Danielle M. Teixeira

Impact of endometriosis and its staging on assisted reproduction outcome: systematic review and meta-analysis.

To evaluate whether the presence or severity of endometriosis affects the outcome of assisted reproductive techniques (ART).

Ovarian hyperstimulation syndrome: pathophysiology, staging, prediction and prevention.

To identify, appraise and summarize the current evidence regarding the pathophysiology, staging, prediction and prevention of ovarian hyperstimulation syndrome (OHSS).

Ultrasound guidance during embryo transfer: a systematic review and meta-analysis of randomized controlled trials

To summarize the current evidence on the effect of using ultrasound (US) guidance during embryo transfer (ET).

Ultrasound for monitoring controlled ovarian stimulation: a systematic review and meta-analysis of randomized controlled trials.

To evaluate the efficacy and safety of monitoring controlled ovarian stimulation (COS) using ultrasonography.

Influence of attenuation on three-dimensional power Doppler indices and STIC volumetric pulsatility index: a flow phantom experiment

Three-dimensional (3D) power Doppler indices (vascularization index (VI), flow index (FI) and vascularization flow index (VFI)) have been shown to correlate with flow and vascularity1; however, these indices are highly susceptible to machine settings and attenuation2. In this study, we sought to verify whether the volumetric pulsatility index (vPI) based on spatiotemporal image correlation (STIC) power Doppler3 is less dependent on attenuation than the original 3D power Doppler indices obtained from both static 3D and STIC datasets by evaluating a flow phantom. The study model is the same as that described in a previous publication4; essentially, it comprises a flow phantom in which a blood-mimicking fluid flows through a silicon tube, powered by an electric pulsatile pump (Figure 1). We inserted one of two different attenuation blocks, made from the same substances used in the flow phantom structure, each measuring 10 mm in thickness, between the ultrasound probe and the flow phantom5. These blocks had different concentrations of glass beads (1.8% and 4.4%) and therefore different coefficients of attenuation: 0.6 dB/MHz/cm (‘low attenuation’ experiment) and 1.0 dB/MHz/cm (‘high attenuation’ experiment). The preset ‘gynecologic’ was used and the following machine settings were maintained for all acquisitions: depth, 4.2 cm; power, 100%; gain, 0.0; WMF, mid1; PRF, 3.2 KHz;

Melatonin supplementation during controlled ovarian stimulation for women undergoing assisted reproductive technology: systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE To examine the best evidence available regarding the effect of melatonin supplementation during controlled ovarian stimulation (COS) on the main assisted reproductive technology (ART) outcomes. DESIGN Systematic review and meta-analysis of randomized clinical trials (RCT). SETTING Not applicable. PATIENT(S) Women undergoing COS for ART. INTERVENTION(S) Melatonin supplementation during COS for women undergoing ART. MAIN OUTCOME MEASURE(S) Live birth rate, clinical pregnancy rate, number of retrieved oocytes, miscarriage rate, ovarian hyperstimulation syndrome (OHSS) rate, and number of congenital abnormalities. Comparisons were performed using risk ratio (RR) or mean difference (MD). RESULT(S) Five RCTs were considered eligible, and their data were extracted and included in a meta-analysis. No studies reported live-birth or congenital abnormalities. Our estimates were imprecise for distinguishing between no effect and benefit considering clinical pregnancy (RR, 1.21; 95% confidence interval [CI], 0.98-1.50, five studies, 680 women, low quality-evidence) and the number of oocytes retrieved (MD, 0.6; 95% CI, -0.2-2.2, five studies, 680 women, low quality-evidence). Our estimates were imprecise for distinguishing among harm, no effect, and benefit considering miscarriage (RR, 1.07; 95% CI, 0.43-2.68, two studies, 143 clinical pregnancies, low quality-evidence) and interventions to reduce the risk of OHSS (RR,1.01; 95% CI, 0.33-3.08, one study, 358 women, low quality-evidence). CONCLUSION(S) More studies investigating the role of melatonin supplementation are still needed before recommending its use in clinical practice.

Low versus atmospheric oxygen tension for embryo culture in assisted reproduction: a systematic review and meta-analysis

OBJECTIVE To appraise the available evidence comparing low oxygen (LowO2) and atmospheric oxygen tension (AtmO2) for embryo culture. DESIGN Systematic review and meta-analysis. SETTING Not applicable. PATIENT(S) Women undergoing assisted reproduction using embryo culture. INTERVENTION(S) Embryo culture using LowO2 versus AtmO2. MAIN OUTCOME MEASURE(S) Reproductive, laboratory, and pregnancy outcomes. RESULT(S) A total of 21 studies were included in this review. All used O2 concentration between 5% and 6% in the LowO2 group. Considering the studies that randomized women/couples, we observed very low quality evidence that LowO2 is better for live birth/ongoing pregnancy (relative risk [RR] = 1.1, 95% confidence interval [CI] 1.0-1.3) and clinical pregnancy (RR = 1.1, 95% CI 1.0-1.2). Considering the studies that randomized oocytes/embryos, we observed low quality evidence of no difference of fertilization (RR = 1.0, 95% CI 1.0-1.0) and cleavage rate (RR = 1.0, 95% CI 1.0-1.1), and low quality evidence that LowO2 is better for high/top morphology at the cleavage stage (RR = 1.2, 95% CI 1.1-1.3). No studies comparing pregnancy outcomes were identified. Several studies used different incubators in the groups-a new model for the LowO2 group and an old model for the AtmO2 group. The risk of detection bias for the laboratory outcomes was high as embryologists were not blinded. CONCLUSION(S) Although we observed a small improvement (∼5%) in live birth/ongoing pregnancy and clinical pregnancy rates (PRs), the evidence is of very low quality and the best interpretation is that we are still very uncertain about differences in this comparison. The clinical equipoise remains and more large well-conducted randomized controlled trials are needed. They should use the same incubators in both groups and the embryologists should be blinded at least when evaluating laboratory outcomes.

Endometrial injury in the menstrual cycle prior to assisted reproduction techniques to improve reproductive outcomes

We read with great interest the article from Baum et al. [1] entitled ‘‘Does local injury to the endometrium before IVF cycle really affect treatment outcome? Results of a randomized placebo controlled trial’’ and published in Gynecological Endocrinology. The authors performed a controlled randomized trial evaluating the effect of endometrial injury on assisted reproductive technology (ART) outcomes in women with recurrent implantation failure. Contrary to other studies published so far, they did not observe a beneficial effect of endometrial injury performed in the month before the ART cycle; they actually observed a trend of worse reproductive outcomes in the group submitted to endometrial injury. It is an interesting result as there is a growing body of evidence pointing to the opposite way. Since, a systematic review and metaanalysis addressing this question was published [2], two other studies [3,4] were completed, and the updated pooled data are shown in Figure 1. All other randomized controlled trials (RCTs) published so far consistently reported a beneficial effect on live birth: risk ratio (RR)1⁄4 1.97; 95% CI from 1.35 to 2.88 (Figure 1); and on clinical pregnancy: RR1⁄4 1.86; 95% CI from 1.46 to 2.38 (Figure 2); without heterogeneity (I1⁄4 0%) for both outcomes. However, when adding the study from Baum et al. [1] to the analysis and applying the test for subgroup differences, inconsistency between the results is substantial: the I increased to 73.9% for live birth and to 77.8% for clinical pregnancy. Nevertheless, we would prefer not to pool these results together. While all other RCTs compared endometrial injury with either no injury or with a mock procedure; the study by Baum et al. compared two interventions: ‘‘endometrial pipelle’’ versus ‘‘cervical pipelle’’. The latter cannot be simply considered as a ‘‘placebo’’. Cervical pipelle causes disturbance to the endocervix, and the procedure may also cause some degree of endometrial injury in some of the participants: the pipelle might be easily inserted beyond internal cervical os unnoticed. There are some other issues to be clarified. As defined in the revised glossary of ART terminology [5], clinical pregnancy is ‘‘a pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive

Maternal flow-mediated dilation and nitrite concentration during third trimester of pregnancy and postpartum period

Objectives. To compare maternal flow-mediated dilation (FMD) of the brachial artery and nitrite concentration between third trimester of pregnancy (3rdT) and postpartum (PP) period. Additionally, we will evaluate whether FMD correlates with nitrite concentration in both periods. Methods. Eligibility criteria was healthy women with singleton pregnancy, gestational age >28 weeks, nonsmokers, and no personal or family history of vascular disease. Each women was examined during 3rdT and between 8 and 12 weeks PP to evaluate FMD and nitrite concentration in whole blood. Women not examined in both periods were excluded. Values between both periods were compared using paired t tests. Correlation between FMD and nitrite was examined by Pearson correlation coefficient. Significance level set as p < 0.05. Results. We invited 42 pregnant women. Among them, 35 were eligible and 7 of them were excluded for not attending the PP evaluation resulting in 28 participants analyzed. We found no significant change in FMD (10.39 ± 5.57% vs. 8.42 ± 4.21%; p = 0.11; 3rdT vs. PP, respectively) and no significant change in nitrite concentration (257.41 ± 122.95 nmol/L vs. 237.16 ± 90.01 nmol/L; p = 0.28). Baseline brachial artery diameter had a significant reduction (3.11 ± 0.30 to 2.75 ± 0.34 mm; p < 0.01). No significant correlation between FMD and nitrite during 3rdT (r = −0.13; p = 0.50) or PP (r = 0.14; p = 0.48) was found. Conclusions. We did not observe significant changes in both FMD and nitrite concentration between third trimester and the PP period. FMD did not correlate with nitrite in both periods. More studies are needed to confirm our findings.

The two sides of the individualization of controlled ovarian stimulation

Dear Sir, We read with great interest the article entitled ‘Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice’, published in Human Reproduction Update (La Marca and Sunkara, 2014). The authors performed a wide literature review over the issue of individualizing the ovarian stimulation in IVF cycles, according to predicting markers of ovarian response. Additionally, two different normograms are proposed for calculating the ideal FSH starting dose, based on age, serum FSH and either antral follicle count or serum anti-Müllerian hormone (AMH). The choice of a particular regime of controlled ovarian stimulation (COS), with FSH doses based on individual characteristics sounds tempting, as individualization might be seen as the key to success in this step of assisted reproductive techniques. Authors justify that individualization may reduce the number of cycles cancelled due to inappropriate ovarian response (hyper or poor) and that this would lead to reduced costs and dropout rates. However, we should always keep in mind that there are two sides to every coin. The choice of an individualized scheme for each patient would demand additional exams to define the expected ovarian response. The need for more examinations, such as AMH, brings additional costs for the couples seeking treatment. If we consider that as many as 22% of couples incur catastrophic expenditure on ART (Dyer et al., 2013), adding costs might make infertility treatment even less accessible to infertile populations. Another important factor to consider is that additional examinations may also be responsible for additional stress for the couples involved. If we keep in mind that 35% of dropouts after a single cycle are due to physical and psychological burden of the treatment (Verberg et al., 2008), the idea of adding even more stress, particularly for those who will be labelled as poor responders, might sound quite questionable. Even considering that individualization of COS should be performed, we do not agree with the suggestion that women with predicted poor ovarian response should always be submitted to high-dose FSH regimens (La Marca and Sunkara, 2014). For this group of women, we should consider less expensive COS: a recent systematic review showed that COS with clomiphene citrate + low dose gonadotropins + GnRH antagonist resulted in a trend to better pregnancy rates and number of oocytes retrievedwhencomparedwith the classichigh-doseFSHregime (Figueiredo et al., 2013). Reducing the costs for these women is even more important than for women with normal ovarian reserve: the pregnancy rate per cycle is much reduced and they will probably need several cycles before achieving pregnancy. Conversely to COS individualization, some large centres are adopting a low cost, mild and fixed COS, regardless of age or expected ovarian response associated with a single embryo transfer policy (Kato et al., 2012). Using such an approach they reported acceptable pregnancy and live birth rates (obviously depending on women’s age), minimizing the costs and risks of assisted reproduction techniques. In summary, we believe that when individualizing COS, low-cost regimens using clomiphene citrate should always be considered for women with predicted poor ovarian response. However, we think that individualization of COS still needs to be looked at with caution: examining assisted reproduction as a whole, and not only to the immediate results, the use of fixed, low cost and low-risk COS seems to be even more interesting.