1 Health Services Research Unit, University of Aberdeen, Aberdeen and 2 University of Bristol, Division of Obstetrics and Gynaecology, Bristol, UK
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Abstract |
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Key words: cumulative conception rates/duration of infertility/post-coital test/semen analysis/sperm function
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Introduction |
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Sperm function tests might offer greater predictive power but at present are recommended only for use in specialized centres (Royal College of Obstetricians and Gynaecologists, 1998). The post-coital test (PCT) requires no expensive equipment and a negative PCT reduced the cumulative chance of conception at 24 months after first attending an infertility clinic almost four-fold (Glazener et al., 1987). It could provide a generally applicable test of sperm function. However its value is the subject of intense controversy and a recent trial that compared outcomes in patients randomized to undergo PCT or not appeared to demonstrate that inclusion of the test increased the number of investigations the couples were subjected to but had no effect on outcome. The authors concluded that the test was of no value and indeed could be actually harmful (Oei et al., 1998
). This study was heavily criticized in subsequent correspondence to the British Medical Journal: Hull and Evers (1999) pointed out that a diagnostic test can only affect outcome if treatment is modified in the light of the result. In Oei's study treatments were applied non-specifically and inconsistently. Since the PCT result did not alter the management of the patients it is hardly surprising that it had no effect on outcome. Oei also failed to give a clear definition of a positive PCT result. The biased selection of references to substantiate the poor prognostic power of the PCT and the ineffectiveness of intrauterine insemination (IUI) was also criticized (Cohlen et al., 1999
). Attention was also drawn to the value of the test in revealing antisperm antibodies (Hendry, 1999
). Therefore despite its powerful statistical design, the Oei study does not answer the question of the efficacy of the PCT and this deserves further analysis.
In judging the value of any test of sperm function a number of points must be borne in mind. First, infertility has a range of discrete causes and any test of a single component (e.g. sperm function) can only effectively predict a successful outcome once other causes have been eliminated. To take an extreme example, even a couple with perfect sperm function cannot achieve a pregnancy if the woman's tubes are blocked. Second, incidental factors like age (Schwartz and Mayaux, 1982) and duration of infertility (Hull et al., 1985
; Eimers et al., 1994
) can be critical and must be controlled for. Furthermore, in the case of the PCT, correlated functions such as sperm production, mucus secretion and coital competence must be accounted for.
A key element in the recent debate has been the effect of duration of infertility on the predictive power of the PCT (Hull and Evers, 1999; Oei et al., 1999
). Our basic hypothesis is that although these factors may be inter-related, duration of infertility is likely to affect prognosis only when a cause for infertility cannot be defined. Couples with a defined cause will always be unlikely to conceive. Those without a defined cause will include fertile couples who have failed to conceive through chance. As time progresses these will achieve pregnancy, leaving those with an unknown but real cause for their infertility who will not conceive even if the defined tests are normal. Consequently, any test of sperm function will be most effective in changing the predicted chance of a couple conceiving when the duration of infertility is short.
In this study, we present the effect of duration of infertility by re-analysing data from a previous study that investigated the power of the PCT and semen analysis to predict natural conception in otherwise normal couples, after complete investigations and control for age (Glazener et al., 1987). This paper addresses the question whether the PCT can refine the ability of the clinician to predict the chance of conception in practice.
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Materials and methods |
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Based on standard semen microscopy, semen quality was classed by an overall estimate of motile, normally developed spermatozoa. This was derived as a composite score by multiplication of the sperm concentration, the percentage motile and the percentage morphologically normal, assessed according to WHO criteria (WHO, 1980), giving the motile normal sperm concentration (MNSC). Previous work showed that it had a better ability to predict natural conception than any other semen analysis parameter or combination thereof (Glazener et al., 1987). The cut-off value which best discriminated for fertility was 4x106/ml.
A pre-ovulatory phase PCT was done 618 h after coitus as previously described (Hull et al., 1982). Mucus was extracted with a standard narrow 1 ml, 10 cm long disposable plastic syringe, without needle, after introducing the neck of the syringe up to its shoulder into the cervical canal. Suction was maintained as the syringe was withdrawn to avoid loss of content and to assess ductility (spinnbarkeit). The volume of mucus was noted before its transfer to a glass microscope slide, where its clarity or turbidity was observed. It was covered with a glass slip and examined at low (x100) and high (x400) magnification. Fully developed mucus (at least 0.3 ml with stretch to 10 cm, and mostly clear to the naked eye) was required to define a negative result, which also required confirmation in a second cycle.
In accordance with evidence presented in a recent review (Oei et al., 1995), a negative PCT result was more strictly defined in the current re-analysis as the absence of at least one progressively motile spermatozoon in most high power microscope fields (hpf) of the mucus. The PCT was classified as follows: positive: at least one forward-progressing spermatozoon per field in most (at least five) hpf; negative: less than one forward-progressing spermatozoon in most (at least five) hpf.
Cox proportional hazards regression analysis was used to estimate the relative predictive power for conception of duration of infertility, age, the PCT result and semen analysis parameters. Cox's regression allows the effects of multiple factors to be compared in the same model. It was designed to handle censored data. The coefficients represent the change in the logarithm of the baseline survival function produced by a unit change in the parameter, in this case the extent to which a change in the parameter alters the probability of pregnancy in a given time. The relative risk (RR) was calculated as the natural anti-logarithm of the coefficient. The method assumes that the effect of the parameters remains constant with time. Here this was confirmed by parallel log-minus-log plots (Norusis, 1993). Univariate relationships were investigated first, after which all parameters were offered together with their interactions.
Outcomes were graphically presented by time-specific cumulative conception rates to first pregnancy using life-table methods and compared between groups using the Wilcoxon (Gehan) statistic.
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Results |
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The woman's age had no effect on the chance of conception (Table I) possibly because few older women were included in the study group, and this parameter was omitted from subsequent analyses. Compared to couples with 12 years infertility, the chance of conception was significantly lower (P = 0.0002) if the duration was over 3 years but not if duration was between 2 and 3 years (Table I
). A negative PCT was also significantly associated with a reduced chance of conception (Table I
). However, conventional semen parameters summarized in the MNSC had no significant effect until the MNSC fell below 2x106/ml and then were only just statistically significant (Table I
).
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Discussion |
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The strength of the current study lies in its thorough exclusion of `noise' from confounding female infertility factors and their treatment, a problem highlighted in other studies (Oei et al., 1995). A strict definition of the PCT was used, including a new requirement for a `poor-positive' PCT to be confirmed in a second cycle, and subsequent reclassification of these couples into the `negative PCT category' as suggested by more recent work (Oei et al., 1995
). By focusing on couples where the woman was normally fertile (tubal patency, ovulation, coitus and normal cervical mucus production), the effect of variations in less well-defined factors could be explored. Although these measures reduced the numbers available for analysis we can be confident that the women were normal so far as current diagnostic procedures allowed us to judge. This enabled us to focus on male and on unexplained infertility. If defined causes of female fertility had not been excluded, the conception rate in the positive PCT group would be lower and the apparent power of the test decreased.
In a recent randomized controlled trial of post-coital testing as part of routine infertility investigations, it was found that the chance of conception amongst those who did and did not have a PCT was similar (Oei et al., 1998). However, this study also reported that the pregnancy rate was the same whether the women had a positive (38%) or negative (34%) result. The low rate in the positive PCT group could be because of failure to exclude women with confounding causes of infertility but the rate in the negative group remains surprisingly high, possibly reflecting the success of treatments such as IUI and in-vitro fertilization (IVF).
The current study describes the natural conception rates without treatment in otherwise unexplained infertility, and describes practice before the advent of IVF and intracytoplasmic sperm injection (ICSI). It would be difficult to repeat these studies today because of the ethical problem of delaying effective treatment to achieve sufficient follow-up time. In-vitro testing of interaction between spermatozoa and mucus has since been shown to be correlated with in-vitro fertilizing ability of spermatozoa for assisted conception (Hull et al., 1986; Aitken et al., 1992
; Berberoglugil et al., 1993
; Biljan et al., 1994
), further underlining the functional ability of the mucus to differentiate between fertile and infertile spermatozoa.
We believe that the PCT is a good test of sperm function when sufficient care is taken to eliminate negative results due to poor mucus quality. Conventional seminology offers much poorer discrimination, the chance of conception only decreasing significantly where the concentration of motile normal spermatozoa is very low.
Once the woman has been proven to be normal, the PCT provides a rational basis for patient management. In couples with less than 3 years infertility, those with a negative PCT can proceed at once to effective treatment such as IUI, IVF or ICSI whereas those with a positive result can be advised to continue to try for a natural conception with good chance of success, thus avoiding these complex and expensive treatments. Couples with more than 3 years infertility should be offered assisted reproduction without further delay.
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Acknowledgments |
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Notes |
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3 To whom correspondence should be addressed at: Health Services Research Unit, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UK.E-mail: c.glazener{at}abdn.ac.uk
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References |
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Submitted on March 14, 2000; accepted on May 30, 2000.