Complete failure of fertilization in couples with unexplained infertility: implications for subsequent in vitro fertilization cycles

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1 r FERTILITY AND STERILITY Copyright ~ 1993 The American Fertility Society Printed on acid-free paper in U.S.A. Complete failure of fertilization in couples with unexplained infertility: implications for subsequent in vitro fertilization cycles Shlomo Lipitz, M.D.* Jaron Rabinovici, M.D. Izhar Ben-Shlomo, M.D. David Bider, M.D. Zion Ben-Rafael, M.D. Shlomo Mashiach, M_D. Jehoshua Dor, M.D. Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer, and The Sackler School of Medicine, Tel Aviv, Israel Objective: To determine whether complete failure of fertilization of oocytes in couples with unexplained infertility persists during subsequent in vitro fertilization (IVF) cycles. Design: A retrospective study of 120 cycles of IVF in 44 couples with unexplained infertility and complete failure of fertilization during their first IVF trial. Setting: In vitro fertilization unit of the Sheba Medical Center. Patients: Forty-four couples undergoing IVF for unexplained infertility. Main Outcome Measure(s): Fertilization rate of retrieved oocytes and pregnancy rate_ Results: Of the initial 44 couples, 37 underwent additional IVF cycles and 30 (81.1%) achieved fertilization. Seven patients conceived during the study period as a result of IVF and two conceived spontaneously. Conclusions: Complete failure of fertilization does not necessarily persist during subsequent IVF cycles. Therefore, at least two more IVF cycles should be attempted before reverting to other therapeutic options. However, although fertilization can be achieved in most couples, the mean oocyte fertilization rate during subsequent cycles in this group is low. This suggests an underlying undiagnosed pathology of oocyte/sperm interaction in some of these patients. Fertil Steril 1993;59: Key Words: In vitro fertilization, unexplained infertility, failure of fertilization In vitro fertilization (IVF) and embryo transfer (ET) have become accepted methods of treatment for unexplained or idiopathic infertility. Classically, the diagnosis of unexplained infertility refers to the inability of standard tests to detect the cause of infertility. In addition to its therapeutic benefits for couples with unexplained infertility, IVF may serve also as a further test of the ability of the husband's sperm to fertilize the wife's oocytes. Experience has shown that in some couples with unexplained infertility complete failure of fertilization may occur during their IVF cycle. Received May 20, 1992; revised and accepted October 6, * Reprint requests: Shlomo Lipitz, M.D., Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer 52621, Israel. After successful oocyte retrieval, failure to achieve fertilization of any of the retrieved oocytes occurs in approximately 10% to 20% of all IVF cycles after successful oocyte retrieval (1-3). Failure of fertilization occurs approximately twice as often in couples with male infertility diagnosed by classic criteria than in couples with normal sperm parameters (3). In addition, the lower rate of fertilization in couples with abnormal sperm parameters often implies a poor prognosis for future IVF cycles (4,5). Little is known about the cause and clinical significance of fertilization failure during the first IVF cycle in couples with unexplained infertility. Does failure of fertilization in these couples signify a previously undiagnosed pathology, either of sperm or of oocytes, that will repeatedly hamper fertilization, or is it a chance occurrence with no predictive significance? 348 Lipitz et ai. Complete failure of fertilization in IVF Fertility and Sterility

2 Table 1 IVF Cycles, Pregnancies, and Cumulative PR After Failure of Fertilization During the First IVF Cycle IVF-related Cycle No. of couples pregnancies Cumulative Spontaneous Cumulative IVF-related PR pregnancies overall PR * This table includes all IVF cycles during the study period. The answers to these questions could provide the clinician with a basis for decisions on additional therapeutic options. Over the past 6 years, 44 couples with idiopathic infertility underwent in our clinic at least one trial of IVF that resulted in failure of fertilization of up to 20 retrieved oocytes. After this first unsuccessful trial, 37 of these couples subsequently underwent additional IVF cycles. The aim of the present retrospective study was to examine the results of IVF cycles in these couples after the complete failure of fertilization in the first trial. Specifically, we were interested in finding out whether complete failure of fertilization in couples with unexplained infertility was a persistent finding during subsequent IVF cycles, and, if not, whether the oocyte fertilization rate during these subsequent cycles was different from that observed with other causes of infertility. MATERIALS AND METHODS We carried out a retrospective file search of our computerized data base that contains all clinical and laboratory records of patients who underwent IVF between 1984 and The search algorithm aimed to identify those couples in whom unexplained infertility was diagnosed before IVF. Only those couples in whom no retrieved oocytes were fertilized during the first IVF -ET treatment cycle were included. In all treatment cycles only the husband's semen was used. In all cases, semen analysis before and during any IVF-ET treatment cycle was found to be normal according to the criteria of the World Health Organization (6). In each case, the diagnosis of unexplained infertility had been reached after the following tests were found to be within the normal range. Female tests: regular menses; biphasic body temperature; luteal phase serum progesterone; prolactin; luteinizing hormone (LH); follicle-stimulating hormone (FSH); thyroid hormones; hysterosalpingography, and sub- sequent laparoscopy. Male tests: repeated sperm analyses; bacteriologic cultures; testicular volume; LH; FSH; testosterone; and repeated postcoital tests. The treatment and monitoring protocols used for IVF -ET were as described previously (7, 8). The term first IVF cycle refers to the initial IVF cycle with complete failure of fertilization. The subsequent cycles are numbered consecutively, e.g., second IVF cycle refers to the cycle after the initial unsuccessful cycle. The patients were neither specifically encouraged nor discouraged to repeat cycles. Repetition of the cycle depended on the expressed desire of the patients. Complete failure of fertilization was not an indication for a change of the ovulation induction regimen. Pregnancy was defined as fetal heart rate motion on ultrasound. Statistical Analysis Data were analyzed by nonparametric methods. Correlation between the number of fertilized oocytes during the different IVF cycles was determined by Kendall's rank correlation coefficient test. Results are expressed as means ± SEM. Significance was assumed at P ~ RESULTS Forty-four couples with unexplained infertility failed to fertilize 270 oocytes during the first IVF cycle (Tables 1 and 2). One couple conceived spontaneously 4 months after the first IVF trial, despite their failure to fertilize six oocytes in vitro. Of the initial 44 couples, 37 (84.1 %) underwent one, 21 underwent two, 11 underwent three, and 6 underwent four additional cycles of IVF-ET (Table 1). The pregnancies that occurred during the study period and the combined cumulative pregnancy rate (PR) for the study population are shown in Table 1. Nine of the initial 44 couples (20.5%) conceived either spontaneously or as a result of IVF during the study period after their first failed IVF cycle. Seven of Lipitz et al. Complete failure of fertilization in IVF 349

3 these pregnancies occurred in the 37 couples who underwent at least one more IVF cycle as a result of IVF (i.e., the IVF -related PR per couple was 18.9% and the PR per cycle was 9.3%), and four pregnancies resulted in deliveries (i.e., the take home baby rate per cycle was 5.3%). Number of IVF Cycles Needed to Overcome Complete Failure of Fertilization Of the 37 couples who elected to undergo at least one more IVF cycle (Fig. 1),30 couples (81.1%) had at least one cycle in which fertilization was achieved. Most of the first-time fertilizations (90%) occurred during the second and third IVF cycles. During the second cycle, 18 of the 37 couples (48.6%) had at least one fertilized oocyte, whereas in all the rest complete failure of fertilization occurred for the second time. Among the 18 couples who achieved fertilization, three pregnancies (1 singleton, 1 set of twins delivered at term, and 1 extrauterine pregnancy) were recorded (Table 1). One couple subsequently conceived spontaneously, even though out of 15 retrieved oocytes only one had been fertilized during the second IVF cycle. Of the 19 couples who again failed to achieve fertilization, 12 (63.2%) underwent a third trial of IVF (Fig. 1), in which 9 were successful. Two IVF -related pregnancies resulted (1 spontaneous abortion and a term delivery of a singleton gestation). Of those couples who again failed to achieve fertilization, 2 succeeded on the fourth attempt of IVF. The third couple persisted after four failed cycles and during the fifth IVF cycle two of four oocytes were fertilized. The resulting pregnancy ended with a spontaneous first-trimester abortion. Fbt Trial: 44 without fertilization ~ Second Triat. 18 with 19 without fertilization fertilization ~ Third Trial: 9 with 3 without fertilization fertilization Fourth Triat. z with 1 without fertilization fifth Trial: fertilizat: with fertifization 7 did!kit rape8t IVF 7 did!kit rape8t IVF Figure 1 Diagram showing the number of IVF cycles needed to achieve the first cycle with successful fertilization and to overcome complete failure of fertilization. Only cycles that immediately follow failure of fertilization during previous IVF are included. Complete fertilization failure occurs in 8%,48%, and 22% of all cycles of couples with tubal infertility, male infertility, and unexplained infertility, respectively. It should be noted that these numbers relate to all treatment cycles (e.g., first, second, third cycle) and not only to the first IVF cycle of the couple. Failure of Fertilization in the First Cycle as a Predictor of Low Fertilization Rate During Subsequent IVF Cycles The 37 couples underwent 75 subsequent IVF cycles after the initial failed cycle. The overall rate of oocyte fertilization during the IVF cycles that followed the unsuccessful first cycle in these patients was considerably lower than the overall oocyte fertilization rate all patients undergoing IVF treatment Table 2 Number of Oocytes Retrieved and Fertilized During IVF Cycles First cycle Second cycle Third cycle Fourth cycle Fifth cycle (n = 44) (n = 37) (n = 21) (n = 11) (n = 6) Oocytes retrieved Total Oocytes/couple 6.1 ± ± ± ± ± 1.7 (1 to 20) (1 to 27) (2 to 12) (2 to 18) (4 to 16) [4.5]* [6] [6] [2] [5] Oocytes fertilized Total Oocytes/couple 1.2 ± ± ± ± 0.6 (0 to 5) (0 to 5) (0 to 4) (0 to 5) [0] [3] [2] [3] Fertilization rate (%) * Values are means ± SE with ranges in parentheses and medians in brackets. 350 Lipitz et ai. Complete failure of fertilization in IVF Fertility and Sterility

4 at our clinic. The overall oocyte fertilization rate during these 75 subsequent IVF cycles was only 27.1 % (compared with 67.6% in couples with tubal infertility, 46.4% in all couples with tubal infertility, and 46.4% in all couples with unexplained infertility) (9). Because some couples returned for multiple subsequent IVF cycles, the fertilization rates were 18.7%,33.1 %, and 33.3% for the second, third, and fourth cycle, respectively (Table 2). Of the 75 additional cycles, 29 cycles (38.7%) ended again with complete failure of fertilization. Successful fertilization during the second IVF cycle was also not a good predictor for subsequent cycles. In couples who achieved fertilization during the second cycle, 6 (31.6%) of 19 subsequent cycles again ended with complete failure of fertilization. No correlation was found between either the number of oocytes retrieved during the first IVF cycle or sperm parameter (count, motility, morphology) and the chances of subsequent fertilization. DISCUSSION The results of our study indicate that complete failure of fertilization in couples with unexplained infertility does not necessarily persist during subsequent IVF cycles. Of the 37 couples with unexplained infertility who elected to undergo additional IVF cycles, 30 (81.1%) had at least one successful cycle in which fertilization was achieved. This finding and especially the fact that most of the firsttime fertilizations (90%) occurred during the second and third IVF cycle suggest that at least two additional IVF cycles should be performed after primary failure of fertilization before reverting to other options. One couple achieved fertilization for the first time only after four consecutive failures, and this fifth IVF cycle led to a clinical pregnancy (Fig. 1). However, although subsequent IVF cycles carry some chance of successful fertilization and of pregnancies (Table 1), our data indicate that initial complete failure of fertilization during the first IVF cycle in couples with unexplained infertility is associated with low oocyte fertilization rates in subsequent cycles (Table 2). In our study, complete failure of fertilization occurred in 38.7% of the subsequent IVF cycles. The oocyte fertilization rates for these subsequent cycles were significantly lower (Table 2) than those obtained during the same period among all our IVF patients with unexplained infertility (including those who were part of the present study). In some previous studies, couples with idiopathic infertility had even higher oocyte fertiliza- tion rates (approximately 80%) than those with tubal lesions, endometriosis, or endocrine disorders (3). In a recent study we examined the fertilization rate of couples with male infertility after at least one previous IVF cycle resulted in complete failure of fertilization (10). Of all couples with male infertility, 81.2% achieved fertilization in a subsequent cycle, and the mean oocyte fertilization rate was 47.7% (10). Unexplained infertility is a frustrating diagnosis for the couples involved. Because of the failure to characterize the pathology, it is difficult to plan an appropriate therapeutic protocol. The relatively lower IVF fertilization rates reported by some authors for couples with unexplained infertility may point to unrecognized gamete abnormalities as a possible cause of infertility in some of these patients. In recent years, IVF -ET has been proposed as an alternative therapy for unexplained infertility. However, cases of idiopathic infertility accompanied by complete failure of fertilization during IVF-ET have received very little attention in the literature. In a recent article, the authors concluded that the prognosis for subsequent IVF cycles in couples with initial complete failure of fertilization was surprisingly favorable (2). In that study, 78% of all couples achieved fertilization of oocytes during the second IVF -ET cycle and an additional 5 % during the third (2). These results are in line with our findings that 81.1 % of couples subsequently achieved fertilization after initial complete failure of fertilization in the first IVF cycle, although only 48.6% of our patients were successful during the second cycle and an additional 24.4 % during the third. Moreover, the overall PR in that study (28% of all couples) was somewhat higher than that in ours (18.9% IVF-related pregnancies; 20.5% of all couples) (2). In addition to its therapeutic potential, IVF may be considered as an important test of the fertility potential of a couple with unexplained infertility; indeed, some may even view it as the ultimate biological test for sperm-oocyte interaction. However, as demonstrated by the present study, the predictive value of such a test is questionable because one failed IVF cycle in couples with unexplained infertility does not exclude future fertilizations and pregnancies. However, the high rate (38.7%) of repeated complete failures of fertilization and the low oocyte fertilization rate might indicate a pathology of sperm/oocyte interaction in at least some of these couples. Although this descriptive study was not designed to determine the nature of this pathology, future evaluation of these couples could be directed Lipitz et a1. Complete failure of fertilization in IVF 351

5 r toward a more detailed analysis of oocytes and sperms. We reported previously that in some cases of failed fertilization the oocytes exhibit chromosomal anomalies (7). It is possible that ultrastructural anomalies of the sperm, undetectable during conventional semen analysis, may also contribute to the low rate of fertilization in these patients. The therapeutic alternatives that may overcome the persistently low rates of fertilization and pregnancy in some of these couples are not well defined. The use of donor gametes (oocytes or sperm) was not offered to these couples. Although this allowed us to evaluate the natural course of IVF -ET therapy in this patient population, the use of donor sperms/ oocytes may help to establish the reason for failed fertilization and to overcome the repeatedly unsuccessful outcome in selected cases. It seems that in most couples with complete initial failure of fertilization, those who eventually achieve fertilization will do so during the second or third IVF cycle. We therefore suggest that the use of donor gametes should be considered only after three successive IVF cycles have resulted in complete failure of fertilization. Micromanipulation techniques might also prove helpful in selected cases in the future. Failure of IVF, in conjunction with other parameters, has been considered as an indication for micromanipulation (11, 12). Our study provides reference data for future comparison of the success of micro rna nipulation techniques with that of the natural course of couples with unexplained infertility during subsequent IVF cycles. In conclusion, the results of this study indicate that complete failure of fertilization during the first IVF cycle in couples with unexplained infertility does not necessarily persist during subsequent IVF cycles. Most couples (81.1 %) will probably achieve fertilization during subsequent treatment cycles and some will conceive. However, because of the low oocyte fertilization rate in these couples and the persistent fertilization failure in some of them, complete failure of fertilization may serve as an indicator of an underlying undiagnosed pathology of oocyte/ sperm interaction. REFERENCES 1. Trounson A, Wood C. In vitro fertilization results, at Monash University, Queen Victoria and Epworth Medical Centers. J In Vitro Fert Embryo Transf 1984;1: Molloy D, Harrison K, Breen T, Hennessey J. The predictive value of idiopathic failure to fertilize on the first in vitro fertilization attempt. Fertil Steril 1991;56: Barlow P, Englert Y, Puissant F, Lejeune B, Delvigne A, Van Rysselberge M, et a1. Fertilization failure in IVF: why and what next? Hum Reprod 1990;5: Hughes EG, King C, Wood EC. A prospective study ofprognostic factors in in vitro fertilization and embryo transfer. Fertil Steril1989;51: Jones HW Jr, Acosta AA, Andrews MC, Garcia JE, Jones GS, Mayer J, et a1. Three years of in vitro fertilization at Norfolk. Fertil Steril 1984;42: World Health Organization. WHO laboratory manual for the examination of human semen and semen-cervical mucus interaction. 2nd ed. Cambridge: The Press Syndicate of the University of Cambridge, 1987:3. 7. Rudak E, Dor J, Mashiach S, Nebel L, Goldman B. Chromosomal analysis of multi pronuclear human oocytes fertilized in vitro. Fertil Steril 1984;41: Dor J, Rudak E, Nebel L, Serr DM, Goldman B, Mashiach S. Successful in vitro fertilization and embryo transfer in a group of patients with tubal infertility. Isr J Med Sci 1984;20: Dor J, Shulman A, Levran D, Ben-Rafael Z, Rudak E, Mashiach S. The treatment of patients with polycystic ovarian syndrome by in-vitro fertilization and embryo transfer: a comparison of results with those of patients with tubal infertility. Hum Reprod 1990;5: Ben-Shlomo I, Bider D, Dor J, Levran D, Mashiach S, Ben Rafael Z. Failure to fertilize in vitro in couples with male factor infertility: what next? Fertil Steril1992;58: Malter HE, Cohen J. Partial zona dissection of the human oocyte: a nontraumatic method using micromanipulation to assist zona pellucida penetration. Fertil Steril 1989;51: Cohen J, Malter H, Wright G, Kort H, Mitchel D. Partial zona dissection of human oocyte when failure of zona pellucida penetration is anticipated. Hum Reprod 1984;4: Lipitz et al. Complete failure of fertilization in IVF Fertility and Sterility