The effectiveness of prolonged downregulation with gonadotrophin-releasing hormone analogue (GnRHa) treatment in women with adenomyosis undergoing IVF/ICSI: A systematic review and meta-analysis.

IMPORTANCE: Adenomyosis can reduce the chance of clinical pregnancy in women undergoing assisted conception. Treatment with prolonged gonadotrophin-releasing hormone analogue (GnRHa) downregulation prior to IVF/ICSI has been postulated to improve pregnancy outcomes. OBJECTIVE: We aimed to evaluate the effectiveness and safety of prolonged GnRHa treatment (minimum one month) versus no pre-treatment in women with adenomyosis undergoing IVF/ICSI using a systematic review and meta-analysis. DATA SOURCES: We searched electronic databases: Embase (OVID), MEDLINE® (OVID), APA PsycInfo (OVID), Maternity & Infant Care Database (MIDIRS (OVID), HMIC Health Management Information Consortium (OVID) and ClinicalTrials.gov from inception until 27th of March 2023. STUDY SELECTION AND SYNTHESIS: We included studies that reported on women with adenomyosis receiving GnRHa to down-regulate the hypothalamic-pituitary-ovarian axis for one to six months before IVF/ICSI. We pooled data using the Haensel-Mantel method and reported using Odds Ratio (OR) with 95 % confidence intervals (CI). We assessed the quality of included studies using the Newcastle-Ottowa Scale and confidence in evidence using the GRADE criteria. Bias analysis was conducted via the Cochrane recommended tool (RevMan Web, Academic License). MAIN OUTCOMES AND RESULTS: We screened 365 citations and eight retrospective studies were included in the meta-analysis (n = 2422 women). The median age was 34 years [IQR 31.95-35.05], median BMI 21.30 kg/m2 [IQR 21.05-23.55] and median duration of GnRHa downregulation was 2.5 months [Range 1-4; IQR 1.37-3]. Women with adenomyosis receiving prolonged GnRHa treatment had a higher implantation rate 1/OR 1.69 [95 % CI 1.09, 2.56], I2 = 81 %, (P = 0.02) and clinical pregnancy rate 1/OR 1.42 [95 % CI 1.03, 2.0], I2 70 %, P = 0.03. There was no overall difference in live birth rate 1/OR 1.12 [95 % CI 0.70, 1.79], I2 = 78 %, p = 0.63), miscarriage rate 1/OR 0.92 [95 % CI 0.63, 1.28, P = 0.61, I2 0 % or mean number of oocytes retrieved (10 oocytes [IQR 8.95; 11.15] vs. 9.28 [IQR 8; 10.20], p = 0.22) between groups. CONCLUSIONS AND RELEVANCE: The benefit of prolonged GnRHa treatment in women with adenomyosis undergoing assisted conception treatment is uncertain based on existing retrospective studies. Implantation and clinical pregnancy rates were higher following prolonged downregulation in this population, though there was no statistically significant difference in live birth and miscarriage rates. Given the limited, low-quality existing data, there is a need for a well-designed, prospective randomised controlled trial to precisely evaluate the effectiveness of prolonged GnRHa treatment in this population.

Comparison of luteal support protocols in fresh IVF/ICSI cycles: a network meta-analysis.

Despite the proven superiority of various luteal phase support protocols (LPS) over placebo in view of improved pregnancy rates in fresh cycles of IVF (in vitro fertilization) and ICSI (intracytoplasmic sperm injection) cycles, there is ongoing controversy over specific LPS protocol selection, dosage, and duration. The aim of the present study was to identify the optimal LPS under six core aspects of ART success, clinical pregnancy, live birth as primary outcomes and biochemical pregnancy, miscarriage, multiple pregnancy, ovarian hyperstimulation syndrome (OHSS) events as secondary outcomes. Twelve databases, namely Embase (OVID), MEDLINE (R) (OVID), GlobalHealth (Archive), GlobalHealth, Health and Psychosocial Instruments, Maternity & Infant Care Database (MIDIRS), APA PsycTests, ClinicalTrials.gov, HMIC Health Management Information Consortium, CENTRAL, Web of Science, Scopus and two prospective registers, MedRxiv, Research Square were searched from inception to Aug.1st, 2023, (PROSPERO Registration: CRD42022358986). Only Randomised Controlled Trials (RCTs) were included. Bayesian network meta-analysis (NMA) model was employed for outcome analysis, presenting fixed effects, odds ratios (ORs) with 95% credibility intervals (CrIs). Vaginal Progesterone (VP) was considered the reference LPS given its' clinical relevance. Seventy-six RCTs, comparing 22 interventions, and including 26,536 participants were included in the present NMA. Overall CiNeMa risk of bias was deemed moderate, and network inconsistency per outcome was deemed low (Multiple pregnancy χ2: 0.11, OHSS χ2: 0.26), moderate (Clinical Pregnancy: χ2: 7.02, Live birth χ2: 10.95, Biochemical pregnancy: χ2: 6.60, Miscarriage: χ2: 11.305). Combinatorial regimens, with subcutaneous GnRH-a (SCGnRH-a) on a vaginal progesterone base and oral oestrogen (OE) appeared to overall improve clinical pregnancy events; VP + OE + SCGnRH-a [OR 1.57 (95% CrI 1.11 to 2.22)], VP + SCGnRH-a [OR 1.28 (95% CrI 1.05 to 1.55)] as well as live pregnancy events, VP + OE + SCGnRH-a [OR 8.81 (95% CrI 2.35 to 39.1)], VP + SCGnRH-a [OR 1.76 (95% CrI 1.45 to 2.15)]. Equally, the progesterone free LPS, intramuscular human chorionic gonadotrophin, [OR 9.67 (95% CrI 2.34, 73.2)] was also found to increase live birth events, however was also associated with an increased probability of ovarian hyperstimulation, [OR 1.64 (95% CrI 0.75, 3.71)]. The combination of intramuscular and vaginal progesterone was associated with higher multiple pregnancy events, [OR 7.09 (95% CrI 2.49, 31.)]. Of all LPS protocols, VP + SC GnRH-a was found to significantly reduce miscarriage events, OR 0.54 (95% CrI 0.37 to 0.80). Subgroup analysis according to ovarian stimulation (OS) protocol revealed that the optimal LPS across both long and short OS, taking into account increase in live birth and reduction in miscarriage as well as OHSS events, was VP + SCGnRH-a, with an OR 2.89 [95% CrI 1.08, 2.96] and OR 2.84 [95% CrI 1.35, 6.26] respectively. Overall, NMA data suggest that combinatorial treatments, with the addition of SCGnRH-a on a VP base result in improved clinical pregnancy and live birth events in both GnRH-agonist and antagonist ovarian stimulation protocols.

Assisted reproduction and congenital malformations: A systematic review and meta-analysis.

Prior studies have explored the links between congenital anomalies and assisted reproduction techniques, among other factors. However, it remains unclear whether a particular technique harbors an inherent risk of major congenital anomalies, either cumulatively or in an organ-specific manner. A meta-analysis was conducted using relevant studies from inception to February 2023 using six databases and two appropriate registers. Sources of heterogeneity were explored using sub-group analysis, using study weight, risk of bias and geographical location of original studies. Neonates conceived through assisted reproduction appear to have a higher risk of major congenital anomalies compared to naturally conceived neonates, OR 0.67 [95% CI 0.59, 0.76], I2 = 97%, p < 0.00001, with neonates conceived through intracytoplasmic sperm injection (ICSI) at a 9% higher chance of being affected in comparison to neonates conceived through in vitro fertilization (IVF). The increase in cardiac, gastrointestinal (GI), and neurological congenital anomalies appears to be independent of the assisted reproduction technique, while urogenital and musculoskeletal (MSK) anomalies were found to be increased in ICSI compared with IVF, OR 0.83 [95% CI 0.69, 0.98]; p = 0.03, I2 = 0%, and OR 0.65 [95% CI 0.49, 0.85]; p = 0.002, I2 = 80%, respectively. Neonates conceived using assisted reproduction techniques appear to be at higher risk of major congenital anomalies, with a higher risk attributable to conception using ICSI. The increase in cardiac, neurological, and GI congenital anomalies does not appear to be technique-specific, while the opposite held true for urogenital and MSK anomalies.

Effectiveness of progesterone rescue in women presenting low circulating progesterone levels around the day of embryo transfer: a systematic review and meta-analysis.

IMPORTANCE: Over the last decade, frozen embryo transfer (FET) has been increasingly used in contemporary fertility units. Despite the rapid increase in FET, there is still insufficient evidence to recommend an optimized protocol for endometrial preparation especially in patients with lower progesterone (P4) levels. Previous studies have concluded that P4 levels <10 ng/mL are associated with poorer pregnancy outcomes than those reported with high levels of circulating P4. OBJECTIVE: To identify whether rescue P4 dosing in patients with low P4 can salvage adverse outcomes associated with low P4 levels, resulting in outcomes comparable to patients with adequate progesterone. DATA SOURCES: The study was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-analyses guidelines and prospectively registered under the PROSPERO database (CRD42022357125). Six databases (Embase, MEDLINE, APA PsycInfo, Global Health, HMIC Health Management Information Consortium, and Google Scholar) and 2 additional sources were searched from inception to August 29, 2022. STUDY SELECTION AND SYNTHESIS: Prospective and retrospective cohort studies, reporting the association between rescue progesterone and one or more pregnancy outcomes, were included. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS), while the quality of evidence by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. Summative and subgroup data as well as heterogeneity were generated by the Cochrane platform RevMan (V. 5.4). MAIN OUTCOME MEASURE(S): To compare ongoing pregnancy rate as primary outcome and clinical pregnancy rate, miscarriage rate, and live birth rate as secondary outcomes between patients with low (<10 ng/mL) receiving rescue progesterone vs. those with adequate levels of P4 (≥10 ng/mL). RESULT(S): Overall, 7 observational studies were included in the analysis, with a total of 5927 patients of median age 34 (interquartile range [IQR]: 31.55, 37.13). Overall, patient group comparison, namely those with low P4 that received a rescue dose and those with adequate P4 levels, did not yield significant differences for either the primary or secondary outcomes. For ongoing clinical pregnancy, patients with low P4 receiving the rescue dose vs. those with adequate P4 levels was odds ratio (OR) 0.98 (95% CI: 0.78, 1.24; P = .86, I2: 41%), whereas for miscarriage events, OR was 0.98 (95% CI: 0.81, 1.17; P = .80, I2: 0). Equally, for clinical pregnancy, OR was 0.91 (95% CI: 0.78, 1.06; P = .24; I2: 33%), and for live birth, OR was 0.92 (95% CI: 0.77, 1.09; P = .33; I2: 43%). Subgroup analysis on the basis or rescue administration route successfully explained summative heterogeneity. CONCLUSION(S): Rescue P4 dosing in patients with low P4 results in ongoing pregnancy rate, clinical pregnancy and live birth rates were comparable to those of patients with adequate P4 levels. However, robust randomized controlled trials assessing rescue treatment in women with low P4 are needed to confirm these findings. Rescue P4 in patients with low circulating P4 around embryo transfer day may result in reproductive outcomes comparable to those with adequate P4 levels. STUDY REGISTRATION: CRD42022357125 (PROSPERO).

Fertility preservation provision in the NHS: a national assessment of care policies.

Fertility preservation has gained momentum in recent years. As cancer survival rates improve, late effects of loss of gonadal function have increased the need to consider fertility preservation. NICE recommends offering cryopreservation of gametes or embryos to patients undergoing gonadotoxic therapy, highlighting that this should be extrapolated to those with non-malignant conditions that pose a risk to fertility. We investigated whether variation in fertility preservation provision exists across the United Kingdom, with a view to identifying equitable models of provision. In England, cryopreservation of gametes and embryos is funded for all patients undergoing treatment for cancer, but eligibility criteria and duration of storage funding vary widely. In Scotland, a national policy is applied, with health boards equitably providing funding for cryopreservation of gametes, embryos, and ovarian and testicular tissue for those undergoing treatment for benign and malignant conditions which impair fertility, including gender incongruence. In Wales and Northern Ireland, cryopreservation of gametes and embryos is funded for those undergoing treatment likely to make them infertile, but ovarian tissue cryopreservation is not funded. Funding criteria for fertility preservation in England, Wales, and Northern Ireland deviates from NICE guidance. Standardization of fertility preservation policies is needed to provide equity of access for patients.

SARS-CoV-2 infection in the first trimester and the risk of early miscarriage: a UK population-based prospective cohort study of 3041 pregnancies conceived during the pandemic.

STUDY QUESTION: Does maternal infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the first trimester affect the risk of miscarriage before 13 week's gestation? SUMMARY ANSWER: Pregnant women with self-reported diagnosis of SARS-CoV-2 in the first trimester had a higher risk of early miscarriage. WHAT IS KNOWN ALREADY: Viral infections during pregnancy have a broad spectrum of placental and neonatal pathology. Data on the effects of the SARS-CoV-2 infection in pregnancy are still emerging. Two systematic reviews and meta-analyses reported an increased risk of preterm birth, caesarean delivery, maternal morbidity and stillbirth. Data on the impact of first trimester infection on early pregnancy outcomes are scarce. This is the first study, to our knowledge, to investigate the rates of early pregnancy loss during the SARS-CoV-2 outbreak among women with self-reported infection. STUDY DESIGN, SIZE, DURATION: This was a nationwide prospective cohort study of pregnant women in the community recruited using social media between 21 May and 31 December 2020. We recruited 3545 women who conceived during the SARS-CoV-2 pandemic who were <13 week's gestation at the time of recruitment. PARTICIPANTS/MATERIALS, SETTING, METHODS: The COVID-19 Contraception and Pregnancy Study (CAP-COVID) was an on-line survey study collecting longitudinal data from pregnant women in the UK aged 18 years or older. Women who were pregnant during the pandemic were asked to complete on-line surveys at the end of each trimester. We collected data on current and past pregnancy complications, their medical history and whether they or anyone in their household had symptoms or been diagnosed with SARS-CoV-2 infection during each trimester of their pregnancy. RT-PCR-based SARS-CoV-2 RNA detection from respiratory samples (e.g. nasopharynx) is the standard practice for diagnosis of SARS-CoV-2 in the UK. We compared rate of self-reported miscarriage in three groups: 'presumed infected', i.e. those who reported a diagnosis with SARS-CoV-2 infection in the first trimester; 'uncertain', i.e. those who did not report a diagnosis but had symptoms/household contacts with symptoms/diagnosis; and 'presumed uninfected', i.e. those who did not report any symptoms/diagnosis and had no household contacts with symptoms/diagnosis of SARS-CoV-2. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 3545 women registered for the CAP-COVID study at <13 weeks gestation and were eligible for this analysis. Data for the primary outcome were available from 3041 women (86%). In the overall sample, the rate of self-reported miscarriage was 7.8% (238/3041 [95% CI, 7-9]). The median gestational age (GA) at miscarriage was 9 weeks (interquartile range 8-11). Seventy-seven women were in the 'presumed infected' group (77/3041, 2.5% [95% CI 2-3]), 295/3041 were in the uncertain group (9.7% [95% CI 9-11]) and the rest in the 'presumed uninfected' (87.8%, 2669/3041 [95% CI 87-89]). The rate of early miscarriage was 14% in the 'presumed infected' group, 5% in the 'uncertain' and 8% in the 'presumed uninfected' (11/77 [95% CI 6-22] versus 15/295 [95% CI 3-8] versus 212/2669 [95% CI 7-9], P = 0.02). After adjusting for age, BMI, ethnicity, smoking status, GA at registration and the number of previous miscarriages, the risk of early miscarriage appears to be higher in the 'presumed infected' group (relative rate 1.7, 95% CI 1.0-3.0, P = 0.06). LIMITATIONS, REASONS FOR CAUTION: We relied on self-reported data on early pregnancy loss and SARS-CoV-2 infection without any means of checking validity. Some women in the 'presumed uninfected' and 'uncertain' groups may have had asymptomatic infections. The number of 'presumed infected' in our study was low and therefore the study was relatively underpowered. WIDER IMPLICATIONS OF THE FINDINGS: This was a national study from the UK, where infection rates were one of the highest in the world. Based on the evidence presented here, women who are infected with SARS-CoV-2 in their first trimester may be at an increased risk of a miscarriage. However, the overall rate of miscarriage in our study population was 8%. This is reassuring and suggests that if there is an effect of SARS-CoV-2 on the risk of miscarriage, this may be limited to those with symptoms substantial enough to lead to a diagnostic test. Further studies are warranted to evaluate a causal association between SARS-CoV-2 infection in early pregnancy and miscarriage risk. Although we did not see an overall increase in the risk of miscarriage, the observed comparative increase in the presumed infected group reinforces the message that pregnant women should continue to exercise social distancing measures and good hygiene throughout their pregnancy to limit their risk of infection. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by a grant from the Elizabeth Garrett Anderson Hospital Charity (G13-559194). The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. J.A.H. is supported by an NIHR Advanced Fellowship. A.L.D. is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support to J.A.H. and A.L.D. as above; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: N/A.

Interventions to optimize embryo transfer in women undergoing assisted conception: a comprehensive systematic review and meta-analyses.

BACKGROUND: Several interventions and techniques are suggested to improve the outcome of embryo transfer (ET) in assisted conception. However, there remains no consensus on the optimal practice, with high variations among fertility specialists. OBJECTIVE AND RATIONALE: We conducted a comprehensive systematic review and meta-analyses of randomized controlled trials (RCTs) aiming to identify effective interventions that could be introduced around the time of ET to improve reproductive outcomes. SEARCH METHODS: We searched the electronic databases (MEDLINE, EMBASE and Cochrane CENTRAL) from inception until March 2021 using a multi-stage search strategy of MeSH terms and keywords, and included all RCTs that evaluated an intervention in the 24-h period before/after ET in women undergoing IVF/ICSI. Our primary outcome was clinical pregnancy rate post-ET confirmed as viable pregnancy on ultrasound scan. We assessed the risk of bias in included trials and extracted data in duplicate. We pooled data using a random-effect meta-analysis and reported using risk ratio (RR) with 95% CI. We explored publication bias and effect modifiers using subgroup analyses. OUTCOMES: Our search yielded 3685 citations of which we included 188 RCTs (38 interventions, 59 530 participants) with a median sample size of 200 (range 26-1761). The quality of included RCTs was moderate with most showing a low risk of bias for randomization (118/188, 62.8%) and attrition (105/188, 55.8%) but there was a significant risk of publication bias (Egger's test P = 0.001). Performing ET with ultrasound guidance versus clinical touch (n = 24, RR 1.265, 95% CI 1.151-1.391, I2 = 38.53%), hyaluronic acid versus routine care (n = 9, RR 1.457, 95% CI 1.197-1.261, I2 = 46.48%) and the use of a soft versus hard catheter (n = 27, RR 1.122, 95% CI 1.028-1.224, I2 = 57.66%) led to higher clinical pregnancy rates. Other pharmacological add-ons also showed a beneficial effect including granulocyte colony-stimulating factor (G-CSF: n = 4, RR 1.774, 95% CI 1.252-2.512, I2 = 0), Atosiban (n = 7, RR 1.493, 95% CI 1.184-1.882, I2 = 68.27%) and hCG (n = 17, RR 1.232, 95% CI 1.099-1.382, I2 = 57.76%). Bed rest following ET was associated with a reduction in clinical pregnancy (n = 6, RR 0.857, 95% CI 0.741-0.991, I2 = 0.01%). Other commonly used interventions, such as non-steroidal anti-inflammatory drugs, prophylactic antibiotics, acupuncture and cervical mucus removal, did not show a significant benefit on reproductive outcomes. Our effect estimates for other important outcomes, including miscarriage and live birth, were limited by the varied reporting across included RCTs. WIDER IMPLICATIONS: Using ultrasound guidance, soft catheters and hyaluronic acid at the time of ET appears to increase clinical pregnancy rates. The use of Atosiban, G-CSF and hCG showed a trend towards increased clinical pregnancy rate, but larger trials are required before adopting these interventions in clinical practice. Bed rest post-ET was associated with a reduction in clinical pregnancy and should not be recommended.

Impact of the SARS-CoV-2 pandemic on access to contraception and pregnancy intentions: a national prospective cohort study of the UK population.

OBJECTIVE: Evaluate the impact of the COVID-19 pandemic on access to contraception and pregnancy intentions. DESIGN: Nationwide prospective cohort study. SETTING: United Kingdom. PARTICIPANTS: Women in the UK who were pregnant between 24 May and 31 December 2020. MAIN OUTCOME MEASURES: Access to contraception and level of pregnancy intentions, using the London Measure of Unplanned Pregnancy (LMUP) in women whose last menstrual period was before or after 1 April 2020. While the official date of the first UK lockdown was 23 March, we used 1 April to ensure that those in the post-lockdown group would have faced restrictions in the month that they conceived. RESULTS: A total of 9784 women enrolled in the cohort: 4114 (42.0%) conceived pre-lockdown and 5670 (58.0%) conceived post-lockdown. The proportion of women reporting difficulties accessing contraception was higher in those who conceived after lockdown (n=366, 6.5% vs n=25, 0.6%, p<0.001) and continued to rise from March to September 2020. After adjusting for confounders, women were nine times more likely to report difficulty accessing contraception after lockdown (adjusted odds ratio (aOR) 8.96, 95% CI 5.89 to 13.63, p<0.001). There is a significant difference in the levels of pregnancy planning, with higher proportions of unplanned (n=119, 2.1% vs n=55, 1.3%) and ambivalent pregnancies (n=1163, 20.5% vs n=663, 16.1%) and lower proportions of planned pregnancies (n=4388, 77.4% vs n=3396, 82.5%) in the post-lockdown group (p<0.001). After adjusting for confounders, women who conceived after lockdown were still significantly less likely to have a planned pregnancy (aOR 0.88, 95% CI 0.79 to 0.98, p=0.025). CONCLUSIONS: Access to contraception in the UK has become harder during the COVID-19 pandemic and the proportion of unplanned pregnancies has almost doubled.

Effectiveness of modified downregulation for women with moderate and severe adenomyosis of the uterus prior to frozen thawed embryo transfer (MODA) study protocol: a pragmatic randomised-controlled trial.

INTRODUCTION: Adenomyosis can adversely reduce chances of pregnancy in couples undergoing assisted conception. We aim to evaluate the effect of two different downregulation protocols on the reproductive outcomes in women with moderate and severe adenomyosis undergoing frozen-thawed embryo transfer (FTET). METHODS AND ANALYSIS: We will conduct a two-armed pragmatic randomised clinical trial comparing modified downregulation with gonadotrophin-releasing hormone (GnRH) analogue for 6 weeks to standard downregulation with GnRH analogue for 1 week prior to FTET. Our primary outcome is clinical pregnancy, defined as a viable intrauterine pregnancy confirmed by ultrasound at greater than 6 weeks gestation, with other secondary reproductive, neonatal and safety outcomes. We aim to randomise 162 patients over 3 years to achieve 80% power for detecting a 20% difference in the primary outcome at 5% significance. ETHICS AND DISSEMINATION: To date there is no consensus on the optimal protocol for management of subfertile women with adenomyosis. Modified downregulation could improve the clinical pregnancy rate by reducing the endometrial inflammatory reaction and/or myometrial contractility and their impact on uterine receptivity in women with moderate and severe adenomyosis of the uterus undergoing FTET. The MODA trial is designed to offer pragmatic, real-life evaluation of the optimal protocol for downregulation for this population during assisted conception treatments. Our findings will be published in peer-reviewed journals and presented at national and international scientific meetings and congresses. Ethical approval was granted by the NHS Research Ethics Committees (19/LO/1567). TRIAL REGISTRATION NUMBER: NCT03946722.

Paternal age over 50 years decreases assisted reproductive technology (ART) success: A single UK center retrospective analysis.

INTRODUCTION: To study whether paternal age exerts an effect, independent of maternal age, on the outcomes of fresh in vitro fertilization/ intracytoplasmic sperm injection (IVF/ICSI) cycles. Semen quality deteriorates with increasing paternal age; however, there is conflicting evidence for any impact paternal age may have on the outcome of IVF/ICSI. Several retrospective and prospective cohort studies have shown that paternal age increases the miscarriage rate and reduces the live birth rate. Some studies have shown no effect of paternal age on live birth rate or miscarriage rate. Studies involving donor oocytes have tended to show no independent effect of paternal age on assisted reproductive technology (ART) outcomes. The age at which paternal age may exert a significant deleterious effect on outcome is not known and there is no limit to paternal age in IVF/ICSI treatment. MATERIAL AND METHODS: A single-center retrospective cohort study was carried out at the Centre for Reproductive and Genetic Health, London, UK. Included in the analysis were all couples with primary or secondary infertility undergoing IVF/ICSI cycles in which the male partner produced a fresh semen sample and the cycle proceeded to fresh embryo transfer. All cycles of IVF/ICSI that used donor oocytes-donor sperm, frozen sperm, cycles leading to embryo storage and cycles including preimplantation genetic testing (PGT-A/PGT-M)-were excluded from analysis. The primary outcome was live birth rate and secondary outcomes were clinical pregnancy rate and miscarriage rate. Multivariate logistic regression analysis with live birth as a dependent variable and maternal and paternal age class as independent variables was performed. RESULTS: During the study period there were 4833 cycles, involving 4271 men, eligible for analysis; 1974/4833 (40.8%, 95% confiene intervals [CI] 39.5-42.2%) cycles resulted in a live birth. A significantly lower proportion of men over 51 years met World Health Organization semen analysis criteria (56/133, [42.1%, 95% CI 34.1-50.6]) compared with men under 51 years of age (2530/4138 [61.1%, 95% CI 60.0-62.6]) (p = 0.001). Both maternal and paternal age were retained in the multivariate model and for all maternal age subgroups the probability of live birth decreased with paternal age over 50 years (odds ratio [OR] 0.674, 95% CI 0.482-0.943) (p = 0.021). Paternal age over 50 years was not an independent predictor of miscarriage (OR 0.678, 95% CI 0.369-1.250) (p = 0.214). CONCLUSIONS: Paternal age over 50 significantly affects the chance of achieving a live birth following ART. Paternal age does not independently affect the risk of miscarriage following ART. There should be a public health message for men not to delay fatherhood.

Risk prediction of major haemorrhage with surgical treatment of live cesarean scar pregnancies.

OBJECTIVE: To evaluate the association between demographic and ultrasound variables and major intra-operative blood loss during surgical transcervical evacuation of live caesarean scar pregnancies. STUDY DESIGN: This was a retrospective cohort study conducted in a tertiary referral center between 2008 and 2019. We included all women diagnosed with a live caesarean scar ectopic pregnancy who chose to have surgical management in the study center. A preoperative ultrasound was performed in each patient. All women underwent transcervical suction curettage under ultrasound guidance. Our primary outcome was the rate of postoperative blood transfusion. The secondary outcomes were estimated intra-operative blood loss (ml), rate of retained products of conception, need for repeat surgery, need for uterine artery embolization and hysterectomy rate. Descriptive statistics were used to describe the variables. Univariate and multivariable logistic regression models were constructed using the relevant covariates to identify the significant predictors for severe blood loss. RESULTS: During the study period, 80 women were diagnosed with a live caesarean scar pregnancy, of whom 62 (78%) opted for surgical management at our center. The median crown-rump length was 9.3 mm (range 1.4-85.7). Median blood loss at the time of surgery was 100 ml (range, 10-2300), and six women (10%; 95%CI 3.6-20) required blood transfusion. Crown-rump length and presence of placental lacunae were significant predictive factors for the need for blood transfusion and blood loss > 500 ml at univariate analysis (p < .01); on multivariate analysis, only crown-rump length was a significant predictor for need for blood transfusion (OR = 1.072; 95% CI 1.02-1.11). Blood transfusion was required in 6/18 (33%) cases with the crown-rump length ≥ 23 mm (≥9+0 weeks of gestation), but in none of 44 women presenting with a crown-rump length < 23 mm (p < .01). CONCLUSION: The risk of severe intraoperative bleeding and need for blood transfusion during or after surgical evacuation of live caesarean scar pregnancies increases with gestational age and is higher in the presence of placental lacunae. One third of women presenting at ≥ 9 weeks of gestation required blood transfusion and their treatment should be ideally arranged in specialized tertiary centers.

Impact of location on placentation in live tubal and cesarean scar ectopic pregnancies.

INTRODUCTION: The objective of this study was to evaluate the impact of implantation outside the normal intra-uterine endometrium on development of the gestational sac. METHODS: We reviewed and compared the ultrasound measurements and vascularity score around the gestational sac in 69 women diagnosed with a live tubal ectopic pregnancy (TEP) and 54 with a cesarean scar ectopic pregnancy (CSP) at 6-11 weeks of gestation who were certain of their last menstrual period. RESULTS: The rate of a fetus with a cardiac activity in the study population was significantly (P < 0.001) higher in CSPs than in TEPs. The median maternal age, gravidity and parity were significantly (P =.005; P < 0.001 and P < 0.001, respectively) lower in the TEP than in the CSP group. The number of gestational sac size <5th centile for gestational age was significantly (P < 0.001) higher in the TEP than in the CSP group. There were no differences between the groups for the other ultrasound measurements. In cases matched for gestational age, the gestational sac size was significantly (P < 0.001) smaller in the TEP compared to the CSP group. There was a significant (P < 0.001) difference in the distribution of blood flow score with CSP presenting with higher incidence of moderate and high vascularity than TEP. DISCUSSION: Both TEP and CSP are associated with a higher rate of miscarriage than intrauterine pregnancies and the slow development of the gestation sac is more pronounced in TEPs probably as a consequence of a limited access to decidual gland secretions.

Googling fibroids: A critical appraisal of information available on the internet.

OBJECTIVE: We aim to evaluate the accuracy, quality, and readability of online patient information concerning fibroids. STUDY DESIGN: We searched the most popular Internet search engine: Google.com. We developed a search strategy in consultation with patients with fibroids, to identify relevant websites. Two independent authors screened the search results. Websites were evaluated using validated instruments across three domains, including assessments of: [1] quality (DISCERN instrument; range 0-85); [2] readability (Flesch-Kincaid instrument; range 0-100); and [3] accuracy. Accuracy was assessed using evidence-based statements. We summarised this data narratively including the use of figures and tables. RESULTS: We identified 750 websites, of which 48 were included. Over a third of websites did not attribute authorship and almost half the included websites did not report the sources of information or academic references. No website provided written patient information in line with recommendations from the American Medical Association. A minority (18%) of websites were assessed as high quality. Twelve webpages provided only accurate statements. Available information was, in general, skewed towards the surgical management of fibroids. No website scored highly across all three domains. CONCLUSION: In the unlikely event that a website reports high quality and accurate health information, it is typically challenging for a lay audience to comprehend. Healthcare professionals and the wider community, should inform women with fibroids of the risk of outdated, inaccurate, or even dangerous information online. The implementation of an Information Standard certification will incentivise providers of online information to establish and adhere to codes of conduct. VIDEO ABSTRACT.

Discovery of non-invasive biomarkers for the diagnosis of endometriosis.

BACKGROUND: Endometriosis is a common gynaecological disorder affecting 5-10% of women of reproductive age who often experience chronic pelvic pain and infertility. Definitive diagnosis is through laparoscopy, exposing patients to potentially serious complications, and is often delayed. Non-invasive biomarkers are urgently required to accelerate diagnosis and for triaging potential patients for surgery. METHODS: This retrospective case control biomarker discovery and validation study used quantitative 2D-difference gel electrophoresis and tandem mass tagging-liquid chromatography-tandem mass spectrometry for protein expression profiling of eutopic and ectopic endometrial tissue samples collected from 28 cases of endometriosis and 18 control patients undergoing surgery for investigation of chronic pelvic pain without endometriosis or prophylactic surgery. Samples were further sub-grouped by menstrual cycle phase. Selected differentially expressed candidate markers (LUM, CPM, TNC, TPM2 and PAEP) were verified by ELISA in a set of 87 serum samples collected from the same and additional women. Previously reported biomarkers (CA125, sICAM1, FST, VEGF, MCP1, MIF and IL1R2) were also validated and diagnostic performance of markers and combinations established. RESULTS: Cycle phase and endometriosis-associated proteomic changes were identified in eutopic tissue from over 1400 identified gene products, yielding potential biomarker candidates. Bioinformatics analysis revealed enrichment of adhesion/extracellular matrix proteins and progesterone signalling. The best single marker for discriminating endometriosis from controls remained CA125 (AUC = 0.63), with the best cross-validated multimarker models improving the AUC to 0.71-0.81, depending upon menstrual cycle phase and control group. CONCLUSIONS: We have identified menstrual cycle- and endometriosis-associated protein changes linked to various cellular processes that are potential biomarkers and that provide insight into the biology of endometriosis. Our data indicate that the markers tested, whilst not useful alone, have improved diagnostic accuracy when used in combination and demonstrate menstrual cycle specificity. Tissue heterogeneity and blood contamination is likely to have hindered biomarker discovery, whilst a small sample size precludes accurate determination of performance by cycle phase. Independent validation of these biomarker panels in a larger cohort is however warranted, and if successful, they may have clinical utility in triaging patients for surgery.

The impact of adenomyosis on the outcome of IVF-embryo transfer.

Our study examined the impact of adenomyosis on the chance of clinical pregnancy after IVF and embryo transfer (IVF-ET). This was a prospective multicentre study from April 2013 to October 2015. We included 375 women with history of infertility who attended for a 3D scan prior to IVF-ET. A total of 150/375 (40.0%, 95% confidence interval [CI] 35.2-45.0) women had clinical pregnancy. Women with any feature of adenomyosis had a lower clinical pregnancy rate (21/72 [29.2%, 95% CI 18.6-39.6] versus 129/303 [42.6%, 95% CI 37.1-48.2], P = 0.044, relative risk (RR) 0.68 [95% CI 0.47-1.00]). Logistic regression selected an adenomyosis score of 4 or higher as an independent predictor of clinical pregnancy (odds ratio [OR] 0.35 [95% CI 0.15-0.82]). Estimated probability of clinical pregnancy decreased from 42.7% (95% CI 37.1-48.3) for women with no adenomyosis features to 22.9% (95% CI 13.4-32.6) for those with four and 13.0% (95% CI 2.2-23.9) for those with all seven. Women with adenomyosis have lower clinical pregnancy rate after IVF-ET. Condition severity expressed as a number of morphological features on ultrasound scan increases the magnitude of the effect.

Variation in antral follicle counts at different times in the menstrual cycle: does it matter?

Antral follicle count (AFC) variation was examined across the menstural cycle and its effect on clinical management assessed. In 79 women, AFC was documented in early (iAFC) and late follicular phase (sAFC). Absolute agreement between iAFC and sAFC and agreement for classification into categories of risk of extremes of ovarian response were examined. Ovarian stimulation protocols designed with iAFC and sAFC, and the predictive value of iAFC and sAFC for extremes of ovarian response, were compared in women undergoing ovarian stimulation. Significant differences were found between iAFC and sAFC (16 [IQR 9-24] versus 13 [IQR 7- 21]; P = 0.001), with moderate agreement for the classification into at risk of extremes of response (k = 0.525). Agreement for protocol selection based on either AFC (k = 0.750) and starting gonadotrophin dose was good (concordance correlation coefficient 0.970 [95% CI 0.951 to 0.982]). Predictive value for iAFC and sAFC was maintained for poor ovarian response and risk of ovarian hyperstimulation syndrome (OR 0.634 [0.427 to 0.920], 0.467 [0.233 to 0.935]) and (OR 1.049 [0.974 to 1.131], 1.140 [1.011 to 1.285]). Across the cycle, AFC varies but does not significantly affect ovarian stimulation protocol design and prediction of extreme ovarian response.

Serum Human Chorionic Gonadotropin (ß- hCG) Clearance Curves in Women with Successfully Expectantly Managed Tubal Ectopic Pregnancies: A Retrospective Cohort Study.

OBJECTIVE: To establish clearance curves for serum ß -hCG in women with successfully expectantly managed tubal ectopic pregnancies. DESIGN: Retrospective cohort study. Non- viable tubal ectopic pregnancy was diagnosed on transvaginal ultrasound. If initial serum ß hCG was less than 5000 IU/L and patients were asymptomatic, expectant management was offered. Patients underwent serial ß hCG measurements until serum ß hCG was less than 20 IU/l, or the urine pregnancy test was negative. SETTING: Early Pregnancy and Gynaecology Assessment Unit, Kings College Hospital, London (December 1998 to July 2006). PATIENTS: We included 161 women with diagnosed non-viable tubal ectopic pregnancy who underwent successful expectant management. MAIN OUTCOME MEASURE: Serum ß hCG level. RESULTS: Mean initial serum ß- hCG was 488 IU/L (41 - 4883) and median serum ß hCG clearance time was 19 days (5 - 82). The average half-life of ß hCG clearance was 82.5 hours (±SD 50.2) in patients with steadily declining serum ß- hCG levels compared to 106.7 hours (±SD 72.0) in patients with primarily plateauing ß-hCG levels in the declining phase. However, these differences were not significant (p>0.05). CONCLUSION: We identified a median follow-up of 19 days until serum ß hCG clearance in women with tubal ectopic pregnancy and successful expectant management. Although non- significant, women with initially plateauing serum ß hCG showed a longer follow-up time until clearance compared to women with steadily declining ß hCG levels. This information may serve as a guideline enabling clinicians to predict the length of follow-up for women with tubal ectopic pregnancy and expectant management.

Natural history of ovarian endometrioma in pregnancy.

BACKGROUND: Ovarian endometriomas are classified as benign ovarian lesions. During pregnancy endometriomas may undergo major morphological changes which are referred to as 'decidualisation'. Decidualised ovarian endometrioma may resemble malignant ovarian tumours on ultrasound examination. The aim was to study variations in the morphology and size of ovarian endometriomas diagnosed on ultrasound during pregnancy. METHODS: We searched our database to identify pregnant women who were diagnosed with ovarian endometriomas on ultrasound in order to study the effect of pregnancy on their morphological characteristics. In women who underwent serial scans during pregnancy we examined the changes in the size of endometriomas with advancing gestation. RESULTS: Twenty four patients with a total of 34 endometriomas were included in the analysis. All women were managed expectantly during pregnancy. On the first ultrasound scan 29/34 (85.3%, 95% CI 73.4 - 97.2) endometriomas appeared unilocular with fine internal echoes ('ground glass' contents) and they were poorly vascularised on Doppler examination. 1/34 (2.9% 95% CI 0.0 - 8.5) endometrioma was multilocular, with regular margins, 'ground glass' contents and it was also poorly vascularised. 4/34 (11.8%, 95% CI 1.0 - 22.6) had sonographic features suggestive of decidualisation such as thick and irregular inner wall, papillary projections and highly vascular on Doppler examination. The endometriomas showed a tendency to decrease in size during pregnancy. CONCLUSIONS: Pregnancy has a major effect on the size and morphological appearances of ovarian endometriomas. Rapid regression of decidualised endometriomas is a helpful feature which could be used to confirm their benign nature.

Ultrasound mapping of pelvic endometriosis: does the location and number of lesions affect the diagnostic accuracy? A multicentre diagnostic accuracy study.

BACKGROUND: Endometriosis is a common condition which causes pain and reduced fertility. Treatment can be difficult, especially for severe disease, and an accurate preoperative assessment would greatly help in the managment of these patients. The objective of this study is to assess the accuracy of pre-operative transvaginal ultrasound scanning (TVS) in identifying the specific features of pelvic endometriosis and pelvic adhesions in comparison with laparoscopy. METHODS: Consecutive women with clinically suspected or proven pelvic endometriosis, who were booked for laparoscopy, were invited to join the study. They all underwent a systematic transvaginal ultrasound examination in order to identify discrete endometriotic lesions and pelvic adhesions. The accuracy of ultrasound diagnosis was determined by comparing pre-operative ultrasound to laparoscopy findings. RESULTS: 198 women who underwent preoperative TVS and laparoscopy were included in the final analysis. At laparoscopy 126/198 (63.6%) women had evidence of pelvic endometriosis. 28/126 (22.8%) of them had endometriosis in a single location whilst the remaining 98/126 (77.2%) had endometriosis in two or more locations. Positive likelihood ratios (LR+) for the ultrasound diagnosis of ovarian endometriomas, moderate or severe ovarian adhesions, pouch of Douglas adhesions, and bladder deeply infiltrating endometriosis (DIE), recto-sigmoid colon DIE, rectovaginal DIE, uterovesical fold DIE and uterosacral ligament DIE were >10, whilst for pelvic side wall DIE and any ovarian adhesions the + LH was 8.421 and 9.81 respectively.The negative likelihood ratio (LR-) was: <0.1 for bladder DIE; 0.1-0.2 for ovarian endometriomas, moderate or severe ovarian adhesions, and pouch of Douglas adhesions; 0.5-1 for rectovaginal, uterovesical fold, pelvic side wall and uterosacral ligament DIE. The accuracy of TVS for the diagnosis of both total number of endometriotic lesions and DIE lesions significantly improved with increasing total number of lesions. CONCLUSIONS: Our study has shown that the TVS diagnosis of endometriotic lesion is very specific and false positive results are rare. Negative findings are less reliable and women with significant symptoms may still benefit from further investigation even if TVS findings are normal. The accuracy of ultrasound diagnosis is significantly affected by the location and number of endometriotic lesions.