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BACKGROUNDThe 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 RATIONALEThe 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 METHODSA 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.OUTCOMESWe 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 IMPLICATIONSThere 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.

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 fetus in women seeking pregnancy. Objective: To determine the risks of congenital malformations and pregnancy loss with letrozole compared with clomiphene primarily, and against other fertility drugs and natural conception. Methods: A systematic review and meta-analysis. Findings: We included 45 studies (18 randomised trials; 20 comparative cohorts; 7 non-comparative cohorts). We did not observe a significant increase in congenital malformations with letrozole vs 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 -0.03, -0.004; I2 = 0%, 10 studies). The risks of pregnancy loss were not increased with letrozole vs 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 vs gonadotrophins, natural conception or natural cycle assisted reproductive technology, but the number of studies was small. Interpretation: There is no evidence that letrozole increases the risk of congenital fetal malformation or pregnancy loss than 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 fetus, clinicians should consider letrozole as first-line agent for ovulation induction. Funding Statement: None. Declaration of Interests: None.

Objective To study the current evidence on the role of immunotherapy in IVF and in the management of recurrent pregnancy loss (RPL). Design Systematic review and meta-analysis. Setting A literature search was performed using MEDLINE, PUBMED, CINAHL, and EMBASE until May 2017. Only randomized controlled trials were included, and a meta-analysis was carried out where appropriate. Patient(s) Women undergoing IVF treatment with or without a history of recurrent implantation failure and women with idiopathic RPL. Intervention(s) Assessment of the efficacy of commonly used immunomodulators such as IV use of [1] immunoglobulin, [2] lymphocyte immunotherapy and [3] intralipid; intrauterine infusion of [4] granulocyte colony-stimulating factor and [5] peripheral blood mononuclear cells; subcutaneous administration of [6] TNF-alpha inhibitors, [7] leukaemia inhibitory factor; and oral administration of [8] glucocorticoids. Main Outcome Measure(s) The primary outcomes were live birth rate and miscarriage rate; secondary outcome was clinical pregnancy rate. Result(s) Of the 7,226 publications identified, 53 were selected during the initial screening; 30 satisfied the selection criteria and were included in this review. Conclusion(s) The available medical literature shows controversial results about the role of immunotherapy when used for improving reproductive outcomes. This study did not show a role for immunotherapy in improving the live birth rate in women undergoing IVF treatment or in the prevention of idiopathic RPL. Currently, immunotherapy should be used in the context of research and should not be used in routine clinical practice to improve reproductive outcomes.

Introduction Intracytoplasmic morphologically selected sperm injection (IMSI) is one of the sperm selection techniques used for assisted reproduction which has been applied for a variety of indications including previously failed fertilization with intracytoplasmic sperm injection (ICSI). A Cochrane review1 found no difference in outcomes between either modality of sperm selection. Since the Cochrane review was published there have been a further two randomized controlled trials comparing IMSI and ICSI. This systematic review and meta-analysis aims to compare IMSI with ICSI as insemination methods regarding live birth rate and miscarriage rate. Material and methods Systematic review of randomized controlled trials, observational studies and similar reviews in electronic databases published before January 2018. Results We found nine randomized controlled trials, evaluating 1610 cycles of in vitro fertilization and 15 observational studies evaluating 1243 cycles of in vitro fertilization. Meta-analysis of the included randomized controlled trials showed no difference in the live birth rate or miscarriage rate between the ICSI and IMSI groups. Meta-analysis of five observational studies showed a significantly higher number of live births in the IMSI group than ICSI group (live birth rate odds ratio 1.47, 95% confidence interval 1.16-4.07), with a moderate degree of heterogeneity (I2 = 41%). Additionally, from six observational studies, a significantly lower miscarriage rate was observed in the IMSI group than in the ICSI group (odds ratio 0.51, 95% confidence interval 0.37-0.70, I2 = 0%). Conclusions Meta-analysis of randomized studies comparing IMSI to ICSI has not shown any difference in live birth rate and miscarriage rate. Meta-analysis of observational studies, which must be interpreted with caution, revealed an increased live birth rate and decreased miscarriage rate with IMSI vs ICSI.

In the lack of evidence consistently supporting the use of continuous vs cyclic oral contraceptives after surgery for endometriosis, we conducted a systematic review and metaanalysis with the objective of comparing a continuous vs a cyclic oral contraceptive schedule administered after surgical excision of ovarian endometriomas. A PubMed, MedLine, and Embase search through December 2014 was conducted, with the use of a combination of key words and text words related to endometrioma, endometriosis, oral contraceptives, oral estroprogestins, laparoscopy, and surgery. Studies directly comparing a continuous vs a cyclic schedule administered after surgical treatment of endometriomas were included, with pain and endometrioma recurrence rates as the primary outcomes. Three reviewers independently assessed methodology and extracted data from selected studies. The primary outcomes were considered pain recurrence (evaluated separately for dysmenorrhea, noncyclic chronic pelvic pain, and dyspareunia) and endometrioma recurrence evaluated at ultrasonography. Dichotomous outcomes from each study were expressed as risk ratio (RR) with a 95% confidence interval (CI). Three randomized clinical trials and 1 prospective controlled cohort study were included, for a total of 557 patients with endometriosis, 343 patients of whom had ovarian endometriomas completing the assigned treatment and follow-up. Lower recurrence rates for dysmenorrhea were obtained with a continuous schedule (RR, 0.24; 95% CI, 0.06–0.91; P = .04). Nonsignificant differences were present for chronic pelvic pain and dyspareunia. A continuous oral contraceptive schedule was associated with a nonsignificant reduction of cyst recurrence rates compared with a cyclic schedule (RR, 0.54; 95% CI, 0.28–1.05; P = .07). A continuous oral contraceptive regimen, as opposed to a cyclic regimen, may be suggested after surgery for endometriomas because of lower dysmenorrhea recurrence rates. Due to the small number and small sample sizes of the included studies, further randomized clinical trials are needed to confirm the findings of the present systematic review. Also, outcomes related to patient satisfaction and quality of life should be addressed.

Men with a body mass index (BMI) of 30 or over are more likely to have reduced fertility and fecundity rates. This systematic review and meta-analysis evaluated the effect of male BMI on IVF and intracytoplasmic sperm injection (ICSI) outcome. An electronic search for published literature was conducted in MEDLINE and EMBASE between 1966 and November 2016. Outcome measures were clinical pregnancy rates (CPR) and live birth rates (LBR) per IVF or ICSI cycle. Eleven studies were identified, including 14,372 cycles; nine reported CPR and seven reported LBR. Pooling of data from those studies revealed that raised male BMI was associated with a significant reduction in CPR (OR 0.78, 95% CI 0.63 to 0.98, P = 0.03) and LBR (OR 0.88, 95% CI 0.82 to 0.95, P = 0.001) per IVF-ICSI treatment cycle. Male BMI could be an important factor influencing IVF-ICSI outcome. More robust studies are needed to confirm this conclusion using standardized methods for measuring male BMI, adhering to the World Health Organization definitions of BMI categories, accounting for female BMI, IVF and ICSI cycle characteristics, including the number of embryos transferred and embryo quality, and use the live birth rate per cycle as primary outcome.

Invasive vulvar cancer has an incidence of 1–2/100 000 women per year and squamous cell carcinoma accounts for approximately 85–90% of all vulvar cancers. Surgery has long been considered as the standard treatment, followed by chemotherapy in case of lymph node involvement. This approach is not only disfiguring, but also carries with it an operative mortality of up to 10%. Several studies have assessed the feasibility of radio-chemotherapy as definitive therapy and/or a neoadjuvant procedure. Nonetheless, combined radio-chemotherapy is associated with considerable toxicity. This study reports our experience with an unconventional schedule of neoadjuvant chemotherapy (topotecan and cisplatin) without radiotherapy in a patient with locally advanced vulvar cancer (International Federation of Gynecology and Obstetrics stage IIIA) who experienced complete clinical remission, followed by minimal surgical treatment.

Study question Is the combined excisional/ablative technique for the treatment of ovarian endometriomas better than the traditional stripping technique in terms of recurrence rate? Summary answer There is no evidence that the combined excisional/ablative technique is better than the traditional stripping technique, as similar recurrence rates were observed for the two techniques. What is known already The stripping technique is associated with better results compared with ablative, non-excisional techniques for the treatment of ovarian endometriomas. Excisional techniques, such as stripping, have, however, been associated with reduced ovarian reserve as evaluated with anti-Mullerian hormone, and surgical techniques that better preserve the ovarian reserve are needed. Study design, size, duration A prospective, multicentre, randomized blinded clinical trial was carried out on 51 patients with bilateral endometriomas larger than 3 cm. For each patient, serving as her own control, one ovary was randomized to the stripping technique and the contralateral to the combined excisional/ablative technique. Patients were enrolled between January 2013 and April 2014. Participants/materials, setting, methods Patients of reproductive age with pelvic pain and/or infertility affected by bilateral endometriomas larger than 3 cm were included (n = 51). The patients underwent laparoscopic removal of endometriomas with two different surgical techniques performed at either side after random assignment: complete removal by stripping on one side versus the combined technique, consisting of partial excisional cystectomy followed by completion with ablative surgery using bipolar coagulation, on the other side. Post-operative follow-up was performed at 1, 3 and 6 months after surgery for the evaluation of endometrioma recurrence (primary outcome) and of antral follicle count (AFC) and ovarian volumes (OVs) to assess ovarian reserve (secondary outcome). Main results and the role of chance Recurrence rates were 5.9% for the stripping technique versus 2.0% for the combined technique (odds ratio 3.00; 95% confidence interval: 0.24-157.5; P = 0.62). AFC in the ovaries treated with the stripping technique did not differ significantly from AFC in ovaries treated with the combined technique at all follow-up visits, whereas OV was significantly lower after the combined technique at the 6-month follow-up visit (P = 0.04). Limitations, reasons for caution A major limitation of this study is the small sample size and particularly for ovarian reserve, the secondary outcome, for which no formal sample size calculation was performed. The lower-than-expected recurrence rates in the present series may be related to the shorter follow-up in our study compared with most studies in the literature. Further studies with larger sample sizes and longer follow-up are needed to confirm the findings of this study. The combined technique using CO2 laser energy instead of bipolar coagulation should also be evaluated. Wider implications of the findings The traditional excisional technique, i.e. the stripping technique, should still be considered the gold standard approach for the surgical treatment of endometriomas. Study funding/competing interests No commercial funding was received. The authors report no relevant conflict of interest. Trial registration number ANZCTR number ACTRN12614000653662. Trial registration date 23 June 2014. Date of first patient's enrolment 1 January 2013.

Objective To evaluate the excised specimen with histologic analysis and to assess the antral follicle count (AFC) at follow-up. This is to determine whether excisional surgery for recurrent endometriomas is more harmful to ovarian tissue and to the ovarian reserve than first surgery. Design Prospective controlled study. Setting University hospital. Patient(s) Consecutive patients with pelvic pain and/or infertility undergoing laparoscopic excision of a monolateral ovarian endometrioma for the first time (17 patients) or for recurrence after previous surgery (11 patients). Intervention(s) Laparoscopic excision of ovarian endometrioma and ultrasonographic evaluation 3 months after surgery. Main Outcome Measure(s) Cyst wall histologic evaluation (specimen thickness, presence and morphology of ovarian tissue) and evaluation of ovarian reserve with AFC and ovarian volumes of both the operated and contralateral, nonoperated ovary at follow-up. Result(s) The cyst wall specimen was significantly thicker in the recurrent endometrioma group than in the first surgery group (1.7 ± 0.3 mm vs. 1.1 ± 0.3 mm). Both main components of the cyst specimen (i.e., endometriosis tissue and ovarian tissue) were more represented in the recurrent endometrioma group than in the first surgery group. At sonographic follow-up, the operated ovary had a significantly lower AFC and volume than the contralateral nonoperated ovary in the recurrent endometrioma group, but not in the primary surgery group. Conclusion(s) Surgery for recurrent endometriomas is associated with evidence of a higher loss of ovarian tissue and is more harmful to the ovarian reserve evaluated by AFC and ovarian volume, if compared with endometriomas operated for the first time. Indications to surgery for recurrent endometriomas should be reconsidered with caution.

A 69-year-old woman had a 4-year history of recurrent giant condylomas (Buschke-Lowenstein tumor) in the anal and perianal regions, with extension to the vulva and vagina. After failure of 3 surgical excisions, one of which was radical, the condition was successfully treated using carbon dioxide laser vaporization and systemic interferon therapy. After 3 years of follow-up, the patient has not experienced a recurrence.

Ludovico Muzii Phone0039 06 4940550Emailludovico.muzii@uniroma1.itChiara di Tucci Chiara Achilli Pierluigi Benedetti Panici Department of Obstetrics and Gynecology,“Sapienza” University ofRome,Viale del Policlinico 155,00161Rome,ItalyThis comment refers to the article available at doi:10.1007/s00404­015­3641­1 and an author’s reply to this comment is available atdoi:10.1007/s00404­015­3780­4.Dear Editor,We read with interest the paper recently published by Zorbas et al. [1].The paper is a systematic review on the use of a continuous versus a cyclicoral contraceptive (OC) schedule after surgery for endometriosis excision.The authors conclude that a continuous OC regimen seems to offersignificant advantages compared to a cyclic regimen. The authors shouldbe commended for their effort to bring new evidences on the issue ofpostoperative management of patients operated for endometriosis.Furthermore, the conclusions of the review seem reasonable, and in fact acontinuous OC schedule is often preferred in the clinical setting.However, in our opinion, there are several issues that limit the conclusionof the study. First of all, the electronic search was incomplete, since onlytwo randomized clinical trials (RCTs) were identified [2, 3], whereas a1,*1111

Purpose Endometriomas are frequently associated with female infertility. In these cases, management options include surgery and IVF. The purpose of the present review is to evaluate current literature on the treatment of endometrioma-associated infertility and to compare the pros and cons of the different therapeutic approaches. Methods Literature search of published studies on the treatment of ovarian endometriomas in infertile patients. Studies were evaluated both on the efficacy of the surgical treatment on postoperative reproductive outcome and on the effect of surgery on the ovarian reserve. Results Pregnancy rates around 50% have been consistently reported after surgery, which compare favorably with those obtained with IVF. Surgery is effective also on associated pain, and the histological evaluation of the excised specimen rules out a possible unexpected ovarian malignancy. Thorough histological analysis of the excised specimen permits the evaluation of the appropriateness of surgery. Conclusions Laparoscopic excision of the ovarian endometrioma in infertile patients should still be considered the treatment of choice, particularly in case of associated pain. Surgery should be performed following appropriate techniques, and by dedicated surgeons, in order to decrease the possible damage to the ovarian reserve that has been recently reported postoperatively.

Invasive vulvar cancer has an incidence of 1-2/100 000 women per year and squamous cell carcinoma accounts for approximately 85-90% of all vulvar cancers. Surgery has long been considered as the standard treatment, followed by chemotherapy in case of lymph node involvement. This approach is not only disfiguring, but also carries with it an operative mortality of up to 10%. Several studies have assessed the feasibility of radio-chemotherapy as definitive therapy and/or a neoadjuvant procedure. Nonetheless, combined radio-chemotherapy is associated with considerable toxicity. This study reports our experience with an unconventional schedule of neoadjuvant chemotherapy (topotecan and cisplatin) without radiotherapy in a patient with locally advanced vulvar cancer (International Federation of Gynecology and Obstetrics stage IIIA) who experienced complete clinical remission, followed by minimal surgical treatment.

Objective Obese patients are at greater risk of gynaecologic surgery. Laparotomy is generally performed, even though this approach is regarded as highly invasive, whereas laparoscopy, though minimally invasive, is relatively contraindicated because of the high conversion rates to laparotomy. In light of this, we propose laparoscopically guided transverse minilaparotomy (LGTM) as a minimally invasive alternative technique. The rationale of diagnostic laparoscopy is to evaluate the feasibility of a minimally invasive approach. We have evaluated the feasibility and compared the outcomes with a historical group treated with laparotomy (LPTM), in morbidly obese patients (MOP) subjected to gynaecologic surgery. Study design From November 2004, MOPs with body mass index (BMI) ≥40 kg/m 2 and admitted for gynaecologic surgery (early stage endometrial cancer and benign disease) were enrolled in this observational study and submitted to LGTM. Patients with a uterine size greater than the umbilical transverse line and with indication for vaginal surgery were excluded operative data and outcome were prospectively recorded. Results LGTM was feasible in 34 cases (87%) out of 39. In two women, the procedure was aborted due to intraperitoneal and ovarian malignant disease spread diagnosed at laparoscopy. In three cases, conversion was necessary due to severe adhesions in one case; laparoscopically unrecognized disease spread in the parametria in the second, and in the remaining case a right common iliac vein injury during lymphadenectomy. When compared to LPTM, haemoglobin drop and postoperative stay were significantly reduced with LGTM. Complications were higher in the control group: due to a significantly higher incidence of wound dehiscence (OR 0.27, 95% CI 0.05–1.32, p Conclusions LGTM is feasible in the vast majority of MOPs and achieves significantly better results when compared to the standard approach.

Cervical carcinoma is the second most common malignant disease worldwide, often occurring in young women who have not completed childbearing. In this era of emphasis on conservative treatments, management of cervical cancer could be influenced by patient desire to preserve fertility, maintaining the uterine corpus. Herein is reported the case of a young woman with locally advanced cervical cancer that was successfully treated using neoadjuvant chemotherapy followed by simple vaginal trachelectomy and laparoscopic lymphadenectomy. The success of such an approach, which is not the standard of care in this disease, suggests that additional studies should be performed in a selected population.