Risk of foetal harm with letrozole use in fertility treatment: a systematic review and meta-analysis.

BACKGROUND: The aromatase inhibitor letrozole is increasingly recommended for ovulation induction, as it is more effective with fewer side-effects than other agents. But many clinicians are reluctant to use the drug for fertility treatment due to a strong-label warning against its use, which warns about congenital malformation risk to the foetus in women seeking pregnancy. OBJECTIVE AND RATIONALE: The aim of this study was to determine the risks of congenital malformations and pregnancy loss with letrozole compared with clomiphene primarily, and with other fertility drugs and natural conception. SEARCH METHODS: A systematic review and meta-analysis using PRISMA harms guidelines. We searched MEDLINE, EMBASE and other sources from inception until January 2020, with the MeSH words for 'letrozole' and pregnancy OR foetal/neonatal outcome. We included studies reported on congenital malformations in foetuses born to mothers conceived after fertility treatment, with letrozole versus clomiphene, placebo, gonadotrophins, metformin, natural conception or other agents, from randomised trials, comparative cohort studies and non-comparative observational cohorts. Quality of the studies was assessed using Cochrane risk of bias tool and Newcastle Ottawa Scale. The McMaster tool was used to assess the quality of reported harm for foetal congenital malformations in the studies. We compared the absolute risk of events using risk difference measures and pooled the findings using a fixed-effect model. We evaluated the statistical heterogeneity using forest plots and the I2 statistic and funnel plot to assess publication bias. We assessed the strength of evidence for congenital malformation and pregnancy loss as per the GRADE recommendations and with the Fragility index. OUTCOMES: We included 46 studies (18 randomised trials; 21 comparative cohorts; 7 non-comparative cohorts). Overall 2.15% (101/4697; 95% CI 1.7 to 2.5) of babies conceived on letrozole for fertility treatment had congenital foetal malformations. We did not observe a significant increase in congenital malformations with letrozole versus clomiphene in the randomised trials (risk difference (RD) 0.01, 95% CI -0.02, 0.03; I2 = 0%; 14 studies) and found a significant reduction in the cohort studies (RD -0.02, 95% CI -0.04, -0.01; I2 = 0%, 11 studies). The fragility index was 44% (7/16) (either an increase in the intervention arm or a decrease in control arm was needed to alter the results). The risks of pregnancy loss were not increased with letrozole versus clomiphene in the 14 randomised trials (RD -0.01, 95% CI -0.06, 0.04; I2 = 0%), and the risks were reduced in the six cohort studies (RD -0.09, 95% CI -0.17, -0.00; I2 = 68%). The GRADE quality of evidence was low to moderate for congenital malformations and pregnancy loss. We did not find any increased congenital malformation risk with letrozole versus gonadotrophins, natural conception or natural cycle ART, but the number of studies was small. WIDER IMPLICATIONS: There is no evidence that letrozole increases the risk of congenital foetal malformation or pregnancy loss compared with clomiphene, natural conception or other fertility agents, to warrant warning against its use. Given its therapeutic benefits and lack of evidence of harm to the foetus, clinicians should consider letrozole as first-line agent for ovulation induction.

Overview of systematic reviews of non-pharmacological interventions in women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a major contributor to subfertility, diabetes and cardiovascular disease in women. The role of non-pharmacological interventions to prevent these outcomes has been reported in many systematic reviews, but robust conclusions have not been made due to variations in the scope, quality and findings of these reviews. OBJECTIVE AND RATIONALE: Our aim was to provide an overview of existing evidence on the effects of non-pharmacological interventions in women with PCOS on fertility and non-fertility outcomes by a review of existing systematic reviews. SEARCH METHODS: We reviewed systematic reviews of randomized trials that have evaluated the effects of non-pharmacological interventions, such as lifestyle interventions, nutritional supplements or alternative medicine therapies in women with PCOS on fertility, endocrine, glycaemic and weight-related outcomes. We assessed the quality of systematic reviews with the AMSTAR tool, and reported the outcomes with regard to: fertility (live birth, clinical pregnancy, ovulation and menstrual cycle regularization); endocrine outcomes (Ferriman-Gallwey score, free androgen index, free testosterone and total testosterone levels); and glycaemic (fasting blood insulin, fasting blood glucose, homoeostatic model assessment) and weight-related (BMI) outcomes. We assessed the strength of evidence for significant outcomes as per the grading of recommendations assessment, development and evaluation (GRADE) system. OUTCOMES: We found twelve eligible systematic reviews which included between three (143 women) and 27 randomized trials (2093 women). Four reviews assessed the effects of lifestyle interventions (diet, physical activity and/or behavioural interventions); four evaluated nutritional supplements (one each on n-acetylcysteine, omega-3 fatty acids, inositol and vitamin D); and four studied alternative medical therapies (Chinese herbal medicine and acupuncture). All of the included reviews were of high quality and scored between 8 and 11 with the AMSTAR tool (with a maximum score of 11).Randomized evidence is lacking for live birth rate. N-acetylcysteine, inositol and the addition of alternative medicine to ovulation induction agents show preliminary potential to improve fertility (odds ratios (OR) for clinical pregnancy rate range from 1.99 to 4.83). Lifestyle interventions show benefits in improving hirsutism (mean difference (MD): -1.01 to -1.19). Lifestyle interventions (MD: -1.10 to -2.02), inositol (MD: -2.1) and acupuncture (MD: -1.90 to -3.43) all show some evidence of improvement in glycaemic outcomes and there is some evidence of reduced BMI with lifestyle interventions (MD: -0.15 to -1.12). All of these outcomes scored either low or very low quality of evidence on the GRADE score. WIDER IMPLICATIONS: Lifestyle interventions in women with PCOS appear to improve glycaemic results, androgenic symptoms and anthropometric outcomes. The role of inositol and N-acetylcysteine in women with PCOS needs further evaluation. Large primary trials on all interventions are needed for an agreed set of core outcomes.

Efficacy and safety of transdermal testosterone in postmenopausal women with hypoactive sexual desire disorder: a systematic review and meta-analysis.

OBJECTIVE: To systematically review and summarize the existing evidence related to the efficacy and safety of transdermal T in postmenopausal women for the treatment of hypoactive sexual desire disorder (HSDD). DESIGN: Systematic reviews and meta-analysis. SETTING: Not applicable. PATIENT(S): Seven randomized controlled trials enrolled 3,035 participants; 1,350 women were randomized to treatment with T patch, and 1,379 women were randomized to placebo. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary outcome: satisfying sexual episodes. SECONDARY OUTCOMES: sexual activity, orgasm, Profile of Female Sexual Function domains (desire), personal distress score, adverse events, acne, increased hair growth, facial hair, alopecia, voice deepening, urinary symptoms, breast pain, headache, site reaction, total adverse events, serious adverse events, withdrawal from study, and follow-up rate. RESULT(S): The T group had significantly more satisfying sexual episodes, sexual activity, orgasms, desire, significant change in Personal Distress Scale score, androgenic adverse events, acne, and hair growth compared with the placebo group. There was no significant difference between the two groups in increase in facial hair, alopecia, voice deepening, urinary symptoms, breast pain, headache, site reaction to the patch, total adverse events, serious adverse events, reasons for withdrawal from the study, and the number of women who completed the study. CONCLUSION(S): The short-term efficacy in terms of improvement of sexual function and safety of transdermal T in naturally and surgically menopausal women affected by HSDD either on or not on estrogen progestin hormone therapy is evident from this systematic review. The use of transdermal T is associated with increase in androgenic adverse events such as acne but is not associated with any serious adverse events.

Hysteroscopy in recurrent in-vitro fertilisation failure (TROPHY): a multicentre, randomised controlled trial.

BACKGROUND: The success rate of in-vitro fertilisation (IVF) remains low and many women undergo multiple treatment cycles. A previous meta-analysis suggested hysteroscopy could improve outcomes in women who have had recurrent implantation failure; however, studies were of poor quality and a definitive randomised trial was needed. In the TROPHY trial we aimed to assess whether hysteroscopy improves the livebirth rate following IVF treatment in women with recurrent failure of implantation. METHODS: We did a multicentre, randomised controlled trial in eight hospitals in the UK, Belgium, Italy, and the Czech Republic. We recruited women younger than 38 years who had normal ultrasound of the uterine cavity and history of two to four unsuccessful IVF cycles. We used an independent web-based trial management system to randomly assign (1:1) women to receive outpatient hysteroscopy (hysteroscopy group) or no hysteroscopy (control group) in the month before starting a treatment cycle of IVF (with or without intracytoplasmic sperm injection). A computer-based algorithm minimised for key prognostic variables: age, body-mass index, basal follicle-stimulating hormone concentration, and the number of previous failed IVF cycles. The order of group assignment was masked to the researchers at the time of recruitment and randomisation. Embryologists involved in the embryo transfer were masked to group allocation, but physicians doing the procedure knew of group assignment and had hysteroscopy findings accessible. Participants were not masked to their group assignment. The primary outcome was the livebirth rate (proportion of women who had a live baby beyond 24 weeks of gestation) in the intention-to-treat population. The trial was registered with the ISRCTN Registry, ISRCTN35859078. FINDINGS: Between Jan 1, 2010, and Dec 31, 2013, we randomly assigned 350 women to the hysteroscopy group and 352 women to the control group. 102 (29%) of women in the hysteroscopy group had a livebirth after IVF compared with 102 (29%) women in the control group (risk ratio 1·0, 95% CI 0·79-1·25; p=0·96). No hysteroscopy-related adverse events were reported. INTERPRETATION: Outpatient hysteroscopy before IVF in women with a normal ultrasound of the uterine cavity and a history of unsuccessful IVF treatment cycles does not improve the livebirth rate. Further research into the effectiveness of surgical correction of specific uterine cavity abnormalities before IVF is warranted. FUNDING: European Society of Human Reproduction and Embryology, European Society for Gynaecological Endoscopy.

Galectin-1 overexpression in endometriosis and its regulation by neuropeptides (CRH, UCN) indicating its important role in reproduction and inflammation.

Endometriosis is an inflammatory disease of women of reproductive age featured by the presence of ectopic endometrium and is strongly related to infertility. Galectins, carbonhydrate-binding proteins, have been found to have pro- or anti-inflammatory roles in the reproductive tract and in pathological conditions concerning infertility. Galectin-1, which is expressed at endometrium and decidua, plays a major role in implantation and trophoblast invasion. Also, the neuropeptides, corticotropin releasing hormone (CRH) and urocortin (UCN) and their receptors are expressed in eutopic and ectopic endometrium showing a differential expression pattern in endometriotic women compared to healthy ones. The aim of this study was to examine the galectin-1 expression in endometriotic lesions and compare its expression in eutopic endometrium of endometriotic and healthy women. Furthermore, we examined the effect of CRH and UCN in galectin-1 expression in Ishikawa cell line and macrophages and investigated the implication of CRHR1 in these responses. Eutopic and ectopic endometrium specimens, Ishikawa cell line and mice macrophages were used. Immunohistochemistry and western blot analysis were performed in order to identify galectin-1 expression in ectopic and eutopic endometrium of women with and without endometriosis and the regulatory effect of CRH and UCN on galectin-1 expression. This study presents for the first time that galectin-1 is overexpressed in endometriotic lesions compared to eutopic endometrium of endometriotic women and is more abundantly expressed in eutopic endometrium of disease women compared to healthy ones. Furthermore, it is shown that CRH and UCN upregulate galectin-1 expression in Ishikawa cell line and macrophages and this effect is mediated through CRHR1. These results suggest that galectin-1 might play an important role in endometriosis pathology and infertility profile of women suffering from endometriosis by being at the same time regulated by CRH and UCN interfering in the immune disequilibrium which characterizes this pathological condition.

Coasting, embryo development and outcomes of blastocyst transfer: a case-control study.

This study compared the effect on blastocyst development and clinical outcome of coasting in women at increased risk of moderate-severe ovarian hyperstimulation syndrome (OHSS; n=389) with a control group matched for age and basal FSH that did not undergo coasting (n=386) in IVF/intracytoplasmic sperm injection (ICSI) cycles. The main outcome measures were rate of blastocyst development and live birth. More cycles progressed to the blastocyst stage in the coasted group (n=169) compared with the control group (n=83; 43.4% versus 21.5%; P<0.001). The biochemical pregnancy, clinical pregnancy and live birth rates were similar (46.5% versus 42.0%; 40.6% versus 37.8%; 31.6% versus 30.1%). The duration of coasting up to 4 days did not affect progression to blastocyst stage. The multivariate model showed that coasting (OR 1.73, P=0.004) and the number of oocytes retrieved (OR 1.17, P=0.001) were positively correlated with blastocyst formation. Coasting, a measure to reduce the risk of OHSS, does not impair blastocyst development or clinical outcome. Coasting should remain an effective measure to prevent OHSS.

Differential expression of CRH, UCN, CRHR1 and CRHR2 in eutopic and ectopic endometrium of women with endometriosis.

Endometriosis is considered as a benign aseptic inflammatory disease, characterised by the presence of ectopic endometrium-like tissue. Its symptoms (mostly pain and infertility) are reported as constant stressors. Corticotropin releasing hormone (CRH) and urocortin (UCN) are neuropeptides, strongly related to stress and inflammation. The effects of CRH and UCN are mediated through CRHR1 and CRHR2 receptors which are implicated in several reproductive functions acting as inflammatory components. However, the involvement of these molecules to endometriosis remains unknown. The aim of this study was to examine the expression of CRHR1 and CRHR2 in endometriotic sites and to compare the expression of CRHR1 and CRHR2 in eutopic endometrium of endometriotic women to that of healthy women. We further compared the expression of CRH, UCN, CRHR1 and CRHR2 in ectopic endometrium to that in eutopic endometrium of women with endometriosis. Endometrial biopsy specimens were taken from healthy women (10 patients) and endometrial and endometriotic biopsy specimens were taken from women with endometriosis (16 patients). Τhe expression of CRH, UCN, CRHR1, and CRHR2 was tested via RT-PCR, immunohistochemistry and Western blotting. This study shows for the first time that CRH and UCN receptor subtypes CRHR1ß and CRHR2α are expressed in endometriotic sites and that they are more strongly expressed (p<0.01) in eutopic endometrium of women with endometriosis compared to healthy women endometrium at the mRNA and protein level. CRH, UCN, CRHR1 and CRHR2 mRNA were also more highly expressed in ectopic rather than eutopic endometrium (CRH, UCN, CRHR2α: p<0.01, CRHR1ß: p<0.05) and protein (CRH and UCN: p<0.05, CRHR1 and CRHR2: p<0.01) in women with endometriosis. These data indicate that CRH and UCN might play an immunoregulatory role in endometriotic sites by affecting reproductive functions such as decidualization and implantation of women with endometriosis.

Can the fall in serum FSH during coasting in IVF/ICSI predict clinical outcomes?

This retrospective cohort study determined whether the total falls in serum FSH and oestradiol concentrations from start to end of coasting in IVF/intracytoplasmic sperm injection could predict clinical outcomes. Ninety-nine cycles, with gonadotrophin-releasing hormone-agonist down-regulation where coasting with serial serum oestradiol and FSH monitoring was adopted due to risk of severe ovarian hyperstimulation syndrome, were consecutively included. The primary clinical outcome was live-birth rate (LBR); other outcomes measured were number of oocytes retrieved and fertilization, implantation and clinical pregnancy rates. LBR for FSH fall>10 IU/l compared with 5-10 and<5 IU/l were 45.4% versus 22.0% and 25.0%, respectively. Mean serum FSH fall was similar with and without live birth (8.4 ± 6.2 versus 7.3 ± 5.0 IU/l) as were mean oestradiol and FSH concentrations on HCG administration, oestradiol fall, percentage fall in FSH/oestradiol and duration of coasting. None of the variables efficiently predicted live birth on regression analysis. The AUC of FSH fall was 0.53 at 11.0 IU/l. Basal FSH, starting and total gonadotrophin dose and duration of coasting were positively correlated with FSH fall. A potentially clinically important association between live birth and FSH fall during coasting was apparent, which requires further evaluation. The purpose of this retrospective cohort study was to determine whether the magnitude of fall in the serum FSH and oestradiol concentrations from start to end of coasting in IVF/intracytoplasmic sperm injection cycles could predict the clinical outcomes. Gonadotrophin-releasing hormone-agonist down-regulated cycles (n=99), where coasting with serial serum oestradiol and FSH monitoring was adopted due to risk of ovarian hyperstimulation, were consecutively included. Live birth was the primary clinical outcome measured; number of oocytes retrieved and fertilization, implantation and clinical pregnancy rates were the other outcomes examined. Live-birth rate tended to be high when FSH fall was >10 IU/l, compared with 5-10 IU/l and <5 IU/l, although not statistically significantly. Mean serum FSH fall were similar in live-birth and no-live-birth cycles (8.4 ± 6.2 versus 7.3 ± 5.0) as were mean oestradiol and FSH concentrations on hCG administration, oestradiol fall, percentage fall in FSH and oestradiol and duration of coasting. None of the variables efficiently predicted live birth. The area under the curve of FSH fall was 0.53. FSH fall of <11.0 IU/l was found to be more likely to predict negative outcome (specificity 84.72%) than predicting positive outcome when FSH fall was >11 IU/l (sensitivity 34.48%). Women's basal FSH, starting and total gonadotrophin dose of ovarian stimulation and duration of coasting had direct positive correlation with the magnitude of FSH fall. A potentially clinically important rise in live birth in association with greater FSH fall during coasting was apparent, which requires further evaluation.

Controlled ovarian hyperstimulation for low responders in in vitro fertilization/intracytoplasmic sperm injection: a low-dose flare protocol.

In this retrospective study of 652 anticipated low response women, the overall clinical outcomes (live birth rate and clinical pregnancy rate [PR]) of low-dose flare (LDF) protocol appeared lower than those of conventional down-regulation (DR) (LDF: 15.1% vs. DR: 20.6% and LDF: 10.3% vs. DR: 17.4%, respectively). The findings that LDF protocol improved the clinical outcome in older women, or when LDF followed an unsuccessful IVF/intracytoplasmic sperm injection (ICSI) cycle with DR (LDF: 19.4% vs. DR: 9.76% and LDF: 13.9% vs. DR: 4.2% respectively), need further evaluation through randomized trials.

The correlation between basal serum follicle-stimulating hormone levels before embryo cryopreservation and the clinical outcome of frozen embryo transfers.

OBJECTIVE: To evaluate the correlation between basal serum FSH level before the fresh IVF/intracytoplasmic sperm injection (ICSI) cycle and the clinical outcome of the subsequent frozen embryo replacement cycles. DESIGN: Retrospective observational study. SETTING: University tertiary referral center, London, United Kingdom. PATIENT(S): Five hundred four consecutive frozen embryo transfer (FET) cycles where serum FSH levels were obtained, on days 1-4 of the cycle before the fresh IVF +/- ICSI cycles. INTERVENTION(S): Frozen-thawed embryo transfer. MAIN OUTCOME MEASURE(S): Clinical pregnancy (CP) and live birth (LB). RESULT(S): Basal serum FSH in 127 women (25.2%) who had a CP was significantly lower compared with that in women who did not have a CP. Multivariate regression analysis showed significant correlation between basal serum FSH levels and clinical pregnancy and a low significance to LB, but there was no statistical significant differences between women who had a CP and those who did not with regard to age, treatment protocol (natural or hormone treatment cycle), or the freeze-thaw interval. The LB rate was higher in natural cycles (n = 71; 21.2%) than in hormone treatment cycles (n = 28; 16.7%). Conceiving in the fresh cycle had a positive influence on the FET outcome. CONCLUSION(S): Basal serum FSH level before fresh IVF/ICSI cycle is inversely correlated to a CP outcome in FET cycles. A trend was present between FSH levels and LB, but this failed to reach statistical significance.

Does measuring early basal serum follicular luteinising [correction of lutinising] hormone assist in predicting in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcome?

BACKGROUND: The aim was to examine the correlation of early follicular serum lutinising hormone (LH) and the clinical outcome of assisted reproduction technique (ART). METHODS: An observational study included 1333 consecutive women undergoing in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). 964 women were having their first cycle of ART. Data were entered prospectively. All women had serum LH measured in the 6 months before the index cycle studied. No repeat cycles were included. The main outcomes measured were clinical pregnancy (CP) and live birth (LB) correlation to serum LH. Forward multivariate stepwise regression analysis was applied, and other statistical tests were used as appropriate. RESULTS: There was non significant correlation between basal serum LH and CP and LB in the polycystic ovary syndrome group (R2 = 0.02, F = 1.7 and P = 0.76) (R2 = 0.01, F = 2.6 and P = 0.77) respectively after adjusting for age, BMI, day of oocyte retrieval, starting dose, total dose of stimulation, type of gonadotrophin used, number of oocytes retrieved, fertilization rate and number of embryos transferred. Other aetiological causes group there was similarly non significant correlation between basal serum LH and CP (R2 = 0.05, F = 13.1 and P = 0.66), nor for LB (R2 = 0.007, F = 4.5 and P = 0.9). CONCLUSION: Early follicular serum LH measurements in the 6 months before IVF/ICSI treatment cycle did not correlate with the clinical pregnancy or the live birth rate.

The management of hydrosalpinges: tubal surgery or salpingectomy?

PURPOSE OF REVIEW: The clinical management of hydrosalpinges in infertile patients remains a contentious issue. This review aims to provide a critical analysis on the available treatments for hydrosalpinges, which have recently created a fierce debate between the promoters of salpingectomy and in-vitro fertilization and those who endorse tubal surgery. RECENT FINDINGS: Hydrosalpinges have a detrimental effect on the outcome of in-vitro fertilization yet their mechanism is still unclear. Salpingectomy prior to in-vitro fertilization restores the likelihood of a successful outcome in a well defined group of patients with ultrasound-visible hydrosalpinges. However, not every woman with large hydrosalpinges should undergo salpingectomy as some fallopian tubes may be amenable to surgical repair. Preserved tubal mucosa indicates a good prognosis for tubal surgery, therefore an appropriate mucosal assessment should be routine prior to deciding upon further management. SUMMARY: As salpingectomy is a definitive procedure it should be performed when the hydrosalpinges are beyond repair or in cases of in-vitro fertilization failure. Tubal surgery should be preferred to salpingectomy in mild to moderate tubal disease. A comparative study of restorative tubal surgery versus salpingectomy and in-vitro fertilization in selected women with hydrosalpinges is needed and will significantly help this debate. Prophylactic salpingectomy prior to in-vitro fertilization and tubal surgery is not competing but complementary in the treatment of hydrosalpinges-related infertility.