Ovarian stimulation havoc

International Congress Series 1279 (2005) 39 – 44

www.ics-elsevier.com

Ovarian stimulation havoc Peter A. van Dop* Catharina-ziekenhuis, Eindhoven, The Netherlands

Abstract. Controlled ovarian hyperstimulation (COH) has wreaked havoc in reproductive medicine. Both multiple pregnancies and ovarian hyperstimulation syndrome may damage patients and their offspring. Costs of both are enormous both financially as emotionally. COH in intra-uterine insemination is only indicated in unexplained and mild male subfertility. There is still a discrepancy between the recommendations of professional societies to avoid multiple pregnancies and daily practice. Not the crude pregnancy rate, but the birth of a healthy singleton baby should be the guideline in reproductive medicine. Physicians, policy makers and insurance companies should work together to reach this goal. D 2005 Elsevier B.V. All rights reserved. Keywords: Controlled ovarian hyperstimulation; Ovulation induction; Intra-uterine insemination; In vitro fertilization; Multiple pregnancies; Ovarian hyperstimulation syndrome; Prevention

1. Introduction A clear distinction must be made between ovarian stimulation for ovulation induction (OI) and stimulation in ovulating women for the purpose of multiple follicular development. The latter is named controlled ovarian hyperstimulation (COH). OI is a necessary medical treatment in subfertile, anovulatory patients. The main risks of ovulation induction: multiple pregnancies, ovarian hyperstimulation syndrome (OHSS) and costs are unavoidable. Close monitoring of ovarian response and patience by doctor and patient may reduce the risks, but ovulation induction is not possible with the same outcome risk profile as in spontaneously ovulating subfertile women. However, these risks are acceptable for the patient, the professional and the public domain, since there is the awareness that the costs (risks) are balanced by the profits, i.e., ovulation to overcome subfertility.

* Corresponding author. Tel.: +31 40 2908883; fax: +31 40 2908885. E-mail address: [email protected]. 0531-5131/ D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2004.12.047

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COH is used to enhance fertility in subfertile, but ovulating patients and in ovulating patients treated with assisted reproductive technologies (ART). The main domains are intra-uterine insemination (IUI) and in vitro fertilization (IVF), either without or with intracytoplasmic insemination (ICSI). 2. Efficiency of COH in unexplained subfertility Hughes et al. [1] carried out a systematic review on the efficiency of clomiphene in unexplained subfertility. Although the absolute treatment effect is small, given the low cost and ease of administration, clomiphene citrate appears to be a sensible first choice treatment for women with unexplained infertility. However, in making this treatment choice, concerns of long-term use and ovarian cancer risk, multiple pregnancy risk and minor symptoms should be discussed. Two papers [2,3] on the use of ovarian hyperstimulation make it unmistakably clear that multiple pregnancies are unavoidable using gonadotropins. Athaullah et al. [4] compared in a systematic review gonadotropins and clomiphene for unexplained subfertility. There is insufficient evidence to suggest that oral agents are inferior or superior to injectable agents in the treatment of unexplained subfertility. Present randomised clinical trials are too small to balance the pros and cons of COH in unexplained subfertility. From 1975 to 1989 multiple birth rates in the Netherlands increased by almost 40%. Only a quarter of the increase can be related to births after in vitro fertilization. Evidence is presented that ovulation induction as an independent therapy or in combination with other forms of assisted reproduction is highly responsible for the rising number of multiplets [5]. 3. Efficiency of COH in IUI The efficiency of IUI as therapy for subfertility has two main aspects: the efficiency of IUI itself and the efficiency of COH in IUI. Hughes [6] published a robust meta-analysis on the efficiency of IUI and COH. Both IUI and FSH independently improved the probability of conception. Meta-analyses have shown [7,8] IUI to be efficient in natural cycles in subfertile couples with male subfertility and cervical hostility. IUI with COH is only efficient in subfertile couples with unexplained and mild male subfertility. IUI with COH should be restricted to these two indications. Cost-effectiveness studies [9,10] comparing COH/IUI with IVF/ET have shown that COH/IUI is more cost-effective. 4. Multiple pregnancies in IUI with COH Multiple pregnancy rates (MPRs) in IUI with COH have been reviewed by Cohlen and Van Dop [11]. MPRs depend on the aggressiveness of the stimulation protocol. MPRs rise from 5% with clomiphene citrate (CC) with or without combination of human menopausal gonadotropins (hMG) with 0% triplets to 31% with 8.5% triplets in hMG/GnRH analog stimulated cycles. Monthly fecundity rates double from 0.09 to 0.20 but MPRs increase sixfold. The golden standard study of Guzick et al. [12] shows a MPR of 30% in COH IUI cycles, with 8% triplets or quadruplets. Despite strong voices both from the USA [13–15] and Europe and the USA together [16] as well as global [17] to reduce MPRs in ART a 2004 fortuitous study in Fertility and

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Sterility on platelet activating factor in IUI [18] shows a total MPR of 31.8% of which 13.6% twins, 9.1% triplets and 9.1% quadruplets. Not a single word in the discussion on the subject of multiple pregnancies due to IUI and COH, neither comments from the editors. 5. Efficiency of COH in IVF Human IVF was started in spontaneous cycles, but the results in on-going pregnancies were so low that already in the late 1970s and early 1980s COH ovarian stimulation was used. Initially clomiphene citrate alone or in combination with urinary gonadotropins was applied, usually with a moderate ovarian response. The undesirable early LH surges were overcome by GnRH agonists. This meant the end of clomiphene citrate in COH for IVF and at the same time the benefit of negative ovarian feedback mechanisms on the central gonadotropin releasing systems. The era of urinary menotropins began, practically always in combination with GnRH agonists. Later bmore potent than urinary gonadotropinsQ recombinant FSH formulations were developed. In combination with GnRH agonists and again with GnRH antagonists an unpredictable number of follicles could develop. Oocytes abound and with that plentiful embryos. All this has resulted in the OHSS [19] and the multiple pregnancy [20] issues. Interest in IVF in a natural ovulatory cycle has recently again been shown [21]. 6. Multiple pregnancies in IVF with COH The present protocols for COH in IVF yield so many embryos that selection for embryo transfer (ET) can be made. Unfortunately, the selection criteria are not that strong that the number of embryos transferred reflects the number of ongoing pregnancies. For this reason, multiple ET is customary. Already in 1993 it was shown that pregnancy rates did not change by transferring two instead of three embryos [22]. The same was demonstrated in a large British study [23]. However, the number of embryos transferred is in (many) countries not in agreement with recommendations from the professional societies. In countries where the number of embryos transferred does not exceed two (mainly Western and Northern Europe), the multiple pregnancy rates are still about 25% and can rise to 50% or more when two embryos of excellent quality are transferred [24]. Crossing the threshold of the transfer of more than two embryos leads to high order multiple pregnancies (HOMP). The adverse effects in perinatal morbidity and mortality [25] as well as costs become an even more serious problem. The limited number of cycles that can be carried out and lack of reimbursement put an enormous pressure on both patients and doctors to transfer more embryos than is advisable. 7. Costs of multiple pregnancies The costs of ART [26] and multiple pregnancies must not be underestimated. In 1994, Callahan et al. [27] showed a dramatic difference in hospital costs from $9845 for a singleton delivery, as compared with $37,947 for twins and $109,765 for a triplet delivery. In their study, ART had been used in 35% of twin and 77% of triplet deliveries. In a recent

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well-designed study by Gerris et al. [28] the neonatal costs in twin pregnancies were eight times higher than in singletons. 8. OHSS OHSS is an iatrogenic condition due to a complication in the luteal phase of a menstrual cycle in which ovulation induction or ovarian hyperstimulation (for ART) has been performed [29]. It is characterised by cystic enlargement of the ovaries and a fluid shift from the intravascular to the third space following increased capillary permeability. OHSS may be life-threatening and even lethal. Treatment for OHSS is at present not available, due to our lack of understanding its aetiology. What remains is management of the patient with OHSS and waiting till OHSS is extinguished by also unknown mechanisms. Textbooks and review papers on IVF [30] mention young age, low body weight and polycystic ovary syndrome (PCOS) as primary risks factors for OHSS. If the first two factors are put on the rack of evidence based medicine [31], these statements are not tenable. PCOS can be considered as a primary risk factor for OHSS. Secondary preventive procedures [32] including coasting, early unilateral follicular aspiration, alternatives to hCG in ovulation triggering, corticosteroids, intravenous macromolecules, intramuscular progesterone and cryopreservation of all embryos may decrease, but never prevent OHHS. The only secondary prevention is avoiding luteinisation by withholding hCG or LH. This means cancellation of cycle. Both patients and physicians are reluctant to accept or propose it. 9. Conclusion The introduction of COH has wreaked havoc in reproductive medicine. Patients are at serious risk due to an overabundance of multiple pregnancies and OHSS. Their offspring are also at serious perinatal risk due to the adverse effects of multiple pregnancies mainly because of preterm delivery. The costs, for the parents or for society, are considerable. COH alone in unexplained subfertility may improve the MFR, but costs–mainly multiple pregnancies–and benefits have not been balanced in a robust way. In IUI, COH is only efficient in unexplained and mild male subfertility. Neither doctors nor patients should be blamed for this havoc. Socio-economic circumstances may strongly influence decision making in ART. Reimbursement policies are probably most important. For this reason medical safety decisions are now in the public domain. 10. Recommendations The rate of (ongoing) pregnancies should not be the guideline of ART, but the rate of live born healthy singletons. National and international scientific societies on reproductive medicine should take the lead in convincing their members and professionals in the field of reproductive medicine that this is a new paradigm. Honest information on the risks of COH, both in the natural cycle and in ART should be given to couples looking for help for their subfertility problem. Policy makers, both in health insurance systems as well in national representative bodies should consider subfertility not as a luxury problem, but as a problem in the DNA domain . The professional field must inform these policy makers that

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the well-being of their clients and voters is at stake. Substantial evidence is presently available that indicates reduction of the number of multiple pregnancies is cheaper than the actual costs and aftermath of multiple pregnancies even when the number of ART attempts has to be extended to meet the reduction in present crude pregnancy rates in COH treatments. So, physicians, patients, insurance companies and policy makers all have a role to play. Hiding behind the responsibilities of the other parties will not solve the serious problem of havoc in COH. Acknowledgements No financial support or grants have been received by the author. The author has no interest in companies supplying goods in the field of reproductive medicine. References [1] E. Hughes, J. Collins, P. Vandekerckhove, Clomiphene citrate for unexplained subfertility in women, Cochrane Database Syst. Rev. (2000) CD000057. [2] R.P. Dickey, T.T. Olar, Hormone treatment for infertility. restrictions won’t prevent multiple pregnancies, BMJ 307 (1993) 1281 – 1282. [3] T.J. Child, D.H. Barlow, Strategies to prevent multiple pregnancies in assisted conception programmes, Baillieres Clin. Obstet. Gynaecol. 12 (1998) 131 – 146. [4] N. Athaullah, M. Proctor, N.P. Johnson, Oral versus injectable ovulation induction agents for unexplained subfertility, Cochrane Database Syst. Rev. (2002) CD003052. [5] Y.A. Van Duivenboden, J.M. Merkus, S.P. Verloove-Vanhorick, Infertility treatment: implications for perinatology, Eur. J. Obstet. Gynecol. Reprod. Biol. 42 (1999) 201 – 204. [6] E.G. Hughes, Stimulated intra-uterine insemination is not a natural choice for the treatment of unexplained subfertility. deffective treatmentT or dnot a natural choiceT? Hum. Reprod. 18 (2003) 912 – 914. [7] B.J. Cohlen, et al., Controlled ovarian hyperstimulation and intrauterine insemination for treating male subfertility: a controlled study, Hum. Reprod. 13 (1998) 1553 – 1558. [8] B.J. Cohlen, E.R. te Velde, Mild ovarian hyperstimulation for intrauterine insemination, in: B. Tarlatzis (Ed.), Ovulation Induction, Elsevier, 2002, pp. 53 – 64. [9] C.M. Peterson, et al., Ovulation induction with gonadotropins and intrauterine insemination compared with in vitro fertilization and no therapy: a prospective, nonrandomized, cohort study and meta-analysis, Fertil. Steril. 62 (1994) 535 – 544. [10] A.J. Goverde, et al., Intrauterine insemination or in-vitro fertilization in idiopathic subfertility and male subfertility: a randomised trial and cost-effectiveness analysis, Lancet 355 (2001) 13 – 18. [11] B.J. Cohlen, P.A. Van Dop, Prevention of multiple pregnancies after non-in vitro fertilization treatment, in: J. Gerris, et al. (Eds.), Assisted Reproductive Technologies, The Parthenon Publishing Group, New York, 2004, pp. 39 – 48. [12] D.S. Guzick, et al., Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National cooperative reproductive medicine network, N. Engl. J. Med. 340 (1999) 177 – 183. [13] H.W. Jones, Multiple births: how are we doing? Fertil. Steril. 79 (2003) 17 – 21. [14] H.W. Jones Jr., A big first step, Hum. Reprod. 19 (2004) 2445. [15] The Practice Committee of the American Society for Reproductive Medicine, Guidelines on the number of embryos transferred, Fertil. Steril. 82 (2004) 773 – 774. [16] J. Cohen, H.W. Jones Jr., How to avoid multiple pregnancies in assistive reproductive technologies, Semin. Reprod. Med. 19 (2001) 269 – 278. [17] E.Y. Adashi, et al., Infertility therapy-associated multiple pregnancies (births): an ongoing epidemic, Hum. Reprod. 19 (2004) 917 – 923. [18] W.E. Roudebush, et al., Platelet-activating factor significantly enhances intrauterine insemination pregnancy rates in non-male factor infertility, Fertil. Steril. 82 (2004) 52 – 56.

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[19] A. Delvigne, Epidemiology and pathophysiology of ovarian hyperstimulation syndrome, in: J. Gerris, et al. (Eds.), Assisted Reproductive Technologies, The Parthenon Publishing Group, New York, 2004, pp. 149 – 162. [20] A. Pinborg, A.N. Andersen, Epidemiology of multiple pregnancy including natural versus iatrogenic multiple pregnancy, in: J. Gerris, et al. (Eds.), Assisted Reproductive Technologies, The Parthenon Publishing Group, New York, 2004, pp. 9 – 22. [21] M.J. Pelinck, et al., Efficacy of natural cycle IVF: a review of the literature, Hum. Reprod. Update 8 (2) (2002 March–April) 129 – 139. [22] C. Staessen, et al., Avoidance of triplet pregnancies by elective transfer of two good quality embryos, Hum. Reprod. 8 (1993) 1650 – 1653. [23] A. Templeton, J.K. Morris, Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization, N. Engl. J. Med. 339 (1998) 573 – 577. [24] E. Van Royen, Embryo selection for elective single-embryo transfer, in: J. Gerris, et al. (Eds.), Assisted Reproductive Technologies, The Parthenon Publishing Group, New York, 2004, pp. 63 – 80. [25] U.-B. Wennerholm, Obstetric risks and neonatal complications of twin pregnancy and high-order multiple pregnancy, in: J. Gerris, et al. (Eds.), Assisted Reproductive Technologies, The Parthenon Publishing Group, New York, 2004, pp. 23 – 38. [26] L. Garceau, et al., Economic implications of assisted reproductive techniques: a systematic review, Hum. Reprod. 17 (2002) 3090 – 3109. [27] T.L. Callahan, et al., The economic impact of multiple-gestation pregnancies and the contribution of assisted-reproduction techniques to their incidence, N. Engl. J. Med. 331 (1994) 244 – 249. [28] J. Gerris, et al., A real-life prospective health economic study of elective single embryo transfer versus twoembryo transfer in first IVF/ICSI cycles, Reprod. Biomed. Online 7 (5) (2003 November) 515 – 542. [29] C.C. Beerendonk, et al., Ovarian hyperstimulation syndrome: facts and fallacies, Obstet. Gynecol. Surv. 53 (1998) 439 – 449. [30] The Practice Committee of the American Society for Reproductive Medicine, Ovarian hyperstimulation syndrome, Fertil. Steril. 80 (2003) 1309 – 1314. [31] Van Dop, Primary risks factors in OHSS, in: F. Olivennes, A. Delvigne, J. Gerris (Eds.), Pre-Congress Course Syllabus Sig Safety and Quality in ART on bOvarian Hyperstimulation SyndromeQ, ESHRE, Berlin, 2004. [32] F. Guibert, F. Olivennes, Ovarian hyperstimulation syndrome: prevention in IVF and non-IVF treatment, in: J. Gerris, et al. (Eds.), Assisted Reproductive Technologies, The Parthenon Publishing Group, New York, 2004, pp. 169 – 180.