UOG Journal Club 1: September 2016

Large randomized trial comparing transabdominal ultrasound-guided embryo transfer with a technique based on uterine length measurement before embryo transfer Revelli et al., UOG 2016 Many technical aspects of embryo transfer have been proposed as factors that affect the probability of pregnancy in IVF Several studies have shown that a transabdominal ultrasound-guided approach (TA-UGET) is superior to the original ‘clinical touch’ method in achieving clinical pregnancy and live birth A transvaginal ultrasound-guided approach (TV-UGET) has also been proposed as a more convenient and tolerable procedure for patients However, the transvaginal approach has been found to be more difficult for providers and uncomfortable for patients, with comparable pregnancy outcomes to TA-UGET

Large randomized trial comparing transabdominal ultrasound-guided embryo transfer with a technique based on uterine length measurement before embryo transfer Revelli et al., UOG 2016 Objective To compare an embryo transfer technique based on uterine length measurement before transfer (ULMbET) with TA-UGET in a large population of patients undergoing in-vitro fertilization

Non-Inferiority Randomized Controlled Trial Large randomized trial comparing transabdominal ultrasound-guided embryo transfer with a technique based on uterine length measurement before embryo transfer Revelli et al., UOG 2016 Methodology Non-Inferiority Randomized Controlled Trial Control Method: TA-UGET Second physician performed transabdominal imaging during ET Embryos discharged when the end of the catheter was visualized at ~1.5cm from the fundal endometrial surface Experimental Method: ULMbET Transvaginal ultrasound scan performed just before ET Cervical length measured and distance between internal uterine os and fundal endometrial surface calculated ET was then performed by clinical touch method, at a point obtained by subtracting 1.5cm from the total length of the cavity

Methodology Eligibility Criteria Primary Outcomes Statistical Analysis Large randomized trial comparing transabdominal ultrasound-guided embryo transfer with a technique based on uterine length measurement before embryo transfer Revelli et al., UOG 2016 Methodology Eligibility Criteria Patients undergoing IVF aged <43 years, absence of a uterine cause of infertility and prior agreement to receive transfer of one to three cleavage-stage fresh embryos Primary Outcomes Clinical pregnancy rate per ET Ongoing pregnancy rate at 10 weeks per ET Implantation rate Statistical Analysis Intention-to-treat analysis

Large randomized trial comparing transabdominal ultrasound-guided embryo transfer with a technique based on uterine length measurement before embryo transfer Revelli et al., UOG 2016

Results: Primary Outcomes (As Treated Analysis) Large randomized trial comparing transabdominal ultrasound-guided embryo transfer with a technique based on uterine length measurement before embryo transfer Revelli et al., UOG 2016 Results: Primary Outcomes (As Treated Analysis) Parameter ULMbET (n=828) TA-UGET (n=820) P Clinical pregnancy rate/ET 38.2% 38.9% 0.83 Implantation rate 24.8% 25.2% 0.78 Ongoing pregnancy rate/ET 33.1% 34.8% 0.47 Intention-to-treat analysis, including those patients who required a catheter change during ET, confirmed the lack of significant differences

Results: Secondary Outcomes Large randomized trial comparing transabdominal ultrasound-guided embryo transfer with a technique based on uterine length measurement before embryo transfer Revelli et al., UOG 2016 Results: Secondary Outcomes There were no significant differences in miscarriage rate, twinning rate or duration of procedure when comparing ULMbET and TA-UGET A significantly higher level of discomfort was observed when using TA-UGET 2.6 vs 1.5 VAS points; P=0.045 The proportion of patients who rated their discomfort as moderate to severe was significantly higher in the TA-UGET group 19.8% vs 1.2%; P=0.003

Large randomized trial comparing transabdominal ultrasound-guided embryo transfer with a technique based on uterine length measurement before embryo transfer Revelli et al., UOG 2016 Conclusions Results from this non-inferiority RCT demonstrate that ULMbET leads to IVF results which are comparable to those obtained with TA-UGEF The ULMbET procedure was slightly shorter in duration and required only one physician operator compared to TA-UGEF In addition, ULMbET was better tolerated by patients, avoiding the discomfort due to prolonged bladder distention required by TA-UGEF ULMbET is a viable alternative to TA-UGEF and can be considered in clinical practice for those who wish to incorporate ultrasound for ET

Strengths Limitations Large randomized trial comparing transabdominal ultrasound-guided embryo transfer with a technique based on uterine length measurement before embryo transfer Revelli et al., UOG 2016 Strengths Limitations Non-inferiority randomized trial Large sample size, adequately powered Single type of transfer catheter used Included both intention-to-treat and as-treated analyses Inability to blind patients and operators No stratification by skill level of operator performing the procedure Did not consider the most clinically relevant outcome of live birth rate

Opinion: Ultrasound guidance for embryo transfer: where do we stand? Nastri and Martins, UOG 2016 In a meta-analysis of RCTs comparing the various methods of ET, TA-UGET improves clinical pregnancy rates compared with clinical touch, with similar results observed using TV-UGET or ULMbET Unrelated to reproductive outcome, ULMbET also has the following clinical advantages: No need for patient to have a full bladder, reducing discomfort Eliminates the need for a second physician/sonographer The ULMbET technique is extremely promising and may contribute to the efforts to simplify fertility treatment, both improving the experience for the patient and reducing cost

Discussion Points What are some of the inherent weaknesses of non-inferiority trials compared with superiority trials? What are the potential clinical benefits of using the ULMbET technique over transabominal or transvaginal ultrasound guidance alone for embryo transfer? The authors chose not to use live birth rate as a primary outcome. What are the advantages and disadvantages of their choice of outcomes? How could the inability to blind the operator to the type of embryo transfer technique have biased the results? What type of operator experience is necessary to achieve competency in the ULMbET technique? What are the clinical implications of the study findings to the field of reproductive medicine?

UOG Journal Club 2: September 2016 Vaginal progesterone decreases preterm birth ≤ 34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study R. Romero, K.H. Nicolaides, A. Conde-Agudelo, J.M. O’Brien, E. Cetingoz, E. Da Fonseca, G.W. Creasy and S.S. Hassan

Vaginal progesterone decreases preterm birth ≤34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study Romero et al., UOG 2016 Short cervix in the mid-trimester of pregnancy is one of the strongest and most consistent risk factors for preterm birth in asymptomatic women Administration of vaginal progesterone in women with a sonographically short cervix has previously been shown to significantly decrease the risk of preterm birth as well as neonatal morbidity and mortality The recent OPPTIMUM study, a double-blind, placebo-controlled trial, reported that vaginal progesterone did not reduce these risks, leading to confusion regarding the efficacy of this intervention

Vaginal progesterone decreases preterm birth ≤34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study Romero et al., UOG 2016 Objective To evaluate the efficacy of vaginal progesterone for preventing preterm birth, perinatal morbidity and mortality in asymptomatic women with a singleton gestation and mid-trimester cervical length <25mm in an updated systematic review and meta-analysis

Methodology Design: Systematic review and meta-analysis Vaginal progesterone decreases preterm birth ≤34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study Romero et al., UOG 2016 Methodology Design: Systematic review and meta-analysis Inclusion Criteria: RCTs in which asymptomatic women with a singleton gestation and a sonographic short cervix (<25mm) in the mid-trimester were allocated randomly to receive vaginal progesterone or placebo/no treatment Exclusion Criteria: Quasi-randomized trials, trials evaluating vaginal progesterone in multiple gestation, preterm labor, arrested preterm labor, premature rupture of membranes, second-trimester bleeding, first-trimester use to prevent miscarriage, studies that did not report clinical outcomes

Methodology Primary Outcome: Preterm birth ≤ 34 weeks or fetal death Vaginal progesterone decreases preterm birth ≤34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study Romero et al., UOG 2016 Methodology Primary Outcome: Preterm birth ≤ 34 weeks or fetal death Analysis: Forest plots: Both fixed- and random-effects models Between-study heterogeneity: Higgin’s I2 Number needed to treat for benefit or harm calculated Subgroup analysis based on daily dose of progesterone Cochrane Collaboration tool used to assess risk of bias

Vaginal progesterone decreases preterm birth ≤34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study Romero et al., UOG 2016

Vaginal progesterone decreases preterm birth ≤34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study Romero et al., UOG 2016 Results

Vaginal progesterone decreases preterm birth ≤34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study Romero et al., UOG 2016 Results Number needed to treat with vaginal progesterone to prevent one preterm birth ≤ 34 weeks or fetal death was 11 (95% CI, 8-21) There interaction effect of vaginal progesterone based on daily dose was non-significant Vaginal progesterone also significantly decreased the risk for RDS, composite neonatal morbidity and mortality, birth weight <1500 g and admission to the neonatal intensive care unit There were no significant differences in neurodevelopmental outcomes at 2 years of age between the vaginal progesterone and placebo groups

Vaginal progesterone decreases preterm birth ≤34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study Romero et al., UOG 2016 Conclusions Vaginal progesterone significantly decreases the risk of preterm birth ≤ 34 weeks of gestation or fetal death among women with a singleton gestation and a mid-trimester CL <25mm These results are in contrast to the recently published OPPTIMUM study, which was notably underpowered to detect a meaningful difference in the subgroup of patients with a CL <25mm Coupled with the safety and cost-effectiveness of this intervention, universal CL screening between 18-24 weeks with the intent to offer vaginal progesterone to those with a short cervix remains a viable method of preterm birth prevention

Strengths Limitations Vaginal progesterone decreases preterm birth ≤34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study Romero et al., UOG 2016 Strengths Limitations Rigorous systematic review with extensive literature search strategy Consistency of results across gestational age categories Strict methodological assessment of study bias Use of subgroup analysis Lack of data on secondary outcomes not reported in the OPPTIMUM study No formal assessment of publication bias OPPTIMUM study at high risk for compliance and attrition bias Lack of individual patient data

Discussion Points What are the strengths and weaknesses of randomized controlled trials compared to meta-analyses? What are some of the pitfalls of the OPPTIMUM study as cited by the authors of this meta-analysis? In regard to the OPPTIMUM study, what biases were identified and how could these biases have potentially affected the study results? What is statistical heterogeneity and how was this assessed in the meta-analysis? Why did the authors choose a composite outcome of preterm birth ≤34 weeks or fetal death? What are the advantages and disadvantages of composite outcomes? What are the benefits of performing a meta-analysis using individual patient data? What are the clinical implications of the study findings in the field of preterm birth prevention?