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  • Protect-me: a parallel-group, triple blinded, placebo-controlled randomised clinical trial protocol assessing antenatal maternal melatonin supplementation for fetal neuroprotection in early-onset fetal growth restriction

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Obstetrics and gynaecology
Protocol
Protect-me: a parallel-group, triple blinded, placebo-controlled randomised clinical trial protocol assessing antenatal maternal melatonin supplementation for fetal neuroprotection in early-onset fetal growth restriction
  1. Kirsten R Palmer1,2,
  2. Joanne C Mockler1,2,
  3. Miranda L Davies-Tuck3,
  4. Suzanne L Miller1,3,
  5. Stacy K Goergen4,5,
  6. Michael C Fahey6,7,
  7. Peter J Anderson8,
  8. Katie M Groom9,
  9. Euan M Wallace1,3
  1. 1 Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
  2. 2 Department of Obstetrics and Gynaecology, Monash Health, Clayton, Victoria, Australia
  3. 3 The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia
  4. 4 Department of Imaging, Monash University, Clayton, Victoria, Australia
  5. 5 Department of Radiology, Monash Health, Clayton, Victoria, Australia
  6. 6 Department of Paediatric Neurology, Monash Health, Clayton, Victoria, Australia
  7. 7 Department of Paediatrics, Monash University, Clayton, Victoria, Australia
  8. 8 Monash Institute of Cognitive and Clinical Neuroscience, Monash University, Clayton, Victoria, Australia
  9. 9 Department of Obstetrics and Gynaecology, Liggins Institute, University of Auckland, Auckland, New Zealand
  1. Correspondence to Dr Kirsten R Palmer; Kirsten.palmer{at}monash.edu

Abstract

Introduction Fetal growth restriction (FGR) is a serious pregnancy complication, associated with increased rates of perinatal death and morbidity among survivors. Most commonly FGR results from placental insufficiency, where the placenta fails to deliver the oxygen and nutrients required for normal fetal growth. This leads to fetal oxidative stress, resulting in organ damage through lipid peroxidation. The early developing brain is particularly susceptible, such that FGR is associated with poorer neurodevelopment, witnessed as cognitive and behavioural dysfunction, and cerebral palsy. Promisingly, melatonin, a lipid soluble antioxidant is neuroprotective in animal models of FGR. We present a protocol outlining a randomised, placebo-controlled trial to explore whether antenatal maternal melatonin supplementation in pregnancies with severe, early-onset FGR can improve neurodevelopment among survivors at 2 years of age.

Methods and analyses We will recruit 336 women with a singleton pregnancy complicated by FGR between 23+0 and 31+6 weeks gestation. Participants will be randomised, stratified by gestational age, to either 30 mg melatonin per day or a visually identical placebo, continued until birth. Measures of maternal and fetal health will be collected until birth. Timing of birth will be determined by the treating clinical team in discussion with the woman. Neonatal and infant neurodevelopmental assessments will be undertaken, consisting of brain MRI at term corrected age, general movements assessment at term and 3 months’ corrected age, and Bayley Scales of Infant & Toddler Development-III and Infant Toddler Social Emotional Assessment at 2.5 years corrected age. Analyses will be on intention to treat. The primary outcome is a difference of 5 points in the cognitive domain of the Bayley-III. Secondary outcomes address maternal and fetal safety.

Ethics and dissemination This trial has Monash Health Human Research and Ethics committee approval (17-0000-583A). Findings will be disseminated through peer-reviewed publications, conference presentations and to participants.

Trial registration number ACTRN12617001515381; Pre-results

  • fetal medicine
  • therapeutics
  • neonatology
  • clinical trials

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

http://dx.doi.org/10.1136/bmjopen-2018-028243

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    Footnotes

    • Contributors The original idea for the trial was generated by EW and SLM. KRP developed the trial protocol with assistance from JM, KMG, PJA, MCF, SKG, MD-T and EW. KRP drafted the protocol for publication and all authors provided contributions to editing and approval of the final manuscript.

    • Funding The trial is supported by funding from the Cerebral Palsy Alliance (Medical Research Future Fund) and the Equity Trustee’s Lynn Quayle Charitable Trust. KRP is funded by a Monash University School of Clinical Sciences Practitioner Fellowship and by the David Healy Clinical Research Fellowship.

    • Competing interests None declared.

    • Ethics approval This trial has received ethics approval from the Monash Health Human Research Ethics Committee (17-0000-583A).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Consent from trial participants will also be sought to enable sharing of de-identified data to assist with individual patient data meta-analyses with similarly planned international trials.

    • Patient consent for publication Not required.