A.M.Stolwijk 1 ' s, G.A.Zielhuis 1, CJ.C.M.Hamilton 2, H.Straatman 1, J.M.G.Hollanders 2, HJ.M.Goverde 2^3, P.A. van Dop 4 and A.L.M.

Transcription

1 Huma Reproductio vol 11 o.10 pp , 1996 Progostic models for the probability of achievig a ogoig pregacy after i-vitro fertilizatio ad the importace of testig their predictive value A.M.Stolwijk 1 ' s, G.A.Zielhuis 1, CJ.C.M.Hamilto 2, H.Straatma 1, J.M.G.Holladers 2, HJ.M.Goverde 2^3, P.A. va Dop 4 ad A.L.M.Verbeek 1 'Departmet of Medical Iformatics, Epidemiology ad Statistics, Uiversity of Nijmege, P.O. Box 9101, NL-6500 HB Nijmege, 2 Departmet of Obstetrics ad Gyaecology, Uiversity Hospital Nijmege, 3 Laboratory of Edocriology ad Reproductio, Uiversity Hospital Nijmege, ad 4 Departmet of Obstetrics ad Gyaecology, Catharia Hospital, Eidhove, The Netherlads ^o whom correspodece should be addressed The aim of this study was to create reliable models to predict the probability of achievig a ogoig pregacy durig i-vitro fertilizatio (IVF) treatmet: model A, at the start of the first treatmet, model B, at the tue of embryo trasfer, ad model C, durig the secod treatmet at the ed of the first IVF treatmet Progostic models were created usig data from the Uiversity Hospital Nijmege ( = 757) ad applied to the data from the Catharia Hospital Eidhove ( = 432), The Netherlads, to test their predictive performace. The predictios of model B (made at time of embryo trasfer) were fairly good (c = i the test populatio). For istace, 93% of the patiets who had a predicted probability of achievig a ogoig pregacy of <10% did ot achieve a ogoig pregacy. However, the predictios of the other two models (A ad C) for Eidhove were less reliable. The predictive value of model C was fairly high i Nijmege (c = 0.673). Its poor performace i the test populatio may be explaied partly by differeces i effectiveess of the ovulatio stimulatio protocols ad the decisio about whe to discotiue the cycle. Thus, before usig progostic models at a IVF cetre, their reliability at that specific cetre should be tested. Key words: i-vitro fertilizatio/ogoig pregacy/pregacy/ progosis/validatio Itroductio The probability that a patiet will achieve a ogoig pregacy should be evaluated as accurately as possible before a patiet eters a programme for i-vitro fertilizatio (IVF) ad durig the course of her treatmet with IVF. I additio to the age of the woma ad the aetiology of ifertility (the stadard idicators for success), better rules would be welcome for physicias whe cousellig a patiet. Potetial predictors of IVF success are: patiet characteristics at etry to the programme, characteristics of the treatmet itself ad durig treatmet, ad itermediate results Most studies o factors that may predict pregacy after treatmet with IVF have ivestigated oly a few idicators, for istace age ad the type of ifertility (Piette et al, 1990; Hull et al, 1992; Check et al, 1993), baselie follicle stimulatig hormoe (FSH), luteiizig hormoe (LH) ad oestradiof cocetratios (Padilla et al, 1990), ovulatio stimulatio treatmet ad ovaria respose (Dor et ah, 1992), edometum thickess ad uterie artery flow (Spemol et al., 1993), sperm characteristics (Egisu et al, 1992) ad age, oestradiol cocetratio, umber ad quality of oocytes ad embryos (Fluker et al, 1993). However, various simultaeous factors may ifluece the probability of achievig a ogoig pregacy after IVF. It would therefore be desirable to create a model to predict the probability of achievig a ogoig pregacy which icludes all the relevat factors. Util ow, oly a few attempts have bee made to do this for IVF (Hughes et al, 1989; Haa et al, 1991) ad other assisted reproductive techiques (Guzick et al, 1989; Nelso et al, 1993). I the study by Hughes et al. (1989), age ad failed fertilizatio due to poor sperm quality had a predictive value for success i subsequet IVF cycles. Haa et al. (1991) foud that the probability of achievig a ogoig pregacy after IVF treatmet was icreased by the presece of idiopathic ifertility ad decreased by the presece of a male factor, oe ovary, the woma's age s= 36 years, primary ifertility of at least 5 years duratio ad by a higher umber of previous IVF treatmets. Multivariate progostic models should ot be cofused with explaatory models such as recetly published by Roseboom et al. (1995). They discussed a multivaate model to explai the variatio i the probability of pregacy after embryo trasfer. The variatio was explaied by the woma's age, average embryo morphology score, umber of trasferred embryos ad a iteractio term betwee tubal pathology ad the woma's age. However, exclusio of the mai effect of tubal pathology i the model makes a meaigful iterpretatio of the multivariate model difficult (Breslow ad Day, 1980) ad may cause bias (Kleibaum et al, 1982). Moreover, their statemet i the results sectio '...with a 1 year icrease of age, the probability of pregacy for o-tubal patiets decreased by 21%...' is obviously mistake as a result of a wrog iterpretatio of the odds ratio i their study. Critical remarks ca also be made about the methods used i the other four studies metioed above (Guzick et al, 1989; Hughes et al, 1989; Haa et al, 1991; Nelso et al., 1993). All the cycles were combied, irrespective of the umber of previous IVF treatmets ad the umber of treatmets per patiet. Some studies based the iclusio of factors o statistical sigificace of the relatioship i uivariate aalyses, which ca be iflueced by other factors, istead of o the icrease i Europea Society for Huma Reproductio ad Embryology

2 Progosis of ogoig pregacy after IVF the predictive power i multivaate models. Moreover, the predictios of these models were ever tested i other populatios Thus, the validity of these progostic models whe used at other IVF cetres ca be questioed. The purpose of this study is to create reliable models to predict the probability of achievig a ogoig pregacy durig the first or secod treatmet cycles with IVF. We used data from the Uiversity Hospital Nijmege, The Netherlads, to develop the models, ad data from aother cetre to test their predictive value. Materials ad methods To develop the progostic models, data were used from couples who were treated by IVF for the first time i the period March 1991 to Jauary 1995 at the Uiversity Hospital, Nijmege, The Netherlads Durig this period IVF treatmet hardly chaged. To test these models, data were used from the Cathaa Hospital, Eidhove, The Netherlads Guidelies o idicatios for IVF treatmet i the Netherlads have bee described by Jase (1993). I short, couples are oly offered IVF treatmet i case of bilateral tubopathology, i cases of uilateral tubopathology, male factor, edometosis or cervical factor whe other ifertility treatmets had ot resolved the problem, ad i case of ldiopathic ifertility after a ifertility duratio of at least 3 years. For both populatios data were oly icluded if the complete IVF treatmet had bee eared out at that particular IVF cetre, o door oocytes had bee used ad o ltracytoplasmatic sperm ijectio (ICSI) had bee performed. Patiet characteristics prior to treatmet are give i Table I. Ogoig pregacy was defied as a pregacy which cotiued for loger tha 12 weeks after embryo trasfer. To predict the probability of achievig a ogoig pregacy, three models were developed that employed differet momets of predictio. To predict the probability of achievig a ogoig pregacy durig the first IVF treatmet, model A was made at the start ad model B at the time of embryo trasfer. For the progosis of achievig a ogoig pregacy durig the secod IVF treatmet, model C was created at the ed of the first IVF treatmet. Table II presets the umber of patiets ad pregacies at each predictio momet Model A This model was based o predictios made at the start of the first IVF cycle regardig the probability of achievig a ogoig pregacy durig the first IVF cycle. To develop this model, data were available from 757 couples whose first IVF cycle took place i Nijmege. To iduce ovulatio, all the patiets received a log protocol of goadotrophi-releasig hormoe (GRH) agoist (usually Leuprobde; Abbott B.V., Amstelvee, The Netherlads or Suprefact; Hoechst Hollad N.V., Amsterdam, The Netherlads) that was started o day 21 of the previous cycle ad huma meopausal goadotrophi (HMG, Humego; Orgao It B.V., Oss, The Netherlads). Additioally, from August 1991 to Jauary 1994, all the patiets received oral cotraceptives durig the cycle that preceded the IVF cycle. To improve sychroizatio of follicle growth, some wome received oral cotraceptives before or after this period. To test the model, data were available from 432 couples from Eidhove who uderwet their first IVF treatmet betwee Jauary 1990 ad Jue 1995 (aother five couples were excluded from this populatio because iformatio about the occurrece of a ogoig pregacy was lackig). I this test populatio, the type of ovulatio iductio used most ofte (92 2%) was a short protocol of GRH agoist (usually Suprefact; Hoechst Hollad N.V) ad HMG (Humego, Orgao It. B.V), i a few cases supplemeted by progestis i the precedig cycle. Potetial progostic factors for the model that employed the oset of the first IVF cycle as the momet of predictio could oly cosist of iformatio kow at that momet, l e. patiet characteristics: age, period of ifertility, reproductive history, basal FSH, mdicatio(s) for IVF treatmet, oe or both ovaries preset, sperm characteristics, ati-sperm atibodies i the woma or ma, ad iformatio about the treatmet protocol beig used at that ume: type of hormoal ovulauo stimulatio, maximum umber of embryos that would be trasferred, timig of huma choriorac goadotrophi (HCG) admiistratio ad type of culture medium. I Nijmege, data o the duratio of ifertility were oly available from patiets who started IVF treatmet betwee Therefore the effect of the duratio of ifertility could oly be estimated usig the data from these 383 couples Door spermatozoa had ot bee used i Nijmege, but it had bee used i the test populatio i four ad six patiets durig the first ad secod IVF cycles respectively. If door spermatozoa had bee used, the sperm characteristics were cosidered to be good ad the idicatio for IVF 'male factor' was cosidered to be abset We disregarded the results of cryopreserved embryo trasfer. Model B Based o predicuos made at the time of embryo trasfer regardig the probability of achievig a ogoig pregacy durig the first IVF cycle Oly the data from couples who uderwet embryo trasfer dug the first cycle were used to develop this model. Data were available from 604 (79.8% of the 757) couples from Nijmege To test the model, data could be used from 300 (69.4% of the 432) couples from Eidhove. At this momet, iformatio was added about precedig evets durig the cycle as potetial progosuc factors, l e quality ad umber of oocytes retrieved, umber of oocytes fertilized, quality ad umber of embryos trasferred ad whether the trasfer had bee ucomplicated as idicated by the use of a Wallace catheter, because i difficult cases a suffer, Frydma catheter was used. I additio, iformatio was kow about the experiece of the physicia who performed the pucture ad trasfer; this could be used as a poteual progostic factor Agai, the results of cryopreserved embryo trasfers were disregarded. Model C Based o predictios made at the ed of the first IVF cycle regardig the probability of achievig a ogoig pregacy durig the secod IVF cycle To create this model, data were used from couples who did ot have a ogoig pregacy after the first IVF cycle or after a trasfer of cryopreserved embryos ad who started a secod IVF cycle I Nijmege ad i Eidhove, 454 ad 278 couples started a secod IVF cycle respectively. I Eidhove, iformatio about ogoig pregacy was lackig for three couples durig the secod cycle, so the data from 275 couples could be used for the test I additio to the factors meuoed above, the pregacy test result after the first IVF cycle was a potetial progostic factor i this model. Statistical aalysis Models were developed by usig logistic regressio aalysis. The first step was to develop a progostic model based o patiet characteristics ad, if appropriate, the itermediate IVF treatmet results The secod step was to evaluate whether treatmet characteristics added ay progostic value to the model. The third step was to test the model. Criteria for acceptig variables as predicuve factors i the model were based o statistical sigificace ad added progostic value, evaluated by usig the c idex [l e (umber of cocordat pairs

3 AJvLStolwijk et al Table L Patiet characteristics of the populatios at the start of the first m-vitro fertilizatio (IVF) cycle Nijmege ( = 757) Eidhove ( = 432) Mm. Max Mea SD Media Mi. Max. Mea SD Media Woma's age (years,) Duratio of ifertility (years)' Basal FSH (IU/I) < *1 Precedig gestatios»1 Precedig spotaeous abortios * 1 Precedig ectopic pregacies * 1 Precedig deliveries Idicatio for IVF Tubal exclusively Tubal ad others) Male factor exclusively Male factor ad other(s) Edometosis exclusively Edometosis ad other(s) Cervical factor exclusively Cervical factor ad other(s) Idiopathic ifertility Two ovaries Sperm characteristics 3»20 X 10 6 /ml *60% Normal forms s>50% Moule Quality of motility»>4 f Ati-sperm atibodies, 3 or 9 I sperm I woma's serum Use of door spermatozoa Percetage d 34 e Percetage c = o iformatio available 'Number of missig values for duratio of ifertility i Nijmege = 374. "Number of missig values i Nijmege: for two ovaries = 1, ati-sperm atibodies 6* or 9, ad i sperm = 2 'Number of missig values i Eidhove for s> 1 precedig spotaeous abortios, ectopic pregacies, deliveries respectively = 81, 81, 80, for the idicatios of IVF = 1, for two ovaries = 9 d Door spermatozoa were used for three patiets. e Door spermatozoa were used for oe patiet (the other idicatio for IVF was tubal factor) f O a scale from 1 (worst) to 5 (best). Table IL Number of patiets ad ogoig pregacies At start of first IVF At embryo trasfer of first IVF At start of secod IVF IVF = i-vitro fertilizatio. Nijmege No Pregacies % Eidhove No Pregacies % X the umber of tied pairs)/total umber of pairs] (Harrell et al, 1982; 1996). The c ca be iterpreted as the probability of a correct predictio for a radom pair of a woma with a ogoig pregacy ad a woma without a pregacy. It is equal to the area uder a receiver operatig characteristic (ROC) curve (Haley ad McNeil, 1982). For the developmet of a progostic model, the erroeous exclusio of ay progostic factors (because of too little power) would be more deleterious tha icludig too may factors. Therefore these criteria were give a high ad low cut-off poit respectively; P <0.10 ad c > The variables were selected accordig to a method aki to a stepwise selectio method. Here, the selectio criteria is based ot oly oaf value (< 0.10), but also o a chage i c (> 0.005). Special attetio was give to multicolliearity. If this was preset, oly the variable with the highest predictive power was icluded m the multivaate model. If a variable did ot meet the criteria i a uivaate aalysis, it thus could still be icluded i the progostic model if the variable met the criteria whe it was icluded i a mul&variate model, i.e. after takig ito accout the progostic value of other variables. I additio, a variable was omitted from the model if aother factor was a stroger predictor ad showed 2300

4 Progosis of ogoig pregacy alter IVF Table HL Progostic models for the probability of achievig a ogoig pregacy (P) durig the first m-vitro fertilizatio (TVF) or secod IVF cycle Model L [P/(l-P)] = SE(P) -21(L /L 2 ) df Nijmege at developmet Eidhove at testig P value N* c JV* c A B C X»1 precedig gestauo x woma's age (years) X *1 precedig gestatio x o fertilized oocytes X o trasferred embryos X o trasferred embryos of at least good quality X woma's age =630 years x woma's age years X idiopathic ifertility X embryo trasfer durig first IVF cycle df = 2 P = df = 4 P = df = 4 P = "Patiets with missig values o oe or more of the variables were excluded, l e. for Nijmege 0, 1 ad 0, ad for Eidhove 1, 129 ad 4 for model A (predictio at start of first IVF cycle regardig probability durig first cycle), model B (predicdo at embryo trasfer regardig probability durig first cycle) ad model C (predictio at ed of first IVF cycle regardig probability durig secod cycle) respectively o additioal predictive value. For sperm characteristics combied variables were created ad their predictive value was evaluated agaist that of the separate sperm characteristics To test the predictive validity of the models, the data from the other cetre were applied. As the data from Nijmege cotaied more potetial predictors tha the data from Eidhove, the models selected as the best predictive could ot always be fully tested If a specific variable was lackig, the model was modified, if possible, by exchagig it with a similar variable, or otherwise by excludig the variable. To evaluate the reliability of the model, the c was calculated If the model had reasoable progostic value, the predicted probability ad the observed result of FVF were compared. Results The models for predictig the probability of achievig a ogoig pregacy, developed with the data from Nijmege ad tested with the data from Eidhove, are preseted i Table m. Model A Durig the first IVF cycle, 88 (11.6%) out of the 757 wome from Nijmege ad 46 (10.6%) out of the 432 wome from Eidhove achieved a ogoig pregacy The oly factors that had predictive value were a previous gestatio ad the woma's age. Durig testig, this model did ot show ay predictive value whe applied to the data from Eidhove (c = 0.497). Model B Embryo trasfer was performed i 604 (79.8%) out of the 757 couples from Nijmege i the first IVF cycle. I Eidhove, embryo trasfer was performed i 300 (69.4%) out of the 432 couples. The ogoig pregacy rate per trasfer was 14.6% i Nijmege ad 15 3% i Eidhove. The progostic model icluded the factors: at least oe precedig gestatio, the umber of fertilized oocytes, the umber of trasferred embryos ad the umber of trasferred embryos of at least good quality. The probability of achievig a ogoig pregacy icreased if there had bee a precedig gestatio ad the higher the umbers. Durig the test, this model showed good predictive value (c = 0 672) ad good predictive performace, as show i Table IV. For istace, 93% of the wome with a predicted probability of achievig a ogoig pregacy of <10% did ot achieve a ogoig pregacy after embryo trasfer. Model C To predict the probability of achievig a ogoig pregacy durig the secod IVF cycle, oly the data from the couples who received a secod treatmet could be used. Of the 454 couples who received a secod IVF treatmet i Nijmege, 61 (13.4%) achieved a ogoig pregacy. I Eidhove this occurred i 29 (10.5%) out of the 275 couples who uderwet a secod IVF treatmet The best progostic model is show i Table HI. Of progostic value were: the woma's age i age-groups, the presece of idiopathic ifertility ad embryo trasfer durig the first IVF cycle. However, this model did ot show ay predictive value i the test populatio (c = 0.528). Discussio This study showed that models for predictio of ogoig pregacy due to IVF treatmet ca be developed with a fairly high progostic value. However, this does ot imply that the same models are predictive for patiets treated at aother cliic or eve at the same cliic. Of the three models, oly the oe that made a predictio at the time of embryo trasfer was fairly reliable i the other populatio. The other two models that made predictios at the start of treatmet or after 2301

5 A.M.Stolwijk et al Table IV. Predicted ad observed percetages ad time of embryo trasfer m Eidhove umbers of wome with a ogoig pregacy durig tbe first i-vitro fertilizatio (IVF) treatmet at the Observed Predicted probability (%) 0-<5 5-< <15 15-<20 20-<25 25-<30 s>30 Total Percetage ogomg pregacy 0 No wome pregat 0 Total umber of wome No predictio could be made for 129 wome, because o iformatio was available about the umber of trasferred embryos of at least good quality. the first IVF cycle, however, seemed to be of little value whe used i Eidhove. Although model B, which predicts at time of embryo trasfer, is of little cliical importace, it gives iformatio about the reasos for the iadequacy of the predictio at the start of the cycle For the two models at the start of the cycle, the ovaria respose ad oocyte aspiratio are very importat, but caot be icluded as progostic factors i the models because this iformatio is ot available at the start of the treatmet, whereas i the model that made a predictio at time of embryo trasfer, the umber ad quality of the retrieved oocytes are potetial progostic factors. Therefore, oe explaatio for the poor reliability might be differeces i the effectiveess of the ovulatio simulatio protocols, the log protocol of GRH agoist i Nijmege ad the short protocol i Eidhove. No oocyte aspiratio was performed durig the first IVF treatmet i 7.4% (56 out of the 757) ad 21.8% (94 out of the 432) of the wome from Nijmege ad Eidhove, respectively. Durig the secod IVF treatmet, these percetages were 4.6% (21 out of the 454) ad 15.3% (42 out of the 275) respectively. Not oly might the effectiveess of the ovulatio stimulatio protocol have iflueced the cacellatio rate, but also the timig of this decisio differed betwee the two cetres. Dug the first IVF cycle, the percetage of cacelled cycles for the reaso of too may follicles was oly 1.8% i Nijmege, but was as high as 31.5% i Eidhove. This decisio was made i Nijmege if >25 follicles were preset i combiatio with a oestradiol cocetratio of > pmol/1, whereas i Eidhove, cycles were cacelled whe >20 follicles were preset. Whether the models developed i Nijmege ca make mere accurate predictios if they are applied to a IVF cetre that uses a log protocol of GRH agoist ad with fewer cacelled cycles remais to be see. The preset models were adapted to make testig possible, give the iformatio available i the test populatio. The chages were egligible. Models A ad C were ot chaged at all. I model B the umber of follicles >15 mm was iitially icluded i the model, but because of lack of this iformatio i the Eidhove populatio, it was exchaged with the umber of fertilized oocytes. Moreover, i model B the sperm characteristics <60% ormal forms ad/or <20X 10 6 spermatozoa per ml added mior predictig value, ad were' excluded from the model. Note that basal FSH had o additioal predictive value, or had the idicatios for IVF, except for idiopathic ifertility i model C. For progosis, the predictive value of a positive test ad of a egative test are of more practical value tha the sesitivity " ad specificity of a test. The predictive value of a positive test is the proportio of patiets with a positive test who achieve a ogoig pregacy, ad the predictive value of a egative test is the proportio of the patiets with a egative test who do ot achieve a ogoig pregacy. Thus, they illustrate whether the progosis was right, whereas the sesitivity ad specificity of a test idicate whether the patiets who achieved a ogoig pregacy were classified well by the test. All these measures ca be easily calculated usig the data of Table IV. For istace, assume the cut-off poit for the test to be a predicted probability of 5%; the test is positive if the predicted probability is 5=5% ad egative if <5%. The positive predictive value of this test is 16% (25/155) ad the egative predictive value is 100% (16716). This demostrates that the test ca idicate patiets who do ot achieve a ogoig pregacy after IVF, but caot predict who achieves a ogoig pregacy. The sesitivity ad specificity of this test are 100% (25/25) ad 11% (16/146) respectively. Obviously, cliicias select their patiets before treatmet with IVF. If the study populatios had icluded more extreme groups, those with a very high or a very low probability of success, the the reliability of the progosis would have bee better. The models we created oly apply to populatios that lie withi the rage of the characteristics preseted i Table I. As wome of 40 years of age or older were poorly represeted i Nijmege ( = 34), the models may ot be valid for them. I additio, iformatio o the duratio of ifertility was oly available from 383 patiets i Nijmege The potetial progostic effect of the duratio of ifertility might ot have bee detected because of too few observatios. As the data were gathered retrospectively, it was ot always possible to obtai full sets of iformatio from the two databases. I some cases data were missig, or they were ot preset i the desired form. Moreover, the two hospitals had their ow method of performig IVF ad the patiet populatios might have differed o other aspects tha those studied Therefore it was more difficult to create a model that would make reliable predictios tha if the data had bee gathered i a stadardized way for the purpose of progostic studies at hospitals which use the same treatmet protocols ad the same defiitios for each variable. To make it possible to create reliable progostic models, we recommed settig up uiform atioal registries which also cotai iformatio about the basic fertility workup. The importace of testig progostic models is evidet. Utested progostic models ca be worthless whe used for predictio at aother (or possibly eve the same) IVF cliic.

6 Progosis of ogoig pregacy after IVF Before a model ca be used by aother FVF cetre, it should be tested with retrospective data from that cetre, to establish whether it is a predictive model i that cetre. Eve before a model is implemeted i the cetre where it was developed, it should be tested with a etirely separate set of data from the same cetre before oe ca rely o its predictive properties. Ackowledgemets This study was made possible by the data from the IVF cetres at the Uiversity Hospital Nijmege ad Cathaa Hospital Eidhove. Refereces Brcslow, N.E. ad Day, N.E (1980) Statistical Methods m Cacer Research. Volume 1 The Aalysis of Case-Cotrol Studies Iteratioa] Agecy for Research o Cacer, Lyo, p 197 Check, JH., Lue, D, Diettech, C et al (1993) Adverse effect of a homogeeous hyperechogeruc edometal soographic patter, despite adequate edometal thickess o pregacy rates followig m-vitro fertilizatio. Hum. Reprod, 8, % Dor, J, Seidma, D S, Be Shlomo, I et al (1992) The progostic importace of the umber of oocytes retrieved ad estradiol levels i poor ad ormal respoders i i vitro fertilizatio (TVF) treatmet J Assist Reprod. Geet, 9, Egisu, ME, Pieters, M.H, Dumouli, JC et al (1992) Male factor as determiat of m-vitro fertilizatio outcome Hum. Reprod., 7, Fluker, M.R., Siu, C.K, Guby, J et al (1993) Cycle characteristics ad outcome i relatio to ovaria respose durig i vitro fertilizatio J Assist Reprod Geet, 10, Guzick, D S, Balmaceda, J P, Ord, T et al (1989) The importace of egg ad sperm factors i predictig the likelihood of pregacy from gamete itrafallopia trasfer Fed Stel, 52, Haa, G, Berardus, R E, Holladers, J.M G et al. (1991) Results of IVF from a prospective multicetre study Hum. Reprod., 6, Haley, J A ad McNeil, B J (1982) The meaig ad use of the area uder a Receiver Operatig Characteristic (ROC) curve Radiology, 143, Harrell, FE, Califf, R M, Pryor, DB et al (1982) Evaluatig the yield of medical tests J Am. Med. Assoc, 247, Harrell, FE, Lee, K.L. ad Mark, D.B. (1996) Multivaable progostic models issues i developig models, evaluatig assumptios ad adequacy, ad measurig ad reducig errors Stat Med., 15, Hughes, EG, Kig, C ad Wood, EC (1989) A prospective study of progostic factors i i vitro fertilizatio ad embryo trasfer FemL Stel, 51, Hull, M G R, Eddowes, H.A, Fahy, U et al (1992) Expectatios of assisted coceptio for ifertility Br. Med. J, 304, Jase, CAM (1993) Idicaues voor m vitro fertilisatie Ned. Tijdschr Obstet Gyaecol, 106, Klembaura, D.G, Kupper, LL ad Morgestem, H (1982) Epidemiologic Research. Priciples ad Quatitative Methods Va Nostrad Remhold Compay, New York, p 454 Nelso, JR., Huppert, L., Corso, SL et al (1993) Predictig success of gamete itrafallopia trasfer FeiL SteL, 60, PadiUa, S L, Bayati, J ad Garcia, J E (1990) Progostic value of the early serum estradiol respose to leuprolide acetate i m vitro fertilizatio. Feml SteL, 53, Piette, C, De Mouzo, J, Bachelot, A et al (1990) I-vitro fertilizatio ifluece of wome's age o pregacy rates Hum. Reprod, 5, Roseboom, TJ., Vermeide, J PW., Schoute, E et al (1995) The probability of pregacy after embryo trasfer is affected by age of the padet, cause of ifertility, umber of embryos trasferred ad the average morphology score, as revealed by multiple logistic regressio aalysis Hum. Reprod, 10, Spemol, R, Hecher, K., Schwarzgruber, J et al (1993) Doppler-Flow- Messuge i der Atea utea Ei Progosefaktor filr de Erfolg bei der Behadlug durch IVF? Ultraschall Med., 14, Received o March 18, 1996, accepted o August 8,