• 1.
  

  a) T b) F c) F d) F e) T

For excluding other causes of infertility in infertile couples, the standard clinical investigations are as follows: semen analysis, tests for assessment of ovulatory status, and tests for checking the tubal patency. Tubal patency can be tested by hysterosalpingogram or diagnostic laparoscopy. Although laparoscopy can identify pelvic endometriosis and tubal adhesions, it is not considered mandatory for diagnosing unexplained infertility. Various aetiological factors are suspected for unexplained infertility (i.e. endocrine, immunological and genetic). No infectious cause, however, has yet been identified in couples with unexplained infertility. The chance of spontaneous pregnancy in unexplained infertility is higher compared with other causes such as ovulatory, tubal or male factors. More than one-third of younger women with unexplained infertility of 2 years duration will conceive naturally in a year’s time. As a consequence, expectant management has an important role to play in unexplained infertility. The prevalence of unexplained infertility has been shown to be between 22–28%. It is, however, diagnosed more commonly in women over 35 years of age.

• 2.
  

  a) F b) F c) F d) T e) T

It is believed that clomifene citrate acts in unexplained infertility by correcting subtle ovulatory dysfunctions (which might not have been detected by standard ovulatory assessment investigations), but this has yet to be proven. Data from randomised-controlled trials have not confirmed the effectiveness of clomifene compared with expectant management. A randomised-controlled trial has not been able to confirm the superiority of IUI compared with expectant management. Super ovulation with IUI is more effective than IUI alone because multiple ovulations lead to a higher number of fertilisable oocytes available during IUI. A systematic review confirmed higher live birth rates after super ovulation with IUI compared with IUI alone. The aim in a super ovulation protocol is to achieve ovulation from more than one follicle (ideally two). The chances of multiple pregnancies are higher with super ovulation with IUI compared with unstimulated IUI because of multiple follicular growth. IVF is an effective treatment option for long-standing unexplained infertility. The chances of live birth are 21-fold with IVF compared with expectant management. Multiple pregnancies and ovarian hyperstimulation syndrome, however, are the associated complications with IVF.

• 3.
  

  a) T b) F c) T d) F e) F

With the move from World Health Organization (WHO) 1999 to 2010 methodology, it is inevitable that patients seen over an extended period of time may apparently be re-classified from ‘fertile’ to ‘infertile’ if their semen parameters are between the new and the old reference ranges. Also, because of the significant changes in laboratory methodology, some values, such as those for sperm morphology, will have become lower in recent years simply as a consequence in the change of laboratory methods. Similarly, because WHO (2010) introduced the concept of confidence intervals for measures of semen quality, a sample with 12 × 10 ⁶ sperm per ml and 31% progressively motile sperm is within the range expected for a sample on the 5th centile of a fertile population and hence is technically not abnormal. To some clinicians, sperm morphology is of limited value in making treatment decisions, but a sperm morphology of 0% is significant and should be considered further. Although globozoospermia is rare, it is associated with the absence of an acrosome, and so both spontaneous and assisted conception are unlikely to work. Although intra-cytoplasmic morphologically selected sperm injection (IMSI) may provide some benefit in identifying sperm with rudimentary acrosomes, fertilisation rates are low. The identification of leucocytes in semen analysis is particularly challenging without the use of specific stains or immunocytochemistry. As such, technicians can mistake germ cells for leucocytes and, if reported uncritically, can suggest infection where none exists. Therefore, any report of leucocytes should be confirmed with specific test for micro-organisms (e.g. Chlamydia trachomatis) before antibiotics are given. Finally, higher sperm concentrations are generally associated with better quality ejaculates, but it cannot be inferred from sperm counts alone whether an ejaculate is from a fertile man, as sperm motility, morphology and antibody production may independently affect fertility. The evaluation of semen quality should include all variables referred to in WHO (2010).

• 4.
  

  a) T b) F c) F d) F e) T

A number of research studies have shown that increased levels of sperm DNA damage correlate with early pregnancy loss in IVF and ICSI cycles, and this has led to many laboratories offering DNA damage tests on a routine basis. Recommendations from the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine, however, are that they should not be used routinely. DNA integrity is an essential part of sperm function and, unfortunately, neither the sperm nor the egg is able to repair DNA damage. Although techniques such as IMSI can select sperm on the basis of nuclear vacuoles, their relationship to DNA fragmentation is unclear. A wide variety of environmental and occupational factors can cause DNA damage, and the sperm of smokers shows more DNA damage than the sperm of non-smokers.

• 5.
  

  a) F b) T c) F d) T e) T

According to current evidence, the binding of sperm to hyaluronic acid is a useful method of sperm selection because bound sperm appear to have better morphology, less residual cytoplasm and, when used in ICSI, give rise to better quality embryos than sperm that are selected according to current methods. Although hyaluronic acid is the major glycosaminoglycan of the cumulus-oopherus complex, no current evidence show that binding triggers the acrosome reaction; moreover, the nature of the receptor by which sperm bind to hyaluronic acid is unknown and it seems unlikely that this in itself is responsible for the improvement in embryo quality and live births observed.

• 6.
  

  a) F b) F c) F d) T e) T

The reference values published by WHO (2010) are based on the fifth centile of the semen characteristics of recent fathers whose partner became pregnant within 12 months of stopping use of contraception. Therefore, it is unlikely that significant changes (e.g. sperm morphology) are influenced by any proposed global decline in semen quality for the first time, but rather as a consequence of adopting real-life data, rather than consensus, for the first time. These values define the range of values observed in recent fathers and so, by definition, 5% of fertile men have semen quality below the reference values so it is not possible to define any patient who has similar values as sub-fertile. The WHO (2010) manual includes many methodological changes, including the requirement to infer semen volume from its weight; however, this does not account for the reduction of the reference range of semen volume to ≥1.5 ml, which again results from the publication of ‘real life’ data. A reference range for seminal pH is not published because information is lacking on pH of semen from fertile men. As a general rule the values for sperm viability should always be higher than those for the percentage of progressively motile sperm, as even immotile sperm can be ‘live’ and could in theory be used in ICSI.

• 7.
  

  a) F b) T c) T d) T e) T

Hysterosonography and hysterosalpingography examination provide information about the uterine cavity as well as evaluation of tubal patency. Hysteroscopy is not routinely carried out in the investigation of infertility except when an intrauterine lesion is suspected. In a randomised-controlled trial of 215 women with endometrial polyps who were scheduled to undergo up to four cycles of intrauterine insemination starting 3 months after surgery, women were allocated into a hysteroscopic polypectomy group (n = 107) or an endometrial biopsy only group (n = 109). The pregnancy rate in the polypectomy group (51.4%) was significantly higher than in the control group (25.4%). Casini et al. conducted a randomised-controlled trial of 52 women and reported that removal of submucous myomas led to a significant increase in pregnancy rate from 27.2% to 43.3% and a decrease in miscarriage rate from 50% to 38.5%. Shokeir et al. conducted another randomised-controlled trial among women with unexplained infertility and found that pregnancy in the myomectomy group was 63.4% and in the control group it was 28.2% (RR, 2.1; 95% CI 1.5 to 2.9). In a prospective study, hysteroscopic removal of a uterine septum (hysteroscopic metroplasty) is associated with a higher pregnancy rate than in those with unexplained infertility. The live birth rate was also higher in the metroplasty group than in the group with idiopathic infertility (34.1% and 18.9%, respectively). Fernandez et al. studied 64 women with severe adhesions. Hysteroscopic removal of the adhesions led to a live birth rate of 32.8%.

• 8.
  

  a) T b) T c) T d) F e) F

The presence of hydrosalpinx impairs IVF outcomes by decreasing the implantation and pregnancy rates. This could be a result of the possible toxicity of hydrosalpinx fluid to the embryo or to the mechanical effect of the fluid impairing implantation. Laparoscopic removal of the hydrosalpinx (salpingectomy) before IVF is the procedure of choice. Randomised-controlled trials have shown that pre-IVF salpingectomy leads to higher IVF-pregnancy and delivery rate. In a randomised-controlled trial, laparoscopic salpingectomy, proximal tubal occlusion and no intervention were compared. The ongoing IVF pregnancy rates after salpingectomy or proximal tubal occlusion were similar. The resulting blocked tube proximally and distally, however, traps the hydrosalpinx fluid and the tube might become dilated. A relatively new application of hysteroscopy in women with hydrosalpinx before IVF treatment is placement of a device occluding the proximal part of the fallopian tube. The most common device used for this purpose is Essure ^® (Conceptus Inc, Scottsdale, AZ). In a small study, the procedure led to a 40% ongoing pregnancy rate and 20% live birth rate after one IVF cycle. This procedure should still be considered experimental however. Because of the possible decreased ovarian function after salpingectomy, it is important to excise the hydrosalpinx close to the tube to avoid compromising the blood supply to the ovary.

• 9.
  

  a) F b) F c) F d) T e) T

Laparoscopic treatment of stage I and II endometriosis is associated with an increased pregnancy rate. The pregnancy rate at 36 weeks after surgery, however, was only 30.7%. In addition, a meta-analysis showed that laparoscopic ablation of endometriosis enhances fecundity slightly only (odds ratio 1.66). The effects are, therefore, minimal. In women with unexplained infertility, a randomised-controlled trial showed that laparoscopy did not increase pregnancy rate. The incidence of ectopic pregnancy after IVF is 1.8 %, which is similar to that in the general population. Ovarian endometriomas can be treated by fenestration and ablation or by excision or stripping the ovarian cyst wall. With fenestration, the ovarian cyst wall is left in situ. The 12- and 24-month cumulative pregnancy rates after excision were 50% and 66.7% and after fenestration were about 15% and 23.5%, respectively. Compared with the fenestration technique, excision of the endometrioma is associated with a higher pregnancy rate and a lower recurrence rate. Excision of ovarian endometriomas is associated with reduced ovarian reserve. Almog et al. recently compared the response of operated and non-operated ovaries to gonadotropin stimulation in 38 women with ovarian endometriomas. The antral follicle count, number of dominant follicles, and number of oocytes collected in the operated ovary were significantly lower than in the non-operated ovary. Tsoumpou et al. conducted a meta-analysis involving five studies and compared the outcome of IVF between women who had surgical treatment of endometriomas and untreated women. No difference was found in the pregnancy rate per cycle (OR 0.92, 95% CI: 0.61 to 1.38) between the two groups. Similarly, the IVF clinical pregnancy rate between the treated and the non-treated groups was comparable.

• 10.
  

  a) F b) F c) F d) T e) F

In women younger than 40 years, the procedure is associated with preservation of ovarian function in 88.6% of cases. The tissue becomes functional 3–4 months after transplantation. The graft might last up to 3 years, depending on the amount of ovarian tissue transplanted. The best method for fertility preservation is embryo cryopreservation, followed by oocyte and then ovarian cryopreservation. For pre-pubertal girls, ovarian cryopreservation is the only alternative for fertility preservation. Today, at least 12 live births have resulted from transplantation of frozen-thawed ovarian tissue.

• 11.
  

  a) T b) F c) F d) F e) T

Weight gain is important, as being underweight is associated with increased risk of obstetric complications, such as hyperemesis gravidarum, anaemia, fetal growth restriction and premature delivery. Clomiphene citrate, being an anti-oestrogen, works by reducing the negative feedback and hence enhancing the endogenous gonadotrophin production. Thus, it does not work in women with hypothalamo-pituitary dysfunction. Women with severe hypothalamo-pituitary dysfunction cannot produce luteinising hormone to support normal ovarian steroidogenesis. Therefore, an exogenous gonadotrophin preparation containing some luteinising hormone activity is needed for ovulation induction. Serum FSH can be normal or low in hypogonadotrophin hypogonadism. Pituitary imaging is recommended to exclude intracranial organic pathology, which can be the underlying cause for suppressed hypothalamo-pituitary function.

• 12.
  

  a) T b) T c) F d) F e) F

Weight optimisation can help reduce obstetric complications associated with maternal obesity. In some women, weight reduction alone may result in resumption of spontaneous ovulation. Clomiphene citrate is the recommended first-line medical treatment because of its convenience as an orally active drug with a low side-effect profile and good efficacy. Metformin is not as effective as clomiphene citrate as a first-line treatment on its own. Although an elevated luteinising hormone: FSH ratio, is a classical feature in polycystic ovarian syndrome (PCOS), it is not universally demonstrable in all women with PCOS because of its high variability, and is now not considered as a diagnostic criteria. Laproscopic ovarian drilling is an alternative, but not superior, to gonadotrophin for ovulation induction.

• 13.
  

  a) F b) T c) T d) F e) T

Treatment is not necessary for asymptomatic ovulatory women who have elevated prolactin levels. Macroprolactinaemia is a possible cause of pseudo-hyperprolactinaemia, which has no clinical significance and does not warrant any treatment. Prolactinoma should be excluded if serum prolactin level is significantly elevated (e.g. to over 1000 mIU/L). Borderline hyperprolactinaemia at lower levels may be caused by other factors and should be re-checked before treatment is offered. The aim of treatment is resumption of ovulation, but not ‘normalisation’ of prolactin level per se. Pregnant women are usually recommended to stop dopamine agonists because of the theoretical uncertainty about its safety profile during pregnancy, and that further treatment would serve no clinical role during pregnancy unless for macroprolactinoma, where tumour expansion is a concern.

• 14.
  

  a) F b) F c) F d) T e) F

In prognostic models female factors outweigh male factors and there are few directly treatable causes diagnosed in men. Up until now, no effective treatment or drug has been identified to improve sperm parameters of the spontaneous chance of conception. There may be a place for antioxidant supplementation, but this need to be confirmed in large prospective cost-effectiveness trials. The relation between varicocele and subfertility is unknown, as is the mechanism by which varicocele may affect fertility. Discussion is ongoing whether varicocele in subfertile men should be treated. A Cochrane meta-analysis of eight randomised-controlled trials showed a combined Peto odds ratio of 1.10 (95% CI 0.73 to 1.68), indicating no benefit of varicocele treatment over expectant management in subfertile couples in whom varicocele in the man is the only abnormal finding. Semen analyses do not correlate well with fertility in many cases.

• 15.
  

  a) T b) F c) F d) F e) F

WHO has provided guidelines for the examination of semen samples. Eventually, men with sperm counts below 1 million may father a child, however, these are exceptions to the rule. When more than 1 million motile sperm are harvested after processing, intra-uterine insemination is the first choice treatment. When less than 1 M sperm are available after processing, according to metanalysis, IUI is not a beneficial treatment. Sperm yield after FNA is too low to allow routine cryopreservation.

• 16.
  

  a) T b) T c) F d) T e) T

GnRH agonists administered before starting IVF has been shown to improve the ongoing pregnancy rate in women with and without endometriosis. Due to reduced success rates with IVF as age increases, IVF should be considered sooner rather than later. Cryopreservation of embryos is the most successful and therefore recognized method of fertility preservation.

• 17.
  

  a) T b) T c) T d) F e) F

A recent meta-analysis has indeed shown that clomiphene citrate challenge testing has limited predictive values. Antral follicle count, ovarian volume and blood flow are the parameters used for ultrasound assessment of ovarian reserve. Anti-Müllerian hormone (AMH) and antral follicle count seem to be the two most accurate predictors of ovarian response to controlled ovarian hyperstimulation. There is little variation in AMH levels either within a cycle or between them.

• 18.
  

  a) T b) F c) T d) F e) T

GnRH antagonist administration can be either fixed or flexible depending upon response and pre-cycle characteristics. Fixed protocols are associated with higher pregnancy rates. There is usually profound Gn production suppression but not always. When looking at high-responders, the use of GnRH antagonist has been shown to decrease the incidence of OHSS compared with GnRH-agonist-based IVF protocols.

• 19.
  

  a) T b) F c) T d) T e) T

While age is associated with reduced ovarian reserve it is too variable to be used. A women needs to meet 2/3 of the following: previous history of poor ovarian response (fewer than three oocytes retrieved after a conventional IVF protocol), an abnormal ovarian reserve test – AFC less than five to seven follicles and/or an AMH over 0.5–1.1 ng/ml.

• 20.
  

  a) T b) T c) F d) T e) T

A consistent application of the maximum welfare standard would mean, in practice that, nobody should knowingly and intentionally bring a child into the world in less than ideal circumstances. As ideal circumstances are only seldom present, the overwhelming majority of the population should refrain from procreation and should be denied access to assisted reproductive technology. Although psychosocial development of the children and the quality of parenting in homosexual families do not differ from heterosexual families, significant differences in self-esteem and psychological well-being were found between children in lesbian families and heterosexual families. As these were in favour of lesbian parents, however, followers of the maximum welfare standard should conclude that lesbian parents are ideal, rather than heterosexual parents, and that, therefore, the latter should be excluded from fertility treatment, not the former. People with cancer are unable to attain the maximum welfare standard owing to their illness and because of the uncertainties about the effect of experimental treatments on the health of their children. These concerns are, however, not worrisome enough to exclude them from treatment when the reasonable welfare standard is applied.

• 21.
  

  a) T b) T c) T d) F e) T

Although the ‘no difference’ view is advocated by pro-homosexual researchers, it is based on anti-homosexual presuppositions, namely that differences are expected between homosexual and heterosexual parenting that have an important effect on the welfare of the children. In this sense, it can be regarded as both too pro-homosexual, and too anti-homosexual. Using heterosexual couples as the control group (either to show that there are or that there are not any differences), and interpreting differences as negative and the absence of differences as positive, does not leave much lee-way to find interesting differences (e.g. in the formation of gender identity) that are neither unanimously negative nor positive. Research on homosexual parenting is disproportionately focused on invalidating differences with heterosexual parenting that are proclaimed by opponents of homosexual parenting as being negative. Although the hypothesis is invalidated, it is still at the centre of the research, whereas there are many other interesting hypotheses to consider.

• 22.
  

  a) F b) T c) T d) F e) T

Waiting for the individual’s own initiative is probably the worst strategy possible, especially given the irreversibility of the decision, the limited time-frame in which a decision needs to be taken and the mental state of the individual who has recently been diagnosed with cancer. Some individuals who request fertility preservation may not meet the inclusion criteria for experimental interventions, whereas other individuals may not be aware of their options and need to be actively informed. That the risks are not prohibitively high and the utility is not prohibitively low is the preliminary assessment that clinicians need to make with the welfare of their patient in mind. When there is room within these side constraints for fertility preservation, the individual should be presented with all the possible options and the final decision about whether and which fertility preservation measures should be taken then rests with the individual. The offer of experimental interventions can be justified if established treatments are not a valid option for a given individual. Experimental procedures, however, should only be offered in a research context, the individual should be well aware of the limitations and uncertainties of the interventions, and only those individuals should be recruited for whom there is a reasonable chance of benefit and for whom the risks are minimal.

• 23.
  

  a) T b) T c) T d) T e) T

It is already difficult for adults with cancer to provide a valid informed consent, given the fact that they have recently been diagnosed with cancer, do not have much time to digest all the information about their fertility preservation options, and are faced with many uncertainties about their future. A pre-pubertal child is also legally incompetent to provide an informed consent. The parents can provide an informed consent and the patient can assent or dissent with the intervention, but these are all suboptimal from an ethical perspective as they do not ascertain that the autonomy of the patient is respected. The lack of informed consent is especially troubling when experimental interventions are carried out. On the one hand, allowing experimentation on children (or anyone unable to give his or her consent) might lead to abuses of power. On the other hand, children may lose out on important advances by being excluded from research. As children only have the option of cryopreserving tissue, malignant cells may be present in this tissue and may be reintroduced into the body together with the transplant. These malignant cells are often at times difficult to track down and, currently, no established approach to prevent reintroduction is available.

• 24.
  

  a) T b) F c) F d) F e) F

No difference in malformation rate has been found between the different IVF techniques. The rate of congenital malformations seems to be increased in singleton as well as in multiples.

• 25.
  

  a) T b) F c) T d) T e) T

A damaged nucleus is more likely to result in spurious results than an intact nucleus removed easily. The indication for the procedure seems to be independent of accuracy.

Allele drop out is a major concern for single gene PGD and must be taken into account. Excluding allele drop out necessitates linkage analysis for polymorphic loci on either side of the mutation being tested. Called preferential amplification, this phenomenon is common. Usually this does not interfere with diagnosis, but at the extreme it is indistinguishable from allele drop out. When double-stranded chromosomal break occurs, the DNA encoding one allele is missing. Thus, no amplification can occur.

• 26.
  

  a) T b) F c) F d) T e) T

Polar-body analysis is amenable, providing complementary information to that present in the oocyte. This allows deduction of oocyte genotype or chromosomal number. Although sperm can be analysed, the testing will destroy the gamete. A single blastomere removed from the cleavage stage embryo is indeed the most common approach at present. Trophectoderm biopsy from the 5-day-old blastocyst indeed provides multiple cells from analysis.

• 27.
  

  a) F b) F c) F d) F e) T

Karyotyping does not provide consistent results. FISH was used in many studies but does not provide information on all chromosomes, and is no longer considered current. FISH for all chromosomes is laborious and technically difficult. PCR amplifies discrete pieces of DNA only. Array comparative genome hybridisation is currently favoured, readily excluding aneuploidy for any chromosome.

• 28.
  

  a) F b) T c) F d) T e) F

The pathophysiology of OHSS is characterised by increased capillary permeability. Human chorionic gonadotrophin (hCG) stimulation plays a key role in triggering this syndrome. Severe OHSS is associated with a higher likelihood of pregnancy, and multiple gestations. Late OHSS is more likely to be severe and to last longer than early OHSS. Ovarian hyperstimulation syndrome can be life-threatening. Life-threatening complications of OHSS include renal failure, hypovolaemic shock, adult respiratory distress syndrome, haemorrhage from ovarian rupture, and thromboembolic episodes.

• 29.
  

  a) F b) T c) T d) T e) F

Women at higher risk of developing OHSS include the following: young age, low body weight, polycystic ovarian syndrome, use of GnRH agonists, higher doses of exogenous gonadotrophins, high absolute or rapidly rising serum oestradiol levels, development of multiple follicles during treatment, exposure to hCG, and previous episodes of OHSS.

• 30.
  

  a) F b) T c) F d) T e) T

Strategies for preventing OHSS include the following: avoidance of hCG for luteal support, GnRH antagonist protocol, triggering ovulation by low dose of hCG, GnRH agonist to trigger final oocyte maturation, and cryopreservation of all embryos.