Vieira, Matias C., Relph, Sophie, Muruet-Gutierrez, Walter, Elstad, Maria, Coker, Bolaji, Moitt, Natalie, Delaney, Louisa, Winsloe, Chivon, Healey, Andrew, Coxon, Kirstie, Alagna, Alessandro, Briley, Annette, Johnson, Mark, Page, Louise M., Peebles, Donald, Shennan, Andrew, Thilaganathan, Baskaran, Marlow, Neil, McCowan, Lesley, and Lees, Christoph
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. Matias C Vieira and colleagues evaluate the Growth Assessment Protocol (GAP) for antenatal detection of small for gestational age in the DESiGN cluster randomised trial. 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. [ABSTRACT FROM AUTHOR]