Fluid accumulation within the uterine cavity reduces pregnancy rates in women undergoing IVF

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1 Human Reproduction Vol.17, No.2 pp , 2002 Fluid accumulation within the uterine cavity reduces pregnancy rates in women undergoing IVF Li-Wei Chien, Heng-Kien Au, Jean Xiao and Chii-Ruey Tzeng 1 Department of Obstetrics and Gynaecology, Taipei Medical University Hospital, Taipei, Taiwan 1 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Taipei Medical University Hospital, No. 252, Wu-Shing Street, Taipei 110, Taiwan. tzengcr@tmu.edu.tw BACKGROUND: The occurrence of fluid accumulation within the uterine cavity was examined in women undergoing IVF to investigate its correlation with tubal disease and impact on the pregnancy outcome. METHODS: A registry of ultrasound procedures spanning 5 years was retrospectively studied. RESULTS: Thirty five out of 746 (4.7%) IVF cycles were identified as having uterine fluid accumulation, and 15 (2.0%) persisted until the day of embryo transfer. Two of the 20 cycles of women with transient fluid accumulation were pregnant, and none of those with fluid retention on the day of embryo transfer conceived. The pregnancy rate was only 5.7% (2/35) in women with uterine fluid accumulation detected during IVF cycles. In contrast, the pregnancy rate was 27.1% (193/711) among women in whose cycles no fluid accumulation was detected (P ). Uterine fluid accumulation during IVF cycles was found in 8% (18/225) of women documented with tubal factor compared with 3.3% (17/521) with nontubal factor (P 0.005). CONCLUSIONS: Fluid accumulation within the uterine cavity during the IVF transfer treatment could be observed in patients with both tubal and non-tubal factors; however, it mainly occurred in women with tubal infertility. Although it is not a common complication of IVF cycles, excessive uterine fluid is detrimental to embryo implantation. Key words: hydrometra/implantation/ivf/tubal infertility Introduction The effect of hydrosalpinx on pregnancy outcome of IVF has been discussed extensively in recent years. Most studies have reported that implantation and pregnancy rates were low in women with hydrosalpinx (Strandell et al., 1994; Fleming and Hull, 1996; Katz et al., 1996; Sharara et al., 1996; Camus et al., 1999). One of the explanations is that fluid of hydrosalpinges may reflux into the uterine cavity and accumulate there, which may disturb embryo implantation (Mansour et al., 1991; Andersen et al., 1994; Bloechle et al., 1997; Sharara and McClamrock, 1997). However, fluid accumulation within the uterine cavity or hydrometra after ovarian stimulation and before embryo transfer has only sporadically been reported in the literature (Welker et al., 1989; Mansour et al., 1991; Gürgan et al., 1993; Andersen et al., 1994; Bloechle et al., 1997; Sharara and McClamrock, 1997; Sharara and Prough, 1999), and most of those cases were also claimed to have hydrosalpinges. How often this complication occurs in women with tubal infertility and whether women with other indications of IVF would also have the same problem are still unknown. The aim of this study was to report our experiences with uterine fluid accumulation in a large consecutive series of IVF cycles and to investigate its correlation with tubal disease. Materials and methods Patients A total of 746 cycles in 547 women receiving IVF treatment from January 1995 to December 1999 was included in this study. Indications for IVF were pure tubal factors (22%), unexplained infertility (8%), endometriosis (21%), male factor (24%), and mixed factors (25%). Before the initiation of treatment, transvaginal ultrasound examination was performed to detect pelvic pathology. Tubal condition was evaluated by hysterosalpingography, laparoscopy with chromopertubation, laparotomy, and/or ultrasonography. IVF procedure Women whose partners had severe male factors were treated with ICSI procedures, while standard IVF techniques were used for other patients. Briefly, GnRH-agonist suppression either in an ultra-short protocol by s.c. injections of buserelin acetate (Supremon ; Hoechst, Frankfurt am Main, Germany), 0.5 mg/day started on the second day of the menstrual cycle for a fixed 3 day treatment course, or in an ultra-long protocol by monthly leuprolide acetate (Leuplin Depot 3.75 mg; Takeda Chemical Industries, Osaka, Japan) injection on the second day of the menstrual cycle for 2 3 months was used. Ovarian stimulation was then initiated with FSH (Metrodin ; Serono, Rome, Italy) and HMG (Pergonal ; Serono). HCG (HCG-SERONO ; Serono) at IU was given i.m. when there were at least two leading follicles with a diameter 16 mm. Oocytes were retrieved European Society of Human Reproduction and Embryology 351

2 L-W.Chien et al. variables were compared by using the Mann Whitney U-test or Student s t-test as appropriate. A P value of 0.05 was considered significant. Figure 1. Fluid accumulation in the uterine cavity detected by transvaginal ultrasound in a patient before embryo transfer. by transvaginal ultrasound-guided follicular aspiration h after HCG injection. All patients had at least one good-quality embryo, as defined by the morphology criteria, for transfer on the second or third day after oocyte retrieval. The embryos were evaluated by a scoring system based on cell number combined with grading of fragmentation pattern (FP) of each embryo according to criteria described previously (Desai et al., 2000). Briefly, the FP was scored as the criteria previously outlined (Alikani et al., 1999) with FP pattern I exhibiting minimal fragments and pattern V as extensive fragmentation. If the FP was greater than II, two points were subtracted from the blastomere number to give the embryo score. An average score of embryos transferred was shown for comparison. Ultrasonography examination Sonographic examinations were performed using an Ultramark 9 HDI (Advanced Technology Laboratories, Bothell, WA, USA) with a 5 9 MHz multi-frequency transvaginal probe. The endometrium was scanned sagittally along the mid-line axis of the uterus, and alterations in the endometrial thickness and echogenic pattern/structure were recorded during gonadotrophin administration, on the day of oocyte retrieval, and on the day of embryo transfer. The thickness of endometrium was measured at the maximum distance between each myometrial/endometrial interface through the longitudinal axis of the uterine body. Fluid accumulation within the uterine cavity was defined as an echolucent ring configuration distended by a certain amount of fluid between the anterior and posterior endometrial linings in a sagittal view (Figure 1). In cases of fluid accumulation, the thickness of endometrium was measured by subtracting the maximal fluid diameter from the maximal distance between the opposing myometrial/ endometrial interfaces. The maximal fluid diameter and the surrounding endometrial thickness were used for analysis. All the ultrasound examinations were performed by two of the authors (L-W.C. and H-K.A.) and the inter-observer variation was below 5%. Women who had fluid accumulation in the uterine cavity during IVF cycles were categorized as the study group, and those without fluid accumulation as the control group. Cycles that involved the use of frozen embryos, donor oocytes, or assisted hatching were excluded. All pregnancies were confirmed by rising serum β-hcg levels and by gestational sacs identified by transvaginal sonographic examination. Statistics Continuous data are presented as the mean SEM. Rates for all results were compared between the patient groups by using the χ 2 test. Fisher s exact test was used for small numbers. Measured 352 Results Fluid accumulation within the uterine cavity during IVF treatment was noted in 35 cycles of 33 women with an incidence of 4.7% (35/746). Of them, persistent fluid accumulation on the day of embryo transfer was found in 15 cycles (2.0%) of 14 women. In the other 20 cycles, transient uterine fluid accumulation was shown during gonadotrophin administration and/or on the day of oocyte retrieval but became undetectable on the day of embryo transfer. Fluid accumulations were noted before HCG injection in four (11%) cycles. In the other 31 (89%) cycles, fluid accumulations were detected after HCG was given. None of the women with persistent uterine fluid accumulation up to the day of embryo transfer conceived. For cycles with transient uterine fluid accumulation, two intrauterine pregnancies (10%) with one aborted and one ectopic pregnancy were noted. Overall, there was only one successful pregnancy (2.8%) in 35 cycles of women with uterine fluid detected during IVF embryo transfer cycles. In contrast, the pregnancy rate was 27.1% (193/711) and the abortion rate was 16.6% (32/193) among cycles with no fluid accumulation (Table I). There were no significant differences between the two groups in terms of duration of infertility, stimulation length, number of oocytes collected, number of embryos transferred, average embryo score or peak serum estradiol and progesterone concentrations on the day of HCG administration and day of embryo transfer. Patients were younger and the endometrium was thinner on the day of embryo transfer in the group with uterine fluid accumulation when compared with the group without fluid (P and P respectively). Clinical data of patients with uterine fluid accumulation are summarized in Table II. Over half (19 out of 35 cycles, 54.3%) of the women who showed fluid accumulation during IVF embryo transfer cycles had tubal infertility. Among the women with non-tubal infertility, endometriosis was the major cause for IVF in 12 cycles (34.3%), five (14.3%) were male factors, and one was polycystic ovarian syndrome (PCOS). There were no significant differences in patient characteristics or treatment outcomes between the two groups with persistent and transient fluid accumulation. The mean maximal fluid diameter was mm (range mm) in cycles with fluid accumulation during gonadotrophin administration or on the day of oocyte retrieval. In cycles with fluid accumulation at embryo transfer, the mean maximal fluid diameter was greater (P 0.028), i.e mm (range mm). The thickness of the endometrium, however, showed no significant difference on the day of embryo transfer between two groups with persistent and transient fluid accumulation ( versus mm, P not significant). Repeated accumulation of fluid in two successive cycles was found in two patients. One of them had been treated with tuboplasty for obstructive tubal disease. Her first IVF cycle showed transient fluid accumulation on the day of oocyte

3 Uterine fluid accumulation in IVF Table I. Comparison of clinical parameters and pregnancy outcome in cycles with and without fluid accumulation within the uterine cavity during IVF treatment Parameter Cycles with fluid Cycles without fluid P (n 35) (n 711) Number of women Age (years) Duration of infertility (years) NS Stimulation length (d) NS Number of oocytes retrieved NS Number of embryos transferred NS Average embryo score a NS E 2 level (HCG day) (pg/ml) NS P 4 level (HCG day) (ng/ml) NS E 2 level (embryo transfer day) (pg/ml) NS P 4 level (embryo transfer day) (ng/ml) NS Endometrial thickness (HCG day) (mm) NS Endometrial thickness (embryo transfer day)(mm) Number of pregnancies (%) 2 (5.7%) 193 (27.1%) Number of ectopic pregnancies (%) 1 (2.9%) 13 (1.8%) NS Number of abortions (%) 1 (50%) 32 (16.6%) NS Values are expressed as the mean SEM. a Defined by cell number and grading of fragmentation pattern of each embryo. E 2 estradiol; P 4 progesterone. Table II. Comparison of patient characteristics and treatment outcomes of women in whom uterine fluid accumulation was detected during IVF treatment Parameter Transient fluid Persistent fluid P accumulation accumulation Number of women Age (years) NS Duration of infertility (years) No. (%) of women with indicated major cause of infertility Tubal factor 8 (40) 9 (61.5) Endometriosis 6 (30) 5 (28.5) Male factor 5 (25) 0 Ovulation 1 (5) 0 Total 20 a 14 Number of oocytes retrieved NS Number of embryos transferred NS Average embryo score b NS E 2 level (HCG day) (pg/ml) NS P 4 level (HCG day) (ng/ml) NS E 2 level (embryo transfer day) (pg/ml) NS P 4 level (embryo transfer day) (ng/ml) NS Endometrial thickness (HCG day) (mm) NS Endometrial thickness (embryo transfer day) (mm) NS Mean fluid diameter (mm) Number of pregnancy (%) 2 (10) 0 NS Number of ectopic pregnancy (%) 1 (5) 0 NS Values are expressed as the mean SEM. a One endometriosis patient had repeated transient fluid accumulation at embryo transfer on two successive cycles. b Defined by cell number and grading of fragmentation pattern of each embryo. retrieval, which ended with an ectopic pregnancy after embryo transfer. Persistent fluid accumulation on the day of embryo transfer was found in the second cycle and did not result in pregnancy. The other patient had undergone vaginoplasty plus pelvic surgery due to agenesis of the upper vagina with severe pelvic endometriosis before IVF treatment began. Fluid accumulations were noted after ovarian stimulation and persisted on the day of embryo transfer. Transmyometrial embryo transfer was performed in the second cycle, yet no pregnancy resulted. In eight women who had more than one IVF cycle with the same protocol of ovarian stimulation, no fluid accumulation was shown in successive cycles. There was no intrauterine fluid accumulation during non-treatment cycles in any of the cases studied. The incidence of fluid accumulation in relation to tubal conditions is shown in Table III. There were 225 cycles in women who had documented tubal disease, and of these, 18 cycles (8%) showed fluid accumulation during the IVF treat- 353

4 L-W.Chien et al. Table III. Incidence of uterine fluid accumulation during IVF cycles in relation to tubal conditions Tubal factor Non-tubal factor Hydrosalpinx Non-hydrosalpinx Total Number of cycles Number of fluid-filled cycles 13 (9.1%) a 5 (6.0%) a 18 (8%) c 17 (3.3 %) c Number of cycles with 8 (5.6%) b 1(1.2%) b 9(4%) d 7 (1.3%) d persistent fluid accumulation a P 0.40; b P 0.071; c P 0.005; d P ment and nine cycles (4%) had persistent fluid accumulation. On the other hand, in 521 cycles of women without tubal lesions, 17 cycles (3.3%) showed fluid accumulation, and the fluid was still detected on the day of embryo transfer in six cycles (1.1%). The incidences of transient and persistent uterine fluid accumulation were both significantly higher in tubal factor cycles than those of non-tubal factor cycles (P and P respectively). Out of 225 tubal factor cycles, 142 had hydrosalpinges. Among these, 13 cycles (9.1%) showed fluid accumulation, and eight (5.6%) persisted on the day of embryo transfer. Of the other 83 cycles of tubal infertility without documented hydrosalpinges, five cycles (6.0%) showed fluid accumulation, and only one (1.2%) was noted on the day of embryo transfer. Although the incidence of uterine fluid accumulation seemed to be higher in tubalinfertility women with hydrosalpinges than those with no hydrosalpinges, the difference did not reach statistical significance. Nine of 14 (64.3%) women who demonstrated fluid accumulation on the day of embryo transfer had obstructive tubal disease, and eight out of nine had hydrosalpinges detected before IVF treatment. Four of eight women with hydrosalpinges also had adnexal cystic masses detected by ultrasonography before treatment was initiated. None of them underwent surgical intervention prior to IVF. Discussion The use of ultrasound to evaluate the uterine cavity for fluid collection prior to embryo transfer was previously reported (Mansour et al., 1991; Andersen et al., 1994; Bloechle et al., 1997), yet it is not performed systematically in most centres during IVF treatment cycles. This study demonstrates that uterine fluid accumulation can be detected in women both with and without concomitant tubal lesions. Although the incidence is low during IVF embryo transfer treatment, it is important to identify this condition because of marked negative consequences on pregnancy outcome. The mechanism of uterine fluid accumulation during IVF treatment is not completely understood. Hydrosalpinx was present in most cases as reported in the literature (Welker et al., 1989; Mansour et al., 1991; Gürgan et al., 1993; Andersen et al., 1994; Bloechle et al., 1997; Sharara and McClamrock, 1997). Our data confirm that tubal obstruction is the major cause of uterine fluid retention during IVF embryo transfer cycles. We also show that it can be detected in women both with and without hydrosalpinges, but those 354 with documented hydropic tubes were more likely to have fluid accumulation. Although visible fluid retention in the uterine cavity does not seem to be a common complication in women with tubal infertility undergoing IVF treatment as shown in this study, it is reasonable to expect that the incidence of occult reflux of fluid into the uterine cavity may be higher in these women. It may help explain the poor pregnancy outcome observed in women with hydrosalpinges receiving IVF embryo transfer demonstrated in many recent reports (Camus et al., 1999). Obstruction of the cervical canal can lead to fluid accumulation, as found in one of our patients who had recurrence in two successive cycles. She suffered from agenesis of the upper vagina, and partial obstruction of the endocervical canal was noted despite reconstruction surgery performed before the IVF procedures. Gürgan also reported a case of fluid accumulation due to endocervical canal obstruction by an endocervical cyst, which was evident after HCG administration (Gürgan et al., 1993). In our case, fluid accumulation was visible soon after gonadotrophin stimulation and increased in amount up to 14 mm in diameter after HCG administration. Patients with subtle cervical canal occlusion may be susceptible to uterine fluid accumulation during the treatment cycles, but it might be difficult to detect it prior to ovarian stimulation. Whether these women may benefit from cervical dilatation before IVF treatment to avoid repeated fluid accumulation in subsequent cycles still needs to be investigated. It is interesting to note that pelvic endometriosis is the main cause of fluid accumulation in non-tubal factor patients. In women with moderate to severe endometriosis, pelvic adhesions may sometimes cause tubal obstruction. Cervical stenosis also has been suggested to coexist in some cases of pelvic endometriosis (Barbieri, 1998). These correlations may contribute to the fluid accumulation observed in patients with endometriosis. This complication is not common in women with endometriosis undergoing IVF treatment, but its significance in affecting the pregnancy outcome may warrant further observation. Recently, Sharara and Prough (1999) reported four cases of endometrial fluid collection in more than 600 IVF cycles. All of them had PCOS and were undergoing ovarian stimulation for IVF but with no concomitant hydrosalpinx (Sharara and Prough, 1999). Their findings suggest that fluid accumulation in the uterine cavity might develop in women without hydrosalpinx. In our study, one patient with PCOS demonstrated transient fluid accumulation after HCG injection. Five women with male factor infertility were shown to have transient fluid

5 Uterine fluid accumulation in IVF accumulation on the day of oocyte retrieval, suggesting that it might not be correlated with PCOS but with the effect of ovarian stimulation. Ovarian stimulation definitely plays an important role in the development and maintenance of uterine fluid accumulation, because none of these patients showed fluid accumulation in the preceding or subsequent resting cycles. We also noted that, under the same stimulation protocol, only two out of 10 women showed fluid accumulation in subsequent cycles, implying that this condition might not necessarily be recurrent. The timing of detection and the amount of fluid collection are important in determining the impact on pregnancy outcome. Most studies (Mansour et al., 1991; Andersen et al., 1994; Bloechle et al., 1997; Sharara and McClamrock, 1997) found that the fluid-filled uterine cavity usually developed after receiving an HCG injection, but others (Sharara and Prough, 1999) reported that endometrial fluid collection could be detected before HCG but after gonadotrophin administration. We found that a large amount of fluid collection ( 3 mmin the largest diameter) usually developed after receiving HCG except in one woman combined with cervical stenosis who showed prominent fluid accumulation before HCG was given. Transient uterine fluid accumulation, usually less than 3 mm in the largest diameter, could be found in some cases during gonadotrophin stimulation and after HCG injection. The fluid accumulation might have disappeared by the time of embryo transfer, but it still had a negative effect on the pregnancy outcome. If fluid accumulation reached a diameter of over 3 mm either before or after HCG was given, it usually persisted until the time of the peri-implantation period and affected embryo implantation (Andersen et al., 1994). The apposition of embryos to the endometrium may enhance embryonic development potential and optimize the synchronization between the embryo and the endometrium, which is important for improved implantation efficiency during IVF treatment. Excessive fluid within the uterine cavity at the time of embryo transfer will interfere with the attachment of the embryo to the endometrial surface. It is interesting to note that glandular cystic atrophy of the uterine glands has been found in goats with development of hydrometra (Wittek et al., 1998), suggesting a pressure effect of a distended uterine cavity on the endometrium. Our data also demonstrate a significantly thinner endometrium at the time of embryo transfer in patients with fluid accumulation during the cycle compared with patients without fluid accumulation. Other explanations for the deleterious effects of fluid include release of intrauterine cytokines, prostaglandins, and other inflammatory compounds directly onto the endometrium (Ben-Rafael and Orvieto, 1992). There might be some embryotoxic substances existing in the fluid, as in hydrosalpinx fluid (Mukherjee et al., 1996; Rawe et al., 1997; Freeman et al., 1998), but this mechanism is still controversial (Spandorfer et al., 1999). Factors that may lead to fluid accumulation must be corrected before IVF treatment to prevent this unfavourable uterine condition. Women with tubal infertility require further evaluation. Before initiation of an IVF cycle, a baseline pelvic ultrasound scan is needed to rule out any adnexal cystic mass of other than ovarian origin. Episodes of hydrorrhoea and of fluid accumulation in the uterine cavity during the luteal phase have been reported in the most severe cases of hydrosalpinx (Andersen et al., 1994). Two prospective randomized studies (Strandell et al., 1999; Statdmauer et al., 2000) have shown that surgical correction of hydrosalpinges before IVF may improve the pregnancy outcome. Salpingectomy or proximal tubal interruption could prevent the reflux of tubal fluid into the endometrial cavity and thus reduce intrauterine fluid accumulation. For women with cervical stenosis and a history of difficult embryo transfer, cervical dilatation is recommended. In patients with fluid accumulation in the previous cycles but without any pelvic pathology, however, there is no evidence that surgical treatment is beneficial. Careful ultrasound monitoring of the endometrium in all women undergoing IVF is required to detect fluid in the uterine cavity. If fluid accumulation is found before HCG administration, cancellation of the cycle should be considered. Evacuation of the fluid can be attempted if noted after HCG is given, but re-collection of fluid immediately after aspiration has been reported in previous trials (Mansour et al., 1991; Bloechle et al., 1997). When fluid accumulation is noted before embryo transfer, transmyometrial embryo transfer may be an alternative method (Kato et al., 1993; Sharif et al., 1996), yet the effectiveness is unproven. Cryopreservation of embryos until a favourable cycle is the treatment of choice at the present time, but it has to be proved in further study. In conclusion, we found that fluid accumulation within the uterine cavity during IVF treatment mainly occurred in patients with tubal infertility. However, it can also be observed in patients with non-tubal factors. 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