Diana Princess of Wales Centre for Reproductive Medicine, St Georgeapos;s Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK
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Abstract |
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Key words: Doppler/hystero-contrastsonography/ovarian reserve/subfertility investigation/ultrasound
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Introduction |
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Within a publicly funded health service the majority of patients presenting with fertility problems are referred to a secondary level fertility clinic. Factors such as the degree of local expertise, high staff turnover rates and long clinic waiting lists often turn this process into a lengthy and unnecessarily repetitive one. If we accept that female age is of important prognostic significance with respect to fertility treatment outcomes then, particularly for older women, this drawn out process may limit the chances of success.
The cost-effectiveness of various assisted reproduction technology strategies has been documented in the literature (Molet al., 2000). However to date there is a dearth of information relating to the cost-effectiveness of subfertility investigation. Surely the development of an appropriate model for investigation will lead to a number of benefits. Firstly, by ensuring the process is as streamlined as possible, patients will be able to access appropriate treatment earlier, thereby minimizing the risks of an age-related fertility effect.
Secondly, by ensuring the process is as cost-effective as possible, this in turn may allow more funds to be allocated to the treatment process. This would obviously be of benefit to a publicly funded fertility service where often the available funding is severely restricted.
Ultrasound and subfertility investigation
The idea of a `one-stop shop' for subfertility investigation is certainly an attractive one for both patients and clinicians alike. In order for such a process to be successful we have to be sure that the process we instigate will give the level of information we desire.
There would be little doubt about integral components such as semen analysis and ovarian reserve testing. However, for the process to be a useful one it is necessary to make the assumption that an ultrasound-based pelvic and tubal assessment is at least as effective as the alternatives.
There is a mounting body of evidence that supports this statement (Ubaldiet al., 1998;Sladkevicius and Campbell 2000
). The concept of a `Pivotal' Pelvic Ultrasound Assessment (Table I
) is gaining more widespread acceptance. Ideally this assessment should be performed at a time which maximizes the amount and quality of information gathered. By convention this is usually in the late pre-ovulatory phase of the menstrual cycle (day 1012) when information about the uterine body, endometrium, Fallopian tubes, ovary and follicles can be acquired. All the features of the Pivotal Ultrasound have been designated a B-grade according to the Clinical Outcomes Group guidelines of the Royal College of Obstetricians and Gynaecologists. This grading system is based upon the level of evidence where an `A-grading' represents evidence based on randomized controlled trials. A `B-grading' is based upon robust experimental or observational studies and this is applicable to the majority of studies involving ultrasound techniques. Lastly, a `C-grading' is based on limited evidence but relies on expert opinion and has the endorsement of respected authorities.
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The presence of lesions such as endometrial polyps or submucous fibroids is known to interfere with implantation (Eldar-Gevaet al., 1998). Identification of these lesions by ultrasound is as effective as hysteroscopy (Shalevet al., 2000
). In addition, the use of saline contrast sonohysterography is a simple and effective means of delineating these lesions further (Pollacket al., 2000
).
More debatable is the role that ultrasound has in the assessment of endometrial receptivity. Previous methods of analysing endometrial receptivity have revolved around endometrial histology samples and their correlation with various biochemical markers. Unfortunately this process lacks both specificity and practicality.
During fertility investigation and treatment, an assessment of endometrial receptivity is generally based on endometrial thickness and appearance in conjunction with an estimation of uterine artery blood flow velocities using Doppler ultrasound (Friedleret al., 1996). A typical trilaminar appearance with a minimum thickness of 7mm and a uterine artery pulsatility index of <3.0 are regarded as sound markers of endometrial receptivity (Steeret al., 1992
;Zaidiet al., 1995
).
Of course one could argue that a pre-treatment assessment of endometrial receptivity is an academic exercise only and that in reality assessment during treatment is of most importance. However, evaluation of endometrial receptivity during a Pivotal Ultrasound may in fact have a useful diagnostic role. Conceivably patients who have an abnormal endometrial receptivity pattern during their natural cycle may in fact constitute a proportion of patients previously described as having `unexplained' infertility (Steeret al., 1994). Identifying these patients prior to treatment would give an opportunity to consider therapy to improve uterine and endometrial blood flow and subsequently endometrial receptivity (Sher and Fisch, 2000
).
The variations in flow with the uterine artery during a normal menstrual cycle as assessed by Doppler ultrasound have been well documented (Sladkeviciuset al., 1993;Tanet al., 1996
). In addition, an elevated uterine pulsatility index (PI >3.0) on the day of embryo transfer during an IVF cycle correlates well with implantation failure (Sterziket al., 1989
;Steeret al., 1994
). What is less clear is the association of abnormal uterine flow parameters determined during subfertility investigation and their effect on subfertility prognosis. There is also very little data to suggest that there is any relationship between blood flow velocities in the uterine (or ovarian) arteries in a natural cycle and their predictive value with respect to treatment outcome (Tinkanenet al., 1994
).
Newer techniques using three-dimensional colour power imaging (CPI) may give us further insight into endometrial receptivity. This technique provides a quantitative assessment of endometrial blood flow and the degree of angiogenesis within the endometrium itself (Schildet al., 2000).
Perhaps an improved understanding of the interrelation between specific hormonal, angiogenic and molecular factors with parameters of ultrasound imaging will allow us to formulate reliable ultrasonographic criteria to determine receptivity.
Tubal assessment
Normal tubes are not visible with ultrasound imaging unless there is fluid within the pouch of Douglas. However, hydrosalpinges are generally visible and can be clearly delineated by operators with moderate experience.
The gold standard for the confirmation or otherwise of tubal patency has historically been either HSG or laparoscopy with chromopertubation. Whilst one could argue that performing laparoscopy affords the opportunity to accurately identify and treat pelvic pathology, there is limited evidence to support treatment in many situations as a resultant improvement in fertility or treatment outcome is often not apparent, as mentioned in the previous debate, (Balasch, 2000).
The development of hystero-contrastsonography (HyCoSy) offers an alternative to the above mentioned modes of investigation. In comparison with HSG it appears to provide similar information with respect to both the uterine cavity and tubal patency. It has an additional benefit for the patient in being a combined pelvic ultrasound assessment and tubal patency test (Ayidaet al., 1996;Strandellet al., 1999
,2000
). More recent evidence suggests, at least from a patientapos;s perspective, that it is a more acceptable investigation compared with X-ray hysterosalpingogram (Ghazeeriet al., 2000
). Total pain scores for HyCoSy are reported to be significantly less than for HSG in the majority of patients. It does not carry the same operative risks as laparoscopy, but is a rapid and reliable screen for tubal patency and is useful for selecting patients who would perhaps benefit from further investigation (Campbellet al., 1994
).
Cost benefits have also been demonstrated with the use of HyCoSy compared with laparoscopy. Instigation of a HyCoSy-based tubal investigation service reduces the number of laparoscopies and allows patients to proceed with corrective surgery without resorting to a second planned operative procedure (Killick, 1999).
One of the difficulties associated with HyCoSy is that it is rarely possible to visualize the complete length of the Fallopian tube in a single scanning plane. Three-dimensional CPI can be employed to overcome this problem. Power Doppler is sensitive to slow flow, enabling the capture of a volume of contrast along the entirety of the tube. Retrospective analysis using surface rendering will give a three-dimensional image of the Fallopian tube as well as confirming intraperitoneal spill of contrast (Sladkeviciuset al., 2000). Real time three-dimensional analysis of tubal contrast flow may help to improve our understanding of tubal function in general and its hitherto poorly recognized impact on fertility.
Ovarian assessment
Ovarian morphology can be assessed accurately by ultrasound. Normal ovaries can easily be differentiated from those that are polycystic. Whilst the finding of polycystic ovaries (PCO) is an important diagnosis, it also has significant implications for treatment (Engmannet al., 1999a). Firstly the `pivotal' ultrasound should be able to differentiate ovulatory from anovulatory PCO. Secondly, patients with PCO undergoing stimulation are more likely to develop ovarian hyperstimulation (MacDougallet al., 1993
). Ultrasound is also an effective method of identifying other ovarian pathologies including functional cysts, endometriomas and dermoid cysts. These lesions can be assessed and a reasoned judgement can be made regarding the need for further treatment prior to instituting fertility treatment.
The use of Doppler to assess ovarian stromal or follicular flow may have a useful predictive role during treatment, but its role in the investigation of subfertility is less clear. It does appear that patients with PCO who have high ovarian stromal flow are more likely to be at risk of ovarian hyperstimulation during treatment and are often those who have high resistance uterine artery flow (Zaidiet al., 1995). The correlation between ovarian stromal flow in the follicular phase of a normal menstrual cycle and ovarian follicular response during IVF holds true for patients with both normal and polycystic ovaries (Zaidiet al., 1996
;Engmannet al., 1999b
).
The changes in follicular blood flow in a natural cycle as ovulation approaches have been well documented (Campbellet al., 1993). From a treatment perspective follicles shown to have high peak systolic velocities are more likely to yield high quality oocytes and embryos with higher implantation potential (Nargundet al., 1996a
,b
;Bhalet al., 1999
). Whether there is any value in assessing periovulatory follicular flow during subfertility investigation remains a debatable point. However, based on available data, it can be assumed that during a natural cycle a follicle that has high blood flow velocities will most likely contain a normal oocyte with maximal attributes for fertilization and embryo formation.
The utilization of ultrasound to assess ovarian reserve has also gained some interest (Tomaset al., 1997;Shararaet al., 1998
). Whilst the most widely utilized method of ovarian reserve testing is an early menstrual FSH estimation, there is continuing debate about its predictive value in relation to stimulation (Barnhart and Osheroff, 1999
). As an investigation for ovarian reserve, whilst it exhibits a significant degree of sensitivity it lacks specificity, thereby diminishing its practicality from a screening perspective. An assessment of ovarian reserve based on ovarian volume and number of antral follicles appears to offer an improved level of specificity. Where ovarian volume is <3 cm3 and there are <5 antral follicles, ovarian reserve is said to be diminished (Lasset al., 1997
;Schefferet al., 1999
;Sharara and McClamrock, 1999
). A reduced ovarian volume as measured by three-dimensional scanning will imply a poor ovarian response to standard treatment protocols. (Changet al., 1998a
,b
;Syropet al., 1999
). This type of ovarian reserve screening can easily be incorporated into a pivotal ultrasound assessment given the availability of appropriate ultrasound equipment.
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Conclusion |
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The use of an ultrasound-based system provides diagnostic information of a calibre comparable with more traditional investigative methods. Newer modes of ultrasound technology may improve our understanding of issues such as ovarian reserve, endometrial receptivity and the relationships between ovarian and follicular blood flows with respect to oocyte quality and treatment outcomes.
There is evidence to suggest that such a system is not only more acceptable to the couple, but is also more cost-effective. This would hopefully allow more precious healthcare funds to be channelled into the treatment process rather than being eroded by prolonged and often unnecessary and overly invasive investigative methods.
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Acknowledgements |
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Notes |
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References: |
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