Infertility and the establishment of pregnancy - overview

Transcription

1 Infertility and the establishment of pregnancy - overview Allan Templeton Department of Obstetrics and Gynaecology, University of Aberdeen, Aberdeen, UK Correspondence to Prof Allan Templeton, Department of Obstetrics and Gynaecology, University of Aberdeen, Aberdeen Maternity Hospital, Foresterhill, Aberdeen AB25 2ZD, UK The last 20 years has been characterised by an increasing awareness and acceptance of the problems faced by those trying to have children. Infertility affects up to 1 in 7 couples in industrialised countries, and even more couples are affected in some non-industrialised countries. In the West, it appears there has been no major change in prevalence, which is perhaps surprising given the increase in chlamydial infection and the suggestion of a decrease in male fertility, or at least reduction in sperm counts. The United Nations has said reproductive health is a 'state of complete physical, mental and social well-being, and not merely the absence of disease or infirmity in all matters relating to the reproductive system, and to its functions and processes'. In this light, infertility can, therefore, be considered to be a disease process worthy of medical support and treatment. Also during the last 20 years, two major developments have shaped fertility management. These are firstly the increasing availability of m vitro fertilisation (IVF) and related techniques, and secondly a much more critical, evidence-based, approach to management, both investigation and treatment. For the first development, it is always appropriate to acknowledge the pioneering work of Edwards and Steptoe. In vitro fertilisation, like the internal combustion engine, has come a long way since its invention, but it is stdl basically the same technique first used successfully in the late 1970s. FVF and its associated techniques have transformed the likelihood of a pregnancy for many infertile couples, and this in turn has transformed the atmosphere in many infertility clinics, where a mood of gloom and empiricism has been replaced by one of optimism and support. An examination of the evidence underlying modern management will form the basis of much of the rest of this chapter. Epidemiology The prevalence of infertility in Western countries is summarised in Table 1. It is likely that interventionist treatment will prove necessary in half of those couples who experience infertility. As indicated above, there is no convincing evidence yet of any major change in prevalence in Western countries over recent years, although many more couples have been seeking British Medical Bulletin 2000, 56 (No 3) C The Bntijh Council 2000

2 Human reproduction: pharmaceutical and technical advances Table 1 Prevalence of infertility Couples experiencing infertility 15% Couples where infertility remains unresolved 8% Of these, proportion with primary infertility 4% secondary infertility 4% Aetiology access to the available services than previously 1. However, future projections based on the National Survey of Family Growth in the US do predict a substantial upward revision in the number of infertile women 2, although much of this anticipated change may be associated with alterations in the female age structure 3. There have also been a number of other important observations that might be expected to impinge on the prevalence of infertility. For example, analysis of retrospective data has indicated that sperm counts may have declined in some parts of the world, particularly as a result of environmental factors 4. This issue will be addressed in a subsequent chapter, as will the reasons behind the more reliable data indicating a world-wide increase in the incidence of testicular cancer. As a result of these observations, there is now increasing recognition of the environmental 4, and occupational 5, as well as the genetic 6 aspects of male infertility. At the same time, chlamydial infection is now recognised as the major cause of tubal disease in the Western world, and the prevention or limitation of upper tract infection with Chlamydia tracbomatis can be expected to have a major impart on the prevalence of tubal disease in women 7. Thus, the importance of screening for sexually transmitted infection is acknowledged as an important strategy in the prevention of infertility in the female, and also increasingly the male 8. The effect of diminishing or eradicating upper tract infection has become increasingly evident in Sweden, where a marked decrease in the prevalence of secondary infertility has been recorded 9. It is likely that, in the foreseeable future, effects in the area of infection control will completely outweigh any likely effect on the prevalence of infertility associated with putatively falling sperm counts, at least at the levels of reduction in sperm count observed so far. The aetiology of infertility is now commonly thought of in terms of diagnostic categories which facilitate management and treatment. These categories usually include male problems, ovulation problems, tubal problems, endometriosis and unexplained infertility. The distribution of these problems will depend on the characteristics of the population, as well as clinic referral patterns, which in turn will reflect the perceived 578 British Medical Bulletin 2OOO;56 (No 3)

3 Infertility and the establishment of pregnancy - overview Table 2 Approximate distribution of diagnostic categories among couples with primary and secondary infertility Diagnostic category Primary (%) Secondary (%) Male Ovulation Tubal Endometriosis Unexplained expertise and interest of individual clinics. Similarly, the distribution will vary according to whether the infertility is primary or secondary, that is the couple have ever conceived a child or had a pregnancy (see Table 2). Of course the above diagnostic categories do not tell us anything of the actual causes of infertility and whether they are congenital or acquired. It is outwith the scope of this overview to describe in detail the known or suspected causes of infertility, which have been examined in detail in recent publications, but suffice to say that there is now much more interest in genetic and environmental causes, and much more awareness of infective and iatrogenic causes. Some of these issues will be discussed later in this volume. Similarly, there are relatively few population-based data that examine the aetiology of infertility and this has been one of the problems in interpreting the effect of environmental factors as a cause of infertility. The effect of life-style factors on fertility has received much attention recently. It is evident that, in women, obesity has a major effect on infertility and the outcome of treatment, whilst smoking and drinking will have a marginal effect at worst. Obesity is particularly important in relation to ovulatory problems, but can affect the outcome of treatment whatever the cause. Occupational factors 5 are confined so far to those, in which individuals, particularly men, come into contact with identified toxins, lead being one example 10 ' 11. Generally speaking, couples from higher socio-economic groups are less likely to be infertile, but more Likely to seek medical help. However, a further major contribution to subfertility in women is the increasing tendency to postpone child bearing, a trend seen among women in industrialised countries world-wide The impact of pelvic infection caused by C. trachomatis, particularly where there is an opportunity for the infection to ascend to the upper tract, such as after pregnancy, has been well documented in the last decade. Of concern is the increasing prevalence of lower tract infection with Chlamydia, particularly among young women, and a rising rate of pelvic inflammatory disease and tubal pregnancy has been documented in many countries. In addition to these external factors, it is evident that certain characteristics of the couple, and particularly the woman, are major determinants Bntish Medial Bulletin 2000, 56 (No 3) 579

4 Human reproduction: pharmaceutical and technical advances Table 3 Factors affecting the likelihood of a live birth occurring without treatment Previous pregnancy Less than 3 years infertility Female age less than 30 years Factor Confidence limits Treatment Male problems Data from Collins et al 2 ' of subfertility and the outcome of treatment. Chief among these characteristics are the woman's age, the occurrence of previous pregnancies and the time trying to become pregnant. A number of large studies have now documented the extent of these factors and the results from one are shown in Table 3. It is evident that these aspects can have a major effect in determining the likelihood of a spontaneous pregnancy (i.e. a pregnancy without treatment) occurring particularly where the problem is unexplained infertility. This in turn plays a major part in the decision when, if at all, it is appropriate to intervene and treat an individual couple. Treatment is now usually considered in the context of each of the widely accepted diagnostic categories: (i) male problems; (ii) ovulation problems; (iii) tubal problems; (IV) endometriosis; and (v) unexplained infertility. Perhaps the most important factor in assessing the extent of a perceived problem with spermatogenesis, is consideration of the issue in the context of both partners. A severe defect of spermatogenesis including reduced sperm count, motility and many sperm with abnormal morphology, will probably always be relevant. However, milder defects may only become relevant as the age of the female partner and the duration of infertility increases. What has also become increasingly clear in recent years is that many drug treatments previously widely used, including anti-oestrogens and androgens are ineffective and should not now be prescribed 12. The management of varicocele remains controversial, with differing interpretations of the available evidence While it is certain that there is no place for the surgical treatment of varicocele in the presence of normal spermatogenesis, if the man is oligospermic, treatment of the varicocele may be expected, at best, to result in a slightly increased possibility of pregnancy. On a number-needed-to-treat basis this is likely to be around 20. In other words, 20 men would have to be treated m order to increase 580 British Medical Bulletin 2000,56 (No 3)

5 Infertility and the establishment of pregnancy - overview Ovulation problems the likelihood of a pregnancy by one. At this kind of success rate, a detailed discussion of costs and complications becomes even more relevant. For many couples it is increasingly likely that a problem with spermatogenesis will result in the female undertaking an IVF procedure where the eggs are injected with individual spermatozoa (the now well-established technique known as intracytoplasmic sperm injection, ICSI). The evidence now points to this being a safe and effective procedure, although there is a continuing need for the follow-up of the children and a better understanding of the long-term genetic implications, particularly where the reduced spermatogenesis is associated with karyotypic abnormalities or deletions of the Y chromosome. Donor insemination will remain an important option for many couples, although there has been a marked decrease in the number of cycles of treatment being carried out in recent years, almost certainly as a result of the introduction of ICSI. Availability of sperm donors and willingness to donate sperm are major issues at present, and there is concern about proposed legislation in the UK relating to anonymity, and the increasing need to screen and counsel donors resulting in further reductions in current availability. Any legislation that would allow the identification of donors, even if this were only prospective, is likely to have a major impact on the current practice of donor insemination. For many anovulatory women, the successful induction of ovulation will result in a pregnancy. This can often be achieved simply with antioestrogen drugs, although pulsatile gonadotropin releasing hormone and gonadotropin drugs may also be used successfully. However, women with clomiphene-resistant polycystic ovarian disease remain a difficult group to treat, and while laparoscopic ovarian diathermy is an effective treatment in some cases, much more research is needed on the long term sequelae of causing ovarian damage in this way. There are, however, one or two major concerns with all methods of ovulation induction. The first is the risk of multiple pregnancy and the need to monitor follicular development closely to minimise the occurrence of multiple ovulation. The recently published RCOG Guidelines on Infertility in Secondary Care 12 recognised this issue, and suggests centres should adopt protocols which minimise the risks of multiple pregnancy, and further recommends that ovulation induction with gonadotropins should only be carried out in situations which permit daily monitoring of ovarian response. The second concern is the suggestion that ovulation induction whether by gonadotropins or prolonged use of clomiphene, is associated with an British Medical Bulletin 2000, 56 (No 3) 581

6 Human reproduction: pharmaceutical and technical advances Tubal problems increased risk of ovarian cancer. The evidence has been reviewed extensively on a number of occasions and the associations remain uncertain 14 ' 15. Certainly there is no evidence to support an increased risk of ovarian cancer when clorruphene is administered for less than 12 cycles of treatment. However, patients do need to be informed about these putative risks, which unquestionably diminish in the event of a pregnancy, and as a precaution, practitioners should confine the use of gonadotropins to the lowest dose and duration of use. There can be no doubt this issue has caused great concern and is one which requires careful and informed counselling in all women undergoing ovulation induction 16. Further experimental work is needed in this important area, as well as future cohort studies, particularly among ovulatory women having gonadotropin drugs for assisted reproduction. This group probably represents the most preventable cause of infertility in women. There is good evidence that many tubal problems occur following pelvic inflammatory disease, which in turn is caused by upper tract infection most commonly with C. trachomatis. Chlamydia is a common infection that is present in the lower tract of up to 10% of sexually active young people, men and women. The circumstances under which it gains access to the upper tract, particularly the fallopian tubes, is not yet well understood, but certainly pregnancy, including induced abortion, affords an important opportunity. Screening for Chlamydia and antibiotic prophylaxis have become an important part of induced abortion practice, and the principles probably need to extend to other pregnancy outcomes, including normal delivery, caesarean section and miscarriage. Thus screening for Chlamydia in the lower tract of young people, generally under the age of 25 years, and particularly teenagers, is an important strategy in reducing the morbidity associated with PID and its major sequelae, namely infertility and ectopic pregnancy. The association between past chlamydial infection and tubal infertility is so well established, that a number of studies have examined the value of measuring chlamydial antibodies in serum as a predictor of tubal disease 17. The results of chlamydial serology may be relevant in the management of certain groups of patients, and may help with clmical decision making, in relation to the need and timing of laparoscopy, a relatively invasive procedure, which is required to make the definitive diagnosis of tubal disease. Invariably the management of infertility in women with tubal disease will involve in vitro fertilisation treatment, although m a few, selected cases, with mild tubal disease or proximal tubal obstruction, tubal 582 Brrtish Medical Bulletin 2000;56 (No 3)

7 Infertility and the establishment of pregnancy - overview Endometriosis Unexplained infertility surgery may still be considered. Where FVF is undertaken in patients with tubal disease there is now some evidence to suggest that the presence of a large or bilateral hydrosalpinx will result in a reduced implantation rate at the time of IVF and that surgical removal of the tube prior to egg recovery should be considered 18 ' 19. Overall, there is the suggestion that FVF pregnancy rates among women with tubal disease are very slightly reduced compared to other diagnostic categories. The association of endometriosis and infertility remains enigmatic 20. Mild disease does seem to be found more frequently in infertile women, but a causal relationship has not yet been established. Treatment of endometriosis with drugs does not improve pregnancy rates 21, and this is now accepted. The value of surgical treatment of mild endometriosis by diathermy or laser ablation of endometrial deposits at the time of laparoscopy, however, remains controversial. A large randomised study in Canada indicated benefit 22 with a significant improvement in pregnancy rates. However, a more recent Italian study, also prospective and randomised, indicated no benefit 23. Thus the jury is still out on the benefits of surgical treatment of mild disease. As far as moderate and severe disease is concerned, there may be a need for medical or surgical treatment on symptomatic grounds (essentially pelvic pain); but, if infertility is the issue, it is likely that assisted reproduction should be considered at an early stage in management. There is no evidence that medical treatment of moderate and severe endometriosis either alone or as an adjunct to surgery will improve fertility. While the surgical treatment of moderate and severe endometriosis may improve fertility, controlled studies and comparisons with assisted reproduction have not yet been earned out 12. A couple whose completed investigations, including semen analysis, confirmation of ovulation and diagnostic laparoscopy, have failed to reveal any abnormality, can be said to suffer from unexplained infertility. This condition can be particularly difficult to manage in the absence of a diagnosis and an acceptable explanation for the couple. Nevertheless, there is an increasing understanding that such couples should now be managed on the basis of certain characteristics, including female age, whether there has been a previous pregnancy, and the duration of infertility 24. Older age, absence of previous pregnancies and longer duration of infertility, all carry a worse prognosis and together British Medical Bulletin 2000, 56 (No 3) 583

8 Human reproduction: pharmaceutical and technical advances have a multiplying effect which has now been quantified in a number of studies including those of Collins et ap 4 and Snick et ap 5. Factors affecting outcome of treatment In recent years, it has become increasingly understood that the factors that affect the likelihood of a spontaneous pregnancy occurring also affect the outcome of infertility treatment 26. Thus, female age, previous pregnancy and duration of infertility will affect the outcome of treatment in any couple, and in many situations these characteristics will be more important in determining the outcome of treatment than the clinical diagnosis itself. For example, with m vitro fertilisation, female age is the most important determinant of outcome. After the age of 36 years, success rates in terms of pregnancy rates or live birth rates, fall considerably. Live births occur with much reduced frequency in women over 40 years while pregnancies are not generally seen at all in women over the age of 45 years using their own eggs for treatment. Similarly, a longer duration of infertility, even when allowing for age, results in a reduction in live birth rates. On the other hand, the occurrence of any previous pregnancy will enhance the outcome of treatment after IVF, and this is particularly true if the pregnancy was a live birth, an effect even more marked if the live birth followed previous IVF treatment 26. The cause of infertility on the other hand seems to have little or no effect on outcome. There have been suggestions that pregnancy rates after IVF are less in women with tubal disease, but this effect is marginal and it has yet to be demonstrated that it applies to women other than those who have an obvious hydrosalpinx. Some authors have also indicated a reduction in pregnancy rates among women with endometriosis 20, but this has not been supported by examination of the large national databases 26. On the other hand, the treatment of male infertility does seem to result in higher pregnancy rates compared to standard IVF and this has been attributed to a direct effect of the lntracytoplasmic sperm injection (ICSI) procedure. However, when this apparent enhancement is corrected for female factors it is no longer apparent 27. The number of embryos transferred also has an effect on the likelihood of a live birth, but what seems as important in predicting the outcome as the number transferred, is the number of embryos available for transfer 28. If a high number of embryos are available this will enhance the likelihood of a live birth, whereas the patient with only one or two embryos available for transfer will have a reduced chance of success, and should be advised accordingly. Transferring high numbers of embryos does, however, carry an increased risk of multiple pregnancy and this is one of the major adverse effects of IVF treatment. 584 British Medical Bulletin 2000,56 (No 3)

9 Infertility and the establishment of pregnancy - overview Most work on the outcome of infertility treatment has been carried out in the context of IVF, but it is likely that the above factors, perhaps with different weightings, apply to all treatments, including donor insemination, ovulation induction and ovarian stimulation and intra-uterine insemination. A clearer understanding of these issues is an important feature in defining treatment, counselling patients, and designing future research studies. Establishment of pregnancy Conclusions IVF still remains a relatively unsuccessful procedure, because of failure at the stage of embryo replacement. Implantation remains the least understood part of the whole process of conception. There is still only a 10-20% chance at best of each replaced embryo implanting within the uterus. Despite attempts to improve replacement techniques, to select embryos for replacement and manipulate the uterine environment, this situation remains essentially unchanged. The selection of embryos for replacement based on morphological criteria seems to enhance slightly the chance of individual embryos successfully implanting, but there is as yet no reliable method of predicting developmental competence or implantation potential with any degree of accuracy. It would of course be possible to carry out genetic diagnosis on biopsied cells as happens in the context of pre-implantation genetic diagnosis, but it is likely that this technique would in itself diminish the number of available embryos. However, the development of this technique is widening the indications for IVF and related treatments to groups of patients other than those with subfertility. In the future, it is likely that better morphological markers will be developed and these may include cellular polarity and spindle alignment 29, areas where there is much experimental interest in other species at the present time. Similarly the endocrine and endometrial environment which best supports implantation does need to be further researched both in the context of basic and also clinical studies, and some of the issues are discussed elsewhere in this book. Thus it is generally accepted that infertility is a health need, deserving of serious consideration and that couples suffering from subfertility are entitled to basic medical management including investigation and such treatment as can be afforded within the circumstances of their health care systems. Two major features have influenced clinical practice in recent years. The first has been an evidence-based approach to management, and British Medical Bulletin 2000, 56 (No 3) 585

10 Human reproduction: pharmaceutical and technical advances References the acceptance that only treatments of proven efficacy should now be made available. The second major influence has been the introduction of IVF and related techniques such as intracytoplasmic sperm injection. However, there is still much to do in the prevention of infertility, and in the improved management of patients even within present knowledge. In addition, we need a much better understanding of the factors promoting and inhibiting implantation, and in tackling these issues there is much to keep reproductive scientists busy for some time to come. 1 Templeton A. The epidemiology of infertility. In: Templeton AA, Dnfe JO. (Eds) Infertility London: Springer, 1992; Stephen EH, Chandra A. Updated projections of infertility in the United States Fertil Steril 1998; 70: Stephen EH Projections of impaired fecundity among women in the United States: 1995 to 2020 Fertil Stertl 1996; 66: Giwercman A, Bonde JP. Declining male fertility and environmental factors. Endocnnol Metab Clm North Am 1998; 27: Tas S, Lauwerys R, Lison D. Occupational hazards for the male reproductive system. Cnt Rev Toxicol 1996; 26: Irvine DS. Epidemiology and aetiology of male infertility. Hum Reprod 1998; 13: Kamwendo F, Forslin L, Bodin L, Danielsson D. Programmes to reduce pelvic inflammatory disease the Swedish experience Lancet 1998; 351: Chief Medical Officers' Expert Advisory Group. Chlamydta tracbomatis. Summary and Conclusions. London: Department of Health, 1996; Akre O, Cnamngius S, Bergstrom R, Kvist U, Tnchopoulos D, Ekbom A. Human fertility does not decline- evidence from Sweden Fertil Steril 1998, 71: Lin S, Hwang SA, Marshall EG, Stone R, Chen J. Fertility rates among lead workers and professional bus drivers: a comparative study. Ann Epidemiol 1996, 6: Viskum S, Rabjerg L, Jorgensen PJ, Grand)ean P. Improvement in semen quality associated with decreasing occupational lead exposure Am J Indust Med 1999; 35' Royal College of Obstetricians & Gynaecologists. The Management of Infertility in Secondary Care. London: RCOG, 1998; Evers JLH. Vancocele. In: Templeton A, Cooke I, O'Brien PMS. (Eds) Evidence Based Fertility Treatment. London: RCOG, 1998; Duckitt K, Templeton A. Cancer in women with infertility. Curr Opin Obstet Gynecol 1998; Mosgaard BJ, Lidegaard O, Kjaer SK, Schou G, Andersen AN. Ovarian stimulation and borderline ovarian tumors: a case-control study Fertil Stenl 1998; 70: Houmard BS, Seifer DB. Infertility treatment and informed consent: current practices of reproductive endocnnologists. Obstet Gynecol 1999; 93: Mol BWJ, Lijmer J, Dijkman B, van der Veen F, Wertheim P, Bossuyt PMM. The accuracy of serum chlamydial antibodies in the diagnosis of tubal pathology: a meta-analysis. Fertil Steril 1997; 67: Nackley AC, Muasher SJ. The significance of hydrosalpinx in in vitro fertilization. Fertil Steril 1998; Strandell A. Hydrosalpinx and IVF outcome: a prospective, randomized, mulocentre mal in Scandinavia on salpingectomy prior to IVF. Hum Reprod 1999; Dokras A, Olive DL. Endometnosis and assisted reproductive technologies. Clm Obstet Gynecol 1999; 42: British Medical Bulletin 2000;S6 (No 3)

11 Infertility and the establishment of pregnancy - overview 21 Hughes EG, Fedorkow DM, Collins JA. A quantitative overview of controlled trials in endometriosis-associated infertility. Fertri Stenl 1993; 59: Marcoux S, Maheux R, Berube S et al. Laparoscopic surgery in infertile women with minimal or mild endometnosis. N Engl J Med 1997, 97: Parazzini F. Ablation of lesions or no treatment in minimal-mild endometnosis in infertile women: a randomized mal. Hum Reprod 1999; 14: Collins JA, Burrows EA, Willan AR. The prognosis for live birth among untreated infertile couples. Fertil Stenl 1995; 64: Snick HKA, Snick TS, Evers JLH, Collins JA The spontaneous pregnancy prognosis in untreated subferole couples: the Walcheran primary care study. Hum Reprod 1997, 12: Templeton A, Morns JK, Parslow W Factors that affect outcome of in vttro fertilisation treatment. Lancet 1996, 348: Templeton A, Morns JK In vitro fertilisation: factors affecting outcome. In: Templeton A, Cooke I, O'Bnen PMS. (Eds) Evidence Based Fertility Treatment London: RCOG, 1998; Templeton A, Morns JK Reducing the nsk of multiple births by transfer of two embryos after in vitro fertilisation. N Engl ] Med 1998; 339: Gardner RL. The early blastocyst is bilaterally symmetrical and its axis of symmetry is aligned with the animal-vegetal axis of the zygote in the mouse. Develop 1997; British Medical Bulletin (No 3) 587