Melatonin to Prevent Brain Injury in Unborn Growth Restricted Babies

A Pilot Study of Maternally Administered Melatonin to Decrease the Level of Oxidative Stress in Human Pregnancies Affected by Intrauterine Growth Restriction.

Intrauterine growth restriction is the term used to describe a condition where an unborn baby does not reach its optimum size. In the short and long term, intrauterine growth restricted babies have a higher risk of serious disease and even death. It is well established that very low levels of oxygen in the baby's blood can harm the baby's health through a state known as oxidative stress. Currently, there is no established treatment available to treat intrauterine growth restriction or its complications. In experimental animal studies however, the naturally occuring hormone, melatonin, has been shown to significantly reduce oxidative stress and improve health of the unborn babies that have suffered from intrauterine growth restriction. This study aims to find out if the use melatonin twice per day throughout pregnancies affected by intrauterine growth restriction will lower the level of oxidative stress experienced by the unborn baby. If this is the case melatonin may help protect the unborn baby from damage caused by oxidative stress, this will be studied in a separate future study.

Study Overview

• Status: Completed
• Conditions: Fetal Growth Retardation
• Intervention / Treatment: Drug: Melatonin

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Southern Health: Monash Medical Centre and Jessie McPherson Private Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 43 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Estimated fetal weight <10th percentile in combination with abnormal fetoplacental Doppler studies.
• Singleton pregnancy.
• Live fetus.
• Gestational age: from 23+0 weeks until 34+0 weeks.
• Normal fetal anatomy on ultrasound.
• Confirmed gestational age.
• No indication for immediate delivery.
• Basic understanding of the English language.
• 18 years or older.
• Consent obtained.

Exclusion Criteria:

• Fetal demise.
• Multiple pregnancy.
• Known abnormal karyotype.
• Presence of any congenital abnormality.
• Unknown duration of pregnancy.
• IUGR attributable to non-placental factors.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Melatonin; Women with IUGR will take 4mg prolonged release melatonin oral tablets twice daily. Treatment will occur as soon as the diagnosis of intrauterine growth restriction is made and the patient has been enrolled to this study until birth. The overall duration of treatment will vary due to the nature of intrauterine growth restriction.	Drug: Melatonin; 4mg prolonged release melatonin oral tablets twice daily; Other Names: Circadin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxidative stress in the umbilical artery	Umbilical artery oxidative stress by measuring levels of malondialdehyde (MDA) and 8-isoprostane. Levels of MDA will be assessed using a Thiobarbituric Acid Reactive Substances Assay Kit (Cayman Chemical Item Number 10009055). Levels of 8-isoprostane will be assessed using an 8-Isoprostane Enzyme Immuno Assay Kit (Cayman Chemical Item Number 516351).	Once, at birth.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxidative stress in maternal venous serum	Maternal serum oxidative stress will be assessed by measuring levels of malondialdehyde (MDA) and 8-isoprostane. Levels of MDA will be assessed using a Thiobarbituric Acid Reactive Substances Assay Kit (Cayman Chemical Item Number 10009055). Levels of 8-isoprostane will be assessed using an 8-Isoprostane Enzyme Immuno Assay Kit (Cayman Chemical Item Number 516351).	Once within one week before start treatment and once per week during the treatment period (estimated to be an average of 4 weeks).
Fetoplacental Doppler studies	Fetoplacental Doppler studies (umbilical artery, uterine artery, middle cerebral artery, ductus venosus). Fetoplacental Doppler studies are performed in the clinical assessment of women diagnosed with intrauterine growth restriction by sonography.	Once within one week before start treatment and twice per week during the treatment period (estimated to be an average of 4 weeks).
Placental oxidative stress	Placental oxidative stress is assessed by measuring levels of malondialdehyde (MDA) and 8-isoprostane. Levels of MDA will be assessed using a Thiobarbituric Acid Reactive Substances Assay Kit (Cayman Chemical Item Number 10009055). Levels of 8-isoprostane will be assessed using an 8-Isoprostane Enzyme Immuno Assay Kit (Cayman Chemical Item Number 516351)	Once, at birth.
Gestational age at birth.	Gestational age at birth will be calculated using the last menstrual period and ultrasound characteristics.	Once, at birth.
Composite neonatal outcome.	Composite neonatal outcome (admission to NICU, duration of admission, need and duration of respiratory support, intraventricular haemorrhage, necrotising enterocolitis, abnormal neurological assessment, mortality before discharge). This composite neonatal outcome will be measured by collecting medical record data after clinical assessments.	Participants will be followed for the duration of hospital stay, up to 12 months.

Collaborators and Investigators

• Sponsor: Monash University
• Investigators: Principal Investigator: Nicole O Alers, MD, The Ritchie Centre, Monash Institute of Medical Research, Monash University; Principal Investigator: Euan M Wallace, MBChB MD FRCOG FRANZCOG, Southern Health, The Ritchie Centre, Monash Institute of Medical Research, Monash University; Principal Investigator: Graham Jenkin, BSc PhD, The Ritchie Centre, Monash Institute of Medical Research; Principal Investigator: Suzanne L Miller, BSc PhD, The Ritchie Centre, Monash Institute of Medical Research

Publications and helpful links

General Publications

• Miller SL, Yawno T, Alers NO, Castillo-Melendez M, Supramaniam VG, VanZyl N, Sabaretnam T, Loose JM, Drummond GR, Walker DW, Jenkin G, Wallace EM. Antenatal antioxidant treatment with melatonin to decrease newborn neurodevelopmental deficits and brain injury caused by fetal growth restriction. J Pineal Res. 2014 Apr;56(3):283-94. doi: 10.1111/jpi.12121. Epub 2014 Feb 22.
• Alers NO, Jenkin G, Miller SL, Wallace EM. Antenatal melatonin as an antioxidant in human pregnancies complicated by fetal growth restriction--a phase I pilot clinical trial: study protocol. BMJ Open. 2013 Dec 23;3(12):e004141. doi: 10.1136/bmjopen-2013-004141.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: September 7, 2012
• First Submitted That Met QC Criteria: September 26, 2012
• First Posted (Estimate): September 27, 2012

Study Record Updates

• Last Update Posted (Estimate): November 18, 2014
• Last Update Submitted That Met QC Criteria: November 14, 2014
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Fetal Diseases; Pregnancy Complications; Growth Disorders; Fetal Growth Retardation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: U1111-1133-4541; ACTRN12612000858897 (Registry Identifier: Australian New Zealand Clinical Trial Registry)