Human Reproduction, Vol. 16, No. 12, 2610-2615,
December 2001
© 2001 European Society of Human Reproduction and Embryology
Endometrial cavity fluid is associated with poor ovarian response and increased cancellation rates in ART cycles*,**
1 Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 2 Reproductive Medicine Associates of New Jersey, Morristown, NJ and 3 Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Walter Reed Army Medical Center, Washington, DC, USA
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Abstract |
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BACKGROUND: Endometrial cavity fluid (ECF) is occasionally observed during assisted reproductive technology (ART) cycles. However, few reports have described its prevalence or significance. METHODS AND RESULTS: We examined the relationships between ECF, clinical pregnancy rate (CPR), tubal factor infertility and ultrasound-visible (USV) hydrosalpinges. In 843 ART cycles involving 721 patients, ECF was observed during stimulation in 57 cycles and after human chorionic gonadotrophin (HCG) administration in 12 cycles, with an overall incidence of 8.2% (69/843). When ECF was observed during stimulation, the cancellation rate due to poor ovarian response was significantly higher (29.8 versus 16.9%, P <0.05) and the CPR per started cycle was significantly lower (26.3 versus 42.4%, P <0.05) than cycles without ECF. When ECF developed after HCG administration, the CPR was similar compared with that of the group for which ECF was not observed. In the 327 cycles involving tubal factor infertility patients, USV hydrosalpinges were noted in 71 cycles (71/327; 21.7%), and ECF developed in five of those cycles (5/71; 7.0%). A total of 27 cycles during which ECF developed (27/57, 47.4%) involved non-tubal factor patients. CONCLUSIONS: ECF during stimulation was associated with increased cancellation rates and lower CPRs per started cycle, and was not associated with USV hydrosalpinges. Furthermore, ECF observed after HCG administration did not impact CPR and may represent a different clinical entity.
Key words: cancellation rates/endometrium/fluid/hydrosalpinx/IVF
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Introduction |
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Several studies have shown a strong association between the presence of hydrosalpinges and poor outcome in assisted reproductive technology (ART) cycles. Hydrosalpinges have been associated with decreased pregnancy rates in fresh IVF cycles (Anderson et al., 1994
; Vandromme et al., 1995; Wainer et al., 1997; Wit et al., 1998; Zeyneloglu et al., 1998; Strandell et al., 1999), frozen embryo transfer cycles (Akman et al., 1996) and donor oocyte cycles (Cohen et al., 1999). Several theories have been proposed to explain the negative impact of hydrosalpinges on ART cycle outcome. These include embryotoxic effects of hydrosalpinx fluid (Beyler et al., 1997; Rawe et al., 1997; Freeman et al., 1998; Spandorfer et al., 1999a), reduced endometrial receptivity (Anderson et al., 1994; Meyer et al., 1997) and mechanical factors or `flushing' effects from the reflux of hydrosalpinx fluid into the endometrial cavity (Mansour et al., 1991; Bloechle et al., 1997; Sharara and McClamrock, 1997; Granot et al., 1998). Hydrosalpinx fluid may also have a deleterious effect upon human sperm motility and survival (Ng et al., 2000). While the precise mechanisms remain speculative, the adverse effects of hydrosalpinx fluid upon both developing embryos and the endometrium suggest that the development of endometrial cavity fluid (ECF) during ART cycles may adversely affect pregnancy rates.
Appropriate endometrial growth and differentiation during IVF cycles are important variables that contribute to IVF success (Noyes et al., 1995; Rinaldi et al., 1996; Oliveira et al., 1997; Sharara et al., 1999; Weissman et al., 1999; De Geyter et al., 2000). While the importance of endometrial thickness during ART cycles has been investigated, the significance of ECF remains unclear. A few studies involving low numbers of patients have reported the development of ECF in patients undergoing ART. Mansour et al. first described endometrial fluid collections in three patients with hydrosalpinges and suggested that the fluid might hinder embryo implantation (Mansour et al., 1991). In 1996, Anderson et al. studied 38 patients with hydrosalpinges who were treated with IVF (Anderson et al., 1996). In their report, three patients developed uterine fluid before human chorionic gonadtrophin (HCG) administration, and six patients were noted to have fluid in the endometrial cavity 5 days after embryo transfer. None of the patients who developed ECF either during gonadotrophin stimulation or after embryo transfer in that study achieved a clinical pregnancy (Anderson et al., 1996). Sharara and McClamrock reported two patients with hydrosalpinges who developed intrauterine fluid only after HCG administration during ART cycles, both of whom failed to become pregnant (Sharara and McClamrock, 1997). Bloechle et al. observed that endometrial fluid collections recurred in one patient with hydrosalpinges, even after tubal aspiration during an IVF cycle (Bloechle et al., 1997). Sharara and Prough reported endometrial fluid collections in four patients with polycystic ovaries who did not have hydrosalpinges (Sharara and Prough, 1999). The authors suggested that the fluid collections resulted from an abnormal endometrial environment in these patients.
What is not known is whether ECF is associated with hydrosalpinges and whether the development of fluid in the uterine cavity negatively impacts ART outcome. The prevalence of ECF during ART cycles also remains undefined. To address these questions, we studied the prevalence of ECF in a large cohort of patients undergoing controlled ovarian hyperstimulation for assisted reproduction. In particular, we investigated the relationship between hydrosalpinges and the development of ECF, as well as the relationship of ECF to clinical pregnancy rates (CPRs) and to infertility diagnoses.
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Materials and methods |
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The study group consisted of 843 consecutive ART cycles from 721 patients between January 1998 and December 1999. The study was reviewed by the Department of Clinical Investigation, Walter Reed Army Medical Center. The study was restricted to cycles in which only fresh, non-donor embryos were transferred. All patients, regardless of age (range 22–43 years), infertility diagnosis, use of intracytoplasmic sperm injection, use of donor sperm, prior ART cycles, or reproductive history were considered. Patients were pre-screened for endometrial abnormalities with saline hysterography prior to the initiation of an ART cycle. For each cycle started, the transvaginal ultrasonographic appearance of hydrosalpinges (unilateral or bilateral), ECF during controlled ovarian hyperstimulation (Figure 1
), and endometrial thickness (from basalis to basalis) were recorded at each visit. The presence or absence of ECF after HCG administration (documented at the time of oocyte retrieval) was also recorded. Clinical records were reviewed for the documentation of ultrasound-visible (USV) hydrosalpinges and/or ECF during stimulation or after HCG administration. Hydrosalpinges were defined as echo-free, irregularly-shaped masses adjacent but outside the ovary visualized by ultrasound. Patient age, basal FSH concentration, day of fluid visualization during stimulation, and day 6 oestradiol concentrations were also recorded.
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All patients underwent pituitary desensitization followed by controlled ovarian hyperstimulation as previously described (Leondires et al., 1999
). Patients who were 
30 years old, those at greatest risk for severe ovarian hyperstimulation, or with polycystic ovaries typically started gonadotrophin releasing hormone (GnRH) agonist (Lupron, 0.5 mg/day; TAP Pharmaceuticals, Deerfield, IL, USA) administration on ~day 21 of the prior menstrual cycle or following an oral contraceptive overlap. After a baseline ultrasound of the ovaries and endometrium, leuprolide acetate was decreased to 0.25 mg/day and gonadotrophin treatment ensued. All other patients received oral contraceptive pills for at least 21 days prior to initiating stimulation and then started a microdose GnRH flare protocol as previously described (Leondires et al., 1999). Patients were generally administered 4–6 ampules of gonadotrophin daily in a split dose as a combination of highly-purified FSH (Fertinex; Serono Laboratories, Norwell, MA, USA) and human menopausal gonadotrophins (Humegon; Organon, West Orange, NJ, USA). Transvaginal ultrasonography (Ultramark 4; ATL, Bothell, WA, USA; Acuson Sequoia 502; Acuson Corporation, Mountain View, CA, USA) was performed as clinically indicated during stimulation. If a patient was noted to have USV hydrosalpinges and/or ECF during stimulation, the data was recorded. Oocyte retrieval was performed 35–36 h following HCG administration. ECF observed at the time of oocyte retrieval was documented and in some cases was aspirated with an Edward–Wallace transfer catheter (Simcare Ltd, West Sussex, UK) at the discretion of the provider. Persistence or disappearance of ECF at the time of embryo transfer was not documented in this study. Progesterone (50 mg daily i.m.) was typically administered to patients for luteal support, starting on the night of oocyte retrieval. Embryo transfer was performed either on day 3 or 5 following oocyte retrieval depending on embryo quality, total number of eight-cell embryos on day 3 and clinical history. The number of embryos transferred varied between patients and was in accordance with American Society for Reproductive Medicine (ASRM) guidelines (ASRM, 1999). All embryo transfers were performed with an Edward–Wallace catheter under ultrasound guidance as described elsewhere (Hearns-Stokes et al., 2000). The principle outcome variable was the establishment of a clinical pregnancy as determined by transvaginal ultrasound at 5–6 weeks gestation. Clinical pregnancy was defined as the presence of a gestational sac with a fetal pole present. CPR was expressed per started cycle. Implantation rate was defined as the total number of embryos transferred divided by the number of gestational sacs documented by transvaginal ultrasound at 5–6 weeks gestation. Cancellation rate was defined as the number of cycles in which patients stopped treatment prior to oocyte retrieval (most commonly due to poor ovarian response; there were no cancellations after oocyte retrieval due to failed fertilization or fragmentation) divided by the total number of cycles studied. Statistical analysis was performed using Fisher's exact test and the unpaired t-test, where appropriate. An alpha error of 0.05 was considered significant. Sample size was determined by the duration of the study (2 years), and was not based on a prospective calculation since the prevalence of ECF was unknown at the start of the study.
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Results |
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From a total of 843 ART cycles involving 721 patients, ECF was detected in 69 cycles, a prevalence of 8.2%. These 69 cycles involved 61 patients. Pregnancy outcome versus the day that ECF was first observed after the start of gonadotrophin administration is presented in Figure 2
. A higher frequency of ECF was observed after 6 days of stimulation compared with other time points, as patients typically first returned for follow-up on day 6 after the start of gonadotrophins. This analysis showed pregnancy rates to be 50% (6/12) if patients developed ECF only after HCG administration, while patients who developed ECF during stimulation appeared to have lower pregnancy rates (15/57; 26.3%). The observation that ECF observed after HCG administration may differ from that seen during stimulation was consistent with a previous report (Sharara and McClamrock, 1997). Based on the apparent differences in clinical outcomes, we analysed the two groups separately: (i) cycles in which patients developed ECF during ovarian stimulation (n = 57) and (ii) cycles in which patients developed ECF only after HCG administration (n = 12).
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In cycles where patients developed ECF during stimulation (n = 57), mean age (± SD) was 34.5 ± 4.5 years; mean basal FSH concentration was 7.1 ± 2.3 mIU/ml; mean day of stimulation when fluid was first visualized was 6.5 ± 1.6 days; mean endometrial thickness (basalis to basalis) on the day of fluid visualization was 8.2 ± 2.4 mm; and mean day 6 oestradiol concentration was 222.0 ± 391.0 pg/ml. Mean age, basal FSH concentration and day 6 oestradiol concentration of patients in these cycles did not differ significantly from patients in cycles when ECF did not develop during ovarian stimulation (n = 786).
The number of embryos transferred on day 3 (3.33 versus 3.22) or on day 5 (2.05 versus 2.14) did not differ between the two groups (ECF versus no ECF). The percentage of patients transferred on day 3 (63.5 versus 65.0%) or on day 5 (36.5 versus 35.0%) also did not differ significantly between the two groups. Similarly, the implantation rate did not differ significantly between patients who developed ECF compared with those who did not (31.5 versus 25.9%). The CPR per started cycle was significantly lower (P < 0.05) for patients who developed ECF during stimulation (15/57; 26.3%) compared with patients who did not (333/786; 42.4%) (Table I). While there was a lower CPR per retrieval in cycles where patients developed ECF during stimulation (37.5 versus 51.0% respectively), the difference did not reach statistical significance.
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Clinical outcomes of the 57 cycles (57/843; 6.8%) in which ECF was observed during stimulation are shown in Table I
. In 27 of these cycles (27/57; 47.4%), patients had an infertility diagnosis other than tubal factor (Table II). A total of 327 of the 843 started cycles involved patients with tubal factor infertility. Of these 327 cycles, USV hydrosalpinges were documented in 71 instances (71/327; 21.7%). ECF developed in only five of those 71 cycles (7.0%) where USV hydrosalpinges were observed (Table I), a prevalence similar to that of all the cycles (n = 843) studied.
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Interestingly, 17 cycles (17/57; 29.8%) where ECF was observed during stimulation were cancelled prior to oocyte retrieval (cancelled exclusively for poor ovarian response, i.e. less than four follicles >14 mm, or low serum oestradiol). For cycles without ECF during stimulation, only 16.9% (133/786; P < 0.05) were cancelled (Table I
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For cycles where ECF was noted only after the administration of HCG (i.e. not during stimulation but at oocyte retrieval), six (6/12; 50.0%) patients achieved a clinical pregnancy (Table III). The CPR in these 12 cycles did not differ significantly from cycles where ECF was not observed at oocyte retrieval.
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Discussion |
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This is the largest cohort of patients undergoing ART in which the prevalence and impact of ECF have been studied. Only a few published case studies involving small numbers of patients exist that report the impact of ECF on ART outcome (Table IV
). In our study, the CPR per started cycle was significantly lower in cycles where patients developed ECF during ovarian stimulation compared with cycles in which ECF was not observed (26.3 versus 42.4%; P < 0.05). We attribute this result to the significantly higher cancellation rate due to poor ovarian response (29.8 versus 16.9%; P < 0.05) in cycles where ECF was detected. None of the patients with ECF were cancelled because of the presence of ECF; cessation of therapy was based exclusively on the lack of an adequate ovarian response.
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While the CPR per retrieval did not differ significantly in cycles where ECF was observed during stimulation compared with cycles where ECF did not develop, there was a trend towards significance that may have become apparent with a larger sample size. Interestingly, implantation rates were similar for both groups. Hence, while ECF was associated with higher cancellation rates, lower CPRs per started cycle, and a trend towards lower CPRs per retrieval, the presence of ECF during stimulation did not appear to negatively impact embryo implantation.
We observed that ECF often developed in patients with diagnoses other than tubal factor infertility; nearly half of the cycles in which ECF developed involved patients with infertility diagnoses other than tubal factor. While it is possible that some of these patients had occult hydrosalpinges not detected at ultrasound during monitoring, it is unlikely since the majority of our patients had either a hysterosalpingogram, laparoscopy or both at some point during their infertility evaluation. In a prior report (Sharara and Prough, 1999), four patients with polycystic ovarian syndrome (PCOS) undergoing ART cycles developed endometrial fluid collections early during stimulation. Not only did ECF develop in patients with PCOS in our study, but it also developed in patients with endometriosis, male factor infertility and unexplained infertility. In the present study, the frequency of USV hydrosalpinges in ART cycles involving patients with tubal factor infertility was 21.7% (71/327), which was somewhat higher than that noted in previous reports of 10–13% (Anderson et al., 1994; Katz et al., 1996). Contrary to our expectations, ECF was detected during stimulation in only five of the 71 cycles where USV hydrosalpinges were present, and two of the five patients with both USV hydrosalpinges and ECF during stimulation achieved a clinical pregnancy.
Of the 12 patients who developed ECF only after HCG administration, eight had a diagnosis of tubal factor, four of whom had USV hydrosalpinges. Previously, investigators reported two patients with hydrosalpinges who developed fluid collections only after HCG administration (Sharara and McClamrock, 1997); both failed to get pregnant. In our study, of the four patients with hydrosalpinges who developed ECF after HCG administration, two patients achieved clinical pregnancies and subsequent live births (one set of twins and one singleton), while one patient had a chemical pregnancy (Table III).
Perhaps most importantly, our data suggest that there may be two clinical scenarios in which ECF may be observed during ART cycles. The first, `early' ECF, was visualized during ovarian stimulation and was associated with significantly increased cancellation rates. The second, `late' ECF, occurred only after the administration of HCG and did not appear to impact CPR in these few patients. Further studies may help to delineate better the significance of these two presentations of ECF.
The mechanisms responsible for the negative effects of hydrosalpinges on IVF outcome are not completely understood. While evidence exists that the cytotoxic effects of hydrosalpinx fluid can impair embryo development and implantation, some studies refute this mechanism (Granot et al., 1998; Strandell et al., 1998). In fact, other factors may play a more important role. Reduced endometrial receptivity, secondary to adverse effects of hydrosalpinx fluid on 
vß3 expression, appears to decrease implantation and pregnancy rates (Anderson et al., 1994; Meyer et al., 1997). The mechanical `flushing' effect of hydrosalpinx fluid at the time of embryo transfer and during the window of implantation may also contribute to lower clinicals pregnancy rates (Mansour et al., 1991; Bloechle et al., 1997; Sharara and Prough, 1999). While surgical correction of hydrosalpinges appears to increase implantation and CPR, the effects of hydrosalpinx fluid upon the endometrium, ovarian function, follicular development and oocyte quality may be permanent (Meyer et al., 1997; Freeman et al., 1998).
Elevated serum Chlamydia trachomatis IgG antibody titres and antibodies to C. trachomatis heat shock proteins are prevalent among patients with tubal factor infertility (Sharara et al., 1997; Ault et al., 1998). Furthermore, it has been postulated that these antibodies may induce immune-mediated pregnancy failure in select patients (Neuer et al., 2000). Studies have demonstrated an association between the production of these antibodies and poor ART outcome (Witkin et al., 1994, 1995; Neuer et al., 1997; Sharara and Queenan, 1999). Others, however, could not detect a relationship between serum antibodies and IVF outcome (Spandorfer et al., 1999b) or an association between antibodies and poor IVF outcome in patients treated with antibiotics prior to stimulation (Sharara et al., 1996, 1997). In our study, 327 cycles (327/843; 38.8%) involved patients with tubal factor infertility, and USV hydrosalpinges were detected in 71 of those cycles (71/327; 21.7%). Moreover, 52.6% (30/57) of patients with ECF during stimulation had a diagnosis of tubal factor infertility. Because markers of infectious disease, specifically C. trachomatis IgG antibodies and antibodies to Chlamydial heat shock proteins, are not routinely measured at our centre, we were unable to make any inferences about these antibodies and the development of ECF in these patients. To draw any further conclusions, a prospective study evaluating these markers of infectious disease, their relationship to the development of ECF, and consequent ART outcome is needed.
The composition of hydrosalpinx fluid has been described (David et al., 1969; Granot et al., 1998). However, the specific content of ECF encountered during ovarian stimulation and after HCG administration has not been fully investigated. These collections may consist of blood, mucus, endometrial secretions, and/or tubal fluid. While cytokines and interleukins originating from hydrosalpinx fluid may exert toxic effects on human embryos (Ben-Rafael and Orvieto, 1992; Jakobs et al., 1992; Tekatani et al., 1992), their release into the endometrial cavity remains to be investigated.
In conclusion, ECF was seen during 8.2% of 843 ART cycles during a 2 year interval. Results of this study suggest that ECF observed during stimulation was associated with lower CPRs per started cycle, higher cancellation rates secondary to poor ovarian response, and was observed in only a small fraction of patients with hydrosalpinges. ECF observed after HCG administration did not appear to impact CPRs. Thus, there may be two clinical scenarios in which ECF may be observed in ART cycles: during stimulation, which is associated with poor ovarian response and increased cancellation rates, and after HCG administration, which does not appear to affect ART outcome. An explanation for the association between the appearance of ECF during stimulation and poor ovarian response remains to be elucidated.
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Acknowledgements |
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We gratefully acknowledge the A.R.T. Institute of Washington, Inc. at Walter Reed Army Medical Center (Lynette Scott, Kerry Polson, Sasha Hennessey, James Broussard and Jessica Presto), the IVF nurses (Donna Materia, Cheri Needham and Darshana Naik) and the clinical staff (Alicia Armstrong and Ruben Alvero) for their dedication to the programme.
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Notes |
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4 To whom correspondence should be addressed at: Walter Reed Army Medical Center, Room 2J06, Building 2, Department of Obstetrics and Gynecology, 6900 Georgia Avenue, NW, Washington, DC 20307, USA. E-mail: mark.leondires{at}na.amedd.army.mil
* The views expressed in this article are those of the author(s) and do not reflect the official policy or position of the Department of the Army, Department of Defense, nor the US Government.
** Presented at the 56th Annual Meeting of the American Society of Reproductive Medicine, San Diego, California, USA, October, 2000.
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Submitted on June 21, 2001; accepted on September 4, 2001.
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