Basal follicle-stimulating hormone level is a better predictor of in vitro fertilization performance than age*

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1 FERTILITY AND STERILITY Copyright e 1991 The Amerian Fertility Soiety Vol. 55, No.4, April1991 Printed on oid-free paper in U.S.A. Basal follile-stimulating hormone level is a better preditor of in vitro fertilization performane than age* James P. Toner, M.D., Ph.D.t Christine B. Philput, Ph.D.:j: Georgeanna S. Jones, M.D. Suheil J. Muasher, M.D. Jones Institute for Reprodutive Mediine, Department of Obstetris and Gyneology, Eastern Virginia Medial Shool, Norfolk, Virginia A study of 1,478 onseutive in vitro fertilization (IVF) yles was made to determine if basal follile-stimulating hormone (FSH) levels and age were independent preditors of IVF performane. Regression analyses indiated independent ontributions of both basal FSH and age in prediting anellation rate, peak estradiol, number of ooytes retrieved, fertilized, and transferred, and total and ongoing pregnany rates. Misarriage rate was unrelated to both age and basal FSH. Follilestimulating hormone level was a better preditor than age for all outome variables examined and remained a signifiant preditor after aounting for age, etiology of infertility, and semen quality. The ombined use of age and basal FSH in ounseling patients improves the auray of prognosis, and may provide an index of funtional ovarian reserve ("ovarian age"). Fertil Steril 55:784, 1991 Outome in in vitro fertilization (IVF) and ovulation indution is strongly dependent on ovarian responsiveness to exogenous stimulation. Preditors of this responsiveness provide the physiian with valuable information when ounseling the patient. Although age, and, in some ases the etiology of infertility have proved helpful indiators, better guides would surely be welome. The value of patient age in prediting performane in assisted reprodutive tehnologies is well established. Feundity in both natural and stimulated ovarian yles delines with maternal age, beginning in the late 2s and beoming more abrupt in the late Reeived August 7, 199; revised and aepted November 29, 199. * Presented as the Prize Paper for the Soiety of Assisted Reprodutive Tehnologies at the Annual Meeting of The Amerian Fertility Soiety, Washington, D.C., Otober 15 to 18, 199. t Reprint requests: James P. Toner, M.D., Ph.D., Jones Institute for Reprodutive Mediine, Department of Obstetris and Gyneology, Eastern Virginia Medial Shool, Norfolk, Virginia :j: Present address: Researh Diretor, Clinial Investigations, Portsmouth Naval Hospital, Portsmouth, Virginia. 3s. This deline has been observed in populationbased studies/ ovulation indution, 2 and in IVF. 3-8 Feundity, however, is probably related more losely to ovarian status than to hronologial age per se. Inreasing age is just one of many proesses that redue the number offolliles; extirpative pelvi surgery, hemotherapy, and radiotherapy have the same effet. It is possible that beause menopause ours at different ages in different women, that the age-related redution in feundity may our at different rates in different women. An index of this redution would be useful for ounseling in IVF. One suh indiator may be the basal follile-stimulating hormone (FSH) level, whih is easily and often obtained during the ourse of an infertility evaluation. The serum level of FSH inreases as ovarian funtion delines. 9 This may reflet dereasing inhibin seretion beause of fewer gonadotropin-responsive folliles. 1 Whatever the mehanism, the serum FSH level on menstrual yle day 3 has been shown to predit IVF outome Whether this preditive ability is more or less than that provided by age is not known. 784 Toner et al. Basal FSH versus age in prediting IVF outome Fertility and Sterility

2 In this study, the relative power of basal FSH and age in prediting IVF outome have been investigated. Basal FSH was studied as a single preditor and as a ombined preditor along with age and other onfounding fators (infertility type, semen harateristis). We hypothesized that basal FSH would be more preditive of IVF outome than age, believing basal FSH to be a more sensitive and diret indiator of ovarian status ("ovarian age") than hronologial age. Subjets MATERIALS AND METHODS Fourteen hundred seventy-eight onseutive IVF yles in whih basal FSH values were known (Norfolk series 28 to 35; July 1987 to June 1989) were studied. These yles enompassed all women initiating IVF regardless of etiology of infertility, stimulation protools, or degree of ovarian responsiveness. Day 3 FSH, luteinizing hormone (LH), and estradiol (E 2) had been obtained in nearly all women (>95%) stimulated for IVF during this period. The basal FSH value in the yle of stimulation was the basis for analysis in all ases exept when leuprolide aetate (LA, Lupron; TAP Pharmaeutials, Chiago, IL) pretreatment had been used; a basal FSH value from a prior yle within 3 months of the IVF attempt was analyzed when the stimulation inluded luteal phase LA. One hundred ten yles (7.4%) were aneled before ooyte retrieval beause of inadequate response; in an additional 42 yles (2.8%), no ooytes were retrieved and in another 96 (6.5%), no transfer ourred despite ooyte reovery (failed or abnormal fertilization, or degeneration of fertilized ooytes). The 1,368 yles with ooyte retrieval (92.6%) were inluded in the statistial analyses of ooyte and pregnany outomes. In Vitro Fertilization Protool Ovarian stimulation with gonadotropins (human menopausal gonadotropin [hmg, Pergonal; Serono Laboratories, Randolph, MA] or FSH [Metrodin; Serono Laboratories] or in ombination) was initiated on the 3rd day of menses and ontinued in an individualized fashion. In 38% of ases, LA was initiated in the midluteal phase of the preeding yle (1 mg subutaneously) and ontinued until the day of human horioni gonadotropin (hcg; Steris Laboratories, Phoenix, AZ) administration. In 62% of yles LA was not used. Ten thousand international units of hcg were administered intramusularly when two or more folliles were 16 mm. Patients with fewer large folliles were ounseled to onsider anellation but were allowed to go to retrieval if they desired. Transvaginal folliular aspiration was performed 34 hours later. Gamete proessing, ell ulture tehniques, and transfer proedures were as previously desribed. 17 Ooyte maturity was lassified by the riteria of V eek et al. 18 Transfer of four or fewer pre-embryos was performed 2 days later. Pre-embryos in exess of 4 were ryopreserved. Progesterone supplementation (25 mg/d IM) was begun on the day of pre-embryo transfer and ontinued until pregnany status was known. If pregnany was onfirmed, 17 a-hydroxyprogesterone aproate (25 mg/wk IM; Steris Laboratories) was administered until the 14th week of pregnany. All linial pregnanies were onsidered in the analyses; those lasting >2 weeks were onsidered ongoing. Chemial pregnanies (falling {3-hCG titers after 1 or 2 values 25 IU /L) were exluded from all analyses. Hormone Assays All determinations were performed in dupliate using standard radioimmunoassay tehniques. Overall variation in the low, mid, and high ranges of the FSH assay were 13.5% (at 13.7 IU/L), 7.2% (at 24.1 IU/L), and 4.5% (at 69 IU/L) for FSH (Leeo Diagnostis, In, Southfield, MI), and 1.3% (at 49 pg/ml), 7.95% (at 96 pg/ml), and 5.3% (at 67 pg/ml) for E 2 (diret method; Pantex, In, Santa Monia, CA). In our lab, the FSH kit applied to infertile women < 36 years of age with two ovaries (n = 721) gave a mean of IU/L on yle day 3 with an SD of 5.77; the upper 5% tail of the distribution began at 22 IU /L. Statistis Data were analyzed by multiple linear regression using SPSS and SAS programs on a VAX/VMS omputer (Digital Equipment Corporation, Marlborough, MA). Data for eah variable were examined for normaly; logarithmi transformation of age and FSH was required to produe aeptably Gaussian distributions. Multiple regressions, whih inluded interation terms for basal FSH and age, were evaluated for all outomes; no interations were signifiant; interation terms were subsequently removed from all models. Separate linear regressions of age and FSH onto eah of 1 outome variables were performed: anellation rate; peak E 2 ; number of folliles as- Vol. 55, No.4, April1991 Toner et al. Basal FSH versus age in prediting IVF outome 785

3 " , sot;:=:::::===; j "' t---., i-' -----j ' Cl 2t<---r'-----j ' * Basal FSH (IU/L) Figure 1 Pregnany and anellation rates in 1,478 IVF yles divided by basal FSH. Misarriages are indiated by the differene between the two pregnany urves. pirated; number of preovulatory ooytes retrieved, fertilized, and transferred; number of pregnanies total, ongoing, and aborted; and implantation rate. The relative ability of FSH and age to predit these outomes was ompared using a z-sore approah derived from eah variable's orrelation oeffiient.19 Dummy variables were reated for three ategorial variables: semen quality, primary etiology of infertility, and seondary etiology of infertility. These dummy variables were inluded in a series of stepwise regression models examining the same 1 outome variables. There were 6 variables for semen harateristis (normal morphology< 4%, 4% to 14%, >14%; presene of antisperm antibodies; morphology < 4% plus low ount or motility; and use of donor sperm) and eight eah for the type of infertility (primary and seondary auses: tubal, male, ervial, endometriosis, diethylstilbestrol [DES] exposure, immunologial, anovulatory, and unexplained). In all stepwise analyses, age, and the 22 dummy variables were fored into the model before the value of FSH or age was assessed. Chi -square testing was applied to frequeny data. For graphial presentation, yles were divided into five ranges of basal FSH and into four ranges of age. Results are reported using both the P value and the R 2 value, whih is the proportion of the total variane explained by the relationship being examined (and also the square of the partial orrelation oeffiient relating the two variables). The R 2, whih ranges from % to 1%, provides a more meaningful measure of the importane of a relationship than the P value, whih only indiates statistial (rather than linial) signifiane. A P <.5 was onsidered statistially signifiant. RESULTS In vitro fertilization performane was strongly related to both age and basal FSH. Total and term pregnany rates (PRs) delined as age and FSH valued inreased (both P <.1). Pregnany rates (total and ongoing) per attempt steadily delined as basal FSH inreased, up to approximately 2 IU /L; thereafter, the deline in PR beame abrupt (Fig. 1). Ongoing PRs for women with basal FSH s 1 IU/L was 18%; at 2 IU/L the rate was 15%, but above 25 IU/L the rate was %. Canellation rate rose dramatially as FSH beame higher than 15 IU/L (P <.1; Fig. 1). The 5% risk of anellation when FSH was <15 IU/L inreased to approximately 1% at 2 IU /L, 2% at 25 IU /L, and 4% at 3 IU/L. Regarding age effets, the deline in PRs (total and ongoing) per attempt was signifiant and steady throughout the observed age range (both P <.1); no hange in the slope of the deline was deteted (Fig. 2). Ongoing PRs fell from 28% in the middle 2s to 12% around age 4. There was no relationship between anellation risk and age (P >.5); the anellation risk flutuated between 4% and 9% aross the range of ages (Fig. 2). Misarriage risk was not related to basal FSH level or to age by regression analysis (P >.5). Nevertheless, all pregnanies in whih FSH was 25 IU/L misarried. No suh utoff was observed for age. Women 4 years of age in the study population were no more likely than women in their 3s to have basal FSH 2 IU/L (13.7% versus 12.1%; P >.5); this may aount in part for the failure to observe an inreased risk of misarriage in the older women. " aa ;====;j \ j "' \ = Cl a; a Age Figure 2 Pregnany and anellation rates in 1,478 IVF yles divided by patient age. Misarriages are indiated by the differenes between the two pregnany urves. 786 Toner et al. Basal FSH versus age in prediting IVF outome Fertility and Sterility

4 The utility of basal FSH to predit various IVF outomes was observed even within defined age ranges. Table 1 provides data on anellation, peak E 2, and ooyte-related IVF outomes. All exhibited systemati hange within the defined age ranges, with inreases in basal FSH being assoiated with poorer performane. For peak E 2 and ooyte-related outomes, the derement in performane was fairly onstant aross the ranges of basal FSH and amounted to an average derement of 46% (range 31% to 82%) when the lowest and highest FSH ranges were ompared. Canellation risk, however, did not learly inrease until FSH rose above 2 IU/L. Figure 3 illustrates the importane of basal FSH in prediting pregnany outomes within defined age ranges. This effet of basal FSH is most apparent and statistially sound for women in their 3s (where the sample sizes are large); there were too few women 4 years old to rely on the form of the FSH histogram for this group. For women in all the other age groups, the basal FSH value biased the expetation of pregnany or anellation by a fator of two or more within eah age range. Note, however, that there is still a general trend for lower PRs with inreasing age, even at the same basal FSH levels. This suggests an age-related derement in IVF performane not explained by basal FSH values alone. Analyses of age and FSH effets related to basal LH "' C1> "'iii 3 a: ;>, <tl 5 FSH lllll tsl D Misarry 2 > C1> a: 1 i l I I Maternal Age Figure 3 Pregnany rates (ongoing and total) in 1,378 IVF yles proeeding to ooyte retrieval divided by age (x axis) and basal FSH (within eah age range). The perentage of these ases leading to pregnany is indiated on the y-axis. and E 2 levels and the day of hcg administration failed to reveal any relationships (P >.5). As a single preditor of IVF outomes, basal FSH surpassed age in all ategories: anellation risk; peak E 2 ; number of folliles aspirated; number of ooytes retrieved; number of preovulatory ooytes retrieved, fertilized, and transferred; and total and ongoing PRs (Table 2). This superiority, as indiated by R 2 values at least twie those of age for all outomes up to pregnany, was also statistially signifiant for all but pregnany outomes (z sore: 4.89, 6.2, 5.31, 4.44, 3.54, 3.22, 3.47, respetively, all Table 1 In Vitro Fertilization Performane in 1,4 78 Cyles of Women Aording to Age and Basal FSH Value" Preovulatory ooytes Folliles Ooytes Age FSHb Caneled Peak E 2 aspirated retrieved Retrieved Fertilized Transferred y IU/L % pgfml <3 <1 (54) to 14 (41) to 19 (14) to 24 (1) (3) to 34 <1 (216) to 14 (194) to 19 (7) to 24 (29) (26) to 39 <1 (271) to 14 (211) to 19 (115) to 24 (53) (42) <1 (35) to 14 (62) to 19 (22) to 24 (1) (9) a Values are means. b Values in parentheses are number of subjets. Vol. 55, No.4, April1991 Toner et al. Basal FSH versus age in prediting IVF outome 787

5 Table 2 Independent and Sequential Ability of FSH and Age to Predit IVF Outome R 2 (%variane explained)" Outome FSH aloneb Age alone FSH when lastd Age when last Tota11 Caneled 1.82 Peak E Folliles aspirated Ooytes retrieved Preovulatory ooytes Retrieved 7.3 Fertilized 4.22 Transferred 2.98 Pregnant Total.63 Ongoing.79 Misarriage O.ol All R 2 values >.3% are signifiant (P <.1). b Value of FSH as sole preditor of IVF outomes. Value of age as sole preditor of IVF outomes. d Value of FSH as a preditor after age, semen harateristis, and infertility type were fored into model. Value of age as a preditor after FSH, semen harateristis, and infertility type were fored into model. I Total amount explained variane in full model (FSH, age, semen, and infertility type). P <.1). Note also that both basal FSH and age were better able to predit outomes more losely related to ovarian responsiveness than outomes that were influened by male fators and implantation (e.g., ooytes fertilized, pregnany). When basal FSH was ombined with age, type of infertility, and semen harateristis in stepwise regression models prediting these same IVF outomes, FSH remained an important preditor even when it was onsidered as the last variable entered into the models. Stepwise linear regression in whih age and dummy variables for infertility type and semen quality were fored into the model before FSH was allowed to enter indiated a signifiant additional benefit of basal FSH in explaining IVF outomes (Table 2). Here too the strength of the assoiation was greater for events more losely related to ovarian response but remained signifiant for all outomes exept anellation and misarriage. A similar analysis based on age also indiated an important role for age in prediting IVF outomes after FSH, semen harateristis, and infertility were fored into the stepwise regression analyses (Table 2). This independent value of age was muh less than that provided by FSH but was signifiant for all but misarriage, anellations, and the number of preovulatory ooytes transferred. Thus there is some influene of age on many IVF outomes not aounted for by FSH or other infertility fators. The full model, whih inluded FSH, age, semen harateristis, and infertility type, was able to explain from 1.2% to 77.1% of the variane in IVF outomes (Table 2). Again, outomes more losely related to ovarian funtion were better predited by these variables than those less losely tied. Implantation rates (the number of gestational sas per number of pre-embryos transferred) delined with both inreasing age and basal FSH. For women, aged <3, 3 to 34, 35 to 39, and >4 years, the implantation rates were 8.%, 5.9%, 6.%, and 4.%, respetively. These differenes were not statistially different by regression analysis. However, when omparing the two extremes of age, a differene was observed (X 2, P <.5). For women with basal FSH < 5, 5 to 9, 1 to 14, 15 to 19, 2 to 24, and >25 IU/L, the implantation rates were 5.3%, 6.6%, 6.1%, 5.4%, 4.7%, and %, respetively. Signifiant differenes were observed only between the 25 IU /L rate and the rates of groups with FSH < 2 IU /L (X 2, P <.5). Regression analysis did not onfirm these differenes. DISCUSSION These results indiate that both basal FSH and age are strong influenes on IVF performane. As a single preditor, basal FSH is better than age for prediting all outomes investigated: anellation risk; peak E 2 ; number of folliles aspirated; number of ooytes retrieved; number of pre-ovulatory ooytes retrieved, fertilized, and transferred; and total and ongoing PRs. Thus, an individual's funtional ovarian reserve ("ovarian age"), as refleted in basal 788 Toner et al. Basal FSH versus age in prediting IVF outome Fertility and Sterility

6 FSH, is more important than her hronologial age in prediting IVF performane. Investigators have reported a variety of age-assoiated derements in IVF performane: anellation rate, 5 6 number of ooytes retrieved, number of ooytes transferred, 6 7 linial PR, ongoing PR, 6 21 multiple PR, 7 2 abortion rate, and implantation rate are all adversely affeted by inreased age. There is ontroversy about the relation between misarriage rate and age; some large studies report no disernible effet. 5-7 Control for other onfounding fators that relate to misarriage risk, suh as immunologial, uterine, and male fators, ould aount for this ontroversy. The adverse effet of aging appears to stem from ooyte defiienies more than endometrial defiienies: women > 4 years old reeiving donor ooytes do as well in IVF as those <4 but do very poorly when using their own ooytes. 22 Further, the use of donor sperm alone does not reverse the age-related derease in feundity. 2 Ovarian funtion is unique for eah individual both in its harater during the years of peak reprodutive performane (e.g., low, mid, and high response) as well as in the onset and progression of its deline as the menopause approahes. Markers of this individuality will perhaps prove to be more sensitive indiators of IVF performane than rude measures suh as maternal age. Serum levels of FSH inrease as the menopause approahes, 9 presumably as a onsequene of inadequate inhibin negative feedbak, though in any given yle in the perimenopause the gonadotropin levels may flutuate from normal to markedly elevated. 23 The value of basal FSH as a preditor of IVF performane has only reently been reported The additional value of LH and E 2 in prediting IVF performane beyond that provided by FSH alone was evaluated in a prior study and found to be marginal. 12 Elevated basal FSH on yle day 3 (> 15 IU /L, and espeially 25 IU /L) is assoiated with poor IVF performanep However, women 4 years of age with basal FSH < 15 IU /L did as well as younger women in a preliminary report from our IVF programy Moreover, some younger women with otherwise unexplained infertility have been found to exhibit elevated basal FSH levels; they do poorly ompared with those with normal basal FSH and unexplained infertility These preliminary observations led to the diret test of the value of basal FSH in relation to age that was the subjet of this study. One a woman displays an elevation of basal FSH, her performane in IVF remains poor even in yles in whih the basal FSH value is normal. 25 This interyle variability appears to reflet the intermittent ovarian failure that ours during the perimenopause; 23 we hypothesize that the remaining ooytes in this irumstane are of relatively poor quality even in yles that are endorinologially normal. Canellation risk did not appreiably inrease with age. However, the anellation risk was losely related to basal FSH. The 5% risk of anellation when FSH was <15 IU/L inreased to approximately 1% at 2 IU /L, 2% at 25 IU /L, and 4% at 3 IU /L. Patients with elevated FSH should be alerted to their higher risk for anellation. Misarriage was not tightly related to age or basal FSH in our study group with one exeption: all pregnanies in whih the basal FSH was 25 IU /L misarried. Beause of smaller numbers, this observation did not reah statistial signifiane. We suspet that misarriage risk for older women may be more losely tied to basal FSH than to age per se. As it happened, in our study population, women 4 were not more likely than women in their 3s to have elevated basal FSH. Thus our inability to detet an age-related inrease in misarriage risk may be beause few of older women had elevated basal FSH. Certainly it is well established in natural reprodution that misarriage is more ommon as women age. Misarriage may be more likely when basal FSH levels are high beause a large subset of these women are also older and have aged ooytes. We speulate that the misarriage rate for younger women with elevated basal FSH due to prior ovarian surgery, for example may not be inreased beause the ooytes, while few, are not old. Several statistial issues deserve omment. One is the hoie of the analyti tool when variables of interest are both ategorial (where the data are labels for ategories, e.g., endometriosis, tubal, et.) and salar (where the data are numbers with real meaning, e.g., peak E 2 = 1,125 pg/ml). One an use a tool (logisti regression) in whih all variables are made ategorial by the investigator (e.g., peak E 2 > or :::;1, pg/ml), or one an use a tool (linear regression) in whih variables of all types are evaluated without modifiation. Logisti regression is simpler but requires establishing arbitrary utoffs in ontinuous (salar) data. Linear regression takes full advantage of ontinuous data but is more diffiult to perform: dummy variables for eah ategorial variable must be generated. We have opted to use linear regression beause no bias is introdued in establishing utoffs and beause it is a powerful Vol. 55, No.4, April1991 Toner et al. Basal FSH versus age in prediting IVF outome 789

7 tehnique that takes full advantage of the information provided by the data. Beause the ultimate performane of retrieved ooytes in establishing pregnany depends in part on the sperm used to inseminate them and the etiology of infertility (e.g., DES exposure), we thought it important to inlude these variables in all statistial models. This required inlusion of the dummy variables related to infertility type and semen harateristis. This guaranteed that any deleterious effet of semen quality or type of infertility was taken into aount before examining the relationships between age, FSH, and various IVF outomes. The amount of variane that age and FSH an aount for is relatively small. Nonetheless, the partiular value of age or basal FSH an alter the expetation of term pregnany from <5% (e.g., FSH > 25 IU/L) to nearly 25% (e.g., age < 3). Basal FSH and age thus onstitute valuable preditors of performane in a setting in whih few preditors are available. The amount of variane aounted for by age and FSH dereases as outomes move from those losely tied to ovarian responsiveness (e.g., peak E 2 and number of folliles aspirated) to those only remotely assoiated with it (e.g., pregnany). This weakening of preditive power is not surprising beause, even after the best of stimulations, pre-embryo implantation rate is <15%, indiating the effet of other as yet undefined variables that prevent a tight statistial relationship between ovarian responsiveness and pregnany outome; In summary, basal FSH was more preditive of various IVF outomes than age, from peak E 2 levels and number of folliles aspirated to ongoing PRs. Even when the value of age was already aounted for in the statistial models, FSH still had a signifiant impat on IVF outome that ould not be explained on the basis of age. We believe this is a sensible and not unexpeted observation based on the underlying physiology of the perimenopause and its variable onset in women. Akrwwledgments. We thank Ms. Debi Jones for maintaining and providing aurate information on the many IVF yles and outomes onsidered in this study, Charlotte Shrader, Ph.D., for editorial omments, Robert Brzyski, M.D., Ph.D., and Howard Seltman, M.D., for statistial review, and Jill T. Flood, M.D., and RihardT. Sott, Jr., M.D., (urrently at Wilford Hall United States Air Fore Medial Center, Lakland Air Fore Base, Texas) for earlier work in this area. REFERENCES 1. Wood JW: Feundity and natural fertility in humans. Oxf Rev Reprod Bioi 11:61, Toma SK, Stovall DW, Talbert LM: Feundability rates in women of inreasing age. (Abstr.) Presented at the 37th Annual Meeting of the Soiety for Gyneologi Investigation, St Louis, Missouri, Marh 21 to 24, 199. Published by the Soiety for Gyneologi Investigation, in the Sientifi Program and Abstrats Supplement, 199, p Piette C, de Mouzon J, Bahelot A, Spira A: In-vitro fertilization: influene of woman's age on pregnany rates. Hum Reprod 5:56, Padilla SL, Garia JE: Effet of maternal age and number of in vitro fertilization proedures on pregnany outome. Fertil Steril 52:27, Hughes EG, King C, Wood EC: A prospetive study of prognosti fators in in vitro fertilization and embryo transfer. Fertil Steril 51:838, Sharma V, Riddle A, Mason BA, Pampiglione J, Campbell S: An analysis of fators influening the establishment of a linial pregnany in an ultrasound-based ambulatory in vitro fertilization program. Fertil Steril 49:468, Corson SL, Dikey RP, Goial B, Batzer FR, Eisenberg E, Huppert L, Maislin G: Outome in 242 in vitro fertilizationembryo replaement or gamete intrafallopian transfer-indued pregnanies. Fertil Steril51:644, Meldrum DR, Hamilton F, Marr B, Stubbs C, Wisot A, Hite R: Ooyte donation (OD) inreases the proportion of embryos implanting and reverses the age-related deline of fertility. Presented at the 38th Annual Meeting of the Paifi Coast Fertility Soiety, Sottsdale, Arizona, April 25 to 29, 199. 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