Background
Several factors adversely influence foetal growth, including maternal disease, problems with establishment of the utero-placental circulation in early pregnancy, maternal nutritional deprivation, chromosomal and other abnormalities in the foetus and/or placenta, pregnancy-related medical conditions such as gestational diabetes and pre-eclampsia, and exposure to adverse environmental conditions such as high altitude, toxins including smoking, drugs and other teratogens, infections and foetal metabolic diseases [
1,
2]. It is well recognised that foetuses with foetal growth restriction (FGR) are at increased risk of stillbirth, foetal compromise, early neonatal death and neonatal morbidity [
3,
4]. Evidence is increasing that exposure to an adverse foetal nutritional environment also causes lifelong changes in the risk profile for metabolic disease, neurodevelopment and cardiac disease [
5,
6], also observed in gene expression, with increased risk of later metabolic diseases seen in neonates born both small- and large-for-gestational-age [
7].
Although the heterogeneity of pathologies leading to FGR results in a wide range of perinatal prognoses, outcomes differ between the underlying causes. Ultrasound identification of foetuses with abnormal growth is often based on a single size parameter, such as abdominal circumference, or a single (but composite) measure of estimated foetal weight [
8]. Small-for-gestational-age babies are usually defined as estimated foetal weight or abdominal circumference below the 10th percentile on a foetal size chart. Nevertheless, current tests do not distinguish well between foetuses at risk of death due to a pathologic process (i.e. the growth restricted foetuses) from foetuses that are small but are otherwise likely to experience good perinatal outcomes without medical intervention. Single size parameters also fail to detect foetuses experiencing FGR later in pregnancy that may still be in the ‘healthy’ range (for example, foetuses that were destined to be on the 50th centile for size but are actually on the 15th) thus not small-for-gestational-age but nevertheless still FGR.
Doppler and other functional studies have proven useful in identifying small foetuses at preterm gestations at risk of demise [
9]; however, the utility of these tests at later gestation (after 32 weeks) is more limited [
10]. Recently, a consensus definition for both early and late FGR was developed that incorporated biometrical as well as functional parameters in which foetuses with measurements above the 10th percentile may be diagnosed as FGR [
11].
Antenatal care has foetal growth monitoring as a central aim in order to identify pregnancies with poor growth that may benefit from surveillance of foetal well-being; this is based on the premise that timely intervention in response to evolving foetal compromise can improve outcomes. Screening for growth restriction in pregnancy may target detection of pregnancies at risk of poor growth or later in pregnancy when growth restriction has occurred, with the aim of preventing stillbirth. Effective preventative interventions in women at risk of growth restriction detected early in pregnancy are few, with aspirin currently recommended for clinical use in a subgroup of women at high risk of pre-eclampsia or FGR due to failure of spiral artery remodelling (placental insufficiency due to maternal vascular malperfusion) prior to 16 weeks’ gestation [
12] and women who smoke being supported to cease [
13]. Later in pregnancy, antenatal corticosteroids and planned early delivery has the potential to avert stillbirth and prematurity-related risks, although moderate to late preterm babies are still at risk of neonatal and longer-term complications [
14,
15].
Clinically important outcomes potentially relevant to FGR are diverse and include both maternal and foetal outcomes. However, there is heterogeneity in the outcomes measured and reported in studies evaluating the effects of interventions for the prevention and treatment of FGR [
16‐
18]. Such heterogeneity limits the ability of clinicians, researchers and reviewers to compare, contrast and synthesise information on similar interventions for similar populations across studies. One of the suggested ways to address this is to develop and apply agreed standardised sets of outcomes, known as ‘core outcome sets’ (COS). A COS is a minimum set of agreed, standardised outcomes to be measured and reported worldwide in all trials on a specific condition [
19]. This minimises the substantial heterogeneity in choice of outcome measures, allowing the efficient comparison and synthesis of trials [
20]. and encourages a more complete reporting of outcomes, which limits reporting bias [
21].
Discussion
Although there is an extensive list of planed/ongoing and completed COSs in the ‘pregnancy and childbirth’ health area on the Core Outcome Measures for Effectiveness in Trials (COMET) website (
www.comet-initiative.org/studies/search), there is currently no published COS for FGR. We acknowledge the potential for overlap between some outcomes in this COS and other COSs such as preterm birth, stillbirth and pre-eclampsia, but believe that a separate COS for FGR, and for other conditions, is valuable and necessary. We propose the development of two COSs (prevention and treatment) to be measured in future studies on pregnancies complicated by FGR. The development of COSs in FGR will ensure the collection and reporting of a minimum dataset agreed by stakeholder consensus and will reduce inconsistencies in the reporting of outcomes across relevant trials. Such standardisation in the reporting of outcomes will improve the synthesis of evidence and generalisability of knowledge in the future by reducing heterogeneity between trials and thus improve the results of systematic reviews and meta-analyses.
The methodology we have chosen (selection of participants, Delphi rounds, consensus meeting) is based on methods successfully used in previously developed COSs. The COS process using the Delphi method is a widely accepted methodology. However, it must be acknowledged that the methods used lack a robust evidence base for all components. According to Gargon et al. ([
25], p. 141), the concept of a COS is still being established, and little is known about what should inform developers’ methodological choices. The credibility of a COS depends on the use of sound methodology; we will consider the potential impact of our methodological decisions in our final study report.
This COS will identify outcomes to be measured (‘what’ to measure). We acknowledge that further work will be needed to identify the tools, timing, etc. required to measure outcomes in the COS (‘how’ to measure). We acknowledge that it will be necessary for us to limit our search to English papers as we do not have the resources for translating non-English papers and recognise this as a potential limitation.
Inviting relevant stakeholders who have experience of FGR (for example, parent or carer of a baby that was growth restricted, health professional involved in the care of mothers and babies affected by FGR, a person with expertise in FGR research) to take part in this study will ensure that the resulting COS has broad consensus, is relevant and is wide reaching.
Ultimately, we hope that the standardisation in trial outcomes will lead to an improvement in the quality of evidence-based clinical practice, enhance patient care and improve the quality and consistency of research.
Project status
The review of the literature is complete and the list of outcomes for the round 1 Delphi has been compiled. We are currently preparing to recruit participants to the Delphi study. The final COS is expected by August 2018.
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