Carole Dietterich, R.T., R.D.M.S., Jerome H. Check, M.D., Ph.D., Jung K. Choe, M.D., Ahmad Nazari, M.D., and Deborah Lurie, Ph.D.

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1 FERTILITY AND STERILITY VOL. 77, NO. 4, APRIL 2002 Copyright 2002 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. 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 Carole Dietterich, R.T., R.D.M.S., Jerome H. Check, M.D., Ph.D., Jung K. Choe, M.D., Ahmad Nazari, M.D., and Deborah Lurie, Ph.D. The University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School at Camden, Cooper Hospital/University Medical Center, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Camden, New Jersey Objectives: To investigate the controversy whether an increased endometrial thickness has an effect on pregnancy, implantation, or abortion rates in in vitro fertilization-embryo transfer (IVF-ET) cycles. Design: Retrospective analysis. Setting: A university-based IVF center. Patient(s): Five hundred seventy women under the age of 40. Intervention(s): Measurements of endometrial thickness on day of human chorionic gonadotropin (hcg) administration. Cycles were compared by endometrial thickness of 14 mm in 510 women to a thickness of 14 mm in 60 women. Main Outcome Measure(s): Implantation, pregnancy, and abortion rates. Result(s): Implantation, pregnancy, and abortion rates were similar in each group. In cycles where the endometrial thickness was 14 mm, the rates were 20.9%, 43.1%, and 11.8% compared with 25.5%, 48.3%, and 13.8% in cycles 14 mm. Conclusion(s): No adverse effects of a thickened endometrium were demonstrated on implantation, pregnancy, or abortion rates in the first IVF-ET cycle. These findings fail to corroborate with those of Weissman et al. (34) and support those of Yakin et al. (35) (Fertil Steril 2002;77: by American Society for Reproductive Medicine.) Key Words: Endometrial thickness, endometrial receptivity, IVF-ET, pregnancy rates, transvaginal sonography Received June 29, 2001; revised and accepted November 9, Presented at the 2001 Pacific Coast Reproductive Society Annual Meeting, Rancho Mirage, California, April 25 29, 2001 Reprint requests: Jerome H. Check, M.D., Ph.D., 7447 Old York Road, Melrose Park, Pennsylvania (FAX: ; laurie@ccivf.com) /02/$22.00 PII S (01) Serum hormonal estradiol (E 2 ) and progesterone (P) levels cannot always accurately predict the development of the endometrium (1). Endometrial biopsies in in vitro fertilization (IVF) cycles have indicated that ovarian stimulation may cause a delay or advance in the maturation of the endometrium (2, 3). Histological studies performed in the early and midluteal phase, however, are too invasive to be performed in a cycle where embryo transfer (ET) has occurred. Sonography has been used as a noninvasive technique to monitor infertile woman for over two decades. The measurements are easy to perform, easily reproducible, and have been shown to have good intraobserver and interobserver correlation (4, 5). In the earliest reports, measurements of follicular size were used to determine the development and maturity of a follicle and estimate the time of ovulation (6, 7). Sonographic changes in the thickness and echo pattern of the endometrium throughout the cycle were then observed (8). The advent of transvaginal sonography greatly increased the visualization of the endometrium, allowing for more accurate and detailed evaluation. Many studies have evaluated the minimal endometrial thickness on subsequent preg- 781

2 nancy rates (PRs) (9 33). Few studies have assessed the effect of a maximum thickness of a late proliferative phase endometrium on implantation and PRs with varying conclusions (19, 24, 31, 32, 34, 35). The objective of the current study was to investigate this controversy. The authors sought to determine whether there was a correlation between thickened endometrium and pregnancy, implantation, or abortion rates on day of hcg administration in IVF-ET cycles using various stimulation protocols in the first IVF-ET cycle of women under 40 years of age. MATERIALS AND METHODS The first cycle of all patients 40 years of age who underwent IVF-ET at the Cooper Center for IVF from January 1997 through June 2000 were reviewed. All patients underwent uterine evaluation by hysterosalpingogram, hysteroscopy, or saline infusion sonography, which demonstrated a normal uterine cavity prior to starting the cycle. Only cycles in which the endometrial thickness on the day of hcg administration was measured in our facility and resulted in ET of at least one embryo were included. No ET occurred if the patient was at risk for ovarian hyperstimulation syndrome (OHSS) or the endometrial thickness was 8 mm on the day of hcg administration; these embryos were cryopreserved for future transfer with the hope of attaining an adequate endometrial thickness. Patients whose uterine position made it difficult to obtain a good plane to accurately measure the endometrial thickness were excluded. Patients and cycles were then divided into two groups by endometrial thickness of 14 mm (Group 1) and 14 mm (Group 2). Because endometrial evaluation is a routine part of our monitoring, Institutional Review Board approval was unnecessary. Controlled ovarian hyperstimulation (COH) was achieved with one of two types of regimens and classified as luteal leuprolide acetate (LA) or Flare. In most of the cycles, LA was administered in the luteal phase until down-regulation was obtained. Once down-regulation was achieved, the patients either discontinued or decreased the dosage of LA and gonadotropins were added. The second type of COH regimen used was a flare protocol in which LA was started in the early follicular phase along with gonadotropins. The gonadotropins used were all follicle-stimulating hormone (FSH) (either urinary or recombinant), or all hmg, or a combination of FSH and hmg. The tendency was to use the Flare protocols for older patients as well as those with higher baseline FSH levels because in these circumstances LA may inhibit gonadotropin response (36). When at least two follicles had reached 20 mm in average diameter, 10,000 IU of hcg was administered. Oocyte retrieval was performed between 34 and 36 hours after the hcg injection. All ETs occurred 3 days after oocyte retrieval and were performed under ultrasound guidance. All patients received P support in the luteal phase. Sonographic assessment was performed on a GE Logic 400 (General Electric Medical Systems, Milwaukee, WI) with a multifrequency endovaginal transducer with both color and Doppler capabilities. On each sonographic examination, endometrial thickness, echo pattern, and follicle sizes were evaluated. Thickness was measured by placing electronic calipers on the outer walls of the endometrium at its widest diameter as seen in the longitudinal axis of the uterine body. Endometrial echo pattern was graded as: triple line (TL) where the endometrium is hypoechoic with welldefined outer walls and a central echogenic line, isoechogenic (IE) where the echogenicity of the endometrium is the same as that of the myometrium with a poorly defined central echogenic line, or homogeneous hyperechogenic (HH) where the endometrium is homogeneously echodense with no visualization of a central echogenic line. Each follicle was measured in three dimensions (length, depth, and width) to determine its size, and the average was reported. Color Doppler evaluation of uterine artery flow impedance as expressed in measures of pulsatility index (PI) and resistance index (RI) was performed on the day of downregulation (luteal LA cycles) on day 2 (Flare cycles), the day of hcg injection, the day of oocyte retrieval, and in the midluteal phase. Color Doppler signals were obtained from the right and left ascending branches of the uterine arteries at a level lateral to the cervix. Once visualized, a pulsed Doppler range gate was placed over each artery to obtain velocity waveforms. When multiple consecutive images of equal intensity were obtained, the PI and RI were measured by electronically tracing the waveform. The average of the right and left uterine arteries was used in the analysis. One sonographer performed all sonographic measurements. Serum hormonal assays of E 2, P, FSH, and LH were obtained on a regular basis to determine down-regulation, ovarian response, and timing of the hcg injection. Beta hcg levels were first obtained 12 days following ET. The main outcome measures were implantation, pregnancy, and abortion rates once a clinical pregnancy was established. A clinical pregnancy was defined as the presence of a gestational sac in the uterus. Other variables included age of the patient, stimulation protocol, baseline and mid-luteal phase endometrial thickness, Doppler measures of PI and RI, endometrial echo pattern, serum E 2,P, FSH, and LH levels, number of eggs retrieved, fertilization rate, and number of ETs. A 2 analysis was used to compare clinical PRs, implantation, and abortion rates by thickness group. A P value of.05 was used to determine significance. RESULTS A total of 570 cycles in women whose ages ranged from 21 to 39 years were included in the analysis. The endometrial thickness ranged from 8 mm to 23 mm. There were Dietterich et al. Pregnancy rates with thickened endometrium Vol. 77, No. 4, April 2002

3 FIGURE 1 Clinical pregnancy rates by individual endometrial thickness in 570 women. The number of pregnancies per number of women are shown for each thickness. women in Group 1 (endometrial thickness 14 mm) and 60 women in Group 2 ( 14 mm). The incidence of thicker endometrium was 10.5%. No threshold was observed above which a pregnancy is unlikely to occur (Fig. 1). Although no clinical pregnancy was seen in five cycles when the endometrial thickness was 18 mm, the number of cycles is too small to demonstrate significance. No differences occurred by age, number of oocytes retrieved, fertilization, number of ETs, or serum E 2, P, FSH, or LH levels by endometrial thickness (Table 1). A 95% confidence interval for FSH levels at baseline and day of hcg administration were (4.8, 5.3) and (17.8, 19.4) in women with a thickness 14 mm and (4.6, 6.8) and (15.8, 19.5) in the women with an endometrial thickness 14 mm. No statistically significant differences in endometrial thickness were seen by stimulation protocol (Table 2). Sonographic parameters of echo pattern, PI, or RI also failed to differ by endometrial thickness. There was, however, statistically significant differences noted when comparing the mean endometrial thickness between the two groups at baseline, day of oocyte retrieval, and in the midluteal phase (Table 3). Clinical PRs, implantation, and abortion rates were similar in both groups (Table 4). A TL pattern was observed in 455/510 (89.2%) of women with a thickness of 14 mm with a PR of 200/455 (39.2%) and in 54/60 (90%) of women with a thicker endometrium where the PR was 27/54 (50%). The occurrence and PRs with an IE echo pattern were 52/510 (10.2%) and 19/52 (36.5%) in the thin group, and 5/60 (8.3%) and 2/5 (40%) in the thicker group. The unfavorable HH echo pattern was seen in three women; in two women the thickness was 14 mm with one pregnancy (50%), and the woman whose endometrial thickness was 14 mm did not achieve a pregnancy. DISCUSSION Numerous studies have focused on determining uterine receptivity through sonographic evaluation of the endometrial thickness in IVF-ET cycles where COH was used but FERTILITY & STERILITY 783

4 TABLE 1 Comparison of stimulation variables by endometrial thickness on day of hcg in the first IVF-ET cycle. a TABLE 3 Comparison of sonographic parameters by endometrial thickness on day of hcg administration. Variable (n 510) (n 60) Variable (n 510) (n 60) Age (y) No. of oocytes retrieved Percent fertilization Average no. of ET Serum hormone levels Baseline (day 2 of IVF cycle) E 2 (pg/ml) P (ng/ml) FSH (miu/ml) LH (miu/ml) Day of hcg administration E 2 (pg/ml) P (ng/ml) FSH (miu/ml) LH (miu/ml) Luteal phase E 2 (pg/ml) P (ng/ml) Note: All values are given as means SD. hcg human chorionic gonadotropin; IVF-ET in vitro fertilization-embryo transfer; E 2 estradiol; P progesterone; LH luteinizing hormone. a P NS have been unable to reach a consensus. There has been an ongoing conflict regarding whether there is a correlation between PRs and a minimum acceptable endometrial thickness (9 13). Confounding these results is the heterogenicity of the various studies, i.e., COH protocols used and the time in the cycle the evaluation was performed. Many studies have also evaluated other parameters such as endometrial echo pattern, impedance to uterine blood flow, subendometrial perfusion, uterine, and endometrial volume and endometrial wavelike activity in combination with endometrial thickness (14 32). Thickness (mm) Baseline a Day of retrieval a Luteal phase a Pulsatility index Baseline Day of hcg administration Day of retrieval Luteal phase Resistance index Baseline Day of hcg administration Day of retrieval Luteal phase Echo pattern Triple line 455 (89.4%) 54 (90.0%) Isoechogenic 52 (10.2%) 5 (8.3%) Homogeneous hyperechogenic 2 (.4%) 1 (1.7%) Note: Thickness, PI, and RI values are given as means SD. hcg human chorionic gonadotropin; SD standard deviation. a P.05 Researchers who believe this correlation exists acknowledge that there are conflicting findings as to the minimum thickness required to support a pregnancy. The endometrial thickness found to correlate with a positive IVF outcome varies between 6 mm and 10 mm (16, 18 20, 24, 28), although studies have reported pregnancies with a thickness of as little as 4 mm (24, 33). Even studies suggesting that there is no correlation between endometrial thickness and pregnancy and implantation rates have reported that no pregnancy occurred if the endometrium measured 7 mm (22, 29, 31, 32). Data in the literature are scant regarding the maximum TABLE 2 Comparison of distribution of stimulation protocol by endometrial thickness on day of hcg administration. Protocol Group 1 ( 14mm) No. of patients (%) Thickness (mm) Group 2 ( 14mm) No. of patients (%) Thickness (mm) Luteal LA 325 (63.7) a 41 (68.3) a Flare 185 (36.3) b 19 (31.7) b Note: Thickness is mean values SD. a P.05 b P.05 TABLE 4 Comparison of outcome variables by endometrial thickness on day of hcg in the first IVF-ET cycle. a Outcome variable Thickness 14 mm Thickness 14 mm Clinical pregnancy rates 43.1% (220/510) 48.3% (29/60) Implantation rates 20.9% (337/1614) 25.5% (50/196) Spontaneous abortion rate 11.8% (26/220) 13.8% (4/29) Note: hcg human chorionic gonadotropin; IVF-ET in vitro fertilization-embryo transfer; NS not significant. a P NS 784 Dietterich et al. Pregnancy rates with thickened endometrium Vol. 77, No. 4, April 2002

5 endometrial thickness that will correlate with PRs and implantation rates. Kupesic et al. (32) reported no pregnancies if the endometrial thickness was 15 mm in a series of 89 patients who were evaluated on the day of ET. Schild et al. (31) reported no pregnancies if the thickness was 16 mm in 49 patients on the day of oocyte retrieval. Neither of these studies found a relationship between endometrial thickness and IVF outcome. Dickey et al. (19) reported no difference in PRs if the endometrial thickness was 14 mm compared with a thickness of 9 13 mm on the day of hcg administration in 200 IVF cycles; they did, however, find a higher incidence of biochemical pregnancies with increased endometrial thickness. Weissman et al. (34) analyzed 809 IVF cycles in 623 patients and found a reduction in pregnancy and implantation rates and an increase in miscarriage rates when an endometrial thickness of 14 mm was seen on the day of hcg administration. In a letter to the editor, Yakin et al. (35) disagreed with these findings in their evaluation of 1,281 cycles. An editorial comment by McDonough suggested that both of these studies were problematic because including more than one cycle of a patient could bias the comparison (37). The investigators found no negative effects of increased endometrial thickness on pregnancy and implantation rates as well as IVF outcome. These findings failed to corroborate with those of Weissman et al. (34) and agree with those of Yakin et al. (35). We cannot corroborate the findings of Dickey et al. (19) suggesting an increased incidence of biochemical pregnancies in women with thickened endometrium. Although biochemical pregnancies were not an aim of the study, the incidence of biochemical pregnancies was 2.9% in the thin group and 4.3% in the thicker group (P NS). The investigators were unable to provide a threshold for endometrial thickness above which a pregnancy or abortion is unlikely to occur. The incidence of thicker endometrium was 10.5%; Weissman et al. (34), Dickey et al. (19), Yakin et al. (35), and Noyes et al. (24) reported this incidence to be 5.3%, 9.6%, 7.18%, and 11.6%, respectively. No clinical pregnancies occurred in five cycles where the endometrial thickness was 18 mm. Incidentally, one of the patients with an endometrial thickness of 19 mm had undergone a second IVF cycle with the same thickness and achieved a pregnancy. The investigators also agree with Yakin et al. that endometrial thickness should be combined with echo pattern when making decisions in an IVF-ET cycle (35). It is generally our policy not to perform an ET if the endometrial thickness is 8 mm and there is no trilaminar echo pattern (TL or IE) on the day of hcg injection (38). The data, however, did not suggest a significant influence on outcome according to TL or IE pattern, confirming our previous findings (18). The only significant finding derived from this study was that the endometrium was thicker at all times of the cycle when comparing the two groups. The baseline endometrial thickness was measured on the day of down-regulation or day 2 of the cycle-depending on the stimulation regimen. The mean thickness in the thinner group was 5.1 mm, whereas it was 6.4 mm in the thicker group. Perhaps midcycle endometrial thickness is related to the early follicular phase thickness. On the day of hcg administration, thickness for the two groups was 11 mm and 16.1 mm, respectively; this certainly does not indicate that there is linear growth. Perhaps there is an amount of growth the endometrium should exhibit to be receptive. Further study may be indicated to prove or disprove this hypothesis. Because a prospective study would be easy to perform, we suggest that future studies that are aimed at corroborating or refuting these data or further investigations should be conducted in this manner. 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