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Endometrial thickness cannot predict ongoing pregnancy achievement in cycles stimulated with clomiphene citrate for intrauterine insemination
RBMOnline - Vol 8. No 1. 115-118 Reproductive BioMedicine Online; www.rbmonline.com/Article/1017 on web 18 November 2003
Article Endometrial thickness cannot predict ongoing pregnancy achievement in cycles stimulated with clomiphene citrate for intrauterine insemination Dr Kolibianakis obtained his specialization in Obstetrics and Gynaecology in 2000 and since then he has been a staff specialist at the Centre for Reproductive Medicine of the Dutch-Speaking Brussels Free University. His particular research interest is in endocrinology of the antagonist cycle.
Dr EM Kolibianakis EM Kolibianakis1, KA Zikopoulos, HM Fatemi, K Osmanagaoglu, J Evenpoel, A Van Steirteghem, P Devroey Centre for Reproductive Medicine, Dutch-Speaking Brussels Free University, Brussels, Belgium 1Correspondence: Fax: +32 2 4776649; e-mail: [email protected]
Abstract To date, limited data exist concerning the relation between endometrial thickness on the day of human chorionic gonadotrohin (HCG) administration and ongoing pregnancy achievement in cycles stimulated with clomiphene citrate for intrauterine insemination (IUI). In a prospective study, 168 couples were stimulated with clomiphene citrate from day 3 to day 7 of the cycle and endometrial thickness was assessed by ultrasound three times on the day of ovulation triggering. Ovulation was induced with HCG as soon as ≥1 follicle of ≥17 mm was present at ultrasound independently of endometrial thickness. IUI was performed 36 h after HCG administration. The main outcome measure was ongoing pregnancy. No difference was observed in endometrial thickness between patients who did or did not achieve an ongoing pregnancy (7.6 ± 0.3 versus 7.6 ± 0.2 respectively; P = 0.7). No discriminative ability of endometrial thickness on the achievement of ongoing pregnancy could be shown by receiver operating characteristic (ROC) curve analysis (area under the ROC curve 0.51, 95% CI: 0.44–0.59). In conclusion, endometrial thickness cannot predict ongoing pregnancy achievement in IUI cycles stimulated with clomiphene citrate. Keywords: clomiphene citrate, endometrial thickness, intrauterine insemination, ovarian stimulation
Introduction Endometrial receptivity is one of the limiting steps for establishing conception in assisted reproduction. Its noninvasive assessment has mainly been performed by evaluation of endometrium by ultrasound. Although several papers have examined the relationship between endometrial thickness on the day of human chorionic gonadotrophin (HCG) administration and pregnancy achievement, reported results are often contradictory (Turnbull et al., 1995). This might reflect a non-consistent relationship between endometrial thickness and the chance of pregnancy across different stimulation schemes or assisted reproduction methods.
Endometrial thickness has been reported to be lower in cycles stimulated with clomiphene citrate than in natural cycles (Eden et al., 1989; Randall and Templeton, 1991; Nakamura et al., 1997), probably due to interference of clomiphene citrate with oestrogen receptor kinetics in human endometrium (Birkenfeld et al., 1986). However, the importance of this finding is not clear, as limited data exist concerning the relation between endometrial thickness, assessed by ultrasound on the day of ovulation triggering, and the achievement of ongoing pregnancy in cycles stimulated with clomiphene citrate for intrauterine insemination (IUI) (Dickey et al., 1993). The purpose of the present study was to evaluate prospectively the relationship between endometrial thickness on the day of HCG administration and achievement of ongoing pregnancy after clomiphene citrate treatment for IUI.
115
Article - Predictive value of endometrial thickness on pregnancy outcome - EM Kolibianakis et al.
Materials and methods
All tests were two-tailed with a confidence limit of 95% (P < 0.05). Values are expressed as mean ± SE.
Patient population One hundred and sixty-eight patients undergoing ovarian stimulation with clomiphene citrate for IUI at the Centre for Reproductive Medicine of the Dutch-Speaking Brussels Free University were included in the study during the period from May 2001 to May 2002. Patients could enter the study only once. Inclusion criteria were age ≤39 years, patent tubes on hysterosalpingography or laparoscopy and FSH concentrations on day 3 of the menstrual cycle <10 IU/l. The mean age of the patients analysed was 32.9 ± 0.4 years. Male factor infertility was diagnosed in 60 couples, 23 of whom opted to undergo donor insemination due to severe male factor. Dysovulation was present in 27 patients. In addition, clomiphene citrate/IUI treatment was performed for 36 lesbian couples in whom donor spermatozoa were used for IUI, while in 45 couples no reason for sub-fertility could be established.
Results Thirty-three ongoing pregnancies occurred in 168 patients (19.6%) who entered the study. Three twin ongoing pregnancies were recorded (9.1% multiple pregnancy rate), while four first trimester miscarriages occurred (10.8% miscarriage rate). Patient and stimulation characteristics according to achievement of an ongoing pregnancy are shown in Table 1. Significantly more follicles ≥17 mm and ≥15 mm and higher oestradiol concentrations were present on the day of HCG administration in the group of patients who achieved an ongoing pregnancy as compared with those who did not. On the other hand, no differences were observed between the two groups of patients in the mean endometrial thickness, and the type of endometrium on the day of HCG administration, as well as in patient diagnosis (Table 1).
Ultrasound assessment Endometrial thickness was measured at the thickest longitudinal plane at three different time moments. The type of endometrium was characterized as hypoechogenic (type 1), triple line (type 2) or hyperechogenic (type 3) as described previously (Gonen and Casper, 1990).
Ovarian stimulation Clomiphene citrate was administered from day 3 to day 7 of the cycle at a dose of either 50 mg (n = 68) or 100 mg (n = 100). HCG 5000 IU was given for ovulation induction as soon as ≥1 follicle of ≥17 mm was present at ultrasound, regardless of endometrial thickness.
Sperm preparation and IUI Sperm preparation and IUI procedure have been described in detail previously (Delaert et al., 1993).
Outcome measures Ongoing pregnancy was defined as the presence of an intrauterine sac on US with fetal heart beat at 7 weeks of gestation.
Statistical analysis
116
Endometrial thickness used in the analysis was calculated on the basis of the mean of the three measurements performed for each patient. Normally distributed (Kolmogorov–Smirnov test with Lilliefors correction) metric variables were tested with the t-test for independent samples, while non-normally distributed metric variables were analysed with the Mann–Whitney U-test. Nominal variables were tested using the Pearson chi-square test. The ability of endometrial thickness to discriminate between patients who achieved an ongoing pregnancy or not was assessed by the area under the receiver operating characteristic curve (ROC) curve. Concerning sample size, it has been suggested that meaningful qualitative conclusions can be drawn from ROC experiments performed with a total of about 100 observations (Metz, 1978).
Six ongoing pregnancies occurred with endometrial thickness of <6 mm on the day of HCG administration (3.8, 4.4, 4.5, 4.6, 5.6, 5.9 mm). Ongoing pregnancy rates observed in three groups of patients with mean endometrial thickness <6, 6 to <8 and ≥8 mm on the day of HCG administration are shown in Table 2. Similar pregnancy rates were observed between the three groups compared. ROC curve analysis with achievement of ongoing pregnancy as a dependent variable and endometrial thickness on the day of HCG as a predictor appears in Figure 1. No predictive value of endometrial thickness was present (Figure 1).
Discussion This study has shown that endometrial thickness assessed on the day of HCG administration cannot discriminate between patients who will or will not achieve an ongoing pregnancy in IUI cycles stimulated with clomiphene citrate. Similar ongoing pregnancy rates were observed in patients with different values of endometrial thickness on the day of HCG administration. To the best of the authors’ knowledge, this is the first prospective study examining the relationship between endometrial thickness and ongoing pregnancy achievement in patients stimulated with clomiphene citrate for IUI who received HCG independently of endometrial thickness. Dickey and Holtkamp (1993) reported that no pregnancies were observed if endometrial thickness was <6 mm on the day of HCG administration in cycles stimulated with clomiphene citrate for IUI. In that study, however, it is not clear if HCG administration for ovulation induction was withheld in the presence of endometrial thickness <6 mm. If endometrial thickness is a criterion for HCG administration, any conclusions for its importance in predicting pregnancy achievement are biased. Prolongation of the follicular phase when endometrial thickness is <6 mm on the day HCG criteria are met is usually performed with the expectation that the endometrial thickness will improve. Indeed, endometrial
Article - Predictive value of endometrial thickness on pregnancy outcome - EM Kolibianakis et al.
Table 1. Patient and stimulation characteristics according to achievement of an ongoing pregnancy following stimulation with clomiphene for IUI.
Age (years) Dose of CC (mg) Interval between last CC dose and HCG administration (days) Number of follicles ≥17 mm on the day of HCG Number of follicles ≥15 mm on the day of HCG Oestradiol on the day of HCG pg/ml Progesterone on the day of HCG ng/ml Mean endometrial thickness on the day of HCG (mm) Endometrium type on the day of HCG Type 1 (%) Type 2 (%) Type 3 (%) Diagnosis in couple Male factor (%) Female factor (%) No cause of infertilityd (%)
Ongoing pregnancy (n = 33)
Not pregnant (n = 135)
P-value
33.1 ±0.8 81.2 ± 4.3 5.1 ± 0.3
32.5 ± 0.4 80.3 ± 2.1 5.0 ± 0.1
0.6a 0.8b 0.9b
2.0 ± 0.2
1.5 ± 0.1
0.001b
2.3 ± 0.2
1.7 ± 0.1
0.007b
854.5 ± 100.2 0.8 ± 0.1 7.6 ± 0.3
617.9 ± 34.2 0.9 ± 0.1 7.6 ± 0.2
0.03b 0.1b 0.7b
8.3 87.5 4.2
9.5 83.2 7.4
0.9c
33.3 15.2 51.5
36.3 16.3 47.4
0.9c
at-test for independent samples, bMann–Whitney test, cChi-squared test. dIncludes IUI in lesbian couples and couples with idiopathic infertility.
Table 2. Ongoing pregnancy rates according to mean endometrial thickness on the day of HCG administration. Endometrial thickness on day of HCG (mm)
<6.0
6.0–<8.0
≥8.0
Ongoing pregnancy ratea (%) n
17.1
19.1
21.5
6/35
13/68
14/65
aP = 0.9 chi-square test.
represents a selected population of patients initially presenting with endometrial thickness <6 mm on the day HCG criteria were met. Any conclusion in this case on the relationship between decreased endometrial thickness and ongoing pregnancy achievement does not reflect their true relationship.
Figure 1. ROC curve on the mean endometrial thickness assessed on the day of HCG administration in relation to achievement of an ongoing pregnancy. Area under the ROC curve = 0.51, 95% CI: 0.44–0.59. thickness will increase beyond 6 mm in a proportion of patients who may or not achieve pregnancy. However, in the remaining patients, endometrial thickness will still be decreased (<6 mm) despite prolongation of the follicular phase for 1 or 2 days. This second group of patients
Although a predictive role of endometrial thickness could not be demonstrated, follicular development was shown to be significant for the achievement of ongoing pregnancy (Table 1). The importance of follicle number for pregnancy achievement has been previously shown (Dickey and Holtkamp, 1996).). A higher number of follicles ≥17 mm and ≥15 mm on the day of ovulation induction with HCG was present in patients who achieved an ongoing pregnancy as compared with those who did not (Table 1). The present study suggests that endometrial thickness assessed on the day of HCG cannot predict the achievement of ongoing pregnancy in patients stimulated with clomiphene citrate for IUI, questioning its routine assessment in these patients.
117
Article - Predictive value of endometrial thickness on pregnancy outcome - EM Kolibianakis et al.
Acknowledgements The authors would like to thank Mr Frank Winter of the Language Education Centre for correcting the manuscript. This work is supported by grants from the Fund for Scientific Research, Flanders.
References Birkenfeld A, Beier HM, Schenker JG 1986 The effect of clomiphene citrate on early embryonic development, endometrium and implantation. Human Reproduction 1, 387–395. Dellaert A, Tournaye H, Verheyen G et al. 1993 Resultaten van kunstmatige inseminatie met cryo-gepreserveerd donorsperma. Tijdschrift voor Geneeskunde 49, 99–104. Dickey RP, Holtkamp DE 1996 Development, pharmacology and clinical experience with clomiphene citrate. Human Reproduction Update 2, 483–506. Dickey RP, Olar TT, Taylor SN et al. 1993 Relationship of endometrial thickness and pattern to fecundity in ovulation induction cycles: effect of clomiphene citrate alone and with human menopausal gonadotropin. Fertility and Sterility 59, 756–760.
118
Eden JA, Place J, Carter GD et al. 1989 The effect of clomiphene citrate on follicular phase increase in endometrial thickness and uterine volume. Obstetrics and Gynecology 73, 187–190. Gonen Y, Casper RF 1990 Prediction of implantation by the sonographic appearance of the endometrium during controlled ovarian stimulation for in vitro fertilization (IVF). Journal of In Vitro Fertilization and Embryo Transfer 7, 146–152. Metz CE 1978 Basic principles of ROC analysis. Seminars in Nuclear Medicine 8, 283–298. Nakamura Y, Ono M, Yoshida Y et al. 1997 Effects of clomiphene citrate on the endometrial thickness and echogenic pattern of the endometrium. Fertility and Sterility 67, 256–260. Randall JM, Templeton A 1991 Transvaginal sonographic assessment of follicular and endometrial growth in spontaneous and clomiphene citrate cycles. Fertility and Sterility 56, 208–212. Turnbull LW, Lesny P, Killick SR 1995 Assessment of uterine receptivity prior to embryo transfer: a review of currently available imaging modalities. Human Reproduction Update 1, 505–514.
Received 16 May 2003; refereed 19 June 2003; accepted 8 October 2003.
Article Endometrial thickness cannot predict ongoing pregnancy achievement in cycles stimulated with clomiphene citrate for intrauterine insemination Dr Kolibianakis obtained his specialization in Obstetrics and Gynaecology in 2000 and since then he has been a staff specialist at the Centre for Reproductive Medicine of the Dutch-Speaking Brussels Free University. His particular research interest is in endocrinology of the antagonist cycle.
Dr EM Kolibianakis EM Kolibianakis1, KA Zikopoulos, HM Fatemi, K Osmanagaoglu, J Evenpoel, A Van Steirteghem, P Devroey Centre for Reproductive Medicine, Dutch-Speaking Brussels Free University, Brussels, Belgium 1Correspondence: Fax: +32 2 4776649; e-mail: [email protected]
Abstract To date, limited data exist concerning the relation between endometrial thickness on the day of human chorionic gonadotrohin (HCG) administration and ongoing pregnancy achievement in cycles stimulated with clomiphene citrate for intrauterine insemination (IUI). In a prospective study, 168 couples were stimulated with clomiphene citrate from day 3 to day 7 of the cycle and endometrial thickness was assessed by ultrasound three times on the day of ovulation triggering. Ovulation was induced with HCG as soon as ≥1 follicle of ≥17 mm was present at ultrasound independently of endometrial thickness. IUI was performed 36 h after HCG administration. The main outcome measure was ongoing pregnancy. No difference was observed in endometrial thickness between patients who did or did not achieve an ongoing pregnancy (7.6 ± 0.3 versus 7.6 ± 0.2 respectively; P = 0.7). No discriminative ability of endometrial thickness on the achievement of ongoing pregnancy could be shown by receiver operating characteristic (ROC) curve analysis (area under the ROC curve 0.51, 95% CI: 0.44–0.59). In conclusion, endometrial thickness cannot predict ongoing pregnancy achievement in IUI cycles stimulated with clomiphene citrate. Keywords: clomiphene citrate, endometrial thickness, intrauterine insemination, ovarian stimulation
Introduction Endometrial receptivity is one of the limiting steps for establishing conception in assisted reproduction. Its noninvasive assessment has mainly been performed by evaluation of endometrium by ultrasound. Although several papers have examined the relationship between endometrial thickness on the day of human chorionic gonadotrophin (HCG) administration and pregnancy achievement, reported results are often contradictory (Turnbull et al., 1995). This might reflect a non-consistent relationship between endometrial thickness and the chance of pregnancy across different stimulation schemes or assisted reproduction methods.
Endometrial thickness has been reported to be lower in cycles stimulated with clomiphene citrate than in natural cycles (Eden et al., 1989; Randall and Templeton, 1991; Nakamura et al., 1997), probably due to interference of clomiphene citrate with oestrogen receptor kinetics in human endometrium (Birkenfeld et al., 1986). However, the importance of this finding is not clear, as limited data exist concerning the relation between endometrial thickness, assessed by ultrasound on the day of ovulation triggering, and the achievement of ongoing pregnancy in cycles stimulated with clomiphene citrate for intrauterine insemination (IUI) (Dickey et al., 1993). The purpose of the present study was to evaluate prospectively the relationship between endometrial thickness on the day of HCG administration and achievement of ongoing pregnancy after clomiphene citrate treatment for IUI.
115
Article - Predictive value of endometrial thickness on pregnancy outcome - EM Kolibianakis et al.
Materials and methods
All tests were two-tailed with a confidence limit of 95% (P < 0.05). Values are expressed as mean ± SE.
Patient population One hundred and sixty-eight patients undergoing ovarian stimulation with clomiphene citrate for IUI at the Centre for Reproductive Medicine of the Dutch-Speaking Brussels Free University were included in the study during the period from May 2001 to May 2002. Patients could enter the study only once. Inclusion criteria were age ≤39 years, patent tubes on hysterosalpingography or laparoscopy and FSH concentrations on day 3 of the menstrual cycle <10 IU/l. The mean age of the patients analysed was 32.9 ± 0.4 years. Male factor infertility was diagnosed in 60 couples, 23 of whom opted to undergo donor insemination due to severe male factor. Dysovulation was present in 27 patients. In addition, clomiphene citrate/IUI treatment was performed for 36 lesbian couples in whom donor spermatozoa were used for IUI, while in 45 couples no reason for sub-fertility could be established.
Results Thirty-three ongoing pregnancies occurred in 168 patients (19.6%) who entered the study. Three twin ongoing pregnancies were recorded (9.1% multiple pregnancy rate), while four first trimester miscarriages occurred (10.8% miscarriage rate). Patient and stimulation characteristics according to achievement of an ongoing pregnancy are shown in Table 1. Significantly more follicles ≥17 mm and ≥15 mm and higher oestradiol concentrations were present on the day of HCG administration in the group of patients who achieved an ongoing pregnancy as compared with those who did not. On the other hand, no differences were observed between the two groups of patients in the mean endometrial thickness, and the type of endometrium on the day of HCG administration, as well as in patient diagnosis (Table 1).
Ultrasound assessment Endometrial thickness was measured at the thickest longitudinal plane at three different time moments. The type of endometrium was characterized as hypoechogenic (type 1), triple line (type 2) or hyperechogenic (type 3) as described previously (Gonen and Casper, 1990).
Ovarian stimulation Clomiphene citrate was administered from day 3 to day 7 of the cycle at a dose of either 50 mg (n = 68) or 100 mg (n = 100). HCG 5000 IU was given for ovulation induction as soon as ≥1 follicle of ≥17 mm was present at ultrasound, regardless of endometrial thickness.
Sperm preparation and IUI Sperm preparation and IUI procedure have been described in detail previously (Delaert et al., 1993).
Outcome measures Ongoing pregnancy was defined as the presence of an intrauterine sac on US with fetal heart beat at 7 weeks of gestation.
Statistical analysis
116
Endometrial thickness used in the analysis was calculated on the basis of the mean of the three measurements performed for each patient. Normally distributed (Kolmogorov–Smirnov test with Lilliefors correction) metric variables were tested with the t-test for independent samples, while non-normally distributed metric variables were analysed with the Mann–Whitney U-test. Nominal variables were tested using the Pearson chi-square test. The ability of endometrial thickness to discriminate between patients who achieved an ongoing pregnancy or not was assessed by the area under the receiver operating characteristic curve (ROC) curve. Concerning sample size, it has been suggested that meaningful qualitative conclusions can be drawn from ROC experiments performed with a total of about 100 observations (Metz, 1978).
Six ongoing pregnancies occurred with endometrial thickness of <6 mm on the day of HCG administration (3.8, 4.4, 4.5, 4.6, 5.6, 5.9 mm). Ongoing pregnancy rates observed in three groups of patients with mean endometrial thickness <6, 6 to <8 and ≥8 mm on the day of HCG administration are shown in Table 2. Similar pregnancy rates were observed between the three groups compared. ROC curve analysis with achievement of ongoing pregnancy as a dependent variable and endometrial thickness on the day of HCG as a predictor appears in Figure 1. No predictive value of endometrial thickness was present (Figure 1).
Discussion This study has shown that endometrial thickness assessed on the day of HCG administration cannot discriminate between patients who will or will not achieve an ongoing pregnancy in IUI cycles stimulated with clomiphene citrate. Similar ongoing pregnancy rates were observed in patients with different values of endometrial thickness on the day of HCG administration. To the best of the authors’ knowledge, this is the first prospective study examining the relationship between endometrial thickness and ongoing pregnancy achievement in patients stimulated with clomiphene citrate for IUI who received HCG independently of endometrial thickness. Dickey and Holtkamp (1993) reported that no pregnancies were observed if endometrial thickness was <6 mm on the day of HCG administration in cycles stimulated with clomiphene citrate for IUI. In that study, however, it is not clear if HCG administration for ovulation induction was withheld in the presence of endometrial thickness <6 mm. If endometrial thickness is a criterion for HCG administration, any conclusions for its importance in predicting pregnancy achievement are biased. Prolongation of the follicular phase when endometrial thickness is <6 mm on the day HCG criteria are met is usually performed with the expectation that the endometrial thickness will improve. Indeed, endometrial
Article - Predictive value of endometrial thickness on pregnancy outcome - EM Kolibianakis et al.
Table 1. Patient and stimulation characteristics according to achievement of an ongoing pregnancy following stimulation with clomiphene for IUI.
Age (years) Dose of CC (mg) Interval between last CC dose and HCG administration (days) Number of follicles ≥17 mm on the day of HCG Number of follicles ≥15 mm on the day of HCG Oestradiol on the day of HCG pg/ml Progesterone on the day of HCG ng/ml Mean endometrial thickness on the day of HCG (mm) Endometrium type on the day of HCG Type 1 (%) Type 2 (%) Type 3 (%) Diagnosis in couple Male factor (%) Female factor (%) No cause of infertilityd (%)
Ongoing pregnancy (n = 33)
Not pregnant (n = 135)
P-value
33.1 ±0.8 81.2 ± 4.3 5.1 ± 0.3
32.5 ± 0.4 80.3 ± 2.1 5.0 ± 0.1
0.6a 0.8b 0.9b
2.0 ± 0.2
1.5 ± 0.1
0.001b
2.3 ± 0.2
1.7 ± 0.1
0.007b
854.5 ± 100.2 0.8 ± 0.1 7.6 ± 0.3
617.9 ± 34.2 0.9 ± 0.1 7.6 ± 0.2
0.03b 0.1b 0.7b
8.3 87.5 4.2
9.5 83.2 7.4
0.9c
33.3 15.2 51.5
36.3 16.3 47.4
0.9c
at-test for independent samples, bMann–Whitney test, cChi-squared test. dIncludes IUI in lesbian couples and couples with idiopathic infertility.
Table 2. Ongoing pregnancy rates according to mean endometrial thickness on the day of HCG administration. Endometrial thickness on day of HCG (mm)
<6.0
6.0–<8.0
≥8.0
Ongoing pregnancy ratea (%) n
17.1
19.1
21.5
6/35
13/68
14/65
aP = 0.9 chi-square test.
represents a selected population of patients initially presenting with endometrial thickness <6 mm on the day HCG criteria were met. Any conclusion in this case on the relationship between decreased endometrial thickness and ongoing pregnancy achievement does not reflect their true relationship.
Figure 1. ROC curve on the mean endometrial thickness assessed on the day of HCG administration in relation to achievement of an ongoing pregnancy. Area under the ROC curve = 0.51, 95% CI: 0.44–0.59. thickness will increase beyond 6 mm in a proportion of patients who may or not achieve pregnancy. However, in the remaining patients, endometrial thickness will still be decreased (<6 mm) despite prolongation of the follicular phase for 1 or 2 days. This second group of patients
Although a predictive role of endometrial thickness could not be demonstrated, follicular development was shown to be significant for the achievement of ongoing pregnancy (Table 1). The importance of follicle number for pregnancy achievement has been previously shown (Dickey and Holtkamp, 1996).). A higher number of follicles ≥17 mm and ≥15 mm on the day of ovulation induction with HCG was present in patients who achieved an ongoing pregnancy as compared with those who did not (Table 1). The present study suggests that endometrial thickness assessed on the day of HCG cannot predict the achievement of ongoing pregnancy in patients stimulated with clomiphene citrate for IUI, questioning its routine assessment in these patients.
117
Article - Predictive value of endometrial thickness on pregnancy outcome - EM Kolibianakis et al.
Acknowledgements The authors would like to thank Mr Frank Winter of the Language Education Centre for correcting the manuscript. This work is supported by grants from the Fund for Scientific Research, Flanders.
References Birkenfeld A, Beier HM, Schenker JG 1986 The effect of clomiphene citrate on early embryonic development, endometrium and implantation. Human Reproduction 1, 387–395. Dellaert A, Tournaye H, Verheyen G et al. 1993 Resultaten van kunstmatige inseminatie met cryo-gepreserveerd donorsperma. Tijdschrift voor Geneeskunde 49, 99–104. Dickey RP, Holtkamp DE 1996 Development, pharmacology and clinical experience with clomiphene citrate. Human Reproduction Update 2, 483–506. Dickey RP, Olar TT, Taylor SN et al. 1993 Relationship of endometrial thickness and pattern to fecundity in ovulation induction cycles: effect of clomiphene citrate alone and with human menopausal gonadotropin. Fertility and Sterility 59, 756–760.
118
Eden JA, Place J, Carter GD et al. 1989 The effect of clomiphene citrate on follicular phase increase in endometrial thickness and uterine volume. Obstetrics and Gynecology 73, 187–190. Gonen Y, Casper RF 1990 Prediction of implantation by the sonographic appearance of the endometrium during controlled ovarian stimulation for in vitro fertilization (IVF). Journal of In Vitro Fertilization and Embryo Transfer 7, 146–152. Metz CE 1978 Basic principles of ROC analysis. Seminars in Nuclear Medicine 8, 283–298. Nakamura Y, Ono M, Yoshida Y et al. 1997 Effects of clomiphene citrate on the endometrial thickness and echogenic pattern of the endometrium. Fertility and Sterility 67, 256–260. Randall JM, Templeton A 1991 Transvaginal sonographic assessment of follicular and endometrial growth in spontaneous and clomiphene citrate cycles. Fertility and Sterility 56, 208–212. Turnbull LW, Lesny P, Killick SR 1995 Assessment of uterine receptivity prior to embryo transfer: a review of currently available imaging modalities. Human Reproduction Update 1, 505–514.
Received 16 May 2003; refereed 19 June 2003; accepted 8 October 2003.