1. UOG Journal Club 1:
September 2016

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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?

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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 weeks with the intent to offer vaginal progesterone to those with a short cervix remains a viable method of preterm birth prevention

22. 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

23. 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?