An initial low response predicts poor outcome in in vitro fertilization/intracytoplasmic sperm injection despite improved ovarian response in consecutive cycles Zdravka Veleva, M.D.,a Ilkka Y. Järvelä, M.D., Ph.D.,a Sinikka Nuojua-Huttunen, M.D., Ph.D.,b Hannu Martikainen, M.D., Ph.D.,a and Juha S. Tapanainen, M.D., Ph.D.a a
Department of Obstetrics and Gynecology, University of Oulu, and b Family Federation of Finland, Oulu, Finland
Objective: To study the predictive value of initial low response (LR) in IVF/intracytoplasmic sperm injection (ICSI). Design: Retrospective analysis. Setting: Two Finnish fertility centers. Patient(s): A total of 3,846 IVF/ICSI cycles performed from 1994 to 2002. Intervention(s): Consecutive cycles in the same subject were identified. The study groups consisted of subjects who had three treatment cycles and at least one LR cycle (n ⫽ 80). Main Outcome Measure(s): Pregnancy rate (PR), total gonadotropin dose, and embryo quality. Result(s): Only 2.5% (2/80) of subjects had a LR in all three consecutive cycles. In 43 women an initial LR was followed by ⱖ1 normal response (NR) cycle, and in 35 women an initial NR was followed by ⱖ1 LR cycle. The PR/cycle was similarly low in women with an initial LR and an initial NR (10.1% vs. 16.2%). An increase in gonadotropin dose resulted in a higher number of oocytes in women with an initial LR (from 2.1 ⫾ 0.9 to 6.7 ⫾ 2.7) but the PR/cycle remained low, compared to the overall mean PR (27.2%). In cycles in which top quality embryos were transferred, subjects with an initial LR had a lower PR than women with an initial NR (17.8% vs. 41.2%). Conclusion(s): An initial LR is a predictor of poor outcome in subsequent cycles, even if ovarian response is improved by increasing the gonadotropin dose or a top quality embryo is replaced. (Fertil Steril威 2005;83: 1384 –90. ©2005 by American Society for Reproductive Medicine.) Key Words: IVF/ICSI, low response, ovary, top quality embryo
A low ovarian response to gonadotropin stimulation (LR) is a significant problem in modern fertility treatment. It is associated with a significant decline in the success rate of fertility treatment (1, 2). Low response is more common in older women (3), but younger women also sometimes exhibit a poor response to stimulation (3), and the rate of LR varies from 9% to 24% in IVF/intracytoplasmic sperm injection (ICSI) cycles (4). Depending on the diagnostic criteria, LR is most often defined based on a low number (⬍4) of retrieved oocytes (5–7), or a peak serum E2 level ⬍500 pg/mL (6, 8). Various strategies have been used to avoid a LR in subsequent treatment cycles, including increased gonadotropin doses (8 –11), minimal pituitary suppression with GnRH Received June 3, 2004; revised and accepted November 10, 2004. Supported by grants from the Academy of Finland, the Sigrid Jusélius Foundation, the Finnish Medical Foundation and the Oulu University Hospital. Presented in part at the 20th Congress of the European Society of Human Reproduction and Embryology (ESHRE), Berlin, Germany, June 27–30, 2004. Reprint requests: Juha S. Tapanainen, M.D., Ph.D., Department of Obstetrics and Gynecology, P.O. Box 5000, FIN-90014 University of Oulu, Oulu, Finland (FAX: 358-8-3154310; E-mail:
[email protected]).
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agonists (13, 14), flare protocols (15, 16), GnRH antagonists (17), pretreatment with oral contraceptives (18, 19), and, ultimately, ovum donation (19). However, the outcomes of these strategies have been conflicting (1, 6, 21, 22), which may be a result of a small number of subjects, different selection criteria, and follow-up periods that are too short. The aim of the study was to investigate the incidence and recurrence of LR in IVF/ICSI treatment, and to compare the outcome in different groups of women with LR. We were especially interested in the prognostic significance of LR in the first treatment cycle. Data from two fertility units, covering an 8-year period was analyzed. MATERIALS AND METHODS Subjects During the period 1994 –2002, data on 2,237 subjects who had an ovum pickup in a total of 3,846 IVF/ICSI cycles were collected from the computerized databases (Babe 3.0; XtremeSolutions, Oulu, Finland) of the IVF Unit of Oulu University Hospital and the Family Federation of Finland, Oulu. Data were obtained on a retrospective basis, and institutional review board permission was not required. At present, there is no consensus on the definition of LR. The
Fertility and Sterility姞 Vol. 83, No. 5, May 2005 Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/05/$30.00 doi:10.1016/j.fertnstert.2004.11.056
most widely used classification is based on the number of collected oocytes (5, 6) and therefore we also used the same criteria. A LR cycle was defined as yielding ⱕ3 oocytes, a normal response (NR) cycle 4 –14 oocytes, and a high response (HR) cycle ⱖ15 oocytes.
were further divided into always low responders (“always LR,” 2/80, 2.5%) and subjects who had a NR in one or more subsequent cycles (LR–⬎NR, n ⫽ 43). In the other 35 subjects the first stimulation cycle was NR, LR occurring in a subsequent cycle (NR–⬎LR).
Study Groups The algorithm for selection of the study groups is shown in Figure 1. All consecutive treatment cycles of the same subject were identified. For a subsequent analysis, only subjects with LR and NR were selected. The following groups were excluded: patients with a HR cycle (665 subjects), those who were stimulated only once or twice (1,290 subjects), repetitive normal responders stimulated more than twice (157 subjects), and women with a history of ovarian surgery or cyst aspiration (45 subjects).
Ovarian Stimulation In the two units, procedures in IVF/ICSI were similar, allowing the analysis of the combined data. A long GnRH agonist (GnRH-a) protocol was used for pituitary downregulation. Details have been previously described (23). Briefly, GnRH-a was started on days 21–23 of the previous cycle, and both depot GnRH-a preparations (goserelin acetate, Zoladex 3.6 mg, Asta-Zeneca, Macclesfield, UK; leuprorelin acetate, Procren 3.75 mg, Abbott Scandinavia, Solna, Sweden or Enanton 3.75 mg, Orion Pharma, Oulunsalo, Finland; triptorelin acetate, Decapeptyl 3.75 mg, Ferring, Kiel, Germany) and daily administered intranasal GnRH-a preparations (buserelin acetate, Suprecur, Hoechst
Study groups were formed on the basis of the first three cycles of subjects who had at least one LR cycle (n ⫽ 80). Of these, in 45 women the first treatment cycle was LR. They
FIGURE 1 Study design (see text for details).
Veleva. Initial low response in IVF/ICSI. Fertil Steril 2005.
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Marion Roussel, Frankfurt am Main, Germany or nafarelin acetate, Synarela, Pharmacia Sverige AB, Stockholm, Sweden) were used. Buserelin was administered at a dose of 150 g four times a day and nafarelin at 400 g twice a day until ovarian stimulation was started, after which the dose was reduced to half. The proportion of depot GnRH-a preparations was similar in the NR–⬎LR and LR–⬎NR groups (9/105, 8.6% vs. 16/129, 12.4%, P ⫽ .4). Ovarian stimulation was started 14 –21 days after the initiation of GnRH-a. Complete down-regulation in the long protocol was based on the absence of functioning follicles (ⱖ10 mm) and by the thin endometrium on ultrasonography. Ovarian stimulation was performed with urinary or recombinant gonadotropins. Just before administration of the first gonadotropin dose, the total number of antral follicles measuring 2–5 mm in both ovaries was counted. Ovarian status was classified in three categories: inactive (⬍5 follicles/2 ovaries), normal (5–15 follicles/2 ovaries), and polycystic ovary-type ovaries (⬎15 follicles/2 ovaries) (24). The starting gonadotropin dose was affected by the age, body mass index (BMI), antral follicle counts, and by the outcome in previous stimulations, and varied from 150 to 300 IU. As elsewhere in the Nordic countries, ovarian stimulation was monitored by ultrasound examination and not by hormonal analysis. In all cycles analyzed, at least three growing follicles with a mean diameter of at least 12 mm were observed on stimulation day 10. If fewer follicles were seen, the cycle was canceled. Follicular maturation was induced by an IM injection of 5,000 or 10,000 IU of hCG when at least two follicles had a mean diameter of ⬎17 mm. Ten thousand IU of hCG were used in 17% of cycles until 1999. The use of this dosage was discontinued thereafter as no benefit to the treatment outcome was observed. Transvaginal oocyte retrieval under ultrasonographic guidance was performed 36 hours later. Before transfer, embryos were evaluated by one of the two embryologists who periodically cross-examine their scoring methods. A top quality embryo had 4 –5 cells and ⬍20% fragmentation if it was cultured for 2 days, or ⱖ8 cells and ⬍20% fragmentation if it was cultured for 3 days (25). The technique of embryo transfer (ET) has been described previously (26) and has remained unchanged during the study period. The ET was carried out on day 2 or 3 after oocyte retrieval, depending of the day of the week— on Monday if the oocytes were collected on Friday and 2 days after the ovum pickup in all other instances. Such a strategy has been adopted to minimize work during the weekends. The ET was followed by 14 days of luteal phase support with 1,500 IU of hCG three times per week or with intravaginal micronized P 600 mg/d. After a positive pregnancy test, clinical pregnancies were confirmed by ultrasonographic examination at 6 –7 weeks of gestation. 1386
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Outcome Measures A primary outcome measure was the pregnancy rate/cycle (PR/cycle). The total gonadotropin dose and embryo quality were secondary outcome measures. The overall mean PR/ cycle in IVF/ICSI in the two study centers during the study period was used as a reference. Similarly, the overall mean PR/cycle in top quality embryo cycles was used as a reference when analyzing top quality embryo cycles in the study groups. Only the outcome after fresh ET has been analyzed, whereas cycles with frozen-thawed ETs were not taken into account. Statistical Analysis Statistical analysis was performed with the SPSS 10.1 package (SPSS Inc., Chicago, IL). For normally distributed continuous variables, Student’s two-tailed t test was used. For comparison of variables with persisting skewed distribution after log transformation, the Mann-Whitney U test was used. For categorical data, the 2 test or Fisher’s exact test was used. Values of P⬍.05 were considered to be statistically significant. Data are presented as mean ⫾ SD unless otherwise indicated. RESULTS Low response cycles (ⱕ3 oocytes) comprised 11.5% (441/ 3,846), NR cycles 66.6% (2,561/3,846), and HR cycles 21.9% (844/3,846) of all IVF/ICSI cycles. In the study period, the overall PR was 27.2% (1,046/3,846), the overall live birth rate was 20.3% (780/3,846) and the overall spontaneous abortion rate was 15.5% (162/1,046). Characteristics of Study Groups The proportion of LR cycles in the LR–⬎NR and the NR–⬎LR groups was similar (Table 1). Due to a low number of cycles, “always LR” subjects were not compared with the other study subjects. The main indications for IVF/ICSI did not differ between the study groups. Ultrasonography before ovarian stimulation revealed that the proportion of inactive ovaries in the LR–⬎NR (42.4%, 53/125) and in the NR–⬎LR groups (27.5%, 28/102, P ⫽ .06) did not reach statistical significance. The mean proportion of inactive ovaries in the study groups remained the same in each consecutive cycle (cycle 1: 26/71, 36.6%; cycle 2: 26/78, 33.3%; cycle 3: 29/78, 37.2%). The time interval between the first and the third treatment cycle was 1.4 ⫾ 1.0 years in NR–⬎LR and 1.2 ⫾ 0.8 years in LR–⬎NR subjects (P ⫽ .3). In the “always LR” women it was 3.0 ⫾ 2.8 years. The age was ⱖ40 years in 14.3% (15 cycles) of the NR–⬎LR group, in 10.1% (13 cycles) of the LR–⬎NR group (P ⫽ .4), and in 50.0% (3 cycles) of the “always LR” group. Clinical Outcome Stimulation characteristics and PRs are shown in Table 2. No statistically significant differences were observed in stimuVol. 83, No. 5, May 2005
TABLE 1 Characteristics of subjects stimulated three times.
Number of subjects Number of LR cycles Age (y) BMI (kg/m2) Main diagnosis Endometriosis Anovulation Male factor Tubal factor Unexplained Number of ICSI cycles
NR->LR
LR->NR
35 42/105 40.0% 34.2 ⫾ 5.5 24.4 ⫾ 5.0
43 61/129 47.3% 34.6 ⫾ 3.9 24.9 ⫾ 3.6
18 (17.1%) 9 (8.6%) 36 (34.3%) 21 (20.0%) 21 (20.0%) 34/102 33.3%
18 (14.0%) 3 (2.3%) 39 (30.2%) 39 (30.2%) 30 (23.3%) 68/108 35.7%
P value
Always LR
.3
2 6
.5 .8 .1
.8
36.8 ⫾ 7.4 25.9 ⫾ 1.3 0 (0%) 0 (0%) 0 (0%) 6 (100.0%) 0 (0%) 0/6 0%
Note: Data of “always LR” subjects were not analyzed. Veleva. Initial low response in IVF/ICSI. Fertil Steril 2005.
lation characteristics when comparing the LR–⬎NR and the NR–⬎LR groups. In LR–⬎NR subjects, after an initial LR the mean gonadotropin dose was increased from 2,349.1 ⫾ 685.3 to 2,977.2 ⫾ 977.8 IU (P⬍.0001), which resulted in a higher number of oocytes recovered (2.1 ⫾ 0.9 vs. 6.7 ⫾ 2.7, P⬍.0001). No statistically significant differences in PR/ cycle were observed between the study groups but they were significantly lower (LR–⬎NR: 10.1%, P⬍.0001; NR–⬎LR: 16.2%, P ⫽ .01), compared to the mean overall PR during the study period. Spontaneous abortion rates were similar in the NR–⬎LR group (6/17, 35.3%) and in the LR–⬎NR group (5/13, 38.5%, P ⫽ 1.0). After a preliminary analysis, the following variables were found not to affect the PR: IVF vs. ICSI (17/53, 11.1% vs. 13/81, 16.0%, P ⫽ .3); urinary vs. recombinant gonadotropins (20/157, 12.7% vs. 9/55, 16.4%, P ⫽ .5); hCG 5,000 IU vs. hCG 10,000 IU (22/158, 13.9% vs. 6/59, 10.2%, P ⫽ .7); ET on day 2 vs. day 3 (28/181, 15.5% vs. 2/15, 13.3%, P ⫽ 1.0); hCG vs. micronized P for luteal support (4/33, 12.1% vs. 25/164, 15.2%, P ⫽ .8). Top Quality Embryo Cycles To determine whether the reason for a lower PR in subjects with a LR was due to embryo quality, an analysis of cycles with top quality embryos was carried out. The proportion of cycles with ⱖ1 top quality embryo transferred was similar in both groups (Table 3). The total numbers of transferred top and non-top quality embryos, as well as endometrial thickness, did not differ. However, PR and live birth rate were two times lower in LR–⬎NR subjects than in NR–⬎LR ones. The PR (41.2%) and the live birth rate (32.4%) in the NR–⬎LR group was similar to the overall mean PR and live birth rate in top quality embryo cycles (37.2%, 724/1946, Fertility and Sterility姞
P ⫽ .7 and 28.4%, 553/1946, P ⫽ .6, respectively) but in the LR–⬎NR subjects they were significantly lower (17.8%, P ⫽ .007 and 11.1%, P ⫽ .011, respectively). Spontaneous abortion rates tended to be higher in the NR–⬎LR (21.4%, 3/14, P ⫽ .4) and LR–⬎NR (37.5%, 3/8, P ⫽ .1) groups compared to the overall mean spontaneous abortion rate in the two centers (14.4%, 104/724). Outcome in Women LR
LR->NR
P value
Always LR
2,522.4 ⫾ 861.5 11.3 ⫾ 1.9 9.1 ⫾ 2.2 5.1 ⫾ 3.1 61.4 ⫾ 31.0 53.5 ⫾ 30.9 1.7 ⫾ 0.9 0.6 ⫾ 1.5 17/105 16.2% 11/105 10.5%
2,690.8 ⫾ 909.5 11.3 ⫾ 1.8 8.7 ⫾ 2.2 4.5 ⫾ 3.1 59.2 ⫾ 32.4 49.4 ⫾ 32.2 1.5 ⫾ 0.9 0.5 ⫾ 1.2 13/129 10.1% 8/129 6.2%
.2 .7 .2 .1 .6 .3 .07 .3 .2
3,125.0 ⫾ 612.4 11.5 ⫾ 1.5 11.3 ⫾ 3.0 2.5 ⫾ 0.8 72.2 ⫾ 32.8 44.4 ⫾ 34.4 1.3 ⫾ 0.5 0 1/6 16.7% 1/6 16.7%
.3
Note: Data of “always LR” subjects were not analyzed. Veleva. Initial low response in IVF/ICSI. Fertil Steril 2005.
The proportion of older women (ⱖ40 years) in the group whose first cycle was LR was relatively low (10.1%). The risk of a poor response has been found to be five times higher in women ⱖ40 years than in younger women (29), although ovarian response is not absolutely related to age (3, 30). A possible explanation for this discrepancy may be that older subjects do not always undergo three treatment cycles as the result of an anticipated poor outcome. A low response in younger women may be associated with early ovarian aging, as suggested previously (31). Women with at least one LR cycle had a relatively high proportion of inactive ovaries (less than five follicles) at the beginning of stimulation compared to that observed in nonselected IVF/ICSI subjects (24). These results confirm previous observations that a low antral follicle count is associ-
ated with lower numbers of collected oocytes (24, 32) and is an important predictor of ovarian response in IVF/ICSI (5, 33, 34). Furthermore, these results also indicate that ovarian morphology remains relatively stable for a time period of 1–1.5 years. The ultrasonographic appearance of the ovaries classified in categories did not change significantly between the first and third treatment cycle. It is not easy to find the most suitable stimulation protocol for subjects with a poor ovarian response (1, 6, 21). The dose of gonadotropin plays an important role and several individual characteristics have to be taken into consideration when determining the optimal dose. The individual response is dependent on age, BMI (4, 35), and genetic and environmental factors such as FSH receptor isoforms (36), the presence of autoantibodies (37), and smoking (5, 24, 33, 34).
TABLE 3 Characteristics of cycles in which at least one top quality embryo was transferred. NR->LR
LR->NR
34/105
45/129
32.4% 1.38 ⫾ 0.49 2.0 ⫾ 0.6 9.3 ⫾ 2.6 14/34 41.2% 11/34 32.4%
34.9% 1.33 ⫾ 0.48 1.9 ⫾ 0.5 9.0 ⫾ 2.6 8/45 17.8% 5/45 11.1%
Number of cycles with ⱖ1 top quality embryo transferred Number of top quality embryos transferred Total number of transferred embryos Final endometrium (mm) Pregnancy rate Live birth rate
P value .8
.7 .4 .7 .026 .026
Always LR 2/6 33.3% 1.00 ⫾ 0.0 1.5 ⫾ 0.7 10.5 ⫾ 0.7 1/2 50.0% 1/2 50.0%
Note: Data of “always LR” subjects were not analyzed. Veleva. Initial low response in IVF/ICSI. Fertil Steril 2005.
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Our clinics have paid much attention, particularly to the starting dose in IVF/ICSI stimulation, and since the early 1990s we have aimed at individualization of the dose. The present results indicate that increasing the gonadotropin dose after a LR cycle results in an improved response in the subsequent cycle. This is supported by the results of other studies showing that a higher gonadotropin dose is required if the initial follicle count is low (5, 32–34, 38). Although the number of oocytes retrieved in women with initial LR increased after increasing the gonadotropin dose, the PR remained lower than the overall PR during the study period. The results of this and other studies also cast doubt on the attempts to increase ovarian responsiveness in low responders (10, 12, 39, 40). An IVF/ICSI cycle in which a top quality embryo is transferred is believed to be optimal for pregnancy (25, 41). Therefore, we performed a subanalysis of cycles in which ⱖ1 top quality embryo was transferred. Although the number of transferred embryos and endometrial thickness were similar in the study groups, PR was lower in the group with an initial LR, compared to subjects with NR in the first cycle. In support to these observations another study has also shown that women with an initial poor response have a lower cumulative PR than women who initially had a normal ovarian response (27). In the present analysis, age, BMI, ovarian activity, or main diagnosis did not differ between the groups with an initial LR or NR and could not explain the lower PR in women with an initial LR. The poor outcome after an initial LR cycle regardless of the quality of embryos transferred or the age of the patient suggests that embryos of good morphological quality may still have a low pregnancy potential in this particular group of patients. In fact, an aneuploidy rate of 30.8% has been found even in good morphology embryos of normal responders (42). Results concerning the quality of embryos in low responders have been controversial. In a previous study in which poor and normal response cycles were compared, a similar PR was found when the same number of top quality embryos was transferred in women aged ⬍37 years (43). However, other investigations have found that 54%– 64% of the embryos in patients with poor prognosis or low response have chromosomal abnormalities (1, 44 – 46), although they look morphologically normal. This may explain low PRs in poor responders (1). Chromosomal abnormalities in embryos of women with a diminished ovarian reserve have also been associated with an increased risk of spontaneous abortions (47). In the present study, spontaneous abortion rates of subjects in both groups who ever had a LR were more than twofold higher than the overall mean abortion rate in the two centers. A similar trend was also observed in cycles in which top quality embryos were transferred, although the numbers were low. Thus, the present findings support the possible association of factors related to ovarian aging and increased spontaneous abortion rate (3, 5, 48, 49). Fertility and Sterility姞
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Vol. 83, No. 5, May 2005
