Cumulative number and morphological score of embryos resulting in success: realistic expectations from in vitro fertilization-embryo transfer

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1 FERTILITY AND STERILITY Copyight" 1995 Ameican Society fo Repoductive Medicine Pinted on acid-fee pape in U. S. A. Cumulative numbe and mophological scoe of embyos esulting in success: ealistic expectations fom in vito fetilization-embyo tansfe Alan B. Coppeman, M.D.*t Cayn E. Selick! M.D. Lawence Gunf-eld, M.D. Benjamin Sandle, M.D. Maia Bustillo, M.D. Division of Repoductive Endocinology, Depatment of Obstetics and Gynecology, The Mount Sinai School of Medicine, New Yok, New Yok Objective: To define statistical thesholds fo the numbe and mophological scoe of embyos tansfeed that would be pedictive of epoductive success in an IVF pogam. Design: A etospective eview of patient ecods. Setting: The Mount Sinai Medical Cente Assisted Repoductive Technologies Pogam. Paticipants: One hunded women who undewent IVF-ET fo a diagnosis oftubal occlusion and late deliveed viable infants. Results: The mean numbe of embyos tansfeed befoe achieving live bith was 1.7 ± 7.9 (mean ± SD), with one half of patients achieving success within the fist seven embyos tansfeed, and 95% achieving success within 25 embyos. Fo high quality embyos, the numbes wee 7.5 ± 6.3,5, and 17, espectively, and, fo the cumulative embyo scoe, a measue of both embyo mophology and metabolic activity, wee ± 86.,83, and 28, espectively. Geate than 5% of live biths occued within the fist two ET attempts. Conclusions: Although moe than half of patients achieved epoductive success within the fist two ETs and the fist five high quality embyos tansfeed, afte this theshold, fecundity declined apidly. The calculation of cumulative embyo scoes offeed additional pognostic infomation. While all pio attempts to define IVF-ET failue have done so by including patients who did not become pegnant, we have found an analysis of ou successes to be a useful adjunct in counseling patients. Fetil Steil 1995 ;64:88-92 Key Wods: Embyo mophology, fetilization-in vito, infetility-teatment, pegnancy, statistical models Couples enteing IVF pogams often equest and ae inundated with complex statistical data egading pobability of success. These figues usually include implantation ate and oveall pegnancy ate pe cycle and ae given as a ough estimate of that couple's chance fo success in a given cycle. Fom Received Octobe 4, 1994; evised and accepted Febuay 3, * Repint equests: Alan B. Coppeman, M.D., Division of Repoductive Endocinology, Depatment of Obstetics and Gynecology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 117, New Yok, New Yok 129 (FAX: )_ t D. Coppeman is the Matin J. Clyman Fellow. 88 Coppeman et al. Realistic expectations fom IVF-ET the viewpoint of the infetile couple at the stat of the IVF pocess, howeve, moe elevant infomation might include the chance oftaking home a baby afte a specified numbe of cycles and a defined financial cost. A lack of patient undestanding of this concept may lead to unealistic expectations fom the onset concening the chance fo a successful outcome (1). Life-table analyses have been pefomed in an attempt to povide pognostic infomation to patients who undego multiple cycles ofivf. Unfotunately, life-table analyses ae limited by possible confounding vaiables, such as spontaneous o backgound pegnancy ate, heteogeneous patient populations, loss to follow-up, and dopouts seconday to mount- Fetility and Steility

2 ,... ing costs o physician discouagement to poo candidates. Similaly, each pogam's sentiments towad aggessiveness of gonadotopin stimulation, attitudes towad multiple ET, and policy and efficiency of cyopesevation may make outcome data pogam specific. A simple method fo offeing accuate cumulative pognostic infomation has not been available. In addition to offeing pognostic infomation to patients, a ational basis fo analysis and appaisal of data is necessay to addess the inceasing medical, ethical, legislative, and financial costs of emeging technology. A well-delineated theshold, up to which a successful outcome will be achieved in the vast majoity of patients, must be defined. Patients not conceiving upon eaching that theshold could be offeed altenative teatment modalities. We analyzed the ecods of patients who conceived though ou IVF pogam in an attempt to offe accuate pognostic infomation to couples enteing ou pogam. We collected and ecoded infomation including the cumulative numbe of high quality embyos tansfeed, the total numbe of embyos tansfeed, and the cumulative embyo scoe (a function of embyo division ate as well as mophology) tansfeed befoe conception and delivey. We included only patients with infetility seconday to tubal disease in an attempt to make the cohot homogeneous. Ou aim was to define a theshold within which nealy all women become pegnant, to offe pognostic infomation to patients while establishing a ational basis fo what should be consideed an adequate tial of IVF. MATERIALS AND METHODS A etospective chat eview was pefomed of all patients who deliveed live bon infants between Januay 1989 and Mach 1994 esulting fom IVF at Mount Sinai Medical Cente in New Yok. Only patients with a pimay diagnosis of tubal occlusion wee included in the analysis. Patients having known cycles of IVF at othe institutions wee excluded. The ovaian stimulation potocols, monitoing of follicula gowth and homone pofiles, administation of hcg, method of oocyte ecovey, IVF of - cytes, gowth of embyos in cultue, and ET technique have been descibed peviously (2). Embyo gading was pefomed using a scale of 1 to 5, accoding to the Veeck Classification System (3, 4). High quality embyos efe to embyos having Veeck gades 1 o 2. Thee was a total of eight embyologists gading the embyos ove the past 5 yeas. In ou laboatoy, embyos ae photogaphed befoe tansfe, and peiodic analysis of inte obseve vai- ation is pefomed. We have calculated inteobseve phi coefficients anging fom.78 to.95, and have completely concodant gades 62% of the time and ageement within one gade (e.g., gade 1 vesus gade 2) >99% of the time. The cumulative embyo scoe was then calculated as a measue of both embyo mophology and metabolic (cleavage) activity (5). To convet conventional gading to cumulative embyo scoe, the Veeck gades wee fist inveted by subtacting the gade fom 5 (e.g., a gade 1 was eclassified as a gade 4, a gade 2 as a gade 3, and so on), and this numbe was then multiplied by the total numbe of blastomees within the embyo (a fou-cell Veeck gade 2 has a cumulative embyo scoe of 12). In cases of fozen embyos, the total numbe of intact blastomees that suvived the thawing pocess was used as the multiplie. The numbe of tansfe cycles included tansfes of eithe fesh o cyopeseved embyos. Cyopesevation of embyos was pefomed in the usual fashion, using 1,2- popanediol as a cyopotectant, as descibed peviously (6). Although the application of cumulative embyo scoes to cyopeseved embyos has not been specifically validated, we believe that this is easonable, because we have shown in ou institution that the implantation potential fo high quality embyos is not significantly impaied by cyopesevation and thawing (7). Statistical analysis was pefomed using the softwae StatView 4.1 (Abacus Systems, Bekeley, CA) on a Macintosh IIci compute. Desciptive data and multiple egession analyses wee used as indicated. A cumulative histogam was ceated athe than a life-table analysis, because the data wee not censoed. RESULTS One hunded patients wee evaluated with a mean age of 34. ::!:: 3.6 yeas (mean::!:: SD) and a ange fom 26 to 42 yeas. They had a mean day 3 FSH of 11.3 ::!:: 3.6 miu/ml, anging fom 4. to 21. miui ml (convesion facto to SI unit, 1.). The 1 pl;lgnancies included 18 twin, 3 tiplet, 1 quaduplet gestation selectively educed to twins, and 1 heteotopic pegnancy, all of which esulted in at least one live bon infant. Sixty-seven pegnancies esulted fom fesh ETs, wheeas 33 wee the poduct of cyopeseved embyos. The esults of the numbe of embyos tansfeed to achieve live bith ae summaized in Table 1. The mean numbe of total embyos was 1.7 ::!:: 7.9, with a ange of 3 to 45, with one half of patients achieving pegnancy within the fist 7 embyos tansfeed, and 95% achieving pegnancy within 25 embyos Coppeman et al. Realistic expectations fom NF-ET 89 I

3 Table 1 Desciptive Data Regading Numbe and Cumulative Embyo Scoe of Embyos Tansfeed Resulting in 1 Live Biths Mean:!: SD No. of fesh 7.4 :!: 5. No. of fesh (high quality embyos) 5.3 :!: 4.4 No. of fozen 3.2 :!: 4.9 No. of fozen (high quality embyos) 2.2 :!: 3.6 Total 1.7 :!: 7.9 Total (high quality embyos) 7.5 :!: 6.3 Cumulative embyo scoe fesh 85.2 :!: 62.1 Cumulative embyo scoe fozen 29.:!: 44.7 Cumulative embyo scoe total :!: 86. Tansfe cycle no. 2.4 :!: 1.8 Minimum Maximum Median 95th pecentile tansfeed. The mean total numbe of high quality embyos was 7.5 ± 6.3 with a median of 5 and a 95th pecentile of 18. The mean cumulative embyo scoe was ± 86., anging fom 2 to 54. The 95th pecentile fo the cumulative embyo scoe was 28. The mean numbe of tansfe cycles equied befoe achieving a live bon infant was 2.4, with moe than half of patients achieving pegnancy within the fist two attempts and 95% achieving pegnancy within the fist six attempts. The statistical data ae summaized in the cumulative fequency histogams in Figues 1, 2, and 3. To pefom egession analysis, nomalization of the data was pefomed using a logaithmic tansfomation. Multiple egession analysis of cumulative embyo scoe, total numbe of embyos, and total numbe of tansfe cycles against age and day 3 FSH showed. a positive but not significant coelation (data not shown), most likely the esult of the selection of only women with tubal facto infetility fo evaluation in this study. DISCUSSION Attempts to estimate the likelihood of pegnancy fo couples undegoing IVF often have evaluated 1 o success on a pe cycle basis. Because the aveage take-home baby ate is appoximately 1% to 15% pe cycle (8), a successful outcome often equies seveal attempts. Fom the viewpoint of the patient, theefoe, the elevant pognostic infomation is the pegnancy and delivey ate that can be expected afte a specified numbe of cycles (9). Life-table analysis has been used fo this pupose (9-13). Conclusions fom these studies suggest that the majoity of pegnancies occu within the fist few cycles and that vaiability in patient age, ovaian function, spem quality, and infetility etiology make genealizing the cumulative infomation to specific patients hazadous. Unfotunately, life-table analyses ae based on the pemise that patients lost to follow-up ae identical to patients who continue to be followed and teated (1). This pemise has not been shown to hold tue fo fetility studies, howeve, because patients who discontinue teatment may have been encouaged to do so because of pevious poo esponse o lack of fetilization (14). Inteest has theefoe been expessed in developing models that update individual pobabilities on an intemittent basis (15). It appeas that the pobability of success in IVF deceases with each unsuccessful attempt. Most women who achieve pegnancy do so quickly, with 2 " :E "l S U 2 o # total embyos Numbe of embyos [] # high quality embyos Figue 1 Cumulative fequency histogam plotting the total numbe and total numbe of high quality embyos tansfeed against the cumulative pecentage of women deliveing live bon infants D.."l S U 4 2 o [ CEStotai 4 5 Figue 2 Cumulative fequency histogam plotting cumulative embyo scoe (CES total) against the cumulative pecentage of women deliveing live bon infants. 9 Coppeman et al. Realistic expectations fom IVF-ET Fetility and Steility

4 1 - _ f! 6 :E, OJ u 2 -- o #ofcycles Figue 3 Cumulative fequency histogam plotting the total numbe ofet cycles against the cumulative pecentage of women deliveing live bon infants. the majoity of pegnancies occuing within the fist two attempts, ageeing with pio published epots (16). Othe patients fail to conceive afte as many as nine attempts at IVF. Thus the statistic "aveage pegnancy pe cycle" fails to account fo the heteogeneity in fecundability among couples poceeding though seveal cycles of IVF (17). One study suggested that this decline in pegnancy ate was the esult of antiovay antibodies developing in patients undegoing successive IVF cycles (18). Thee is an accumulating body of evidence pointing to the impotance of immunologic factos in evaluating the infetile couple. n is possible that epeat failues may be evidence of efactoy infetility, pehaps sufficiently impaied to waant a cessation of futhe attempts at IVF-ET. The need theefoe aises fo the ceation of a statistical model to evaluate success within pogams, compae success ates between pogams, and offe an accuate potayal of cumulative pognosis to patients. The selection of patients with tubal facto infetility fo this model was made fo seveal easons: [1] this goup is moe likely to be homogeneous, [2] subfetile patients with unexplained infetility ae theoetically moe likely to conceive spontaneously, and [3] it eliminates the bias of intecycle vaiability intoduced by vaiables such as poo quality spem. It is possible that subgoups of patients with vaiable pognoses may exist within ou tubal facto infetility cohot. Thoough sonogaphic evaluation of the uteine cavity befoe IVF-ET theoetically allowed identification and sugical intevention of patients with uteine and cevical pathology befoe initiating thei cycles. Cetainly, futhe application of this scoing system to geate numbes of patients with moe specific pathologies might allow futhe subgoup analyses, fo example, tubal occlusion seconday to steilization vesus tubal occlusion second- ay to pelvic inflammatoy disease. The use of live biths athe than clinical pegnancy was chosen as an endpoint, as this is, afte all, the desied outcome. Combining infomation about embyo mophology (19) and embyo gowth ates (2) epotedly impoves pedictive accuacy, thus the cumulative embyo scoe, fist descibed by Stee et al. (5), was calculated fo each patient. Ou esults suggest that the pognosis fo successful outcome diminishes with each successive attempt at IVF. Moe than half of patients who had successful pegnancies did so within the fist five high quality embyos tansfeed. Ninety-five pecent of patients who achieved epoductive success did so within the fist six tansfe cycles o 25 embyos tansfeed. This esult may be influenced by an unknown numbe of patients who initially wee unsuccessful and dopped out, had tansfeed to othe pogams, had exhausted financial o emotional esouces, o wee discouaged by physicians fom continuing. Inteestingly, fou patients eventually became pegnant afte not succeeding within the fist 3 embyos tansfeed. The value of calculating the cumulative embyo scoe is demonstated in Figue 4. The 95th pecentile fo cumulative embyo scoe was aived at faily quickly in some patients (within thee ETs in one patient), pehaps suggesting that an adequate tial of IVF aleady had been achieved. Othe patients equied up to eight tansfe cycles to each the cumulative embyo scoe theshold. By evaluating a homogeneous cohot of patients with only tubal facto as the indication fo IVF, all of whom wee successful, we have intoduced a new method to offe pognostic infomation to patients initiating IVF attempts, as well as to patients eaddessing thei chances afte initially unsuccessful cycles. The statistical elevance of cumulative num ;;;3 w #cycles Figue 4 Scattegam plotting the numbe of ET cycles against the cumulative embyo scoe eached at the time of pegnancy (CES total). CES total = X no. of cycles. R2 =.756. Coppeman et al. Realistic expectations fom NF-ET 91 o

5 be of cycles and embyos may lie in its ability to give the infetile couple impotant oveall pognostic infomation fom the onset of teatment. The numbe of high quality embyos and cumulative embyo scoes may be used as indicatos of ETs to date and theefoe may be moe meaningful afte seveal teatment cycles have been ecoded. In view of the psychological impact of epeated unsuccessful attempts at IVF in some patients (21), it is impotant to be able to single out some pognostic factos that would allow a moe exact estimation ofthe pobability fo success in each case. A compehensive statistical model will allow the clinician to offe pecise pognostic infomation egading the numbe of embyos equied fo success in patients with vaious infetility etiolpgies. In patients who do not conceive despite a high cumulative numbe of embyos and a high cumulative embyo scoe, one might be guided towad an evaluation of possible uteine o immunologic dysfunction. This technique, if veified using lage numbes and coss-validated among pogams, may pove to be a valuable adjunct in the counseling of the infetile couple and the allocation of health cae esouces. REFERENCES 1. Paulson RJ, Saue MY. Counseling the infetile couple: when is enough enough. Obstet GynecoI1991;78: Laufe N, Gunfeld L, Gaisi GJ. In-vito fetilization. In: Seibel MM, edito. Infetility. A compehensive text. Nowalk (CT): Appleton & Lange, 199: Veeck' L. The mophological assessment of human oocytes and ealy concepti. In: Keel BA, Webste BW, editos. Handbook of the laboatoy diagnosis and teatment of infetility. Boca Raton (FL): CRC Pess, 199: Veeck L. Peembyo gading. Atlas of the human oocyte and ealy conceptus. Vol. 2. Baltimoe: Williams and Wilkins, 1991: Stee CV, Mills CL, Tan SL, Campbell S, Edwads RG. The cumulative embyo scoe: a pedictive embyo scoing technique to select the optimal numbe of embyos to tansfe in an in-vito fetilization and embyo tansfe pogam. Hum Repod 1992;7: Gaisi G, Navot D. Cyopesevation of semen, oocytes, and embyos. Cu Opin Obstet GynecoI1992;4: Selick CE, Hofmann GE, Albano C, Hoowitz GM, Coppeman AB, Navot D. Pegnancy potential of fesh vs fozen embyos-is feezing detimental to high quality embyos? Hum Repod. 1995;1: Society fo Assisted Repoductive Technology. The Ameican Fetility Society. Assisted epoductive technology in the United States and Canada: 1991 esults fom the Society fo Assisted Repoductive Technology geneated fom the Ameican Fetility Society Registy. Fetil SteiI1993;59: Guzick DS, Wilkes C, Jones HW J. Cumulative pegnancy ates fo in vito fetilization. Fetil SteiI1986;46: Guzick DS, Rock JA. Estimation of a model of cumulative pegnancy following infetility theapy. Am J Obstet Gynecol 1981 ;14: Kovacs GT. The likelihood of pegnancy with IVF and GIFT in Austalia and New Zealand. Med J Aust 1993;158: Tan SL, Doyle P, Maconochie N, Edwads RG, Balen A, Beki J, et al. Pegnancy and bith ates of live infants afte in vito fetilization in women with and without pevious in vito fetilization pegnancies: a study of eight thousand cycles at one cente. Am J Obstet GynecoI1994;17: Wilcox LS, Peteson HB, Haseltine FP, Matin MC. Defining and intepeting pegnancy success ates fo in vito fetilization. Fetil Steil1993;6: Heshlag A, Kaplan EH, Loy RA, DeCheney AH, Lavy G. Heteogeneity in patient populations explains diffeences in in vito fetilization pogams. Fetil SteiI1991;56: Bouckaet A, Baeten S, de Cooman S, Thomas K, Loumaye E. In-vito fetilization: how many attempts befoe success? Hum Repod 1989;4: Seibel MM, Ranoux C, Keanan M. In vito fetilization: how much is enough? [lette]. N Engl J Med 1989;321: Kaplan EH, Heshlag A, DeCheney AH, Lavy G. To be o not to be? That is conception! Managing in vito fetilization pogams. Manage Sci 1992;38: Babaino-Monnie P, Gobet B, Guillet-Rosso F, Bene MC, Landes P, Faue G. Antiovay antibodies, epeated attempts, and outcome of in vito fetilization. Fetil Steil 1991; 56: Scott RT J, Hofmann GE, Veeck LL, Jones HW J, Muashe SJ. Embyo quality and pegnancy ates in patients attempting pegnancy though in vito fetilization. Fetil Steil 1991 ;55: Cummins JM, Been TM, Haison KL, Shaw JM, Wilson LM, Hennessey JF. A fomula fo scoing human embyo gowth ates in in vito fetilization: its value in pedicting pegnancy and in compaison with visual estimates of embyo quality. J In Vito Fet Embyo Tansf 1986;3: Black RB, Walthe VN, Chute D, Geenfeld DA. When in vito fetilization fails: a pospective view. Soc Wok Health Cae 1992;17: Coppeman et ai. Realistic expectations fom NF-ET Fetility and Steility