Leuven Institute for Fertility and Embryology, Tiensevest 168, B-3000, Leuven, Belgium
1 To whom correspondence should be addressed. Email: ivo.brosens{at}med.kuleuven.ac.be
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Abstract |
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Key words: endometriosis/infertility exploration/natural family planning/time to pregnancy
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Introduction |
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The duration of infertility, or time to conception, has been used as a major factor for timing routine exploration and starting treatment. It has been assumed that the longer the interval, the lower is the probability of conception, and therefore investigations are usually not started before 1 year of infertility. On the other hand, a prolonged duration of infertility has also been proposed as an indication to use assisted reproductive technology (ART), even without routine investigation of the female infertility. Therefore, a delayed diagnosis may paradoxically favour both under- and overconsumption of ART.
Recent prospective studies on fecundity have shown that human beings may be more fertile than has previously been estimated. In view of the new data on fecundity and the conception window, and the availability of more accurate diagnostic tools and effective treatments such as surgery and ART, our current approach in the routine exploration of female infertility needs to be revisited.
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Time to pregnancy |
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Recent prospective population-based studies have demonstrated that the time to clinical pregnancy in most women is not more than 6 months. Wang et al. (2003) investigated in China a population-based cohort of newly married textile workers with an age range between 20 and 34 years who intended to conceive. They found that the monthly fecundity varied between 30% and 35%, and
50% were pregnant within two cycles and 88% within 6 months. Of the 971 women who were eligible, 518 (53%) were included in the study. The reasons for excluding 453 women were, in 75% of cases, related to violation of the strict study protocol of recording intercourse and collecting daily early morning urine sample, and the exclusions apparently did not give rise to a selected group of couples with higher or lower fertility. The study also included, in addition to clinical pregnancy, conception rate and early pregnancy loss. The authors found no negative correlation between early pregnancy loss and the time to clinical pregnancy, which led to the conclusion that early pregnancy loss can be regarded as a positive indicator that the stages of reproduction leading to implantation are intact. Obviously, caution is needed before generalizing the results of this population-based cohort study in China to other populations.
A large prospective European study was carried out based on users of natural family planning methods trying to achieve a pregnancy (Gnoth et al., 2003). The authors prospectively studied 346 unselected women who used natural family planning methods to conceive from their first cycle onward. They made optimal use of their fertility potential by timing intercourse according to vulvar mucus symptoms to identify the peak days of fertility. The estimated cumulative probabilities of conception for the total group at 1, 3, 6 and 12 months were respectively 38, 68, 81 and 92%. The authors estimated that after 6 months, 50% of the remaining couples were subfertile or infertile.
It can be concluded from both prospective studies that 50% of healthy women become clinically pregnant during the first two cycles, and between 80 and 90% during the first 6 months. These results provide a more optimistic figure of the normal monthly fecundity than previous retrospective studies. While these cohort studies may not be representative for a general population, they indicate that under appropriate circumstances, most couples are likely to conceive early, and the question of subfertility can be raised after 6 months of unprotected intercourse without conception.
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Timing of fertility-oriented intercourse |
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Vulvar mucus observation is likely to become an essential part in the conservative management of patients attempting pregnancy. If the patient is fertile and able to observe vulvar mucus changes, she is highly likely to conceive by fertility-oriented intercourse within a period of 6 months. In case where conception does not occur after 6 months or where the woman is unable to detect mucus changes, she can be advised at an early stage to undergo infertility investigation. In cases of unexplained infertility, the early start of intrauterine insemination is in line with the recommendation of a progression from low-tech to high-tech treatment (Collins, 2003). The approach is likely to shorten the currently recommended waiting period of 2 or 3 years before intrauterine insemination is attempted and, in case of failure, the time before IVF is attempted.
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The age factor |
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In older couples, some argue that laparoscopy can be omitted from the infertility work-up when the hysterosalpingography is normal and there is no abnormal contributing history, and, as a consequence, the cost of fertility treatment is reduced without compromising success rates (Fatum et al., 2002). Balasch (2000)
argued that in relatively older women an evaluation would find more diseases known to cause infertility, such as pelvic adhesions and endometriosis. However, two studies aimed at determining infertility factors in women of advanced reproductive age concluded that there is no unique pattern of infertility diagnosis in such patients (Balasch et al., 1992
; Miller et al., 1999
). This supports the view that the routine investigation of infertility should not differ based on the age of the patient. Karande et al. (1999)
found, in a prospective randomized trial, that a higher pregnancy rate with lower costs is achieved with a traditional treatment algorithm than with IVF-embryo transfer as first-line therapy.
Women should be informed that the chance of a live birth following IVF treatment varies with age, and that the chance of a live birth is significantly decreased after the age of 35 years, and is <10% after the age of 40 years. On the other hand, after surgical treatment, as shown in well-selected cases of tubal infertility with absence of tubal mucosa damage, such as tubal sterilization, the results may be surprisingly good in women >40 years of age (Trimbos-Kemper, 1990). Therefore, a delay in the investigation in older patients may be more unfavourable for subsequent ART than surgical treatment.
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Role of endometriosis |
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The view that the diagnosis and treatment of minor endometriosis in an early stage of subfertility is beneficial is supported by the results of the Canadian Collaborative Group on endometriosis (Marcoux et al., 1997). In a study 341 infertile patients with minimal and mild endometriosis who were randomized to laparoscopic ablation or expectant management, the authors found that laparoscopic ablation of minimal or mild endometriosis doubled the cumulative fecundity rate after a follow-up period of 36 weeks: 30.7% in the treatment group versus 17.7% in the no treatment group. A second Italian study could neither reject or confirm this observation. The study included 101 infertile patients, but demonstrated no difference in fecundity rates after a follow-up period of 1 year (Parazzini, 1999
). A recent review combined the results of these two randomized controled trials into a meta-analysis and showed that surgical treament is more favourable than expectant management (odds ratio for pregnancy 1.7; 95% confidence interval 1.12.5) (Olive and Pritts, 2002
).
While it is generally accepted that moderate and severe endometriosis affects fertility and requires surgical treatment, it is frequently overlooked in the discussion that without endoscopy no staging of endometriosis can be performed. For example, in the absence of endoscopy there is no reliable technique to diagnose the presence and extent of endometriotic adhesions or the presence of ovarian endometriomas when the diameter not >2 cm.
In a recent meta-analysis of IVF outcome for patients with endometriosis, Barnhart et al. (2002) recommended that patients with endometriosis of any stage should be referred for early aggressive infertility treatment, including IVF, to increase chances of conception. It remains an unfortunate fact that the diagnosis of endometriosis is still unduly delayed in many patients with infertility (Dmowski et al., 1997
).
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Other factors delaying the time to pregnancy |
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The results of treatments with a large effect size also show an early high pregnancy rate when no other infertility factors are present. Braat et al. (1991) found, in patients treated for anovulation with intravenous GnRH, a cumulative pregnancy rate of 78% at 6 months, and in the presence of additional infertility factors a cumulative pregnancy rate of 60%.
In a retrospective study of ovulation induction, Capelo et al. (2003) found significant pelvic pathology in one-third of the patients failing to conceive after four ovulatory cycles of clomiphene citrate, and concluded that early endoscopic diagnosis of such pathology would have allowed the couple to proceed directly to IVF.
Oliveira et al. (2003) found a high incidence of pathological findings on hysteroscopy in patients with repeated failures of IVF-embryo transfer despite transfer of good-quality embryos. Relevant therapeutic interventions before the third cycle significantly improved clinical pregnancy and implantation rates in comparison with a control group.
In a retrospective study of 495 patients, Tanahatoe et al. (2003) found that laparoscopy after an hysterosalpingogram and before intrauterine insemination altered the treatment decision in 25% of the patients.
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First-line investigation of female infertility |
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Conclusions |
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There is a need to use a more accurate first-line technique than hysterosalpingography for the early investigation of female infertility. It remains to be assessed whether the use of new ultrasound- or endoscopy-based techniques is cost effective and whether the diagnosis related to such interventions results in improved pregnancy rates.
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References |
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Balasch J (2000) Investigation of the infertile couple in the era of assisted reproductive technology: a time for reappraisal. Hum Reprod 15, 22512257.
Balasch J, Fábregues F, Jové IC, Carmona F and Vanrell JA (1992) Infertility factors and pregnancy outcome in women above age 35. Gynecol Endocrinol 6, 3135.[Medline]
Barnhart K, Dunsmoor-Su R and Coutifaris C (2002) Effect of endometriosis on in vitro fertilization. Fertil Steril 77, 11481155.[CrossRef][Medline]
Bérubé S, Marcoux S, Langevin M and Maheux R (1998) Fecundity of infertile women with minimal or mild endometriosis and women with unexplained infertility. The Canadian Collaborative Group on Endometriosis. Fertil Steril 69, 10341041.[CrossRef][Medline]
Bigelow JL, Dunson DB, Stanford JB, Ecochard R, Gnoth C and Colombo B (2004) Mucus observations in the fertile window: a better predictor of conception than timing of intercourse. Hum Reprod 19, 889892.
Braat DD, Schoemaker R and Schoemaker J (1991) Life table analysis of fecundity in intravenously gonadotropin-releasing hormone-treated patients with normogonadotropic and hyogonadotropic amenorrhea. Fertil Steril 55, 266271.[Medline]
Capelo FO, Kumar A, Steinkampf MP and Azziz R (2003) Laparoscopic evaluation following failure to achieve pregnancy after ovulation induction with clomiphene citrate. Fertil Steril 80, 14501453.[CrossRef][Medline]
Collins J (2003) Current best evidence for the advanced treatment of unexplained subfertility. Hum Reprod 18, 907912.
Dmowski WP, Lesniewicz R, Rana N, Pepping P and Noursalehi M (1997) Changing trends in the diagnosis of endometriosis: a comparative study of women with pelvic endometriosis presenting with chronic pelvic pain or infertility. Fertil Steril 67, 238243.[CrossRef][Medline]
Doll H, Vessey M and Painter R (2001) Return of fertility in nulliparous women after discontinuation of the intrauterine device: comparison with women discontinuing other methods of contraception. BJOG 108, 304314.[Medline]
Dunson DB, Colombo B and Baird DD (2002) Changes with age in the level and duration of fertility in the menstrual cycle. Hum Reprod 17, 13991403.
Evers JLH (2002) Female infertility. Lancet 360, 151159.[CrossRef][Medline]
Fatum M, Laufer N and Simon A (2002) Investigation of the infertile couple: should diagnostic laparoscopy be performed after normal hysterosalpingography in treating infertility suspected to be of unknown origin? Hum Reprod 17, 13.
Gnoth C, Godehardt D, Godehardt E, Frank-Herrmann P and Freundl G (2003) Time to pregnancy: results of the German prospective study and impact on the management of infertility. Hum Reprod 18, 19591966.
Gordts S, Campo R, Puttemans P, Verhoeven H, Gianaroli L, Brosens J and Brosens I (2002) Investigation of the infertile couple: a one-stop outpatient endoscopy-based approach. Hum Reprod 17, 16841687.
Hassan MAM and Killick SR (2004) Is previous use of hormonal contraception associated with a detrimental effect on subsequent fecundity? Hum Reprod 19, 344351.
Karande VG, Korn A, Morris R, Rao R, Balin M, Rinehart J, Dohn K and Gleicher N (1999) Prospective randomized trial comparing the outcome and cost of in vitro fertilization with that of a traditional treatment algorithm as first-line therapy for couples with infertility. Fertil Steril 71, 468475.[CrossRef][Medline]
Kelly S, Sladkevicius P, Campbell S and Nargund G (2001) Investigation of the infertile couple: a one-stop ultrasound-based approach. Hum Reprod 16, 24812484.
Marcoux S, Maheux R and Bérubé S (1997) for The Canadian Collaborative Group on Endometriosis Laparoscopic surgery in infertile women with minimal or mild endometriosis. N Engl J Med 337, 217222.
Miller JH, Weinberg RK, Canino NL, Klein NA and Soules MR (1999) The pattern of infertility diagnoses in women of advanced reproductive age. Am J Obstet Gynecol 181, 952957.[Medline]
Olive DL and Pritts EA (2002) The treatment of endometriosis: a review of the evidence. Ann N Y Acad Sci 955, 360372.
Oliveira FG, Abdelmassih VG, Diamond MP, Dozortsev D, Nagy ZP and Abdelmassih R (2003) Uterine cavity findings and hysteroscopic interventions in patients undergoing in vitro fertilization-embryo transfer who repeatedly cannot conceive. Fertil Steril 80, 13711375.[CrossRef][Medline]
Parazzini F (1999) Ablation of lesions or no treatment in minimal-mild endometriosis in infertile women: a randomized trial. Hum Reprod 14, 13321334.
Stanford JB, Smith KR and Dunson DB (2003) Vulvar mucus observations and the probability of pregnancy. Obstet Gynecol 101, 12851293.
Tanahatoe S, Hompes PG and Lambalk CB (2003) Accuracy of diagnostic laparoscopy in the infertility work-up before intrauterine insemination. Fertil Steril 79, 361366.[CrossRef][Medline]
Trimbos-Kemper TCM (1990) Reversal of sterilization in women over 40 years of age: a multicenter survey in the Netherlands. Fertil Steril 53, 575577.[Medline]
Wang X, Chen C, Wang L, Chen D, Guang W and French J (2003) Conception, early pregnancy loss, and time to clinical pregnancy: a population-based prospective study. Fertil Steril 79, 577584.[CrossRef][Medline]
Wilcox AJ, Weinberg CR and Baird DD (1995) Timing of sexual intercourse in relation to ovulation. N Engl J Med 333, 15171521.
Submitted on February 2, 2004; accepted on April 22, 2004.