Melatonin in Assisted Reproductive Technology: A Pilot Double-Blind Randomized Placebo-Controlled Clinical Trial

Purpose: To explore in a small pilot study whether oral melatonin, administered during ovarian stimulation increases clinical pregnancy rate (CPR) after IVF and what dose might be most effective.Methods: Pilot double-blind, dose-finding, placebo-controlled randomized clinical trial in private IVF clinics in Australia between September 2014 and September 2016. One hundred and sixty women having their first cycle of IVF or ICSI were randomized to receive placebo (n = 40), melatonin 2 mg (n = 41), melatonin 4 mg (n = 39), or melatonin 8 mg (n = 40) twice per day (BD) during ovarian stimulation. The primary outcome was CPR. Secondary outcomes included serum and follicular fluid (FF) melatonin concentrations, oocyte/embryo quantity/quality, and live birth rate (LBR). Analysis was performed using the intention-to-treat principle.Results: There was no difference in CPR or LBR between any of the four groups (p = 0.5). When all the doses of melatonin were compared as a group with placebo, the CPR was 21.7% for the former and 15.0% for the latter [OR 1.57 (95% CI 0.59, 4.14), p = 0.4]. There were also no differences between the groups in total oocyte number, number of MII oocytes, number of fertilized oocytes, or the number or quality of embryos between the groups. This is despite mean FF melatonin concentration in the highest dose group (8 mg BD) being nine-fold higher compared with placebo (P < 0.001).Conclusion: No significant differences were observed in CPR or oocyte and embryo parameters despite finding a nine-fold increase in FF melatonin concentration. However, this study was not sufficiently powered to assess differences in CPR and therefore, these results should be interpreted with caution. Because this was a small RCT, a beneficial effect of melatonin on IVF pregnancy rates cannot be excluded and merits confirmation in further, larger clinical trials. ANZCTR (http://www.anzctr.org.au/ Project ID: ACTRN12613001317785)

The pitfalls of using birthweight centile charts to audit care.

ObjectivesTimely delivery of fetal growth restriction (FGR) is important in reducing stillbirth. However, targeted earlier delivery of FGR preferentially removes smaller babies from later gestations, thereby right-shifting the distribution of birthweights at term. This artificially increases the birthweight cutoffs defining the lower centiles and redefines normally grown babies as small by population-based birthweight centiles. Our objective was to compare updated Australian national population-based birthweight centile charts over time with the prescriptive INTERGROWTH-21st standard.MethodsA retrospective descriptive study of all singleton births ≥34 weeks' gestation in Victoria, Australia in five two-year epochs: 1983-84, 1993-94, 2003-04, 2013-14, and 2016-17. The birthweight cutoffs defining the 3rd and 10th centile from three Australian national population-based birthweight centile charts, for births in 1991-1994, in 1998-2007, and 2004-2013 respectively, were applied to each epoch to calculate the proportion of babies with birthweight ResultsFrom 1983-84 to 2016-17, the proportion of babies with birthweight ConclusionsLocally-derived population-based birthweight centiles are better for clinical audit of care but should not be updated. Prescriptive birthweight standards are less useful in defining 'small' due to their significant left-shift

Ventilation before Umbilical Cord Clamping improves the physiological transition at birth.

The transition from a fetus to a neonate at birth represents a critical phase in our life. Most infants make this transition without complications, but preterm infants usually require some form of assistance due to immature cardiopulmonary systems that predispose them to lifelong sequelae. As the incidence of preterm birth is increasing, there is now an urgent need for the development of management strategies that facilitate this transition, which will likely include improved strategies for the management of the maternal third stage of labour. For instance, recent studies on the physiological transition at birth have led to the discovery that establishing ventilation in the infant before the umbilical cord is clamped greatly stabilizes the cardiovascular transition at birth. While most benefits of delayed clamping have previously been attributed to an increase in placenta to infant blood transfusion, clearly there are other significant benefits for the infant, which are not well understood. Nevertheless, if ventilation can be established before cord clamping in a preterm infant, the large adverse changes in cardiac function that normally accompanies umbilical cord clamping can be avoided. As preterm infants have an immature cerebral vascular bed, large swings in cardiovascular function places them at high risk of cerebral vascular rupture and the associated increased risk of mortality and morbidity. In view of the impact that cord clamping has on the cardiovascular transition at birth, it is also time to re-examine some of the strategies used in the management of the third stage of labour. These include the appropriate timing of uterotonic administration in relation to delivery of the infant and placenta. As there is a lack of evidence on the effects these individual practices have on the infant, there is a necessity to improve our understanding of their impact in order to develop strategies that facilitate the transition to newborn life

Risk factor assessment for fetal growth restriction, are we providing best care?: early risk factor assessment for FGR

Serial third trimester ultrasound examinations for fetal biometry are recommended for women with risk factors of fetal growth restriction (FGR). We conducted a retrospective cohort study on all singleton births in Victoria from 2009 to 2017 to assess how many women with major risk factors for FGR had serial third trimester biometry. Only 19.5% of women with at least one major risk factor for FGR had evidence of serial third trimester ultrasound assessments. The development and implementation of a state-wide or nationwide guideline for early pregnancy risk factor assessment in FGR may be beneficial

A systematic review of cardiac time intervals utilising non-invasive fetal electrocardiogram in normal fetuses

Abstract Background Non-invasive fetal electrocardiogram (NIFECG) is an evolving technology in fetal surveillance which is attracting increasing research interest. There is however, only limited data outlining the reference ranges for normal cardiac time intervals (CTIs). The objective of our group was to carry out a systematic review to outline normal fetal CTIs using NIFECG. Methods A systematic review of peer reviewed literature was performed, searching PUBMED,Ovid MEDLINE and EMBASE. The outcomes of interest included fetal CTIs (P wave duration, PR interval, QRS duration and QT interval) and a descriptive summary of relevant studies as well. The outcomes were grouped as early pre-term (≤ 32 weeks), moderate to late pre-term (32–37 weeks) and term (37–41 weeks). Results 8 studies were identified as suitable for inclusion. Reference ranges of CTIs were generated. Both PR interval and QRS duration demonstrated a linear correlation with advancing gestation. Several studies also demonstrated a reduction in signal acquisition between 27 and 32 weeks due to the attenuation by vernix caseosa. In this group, both the P wave and T waves were difficult to detect due to signal strength and interference. Conclusion NIFECG demonstrates utility to quantify CTIs in the fetus, particularly at advanced gestations. Larger prospective studies should be directed towards establishing reliable CTIs across various gestations

Defining the clinician's role in early health technology assessment during medical device innovation - A systematic review

BACKGROUND: Early Health Technology Assessment (EHTA) is an evolving field in health policy which aims to provide decision support and mitigate risk during early medical device innovation. The clinician is a key stakeholder in this process and their role has traditionally been confined to assessing device efficacy and safety alone. There is however, no data exploring their role in this process and how they can contribute towards it. This motivated us to carry out a systematic review to delineate the role of the clinician in EHTA as per the PRISMA guidelines. METHODS: A systematic search of peer reviewed literature was undertaken across PUBMED, OVID Medline and Web of science up till June 2018. Studies that were suitable for inclusion focused on clinician input in health technology assessment or early medical device innovation. A qualitative approach was utilised to generate themes on how clinicians could contribute in general and specific areas of EHTA. Data was manually extracted by the authors and themes were agreed in consensus using a grounded theory framework. The specific stages included: All stages of EHTA, Basic research on mechanisms, Targeting for specific product, Proof of principle and Prototype and product development. Bias was assessed utilising the NICE Qualitative checklist. RESULTS: A total of 33 articles met the inclusion criteria for the review. Areas identified in which the clinicians could contribute to EHTA included: i) needs driven problem solving, ii) conformity assessment of MDs, iii) economic evaluation of MDs and iv) addressing the conflicts in interest. For clinicians' input across the various specific areas of EHTA, an innovation framework was generated based on the subthemes extracted. CONCLUSIONS: The following review has identified the various segments in which clinicians can contribute to EHTA to inform stakeholders and has also proposed an innovation framework