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Evaluation of the Growth Assessment Protocol (GAP) for antenatal detection of small for gestational age: The DESiGN cluster randomised trial [1]

['Matias C. Vieira', 'Department Of Women', 'Children S Health', 'King S College London', 'London', 'United Kingdom', 'Department Of Obstetrics', 'Gynaecology', 'University Of Campinas', 'Unicamp']

Date: 2022-07 

Abstract Background Antenatal detection and management of small for gestational age (SGA) is a strategy to reduce stillbirth. Large observational studies provide conflicting results on the effect of the Growth Assessment Protocol (GAP) in relation to detection of SGA and reduction of stillbirth; to the best of our knowledge, there are no reported randomised control trials. Our aim was to determine if GAP improves antenatal detection of SGA compared to standard care. Methods and findings This was a pragmatic, superiority, 2-arm, parallel group, open, cluster randomised control trial. Maternity units in England were eligible to participate in the study, except if they had already implemented GAP. All women who gave birth in participating clusters (maternity units) during the year prior to randomisation and during the trial (November 2016 to February 2019) were included. Multiple pregnancies, fetal abnormalities or births before 24+1 weeks were excluded. Clusters were randomised to immediate implementation of GAP, an antenatal care package aimed at improving detection of SGA as a means to reduce the rate of stillbirth, or to standard care. Randomisation by random permutation was stratified by time of study inclusion and cluster size. Data were obtained from hospital electronic records for 12 months prerandomisation, the washout period (interval between randomisation and data collection of outcomes), and the outcome period (last 6 months of the study). The primary outcome was ultrasound detection of SGA (estimated fetal weight <10th centile using customised centiles (intervention) or Hadlock centiles (standard care)) confirmed at birth (birthweight <10th centile by both customised and population centiles). Secondary outcomes were maternal and neonatal outcomes, including induction of labour, gestational age at delivery, mode of birth, neonatal morbidity, and stillbirth/perinatal mortality. A 2-stage cluster–summary statistical approach calculated the absolute difference (intervention minus standard care arm) adjusted using the prerandomisation estimate, maternal age, ethnicity, parity, and randomisation strata. Intervention arm clusters that made no attempt to implement GAP were excluded in modified intention to treat (mITT) analysis; full ITT was also reported. Process evaluation assessed implementation fidelity, reach, dose, acceptability, and feasibility. Seven clusters were randomised to GAP and 6 to standard care. Following exclusions, there were 11,096 births exposed to the intervention (5 clusters) and 13,810 exposed to standard care (6 clusters) during the outcome period (mITT analysis). Age, height, and weight were broadly similar between arms, but there were fewer women: of white ethnicity (56.2% versus 62.7%), and in the least deprived quintile of the Index of Multiple Deprivation (7.5% versus 16.5%) in the intervention arm during the outcome period. Antenatal detection of SGA was 25.9% in the intervention and 27.7% in the standard care arm (adjusted difference 2.2%, 95% confidence interval (CI) −6.4% to 10.7%; p = 0.62). Findings were consistent in full ITT analysis. Fidelity and dose of GAP implementation were variable, while a high proportion (88.7%) of women were reached. Use of routinely collected data is both a strength (cost-efficient) and a limitation (occurrence of missing data); the modest number of clusters limits our ability to study small effect sizes. Conclusions In this study, we observed no effect of GAP on antenatal detection of SGA compared to standard care. Given variable implementation observed, future studies should incorporate standardised implementation outcomes such as those reported here to determine generalisability of our findings. Trial registration This trial is registered with the ISRCTN registry, ISRCTN67698474.

Abstract Why was this study done? Antenatal detection and appropriate management of small for gestational age (SGA) infants is a recognised strategy to prevent stillbirth; previous reports have suggested the rate of stillbirth is halved when SGA is antenatally detected, compared to undetected SGA.

Large observational studies provide conflicting results on the effect of Growth Assessment Protocol (GAP), an antenatal care package, with both findings of increased and no difference in detection of SGA and reduction of stillbirth.

The observational nature of all previous studies about GAP limits the assessment of causality in any observed associations. What did the researchers do and find? To the best of our knowledge, this is the first randomised control trial of GAP, comparing 11,096 births exposed to the intervention (5 clusters) to 13,810 exposed to standard care (6 clusters) during the outcome period.

We observed no significant effect on antenatal detection of SGA compared to standard care (25.9% versus 27.7%; adjusted difference 2.2%, 95% confidence interval (CI) −6.4% to 10.7%).

The lack of effect should be interpreted in the context of the variable implementation of GAP. What do these findings mean? This randomised control trial of GAP compared to standard care did not observe improvement in ultrasound detection of SGA; variable implementation of GAP was observed consistent with previous studies.

It is imperative that future studies of GAP assess implementation using standardised outcomes (fidelity, reach, and dose), in order to determine generalisability of our findings, identify barriers to implementation, and hence better inform policy for improving perinatal outcomes.

Use of routinely collected data is both a strength (cost-efficient) and a limitation (occurrence of missing data); the modest number of hospitals in this study limits our ability to study small differences between groups.

Citation: Vieira MC, Relph S, Muruet-Gutierrez W, Elstad M, Coker B, Moitt N, et al. (2022) Evaluation of the Growth Assessment Protocol (GAP) for antenatal detection of small for gestational age: The DESiGN cluster randomised trial. PLoS Med 19(6): e1004004. https://doi.org/10.1371/journal.pmed.1004004 Academic Editor: Jenny E. Myers, University of Manchester, UNITED KINGDOM Received: September 14, 2021; Accepted: April 29, 2022; Published: June 21, 2022 Copyright: © 2022 Vieira et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: Data cannot be shared publicly because consent was not obtained from women; permission for sharing data was not sought as part of ethical approval. Data is only available following approval from Research Ethics Committee and Confidentiality Advisory Group. Enquiries and requests should be made to DESiGN trial team and sponsors through the Department of Women and Children’s Health at King’s College London (SoLCS_research@kcl.ac.uk). Funding: This study was funded by Guy’s and St Thomas’ Charity (MAJ150704), Stillbirth and Neonatal Death Charity - SANDS (RG1011/16) and Tommy’s Charity. MCV was supported by CAPES (BEX 9571/13–2). SR, KC, AH and JS were supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South London at King’s College Hospital NHS Foundation Trust. NM receives a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme at UCLH/UCL. DAL’s contributions were supported by the Bristol NIHR Biomedical Research Centre and her NIHR Senior Investigator Award (NF-0616-10102). JS is supported by an NIHR Senior Investigator Award. DP was funded by Tommy’s Charity during the period of the study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: NM reports personal fees from Takeda, personal fees from RSM Consulting, personal fees from Novartis, outside the submitted work. BT is the Clinical Director of the Tommy’s National Centre for Maternity Improvement based at the Royal College of Obstetrics and Gynaecology (RCOG); the Centre’s objective is to translate the latest evidence into clinical practice in the UK. DAL has received support from Medtronic Ltd and Roche Diagnostics for research unrelated to that presented here. LP is clinical advisor [and from Sept 2021 deputy clinical director] for Healthcare Safety Investigation Branch maternity investigation programme, President of the British Intrapartum Care Society (BICS), invited member of some RCOG working groups and co-opted member of the British Maternal and Fetal Medicine Society (BMFMS) committee; she also received support from Pharmacosmos for clinical consultancy in work unrelated to that presented here. Abbreviations:: CI, confidence interval; DESiGN, DEtection of Small for GestatioNal age fetus; EFW, estimated fetal weight; GAP, Growth Assessment Protocol; GROW, Gestation-Related Optimal Weight; HRA, Health Research Authority; mITT, modified intention to treat; SGA, small for gestational age; WHO, World Health Organization

Introduction In 2014, the World Health Organization (WHO) launched the Every Newborn Action Plan with the aim to end preventable perinatal deaths by 2030; reducing stillbirth is thus a global priority [1]. While national strategies to tackle stillbirth vary according to leading causes locally, the importance of risk stratification and screening strategies that target improved detection of small for gestational age (SGA) (birthweight <10th centile) and appropriate management and timely delivery has been emphasised for high-income countries [2,3]. Antenatal detection of SGA has been associated with a halved risk of stillbirth compared to undetected SGA [4,5]. A review of guidelines from 6 high-income countries described a consensus on recommendations for stratifying women by risk of SGA, but noted variation in other aspects of screening and management, such as the use of customised fetal charts to identify SGA and the role of universal third trimester ultrasound [6]. The Growth Assessment Protocol (GAP), developed by the Perinatal Institute [7], is a complex intervention that includes the use of customised centile charts for fundal height and estimated fetal weight (EFW) measurements (Gestation-Related Optimal Weight (GROW) charts), evidence-based protocols and risk assessment, training and accreditation of clinical staff, a rolling audit programme and benchmarking of performance [8]. A nonrandomised control trial in the United Kingdom (UK) of standardised fundal height measurements plotted on customised charts demonstrated an increase in antenatal detection of SGA (29% versus 48%, odds ratio 2.2; 95% confidence interval (CI) 1.1 to 4.5) [9]. A recent study in New Zealand reported an almost 3-fold increase in detection of SGA (22.9% versus 57.9%; p < 0.001) when comparing rates before and after implementation of GAP [10]. In the UK, national uptake of GROW charts or GAP increased between 2007 and 2012 with a concomitant 22% reduction of stillbirth rates in regions of high uptake [11]. However, a study comparing the trend of stillbirth rates during 2010 to 2015 in England and Wales to that in Scotland where uptake of GAP was very low reported a greater decline in Scotland [12]. The authors concluded that any association between GAP and reductions in stillbirth rates was coincidental rather than causal. To our knowledge, there has been no randomised control trial studying the impact of GAP versus standard care on detection of SGA. There is also paucity of data on the impact of GAP on service usage (e.g., number of ultrasound scans and induction of labour) and on unwanted potential effects, such as a possible increase in neonatal adverse outcomes related to iatrogenic late preterm/early term birth. The primary aim of the DESiGN trial (DEtection of Small for GestatioNal age fetus) was to determine whether implementation of GAP results in improved ultrasound detection of SGA, when compared to standard care. We also planned to explore the effect on related maternal and neonatal outcomes and to conduct a process evaluation of fidelity, reach, dose, acceptability, feasibility, and resource use.

Methods Study design and population The DESiGN trial was a pragmatic, superiority, 2-arm, parallel group, open, cluster randomised control trial, including 13 maternity units in England [13]. All women who gave birth in participating clusters (maternity units) during the trial (between November 2016 and February 2019) were included. Baseline data were also collected on women who gave birth during the year prior to cluster randomisation. Pregnancies with significant fetal abnormalities, multiple pregnancies, and pregnancies ending before 24+1 weeks of gestation (referred to as weeks in the paper) were excluded. The study design and methodology of this trial have been prospectively registered (ISRCTN67698474), and both the study protocol (S1 Protocol) and the prespecified analysis plan (S1 Appendix) have been approved by the Trial Steering Committee. We enrolled maternity units primarily in London given the lower uptake of GAP in this area at the time the trial was proposed compared to the whole of the UK, where uptake was 64% [14]. A cluster trial was undertaken because the intervention requires implementation of site-wide guidelines for screening and management of SGA and additional staff training. Within-site contamination would limit the validity of individual randomisation. The trial was pragmatic to capture the reality of the introduction of this complex intervention into clinical practice with support from the Perinatal Institute. Randomisation and masking Clusters were randomly allocated by the trial statistician to immediate implementation of GAP (intervention arm) or to continue standard care during the study period (standard care arm). Randomisation occurred in 3 strata according to time of inclusion in the study (8, 3, and 2 clusters, respectively); the randomisation of the first 8 clusters were further stratified by size of maternity unit (number of births during the year 2013 to 2014). Randomisation was by random permutation within strata, providing exact 1:1 allocation except in the second stratum of 3 clusters where it was determined at random which arm would receive 2 clusters. The random permutation was conducted in Stata v14 (StataCorp LP, College Station, Texas, USA). Due to the nature of the intervention, concealment was not possible. Procedures Data were collected from a prerandomisation period of 12 consecutive months, which differed by randomisation stratum, the washout period (variable duration) during which the intervention arm clusters were implementing GAP, and for an outcome comparison period (outcome period) of 4 to 6 months from 1 September 2018 to 28 February 2019. The outcome period commenced when women giving birth in intervention clusters had had time to receive full antenatal exposure to GAP. One cluster from the control arm provided outcome data earlier due to a previously planned introduction of GAP at the original trial end date. This was a consequence of the washout period being extended after delays in GAP implementation at the last cluster randomised to the intervention. Data were obtained from 4 types of routinely collected electronic patient record system at each cluster: maternity, ultrasound, neonatal, and administrative [15]. Additional data were collected to assess compliance with the intervention in allocated clusters from review of a subset of women’s paper maternity records (n = 120 per cluster). Data were anonymised locally by the trial team before being sent centrally for data management, storage, and analysis. Following randomisation, maternity units allocated to the intervention were expected to contact the providers of GAP to commence training and implementation support. The components of GAP implementation are detailed in Table 1, by stage of implementation. Following consultation with cluster sites, the e-learning training requirement was amended by the Perinatal Institute to allow compliance with e-learning certification to be achieved within 3 months of going “live.” The prespecified requirements that describe how an implementing cluster would be considered as GAP compliant are further detailed in the study protocol (S1 Protocol; page 74). These were GAP recommendations during this trial; there were changes introduced subsequent to this study [16]. PPT PowerPoint slide

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TIFF original image Download: Table 1. Expected components of GAP implementation. https://doi.org/10.1371/journal.pmed.1004004.t001 In the standard care arm, women received routine antenatal care as per the local guidelines for screening and management of SGA in each cluster. There was no prespecification of policies in this arm, except that these clusters should not implement GAP or use customised centiles for fundal height or ultrasound monitoring of fetal growth. At the time this trial started, standard care for screening and management of SGA was guided by an RCOG guideline [17]. This recommends stratification of pregnant women by presence of risk factors for SGA. Women at low risk of SGA are further screened using measurement of fundal height at each antenatal appointment after 24 weeks. Women with risk factors are either offered serial fetal growth ultrasound scans or further stratification using doppler assessment of the uterine arteries at 20 weeks of gestation, dependent on the number or significance of the risk factors present. RCOG does not guide frequency of serial growth scans. Following a request from reviewers, a summary description of recommended practice in standard care clusters is provided on S2 Appendix (page 2) based on review of local guidelines for screening and detection of SGA. The Saving Babies’ Lives care bundle is a complex antenatal intervention that started to be implemented nationally during the trial. Clusters in the standard care arm were exempted from compliance with element 2 (risk assessment and surveillance of fetal growth restriction) of the Saving Babies’ Lives bundle. However, it was considered unethical to stop clusters in the standard care arm that were willing to implement concomitant strategies for improved detection of SGA and prevention of stillbirths initiated locally or nationally, which could include the Saving Babies’ Lives care bundle [18]. Process evaluation of implementation The process evaluation examined implementation compliance, acceptability, feasibility, contextual factors, and mechanisms of impact. To assess compliance with the intervention in implementing sites, we assessed fidelity, reach, and dose [19], by comparing site guidelines to those recommended by GAP, assessing compliance with training targets and by a review of 600 women’s maternity records (40 randomly selected singleton nonanomalous births in each of 3 months during the outcome period at 5 implementing clusters). Acceptability and feasibility of GAP implementation were explored through interviews with clinicians including clinical leads. A summary of implementation is provided in this report to support interpretation of the main findings (methodology provided in S2 Appendix; page 3). We also collected guideline on screening for SGA from clusters in the standard care arm. A more detailed process evaluation analysis will be reported separately. Outcomes The primary outcome of this study was antenatal ultrasound detection of SGA (after 24 completed weeks) defined for infants who are SGA (i.e., birthweight less than 10th centile) according to both population (UK1990 birthweight centiles) and customised (GROW) charts [20,21]. This definition was chosen because GAP targets detection of babies who are SGA by customised centiles, whereas standard care largely uses population centile charts. Antenatal detection of SGA was defined as ultrasound-derived EFW <10th centile by customised (GROW) charts in the intervention arm during the outcome period and by population [22] fetal charts for babies born in intervention sites during the prerandomisation period and all babies born in the standard care arm [20–22]. For calculation of ultrasound detection of SGA, data were obtained from electronic ultrasound records to identify EFW <10th centile and from electronic maternity records to identify birthweight <10th centile; these were calculated for all births in each cluster. A detailed description of methodology for calculating the rate of antenatal detection of SGA is provided in S2 Appendix (page 4). The 26 planned secondary outcomes included the test positive rate for antenatal detection of SGA (defined by both definitions as per primary outcome), antenatal detection and false positive rate of antenatal ultrasound detection of SGA confirmed at birth by customised centiles and by population centiles, maternal outcomes (induction of labour, mode of birth, postpartum haemorrhage, severe perineal tear (third/fourth degree), epidural and episiotomy), neonatal parameters and measures of condition at birth (gestational age at birth, preterm birth, birthweight, Apgar score <7 at 5 minutes, arterial cord pH <7.1, respiratory support at birth), neonatal unit admission, major neonatal morbidity (defined as one or more of: receipt of supplemental oxygen at 28 days of age, necrotising enterocolitis, sepsis, neonatal retinopathy, hypoxic–ischemic encephalopathy, intraventricular haemorrhage), minor neonatal morbidity (defined as one or more of hypothermia, hypoglycaemia, nasogastric tube feeding), stillbirth, neonatal death, and perinatal mortality. Utilisation of ultrasound scan was a process outcome (proportion of pregnancies with a scan, proportion of pregnancies with a scan between 18+0 and 24+0 weeks, proportion of pregnancies with a scan after 24+0 weeks with EFW, number of scans per pregnancy after 24+0 weeks with EFW, proportion of pregnancies with no record of ultrasound). Timing of scans after 24 weeks (i.e., utilisation per week gestation) was described following a request from reviewers and the academic editor, with the aim of better understanding differences in practice between trial arms. These process measures were reported to provide context to results. Statistical analysis Data management was performed to harmonise and amalgamate datasets from all clusters. This process has previously been described in detail and published [15]. The approach for multiple imputation of missing data is summarised in the S2 Appendix (page 5). Characteristics of the individual participants in the prerandomisation and trial outcome period were summarised for each trial arm using means and standard deviations, medians and interquartile ranges or frequencies and percentages, as appropriate. These results are reported using imputed data, where available; results from available case analyses are provided in the Supporting information. Main analyses. The primary analysis was performed using a modified intention to treat (mITT) approach. This involved excluding any cluster in the intervention arm that did not contact the GAP provider to initiate implementation of the intervention due to changes in local strategy, since such changes are not considered informative of how GAP would have performed in the cluster. Due to the modest number of clusters, the analysis was performed using an unweighted 2-stage cluster-summary statistical approach [23]; detailed description provided in S2 Appendix (page 6). Intervention effects (absolute difference of intervention minus standard care arm) are presented with 95% CIs. A sensitivity analysis was also performed at the request of reviewers, excluding 1 cluster without ultrasound measurement data for the baseline period, which are imputed in our main analysis (S2 Appendix; page 5). Prespecified secondary, subgroup, and sensitivity analyses. A secondary analysis was planned using a per protocol approach restricting analysis of the intervention arm to clusters that complied with the GAP preimplementation requirements (S1 Protocol; page 74) in full. A further secondary analysis was a full intention to treat (ITT) analysis in which data from all clusters were used as randomised, irrespective of whether or not GAP was implemented. A prespecified subgroup analysis was planned to explore the effect of the intervention on 21 clinical and neonatal outcomes, only in SGA infants. A sensitivity analysis explored the intervention effect when restricted only to women who had an ultrasound scan between 18+0 and 24+0 weeks (presumed fetal anomaly scan) at the cluster where she later gave birth, reflecting antenatal care primarily within a single cluster and consistent exposure to the intervention from 24 weeks. A reviewer requested a further post hoc sensitivity analysis of the stillbirth outcome, concerned that our 2-stage analysis approach may be unsuitable for rare outcomes. After preferred 1-stage methods were found unfeasible or did not converge, we applied the standard logistic regression approach but with robust standard errors to acknowledge clustering (see S2 Appendix, page 6 for details). We use the standard 5% significance level for testing across our secondary outcomes and subgroup and sensitivity analyses. Due to multiple testing, significant results for secondary outcomes should be treated with caution. These analyses were conducted following a prespecified analysis plan (S1 Appendix). All prespecified subgroup and sensitivity analyses were detailed in the trial protocol (S1 Protocol) and approved by the trial steering committee. This study has been reported as per the Consolidated Standards of Reporting Trials (CONSORT) statement (S1 CONSORT Checklist). Sample size calculation. The power calculation for this study determined a minimum target sample size of 12 clusters (6 per arm) based on information collected during protocol development [13]. We were unable to identify reports of an intracluster correlation coefficient for detection of SGA; therefore, a coefficient of the most approximate outcome (rate of fetal growth restriction) was used (0.019) [24]. A cluster size that included an average of 126 SGA infants (defined by customised and population centile charts) with 6 clusters per arm provides 84% power to detect an improvement in the detection of SGA, assuming 20% are detected using standard care and 33% detected using GAP (doubling of odds ratio for detection) at the 5% significance level (2-sided test) [13]. We made no explicit allowance for the additional baseline data from each cluster, their inclusion is likely to increase power. Power calculations were performed using the user-written programme “clustersampsi” for Stata. Protocol changes The trial protocol was amended during the study period for logistical and methodological reasons, including changes to data flow and storage, and following a change to the trial sponsor in 2017. A further change occurred prior to the randomisation of recruited clusters, whereby the definition of the primary outcome was refined. The registration of this change was delayed until after randomisation because of the change in study sponsor. Nevertheless, the amendment was approved before any women included in the primary analysis had given birth. These and other minor study amendments are recorded in the current version of the study protocol (S1 Protocol). All amendments were approved by the Research Ethics Committee and participating sites’ Research and Development departments. Approval was also sought from the trial steering committee, Confidentiality Advisory Group and funders, where appropriate. During data management and analysis, the definition of major neonatal morbidity changed in relation to the study protocol, as the data was insufficiently detailed to determine Bell stage of necrotising enterocolitis, culture status in sepsis, and need for ophthalmic intervention related to retinopathy. Ethical approval Ethical approval for this trial was obtained from the Health Research Authority (HRA) through the London Bloomsbury Research Ethics Committee (Ref. 15/LO/1632) and the Confidentiality Advisory Group (Ref. 15/CAG/0195). Individual informed consent was not obtained, but women could request to opt out from sharing their data. A key professional for each cluster provided written cluster consent prior to randomisation. Patient and public involvement Patient groups and stakeholders (representing both PPI and professional groups) were involved from the conceptualisation of this study. Patient groups were provided with a summary for the study and procedures in lay terms and asked their opinion about key points including the relevance of the study and the use of data without individual informed consent given the cluster intervention/design. Their feedback was used to inform the final study protocol and ethical application. Stakeholders such as Stillbirth Clinical Study Group from RCOG, SANDS Charity, and Tommy’s Charity were also involved in the conceptualisation of this study. We have a patient representative in our coinvestigator group who has provided their perspective throughout the study, including in interpretation and explanation of results to a lay audience.

Discussion The DESiGN trial has found that GAP was not superior to standard care for the antenatal detection of SGA, confirmed at birth by both population and customised centiles. All intervention clusters achieved the preimplementation requirements for access to GROW software, except for the e-learning target. In intervention clusters, GAP was implemented with varied levels of fidelity (high rates of face-to-face training, varied concordance of cluster site guidelines with GAP, high concordance with GAP risk stratification protocols), high levels of reach (majority of women had a GROW chart), but variable dose (low number of fundal height measurements plotted, number of growth scans below that which is recommended by GAP, high rates of referral for suspected SGA). To the best of our knowledge, the DESiGN trial is the first randomised control trial that compared the effect of GAP and standard care on the ultrasound-detection of SGA. The intervention was not superior to standard care when implemented in this study setting. It is important to note that at the time of the DESiGN trial, there was concurrent national implementation of the “Saving Babies” Lives’ care bundle, which aimed to reduce rates of stillbirth through 4 components (smoking cessation, risk assessment for and surveillance of fetal growth restriction, raising awareness of reduced fetal movements, and effective fetal monitoring during labour) [18]; this has been shown to increase use of ultrasound and improve the detection of SGA [25]. The outcome period of this trial was in 2018/2019, at least 2 years after the implementation of the care bundle. While the NHS England and NHS Improvement (London) Clinical Leadership Group exempted the 5 London-based clusters in the standard care arm of this study from implementing the care bundle component related to fetal growth restriction during the study period, most units chose to implement at least some of the care bundle strategies. In previous observational studies reporting increased antenatal detection of SGA or reduced stillbirth following GAP implementation, preimplementation groups were not affected by this care bundle. This may explain some of the differences observed in antenatal detection of SGA between this and previous studies; the different study design between this randomised control trial and previous studies, which were all observational, may also explain the different results observed. Our process evaluation highlights variation in implementation of GAP, which was also reported in the SPiRE Study [25], where 15 of 19 included maternity units had implemented GAP. The SPiRE study group found that most of the 15 local guidelines collected from GAP-implementing sites were only partially compliant with 4 out of 5 components that feature both in the fetal growth restriction element of the Saving Babies’ Lives care bundle and in GAP guidelines [26]. We also observed partial concordance with GAP guidelines in this trial, demonstrated through variable implementation fidelity. In England, multiparous women are routinely offered fewer antenatal appointments than required for compliance with GAP fundal height measurement frequency, this may partly explain why the number of fundal heights plotted is lower than that recommended by GAP (every 3 weeks). Implementation dose in terms of number of scans conducted for each woman at high risk of SGA was lower than that which is recommended by GAP (3 versus 4 scans for women with term birth). This may be explained by common practice in England whereby serial growth scans are offered at 28, 32, and 36 weeks, rather than 3-weekly. Indeed, post hoc exploration of implementation dose data has shown that 74% of high-risk women in the intervention arm of this study had 2 or more growth scans after 24 weeks, suggesting a less frequent surveillance programme than recommended by GAP. The exploratory analysis of timing of ultrasound utilisation requested by the reviewers/academic editor also supports this hypothesis and describe a similar surveillance pattern in the standard care arm. The costs related to GAP include both the annual charge from the Perinatal Institute to access the programme, training costs, and any potential increase in use of clinical resources; these need to be considered when evaluating utility of GAP. A detailed economic analysis will be reported separately. We observed a lower rate of overall stillbirth and perinatal mortality, as well as SGA stillbirth in the intervention arm compared to standard care arm during the outcome period. The fact that this was not achieved though the expected pathway of improving detection of SGA at birth, our primary outcome, does raise the possibility of a chance finding, and the finding was not confirmed in the (albeit post hoc) sensitivity analysis. Although we are limited in our ability to ascertain the drivers of this potential effect, it is plausible that the lower proportion of births at or after 39 weeks observed among SGA babies in the intervention arm may have mediated this effect. There is conflicting evidence regarding the benefit of offering earlier iatrogenic birth to women with SGA fetuses as while it may prevent stillbirth/perinatal mortality [27], adversely, it may increase rates of short-term neonatal morbidity and poorer developmental outcomes in childhood [28,29]. Complex interventions such as GAP may have effects that do not necessarily lie on the expected pathway; however, we note the need to replicate these findings before they can be considered robust given the number of secondary outcomes in this study. We have not performed statistical testing to assess for changes between prerandomisation and outcome period as per prespecified analysis plan; however, we did observe some differences. In particular, the use of ultrasound seems to have markedly increased during the study in standard care clusters, which likely relates to the rollout of the Saving Babies’ Lives care bundle, at least in part. The SPiRe Study reported increased utilisation of ultrasound with implementation of the care bundle; the association was related to the overall care bundle and not to any specific component. Despite exempt from the fetal growth restriction component of the care bundle, clusters in this trial may have increased the utilisation of ultrasound by other related strategies such as the reduced fetal movements component. The antenatal detection of neonates confirmed to be SGA at birth by customised centiles (secondary outcome) in this study was not higher in the intervention arm, which suggests the choice of growth chart may have limited influence in detection of SGA. Previous observational studies explored the value of customised centiles alone (not as part of GAP). We recognise that these studies have reported that population and customised charts have similar performance in detecting adverse perinatal outcomes after accounting for false positive rates for term births [30] and that the stronger associations between customised centiles and adverse perinatal outcomes (when compared to population centiles) were explained by confounding with preterm birth and maternal obesity [31], even though this is challenged by other authors. The strength of this study is that, to the best of our knowledge, it is the first randomised trial assessing the effect of the GAP. DESiGN was a pragmatic trial capturing the real-life challenges of implementing complex interventions into clinical care and included a robust process evaluation and examination of implementation strength and variability. The trial has primarily used data from routinely collected electronic patient records, which has allowed cost-efficient inclusion of data from a large number of pregnancies. The primary outcome was antenatal ultrasound detection of SGA (after 24 completed weeks). We defined this as infants who are SGA (i.e., birthweight less than 10th centile) according to (i) population (UK1990 birthweight centiles) and (ii) customised (GROW) charts; this is considered to identify those at highest risk of adverse perinatal outcomes [32]. This is an important strength as both GAP and standard care target the detection of these infants. We were unable to assess the impact of complete attainment of the GAP preimplementation requirements because only 1 implementing cluster achieved the training target for e-learning. The optimal interval between commencing GAP use and assessment of its effect is unknown. This study had a median interval of 9 months (range 6 to 12) from antenatal booking of women with the opportunity of exposure to GAP until commencement of outcome data collection. While the learning process of care providers may delay full programme effectiveness, an alternative “pioneering effect” may be working in the opposite direction [33]. Other limitations include issues related to the availability, or format, of data that are inherent in the use of routinely collected data, though we followed clear protocols in harmonisation and linkage of data from multiple electronic systems to minimise any variations in data quality between the randomised arms [15]. Missingness for characteristics (including customisation factors) was dealt with by multiple imputation, which is dependent on the assumption that results after inclusion of variables in the imputation model will be consistent between those with and without missing data. It is unlikely that randomisation to GAP or standard care would alter completeness of routine data collection in any cluster; therefore, this assumption is likely to be met. Ethnicity documented in hospital systems was often not as granular as that required by the customised calculator. One prespecified subgroup analysis exploring the effect of intervention in women stratified as high risk and low risk separately was not possible given lack of detailed data on some risk factors used to stratify women. The number of units randomised was modest and power was somewhat reduced by the failure of 2 units to contact the provider of GAP leading to their exclusion from our main analyses; however, the observed intracluster correlation coefficient was lower than that assumed for the power calculation; this would have preserved power to some extent. We are not aware of other studies of GAP implementation that report as detailed assessment of the standardised implementation outcomes (fidelity, reach, and dose) as that performed in this trial [19], and by which we can benchmark these findings. While it is possible that the variable dose of implementation may explain the results of this trial, DESiGN was a pragmatic trial intended to reflect implementation in the real world. It is therefore possible that the implementation variability seen in this trial reflects the reality of implementing a complex intervention in a health service with competing needs on resources. A recent observational study of GAP implementation across the UK also described variation in implementation using nonstandardised outcomes. Their analysis demonstrated a greater reduction of stillbirth rates in maternity units that had completely implemented GAP (defined by reporting the birthweight and outcomes of more than 75% of births via the GAP online tool) compared with those that did not implement GAP [34]. A third of maternity units (31%; n = 29/94) implementing GAP achieved only partial implementation. The rate of stillbirth was no different between maternity units with partial or no implementation of GAP. The collective evidence from these studies highlights the challenges and variation in implementation of GAP. This pragmatic study provides the only evidence from a randomised control trial regarding the effect of GAP, to the best of our knowledge. The GAP programme was not superior to standard care in the detection of SGA at birth by both population and customised centiles in this setting. Given the variable implementation observed, it is imperative that future studies assessing implementation of GAP or other interventions to improve perinatal outcomes, use standardised implementation outcomes (fidelity, reach, and dose) in order to determine the generalisability of our findings, identify barriers to implementation, and hence better inform policy for improving perinatal outcomes. Dissemination to participants and related patient and public communities Participating institutions and maternity units will be informed of the results soon after acceptance and any embargo period. We expect participating maternity units to share results locally in their communities aiming to also reach women that were pregnant during the study period. We will communicate with relevant stakeholders including SANDS and Tommy’s Charities. The main results of the current research will also be disseminated to related patients and the public through blogs, press releases, newspapers, and conferences.

Acknowledgments We would like to thank the members of the DESiGN Collaborative Group for their contribution to this study: Spyros Bakalis, Claire Rozette and Marcelo Canda (from Guy’s and St Thomas’ Hospital NHS Foundation Trust), Simona Cicero, Olayinka Akinfenwa, Philippa Cox and Lisa Giacometti (from Homerton University Hospital NHS Foundation Trust), Elisabeth Peregrine, Lyndsey Smith and Sam Page (from Kingston Hospital NHS Foundation Trust), Deepa Janga and Sandra Essien (from North Middlesex University Hospital NHS Trust), Renata Hutt (from Royal Surrey County Hospital NHS Foundation Trust), Yaa Acheampong, Bonnie Trinder and Louise Rimell (from St George’s University Hospitals NHS Foundation Trust), Janet Cresswell and Sarah Petty (from Chesterfield Royal Hospital NHS Foundation Trust), Bini Ajay, Hannah O’Donnell and Emma Wayman (from Croydon Health Services NHS Trust), Mandish Dhanjal, Muna Noori, and Elisa Iaschi (from Imperial College Healthcare NHS Trust), Raffaele Napolitano, Iris Tsikimi and Rachel Das (from University College London Hospitals NHS Foundation Trust), Fiona Ghalustians and Francesca Hanks (from Chelsea and Westminster Hospital NHS Foundation Trust), Laura Camarasa (from Hillingdon Hospitals NHS Foundation Trust), Hiran Samarage and Stephen Hiles (from London North West Healthcare NHS Trust). We would also like to thank the DESiGN Trial Steering Commetee/Data Monitoring Committee members: Anna David (from University College London), David Howe (from University Hospital Southampton), Nadine Seward (from King’s College London), Elizabeth Allen (from the London School of Hygiene and Tropical Medicine), and Jillian Francis (from The University of Melbourne). At last, we wish to thank the Stillbirth Clinical Study Group and the Royal College of Obstetricians and Gynaecologists for reviewing the study protocol during development of the study. The views expressed are those of the author[s] and not necessarily those of the NIHR, the Department of Health and Social Care, or any of the other listed funders.

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[1] Url: https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004004

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