Is early initiation of infertility treatment justified in women over the age of 35 years?

RESEARCH QUESTION: Natural fecundity and the success of IVF and intracytoplasmic sperm injection (ICSI) rate both decrease with age. For this reason, in women older than 35 years, it is generally recommended to start the infertility work-up after only 6 months. This assumption, however, may expose couples to over-diagnosis and over-treatment. DESIGN: A theoretical model aimed at assessing the effects of starting the infertility work-up after 6 rather than 12 months of trying to conceive naturally was developed. The assumptions of the model were as follows: infertile women are treated with IVF/ICSI for up to three cycles; IVF/ICSI success rate at first cycle linearly declines with age (3% per year between the ages of 35 and 45 years); the drop-out rate after the first and second cycle is 18% and 25%, respectively; the relative reduction of the success rate at second and third cycle is 16% and 26%, respectively. RESULTS: Early initiation of treatment moderately improved the cumulative chances of live birth resulting from a full IVF/ICSI programme. This improvement is dependent on age. Specifically, it increased from 2.0% at age 35 years to 3.0% at age 43 years. Conversely, the incremental success rate per single IVF cycle was mainly stable, varying only from 1.4% at age 35 years to 1.3% at age 43 years. CONCLUSIONS: In women older than 35 years, early initiation of the infertility work-up is associated with only a modest increase in the rate of success of IVF/ICSI. In most scenarios, this advantage may compare unfavourably with the chances of natural conception during the 6-month period.

How common is real repeated implantation failure? An indirect estimate of the prevalence.

RESEARCH QUESTION: What is the real prevalence of repeated implantation failure (RIF) and what reliable estimates can be given on the risk of false-positive diagnosis after two or three failed IVF attempts. DESIGN: A recent theoretical model suggested that commonly used definitions (two or three failed IVF attempts in good-prognosis couples) may expose couples to substantial odds of overdiagnosis and overtreatment. This model, however, was theoretical and based on unproven assumptions that the pregnancy rate in the non-RIF population was 30% and the prevalence of RIF was 10%. In the present study, we applied this model to real data to distinguish the real prevalence of RIF and to provide more reliable estimates on the risk of false-positive diagnosis after two or three failed IVF attempts. To this aim, we retrospectively selected 1221 good-prognosis couples and evaluated pregnancy rates up to the third cycle. RESULTS: The clinical pregnancy rate at first, second and third IVF cycle was 52%, 41% and 28%, respectively. A pregnancy rate of 61% was extrapolated in the non-RIF population and 15% among women who had experienced RIF. Therefore, the rate of false-positive diagnoses of RIF after two, three and six failed cycles would be 46%, 25%, and 2%, respectively. CONCLUSIONS: Our analyses show that estimated prevalence of RIF is 15%. The frequently used definition of RIF based on three failed attempts (but not two) in good-prognosis couples seems justified. Physicians, however, should bear in mind that couples may be inappropriately labelled with this condition in one out of four cases.

Repeated implantation failure at the crossroad between statistics, clinics and over-diagnosis.

The most common definition of repeated implantation failure (RIF) is the failure to obtain a clinical pregnancy after three completed IVF cycles. This definition, however, may lead to misuse of the diagnosis. To disentangle this, we set up a mathematical model based on the following main assumptions: rate of success of IVF constant and set at 30%; and RIF postulated to be a dichotomous condition (yes or no) with a prevalence of 10%. On this basis, the expected cumulative chance of pregnancy after three and six cycles was 59% and 79%, respectively. Consequently, the false-positive rate of a diagnosis of RIF is 75% and 51%, respectively. Increasing the rate of success of IVF or the prevalence of RIF lowers but does not make unremarkable the rate of false-positive diagnoses. Overall, this model shows that the commonly used definition of RIF based on three failed attempts in a standard population with good prognosis leads to over-diagnosis and, potentially, to over-treatments.

Oocyte retrieval difficulties in women with ovarian endometriomas.

RESEARCH QUESTION: What are the frequency, characteristics and consequences of technical diffiiculties encountered by physicians when carrying out oocyte retrieval in women with ovarian endometriomas? DESIGN: We prospectively recruited women undergoing IVF and compared technical difficulties between women with (n = 56) and without (n = 227) endometriomas. RESULTS: In exposed women, the cyst had to be transfixed in eight cases (14%, 95% CI 7 to 25%) and accidental contamination of the follicular fluid with the endometrioma content was recorded in nine women (16%, 95% CI 8 to 27%). Moreover, follicular aspiration was more frequently incomplete (OR 3.6, 95% CI 1.4 to 9.6). In contrast, the retrievals were not deemed to be more technically difficult by the physicians and the rate of oocytes retrieved per developed follicle did not differ. No pelvic infections or cyst ruptures were recorded (0%, 95% CI 0 to 5%). CONCLUSIONS: Oocyte retrieval in women with ovarian endometriomas is more problematic but the magnitude of these increased difficulties is modest.

Frozen-thawed blastocyst transfer in natural cycle: feasibility in everyday clinical practice.

PURPOSE: Transfer of frozen-thawed embryos in natural cycle is gaining consensus but evidence on this approach is scanty. The aim of this study is reporting on the feasibility of this type of policy in everyday clinical practice. METHODS: We retrospectively selected all women undergoing the procedure between July 2013 and December 2014. During the study period, women were systematically scheduled for natural cycle if they referred regular menstrual cycles. Hormone replacement therapy (HRT) was conversely prescribed if the woman had irregular menstrual cycles or if the monitoring of the natural cycle failed. The analysis exclusively focussed on the first cycle per woman. RESULTS: Overall, 251 women were selected. HRT was initially chosen in 52 women, leaving 199 women suitable for the natural cycle. This procedure could be performed in 194 of these women (97%, 95% CI 95-99%). Two additional women initially allocated to HRT ultimately performed the blastocyst transfer with natural cycle. Overall, 196 were thus treated with natural cycle (78%, 95% CI 73-83%). The basal characteristics of the women who did and did not undergo natural cycles were similar with the exceptions of serum FSH (p < 0.001) and AMH (p = 0.03). The live birth rate did not also differ (34% versus 31%, p = 0.63). Characteristics of women treated with the natural cycle who did (n = 67) and did not (n = 129) achieve a live birth did not differ. CONCLUSION: Frozen-thawed blastocyst transfer in natural cycle can be successfully performed in the vast majority of women.

Sperm cryopreservation and reproductive outcome in male cancer patients: a systematic review.

This systematic review of the literature reports on the use and effectiveness of sperm banking programmes for cancer patients. Thirty studies with 11798 patients were included. The aggregated rate of use of cryopreserved semen was 8% (95% CI 8 to 9%). A statistically significant correlation emerged between the mean and median duration of follow-up and the rate of use (R(2) = 0.46; P = 0.03). The rate of patients discarding their frozen sample was reported in 11 studies. The aggregated rate was 16% (95% CI 15 to 17%). The rate of patients who used their frozen semen and achieved parenthood was reported in 19 papers. The aggregated rate was 49% (95% CI 44 to 53%). The rate of patients achieving parenthood with the use of frozen sperm is low and, from an economical perspective, the effectiveness of programmes of sperm banking might therefore be questioned. On the other hand, the low rate of patients discarding their frozen samples and the correlation between rate of use and duration of follow-up suggest that the calculated 8% rate of use may be an under-estimation and that cumulative rate of use may be substantially higher. Specific studies are, however, required to clarify this issue.

Oocyte quality in women with thalassaemia major: insights from IVF cycles.

BACKGROUND: Women with thalassaemia major typically experience hypogonadotropic hypogonadism because of the toxic effects of iron overload on the anterior pituitary. Moreover, in affected women, serum anti-Mullerian hormone (AMH) and antral follicle count (AFC) are also shown to be reduced, suggesting that the peripheral excess of iron could also harm the ovarian reserve. To date, the detrimental effects of the disease on oocyte quality have not been investigated. MATERIALS AND METHODS: Women with thalassaemia major who underwent in vitro fertilization (IVF) cycles were retrospectively identified over a 9 years period. They were matched (with a 1:5 ratio) by study period and age to a control group of infertile women undergoing IVF. Embriological variables were compared between the two groups. The primary outcome was the rate of top quality embryos. RESULTS: Twenty-one women with thalassaemia major (exposed group) and 105 controls (unexposed group) were ultimately included. Serum AMH was 0.6 [0.2-1.8] and 1.5 [0.7-3.5] ng/ml, respectively (p = 0.05). AFC was 4 (1-7.5) and 11 (5.5-16), respectively (p < 0.001). The total dose of gonadotropins used was higher in exposed women but the number of retrieved oocytes and oocytes used did not differ. The fertilization rate was higher in exposed compared to unexposed women, being 100% (76-100%) and 75% (50-100%). respectively (p = 0.03). The cleavage rate was also higher, being 75% (39-100%) and 50% (29-64%), respectively (p = 0.04). In contrast, the rate of top quality embryos did not differ, being 20% (0-76%) and 25% (5-50%), respectively (p = 0.98). CONCLUSIONS: Despite lower ovarian reserve, oocyte quality is not significantly affected in women with thalassaemia major.

First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine. OBJECTIVE AND RATIONALE: We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. SEARCH METHODS: We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. OUTCOMES: IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06). WIDER IMPLICATIONS: In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.

Damage to ovarian reserve associated with laparoscopic excision of endometriomas: a quantitative rather than a qualitative injury.

OBJECTIVE: Retrospective studies suggest that laparoscopic excision of endometriomas is associated with a reduced responsiveness to ovarian hyperstimulation. In this study, we prospectively evaluated ovarian response to hyperstimulation in women selected for in vitro fertilization and intracytoplasmic sperm injection cycles who previously underwent laparoscopic enucleation of a monolateral endometrioma. STUDY DESIGN: Operated and contralateral intact ovaries of the same patient were compared in terms of number of follicles, number of oocytes retrieved, fertilization rate, and rate of high-quality embryos. RESULTS: Thirty-eight subjects were included. A reduced number of dominant follicles, oocytes, embryos, and high-quality embryos was observed in the operated gonad. The mean percentage of reduction was 60% (95% confidence interval 38-81%), 53% (95% confidence interval 30-75%), 55% (95% confidence interval 28-81%), and 52% (95% confidence interval 17-87%), respectively. Fertilization rate and rate of good-quality embryos were similar. CONCLUSION: Laparoscopic excision of endometriomas is associated with a quantitative but not a qualitative damage to ovarian reserve.

Timing of intrauterine insemination: where are we?

Correct timing of insemination remains a controversial aspect of IUI cycles associated with ovarian hyperstimulation. Although it is currently believed that insemination at 32-38 hours after hCG administration provides the best results, clinical evidence supporting this conclusion is scarce. Double insemination might be an alternative, effective strategy, but studies on this topic are few, heterogeneous, and controversial.

FSH and folliculogenesis: from physiology to ovarian stimulation.

FSH is a glycoprotein hormone consisting of two peptide subunits. The role of FSH in folliculogenesis is well known: to stimulate the formation of a large pre-ovulatory follicle that, because of its FSH-dependent maturation, is capable of ovulation and forming a corpus luteum in response to the mid-cycle surge of LH. FSH is widely used in ovarian stimulation for assisted reproduction techniques. Ovarian stimulation protocols combine the use of human menopausal gonadotrophin, urinary FSH or recombinant FSH with gonadotrophin-releasing hormone (GnRH) agonists or antagonists in order to increase oocyte number and to avoid premature LH surge. Recently, the availability of recombinant LH has permitted new stimulation protocols, combining recombinant FSH, recombinant LH and GnRH antagonists. Due to the limitations of the new Italian law in terms of the number of oocytes that can be fertilized, protocols with a softer ovarian stimulation are now considered, reducing risk of ovarian hyperstimulation syndrome, multiple pregnancies and emotional and physical burdens on the patients. Long-acting FSH preparations are also under clinical study. Knowledge of the stereochemical three-dimensional structure of FSH and its receptor will allow the study of new non-peptide orally administered molecules that fit the FSH receptors.

Chromosomal segregation in spermatozoa of 14 Robertsonian translocation carriers.

Male carriers of Robertsonian (Rob) translocations can have fertility problems associated with low sperm counts and abnormal sperm morphology. In this study, spermatozoa from 14 Rob translocation carriers, seven der(13;14), two der(13;15), two der(14;15), two der(14;21) and one der(21;22), were tested by fluorescence in-situ hybridization (FISH) for the chromosomes involved, to study meiotic segregation behaviour. It was shown that in each type of Rob translocation, meiotic segregation behaviour is similar, comparable and occurs non-randomly. Most of the spermatozoa results from alternate segregation (range: 76-89.47%). There is, however, still much unbalanced spermatozoa resulting from adjacent segregation mode (range: 10.24-23.41%). These data provide useful information for genetic counselling purposes. Moreover, aneuploidy for chromosomes 13,18, 21, X and Y was studied in five patients and suggested an inter-chromosomal effect.

Effectiveness of sonohysterography in infertile patient work-up: a comparison with transvaginal ultrasonography and hysteroscopy.

OBJECTIVE: The aim of this comparative study was to evaluate the accuracy of transvaginal ultrasonography (TVU), sonohysterography (SHG) with sterile saline solution compared to hysteroscopy in the diagnosis of intrauterine pathology in a population of infertile patients before an in vitro fertilization (IVF) program. PATIENTS/METHODS: 98 infertile patients with a mean age of 33.9 years (range 27-41) underwent TVU assessment and SHG with sterile saline solution immediately followed by hysteroscopy. RESULTS: The clinical findings obtained by TVU, SHG and hysteroscopy were compared. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of TVU and SHG compared to hysteroscopy were calculated. The TVU sensitivity and specificity compared with hysteroscopy were 91 and 83% respectively. Using TVU, a 9.2% false positive rate (9 cases) and a 5.1% false negative rate (5 cases) were detected compared to hysteroscopy. The TVU PPV and NPV were 85.4 and 90% respectively. SHG yielded better results: sensitivity and specificity when compared to hysteroscopy were 98 and 94% respectively. The SHG PPV and NPV were 95 and 98% respectively. Accuracy of SHG was significantly better than TVU considering all intrauterine pathologies and polyps. CONCLUSION: In experienced hands, SHG is an easy, safe, and well-tolerated alternative to diagnostic hysteroscopy in the initial evaluation of uterine cavity infertile patients.

Health-related quality of life and need for IVF in 1000 Italian infertile couples.

BACKGROUND: A specific and still poorly investigated issue in the field of infertility is represented by the impact that the need for IVF techniques may have on health-related quality of life (HRQoL). METHODS: A total of 1000 consecutive couples (1000 women and 1000 men) were invited to complete the Health Survey Short Form (SF-36) questionnaire separately, prior to initiating their first IVF attempt in our unit. Patients were also invited to report about demographic and clinical characteristics. RESULTS: A total of 1936 (96.8%) agreed to participate. Male SF-36 scores were higher than those reported by women. Duration of infertility and previous IVF attempts significantly influenced HRQoL (P < 0.01). When scores were plotted in relation to the normative source of the Italian general population stratified by gender, corresponding age and geographical area, the subjective health profile did not significantly differ from the normative sample for both women and men. CONCLUSION: The need for IVF did not seem to markedly influence subjective health status. Conversely, duration of infertility and failure to achieve a pregnancy through IVF might have a negative impact.

Resumption of fertility with diet in overweight women.

In young women being overweight appears to be one of the major and still neglected causes of subfertility. Not only the excessive amount but also the distribution of body fat is clearly related to loss of fertility. The mechanism through which obesity impairs ovulation and fertility is largely unknown, but it is well known that being overweight lowers the concentration of sex hormone binding globulin and increases androgen and insulin secretion and insulin resistance. These high concentrations of androgen and insulin in turn are important factors in the preferential abnormal localization of body fat. In addition, ovulation induction or ovarian stimulation in overweight women is a not easy task, since these patients are often unresponsive to the stimulatory drugs and, in addition, have a higher rate of miscarriages. Weight reduction improves these patients' biochemical indices and fertility rates. The spontaneous pregnancy rate can be expected to be around 30%, but an additional 40-50% drug-induced pregnancy rate can be achieved with a 10-15% weight loss. Drugs increasing insulin sensitivity also improve spontaneous ovulation and fertility in obese women but still need to be tested in larger controlled trials. In conclusion, appropriate counselling about weight reduction through diets and exercise can restore both health and fertility, avoiding much frustration, and saving time and money.

Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarian physiology and fertility rate induced by diet.

BACKGROUND: This prospective study evaluated the effect of weight reduction on anthropometric indices and ovarian morphology in anovulatory overweight patients with polycystic ovary syndrome (PCOS). METHODS: Thirty-three anovulatory overweight patients with PCOS were enrolled in the study. All had patent Fallopian tubes and chronic anovulation: 27 of them were oligo-amenorrhoeic. The partners were normospermic. Patients were prescribed a 1200 kcal/day diet, and physical exercise was recommended. Anthropometric indices and ovarian imaging parameters were assessed at baseline and after weight loss of 5 and 10%. RESULTS: Twenty-five patients (76%) lost at least 5% of their body weight. Eleven of these patients (33%) reached a 10% decrease in weight. Waist circumference at the umbilical level, hip circumference, four skin folds, body mass index and fatty mass ratio were significantly reduced after 5 and 10% weight loss. Ovarian morphology changed during the diet: we observed a significant reduction in ovarian volume and in the number of microfollicles per ovary. Among the 27 patients with oligo-amenorrhoea, 18 had a resumption of regular cycles and 15 experienced spontaneous ovulation; 10 spontaneous pregnancies occurred in patients who lost at least 5% of their weight. CONCLUSIONS: Weight loss through a controlled low-calorie diet improves anthropometric indices in obese PCOS patients, reduces ovarian volume and microfollicle number and can restore ovulatory cycles, allowing spontaneous pregnancy.