Association Between Iatrogenic Delivery for Suspected Fetal Growth Restriction and Childhood School Outcomes.

Importance: Timely delivery of infants suspected of having fetal growth restriction (FGR) is a balance between preventing stillbirth and minimizing prematurity, particularly because many infants with suspected FGR have normal growth. Objective: To explore the association between iatrogenic delivery for suspected FGR and childhood school outcomes. Design, Setting, and Participants: A retrospective whole-population cohort study linking perinatal data from births 32 weeks' or more gestation between January 1, 2003, to December 31, 2013, to developmental and educational test scores at preparatory school, and at school grades 3, 5, and 7 in Victoria, Australia. Follow-up was concluded in 2019. Exposures: Suspicion or nonsuspicion of FGR, presence or absence of iatrogenic delivery (defined as early induction of labor or cesarean delivery prior to labor) for suspected FGR, and presence or absence of small for gestational age (SGA). Main Outcomes and Measures: The coprimary outcomes were being in the bottom 10th percentile on 2 or more of 5 developmental domains at school entry and being below the national minimum standard on 2 or more of 5 educational domains in grades 3, 5, or 7. Results: In the birth population of 705 937 infants, the mean gestation at birth was 39.1 (SD, 1.5) weeks and the mean birth weight was 3426 (SD, 517) grams. The birth population linked to 181 902 children with developmental results and 425 717 children with educational results. Compared with infants with severe SGA (birth weight <3rd percentile) not suspected of having FGR, infants with severe SGA delivered for suspected FGR were born earlier (mean gestation, 37.9 weeks vs 39.4 weeks). They also had a significantly increased risk of poor developmental outcome at school entry (16.2% vs 12.7%; absolute difference, 3.5% [95% CI, 0.5%-6.5%]); adjusted odds ratio [aOR], 1.36 [95% CI, 1.07-1.74]) and poor educational outcomes in grades 3, 5, and 7 (for example, in grade 7: 13.4% vs 10.5%; absolute difference, 2.9% [95% CI, 0.4%-5.5%]); aOR, 1.33 [95% CI, 1.04-1.70]). There was no significant difference between infants with normal growth (birth weight ≥10th percentile) delivered for suspected FGR and those not suspected of having FGR in developmental outcome (8.6% vs 8.1%; absolute difference, 0.5% [95% CI, -1.1% to 2.0%]); aOR, 1.17 [95% CI, 0.95-1.45]) or educational outcome in grade 3, 5 or 7, despite being born earlier (mean gestation, 38.0 weeks vs 39.1 weeks). Conclusions and Relevance: In this exploratory study conducted in Victoria, Australia, iatrogenic delivery of infants with severe SGA due to suspected FGR was associated with poorer school outcomes compared with infants with severe SGA not suspected of having FGR. Iatrogenic delivery of infants with normal growth due to suspected FGR was not associated with poorer school outcomes compared with infants with normal growth not suspected of having FGR.

Trends in preterm birth in twin pregnancies in Victoria, Australia, 2007-2017.

BACKGROUND: Preterm birth is a major cause of perinatal morbidity and mortality worldwide. In many countries, the preterm birth rate in women with a multiple pregnancy is increasing, mostly due to an increase in iatrogenic preterm birth. AIMS: To investigate trends in preterm birth in twin pregnancies in Victoria, Australia, in relation to maternal and perinatal complications. MATERIALS AND METHODS: We conducted a retrospective population-based cohort study in all women with a twin pregnancy who delivered at or after 20 weeks of gestation in the state of Victoria, Australia between 2007 and 2017. Annual spontaneous and iatrogenic preterm birth rates were calculated and trends analysed. Incidence of adverse pregnancy outcomes, maternal complications and risk factors for preterm birth were analysed. RESULTS: We studied 12 757 women with a twin pregnancy. Between 2007 and 2017 the preterm birth rate increased from 641/1231 (52%) to 803/1158 (69%), mainly due to an increase in iatrogenic preterm birth from 342/1231 (28%) to 567/1158 (49%). This was irrespective of the presence of pregnancy complications. Our study showed neither a decrease in perinatal mortality from 28 weeks of gestation nor in preterm average weekly prospective stillbirth risk. CONCLUSION: Preterm birth rates in twins in Victoria are increasing, mainly driven by an increase in iatrogenic preterm birth. This occurred both in complicated and non-complicated twin pregnancies, and has not been accompanied by reduction in perinatal mortality from 28 weeks.

The Effectiveness of Virtual Reality in Managing Acute Pain and Anxiety for Medical Inpatients: Systematic Review.

BACKGROUND: Virtual reality is increasingly being utilized by clinicians to facilitate analgesia and anxiolysis within an inpatient setting. There is however, a lack of a clinically relevant review to guide its use for this purpose. OBJECTIVE: To systematically review the current evidence for the efficacy of virtual reality as an analgesic in the management of acute pain and anxiolysis in an inpatient setting. METHODS: A comprehensive search was conducted up to and including January 2019 on PubMed, Ovid Medline, EMBASE, and Cochrane Database of Systematic reviews according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Search terms included virtual reality, vr, and pain. Primary articles with a focus on acute pain in the clinical setting were considered for the review. Primary outcome measures included degree of analgesia afforded by virtual reality therapy, degree of anxiolysis afforded by virtual reality therapy, effect of virtual reality on physiological parameters, side effects precipitated by virtual reality, virtual reality content type, and type of equipment utilized. RESULTS: Eighteen studies were deemed eligible for inclusion in this systematic review; 67% (12/18) of studies demonstrated significant reductions in pain with the utilization of virtual reality; 44% (8/18) of studies assessed the effects of virtual reality on procedural anxiety, with 50% (4/8) of these demonstrating significant reductions; 28% (5/18) of studies screened for side effects with incidence rates of 0.5% to 8%; 39% (7/18) of studies evaluated the effects of virtual reality on autonomic arousal as a biomarker of pain, with 29% (2/7) demonstrating significant changes; 100% (18/18) of studies utilized a head mounted display to deliver virtual reality therapy, with 50% being in active form (participants interacting with the environment) and 50% being in passive form (participants observing the content only). CONCLUSIONS: Available evidence suggests that virtual reality therapy can be applied to facilitate analgesia for acute pain in a variety of inpatient settings. Its effects, however, are likely to vary by patient population and indication. This highlights the need for individualized pilot testing of virtual reality therapy's effects for each specific clinical use case rather than generalizing its use for the broad indication of facilitating analgesia. In addition, virtual reality therapy has the added potential of concurrently providing procedural anxiolysis, thereby improving patient experience and cooperation, while being associated with a low incidence of side effects (nausea, vomiting, eye strain, and dizziness). Furthermore, findings indicated a head mounted display should be utilized to deliver virtual reality therapy in a clinical setting with a slight preference for active over passive virtual reality for analgesia. There, however, appears to be insufficient evidence to substantiate the effect of virtual reality on autonomic arousal, and this should be considered at best to be for investigational uses, at present.

The pitfalls of using birthweight centile charts to audit care.

OBJECTIVES: Timely 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. METHODS: A 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 <3rd and <10th centile. The same analysis was done using the INTERGROWTH-21st birthweight standard. To assess change over gestation, proportions were also calculated at preterm, early term and late term gestations. RESULTS: From 1983-84 to 2016-17, the proportion of babies with birthweight <3rd fell across all birthweight centile charts, from 3.1% to 1.7% using the oldest Australian chart, from 3.9% to 1.9% using the second oldest Australian chart, from 4.3% to 2.2% using the most recent Australian chart, and from 2.0% to 0.9% using the INTERGROWTH-21st standard. A similar effect was evident for the <10th centile. The effect was most obvious at term gestations. Updating the Australian population birthweight chart progressively right-shifted the birthweight distribution, changing the definition of small over time. The birthweight distribution of INTERGROWTH-21st was left-shifted compared to the Australian charts. CONCLUSIONS: Locally-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.

Risk factor assessment for fetal growth restriction, are we providing best care?

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.

Mirroring preeclampsia: the molecular basis of Ballantyne syndrome.

Objectives: The purpose of this article was to further elucidate the pathophysiology of Mirror (Ballantyne) syndrome within the context of known biomarkers for preeclampsia.Methods: This novel insight from clinical practice involved a case of post-twin-to-twin transfusion syndrome-laser hydrops in an ex-donor twin, corroborated by histopathologic placental territory edema and maternal sequelae of Mirror syndrome. We serially measured the levels of activin A, follistatin, endothelin-1 (ET-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), soluble fms-like tyrosine kinase 1 (sFlt), and von Willebrand factor (vWF) in the maternal serum from disease evolution through to recovery.Results: The paired finding of hydropic ex-donor twin and placenta, supports the theory of placental injury as the source of potential molecular mediators, leading to local placental edema, associated fetal hydrops and the maternal preeclamptic picture. Notably, we elucidated a temporal spectrum of maternal serum mediators (soluble Flt-1, endothelin-1, 8-isoprostane, activin-A, ICAM-1, and vWF) involved in the pathogenesis of Mirror syndrome.Conclusion: Better understanding of the pathogenesis of Mirror syndrome has important implications for clinical management.

The effect of melatonin on ultrasound markers of follicular development: A double-blind placebo-controlled randomised trial.

BACKGROUND: Melatonin is a potent oxygen scavenger and is capable of altering blood flow in various vascular beds. AIMS: We aimed to determine the effect of melatonin on ovarian vascular indices during ovarian stimulation for in vitro fertilisation (IVF). MATERIALS AND METHODS: This is a pilot double-blind placebo-controlled randomised trial. Sixty-nine women (mean age 35.8 ± 4.3 years) undergoing their first cycle of IVF were randomised to receive either placebo, 2, 4 or 8 mg of melatonin, twice a day. Each participant underwent a transvaginal ultrasound at days 6-10 assessing follicular number and size. The vascularisation index (VI), flow index (FI) and vascularisation-flow index (VFI) were measured. These indices were then correlated with embryological outcomes. Informed consent was obtained from participants. This trial was registered with the Australia New Zealand Clinical Trials Registry (ACTRN12613001317785). RESULTS: The number of follicles did not differ between groups (P = 0.4). There were no differences in the VI (P = 0.4), FI (P = 0.1) or VFI (P = 0.3) in the right ovary or the FI (P = 0.3) or VFI (P = 0.3) in the left ovary between groups. When comparing placebo to any dose of melatonin, there were no differences in any measured parameter. While there was correlation between the number of follicles on ultrasound and all measured embryological outcomes, there was no correlation between ovarian vascular indices and these important clinical outcomes. CONCLUSIONS: Melatonin does not appear to change ovarian vascular indices during ovarian stimulation. In addition, such vascular indices cannot predict the number or quality of oocytes or embryos obtained in an IVF cycle. These findings require confirmation in future larger studies.

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.

A systematic review on the utility of non-invasive electrophysiological assessment in evaluating for intra uterine growth restriction.

BACKGROUND: Non-invasive electrophysiological assessment (NIEA) is an evolving area in fetal surveillance and is attracting increasing research interest. There is however, limited data outlining its utility in evaluating intra uterine growth restriction (IUGR). The objective of this study was to carry out a systematic review to outline the utility of NIEA parameters in evaluating IUGR. METHODS: A systematic review of peer reviewed literature was performed, searching PUBMED, Ovid MEDLINE and EMBASE. The outcomes of interest included NIEA parameters [P wave duration, PR interval, QRS duration, QT interval, T/QRS ratio, short term variability (STV) and long term variability (LTV)] and a descriptive summary of relevant studies as well. RESULTS: Sixteen studies were identified as suitable for inclusion. The utility of NIEA parameters were investigated in tabular form. In particular, QRS and QT duration, T/QRS ratio, STV and PRSA analysis displayed utility and merit further consideration in evaluating for IUGR. Issues identified in the review were in relation to variances in definition of IUGR, small sample sizes and the lack of technological consistency across studies. CONCLUSION: NIEA shows promise as an adjunct surveillance tool in fetal diagnostics for IUGR. Larger prospective studies should be directed towards establishing reliable parameters with a focus on uniformity of IUGR definition, technological consistency and the individualisation of NIEA parameters.

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).

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

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.

The impact of melatonin on the sleep patterns of women undergoing IVF: a double blind RCT.

STUDY QUESTION: Does melatonin result in a dose-response effect on sleep quality and daytime sleepiness in women undergoing IVF? SUMMARY ANSWER: Melatonin, even when given at high doses twice per day, does not cause significant daytime sleepiness or change night time sleep quantity or quality. WHAT IS KNOWN ALREADY: Melatonin is being increasingly used as an adjuvant therapy for women undergoing IVF owing to its antioxidative effects. It is widely considered to be sedative but there are scant objective data on the effects of melatonin on sleep in the setting of IVF. STUDY DESIGN SIZE DURATION: The study was a double-blind placebo-controlled randomized trial of 116 women recruited between September 2014 and September 2016. PARTICIPANTS/MATERIALS SETTING METHOD: Women who were undergoing their first cycle of IVF at private IVF centers were recruited into the RCT and randomized to receive either placebo, 2 mg, 4 mg or 8 mg of melatonin, twice per day (BD) from Day 2 of their cycle until the day before oocyte retrieval. Each participant wore an accelerometer that provides an estimate of sleep and wake activity for up to 1 week of baseline and throughout treatment (up to 2 weeks). They also kept sleep diaries and completed a Karolinska sleepiness score detailing their night time sleep activity and daytime sleepiness, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 116 women were included in the intention-to-treat analysis (placebo BD (n = 32), melatonin 2 mg BD (n = 29), melatonin 4 mg BD (n = 26), melatonin 8 mg BD (n = 29)). There were no significant differences in daytime Karolinska sleepiness score between groups (P = 0.4), nor was there a significant dose-response trend (ß=0.05, 95% CI -0.22-0.31, P = 0.7). There were no differences in objective measures of sleep quantity or quality, including wake after sleep onset time, sleep onset latency, and sleep efficiency before and after treatment or between groups. There was an improvement in subjective sleep quality scores from baseline to during treatment in all groups, except 8 mg BD melatonin: placebo (percentage change -13.3%, P = 0.01), 2 mg (-14.1%, P = 0.03), 4 mg (-8.6%, P = 0.01) and 8 mg (-7.8%, P = 0.07). LIMITATIONS REASONS FOR CAUTION: As this was a subset of a larger trial, the melatonin in ART (MIART) trial, it is possible that the sample size was too small to detect statistically significant differences between the groups. WIDER IMPLICATIONS OF THE FINDINGS: While this study suggests that melatonin can be used twice per day at high doses to achieve sustained antioxidation effects, with the reassurance that this will not negatively impact daytime sleepiness or night time sleep habits, the sample size is small and may have missed a clinically significant difference. Nevertheless, our findings may have implications not only for future studies of fertility treatments (including meta-analyses), but also in other medical fields where sustained antioxidation is desired. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Monash IVF Research and Education Foundation (PY12_15). S.F. is supported by the National Health and Medical Research Council (Postgraduate Scholarship APP1074342) and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists Ella Macknight Memorial Scholarship. E.W. is supported by an National Health and Medical Research Council Program Grant (APP1113902). S.F., E.W., R.H., B.V., N.L., N.H., M.W., M.L., A.L., P.T., K.L. have nothing to declare. L.R. is a Minority shareholder in Monash IVF Group, has unrestricted grants from MSD®, Merck-Serono® and Ferring® and receives consulting fees from Ferring®. S.N.B. reports consulting fees from Johnson & Johnson Consumer Inc®, outside the submitted work. TRIAL REGISTRATION NUMBER: This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (Project ID: ACTRN12613001317785). TRIAL REGISTRATION DATE: 27/11/2013. DATE OF FIRST PATIENT'S ENROLMENT: 1/9/2014.