Melatonin for women in pregnancy for neuroprotection of the fetus

  • Protocol
  • Intervention

Authors

  • Dominic Wilkinson,

    Corresponding author
    1. Women's and Children's Hospital, University of Adelaide, Discipline of Obstetrics and Gynecology, North Adelaide, SA, Australia
    • Dominic Wilkinson, Discipline of Obstetrics and Gynecology, Women's and Children's Hospital, University of Adelaide, 72 King William Road, North Adelaide, SA, 5006, Australia. dominic.wilkinson@adelaide.edu.au.

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  • Emily Bain,

    1. The University of Adelaide, ARCH: Australian Research Centre for Health of Women and Babies, The Robinson Institute, Discipline of Obstetrics and Gynaecology, Adelaide, South Australia, Australia
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  • Euan Wallace

    1. Monash University, Department of Obstetrics and Gynaecology, Monash, Victoria, Australia
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of melatonin when used for neuroprotection of the fetus.

Background

Description of the condition

Fetal brain injury: risk factors and consequences

Injury to the fetal brain is a major contributor to morbidity and mortality in infants and children born preterm (at less than 37 weeks' gestation) and at term (at 37 weeks' gestation and later) (Vexler 2001; Volpe 2000). The pathogenesis of brain injury is known to be complex and multifactorial, with a number of interrelated pathways contributing to central nervous system cellular dysfunction and death, including the accumulation of reactive oxygen species, the release of excitatory amino acids, energy depletion and apoptosis (Inder 2000; Vexler 2001). While there are known to be multiple causes of such brain injury, including hypoxia-ischaemia (characterised by a reduction of oxygen in the blood combined with reduced blood flow to the brain), haemorrhage, infection and metabolic derangement, hypoxia-ischaemia is believed to be an important cause of brain injury in a large number of cases (Volpe 2000). Brain hypoxia (deficiency of oxygen) and ischaemia (insufficient blood supply) may lead to different neuropathology in infants born prematurely and at term, with neuronal cell injury predominating in term infants, and cerebral white matter injury predominating in premature infants (Volpe 2000). Injury to the developing brain is known to be associated with a number of long-term sequelae for the infant and child, including hearing, sight and speech disorders, seizures, intellectual disabilities, and motor impairments, such as cerebral palsy (Vexler 2001).

Cerebral palsy is a broad term, encompassing non-progressive (but not unchanging) permanent physical disorders of movement or posture acquired in early life, resulting from complications in brain development (interferences, lesions or abnormalities) (ACPR Group 2009; Blair 2006). Cerebral palsy is the most frequent cause of childhood motor disability, affecting approximately two per 1000 live births in high-income countries (ACPR Group 2009). It is estimated that in approximately 94% of cases (13 in 14), the brain injury leading to cerebral palsy occurs to the fetus in utero, or before one month of age (ACPR Group 2009). Other neurologic impairments and neurosensory disabilities frequently associated with cerebral palsy include hearing, sight and speech disorders, intellectual disability and epilepsy.

Preterm birth is one of the principal risk factors for cerebral palsy and associated neurologic impairments and neurosensory disabilities (Blair 2006; Drummond 2002; Himpens 2008). The degree of prematurity is associated with vulnerability of cerebral white matter, and is predictive of an increasing risk of white matter injury such as periventricular leukomalacia, and of intraventricular haemorrhage (Larroque 2003) - established risk factors for the development of cerebral palsy and associated neurosensory disabilities (Saliba 2001). Although preterm birth is acknowledged as a major risk factor for cerebral palsy (ACPR Group 2009), accounting for approximately 40% of all cases, most children with cerebral palsy are in fact born at term (ACPR Group 2009; Wu 2003).

Along with very preterm birth, low birthweight is an independent, important risk factor for cerebral palsy and associated neurosensory disabilities, particularly in infants born at term or moderately preterm (Blair 1990). A number of studies have revealed high risks of neurosensory impairments and disabilities (including cerebral palsy, blindness, deafness and intellectual impairment) for very low birthweight (less than 1500 g) and extremely low birthweight (less than 1000 g) infants, when compared to normal birthweight controls (Doyle 2001). Intrauterine growth restriction and being small-for-gestational age at birth have additionally been shown to be important risk factors for neurologic injury and long-term sequale for both preterm and term fetuses (Jacobsson 2008; Leitner 2000; Low 1992; O’Keeffe 2003). For term infants, perinatal asphyxia (a condition resulting from deprivation of oxygen to a newborn infant, lasting long enough to cause physical harm) has been shown to be an important cause of brain injury and later neurodevelopmental disabilities (Dilenge 2001; Greenwood 2005).

Though conflicting evidence exists, further suggested risk factors for neurologic injury and associated longer-term consequences (including cerebral palsy) include increasing plurality (with pregnancies of higher plurality being more likely to be of shorter gestation and associated with slower uterine growth) (Blair 2006), infection such as chorioamnionitis (Blair 2006; Greenwood 2005; Wu 2003), and pre-eclampsia (Blair 2006; Greenwood 2005).

While a great number of potential risk factors for neurosensory disabilities have been identified, their commonality is that separately, or in combination, they may lead to fetal brain injury. The aim of primary preventative strategies, therefore, is to target early stages in the multifactorial, interrelated pathways before brain injury becomes irreversible.

Description of the intervention

Melatonin

Melatonin (N-acetyl-5-methoxytryptamin) is a small lipid-soluble molecule that is primarily synthesised and secreted by the pineal gland at night, under normal environmental conditions (Claustrat 2005); it has recently been recognised as a "ubiquitously distributed and functionally diverse molecule" (Reiter 2010). The key physiological functions of melatonin include mediating seasonality and circadian rhythm (Claustrat 2005). The endogenous rhythm of melatonin secretion is related to the light-dark cycle, however, the regulating system of secretion is complex, following both central and autonomic pathways (Claustrat 2005). There are thus many pathophysiological situations where melatonin secretion can be disturbed, and alterations of regulation can increase predisposition to disease, and modify the courses and outcomes of disorders (Claustrat 2005; Reiter 2010).

A feature that characterises melatonin is the variety of mechanisms that it employs to modulate the physiology and molecular biology of cells (Reiter 2010). In addition to mediating action through well-characterised G-protein coupled melatonin receptors in cellular membranes, melatonin is able to detoxify oxygen free radicals and related oxygen derivatives, and thus can also influence cellular physiology via receptor-indepedent means (Reiter 2010). The complexities of such processes have made it at times difficult to determine how melatonin functions to exert particular actions (Reiter 2010). Despite this, melatonin has been regarded as a molecule with "virtual absence of toxicity" (Reiter 2010), with great potential for application in human medicine, due to its ability to contribute to improved cellular physiology.

Clinically, melatonin has been shown to be effective in preventing and reducing jet lag (Herxheimer 2002), and some benefits have been seen when it is given for dementia, with a reduction in dementia-related psychopathologic behaviour disturbances observed (Jansen 2006). Melatonin has also been used to treat non-respiratory related sleep disorders in children, though benefits for this indication are currently undetermined (Khan 2011; Khan 2011b). Melatonin has been shown to reduce oxidative stress in human newborns with septicaemia, and lead to improved clinical outcomes (Gitto 2001). It has, in addition, been shown to reduce products associated with oxidative stress and damage in the blood of asphyxiated human newborns (Fulia 2001).

How the intervention might work

Melatonin for fetal neuroprotection

While the pathogenesis of white matter brain injury (such as periventricular leukomalacia), associated with perinatal mortality and long-term neurosensory disabilities, is complex and multifactorial, free radical-induced oxidative damage and infection or inflammatory-induced damage appear to be important. Free radical-induced damage also appears to be important in neonatal haemorrhagic brain injury (such as intraventricular haemorrhage) (Lekic 2011), which may subsequently lead to neurosensory disabilities, including cerebral palsy.

In adult animals, melatonin has been shown to be neuroprotective in models of focal cerebral ischaemia (stroke) (Macleod 2005), and in neonatal mice, melatonin has been shown to attenuate the development of white matter cysts following acute excitotoxic brain injury (Husson 2002). More recently, the neuroprotective effects of melatonin in the fetal brain have been assessed. Following intrauterine asphyxia (via umbilical cord occlusion), melatonin administration to both preterm and near-term fetal sheep has been shown to reduce oxidative stress (Miller 2005) and attenuate cell death (including apoptosis) in the fetal brain, in association with a reduced inflammatory response (Welin 2007). Systemic administration of melatonin following acute neonatal haemorrhagic brain injury in rats, has additionally been shown to protect against post-haemorrhagic consequences of brain atrophy, splenomegaly and cardiac hypertrophy (Lekic 2011). Importantly, melatonin has been shown to improve functional outcomes following such brain injury - ameliorating cognitive and sensorimotor dysfunction in the juvenile rat (Lekic 2011).

In addition to the direct fetal and neonatal administration of melatonin being associated with neuroprotective effects, the maternal administration of melatonin has been shown to lead to benefits for the offspring. The prophylactic administration of melatonin to pregnant rats immediately prior to an acute ischaemic episode (Watanabe 2004) and regularly throughout pregnancy (Watanabe 2011), has been shown to reduce ischaemia-reperfusion-induced oxidative damage in the premature fetal rat brain (Watanabe 2004; Watanabe 2011). Maternal administration of melatonin one hour after an ischaemic episode has also been shown to prevent against ischaemia-reperfusion-induced oxidative brain damage and degeneration in neonatal rats (Hamada 2010). At three to 12 hours post reperfusion however, melatonin has failed to protect against oxidative brain injury in neonatal rats (Hamada 2010), suggesting that there may be a critical window of time to administer melatonin, after which the molecule no longer has therapeutic benefit.

In view of the evidence from such studies, it is plausible that melatonin, an antioxidant agent with apparent anti-inflammatory and anti-apoptotic effects (Cheung 2003), may protect the human fetal brain against free radical-induced brain damage occurring during times of increased oxidative stress in pregnancy (such as in pregnancies complicated by pre-eclampsia, intrauterine growth restriction, infection, and preterm delivery) when administered fetally or maternally.

Why it is important to do this review

Melatonin is an antioxidant agent with anti-inflammatory and anti-apoptotic effects. Animal studies have supported a fetal neuroprotective role for melatonin when administered maternally. It is important to assess whether melatonin, when given to the mother, may reduce the risk of neurosensory disabilities (including cerebral palsy) and death, for the preterm or term compromised fetus.

Objectives

To assess the effects of melatonin when used for neuroprotection of the fetus.

Methods

Criteria for considering studies for this review

Types of studies

All published, unpublished and ongoing randomised trials and quasi-randomised trials assessing melatonin for fetal neuroprotection will be included. Cross-over and cluster-randomised trials will be excluded. Studies reported as abstracts only will be included.

Types of participants

Any pregnant woman administered melatonin, regardless of whether the pregnancy was single or multiple, and regardless of the gestation period at which melatonin was given, will be included. This may include trials where melatonin was given as the fetus was preterm or growth restricted, for chorioamnionitis, for prelabour rupture of membranes, for antenatal/intrapartum fetal distress, for pre-eclampsia, or other reasons.

Types of interventions

All randomised comparisons of melatonin given to women, compared with a placebo or no treatment, or to an alternative agent aimed at providing fetal neuroprotection. We will also include randomised comparisons of different regimens for administration of melatonin. We will include studies regardless of the route (i.e. oral, intramuscular or intravenous), timing, dose and duration of melatonin administration.

Types of outcome measures

Primary outcomes

Primary outcomes have been chosen to be most representative of the clinically important measures of effectiveness and safety, including serious outcomes and adverse effects.

For the infant/child
  • Death or any neurosensory disability (at latest time reported) (this combined outcome recognises the potential for competing risks of death or survival with neurological problems)

  • Death (defined as all fetal, neonatal or later death) (at latest time reported)

  • Neurosensory disability (any of cerebral palsy, blindness, deafness, developmental delay/intellectual impairment) (at latest time reported)

Definitions
  • Cerebral palsy: abnormality of tone with motor dysfunction (as diagnosed at 18 months of age or later)

  • Blindness: corrected visual acuity worse than 6/60 in the better eye

  • Deafness: hearing loss requiring amplification or worse

  • Developmental delay/intellectual impairment: a standardised score less than minus one standard deviation (SD) below the mean

For the mother
  • Any adverse effects severe enough to stop treatment

Secondary outcomes

Secondary outcomes include other measures of effectiveness and safety.

For the fetus/infant
  • Abnormal fetal and umbilical Doppler ultrasound study (as defined by trialists)

  • Fetal death

  • Neonatal death

  • Gestational age at birth

  • Birthweight (absolute and centile)

  • Apgar score (less than seven at five minutes)

  • Active resuscitation via an endotracheal tube at birth

  • Use and duration of respiratory support (mechanical ventilation or continuous positive airways pressure, or both)

  • Intraventricular haemorrhage (including severity – grade one to four) (as defined by trialists)

  • Periventricular leukomalacia (as defined by trialists)

  • Hypoxic ischaemic encephalopathy (as defined by trialists)

  • Neonatal encephalopathy (as defined by trialists)

  • Proven neonatal sepsis

  • Necrotising enterocolitis

  • Abnormal neurological examination (however defined by the trialists, at a point earlier than 18 months of age)

For the mother
  • Side effects and serious adverse events associated with treatment

  • Maternal white cell count and platelet count

  • Women’s satisfaction with the treatment

  • Mode of birth (normal vaginal birth, operative vaginal birth, caesarean section), and indication for non-elective mode of birth

For the infant/child
  • Cerebral palsy (any, and graded as severe: including children who are non-ambulant and are likely to remain so; moderate: including those children who have substantial limitation of movement; mild: including those children walking with little limitation of movement)

  • Death or cerebral palsy

  • Blindness

  • Deafness

  • Developmental delay/intellectual impairment (classified as severe: a developmental quotient or intelligence quotient less than minus three SD below the mean; moderate: a developmental quotient or intelligence quotient from minus three SD to minus two SD below the mean; mild: a developmental quotient or intelligence quotient from minus two SD to minus one SD below the mean)

  • Major neurosensory disability (defined as any of: moderate or severe cerebral palsy, legal blindness, neurosensory deafness requiring hearing aids, or moderate or severe developmental delay/intellectual impairment)

  • Death or major neurosensory disability

  • Growth assessments at childhood follow- up (weight, head circumference, length/height)

Use of health services
  • Admission to intensive care unit for the mother

  • Length of postnatal hospitalisation for the women

  • Admission to neonatal intensive care for the infant and length of stay

  • Costs of care for the mother or infant, or both

Search methods for identification of studies

Electronic searches

We will contact the Trials Search Co-ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register. 

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE;

  3. weekly searches of EMBASE;

  4. handsearches of 30 journals and the proceedings of major conferences;

  5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and EMBASE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords. 

We will not apply any language restrictions.

Data collection and analysis

Selection of studies

Two review authors will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, we will consult a third review author.

Data extraction and management

We will design a form to extract data. For eligible studies, two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a third review author. We will enter data into Review Manager software (RevMan 2011) and check for accuracy.

When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions ( Higgins 2011). We will resolve any disagreement by discussion or by involving a third assessor.

(1) Random sequence generation (checking for possible selection bias)

We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);

  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);

  • unclear risk of bias.   

(2) Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);

  • unclear risk of bias.   

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess the methods as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess methods used to blind outcome assessment as:

  • low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re-include missing data in the analyses which we undertake.

We will assess methods as:

  • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

  • high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);

  • unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as:

  • low risk of bias (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk of bias (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We will describe for each included study any important concerns we have about other possible sources of bias.

We will assess whether each study was free of other problems that could put it at risk of bias:

  • low risk of other bias;

  • high risk of other bias;

  • unclear whether there is risk of other bias.

(7) Overall risk of bias

We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis

Measures of treatment effect

Dichotomous data

For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals. 

Continuous data

For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.  

Unit of analysis issues

Cluster-randomised trials

We consider cluster-randomised trials as inappropriate for this research question.

Cross-over trials

We consider cross-over trials as inappropriate for this research question.

Multiple pregnancies

As infants from multiple pregnancies are not independent, we plan to use cluster trial methods in the analyses, where the data allow, and where multiples make up a substantial proportion of the trial population, to account for non-independence of variables (Gates 2004).

Multi-armed studies

If multi-armed studies are included in the review, we plan to combine groups where appropriate in order to create a single pair-wise comparison (e.g. melatonin versus alternative neuroprotective treatments).

If an included trial has an intervention arm that is not relevant to the review question, we will comment on this in the table of 'Characteristics of included studies', and include in the review only the intervention and control groups that meet the eligibility criteria.

Dealing with missing data

For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we will carry out analyses, as far as possible, on an intention-to-treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and all participants will be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We will assess statistical heterogeneity in each meta-analysis using the T², I² and Chi² statistics. We will regard heterogeneity as substantial if an I² is greater than 30% and either a T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity. 

Assessment of reporting biases

If there are 10 or more studies in the meta-analysis we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We will carry out statistical analysis using the Review Manager software (RevMan 2011). We will use fixed-effect meta-analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random-effects meta-analysis to produce an overall summary if an average treatment effect across trials is considered clinically meaningful. The random-effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials.

If we use random-effects analyses, the results will be presented as the average treatment effect with 95% confidence intervals, and the estimates of  T² and I².

Subgroup analysis and investigation of heterogeneity

We will perform separate comparisons for those trials comparing melatonin with no treatment or a placebo, and those comparing melatonin with an alternative neuroprotective agent.

If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful, and if it is, use random-effects analysis to produce it.

Maternal characteristics, and characteristics of the intervention, are likely to affect health outcomes. We will carry out subgroup analyses, if sufficient data are available, based on:

  • gestational age at which the woman commenced melatonin treatment (e.g. < 26 weeks versus 26 to < 28 weeks versus 28 to < 30 weeks versus 30 to < 32 weeks versus 32 to < 34 versus 34 to < 37 weeks versus 37 weeks and over);

  • reasons the mother was considered for melatonin treatment (e.g. preterm versus growth-restricted fetus versus prolonged prelabour rupture of membrane versus increased risk of chorioamnionitis versus pre-eclampsia/eclampsia versus increased risk of perinatal asphyxia versus other);

  • total daily dose of melatonin administered (e.g. low (≤ 10 mg daily) versus moderate (≤ 40 mg daily) versus high (> 70 mg daily));

  • mode of administration (e.g. intramuscular versus intravenous versus oral);

  • number of babies in utero (e.g. singleton versus multiple).

We will use primary outcomes in subgroup analyses.

We will assess subgroup differences by interaction tests available within RevMan (RevMan 2011). We will report the results of subgroup analyses quoting the χ2 statistic and P value, and the interaction test I² value.

Sensitivity analysis

We will carry out sensitivity analysis to explore the effects of trial quality assessed by allocation concealment and other risk of bias components, by omitting studies rated as 'high risk of bias' for these components. We will restrict this to the primary outcomes.

Acknowledgements

We thank Caroline Crowther and Philippa Middleton for their advice on the development of this protocol.

As part of the pre-publication editorial process, this protocol has been commented on by three peers (an editor and two referees who are external to the editorial team) and the Group's Statistical Adviser.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Pregnancy and Childbirth Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

Contributions of authors

Emily Bain drafted the first version of this protocol, with Dominic Wilkinson and Euan Wallace making comments and contributing to the final draft.

Declarations of interest

Euan Wallace is a principal investigator on 'A Pilot Study of Maternally Administered Melatonin to Decrease the Level of Oxidative Stress in Human Pregnancies Affected by Intrauterine Growth Restriction', which may be considered for inclusion in this review. Therefore, assessment of eligibly of this trial, and if included, data collection and analysis (including 'Risk of bias' assessment) for this trial, will be carried out by the other two review authors not involved in this trial (Dominic Wilkinson and Emily Bain).

Sources of support

Internal sources

  • ARCH: Australian Research Centre for Health of Women and Babies, Robinson Institute, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Australia.

External sources

  • National Health and Medical Research Council, Australia.

Ancillary