single spermatozoon into an oocyte. Lancet 1992;340:17-8. 2. Alsalili M, Yuzpe A, Tummon I, Parker J, Martin J, Nisker J, Daniel S, Rebel M. Cumulative pregnancy rates and pregnancy outcome after in vitro fertilization: five thousand cycles at one centre. Hum Reprod 1995;10:470-4. 3. Fluker MR, Tiffen GW. Assisted reproductive technologies-a primer for Canadian physicians. J SOGC 1996;5:451-65. 4. Polansky FF, Lamb EJ. Do the results of semen analysis predict future fertility? A survival analysis study. Fertil SteriI1988;49:1059-65. 5. Mortimer D, Goel N, Shu MA. Evaluation of the CeliSoft automated semen analysis system in a routine laboratory setting. Fertil SteriI1988;50:960-8. 6. Aboulghar MA, Mansour RT, Serour GI, Sattar MA, Amin YM. Intracytoplasmic sperm injection and conventional in vitro fertilization for sibling oocytes in cases of unexplained infertility and borderline semen. J Assist Reprod Genet 1996;13:38-42. 7. Palermo G, Joris H, Derde M-P, Camus M, Devroey P, Van Steirteghem AC. Sperm characteristics and outcome of human assisted fertilization by subzonal insemination and intracytoplasmic sperm injection. Fertil Steril 1993;59:826-35. 8. Edwards RG, Van Sterteghem AC. Intracytoplasmic sperm injections (ICSI) and human fertilization: does calcium hold the key to success? Hum Reprod 1993;8:988-9. 9. Svalander P, Forsberg AS, Jakobsson AH, Wikland M. Factors of importance for the establishment of a successful program of intracytoplasmic sperm injection treatment for male infertility. Fertil Steril 1995;63:828-37. 10. Catt J, O'Neill C. Manipulation of sperm before intracytoplasmic sperm injection improves fertilization rates. Fertil Steril 1995;64:1210-2.

In bypassing natural selection, micromanipulation may escalate the risk of fertilization with genetically abnormal gametes. Genetically abnormal sperm that are not competent to fertilize in vivo may pass on their defects as a result of intracytoplasmic sperm injection. OOCYTE QUALITY AND OVARIAN RESERVE ARE THE LIMITING FACTORS TO SUCCESS

It is a paradox, but the success of intracytoplasmic sperm injection is dependent primarily on oocyte quality and adequacy of ovarian reserve. 2S Ovarian reserve is estimated by the measurement of basal follicle stimulating hormone levels. 29 Oocyte number and egg quality are now the main determinants of success in treating male infertility,21 There is no important influence from sperm concentration, density or motility on the outcome of intracytoplasmic sperm injection. 12

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, , , 11. Mortimer D. The essential partnership between diagnostic andrology and modern assisted reproductive technologies. Hum Rep 1994;9:1209-13. 12. Nagy ZP, Liu J, Joris H, Verheyen G, Tournaye H, Camus M, Derde MC, Devroey P, Van Steirteghem AC. The result of intracytoplasmic sperm injection is not related to any of the three basic sperm parameters. Hum Reprod 1995;10:1123-9. 13. Tummon IS, Yuzpe AA, Daniel SAJ, Deutsch A. Total acrosin activity correlates with fertility potential after fertilization in vitro. Fertil Steril1991 ;56:933-8. 14. Clarke GN, Elliott PJ, Smaila C. Detection of sperm antibodies in semen using the immunobead test: a survey of 813 consecutive patients. Am J Reprod Immunol Microbiol 1985;7:118-23. 15. Lopata A, Patullo MJ, Chang A, James B. A method for collecting motile spermatozoa from human semen. Fertil SteriI1976;27:677-84. 16. Kruger TF, Acosta AA, Simmons KF, Swanson RJ, Matta JF, Oehninger S. Predictive value of abnormal sperm morphology in in vitro fertilization. Fertil Steril 1988;48:112-17. 17. Svalander P, Jakobsson AH, Forsberg AS, Bengtsson AC, Wikland M. The outcome of intracytoplasmic sperm injection is unrelated to 'strict criteria.' Hum Reprod 1996;11:1019-22. 18. Bany BM, Winger Q, Deutsch A, Martin JSB, Tummon IS. Intracytoplasmic sperm injection is treatment of choice for subnormal total sperm acrosin activity. Presented at the Annual Meeting of the American Society of Andrology, Minneapolis MN, April 25-27, 1996. 19. Coulam CB, Opsahl MS, Sherins RJ, Thorsell LP, Dorfman A, Krysa L, Fugger E, Schulman JD. Comparisons of pregnancy loss patterns after intracytoplasmic sperm injection and other assisted reproductive technologies. Fertil Steril 1996;65: 1157 -62. 20. Schulman JD. On reporting of results on assisted human reproduction. What's your success rate? Dr. X comes to America. Hum Reprod 1996;11 :697-9.

21. Sherins RJ, Thorsell LP, Dorfmann A, Dennison-Lagos L, Calvo LP, Krysa L, Coulam CB, Schulman JD. Intracytoplasmic sperm injection facilitates fertilization even in the most severe forms of male infertility: pregnancy outcome correlates with maternal age and number of eggs available. Fertil Steril 1995;64:369-75. 22. Nagy Z, Liu J, Cecile J, Silber S, Devroey P, Van Steirteghem AC. Using ejaculated, fresh, and frozenthawed epididymal and testicular spermatozoa gives rise to comparable results after intracytoplasmic sperm injection. Fertil Steril1995;63:808-15. 23. Girardi SK, Schlegel PN. Microsurgical epididymal sperm aspiration: review of techniques, preoperative considerations, and results. J AndroI1995;17:5-9. 24. Gerris J, Van Royen E, Mangel Schots K, Joostens M, de Vits A. Pregnancy after intracytoplasmic sperm injection of metaphase II oocytes with spermatozoa from a man with complete retrograde ejaculation. Hum Reprod 1994; 9:1293-6. 25. Collins J. Reproductive technology-the price of success. N Engl J Med 1994;331 :270-1. 26. Liebaers I, Bonduelle M, Van Assche E, Devroey P, Van Steirteghem AC. Sex chromosome abnormalities after intracytoplasmic sperm injection. Lancet 1995;346:1095. 27. Ray BD, Howell RT, McDermott A, Hull MGR. Testing the mutagenic potential of polyvinylpyrrolidone and methyl cellulose by sister chromatid exchange analysis prior to use in intracytoplasmic sperm injection procedures. Hum Reprod 1995; 10:436-8. 28. Oehninger S, Veeck L, Lanzendorf S, Maloney M, Toner J, Muasher S. Intracytoplasmic sperm injection: achievement of high pregnancy rates in couples with severe male factor infertility is dependent primarily upon female and not male factors. Fertil Steril1995;64:977-81. 29. Martin J5B, Nisker JA, Tummon IS, Daniel SAJ, Auckland JL, Feyles V. Future in vitro fertilization pregnancy potential of women with variably elevated day 3 follicle stimulating hormone levels. Fertil SteriI1996;65:1238-40.

ERRATUMS

In the November 1996, Volume 18, Number 11 issue of the Journal SOGC, page 1157, we published a newspaper article titled "Physician Honored for Distinguished Service". The article incorrectly stated that Dr. Terry Riley is the only family physician member of the Society of Obstetricians and Gynaecologists of Canada. There are in fact over 167 family physician members of the SOGC in the Associate MD category. The article should have stated that Dr. Riley was the first member of the Associate MD section to be elected to the National Advisory Council. The publisher wishes to apologize to Dr. Riley and to the other Associate MD members of the SOGe. We regret any misunderstanding or embarrassment that this error may have caused. In the December 1996, Volume 18, Number 12 issue of the Journal SOGC we published a description of the front cover image which highlighted the article on the International Symposium on Screening for Cancer of the Cervix. The description was missing a portion of a sentence which may have caused the reader some confusion. The caption should have read as follows: The overlaid image on the front cover represents various components of Morphometrix Technology Inc's automated pap smear analysis sy&tern. Morphometrix Technology Inc., a Canadian company, is in the international forefront of developing an imaging system that will significantly advance the early detection and prevention of cervical cancer. The system encompasses servo-mechanisms, robotic devices and microscopes, along with a proprietary parallel processor designed to implement proprietary image processing and pattern recognition algorithms. For further information please contact Morphometrix Technology Inc., Toronto, Ontario 120 Adelaide Street East, Toronto, ON M5C lK9 Tel: 416-361-6232.

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