Implementation of national guidelines on antenatal magnesium sulfate for neonatal neuroprotection in England, Scotland and Wales: Extended evaluation of the effectiveness and cost-effectiveness of the National PReCePT Programme

MgSO 4 administration rose from 65.8% in 2017 to 85.5% in 2022 in En gland. 46 PReCePT was associated with 5.8 percentage points improvement in uptake (95%CI 2.69 to 47 8.86, p<0.001). Improvement was greater when including older preterm births (<34 weeks’ 48 gestation, 8.67 per centage points, 95%CI 6.38 to 10.96, p<0.001). Mo st gains occurred in the 49 first two years following implementation. PReCePT had a NMB of £597,000 with 89% 50 probability of being cost-effective. Following implementation, English up take appeared to 51 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 3 accelerate compared to Scotland and Wales. There was some decline in use coinciding with 52 the onset of the pandemic. 53

The PReCePT Quality Improvement programme cost-effectively improved use 54 of antenatal MgSO 4 , with benefits to the babies who have been protected from cerebral 55 palsy. 56 57 What is alr eady kno wn on t his t opic 58 • Ant enatal magnesium sulphate (MgSO 4 ) reduces the risk of cer ebral palsy in babies born 59 pret erm. 60 • The National PReCePT Quality Improvement Pr ogramme (NPP) eff ectively and cost-61 eff ectively improved use of MgSO 4 in England in the first 12 months of implementation, 62 but sustaining quality improvements over ti me is often challenging. 63 What th is stu dy ad ds 64 • Using a quasi-experimental design and r outinely collected, longitudinal, patient-level 65 data, this study found that the NPP had sustained effectiveness and cost-effectiveness 66 over four year s following implementation. 67 • Impr ovement may have been accelerated in England, compared to Scotland and W ales, 68 where the NPP was not formally implement ed. 69 How t his s t udy might aff ec t research, practice or polic y 70 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 4 • This study demonstrates that dedicated national pr ogrammes can cost-effectively 71 achieve impr ovements in perinatal care. The PReCePT model could be used as an 72 implementation blueprint for other quality impr ovement initiatives in perinatal car e. 73 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 5 INTR OD UCTI ON 74 Since 2015 the World Health Organisation (WHO)(1) and the UK National Institute for Health 75 and Care Excellence (NICE)(2) have recommended administration of magnesium sulfate 76 (MgSO 4 ) in preterm deliveries <30 weeks’ gestation as a core part of maternity care. This 77 follows strong evidence that when given antenatally to women in preterm labour, MgSO 4 78 reduces the risk of cerebral palsy (CP) in preterm babies by around 30%(3). Historically, use 79 of this treatment has been inconsistent, with only 64% of eligible women in England being 80 treated in 2017. High regional variation in uptake also indicates inequalities in perinatal 81 care(4). 82 As well as the significant impact of CP on affected individuals and their families(5), there are 83 lifetime societal costs of approximately £1m per affected indiv idual(6), and £1.8 billion 84 annually on NHS clinical negligence litigation (half of the total NHS litigation expenditure)(7). 85 Incidence of CP has been estimated at around 1.5 per 1000 livebirths in the UK(8), with 86 preterm birth as the leading risk factor(9-11). This highlights the importance of funding 87 effective, and cost-effective, strategies to reduce the risk of CP associated with preterm 88 birth. It is estimated that one case o f CP can be prevented, below 30 weeks’ gestation, for 89 every 37 mothers treated with MgSO 4 , and around 200 cases of CP per year could be 90 avoided by con sistent administration of MgSO 4 during labour(3). 91 In 2018, NHS En gland rolled-out the National PReCePT (Prevention of cerebral palsy in 92 preterm labour) Programme (NPP). This was a quality improvement (QI) programme for 93 maternity units, providing clinical guidance, training, learning resources, midwife backfill 94 funding, and QI support, to improve maternity staff awareness, and increase use of MgSO 4 95 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 6 for mothers in preterm labour. The aim was to reach ≥85% uptake in eligible mothers across 96 all maternity units in England. The programme was delivered by regional Academic Health 97 Science Networks (AHSNs, now Health Innovation Networks). Evaluation of the first 12 98 months of the programme found it to be effective, improving MgSO 4 use by an estimated 99 6.3 percentage points, with an estimated net monetary benefit of £866 per preterm baby, 100 and >95% probability of being cost-effective(12). However it is unknown whether these 101 improvements were sustained over time, and sustainability in large scale implementation 102 programmes is often a problem (and measurement of sustained effect often neglected)(13). 103 The primary aim of this study, therefore, was to evaluate the NPP’s longer-term, sustained 104 effectiveness and cost-effectiveness over the first four years following implementation. A 105 key secondary aim was to explore the impact of the NPP on all babies born up to 34 weeks’ 106 gestation; NICE guidelines recommend treatment for births up to 30 weeks’, and 107 ‘consideration of treatment’ for older preterm births up to 34 weeks’. Other secondary aims 108 were to explore the impact of the COVID-19 pandemic on MgSO 4 use, and to compare 109 MgSO 4 use in England with that in the devolved nations Scotland and Wales. This evaluation 110 is part of a larger programme of work, including qualitative interviews to explore how the 111 devolved nations were responding to the NICE guidance, reported elsewhere(14). 112 MET H O DS 113 De sign 114 This was a quasi-experimental study for the evaluation of the NPP’s effectiveness and cost-115 effectiveness. The pre-registered Statistical Analysis Plan and Health Economic Analysis Plan 116 were uploaded to the Open Science Framework prior to analyses: ht tps: //o sf.io/be76 s/ . 117 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 7 Int ervent io n 118 The intervention being implemented was the National PReCePT Programme (NP P), as 119 described above and fully detailed elsewhere(12), for the adoption of MgSO 4 a s a 120 neuroprotectant in preterm births. 121 Sett ing 122 NHS maternity units in England, Scotland and Wales. Within maternity units, analysis was 123 performed on aggregated data on babies born preterm <30 weeks’ gestation, and admitted 124 to an NHS neonatal unit, between January 2014 to December 2022. All maternity units in 125 England, Scotland and Wales were included, excepting the five units in England that took 126 part in the original PReCePT pilot study(15) and were therefore not part of the NPP. 127 Data so urces 128 Data on eligible babies and their mothers were obtained from the National Neonatal 129 Research Database (NNRD), which holds individual-level, pseudonymised, routinely 130 collected patient data on babies admitted to an NHS neonatal unit. Costs associated with 131 the NPP were estimated in the original evaluation(12). 132 Effe c t iv e ness e valuation 133 Outcome 134 The main implementation outcome was MgSO 4 uptake over time. MgSO 4 uptake was 135 defined as the proportion of eligible mothers recorded as receiving MgSO 4 a t a ma terni ty 136 unit, expressed as a percentage. For consistency with nationally reported data, mothers 137 w i t h m i s s i n g Mg S O 4 data were excluded from this calculation. This was computed per 138 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 8 month per unit, and reported as a percentage. For consistency with nationally reported data 139 only data on singletons and the first born (i.e. one infant) from each multiple birth were 140 included in the calculation. 141 Descriptive analysis 142 Maternity unit, population characteristics, and MgSO 4 use were descriptively reported by 143 nation and time-period. 144 Primary analysis 145 Primary analysis was an interrupted time series using English data aggregated to the 146 national level (mean national MgSO 4 uptake per month, across all English maternity units). A 147 multivariable linear regression model was used to estimate the difference in mean MgSO 4 148 uptake from before (the 1-year period before) to after (the four-years follow-up) 149 implementation of the NPP in England. The model adjusted for an underlying linear time 150 trend, and mother and baby characteristics aggregated nationally per month (mean 151 maternal age, Index of Multiple Deprivation (IMD) decile(16), baby’s birthweight adjusted 152 for gestational age as a z-score, and proportion reported smokers, white British ethnicity, 153 type of birth (c-section versus vaginal delivery), and multiple births. The model was further 154 adjusted for a non-linear temporal component to account for the ceiling effect and 155 reduction in rate of change at levels close to the ceiling. Data on paternal age and ethnicity 156 were explored as potential confounding factors, but were excluded due to high levels of 157 missing data, and expected collinearity with other variables (maternal and paternal age 158 tends to correlate, as does maternal and paternal ethnicity). Potential interaction was 159 explored between mean MgSO 4 uptake and level of maternity unit (Neonatal Intensive Care 160 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 9 Unit (NICU), the highest-level unit versus Special Care Baby Unit (SCBU) or Local Neonatal 161 Unit (LNU), lower level units)). This was because it was anticipated that performance might 162 differ by type of unit: data from the original study indicated that smaller units tended to 163 have lower starting uptake levels, so more room for improvement compared to larger 164 NICUs. 165 Sensitivity and subgroup analyses 166 As sensitivity analyses the above model was run on data aggregated to (a) the maternity-167 unit-level rather than the national level, and (b) the individual rather than national level. 168 These two models additionally adjusted for type of maternity unit (NICU vs SCBU/LNU), 169 regional clustering by AHSN, and were weighted on the number of eligible births per unit 170 per month. Other sensitivity analyses included assessing (c) the impact of excluding a ‘fuzzy’ 171 implementation start window of +/-2 months, to account for some units starting slightly 172 earlier or later than their officially recorded start date; (d) the impact of excluding the final 2 173 months of data, due to concerns about completeness of the most recent data for some 174 units; (e) the impact of using a longer pre-NPP comparison period of four years; and (f) the 175 impact of including more mature pre-term babies up to 34 weeks’ gestation in the analysis. 176 A sub-group analysis was performed on the 40 units that had participated in a connected 177 study, an RCT nested within the main NPP(17), as their performance could plausibly differ 178 from other maternity units. 179 Economic e valuation 180 MgSO 4 treatment cost-effectiveness 181 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 10 Economic analysis combines evidence of the treatment (MgSO 4 ) effect with evidence of the 182 implementation (NPP) effect(18). For the former, estimates of the cost-effectiveness of 183 MgSO 4 treatment were adopted from Bickford and colleagues' results(6, 19, 20), with their 184 estimates converted to GBP currency and 2019 prices (Supplementary Table 1). This analysis 185 accounts for the health impacts and cost savings of MgSO 4 administered in births <30 and 186 <32 weeks’ gestation. 187 NPP implementation costs and effectiveness 188 The mean implementation cost per unit of the NPP was estimated from data supplied by the 189 NPP team and PReCePT study team, and reported previously(12, 17). The total cost of the 190 NPP at a national level was estimated at £936,747(12) (which includes the funded backfill of 191 clinical time for NPP ‘champion’ midwives at each maternity unit, and regional support from 192 AHSNs). 193 From the multivariable linear regression model described above, we estimated the NPP 194 effectiveness as the difference between the predicted level of MgSO 4 u se o ver time 195 compared to a counterfactual level of MgSO 4 use, representing what may have occurred in 196 the absence of the NPP, assuming a continuation of the pre-NPP trend in MgSO 4 uptake. The 197 main measure of NPP effectiveness was the area-between-the-curves. Primary analysis used 198 a linear distribution to estimate the counterfactual based on the pre-NPP predicted trend. 199 Sensitivity analysis used a beta distribution to estimate this counterfactual, to account for 200 MgSO 4 uptake as a proportion. 201 Policy cost-effectiveness analysis 202 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 11 The cost-effectiveness analysis was conducted from a societal lifetime perspective. Net 203 monetary benefit (NMB) of the NPP was estimated over the four years since its launch, by 204 combining analysis of the cost s and effectiveness of the NPP with the lifetime societal cost, 205 and health gains associated with MgSO 4 treatment. This analysis used a framework 206 previously developed to conduct economic evaluations of implementation initiatives(21). A 207 willingness-to-pay threshold of £20,000 per Quality Adjusted Life Year (Q ALY) gained was 208 used to determine NPP cost-effectiveness, following NICE guidelines(22). A positive NMB 209 indicated that the implementation initiative was cost-effective. The net increment of the 210 number of patients that received MgSO 4 , and the implementation cost-effectiveness per 211 additional patient treated, was also estimated. The analysis used the area-between-the-212 curves estimate of NPP effectiveness with a linear counterfactual, and a sensitivity analysis 213 using a beta counterfactual. 214 Probabilistic analysis was conducted using a Monte Carlo simulation with 10,000 samples 215 drawn from parameter distributions. Point estimates, probabilistic distribution assumptions, 216 and parameter source estimates are reported in Supplementary Table 2. Cost-effectiveness 217 planes and cost-effectiveness acceptability curves were plotted for willingness-to-pay 218 thresholds from zero to £100,000 per QALY gained for the policy cost-effectiveness of the 219 NPP intervention. 220 Secondary economic analysis 221 As evidence on the lifetime cost-effectiveness of antenatal MgSO 4 covers babies born up to 222 32 weeks’ gestation, cost-effectiveness analysis was performed only for babies <30 and <32 223 weeks’ gestation. 224 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 12 Statistical software Stata version 17 and R version 4.3.1 were used for all statistical analyses. 225 RESUL TS 226 Baseline character istics 227 In 2017, the year before NPP roll-out, a total of 4091 babies born under 30 weeks’ 228 gestational age were admitted to neonatal units in England, 296 in Scotland, and 182 in 229 Wales. The majority of births were in maternity units with a NICU (62.6% in England, 83.5% 230 in Scotland, 63.0% in Wales). Other than the number of babies admitted, study populations 231 were largely comparable across the three nations with respect to other covariates (Table 1). 232 His t orical trends 233 In 2014, MgSO 4 uptake was around 20% in England, 40% in Scotland, and 10% in Wales. 234 Uptake improved over time in all three nations, with the rate of change slowing down at 235 higher levels of treatment (ceiling effect). Although national lev els appeared to converge in 236 the latest 2022 data, there was visual suggestion that since the launch of the NPP, uptake 237 may have been accelerated in England compared to the devolved nations. However, due to 238 relatively smaller numbers, there was high variation in monthly uptake for Scotland and 239 Wales, which limited formal assessm ent of parallel trends (Figure 1). 240 Pr e/ po s t - NP P c omparison 241 In England, overall MgSO 4 uptake rose from 65.8% in 2017 to 85.5% in 2022 (62.3% to 81.4% 242 in Scotland, 61.6% to 86.6% in Wales). The amount of missing data fell from around 5% in 243 2017 to under 1% in 2022. Imminent delivery was the most commonly recorded reason for 244 not giving MgSO 4 , accounting for around 15% of eligible babies in 2017, dropping to around 245 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 13 10% in England and Wales in 2022. The number recorded as not offered MgSO 4 f e l l f r o m 246 around 7% to around 1% across all three nations (Supplementary Table 3). 247 Estimat e of N P P effectiv eness 248 The adjusted model estimated an average 5.8 (95% CI 2.7 to 8.9, p<0.001) percentage point 249 increase in MgSO 4 uptake in England across the four years post-NPP, compared to the one 250 year pre-NPP. Much of the gains app eared to take place as a step-change in the first two 251 years of the programme. There were additional gains in years three and four (at which point 252 the improvement became statistically significant), although confidence intervals overlap 253 with estimates from the first two years (Table 2). 254 Estimates were robust to sensitivity analyses (Table 2). There was indication of greater 255 improvement in MgSO 4 use when including babies up to 34 weeks’ gestational age in the 256 analysis (8.7 percentage point increase in MgSO 4 uptake, 95%CI 6.4 to 11.0, p<0.001), and in 257 the 40 units in the PReCePT RCT (8.6 percentage point increase in MgSO 4 uptake, 95%CI 2.4 258 to 14.9, p=0.007). There was some evidence that lower-level maternity units improved more 259 than higher-level units (SCBUs and LNUs: 9.1 percentage points change, 95%CI 3.9 to 14.3, 260 p=0.001. NICUs: 4.1 percentage points change, 95%CI 0.6 to 7.6, p=0.022) , reflecting the fact 261 that NICUs tended to have higher starting levels. 262 Impact o f the COVI D-19 pa nd emic 263 In 2020 there was a slight declining trend in MgSO 4 u s e c o i n c i d i n g w i t h t h e s t a r t o f t h e 264 COVID-19 pandemic, which continued to the end of the dataset at the end of 2022. The use 265 of antenatal steroids (another, more well-established protective treatment for preterm 266 babies) had an almost identical decline over this same period (Supplementary Figure 1). 267 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 14 Economic e valuation 268 The impact of the NPP is illustrated in Figure 2, using a linear distribution (Figure 2a) and a 269 beta distribution (Figure 2b) as counterfactuals. Probabilistic analysis estimated that the 270 additional use of MgSO 4 attributed to the NPP was equivalent to 3.0 percentage point 271 improvement on average over seven months, which equates to an additional 64 of the 2136 272 pre-term (<30 weeks’ gestation) babies receiving treatment (Table 3). The lifetime and 273 societal NMB of the NPP was about £597000, or £279 per preterm baby. The probability of 274 the NPP being cost-effective was 89% (Table 3, Supplementary Figure 2). 275 The sensitivity analysis with the beta distribution counterfactual, estimated a longer period 276 of impact (an additional three months) over which there was additional use of MgSO 4 277 attributed to the NPP equivalent to a 2.9 percentage point improvement on average over 10 278 months, which equates to an additional 92 of 3129 pre-term babies receiving treatment 279 (Figure 2b). Accounting for the total cost of the NPP, and the lifetime health gains and cost 280 savings of MgSO 4 treatment, the NMB was estimated to be £1.3m, or £400 per preterm 281 baby. The probability of the NPP being cost-effective in this analysis was 100% (Table 3). 282 Expanding the analysis to include babies up to 32 weeks’ gestation estimated additional use 283 of MgSO 4 attributed to the NPP equivalent to a 4.4 percentage point improvement on 284 average over nine months, which equates to an additional 215 pre-term babies treated. As 285 the total cost of the NPP was fixed, and not sensitive to the number of babies treated, the 286 NMB of the NPP was about £4.2m, or £853 per pre-term baby. The probability of NPP being 287 cost-effective was 100% at the willingness-to-pay threshold of £20,000 per QALY gained 288 (Supplementary Table 4 and Supplementary Figure 3). For the sensitivity analysis with the 289 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 15 beta distribution the NMB of NPP was about £5.4m, or £700 per preterm baby. The 290 probability of cost-effectiveness was 100% (Supplementary Table 4). 291 Expanding the analysis further again to include babies up to 34 weeks’ gestation shows that 292 the additional use of MgSO 4 attributed to the NPP was equivalent to 7.3 percen tag e poin t 293 improve ment on average over seven months. This means an additional 961 babies receiving 294 treatment. Using a beta distribution for the counterfactual showed a 6.5 percentage point 295 improvement attributed to the NPP over 12 months (698 additional patients). The NMB of 296 the NPP was not calculated for this more mature group of preterm babies, as currently there 297 is no available estimate for the cost-effectiveness of MgSO 4 treatment for babies born 298 above 31 +6 weeks’ gestation. 299 DI S CU S SI ON 300 The original NPP evaluation found evidence of improved MgSO 4 use over the first 12 months 301 following implementation. This extended evaluation found that the improvements have 302 largely been sustained over the first four years following implementation, although there 303 was suggestion of a slight decline in use coinciding with the pandemic. The benefits applied 304 both to the target population of births <30 weeks’ gestation, but also to more mature 305 preterm babies up to 34 weeks’ gestation. The programme was associated with a net 306 monetary benefit of about £0.6m for babies up to 29 weeks’ gestation, rising to about 307 £4.2m when babies up to 31 weeks’ gestation are included. Compared to the devolved 308 nations, uptake appeared to improve faster in England in the first two years following the 309 NPP launch. By the end of 2022 however, the three nations were broadly comparable with 310 delivery of MgSO 4 to around 81-87% of eligible mothers. This is at the higher end of levels 311 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 16 reported internationally (69% to 87%(23-26)) following guidelines or interventions to 312 increase MgSO 4 uptake. 313 Comparisons between England, Scotland, and Wales should be interpreted with caution: 314 firstly because there is high variability due to small numbers in the devolved nations data, 315 which limits formal statistical comparison of trends. Secondly because Scotland and Wales 316 were implementing their own MgSO 4 initiatives (e.g. MCQIC(27), PERIPrem Cymru(28)), 317 complicating their position as a cont rol group. Thirdly because there was also accessing of 318 the English PReCePT toolkit and implementation resources during this time period (66 319 downloads from Wales, 32 from Scotland, 2018-2022, AHSN data, unpublished). This 320 ‘contamination’ means that the boundaries of the target population are fuzzy, and again the 321 devolved nations cannot be consider ed optimal controls. Finally, the three nations’ trends in 322 uptake prior to the NPP were also not parallel, due to variation in starting levels in 2014, 323 and this meant that formal statistical comparison of their improv ements (for example 324 including all three nations in an interrupted time series or difference in difference analysis) 325 was not appropriate. 326 The COVID-19 pandemic could plausibly have impacted on MgSO 4 use: the broad impact on 327 staffing and quality of care affecting all parts of the NHS(29), and a specific impact on 328 expecting mothers who may have presented at hospital later due to concerns about 329 infection and giving birth alone, could both lead to missed opportunities to give MgSO 4 (30, 330 31). Analysis of future data will be important to explore what may be a temporary negative 331 effect of the pandemic, versus what might be a natural waning of the initially positive 332 effects of the NPP. From the observation that antenatal steroid use (historically well-333 established at high levels) declined almost identically to MgSO 4 u s e o v e r t h e p a n d e m i c 334 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 17 period, the national decline may be associated with the pandemic. This finding is concerning 335 and may illustrate the fragility of complex healthcare systems. Further follow up is 336 important to monitor both metrics. 337 The observation of greater improvements in uptake when including more mature preterm 338 births (all babies born up to 34 weeks’ gestation) is interesting. While the more mature 339 preterm infants represent a much larger proportion of preterm births, interpretation is 340 complex; their profile of underpinning antenatal disease, and hence their presentation to 341 healthcare, may vary from the more extreme preterm presentation. This could be expected 342 to impact on the subsequent ease of delivering antenatal MgSO 4 . Evidence on the protective 343 effect of MgSO 4 in babies 30-34 weeks’ is less clear(3, 32, 33) and although long term 344 neurological impacts remain higher in these groups than term-born peers(34), due to their 345 greater numbers, even small shifts in risks may have substantial population benefits(35). 346 It is likely to be more difficult to improve from 85% to 90% uptake, compared to improving 347 from 65% to 70% uptake. Further overall increases in MgSO 4 use may be a challenge without 348 concerted effort at the lower-performing units. However, as some units do report higher 349 (>90%) uptake (perhaps through better triaging and monitoring of symptoms), we argue 350 that their performance should be used as the benchmark for quality of care, and investment 351 in supporting the lower-performing units is likely to be cost-effective. 352 The creation of clinical guidelines alone is often not enough to ensure that evidence-based 353 interventions become standard practice. A relevant example here is the case of antenatal 354 steroids, which in the absence of a programme dedicated to getting this evidence into 355 practice, took several decades for their use to become standard care. In contrast, and in the 356 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 18 c o n t e x t o f t h e N P P , t h e s a m e i m p r o v e m e n t s i n u s e o f Mg S O 4 were achieved within a few 357 years. 358 Str engths a nd limitat ions 359 This evaluation included effectiveness and cost-effectiveness analysis to capture the impact 360 of the NPP implementation. These types of analysis have been highlighted as key 361 components of implementation science research(18, 36). Results from the main and 362 sensitivity analyses were consistent. Data covered a period of eight years, giving adequate 363 time for analysis of trends. The study benefitted from high quality, routinely collected, 364 national, longitudinal patient-lev el data. The key advantages of this comprehensive real-365 world data is that it provides high generalisability (included all maternity units in England, 366 Scotland, and Wales, reflecting the nationwide situation), shows effectiveness in real-world 367 conditions, and is less vulnerable to some biases such as recall, observer, and attrition bias. 368 A limitation is that this sort of data does not necessarily include all the covariates of interest, 369 and data quality and completeness is not always consistent across all sites. 370 A key limitation is that residual confounding cannot be excluded. We have tried to minimise 371 the impact of confounding through robust analytic methods, and interpret findings with 372 caution. In addition to the PReCePT programme, there are other factors that likely will have 373 impacted on uptake, including the publication of definitive evidence on the protective 374 effective of MgSO 4 in 2009(37) MgSO 4 use being reliably recorded as a Neonatal Data 375 Analysis Unit (NDAU) audit quality metric for maternity units in 2014-15, and its use 376 becoming a formal recommendation in the NICE Guidance in 2015(2). Other factors related 377 to PReCePT include the original pilot study publishing positive results in 2017; and 378 discussions with unit leads about the proposed NPP in 2017. The National Neonatal Audit 379 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 19 Programme (NNAP) concluded in their report on 2020 data that “This rapid improvement [in 380 MgSO 4 use], particularly seen in England, is likely to result from the targeted approach of 381 the PReCePT quality improvement initiative.”(38) 382 Another limitation is that the population investigated here included liveborn babies 383 admitted to a neonatal unit, rather than the total population of mothers eligible for MgSO4. 384 The rate of MgSO 4 uptake may be different between these two populations, although any 385 health benefit would only be realised in those investigated in this work. It would be an 386 advantage if future research could explore, and compare, uptake in both populations, and 387 the survival and neurodevelopmental outcomes for those preterm babies who did, and did 388 not, receive MgSO 4 . 389 The Health Foundation and Health Data Research UK recently listed PReCePT as a case study 390 model for a Learning Health System (i.e. a systematic approach to iterative, data-driven 391 quality improvement(39)) and we propose that the PReCePT model could be used as an 392 implementation blueprint for other quality improvement initiatives. 393 CON C LU SION S 394 Implementation of the National PReCePT Programme has plau sibly helped accelerate 395 uptake of MgSO 4 in England, improving maternal and neonatal care, and positively 396 impacting society in terms of direct patient benefit and future cost savings. Failure to deliver 397 MgSO 4 to eligible mothers should be considered inadequate care, and not financially 398 sustainable for the NHS. MgSO 4 as a quality metric should continue to be closely monitored, 399 and further intervention may be warranted to achieve optimal treatment lev els. Future 400 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 20 research should quantify the patient outcomes in this same population, specifically the 401 cases of cerebral palsy prevented, associated with the improvements in use of MgSO 4 . 402 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 21 Ab breviation s 403 CP Cerebral Palsy MgSO 4 Magnesium Sulphate NDAU Neonatal Data Analysis Unit NMB Net Monetary Benefit NN RD National Neonatal Research Database NPP National PReCePT Programme PReCePT Prevention of Cerebral Palsy in PreTerm Labour QI Quality Improvement 404 REFERE NCE S 405 1. Or g aniza tion ) WWH. WHO re commen da tion s on int erven tion s to im prov e pre ter m birth 406 outco me s . Swit zerl and; 2 015. C on trac t N o.: ISBN : 978 9 2 4 150 898 8. 407 2. (NI CE) NI fH a C E. Pr et erm labo u r a nd bir th (NG 25 ). 2015. 408 3. Crowth er C A, Mid dl eto n PF, Voys ey M, A skie L, Dul e y L, Pryde P G, e t a l. 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(which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 24 Table 1: Baby, mother , and mater nity unit c har ac t eristics by na t ion at ba seline 0 523 England Scotland Wales Socio-demographic characteristics of babies Number o f ba bie s (N) 1 409 1 2 9 6 182 G e s t at i o na l a g e ( m e d i a n we ek s , I QR ) 2 7 . 7 ( 2 6 . 0, 28 .9 ) 27 . 9 (2 6 .6,28. 9 ) 28 .0 ( 2 6. 6, 2 8 .9 ) 22 wee k s 14 ( 0 . 3 % ) 0 ( 0. 0 %) 3 ( 1.7%) 23 wee k s 22 5 (5.5 % ) 1 2 ( 4. 1 %) 6 ( 3.3%) 24 wee k s 37 4 (9.1 % ) 2 4 ( 8. 5 %) 9 ( 5.0%) 2 5 w e ek s 4 0 7 ( 10 .0 %) 1 9 (6 .4 % ) 1 2 (6 . 6 % ) 26 wee k s 530 (1 3 . 0 % ) 34 ( 1 1 .5 %) 2 2 ( 1 2 . 1%) 27 wee k s 644 (1 5 . 7 % ) 58 ( 1 9 .6 %) 3 4 ( 1 8 . 7%) 28 wee k s 886 (2 1 . 7 % ) 74 ( 2 5 .0 %) 5 6 ( 3 0 . 8%) 29 wee k s 10 11 ( 2 4 . 7 % ) 74 ( 2 5 .0 %) 4 0 ( 2 2 . 0%) B i r th w ei gh t ( m ed i an g r am s , I QR ) 9 61 (760, 1180) 101 0 ( 78 0 , 1 21 8) 10 3 0 (7 8 2 , 124 0 ) Male sex (N, %) 22 71 ( 5 5 . 5 % ) 1 5 6 (52. 7 %) 102 (56.0%) M u l t i p l e b ir t h s ( N , % ) 1 0 0 4 ( 2 4. 5% ) 7 8 ( 26 . 4% ) 40 ( 22 .0 % ) Socio-demographic characteristics of parents Number o f mo th e rs (N) 2 357 3 2 5 4 162 Materna l ag e (ye ar s, me an, S D) 3 0 .5 ( 6 . 1) 2 9 . 5 (5. 9 ) 28.7 ( 6.0) Mo t hers r e p orti n g w h ite B r itis h e thn icity (N , %) Non -w hite B ri tish Mi ss i ng data 17 93 ( 5 0 . 2 % ) 11 86 ( 3 3 . 2 % ) 594 (1 6 . 6 % ) 1 5 5 (61. 0 %) 3 4 (1 3. 4 % ) 6 5 (2 5. 6 % ) 116 (71.6%) 15 ( 9.3%) 31 ( 19 .1 % ) Le v el of deprivati on (IMD quint il e , N, %) 3 ( Most d e p rive d ) 1 12 15 ( 3 4 . 0 % ) 88 ( 3 4 .7 %) 5 1 ( 3 1 . 5%) 2 804 (2 2 . 5 % ) 60 ( 2 3 .6 %) 3 0 ( 1 8 . 5%) 3 611 (1 7 . 1 % ) 33 ( 1 3 .0 %) 3 7 ( 2 2 . 8%) 4 487 (1 3 . 6 % ) 36 ( 1 4 .2 %) 2 0 ( 1 2 . 4%) ( L east d e p rive d ) 5 391 (1 0 . 9 % ) 28 ( 1 1 .0 %) 2 1 ( 1 3 . 0%) Mi ss i ng data 65 ( 1 . 8 % ) 9 ( 3. 5 %) 3 ( 1.9%) An y re p orte d smoki ng h ist ory (N, %) 602 (1 6 . 9 % ) 38 ( 1 5 .0 %) 4 3 ( 2 6 . 5%) Clinical characteristics of mothers Hypert e n s i on i n pregna n cy (N, %) 16 3 (4.6 % ) 1 6 ( 6. 3 %) 5 ( 3.1%) Prema tu re ru pture o f me mbranes (N, %) 603 (1 6 . 9 % ) 49 ( 1 9 .3 %) 30 ( 18 .5 % ) C a e s a re a n s e c t i o n ( N , % ) 1 8 8 8 ( 5 2. 8% ) 15 2 ( 5 9 . 8% ) 87 ( 53 .7 % ) An te n a ta l steroid s give n (N, %) 32 68 ( 9 1 . 5 % ) 2 3 1 (90. 9 %) 149 (92.0%) Maternity Unit characteristics Total n um ber of m ate rn ity u n its Wi t h no ne o nata l se r vice Wi t h S pecial C a re Ba by Unit / L o c al Ne o na ta l U ni t W it h Ne o nata l I ntensive Care Uni t 15 0 3 10 6 41 18 3 6 9 12 2 7 3 Bi rt hs p e r l e v e l of u nit (N, %) Wi t h no ne o nata l se r vice Wi t h S pecial C a re Ba by Unit / L o c al Ne o na ta l U ni t W it h Ne o nata l I ntensive Care Uni t 6 ( 0. 2% ) 13 29 ( 3 7 . 2 % ) 22 38 ( 6 2 . 6 % ) 6 ( 2. 4 %) 3 6 (1 4. 2 % ) 2 1 2 (83. 5 %) 11 ( 6.8%) 49 ( 30 .3 % ) 102 (63.0%) Averag e n um ber of e l igi b l e births per h o sp ita l pe r mon th (me an, sd) 2 .8 (2 .1 ) 2 . 3 (1 .3 ) 2 .1 (1 .6 ) 0. Bas eli ne p e rio d is m eans/p ropo rtions a c r os s J a n-D e c 2 017, the y e ar b e fo r e th e N P P wa s r oll ed-ou t in Eng l a n d . 524 1 .B a b ie s u p t o 3 0 we ek s ’ g es t a t i on a l ag e. Des cr i p t ive d a ta i s on a l l b a bie s i n clu di ng mu lt i ple s . A na ly s is i s res t r ic te d t o s ing l etons a nd fir st-525 bo r n of multi p l e s . 526 2 . Un i q ue m o t he r I Ds 527 3 . En g l ish , Sco t ti s h a n d Wels h In d i ce s o f Mu lt i ple Dep r i vat i o n are c a l c u l a te d di ffe ren tl y an d are no t c o mp ar a b le be twee n n a t io n s . 528 529 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 25 Table 2: Change in Mg SO 4 uptak e in England fr om bef ore to a f ter t he NP P 0 530 Step-change in MgSO 4 uptake after intervention (percentage points) 1 95 % CI p- v a l ue Change in slope post- intervention compared to pre- intervention 95 % CI p - v a lu e Overall slope post-intervention 95 % CI p- v a l ue Unadjusted 2 1 1. 8 1 0. 0 to 13 .6 < 0 . 0 01 - - - Ful l y a d justed 3 5 . 8 2 . 7 to 8 . 9 <0.0 0 1 -0 .87 -1 .18 t o - 0 . 57 < 0 .001 0 . 02 -0 .0 6 t o 0.1 0 0 . 6 2 2 Cumulative increase per-year across the follow-up period 2 Year 1 3 . 1 -1 .3 t o 7.4 0 . 167 -0 .76 -1 .48 t o - 0 . 05 0. 0 3 7 0 . 19 -0 .3 1 t o 0.6 9 0 . 4 5 0 Yea r 1 - 2 3 . 5 -0 .2 t o 7.3 0 . 067 -0 .57 -0 .91 t o - 0 . 23 < 0 .001 0 . 25 0 . 09 t o 0 . 4 1 0 . 0 0 2 Yea r 1 - 3 5 . 6 2 . 1 to 9 . 1 0 . 002 -0 .86 -1 .25 t o - 0 . 48 < 0 .001 0 . 05 -0 .0 5 t o 0.1 6 0 . 3 0 2 Ye a r 1- 4 5 . 8 2 . 7 to 8 . 9 <0.0 0 1 -0 .87 -1 .17 t o - 0 . 57 < 0 .001 0 . 02 -0 .0 6 t o 0.1 0 0 . 6 2 2 Secondary, sensitivity and sub-group analyses 2 An a l y sis at mat erni ty -un i t lev el 4 5 . 8 2 . 8 to 8 . 8 <0.0 0 1 -0 .83 -1 .47 t o - 0 . 18 0. 0 1 2 0 . 003 -0 .0 5 t o 0.0 6 0 . 9 2 3 An a l y sis at in d iv id u a l-le v el 4 5 . 9 2 . 5 to 9 . 3 0 . 001 -0 .76 -1 .17 t o - 0 . 34 < 0 .001 0 . 02 -0 .0 3 t o 0.0 7 0 . 4 4 9 Ex clu di n g im pleme ntati on start w i nd o w ( 2 m on t h s e a c h s i de of s t a r t ) 6 . 6 2 . 9 to 1 0 . 3 <0.0 0 1 -0 .86 -1 .17 t o - 0 . 54 < 0 .001 -0 .0 1 -0 .0 9 t o 0.0 7 0 . 8 2 0 E x c l ud i ng f i na l 2 m on t h s ( ? da t a qua lity) 5 . 8 2 . 6 to 8 . 9 <0.0 0 1 -0 .82 -1 .14 t o - 0 . 50 < 0 .001 0 . 04 -0 .0 4 t o 0.1 2 0 . 3 4 6 Co m p a ring 4 y ears pre with 4 yea rs po st 6 . 0 3 . 7 to 8 . 4 <0.0 0 1 -0 .74 -0 .82 t o - 0 . 65 < 0 .001 0 . 01 -0 .0 7 t o 0.0 8 0 . 8 9 5 PR e C e P T c R CT u nits o n ly (n = 40) 8 . 6 2 . 4 to 1 4 . 9 0 . 007 -0 .79 -1 .37 t o - 0 . 20 < 0 .001 0 . 04 -0 .0 9 t o 0.1 6 0 . 5 6 3 I n c l ud i n g b a b i es up to 3 4 w ee ks gestatio n 8 . 7 6 . 4 to 1 1 . 0 <0.0 0 1 -0 .69 -0 .90 t o - 0 . 48 < 0 .001 0 . 046 -0 .0 2 t o 0.1 1 0 . 1 5 7 0 A ll d at a on sin gl et o n s an d first b o rn of m ulti pl es <30 w e e k s’ g e st ati o n an d ad mitt ed to an NHS N e o na tal un i t 531 1 P e r c ent a g e poi nt diff er e n c e i n uptake betw e en m ean a c ros s th e 12m pr e-N P P, a nd mean ac ross the four y ea r s p ost-N P P 2 C ru d e r eg r e s s i o n of u pt a k e p o s t - i m pl e m e nt a t i on c o m pa r e d w i t h p r e - i m p l e m en t a t i o n . 532 3 F ul l y a d j u s te d m od e l: in c l u de s i n ter a c t io n be twe e n p re -p os t per i od a nd s t ud y mo n th to c a p tu re c h a n ge i n s lop e a s we ll a s s te p -c h an ge . Adjust ed for co v ari at es a s m o n thly ag g r egat es: m ean ma t e rnal a g e , 533 propor tion w h o i dentifi e d as of wh i t e B r iti sh et hn i city, mean I M D de ci l e , p ro p o r ti on o f mu l ti pl e b irth s, prop o rti o n wi th pr egn a n cy hyp ert ensi on, r eport ed sm oker s, type of b i rth ( c-s e c t io n ver sus v agi nal del i v e ry ), 534 b i r t h w e i g ht a dj u s t e d f o r g e st at i on a l a g e a s a z - s c o r e . M o d e l w ei g ht e d o n un i t s i z e . 535 4 A d diti o na lly adjust ed for l ev e l of bi rth u nit, and r e g ional c lust eri ng b y A HSN. 536 537 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 26 Table 3. Pr obabilistic C os t -Effectiven e s s Re s u lts o f the N PP fr om Int erru pted Time Ser ies A nalys is (<30 we eks ’ gestat ion) 538 Main analysis (lin e ar dis tri buti o n c o u nt erfactu a l) Sensitivity analysis (beta d i s tri buti o n c o un te r f a c tu a l ) Pe r i o d o f benefi t, m o nt h s 7 1 0 Nu mber of pre-t erm b abies (≤ 3 w eeks), N 213 6 31 2 9 Ch a n ge i n pr o po rt i o n o f pre-ter m babi es treate d wit h M g SO 4 , Δb i , % 3. 0% (1 . 5 %; 4.5% ) 2.9% (2. 3% ; 3. 6%) Net I n c remen t of pre- te rm babies t re at ed w it h MgSO 4, Δpat 64 (32 ; 97 ) 92 (72; 11 2 ) Net c ost of im plement ati o n , ΔC i , £ 9 3 6 7 4 7 9 367 47 I m p l em en ta ti on c os - e f fe ct iv en e s s , Δ Ci / ΔPat , £ pe r ad diti o na l p at ie n t trea ted 145 76 ( 29 28 4 ; 9 669 ) 10 2 19 (13 040 ; 838 6 ) L i f e t im e he a lt h e f fe c t o f Mg S O4 t r e a tmen t p e r patie nt , Δbt , Q ALY 0. 24 ( 0.1 6; 0 . 3 3 ) 0.2 4 ( 0 . 1 6 ; 0. 33) Lifeti me c ost s of M g SO 4 treatm ent p er p ati ent, Δct , £ -1 9 0 6 4 (- 133 10; -25 6 48) -1 906 4 (- 1 331 0; -2 5 64 8) Net Mon et a r y B e n efit of th e P olic y , NMB P , £ 1 596 538 ( -2 21 748 ; 15 417 86 ) 12 5 15 11 ( 5581 15 ; 207 1 24 4 ) Proba bil i t y of bei ng c o s t-e ff ec tive, % 8 9% 1 00% 1 A t a w ill i n gnes s -t o - pa y t hres hold of £ 20 , 00 0 p e r Q AL Y gai ne d 539 540 541 542 543 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint 27 544 Figure 1: Mg SO4 upt ak e in En gland, Sco tland and Wales, 2 01 4 t o 20 22 545 Figure 2: Pr edicted Mg S O 4 upt ake, C ounter factual and A rea-B etween-C u rves f rom In terr upt ed Time Series an alys es 546 547 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint Figure 1. MgSO 4 uptake in England, Scotland and Wales, 2014 to 2022 Figure 2. Predicted MgSO 4 uptake, Counterfactual and Area-Between-Curves from Interrupted Time Series analyses . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 16, 2024. ; https://doi.org/10.1101/2024.07.16.24310419doi: medRxiv preprint