Changes in measured endometrial thickness predict in vitro fertilization success

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1 Changes in measured endometrial thickness predict in vitro fertilization success Grant D. E. McWilliams, D.O., a and John L. Frattarelli, M.D. b a Tripler Army Medical Center, Honolulu, Hawaii; and b Reproductive Medicine Associates of New Jersey, Somerset, New Jersey Objective: To assess the predictive ability of endometrial thickness and changes in endometrial thickness on pregnancy outcomes in patients undergoing IVF. Design: Retrospective cohort analysis. Setting: Academic IVF center. Patient(s): Infertile patients undergoing 132 fresh autologous IVF cycles. Intervention(s): Transvaginal ultrasound to assess endometrial thickness at three defined points during IVF (after pituitary suppression, on the sixth day of gonadotropin stimulation, and on the day of hcg administration). Main Outcome Measure(s): Primary outcome variables included endometrial lining thickness at baseline, on day 6 of gonadotropins, the day of hcg administration, and the change in endometrial thickness during gonadotropin stimulation. Result(s): Patients attaining pregnancy had significantly greater endometrial thickness on day 6 and endometrial thickness on day of hcg administration. Pregnant patients had a greater change in endometrial thickness from the baseline to day 6 when compared to nonpregnant patients. Threshold analysis and receiver operator characteristic curves noted significant endometrial thickness levels for implantation and pregnancy rates. Conclusion(s): Endometrial responsiveness and thickness during the early IVF stimulation seem to be better prognostic predictors of success than endometrial thickness at the start or the end of the IVF cycle. (Fertil Steril 2007;88: by American Society for Reproductive Medicine.) Key Words: Infertility, endometrial thickness, endometrial growth, transvaginal ultrasound, pregnancy outcome, IVF, endometrium, implantation Many factors contribute to obtaining a successful pregnancy. Understanding these factors can help in counseling patients regarding their chances of success and in offering interventions for improvement. Factors of both embryologic development and endometrial differentiation have been evaluated (1 15). With respect to endometrial differentiation, the possible predictors of pregnancy that have been evaluated are endometrial blood flow, endometrial pattern, and endometrial thickness (3 15). Endometrial thickness has been evaluated as a possible predictor of pregnancy in multiple studies with conflicting results (6, 11 16). Some studies have shown no differences in pregnancy rates with respect to endometrial thickness (6, 12). Rinaldi et al. (13) noted decreased pregnancy success with thin endometrial linings ( 10 mm) on the day of hcg administration (13). Others have found contrasting data in evaluating thicker endometrial linings on the day of hcg administration (12, 15). Received April 9, 2006; revised and accepted November 17, This study was supported by the Department of Clinical Investigation at Tripler Army Medical Center, Honolulu, HI. The views expressed in this manuscript are those of the investigators, and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U. S. Government. Reprint requests: John L. Frattarelli, M.D, Reproductive Medicine Associates of New Jersey, 100 Franklin Square Drive, Suite 200, Somerset NJ (FAX: , jfrattarelli@rmanj.com). Few studies have evaluated the change in endometrial thickness occurring during IVF stimulation (8, 11, 16). Based on the lack of available literature, this study was designed to assess the change in endometrial thickness throughout the IVF stimulation in patients undergoing IVF. MATERIALS AND METHODS Population This is a retrospective cohort analysis of 132 couples undergoing 132 fresh autologous IVF cycles at the Tripler Army Medical Center In Vitro Fertilization Institute. Institutional review board approval was obtained from the Tripler Army Medical Center institutional review board, Honolulu, HI. All infertile women undergoing IVF were eligible to participate in the study. Inclusion criteria included: normal basal FSH concentration per our laboratory ( 12 miu/ml), documented measurement of endometrial thickness at cycle baseline, on day 6 of gonadotropin stimulation, and on the day of human menopausal gonadotropin (hcg) administration. Patients were included independent of their diagnoses or reproductive history. Diminished ovarian reserve was defined as women having an FSH 10 miu/ml, basal antral follicle count of 4, or age 40 years. Exclusion criteria included: patients who did not have the transvaginal ultrasound on the specified dates, patients Fertility and Sterility Vol. 88, No. 1, July /07/$32.00 Copyright 2007 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 years, and patients without documented endometrial lining thickness. All endometrial measurements were performed by the author (JLF) using an ATL Ultramark HDI 3000 (Philips Medical Systems, Bothell, WA) with a 7-MHz vaginal transducer. The full thickness of the endometrial stripe was measured from the outer margin to the outer margin of the stripe. The stripe measurement was obtained approximately 1 cm from the fundus of the uterus. Experimental Design All patients started oral contraceptive pills (OCs) (30 g ethinyl estradiol, 0.15 mg norgestrel) the evening of menstrual day 3. The patients continued the OCs for 21 days before pituitary suppression with GnRH-a (500 g) (Luprolide acetate, Lupron; TAP Pharmaceuticals, North Chicago, IL). There was a 7-day overlap of the GnRH-a with the OCs. After 14 days of GnRH-a, the dose was decreased to 250 g, and stimulation with exogenous gonadotropins was initiated 5 days later. Baseline endometrial stripe measurement was determined on the day the patient decreased the GnRH-a dose to 250 g. When the largest cohort of follicles reached the 16 mm to 18 mm range, a single 10,000 IU intramuscular dose of hcg was administered. Transvaginal follicular aspiration was performed approximately 35 hours after hcg administration. Using a Wallace transfer catheter (Cooper Surgical, Shelton, CT), embryos were transferred under transabdominal ultrasound guidance 72 to 120 hours after follicular aspiration. Outcome Measures Primary outcome measures [1] were endometrial lining thickness on the baseline day after pituitary suppression with GnRH-a and 5 days before gonadotropin initiation (EMT Baseline ), [2] on day 6 of gonadotropin stimulation (EMT Day 6 ), [3] on the day of hcg administration (EMT hcg ), [4] the change in endometrial thickness from the EMT Baseline to EMT Day 6 ( EMT Day 6 Baseline ), [5] the change in endometrial thickness from the EMT Day 6 to EMT hcg ( EMT hcg - Day 6 ), and [6] the change in endometrial thickness from the EMT Baseline to EMT hcg ( EMT hcg - Baseline ). Secondary outcome measures were age, body mass index, IVF stimulation parameters (day 3 FSH, day 3 LH, day 3 estradiol, total ovarian volume, total antral follicle count, baseline estradiol, stimulation day 6 estradiol, day of hcg estradiol, total oocytes retrieved, total embryos obtained, ampules of gonadotropins used, and days of stimulation), and pregnancy outcomes (implantation rate, initial pregnancy rate, spontaneous pregnancy loss rate, and live birth rate). Pregnancies and the accompanying rates were defined as follows. Initial pregnancy was documented by a rising serum hcg concentration on luteal days 14 and 16. Spontaneous pregnancy loss was defined as a pregnancy loss following sonographic visualization of an intrauterine gestational sac at 5 to 6 weeks of gestation. Live birth rate was defined as those pregnancies proceeding to deliver a live infant. Implantation rate was calculated by dividing the number of gestational sacs visualized on transvaginal ultrasound by the number of embryos transferred. Statistical Analysis Statistical analysis was performed using SPSS 12.0 (SPSS Inc., Chicago, IL). For normally distributed data, a t test was used to compare the means between two groups, and a one-way analysis of variance was used to compare the means between multiple groups. For data not normally distributed, a Mann- Whitney rank sum test was used to compare means between two groups and a Kruskal-Wallis one-way analysis of variance on ranks was used to compare the means of multiple groups. A Tukey test was used for pairwise multiple comparisons. Patients were grouped by EMT Baseline, EMT Day 6, and EMT hcg at increments of 1 mm from 2 mmto 10 mm. Patients were then grouped by EMT Day 6 Baseline, EMT hcg - Baseline, and EMT hcg - Day 6 at increments of 1 mm from 4 mmto 10 mm. Implantation rates, pregnancy rates, pregnancy loss rates, and live birth rates were calculated for each increment. The rates above and below each threshold were evaluated to determine if there were any obvious break points at which there was a significant change in these rates. Contingency table analysis and receiver operator characteristic (ROC) curves were then used to evaluate the outcome rates above and below the selected threshold value. Differences in outcome rates were analyzed using a chi-square or two-tailed Fisher exact test where appropriate. Univariate analysis included regression and correlation coefficients examining the association of endometrial lining measurements and changes with parameters of ovarian reserve and response. An alpha error of 0.05 was considered significant for all comparisons. Relative risk and 95% confidence intervals are displayed where appropriate. All data were reported as means with their associated standard deviations. RESULTS A total of 132 IVF cycles were analyzed. The patient demographics, prestimulation, and stimulation parameters are depicted in Table 1. When subdividing the patients into those who conceived (n 70) and those who did not conceive (n 62), there were expected significant differences between these two groups with regard to age, total number of antral follicles, peak estradiol level on day of hcg administration, number of oocytes obtained, and total number of embryos. EMT measurements from the subgroup of pregnant patients were compared to the nonpregnant patients (Table 2). The pregnant patients had significantly thicker endometrial linings on EMT Day 6,onEMT hcg, and a greater change with EMT Day 6 Baseline. The overall change in endometrial Fertility and Sterility 75

3 TABLE 1 Population demographics, prestimulation, and stimulation parameters for the IVF study group, which was further subdivided into patients who conceived and patients who did not conceive. Variables All patients N 132 Pregnant N 70 Not pregnant N 62 a P value Age (years) b BMI (kg/m 2 ) b Day 3 FSH (miu/ml) c Day 3 LH (miu/ml) b Day 3 estradiol (pg/ml) b Total ovarian volume (cm 3 ) c Total antral follicles b Baseline estradiol (pg/ml) b Day 6 estradiol (pg/ml) b Day of hcg estradiol (pg/ml) b Number of oocytes retrieved b Number of embryos b Ampules of gonadotropins used b Days of stimulation b Note: Values represent means and the associated standard deviation. BMI body mass index. a Comparing pregnant patients with those not pregnant, P.05 is considered statistically significant. b Normality test failed. Mann-Whitney Rank Sum Test was used to determine significance. c Normality test passed. t Test was used to determine significance. thickness, EMT hcg Baseline, trended toward significance (P.05). Our patients had the following primary etiologies for their infertility: male factor (28%), anovulation (23%), tubal factor (19%), unknown (14%), diminished ovarian reserve (10%), and endometriosis (6%). Etiologies of infertility were compared to the endometrial stripe measurements in Table 3. Patients with the diagnosis of diminished ovarian reserve had the thinnest endometrium on EMT Day 6 and on EMT hcg, as well as the least amount of overall change from EMT hcg Baseline. Patients with the diagnosis of either endometriosis or male factor had the thickest endometrium on EMT hcg. Patients with the diagnosis of male factor had the greatest change from EMT hcg Baseline. TABLE 2 Pregnant patients compared to nonpregnant patients with respect to their endometrial thickness and the change in the endometrial thickness during the IVF cycle. Measurements Pregnant (n 70) Not Pregnant (n 62) a P value EMT Baseline (mm) b EMT Day 6 (mm) c EMT hcg (mm) b EMT Day 6 Baseline (mm) c EMT hcg Day 6 (mm) c EMT hcg Baseline (mm) c Note: Values represent means and the associated standard deviation. a P.05 is considered statistically significant. The pregnant patients were compared with those who were not pregnant. b Normality test failed. Mann-Whitney rank sum test was used to determine significance. c Normality test passed. t Test was used to determine significance. 76 McWilliams and Frattarelli Endometrial thickness and IVF success Vol. 88, No. 1, July 2007

4 TABLE 3 Etiologies for infertility compared to endometrial thickness (EMT) and change in endometrial thickness ( EMT). Anovulation DOR Endometriosis Male factor Tubal factor Unexplained a P value EMT Baseline (mm) b EMT Day 6 (mm) d e d d d d.05 c EMT hcg (mm) d e f f d d.001 c EMT Day 6 Baseline b (mm) EMT hcg Day c (mm) EMT hcg Baseline (mm) d e d f d d.05 c Note: DOR diminished ovarian reserve. a P.05 is considered statistically significant. b Normality test failed. Kruskal-Wallis one-way analysis of variance on ranks was used to determine significance. c Normality test passed. One-way analysis of variance was used to determine significance. d,e,f Values with different superscripts are statistically different based on pair-wise multiple comparison with a Tukey test. Univariate analyses were completed comparing endometrial thickness to the demographics, prestimulation, and stimulation parameters were performed. As expected, EMT and EMT measurements significantly correlated with each other. The EMT Baseline significantly correlated with the patient s level of estradiol on day 3 (r 0.38, P.001). The EMT Day 6 significantly correlated with most of the parameters including age (r 0.26, P.05), the level of FSH on day3(r 0.22, P.05), the total ovarian volume (r 0.27, P.05), the total number of antrals (r 0.30, P.05), the level of estradiol at baseline (r 0.19, P.05), the level of estradiol on day 6 of gonadotropin stimulation (r 0.45, P.001), the level of estradiol on day of hcg administration (r 0.45, P.001), the number of oocytes (r 0.34, P.001), the number of embryos (r 0.27, P.05), the number of ampules of gonadotropins used (r 0.19, P.05), and the number of days of stimulation (r 0.27, P.01). The EMT hcg significantly correlated with age (r 0.26, P.05), the level of estradiol on day of hcg administration (r 0.28, P.001), and the number of oocytes (r 0.26, P.05). Univariate analyses were completed comparing the change in endometrial thickness to the demographics; prestimulation and stimulation parameters were also performed. The EMT Day 6 Baseline significantly correlated with age (r 0.27, P.05), the total ovarian volume (r.30, P.05), the total number of antral follicles (r.35, P.001), the level of estradiol on day 6 of gonadotropin stimulation (r 0.40, P.001), the level of estradiol on day of hcg administration (r 0.37, P.001), the number of oocytes (r 0.32, P.001), the number of embryos (r 0.23, P.05), the number of ampules of gonadotropins used (r 0.22, P.05), and the number of days of stimulation (r 0.29, P.05). The EMT hcg - Day 6 significantly correlated with the level of FSH on day 3 (r 0.23, P.05), the total ovarian volume (r 0.21, P.05), the total number of antral follicles (r 0.28, P.05), the level of estradiol on day 6 of gonadotropin stimulation (r 0.34, P.001), the level of estradiol on day of hcg administration (r 0.27, P.05), and the number of embryos (r 0.20, P.05). The EMT hcg Baseline significantly correlated with age (r 0.20, P.05), the level of estradiol on day of hcg administration (r 0.19, P.05), and the number of oocytes (r 0.23, P.05). Threshold levels for EMT Baseline, EMT Day 6 and EMT hcg as well as the changes in thickness ( EMT Day 6 Baseline, EMT hcg Baseline, EMT hcg - Day 6 ) during the course of an IVF cycle were evaluated using contingency table analysis and ROC curves (Figs. 1 and 2). Table 4 shows the area under the ROC curves with 95% confidence intervals for implantation and pregnancy rates. An EMT Baseline of 3 mm was found to have a significantly higher implantation rate (35.4%) than an EMT Baseline of 3 mm (23.9%) (P.05, RR 1.48 [1.03, 2.12]). No significant threshold level was found for pregnancy rate or pregnancy loss rate. An EMT Day 6 of 6 mm was found to have a significantly lower implantation rate (17.1% vs. 33.3%) (P.001, RR 0.51 [0.34, 0.77]) and pregnancy rate (38.0% vs. 64.5%) (P.01, RR 0.59 [0.40, 0.87]) compared to an EMT Day 6 of 6 mm. No significant threshold level was found for pregnancy loss rate. An EMT hcg of 7 mm was found to have a significantly lower implantation rate (11.9% vs. 28.6%) (P.01, RR Fertility and Sterility 77

5 FIGURE 1 Receiver operator characteristic curves for implantation rates of patients undergoing IVF based on the endometrial lining thickness (EMT) and the change in EMT ( EMT) during the stimulation cycle. Endometrial measurements were taken at baseline before gonadotropin stimulation (EMT Baseline ), on day 6 of gonadotropin stimulation (EMT Day 6 ), and on the day of hcg administration (EMT hcg ). Calculations were also made based on the change in endometrial thickness from the EMT Baseline to EMT Day 6 ( EMT Day 6 Baseline ), the change in endometrial thickness from the EMT Day 6 to EMT hcg ( EMT hcg Day 6 ), and the change in endometrial thickness from the EMT Baseline to EMT hcg ( EMT hcg Baseline ). The most significant measurements as determined by the area under the curve were the EMT Day 6 and the EMT Day 6 Baseline [0.20, 0.85]) compared to an EMT hcg of 7 mm. An EMT hcg of 8 mm was found to have a significantly lower pregnancy rate (34.1% vs. 60.7%) (P.01, RR 0.56 [0.36, 0.89]) compared to an EMT hcg of 8 mm. Of note, only 1 of 24 (4.2%) transferred embryos implanted and only 1 of 8 (12.5%) patients got pregnant with an EMT hcg of 6 mm. No significant threshold level was found for pregnancy loss rate. A EMT Day 6 Baseline 3 mm was found to have a significantly lower implantation rate (22.4% vs. 35.7%) (P.01, RR 0.63 [0.44, 0.88]) compared to a EMT Day 6 Baseline of 3 mm. A EMT Day 6 Baseline of 2 mm was found to have a significantly lower pregnancy rate (42.0% vs. 62.7%) (P.05, RR 0.67 [0.46, 0.97]) compared to a EMT Day 6 Baseline of 2 mm. No significant threshold level was found for pregnancy loss rate. A EMT hcg Day 6 of 0 mm was found to have a significantly higher implantation rate (43.2% vs. 24.8%) (P.05, RR 1.75 [1.15, 2.65]) and pregnancy rate (70.4% vs. 48.5%) (P.05, RR 1.45 [1.06, 2.00]) compared to a EMT hcg Day 6 of 0 mm. No significant threshold level was found for pregnancy loss rate. A EMT hcg Baseline of 3 mm was found to have a significantly lower implantation rate (13.3% vs. 29.7%) (P.01, RR 0.45 [0.25, 0.82]) and pregnancy rate (24.0% vs. 59.4%) (P.01, RR 0.40 [0.20, 0.83]) compared to a EMT hcg Baseline of 3 mm. No significant threshold level was found for pregnancy loss rate. DISCUSSION Previous literature has noted conflicting results regarding the prognostic ability of endometrial thickness on the day of hcg administration (6, 11 16). In reviewing our data, correlations were seen from which general principles can be derived. The endometrial thickness on day 6 of stimulation, EMT Day 6, and the change in the initial endometrial thickness from the baseline appointment to day 6 of stimulation, EMT Day 6 Baseline, seemed to have the most significant association with IVF stimulation and pregnancy outcomes. 78 McWilliams and Frattarelli Endometrial thickness and IVF success Vol. 88, No. 1, July 2007

6 FIGURE 2 Receiver operator characteristic curves for pregnancy rates of patients undergoing IVF based on the endometrial lining thickness (EMT) and the change in EMT ( EMT) during the stimulation cycle. Endometrial measurements were taken at baseline before gonadotropin stimulation (EMT Baseline ), on day 6 of gonadotropin stimulation (EMT Day 6 ), and on the day of hcg administration (EMT hcg ). Calculations were also made based on the change in endometrial thickness from the EMT Baseline to EMT Day 6 ( EMT Day 6 Baseline ), the change in endometrial thickness from the EMT Day 6 to EMT hcg ( EMT hcg - Day 6 ), and the change in endometrial thickness from the EMT Baseline to EMT hcg ( EMT hcg - Baseline ). The most significant measurements as determined by the area under the curve were the EMT Day 6 and the EMT Day 6 Baseline. This significance was confirmed using contingency table analysis and ROC curves. Using contingency tables and ROC curves, we have shown that implantation rates were higher if the EMT was 3 mm for EMT Baseline, 6 mm for EMT Day 6, 7 mm for EMT hcg, 3 mmfor EMT Day 6 Baseline, 0 mmfor EMT hcg Day 6, and 3 mm for EMT hcg Baseline. Likewise, pregnancy rates were higher if the following EMT values were noted: 6 mm for EMT Day 6, 8 mmfor EMT hcg, 2 mm for EMT Day 6 Baseline, 0 mm for EMT hcg Day 6, and 3 mmfor EMT hcg Baseline. Based on these data, if the EMT is less than the threshold, or if the endometrial thickness decreases during the stimulation cycle, the implantation and pregnancy rates decrease dramatically. An EMT hcg of 7 mm was found to have a significantly lower implantation rate (11.9% vs. 28.6%) (P.01, RR 0.42 [0.20, 0.85]) compared to an EMT hcg of 7 mm. An EMT hcg of 8 mm was found to have a significantly lower pregnancy rate (34.1% vs. 60.7%) (P.01, RR 0.56 [0.36, 0.89]) compared to an EMT hcg of 8 mm. Of note, only 1 of 24 (4.2%) transferred embryos implanted and only 1 of 8 (12.5%) patients got pregnant with an EMT hcg of 6 mm. The clinical significance concerning endometrial thickness 6 mmon day 6 or 8 mm on day hcg is unknown. The exact pathophysiology for endometrial receptivity is still unknown. In a previous manuscript, we showed that using Fertility and Sterility 79

7 TABLE 4 Area under the curve and 95% confidence intervals for implantation and pregnancy rates. Implantation rate Pregnancy rate EMT Baseline 0.37 (0.20, 0.53) 0.53 (0.43, 0.61) EMT Day (0.47, 0.72) 0.67 (0.58, 0.77) EMT hcg 0.48 (0.31, 0.65) 0.63 (0.54, 0.73) EMT Day 6 Baseline 0.65 (0.51, 0.78) 0.64 (0.54, 0.74) EMT hcg Day (0.40, 0.72) 0.60 (0.50, 0.71) EMT hcg Baseline 0.41 (0.24, 0.57) 0.46 (0.36, 0.56) adjuvant therapy in patients with thin endometrial linings did not improve outcomes (17). The endometrial thickness on the day of hcg administration, EMT hcg, is often used to document adequate endometrial development. The pregnancy rate threshold for EMT hcg calculated in this study was 8 mm; this is consistent with the findings of Basir et al. (4), who developed an ROC curve looking for a threshold on day of hcg. Both Basir et al. (4) and our study agree that IVF patients with a EMT hcg 8 mm have a statistically significant increased pregnancy rate (4). EMT hcg correlated with the estradiol concentration on the day of hcg, the number of oocytes, and was inversely correlated with age. Based on ROC curves, EMT hcg was less predictive than EMT Day 6 and EMT Day 6 Baseline.In contrast to our design, other studies that have evaluated EMT hcg measurements have used arbitrary threshold values (5, 10, 12, 13, 15). Another difference between our study and other studies includes the timing of the EMT evaluation. Studies have evaluated the endometrial lining on the day before hcg administration (6, 8, 11), the day of hcg administration (4 6, 9, 11 13, 15), the day after hcg administration (8, 10), the day of oocyte retrieval (9, 11, 16), and the day of embryo transfer (7, 11, 14). We could find only two studies, which produced conflicting results, that evaluated the change in endometrial thickness occurring at different points in the IVF cycle (8, 11). Bassil et al. (8) prospectively evaluated the change in endometrial growth from day 10 to day after hcg administration and found that a statistically significant increase in endometrial thickness correlated with a patient s ability to conceive. Noyes et al. (11) found no correlation between pregnancy rates and the endometrial thickness at any time during ovarian stimulation; however, their data showed that the largest change occurred in the first seven days of stimulation. In our study, day 6 was used as our first evaluation of EMT after initiation of exogenous gonadotropins. There was no significant difference in baseline endometrial thickness between those who became pregnant and those who did not become pregnant. There was a significant threshold value of 3 mm for implantation rate, but none for pregnancy rate. This finding is important because the initial thickness of the endometrium may not be as important as endometrial responsiveness early in the stimulation process, as evidenced by the significance values for the EMT Day 6 and EMT Day 6 Baseline. Early endometrial evaluation during gonadotropin stimulation seems to be significant in that it shows which patients have responsive endometrium. Data from Basir et al. (4) support the theory that there is a difference in pregnancy rates with respect to how receptive the endometrial lining is towards stimulation. With the statistically significant and clinically significant findings for the EMT Day 6 and EMT Day 6 Baseline values, our data confirm that the early responsiveness of the endometrium is critical for improved pregnancy success. Both EMT Day 6 and EMT Day 6 Baseline were found to correlate with pregnancy outcomes as well as the IVF prestimulation and stimulation parameters of age, ovarian volume, antral follicles, estradiol levels, oocytes, number of embryos, ampules of gonadotropins used, and number of days of stimulation. Etiologies of infertility were not compared against one another with respect to pregnancy outcomes; however, diminished ovarian reserve showed significantly decreased thickness on EMT Day 6, EMT hcg, and with EMT hcg Baseline, as opposed to anovulation, endometriosis, male factor, tubal factor, or unexplained infertility. It is noteworthy that on EMT Day 6, EMT hcg, and EMT hcg Baseline there was also a statistical difference between those patients pregnant and those not pregnant. This difference between diminished ovarian reserve and other infertility etiologies supports previous findings where patients with diminished ovarian reserve have low probability of conception and decreased fecundity (18). Possible weaknesses of this study include its retrospective nature. However, the data were derived from a prospective database. Therefore, there was no chart review and no patients were lost to follow-up. This decreases the possibility of selection and information biases. The use of contingency table analysis and ROC curves to create significant threshold values so as not to use arbitrary cutoff points was a major strength of the study. Likewise, all stimulation cycles, ultrasounds, oocyte retrievals, and embryo transfers were performed by the author (JLF). 80 McWilliams and Frattarelli Endometrial thickness and IVF success Vol. 88, No. 1, July 2007

8 In summary, continued use of transvaginal ultrasound to evaluate endometrial thickness and the change occurring during ovarian stimulation can aid providers in counseling patients and predicting IVF success. Increased endometrial responsiveness seen on day 6 of gonadotropin stimulation compared to the baseline EMT is important to IVF success. An increase in endometrial response seems to prognosticate better IVF success. Endometrial receptivity is still difficult to prognosticate. It is unclear if the improved IVF success is because of a more responsive or sensitive endometrial lining or if the responsiveness of the endometrial lining is only a marker of better gonadotropin stimulation of the ovary with downstream effects on the endometrium. EMT during the early part of the IVF cycle seems to be a more important prognostic variable than does EMT at the start or end of the IVF cycle. Measuring the EMT earlier or looking at the initial change in endometrial thickness may be an important factor in stratifying those patients with an optimal response from those with a suboptimal response. REFERENCES 1. Erenus M, Zouves C, Rajamahendran P, Leung S, Fluker M, Gomel V. The effect of embryo quality on subsequent pregnancy rates after in vitro fertilization. Fertil Steril 1991;56: Wittemer C, Bettahar-Lebugle K, Ohl J, Rongieres C, Nisand I, Gerlinger P. Zygote evaluation: an efficient tool for embryo selection. Hum Reprod 2000;15: Yuval Y, Lipitiz S, Dor J, Achiron R. The relationships between endometrial thickness, and blood flow and pregnancy rates in in-vitro fertilization. Hum Reprod 1999;14: Basir GS, O WS, So WW, Ng EH, Ho PC. Evaluation of cycle-to-cycle variation of endometrial responsiveness using transvaginal sonography in women undergoing assisted reproduction. Ultrasound Obstet Gynecol 2002;19: Dickey RP, Olar TT, Curole DN, Taylor SN, Rye PH. Endometrial pattern and thickness associated with pregnancy outcome after assisted reproduction technologies. Hum Reprod 1992;7: De Geyter C, Schmitter M, De Geyter M, Nieschlag E, Holzgreve W, Schneider HP. Prospective evaluation of the ultrasound appearance of the endometrium in a cohort of 1,186 infertile women. Fertil Steril 2000;73: Puerto B, Creus M, Carmona F, Civico S, Vanrell JA, Balasch J. Ultrasonography as a predictor of embryo implantation after in vitro fertilization: a controlled study. Fertil Steril 2003;79: Gonen Y, Casper RF, Jacobson W, Blankier J. Endometrial thickness and growth during ovarian stimulation: a possible predictor of implantation in in vitro fertilization. Fertil Steril 1989;52: Sharara FI, Lim J, McClamrock HD. Endometrial pattern on the day of oocyte retrieval is more predictive of implantation success than the pattern or thickness on the day of hcg administration. J Assist Reprod Genet 1999;16: Noyes N, Liu HC, Sultan K, Schattman G, Rosenwaks Z. Endometrial thickness appears to be a significant factor in embryo implantation in in-vitro fertilization. Hum Reprod 1995;10: Bassil S. Changes in endometrial thickness, width, length and pattern in predicting pregnancy outcome during ovarian stimulation in in vitro fertilization. Ultrasound Obstet Gynecol 2001;18: Dietterich C, Check JH, Choe JK, Nazari A, Lurie D. Increased endometrial thickness on the day of human chorionic gonadotropin injection does not adversely affect pregnancy or implantation rates following in vitro fertilization-embryo transfer. Fertil Steril 2002;77: Rinaldi L, Lisi F, Floccari A, Lisi R, Pepe G, Fishel S. Endometrial thickness as a predictor of pregnancy after in-vitro fertilization but not after intracytoplasmic sperm injection. Hum Reprod 1996;11: Kovacs P, Matyas S, Boda K, Kaali SG. The effect of endometrial thickness on IVF/ICSI outcome. Hum Reprod 2003;18: Weissman A, Gotlieb L, Casper RF. The detrimental effect of increased endometrial thickness on implantation and pregnancy rates and outcome in an in vitro fertilization program. Fertil Steril 1999;71: Gonen Y, Casper RF. Prediction of implantation by the sonographic appearance of the endometrium during controlled ovarian stimulation for in vitro fertilization (IVF). J In Vitro Fert Embryo Transfer 1990; 7: Frattarelli JL, Miller BT, Scott RT. Adjuvant therapy enhances endometrial receptivity in patients undergoing assisted reproduction. Reprod Biomed Online 2006;12: Levi AJ, Raynault MF, Bergh PA, Drews MR, Miller BT, Scott RT Jr. Reproductive outcome in patients with diminished ovarian reserve. Fertil Steril 2001;76: Fertility and Sterility 81