Ebook Infertility in practice (4/E): Part 2

BQ) Part 2 book “Infertility in practice” has contents: Unexplained infertility, assisted conception, the human fertilisation and embryology authority and regulation, ethical issues, emerging technologies, recurrent miscarriage, ectopic pregnancy,…. And other contents.

13 Unexplained Infertility Introduction One can consider two approaches to the diagnosis and management of unexplained infertility The first approach is strictly scientific, with a quest for and exclusion of each known cause of infertility before the label unexplained infertility can be given The second approach is a pragmatic approach based upon a management-oriented policy, whereby treatment is commenced after the common obstacles to fertility have been excluded [1] The treatment of unexplained infertility essentially aims to boost fertility, usually by a combination of superovulation and close apposition of sperm and egg(s) Sometimes, the use of assisted conception techniques provides clues to the underlying diagnosis, for example, if there are problems with fertilisation that can only be detected during in vitro fertilisation (IVF) therapy Assessing the Cause of Infertility Many centres have their own highly specialised areas of interest and research that they then promote as the missing cause of unexplained infertility (Box 13.1) Thus, it is possible to draw long lists of putative and subtle causes of infertility, many of which cannot be proven with certainty and few of which are actually amenable to a corrective remedy that has been shown to enhance fertility One also should remember that couples with normal fertility can have abnormal test results Once the well-known and obvious causes of infertility have been excluded (see Chapter 5), the treatment of couples with unexplained infertility should follow clear protocols The important tests are the assessment of ovulation (by serum progesterone), sperm function (basic semen analysis) and tubal patency (hysterosalpingogram) Supplementary investigations, such as follicular scanning, endometrial biopsy, laparoscopy/hysteroscopy and complex sperm function tests, are useful in helping to predict the chance of conception, but they may not influence the outcome of treatment Studies of populations of patients with infertility indicate that approximately 10%–25% have unexplained infertility, 20%–30% ovulatory dysfunction, 20%–35% tubal damage, 10%–50% sperm dysfunction, 5%–10% endometriosis, 5% cervical mucus problems and 5% coital dysfunction [2] A degree of subfertility is found in both partners in 30%–50% of couples, as usually a couple’s subfertility is a relative rather than an absolute barrier to conception It should be remembered that the greater © 2011 Taylor & Francis Group, LLC 315 316 Infertility in Practice BOX 13.1  POSSIBLE SUBTLE CAUSES PROPOSED FOR SUBFERTILITY Subtle causes of subfertility that have been proposed as underlying unexplained infertility, many of which have been found in couples of normal fertility (correction of the abnormality has not always been shown to improve fertility) Ovarian and endocrine factors • • • • • • • • Abnormal follicle growth Luteinised unruptured follicles and functional ovarian cysts Hypersecretion of luteinising hormone (LH) Hypersecretion of prolactin in the presence of ovulation Reduced growth hormone secretion/sensitivity Cytological abnormalities in oocytes Genetic abnormalities in oocytes Antibodies to zona pellucida Peritoneal factors • Altered macrophage and immune activity • Mild endometriosis • Antichlamydial antibodies Tubal factors • Abnormal peristaltic or cilial activity • Altered macrophage and immune activity Endometrial factors • • • • • Abnormal secretion of endometrial proteins Abnormal integrin/adhesion molecules Abnormal T-cell and natural killer cell activity Secretion of embryotoxic factors Abnormalities in uterine perfusion and contractility Cervical factors • Altered cervical mucus • Increased immunogenicity General immune factors • Altered cell-mediated immunity Male factors • Reduction in motility, acrosome reaction, oocyte binding and zona penetration • Ultrastructural abnormalities of head morphology © 2011 Taylor & Francis Group, LLC 317 Unexplained Infertility Embryological factors • Poor quality embryos • Reduced progression to blastocyst in vitro • Abnormal chromosomal complement – increased miscarriage rate 100 90 80 1–2 years Couples (%) 70 2–3 years 60 50 40 3–5 years 30 ≥5 years 20 SE 10 0 12 18 24 Months (cycles) FIGURE  13.1  Cumulative conception rates in patients with unexplained infertility without any treatment related to the duration of infertility at the time of initial investigations (From Hull MG et al., BMJ 291, 1693–7, 1985 With permission.) the prevalence of a condition, the greater the predictive value of its screening test, so everyday tests are of most value in detecting the commonest causes of subfertility The limitations of the various tests, however, also should be appreciated: tubal patency does not necessarily equate with normal function, and an elevated luteal-phase progesterone concentration does not confirm that an oocyte has been released from the follicle Unexplained infertility has been defined as the inability to conceive after year in the absence of any abnormalities The natural pregnancy rate in couples with unexplained infertility has been reported as between 2% and 4% per menstrual cycle [3] One study reported conception rates of 15% of couples with unexplained infertility within year and 35% within years [4] And the cumulative chance of pregnancy over years has even been reported as being 80% [2,5] Therefore, it has been suggested that treatment should be deferred until the couple has been trying to conceive for 2–3 years, as before this time therapy may not confer any benefit over the natural chance of conception (Figure 13.1) [2] © 2011 Taylor & Francis Group, LLC 318 Infertility in Practice It appears that the most important prognostic factors are the duration of infertility and the age of the female partner Of course, the rate of progression to treatment through the various therapies that are used to boost fertility will depend upon the age of the couple and their levels of anxiety together with the available (and affordable) resources The management of unexplained infertility is usually empirical, but couples undergoing treatment should always be treated as individuals Management of Unexplained Infertility Several approaches have been used in the management of unexplained infertility Some of the therapies that have been used are discussed here, and we propose a stratified protocol used in practice Therapy should aim to boost the monthly pregnancy rate above the natural rate of 1.5%–3% that is expected for couples who have been trying to conceive for over a year Clomifene Citrate It used to be thought that clomifene enhanced fertility by correcting a subtle defect in ovarian function – either of follicular development or of luteal-phase defect It appears more likely, however, that stimulation of ovulation achieves its effect by increasing the number of follicles that develop and consequently the oocytes that are released When using clomifene citrate, one should always remember the side effects of multiple pregnancy and the possible association between its prolonged use (>12 cycles) and the putative risk of ovarian cancer (see Chapter 18) Over the years, many studies have been published and systematic reviews have ­fluctuated in and out of favour for the use of clomifene for the management of u­ nexplained infertility The latest Cochrane review of data relating to 1159 ­participants from seven randomised trials reports no evidence that clomifene was more e­ ffective than no treatment or than placebo for live birth (odds ratio (OR) 0.79, 95% CI 0.45–1.38; p = 41) or for clinical pregnancy both with intrauterine ­insemination (IUI) (OR 2.40, 95% CI 0.70–8.19; p = 16), without IUI (OR 1.03, 95% CI 0.64–1.66; p = 91) and without IUI but using human chorionic gonadotropin (hCG) (OR 1.66, 95% CI 0.56–4.80; p = 35) [6] Superovulation with IUI There are few prospective randomised studies involving the use of gonadotropins alone in the treatment of unexplained infertility, and most of the studies that have evaluated gonadotropins with IUI are retrospective analyses Gonadotropin therapy requires careful monitoring with serial ultrasound scans to minimise the risks of ovarian hyperstimulation syndrome and multiple pregnancy (see Chapter 18) It is reasonable to expect that the combination of gonadotropins to induce superovulation, with the release of two or three oocytes, with insemination of a prepared sample sperm into the uterine cavity should boost fertility There are, however, contrasting studies in the literature Melis et al [7] have reported a large, prospective, randomised study comparing gonadotropin therapy and timed intercourse with gonadotropin therapy and IUI Two hundred couples with at least years’ unexplained infertility received superovulation with follicle-stimulating hormone (FSH) © 2011 Taylor & Francis Group, LLC Unexplained Infertility 319 to produce at least two follicles There was no significant difference in the outcome of the two groups, with a cumulative conception rate of approximately 43% after three cycles and a multiple pregnancy rate of 10% A similar study from Glasgow [8] randomised 100 patients to receive ovulation induction, using pituitary desensitisation with a gonadotropin-releasing hormone (GnRH) agonist followed by FSH, with timed intercourse or IUI There was a significant increase in the ongoing pregnancy rate after three cycles of 42% in the IUI group compared with 18% in the timed intercourse group A meta-analysis in the Cochrane database has recently published the evidence [9] There was no evidence of a benefit of IUI alone with expectant management, but when ovarian stimulation was used, IUI increased the chance of pregnancy compared with timed intercourse (6 randomised controlled trials (RCTs), 517 women: OR 1.68, 95% CI 1.13–2.50) [9] A significant increase in live birth rate was found for women where IUI with ovarian stimulation was compared with IUI in a natural cycle (four RCTs, 396 women: OR 2.07, 95% CI 1.22–3.50) However, the trials provided insufficient data to investigate the impact of IUI with or without ovarian hyperstimulation (OH) on several important outcomes, including live births, multiple pregnancies, miscarriage and risk of ovarian hyperstimulation There was no evidence of a difference in pregnancy rate for IUI with ovarian stimulation compared with timed intercourse in a natural cycle, and interestingly, IUI in natural cycle was better than timed intercourse with ovarian stimulation (1 RCT, 342 women: OR 1.95, 95% CI 1.10–3.44) [9] In summary, there is evidence that IUI with ovarian stimulation increases the live birth rate compared with IUI alone The likelihood of pregnancy also was increased for treatment with IUI compared with timed intercourse in stimulated cycles Overall, IUI with ovarian stimulation appears to have a potential, albeit relatively limited role in the management of unexplained infertility Superovulation with IUI Protocols The rationale behind superovulation with IUI [10] encompasses the deposition of a prepared or enhanced preparation of sperm as close as possible to at least one oocyte (Figure 13.2) Sperm can be prepared in many ways, the most common of which includes simple sperm washing, swim-up techniques and gradient separation techniques Sperm washing is achieved by diluting a sample of liquefied sperm in culture medium, followed by centrifugation and resuspension in the medium, thereby removing seminal plasma but leaving bacteria and immotile spermatozoa in the preparation [10] The sample is enhanced further if the wash is repeated and the sperm then left to swim up to the surface of the media for 30–60 min, whence it is recovered, leaving debris, bacteria and immotile spermatozoa at the bottom of the tube The supernatant should now contain 80%–100% motile sperm and a significantly higher percentage with normal morphology Alternatively, sperm can be layered on an isotonic Percoll column, which provides a density gradient for the separation of morphologically normal, motile spermatozoa Ovarian stimulation is optimally achieved using gonadotropin injections without prior pituitary desensitisation We have found a step-down protocol to be of benefit, with the aim of recruiting two or three dominant follicles, using a starting dose of 150  units (75–100 units if under 30 years or polycystic ovarian morphology on © 2011 Taylor & Francis Group, LLC 320 Infertility in Practice FIGURE 13.2  Intrauterine insemination baseline ultrasound scan) and dropping to 75 units (50–37.5 units) after three doses Treatment is started on day of the cycle, and ultrasound monitoring is commenced on day Stimulation is continued and the dose adjusted, as necessary until there are two follicles of 16-mm diameter or more, with the largest follicle having a diameter of at least 18 mm and no more than three follicles in total greater than 14 mm With this approach, the monthly rate of conception is approximately 15%–20% and the 4-month cumulative conception rate is 40% The risk of twins is in the region of 20% and the rate of triplet pregnancies is less than 1% The main concern is that ovarian stimulation increases multiple pregnancies Nonetheless, we believe that with careful ultrasound monitoring and strict criteria for cancellation if there are more than two mature pre-ovulatory follicles, the multiple pregnancy rates should be able to be kept to less than 5% Gamete Intrafallopian Transfer Gamete intrafallopian transfer (GIFT goes one step further than superovulation/IUI as it involves the collection of oocytes and the direct transfer of oocytes and sperm into a fallopian tube (Figure 13.3 and see Chapter 14) GIFT was evolved for the treatment of unexplained infertility because it was thought that the fallopian tube provided a more physiological environment for fertilisation than a dish in an incubator The main disadvantages compared with IUI are the need for a laparoscopy and a more complicated ovarian stimulation regimen (see Chapter 14) Compared with IVF, GIFT fails to provide the couple with fertilised oocytes, although surplus oocytes can be fertilised in vitro and cryopreserved for future use GIFT is seldom used these days In Vitro Fertilisation IVF is a less invasive therapy than GIFT and confers the advantages of being able to study fertilisation and the selection of good quality pre-embryos for transfer into the © 2011 Taylor & Francis Group, LLC Unexplained Infertility 321 FIGURE 13.3  Gamete intrafallopian transfer (GIFT) Laparoscopic aspiration of oocytes before cannulation of the fallopian tube and transfer of oocytes and sperm uterus The Cochrane database included six studies and showed that the live birth rate (LBR) per woman was significantly higher with IVF (45.8%) than expectant management (3.7%) (OR 22.00, 95% CI 2.56–189.37, RCT, 51 women) [11] There was no difference in LBR between IVF and IUI alone (40.7% vs 25.9%, OR 1.96, 95% CI 0.88–4.36, one RCT, 113 women) In studies comparing IVF with IUI + ovarian stimulation, LBR per woman did not differ significantly between the groups among women who had yet to receive any treatment (OR 1.09, 95% CI 0.74–1.59, two RCTs, 234 women) but was significantly higher in a large RCT of women pretreated with IUI + clomifene citrate who then had IVF compared with IUI (OR 2.66, 95% CI 1.94–3.63, RCT, 341 women) There was no evidence of a significant difference in multiple pregnancy rate or ovarian hyperstimulation syndrome between the two treatments [11] We believe that it seems sensible to progress to IVF in couples with unexplained infertility after initial treatment with superovulation/IUI In women more than 35 years of age, we believe that IVF should be offered as first-line therapy Strategy for Management of Unexplained Infertility In developing a strategy for the management of unexplained infertility, one has to balance the efficacy of treatment, including cost-effectiveness, against the relative invasiveness of the various therapeutic options The available evidence suggests that there is little to be gained by commencing therapy before a couple have been trying for at least 2–3 years However, it is difficult to enforce this guideline in practice when confronted in the clinic by a distressed couple with unexplained infertility Furthermore, some of these couples will have as yet unidentified sperm, oocyte or fertilisation defects that will only be discovered during the process of IVF There is © 2011 Taylor & Francis Group, LLC 322 Infertility in Practice a certain logic, therefore, in proceeding straight to IVF and if fertilisation is normal, reverting to either no treatment until years have elapsed or a less invasive treatment such as IUI with superovulation The age of the female partner also should be considered, and there is a case for treating women more than the age of 35 years more aggressively IVF is the most effective way to enhance the chance of conception and live birth and has been increasingly used for the management of unexplained infertility The pace and intensity of treatment often are governed by the couple’s desires and anxiety, some wishing to proceed swiftly to assisted reproduction technology and others wishing to avoid high-tech treatments for as long as possible It is essential to present the couples with a realistic appraisal of their chance of pregnancy with and without treatment and also to counsel them fully about the risks and side effects of the various therapies REFERENCES Siristatidis C, Bhattacharya S Unexplained infertility: does it really exist? Does it matter? Hum Reprod 2007; 22: 2084–7 Hull MG, Glazener CM, Kelly NJ, et al Population study of causes, treatment and outcome of infertility BMJ 1985; 291: 1693–7 Polyzos NP, Tzioras S, Mauri D, et  al Treatment of unexplained infertility with aromatase inhibitors or clomiphene citrate: a systematic review and meta-analysis Obstet Gynecol Surv 2008; 63: 472–9 Isaksson R, Tiitinen A Obstetric outcome in patients with unexplained infertility: comparison of treatment-related and spontaneous pregnancies Acta Obstet Gynecol Scand 1998; 77: 849–53 Guzick DS, Sullivan MW, Adamson GD, et al Efficacy of treatment for unexplained infertility Fertil Steril 1998; 70: 207–13 Hughes E, Brown J, Collins JJ, Vanderkerchove P Clomiphene citrate for unexplained subfertility in women Cochrane Database Syst Rev 2010; (1): CD000057 Melis GB, Paoletti AM, Ajossa S, Guerriero S, Depau GF, Mais V Ovulation induction with gonadotropins as sole treatment in infertile couples with open tubes: a randomized prospective comparison between intrauterine insemination and timed vaginal intercourse Fertil Steril 1995; 64: 1088–93 Chung CC, Fleming R, Jamieson ME, Yates RW, Coutts JR Randomized comparison of ovulation induction with and without intrauterine insemination in the treatment of unexplained infertility Hum Reprod 1995; 10: 3139–41 Veltman-Verhulst SM, Cohlen BJ, Hughes E, Heineman MJ Intra-uterine insemination for unexplained subfertility Cochrane Database Syst Rev 2012; (9): CD001838 10 The ESHRE Capri Workshop Group Intrauterine insemination Hum Reprod Update 2009; 15: 265–77 11 Pandian Z, Gibreel A, Bhattacharya S In vitro fertilisation for unexplained subfertility Cochrane Database Syst Rev 2012; (4): CD003357 © 2011 Taylor & Francis Group, LLC 14 Assisted Conception Introduction Assisted conception techniques involve the laboratory preparation of gametes, artificially bringing them closer together and hence enhancing fertility by either by-­passing an absolute obstruction to fertilisation or boosting fecundity above that expected without treatment Indications for Assisted Conception Assisted conception is used in treatment of the following conditions or indications Tubal Damage Assisted conception is indicated if the prognosis for tubal surgery is considered too poor or if conception has failed to occur within 6–12 months of tubal surgery (see Chapter 11) Consideration should be given to discussion of pre-treatment tubal sterilisation, to minimise the risk of ectopic pregnancy after treatment, although in practice this discussion is seldom performed The presence of hydrosalpinges, if visible on a pelvic ultrasound scan, is associated with a reduced implantation rate, which has been shown to improve after salpingectomy (see Chapter 11) Endometriosis In vitro fertilisation (IVF) is indicated for moderate to severe disease if conception has failed to occur within 12 months of ablative laparoscopic surgery, depending, of course, on age and other fertility factors (see Chapter 10) Consideration also should be given to pre-treatment management of endometriotic cysts (see Chapter 10) Male Factor Infertility When there is severe sperm dysfunction and sperm preparation provides an inadequate specimen for superovulation with intrauterine insemination (IUI; see Chapters 12 and 13) or if conception has failed to occur after three or four cycles of superovulation/IUI, IVF should be offered Micromanipulation techniques such as intracytoplasmic sperm injection (ICSI) may be required to achieve fertilisation if there is severe male factor infertility © 2011 Taylor & Francis Group, LLC 323 324 Infertility in Practice IVF is also indicated in couples in whom there is azoospermia and conception has not occurred with donor insemination (DI) The number of cycles of DI treatment should be governed by the female partner’s age and other fertility problems: in women under 35 years of age, it is reasonable to attempt 12 cycles, although ­conception should occur in 50%–60% of couples by six cycles of treatment; women over the age of 35 may take longer to conceive, but results of assisted conception treatments also are reduced, so the more successful therapies should not be delayed Unexplained Infertility An argument can be made for a cycle of IVF to test the ability of the sperm to achieve fertilisation, albeit in an artificial environment If fertilisation occurs and yet there is no pregnancy, then a less high-tech treatment, such as superovulation/IUI (see Chapter  13), could be used for a few cycles before reverting to IVF, although this sequence is not a sequence that we have used Most couples and clinicians prefer a stepwise progression through therapies, culminating in IVF as the last resort It is obviously appropriate to discuss the options with the couple and to map out a management plan Most couples feel more secure in the knowledge that they are to have a certain number of cycles of a particular treatment before moving on to another therapy Sometimes, the hardest part of fertility therapy, for both patients and clinician, is knowing when to move on, because there is a tantalising uncertainty about the outcome if another cycle of a particular treatment is undertaken Cervical Infertility Cervical infertility accounts for fewer than 5% of cases of infertility, and in the past this condition was overdiagnosed Whether the real cause is unexplained or cervical infertility, the treatment of choice is superovulation/IUI (see Chapter 13), followed by IVF, if IUI fails So, the diagnosis of cervical infertility and studies of cervical mucus have become redundant Coital Dysfunction Psychosexual counselling should be offered in the first instance (see Chapter  6), unless there is an organic cause for the sexual dysfunction (see Chapter 12) If assisted conception is required, then the treatment of choice is IUI (plus or minus superovulation; see Chapter 13), followed by IVF if IUI fails It may be advisable to cryopreserve sperm as a backup for the day of treatment in case there is difficulty in producing on the day Pre-Implantation Genetic Diagnosis IVF can be used to generate embryos from which single cells can be obtained for genetic studies or simple sexing in cases where there are life-threatening congenital diseases Each cell in the pre-embryo is pluripotent, so a single cell can be removed up to the blastocyst stage without damaging the development of the fetus Using this technique, it is possible to transfer only healthy pre-embryos and avoid the risks of © 2011 Taylor & Francis Group, LLC (a) (b) FIGURE 5.39  Laproscopic views of the liver and undersurface of the diaphragm to illustrate the importance of assessing this area (a) Fitz-Hugh–Curtis syndrome (b) Endometriosis FIGURE  5.41  Laparoscopy with intubation of methylene blue dye There is bilateral cornual obstruction to flow and, on the right, the dye can be seen suffusing the myometrium and vessels of the broad ligament Externally the pelvic structures appear normal Response to treatment 100% * 80% 60% 40% 20% + 0% PCOS 603 HH 503 WRA 121 Number of cycles * + P = 012 P = 003 Overstimulated Inadequate Anovulatory Ovulatory FIGURE 7.27  Response to treatment: patients with polycystic ovary ­syndrome were less likely to have anovulatory cycles, with the usual reason being the need to abandon the cycle because of an overexuberant response and the production of too many follicles HH, hypogonadotropic hypogonadism; WRA, weight-related amenorrhoea (From Balen AH, et al., Hum Reprod 9, 1563–70, 1994.) (a) (b) FIGURE 7.29  (a) Laparoscopic ovarian diathermy The needle enters the ovarian capsule while the ovarian ligament is held steady, with the ovary supported on the front of the uterus (b) At the end of the procedure, the ovary has been diathermised at four sites FIGURE 8.2  Colour Doppler studies of a polycystic ovary Transvaginal ultrasound (5 MHz) with superimposed pulsed Doppler demonstrating a typical ovarian stromal flow velocity waveform In the early follicular phase, the normal velocity is