1 Kaali Institute IVF Center, Budapest and 2 Department of Medical Informatics, University of Szeged, Szeged, Hungary
3 To whom correspondence should be addressed at: Kaali Institute, Istenhegyi ut 54/A, 1125 Budapest, Hungary. e-mail: peterkovacs1970{at}hotmail.com
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Abstract |
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Key words: clomiphene citrate/endometrial thickness/gonadotrophin/IVF/pregnancy
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Introduction |
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With certain endometrial abnormalities (e.g. Ashermans syndrome) that prevent normal endometrial changes from occurring, implantation rates are low and abortion rates are high (Schenker and Margalioth, 1982).
Several studies have evaluated the effect of endometrial thickness and pattern on cycle and pregnancy outcome (Check et al., 1991; 1993; Dickey et al., 1992
; Noyes et al., 1995
; Rinaldi et al., 1996
; Yuval et al., 1999
; De Geyter et al., 2000
; Bassil, 2001
; Schield et al., 2001
), but the results obtained have been controversial. For example, some authors have demonstrated a greater probability of pregnancy once the endometrium attains a threshold thickness (Check et al., 1991
; 1993; Dickey et al., 1992
; Noyes et al., 1995
; Rinaldi et al., 1996
), while others have not reproduced these findings (Yuval et al., 1999
; De Geyter et al., 2000
; Bassil, 2001
; Schield et al., 2001
). This variation might be due to the limited power of the smaller studies, to differences in the stimulation protocols, or to differences in patient characteristics. In the present study, an investigation was made in 1228 IVF/ICSI cycles to determine whether the method of stimulation was related to endometrial thickness, or if endometrial thickness was related to achievement of pregnancy or was predictive of first-trimester pregnancy loss.
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Materials and methods |
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Statistical analysis
The MannWhitney U-test was used to compare continuous variables between cycles that resulted in pregnancy and those that did not. Categorical variables were compared using the chi-square test. A multiple logistic regression was used to evaluate further the association between cycle outcome and those factors that might potentially influence outcome. The independent factors studied were endometrial thickness, number of follicles, number of metaphase II oocytes, number of oocytes fertilized, embryo quality, number of embryos transferred, baseline FSH, age and type of protocol. The model of logistic regression was gained by a stepwise procedure, and specific interactions between parameters of interest were also investigated. Models were compared by the likelihood ratio test. A P-value < 0.05 was considered to be statistically significant.
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Results |
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The overall pregnancy rate was 32.8% (n = 402). The clinical pregnancy rate was 35.9% in the GnRH agonist + gonadotrophin group and 26.2% in the CC + gonadotrophin cycles (P = 0.001). First-trimester outcome was known for 365 pregnancies; in total, 323 of the 365 pregnancies (88.5%) were normal or ongoing.
In cycles that resulted in pregnancy, the patients were younger, had more mature oocytes, had more embryos transferred, and the embryo quality was higher (Table I). Mean (± SD) endometrial thickness on the day of transfer was significantly greater in cycles where pregnancy was achieved (10.84 ± 1.8 versus 10.46 ± 1.7 mm; P = 0.003) (Table I). In order to compare endometrial thickness by the day of transfer (day 2 versus day 3) in addition to cycle outcome, a two-way ANOVA was performed. Mean endometrial thickness was similar between day 2 and day 3 cycles (10.5 ± 1.7 versus 10.7 ± 1.8 mm; P = 0.079). The proportion of cycles with day 2 or day 3 transfers was also similar for the two stimulation protocols [day 2: 623/964 (64.7%) versus 233/382 (61.0%); day 3: 341/964 (35.3%) versus 149/382 (39.0%)].
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It was noted that 88.5% of the pregnancies were ongoing. Baseline demographic and stimulation parameters were similar between ongoing and pathological pregnancies, and endometrial thickness did not differ between ongoing and abnormal pregnancies (Table IV). The rate of pathological pregnancy was similar in the GnRH agonist + gonadotrophin group when compared with the CC + gonadotrophin group (11.1 versus 7.5%; P = NS).
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Discussion |
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One group (Dickey et al., 1992) found that fecundity was increased when the endometrium was at least 9 mm thick, and had a triple-line appearance during IVF cycles. However, biochemical pregnancies were more frequent with a thinner endometrium (Dickey et al., 1992
). Others (Check et al., 1991
) demonstrated an improved pregnancy rate with a thicker endometrium, and also identified a thicker endometrium among pregnant women treated with GnRH agonist when compared to those treated with CC. In a later study, the same group reported higher pregnancy rates among donor oocyte recipients with an endometrium that was
10 mm thick (9 versus 38.7%; P < 0.01) (Check et al., 1993). Another group (Noyes et al., 1995
) subsequently evaluated 516 IVF cycles and found pregnancy and ongoing pregnancy rates to be higher when the endometrial thickness was
9 mm. Likewise, a minimum thickness of 10 mm during IVF was found to produce a higher pregnancy rate (Rinaldi et al., 1996
).
In more recent studies, however, no significant association between endometrial thickness and pregnancy outcome was seen (Yuval et al., 1999; De Geyter et al., 2000
; Bassil, 2001
; Schield et al., 2001
). It is possible that, with more advanced laboratory and stimulation methods, a small effect of endometrial thickness on outcome might become obscured or overridden. The day of measurement might also influence the association between endometrial thickness and cycle outcome. In the present study, an increased endometrial thickness was not related to improved pregnancy rates, although the measurements were made on the day of transferthat is, at 4 or 5 days after the hCG injection. Endometrial thickness evaluated on the day of embryo transfer might be influenced by an increased luteal phase progesterone secretion, and various measurement methods (including outer edge to outer edge, or outer edge to inner edge) could further affect outcome. Differences in the analysis might also provide a further explanation for the conflicting results. Some studies evaluated cut-off values (Noyes et al., 1995
; Rinaldi et al., 1996
; De Geyter et al., 2000
), while others compared mean endometrial thickness (Yuval et al., 1999
; Schield et al., 2001
) or compared endometrial thickness among percentile groups (De Geyter et al., 2000
). Re-allocating the groups according to these different criteria might result in groups which contain few subjects and have only limited power to detect a small difference.
The effect of increased endometrial thickness has also been evaluated. For example, one group (Weissman et al., 1999) reported lower implantation and pregnancy rates among women with an endometrial thickness
14 mm on the day of hCG administration. However, no adverse effect of thickened (>14 mm) endometrium on implantation, pregnancy or abortion rates was identified by others (Dietterich et al., 2002
).
In the present study, a possible association was also sought between endometrial thickness and pregnancy rate based on data from 1228 IVF cycles. The endometrium was found to be slightly but significantly thicker in cycles that resulted in pregnancy. Furthermore, pregnancy rates were shown to be higher when an endometrial thickness of at least 10 mm was achieved. While this improvement is small, the data suggest that adequate endometrial development is one of the factors that play a significant role in IVF outcome. Other variables such as age, embryo quality, number of embryos transferred and stimulation protocol were also shown to have a significant impact on treatment outcome.
In previous studies, the endometrium was found to be thinner when CC was combined with hMG (Gonen and Casper, 1990; Check et al., 1991
; Saito et al., 1991
). A similar negative endometrial effect was not observed in the present CC + gonadotrophin cycles; rather, the endometrial thickness was similar to that in the ultrashort GnRH agonist cycles. It is likely that the supraphysiological estradiol level reached during CC + gonadotrophin stimulation was able to correct for the negative endometrial effects of CC alone. Estrogen supplementation during stimulation with CC has been shown to improve endometrial development and to result in thicker endometria and improved morphology (Gerli et al., 2000
; Elkind-Hirsch et al., 2002
).
In the present study an assessment was also made of whether endometrial thickness had an effect on pregnancy outcome. Pregnancies were followed for up to 810 weeks before patients were referred back to their primary provider. Once the patient was discharged from the authors centre, it was difficult to obtain accurate follow-up information; hence, outcomes were reported only up to the time of discharge and it is possible that some pregnancies were lost during the subsequent few weeks. As no differences were observed in the loss rate up to this point, significant differences would not necessarily be expected to emerge beyond this point. As the number of abnormal pregnancies was low to start with (n = 43), subgroups were not created based on the exact outcome in order to avoid the comparison of subgroups with only a few casesfor example, with only six extrauterine pregnancies. Endometrial thickness on the day of transfer however, was found to be similar between ongoing and pathological pregnancies.
In conclusion, the results of the present study identified a statistically significant difference in mean endometrial thickness between cycles that resulted in pregnancy and those that did not. Adequate endometrial development is required for pregnancy to occur, and pregnancy rates were found to be higher when the endometrium reached at least 10 mm thickness. Consequently, clinicians providing IVF for infertile couples must pay close attention to endometrial development as well as to follicle growth.
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Acknowledgements |
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References |
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Submitted on March 25, 2003; resubmitted on July 15, 2003; accepted on July 25, 2003.