Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China
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Abstract |
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Key words: assisted reproduction/Doppler ultrasound/IVF/uterine fibroids
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Introduction |
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There are only a few retrospective studies addressing the impact of fibroids on the outcomes of assisted reproduction treatment (ART; Table I). Implantation and pregnancy rates were not impaired in those patients with fibroids not distorting the uterine cavity (Seoud et al., 1992
; Farhi et al., 1995
; Ramzy et al., 1998
; Surrey et al., 2001
). In contrast, Eldar-Geva et al. and Stovall et al. found that patients with intramural fibroids had significantly reduced implantation and pregnancy rates when compared with those without fibroids or with subserosal fibroids only (Eldar-Geva et al., 1998
; Stovall et al., 1998
). A recent systematic review (Pritts, 2001
) suggests that only those fibroids with a submucosal component are associated with adverse outcomes of ART. Therefore, there is still no consensus on whether fibroids have any adverse effects on the success of ART.
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The objectives of this study were: (i) to compare the outcomes of women with and without fibroids undergoing IVFembryo transfer treatment and (ii) to assess the significance of uterine blood flow indices measured by transvaginal Doppler ultrasound on the day of oocyte retrieval in those patients with fibroids.
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Materials and methods |
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The details of the long protocol of ovarian stimulation regimen and gamete handling at our centre have been previously published (Ng et al., 2000). All patients were pre-treated with buserelin (Suprecur; Hoechst, Frankfurt, Germany) nasal spray 150 µg four times a day from the mid-luteal phase of the cycle preceding the treatment cycle. On day 2 of the treatment cycle, transvaginal scanning was performed by E.H.Y.N. using a 6.5 MHz vaginal probe (Aloka Model SSD-5500; Aloka Co. Ltd., Tokyo, Japan). The uterus was visualized in both sagittal and coronal planes to determine the presence or absence of fibroids. The length, height and width of the largest fibroid was measured when multiple fibroids were seen. The diameter of the fibroid was the average of length, height and width and its volume was obtained using a formula for the volume of an ellipsoid (
/6xlengthxheightxwidth). Oocyte retrieval was scheduled 36 h after the HCG injection, which was given i.m. when the leading follicle reached 18 mm in diameter and there were at least three follicles >15 mm in diameter. A maximum of three normally cleaving embryos were replaced into the uterine cavity 48 h after oocyte retrieval. Excess good quality embryos were frozen for subsequent transfer.
All Doppler ultrasound examinations of uterine arteries in those patients with fibroids were carried out by E.H.Y.N. at ~09.00 h, after the bladder was empty and prior to oocyte retrieval. Verbal consent was obtained from these patients prior to the Doppler ultrasound examination. Flow velocity waveforms were obtained from the ascending main branch of the uterine artery on the right and left side of the cervix in a longitudinal plane before it entered the uterus. The `gate' of the Doppler was positioned when a vessel with good colour signals was identified on the screen. The pulsatility index (PI) and resistance index (RI) of the uterine arteries were calculated electronically when three similar, consecutive waveforms of good quality were obtained. Subsequent clinical management was not affected by the information on the blood flow indices, which were stored in the computer and retrieved for analysis only after completion of the treatment cycle. The intra-observer coefficient of variation was 9.6% for PI and 4.1% for RI.
Statistical analysis
Only clinical pregnancies were considered and were defined by the presence of one or more gestation sacs or the histological confirmation of gestational product in miscarriages. Ongoing pregnancies were those pregnancies beyond 1012 weeks gestation, at which stage the patients were referred out for antenatal care. Implantation rate was the proportion of embryos transferred resulting in an intrauterine gestational sac.
Patients were classified as those with fibroids (fibroid group) and without (control group). The primary outcome measures were implantation and pregnancy rates. Secondary outcome measures were Doppler indices of uterine arteries between pregnant and non-pregnant patients in the fibroid group. Continuous variables were not normally distributed and were given as median (2.597.5 centiles), unless indicated. Statistical comparison was carried out by MannWhitney U-test, 2 test and Fishers' Exact test, where appropriate. A P-value (two-tailed) of < 0.05 was taken as significant.
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Results |
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The patients in the fibroid group were significantly older and had more cycles with endometriosis as the cause of infertility, when compared with the control group (Table II). There were no differences in the type and duration of infertility. Both groups had a similar distribution of cycle attempts and proportion of conventional IVF and ICSI cycles (data not shown).
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Discussion |
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Fibroids can be classified according to their position in relation to the uterus as submucous, intramural or subserosal (Tindall, 1987). A submucous fibroid distorts the uterine cavity and surgical removal is usually advised because of adverse effects on implantation and associated menorrhagia (Vercellini et al., 1998
). Significantly lower pregnancy rates were noted during assisted reproduction cycles in those patients with fibroids distorting the uterine cavity (Farhi et al., 1995
) or with submucosal fibroids (Eldar-Geva et al., 1998
). A normal uterine cavity was confirmed in this study by transvaginal scanning on both the second day of the treatment cycle and the day of HCG injection. Transvaginal ultrasound examination of the contour of the endometrium is an accurate tool in the identification of submucous fibroids and polyps when compared with hysterosalpingogram and hysteroscopy (Stadtmauer and Grunfeld, 1995
).
A fibroid is considered to be intramural when <50% of the fibroid protrudes into the serosal surface of the uterus and normal uterine cavity, whereas a subserosal fibroid has >50% protruding out of the serosa (Tindall, 1987). Intramural and subserosal fibroids were not treated separately in this study and peduculated subserosal fibroids were excluded. The above classification may not be applicable to infertile patients attempting to become pregnant, as the mechanisms leading to infertility in case of fibroids are poorly investigated and understood. The degree of myometrial wall involvement and the extension of fibroids close to the mucsoal surface may be more relevant in infertile patients. These parameters have been poorly described in most imaging studies (Cohen and Valle, 2000
). Moreover, there is a lack of consensus in the literature as to exactly how these categories are defined (Bajekal and Li, 2000
).
Different methods have been used to document the size of fibroids, including the mean diameter of the largest fibroid (Seoud et al., 1992; Ramzy et al., 1998
; Stovall et al., 1998
), mean of the sum of all fibroids' diameters (Eldar-Geva et al., 1998
; Surrey et al., 2001
) and total volume (Surrey et al., 2001
). There is a large range in the diameter and volume of the largest fibroid noted in the current study. The mean diameter of the largest fibroid in this study was 2.1 cm, while those reported by others (Seoud et al., 1992
; Ramzy et al., 1998
; Stovall et al., 1998
) were 34 cm. This may be related to the prospective nature of this study. Although Surrey et al. in a regression model did not find any correlation between the diameter/volume of fibroids and implantation rate, it would be too early to conclude that large fibroids have no adverse effect on the implantation rates (Surrey et al., 2001
). Large fibroids were usually excluded from studies (Farhi et al., 1995
; Ramzy et al., 1998
). Myomectomy is more often performed in patients with large fibroids as symptoms such as dysmenorrhoea, menorrhagia and pressure symptoms tend to be more frequent and severe in these patients (Buttram and Reiter, 1981
).
Fibroids may lead to infertility because of obstruction of gamete transport and impaired implantation. IVFembryo transfer treatment performed on patients with fibroids clearly provides a good model to study the implantation process. During IVF treatment, uterine blood flow measured by Doppler ultrasound is an important factor contributing to uterine receptivity. Patients who become pregnant usually show lower vascular impedance than those who do not. The implantation rate is decreased when uterine artery PI is 3.33.5 at the time of HCG administration, oocyte retrieval or embryo transfer (Dickey, 1997
). It has also been reported that the chance of pregnancy was maximal when uterine arterial PI was in the range 2.002.99 and that lower arterial impedance indices on the day of embryo transfer did not lead to higher pregnancy rates (Steer et al., 1992
).
Previous studies (Kurjak et al., 1992; Sladkevicius et al., 1996
) indicated that significantly lower PI (range 1.362.17) and RI (range 0.740.8) were recorded in the uterine arteries of patients with fibroids than in those with normal uteri. Surrey et al. measured baseline uterine artery blood flow (PI) during the mid-follicular phase of natural cycles, but could not find any difference between those with and without fibroids (Surrey et al., 2001
). A significant difference in uterine artery blood flow exists between natural and stimulated cycles (Coulam et al., 1994
; Tekay et al., 1996
). To the best of our knowledge, we are the first group to examine the uterine blood flow during stimulated cycles of patients with fibroids. In the fibroid group, non-pregnant patients had a significantly lower uterine PI and RI compared with pregnant patients, although a significant overlap existed between pregnant and non-pregnant women.
Our finding was in contrast to data published regarding general IVF patients (Dickey, 1997). We postulate that the presence of fibroids results in significantly reduced uterine PI and RI, but the blood flow towards the endometrium may be compromised because of drainage of blood towards fibroids. Vascularized fibroids showed significantly lower uterine PI and RI than avascularized fibroids (Kurjak et al., 1992
). Blood flow to the endometrium was not documented in this study, as the visualization of endometrial colour signals would be difficult in the case of anterior wall fibroids. We have recently demonstrated that excessive levels of serum estradiol (>20 000 pmol/l) may result in suboptimal blood flow to the endometrium, despite very low uterine PI and RI in these group (Basir et al., 2001
). There was an increase in the number of subjects demonstrating absent or minimal endometrial colour signals in these excessive responders. The increased blood flow shown by low uterine PI and RI might be directed through the uteroovarian collaterals to the enlarged ovaries.
In conclusion, the presence of fibroids not seen to be distorting the endometrial lining on transvaginal ultrasound scanning would not adversely affect implantation and pregnancy rates during IVFembryo transfer treatment. Doppler ultrasound examination prior to oocyte retrieval showed significantly lower uterine PI and RI in non-pregnant women with fibroids than in their pregnant counterparts.
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Notes |
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References |
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accepted on November 21, 2001.