(Abstracted from BJOG 2024;131:1673–1683) Fetal growth restriction (FGR) occurs when a fetus grows slower than expected for gestational age. Severe early-onset cases are associated with stillbirth, neonatal death, and developmental disorders.

OBJECTIVE:Severe early-onset fetal growth restriction (FGR) causes stillbirth, neonatal death and neurodevelopmental impairment. Poor maternal spiral artery remodelling maintains vasoactive responsiveness but is susceptible to treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, which may improve perinatal outcomes. DESIGN:Superiority, double-blind randomised controlled trial. SETTING:A total of 20 UK fetal medicine units. POPULATION:Pregnancies affected by FGR, defined as an abdominal circumference below the tenth centile with absent end-diastolic flow in the umbilical artery between 22+0 and 29+6 weeks of gestation. METHODS:Treatment with sildenafil (25 mg three times/day) or placebo until delivery or 32 weeks of gestation. MAIN OUTCOME MEASURES:All infants alive at hospital discharge were assessed for cardiovascular function and cognitive, speech/language and neuromotor impairment at 2 years of age. The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley-III composite score of >85. RESULTS:In total, 135 women were randomised between November 2014 and July 2016 (70 to sildenafil and 65 to placebo). We previously published that there was no improvement in time to delivery or perinatal outcomes with sildenafil. In all, 75 babies (55.5%) were discharged alive, with 61 infants eligible for follow-up (32 sildenafil and 29 placebo). One infant died (placebo), three mothers declined and ten mothers were uncontactable. There was no difference in neurodevelopment or blood pressure following treatment with sildenafil. Infants who received sildenafil had a larger head circumference at 2 years of age (median difference 49.2 cm, IQR 46.4-50.3, vs 47.2 cm, 95% CI 44.7-48.9 cm). CONCLUSIONS:Sildenafil therapy did not prolong pregnancy or improve perinatal outcomes and did not improve infant neurodevelopment in FGR survivors. Therefore, sildenafil should not be prescribed for this condition.

OBJECTIVE:To identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies. DESIGN:Cross-sectional survey. SETTING:International. POPULATION:Clinicians involved in the management of MCDA twin pregnancies with sFGR. METHODS:A structured, self-administered survey. MAIN OUTCOME MEASURES:Clinical practices and attitudes to diagnostic criteria and management strategies. RESULTS:Overall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of <10th centile for the smaller twin and an inter-twin EFW discordance of >25% for the diagnosis of sFGR. For early-onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early-onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early-onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early-onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide. CONCLUSIONS:There is significant variation in clinician practices and attitudes towards the management of early-onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high-level evidence to guide management.

Background Severe early-onset intrauterine growth restriction is associated with stillbirth, neonatal death and neurodevelopmental impairment. There is no treatment for intrauterine growth restriction with timely delivery being the only management option. Placentas from intrauterine growth restriction pregnancies often show failure to remodel maternal spiral arteries leading to a persistent vasoactive responsiveness. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates naturally occurring nitrous oxide, encouraging vasodilation of vasoactive vessels. Previous studies in animal models and humans show recovery of placental function and improvement in fetal growth. The STRIDER trial aimed to address whether treatment with sildenafil is beneficial to fetal growth and perinatal and toddler outcomes. Methods The STRIDER trial was a superiority, randomised double-blind placebo-controlled trial that was carried out in 19 fetal medicine units in the United Kingdom. Women with a singleton pregnancy between 22+0 and 29+6 weeks’ gestation, with severe early-onset intrauterine growth restriction, were asked to participate. Women were randomised (1 : 1) to receive either sildenafil 25-mg three times daily or placebo until 31+6 weeks’ gestation or delivery. Women were stratified by site and their gestational age at randomisation (before 26+0 or at 26+0 weeks or later). Severe intrauterine growth restriction was defined as a combination of estimated fetal weight or abdominal circumference below the 10th percentile and absent or reversed end-diastolic blood flow in the umbilical artery on Doppler velocimetry. The primary outcome was the time from randomisation to delivery, measured in days with a 1-week difference deemed to be clinically significant. The phase 2 study followed up all babies alive at discharge to assess for cardiovascular function and neurodevelopment at 2 years of age. Results Between 21 November 2014 and 6 July 2016, a total number of 135 women were recruited to the study, of these 70 were assigned to sildenafil and 65 to the placebo. No difference was found in the median randomisation to delivery interval between sildenafil [17 days (interquartile range 7–24)] and placebo [18 days (8–28), p = 0.23]. Live births [relative risk 1.06, 95% confidence interval 0.84 to 1.33; p = 0.62], fetal deaths (relative risk 0.89, 95% confidence interval 0.54 to 1.45; p = 0.64), neonatal deaths (relative risk 1.33, 95% confidence interval 0.54 to 3.28; p = 0.53), and birthweight [mean difference −14 g (95% confidence interval −100 to 126); p = 0.81] did not differ between the treatment arms and no differences were found for other maternal or perinatal secondary outcomes. Eight serious adverse events were reported during the study (six in the placebo group and two in the sildenafil group); none of these were attributed to sildenafil. Seventy-five babies were discharged alive from the neonatal unit and of those 61 were available for follow-up with 32 treated with sildenafil and 29 with placebo. Of those that did not have a follow-up 1 baby died (placebo) and 3 declined follow-up and 10 were uncontactable. There was no difference in neurodevelopment, or blood pressure for infants treated with sildenafil versus placebo. Infants who received sildenafil had a greater head circumference compared to those who received placebo (median difference 49.25 cm, interquartile range 46.4–50.26 vs. 47.17 cm, 95% confidence interval 44.71 to 48.95). Conclusion Sildenafil did not prolong pregnancy or improve pregnancy outcomes. There was no effect from sildenafil treatment on infant neurodevelopment. Our data show that sildenafil should not be prescribed for fetal growth restriction. Trial registration This trial is registered as ISRCTN39133303. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/62/109) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 18. See the NIHR Funding and Awards website for further award information. Plain language summary Babies that are very small in the womb are at greater risk of a poor outcome to the pregnancy such as stillbirth and learning difficulties in surviving children. Usually, a baby grows small because the placenta, which feeds the baby, is poorly formed. The study wanted to know whether using a medication, which improves the blood supply to the placenta, will give the baby more nutrition and allow better growth. This would allow doctors to keep the baby inside the womb for longer. The study used a medication called sildenafil to improve the blood supply. To be sure if it worked, the study wanted to compare this drug against an identical looking blank tablet (placebo) so women and their healthcare professionals would not know what medication was being given. Women with very small babies and who were pregnant between 22 weeks and 0 days to 29 weeks and 6 days were asked to take part in the study. Treatment was three times a day and continued until delivery or 31 weeks and 6 days. A total of 135 women agreed to take part in the study. Seventy were given sildenafil and 65 were given placebo. A computer decided which medication would be given to which women with a 50 : 50 chance of each. Women were kept in the study until discharge of their baby from hospital. Surviving babies were seen with their mothers at 2 years of age to test for brain injury and problems with thinking, speech and language, or movement (neurodevelopment). The study showed no benefit of sildenafil when compared to placebo in helping the baby grow or in preventing early delivery. In surviving babies there was no benefit for neurodevelopment 2 years after treatment with sildenafil. The findings of our study mean that sildenafil should not be used for the treatment of small babies. Scientific summary Background Severe early-onset intrauterine growth restriction (IUGR) is associated with stillbirth, neonatal death and neurodevelopmental impairment. There is currently no treatment for IUGR with timely delivery being the only management option available. The researchers know from human placentas from IUGR pregnancies that there is often a failure to remodel the maternal spiral arteries within the uterus and myometrium. This inadequate remodelling leads to the persistence of a vasoactive responsiveness within these vessels. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates naturally occurring nitrous oxide (NO), encouraging vasodilation of vasoactive vessels. Previous studies in animal models and human ex vivo samples have shown recovery of placental function and improvement in fetal growth. Small numbers of clinical trials have also shown an increase in fetal growth or vascular flow (Doppler studies) from maternal use of sildenafil. The STRIDER trial aims to address whether maternal treatment with sildenafil is beneficial to fetal growth and perinatal and toddler outcomes. Objectives The STRIDER United Kingdom (UK) study was designed to answer the following objectives in two phases; phase 1 – recruitment to a randomised controlled trial of sildenafil versus placebo for the treatment of early-onset intrauterine fetal growth restriction, and phase 2 – follow-up at 2 years of age to assess cardiovascular and neurodevelopmental outcomes effect the surviving infants. The primary objective of the phase 1 study was to determine whether sildenafil, compared to placebo therapy, delays the need to deliver a severely growth-restricted fetus by a minimum of 1 week. The secondary objectives were as follows: To investigate impact on fetal growth and fetal well‐being by comparing differential effect on vascular resistance in the uterine arteries, umbilical, fetal middle cerebral artery and fetal ductus venosus and differences in birthweight centiles in infants treated in utero with sildenafil and placebo. To examine, through collaboration with an international consortium, the hypothesis that sildenafil therapy compared to placebo therapy increases the rate of infant survival free of major neurodisability. To report frequency of adverse and serious adverse events (SAEs) associated with sildenafil use. To investigate the impact on maternal cardiovascular parameters by measurements of maternal heart rate and peripheral blood pressure (BP) before and after administration of study medication. To elucidate the precise mechanism and location of action of sildenafil in pregnancy by investigating the effects of sildenafil therapy on omental (representative of the wider maternal systemic vasculature), myometrial (uterine vasculature) and chorionic plate artery (placental vasculature) reactivity. The objective of the phase 2 follow-up study was to examine neurodevelopmental and cardiovascular outcomes at 2 years of age in children born to mothers who received sildenafil compared with placebo during pregnancy. It was hypothesised that: STRIDER UK children whose mothers received sildenafil will have improved neurodevelopmental outcomes at age 2–3 years (corrected) compared with controls exposed to placebo. There will be no difference in BP at 2–3 years (corrected) between STRIDER UK children whose mothers received sildenafil compared with controls exposed to placebo. Methods The STRIDER study was a Phase III clinical trial to quantify the effects of administration of sildenafil on pregnancy outcome in severe early‐onset IUGR. The study was designed as a randomised double-blind, placebo-controlled trial with sildenafil or placebo prescribed orally at a dose of 25 mg three times per day. All participants recruited had a singleton pregnancy between 22+0 weeks’ gestation and 29+6 weeks’ gestation with a diagnosis of IUGR and had agreed to expectant management. For the purpose of the study, IUGR was defined as a fetus with an estimated fetal weight or abdominal circumference below the 10th centile using local charts and absent or reversed end-diastolic flow in the umbilical artery on Doppler velocimetry. All participants were recruited from one of the 19 STRIDER research sites located in the UK. All sites were leading obstetric units within the UK with a high level of fetal medicine and neonatal services provided. Gestational age was confirmed by first trimester ultrasound and in each case, the diagnosis of severe early-onset IUGR was confirmed by a fetal medicine expert having excluded fetal anatomical abnormalities. Following diagnosis and informed consent, a full history, measurements of maternal cardiovascular parameters (BP and pulse rate), fetal biometry and Doppler velocimetry were taken. Maternal venepuncture for angiogenic biomarkers was also performed. All participants had further BP and pulse rate measurements and blood sampling 2 hours after receiving the first dose of the study drug. Subsequently, participants were followed up within 3–4 days and at weekly intervals thereafter, or earlier if clinically indicated. The remainder of clinical care was at the discretion of the local fetal medicine experts and included regular ultrasound assessment of growth and Doppler blood flow and antenatal cardiotocography. Study medication was over encapsulated (Sharp Clinical Services, Crickhowell, UK) to ensure that participants, clinicians and pharmacists were masked to the study drug. Medication was dispensed in 10-day supplies with a new supply being provided weekly to ensure there was no period where medication was missed. Treatment ended at 31+6 weeks’ gestation or delivery, whichever came first. All participants were advised of the potential side effects. Data on pregnancy outcome were collected prospectively from clinical maternity notes and entered onto a secure electronic case report form (eCRF) platform at research sites. Data quality and protocol compliance were monitored regularly by central and on-site monitoring methods. All surviving infants of mothers recruited to the STRIDER study were eligible and invited for follow-up. A study invitation pack was sent to all parents/carers of surviving children. This included an invitation letter, participant information sheet and informed consent form. Participants who did not contact the research team within 2 weeks were contacted by a member of the research team. Assessments took place in a clinical research setting or in the child’s home. Informed written consent was obtained before the assessment began. All assessments were performed by a single senior research psychologist with expertise in developmental assessment techniques. This researcher was blinded to treatment allocation. Assessments included the Cognitive, Language and Motor Subscales of the Bayley Scales of Infant and Toddler Development – III (BSID-III); Hempel’s Neurological Examination for Toddler Age to identify major neurological impairment (cerebral palsy; CP) and subtle deviations from typical neurological and neuromotor function. In addition, a cardiovascular assessment was undertaken, which included brachial systolic BP and diastolic BP and arterial stiffness, assessed as aortic (central) augmentation index (AIx). Where potential participants cancelled or failed to attend follow-up appointments on more than three occasions, they were invited to participate remotely. All such participants received a Follow-up questionnaire pack, which included participant information sheet, consent form and all questionnaires detailed as part of the main study in addition to the Ages and Stages Questionnaire-3 (in place of the BSID-III, neurodevelopmental assessment). The health status classification system – preschool version (HSCS-PS) is a parental (or clinician) proxy measurement of the health status of a child. The overall health status is described as a 10-element vector consisting of one level for each domain. In this study, to facilitate comparisons between groups, a total ‘disability score’ for the overall health state of a child was calculated as the sum of the level codes for the original domains. Therefore, the range of the disability score varied from 10 (no disability on any domain) to 41 (maximum disability on all 10 domains). The child behaviour checklist (CBCL) 1.5–5 was used to assess emotional and behavioural difficulties. Raw scores are normalised into T-scores [mean: 50, standard deviation (SD): 10]. Higher T-scores represent more problematic behaviour. T-scores below 60 are in the normal range, T-scores of 60–63 (84th to 90th percentile) are in the borderline range, and T-scores above 63 (above 90th percentile) are in the clinical range. The T-scores are dichotomised into typical (scores in the normal range) and atypical (scores in the borderline and clinical range). The behaviour rating inventory of executive function – preschool version (BRIEF-P) is a parent questionnaire for early assessment of executive function to assess severity of executive dysfunction in day-to-day situations. Age-based T-scores are computed for each subscale and index, and a score of 65 or higher is considered a clinically significant problem. Results The study recruited 135 participants between 21 November 2014 and 6 July 2016. A number of 75 participants were recruited before 26+0 weeks’ gestation and 60 between 26+0 and 29+6 weeks’ gestation. A total of 70 participants were randomly assigned to receive sildenafil and 65 to placebo. None of the participants withdrew their consent nor were lost to follow-up prior to delivery, therefore, additional ‘per-protocol’ analysis was not performed. Differences at baseline were not clinically important between the sildenafil group and the placebo group. The median gestation at randomisation was 24.4 weeks [interquartile range (IQR) 24.0–27.5]. Two babies were postnatally diagnosed with Down syndrome (one sildenafil and one placebo) and two had confirmed cytomegalovirus infection (one sildenafil and one placebo); all four babies were included in the intention to treat (ITT) analysis. There was no beneficial effect on maternal cardiovascular function from treatment with sildenafil. The follow-up phase was delayed due to the impact of the COVID-19 pandemic on research staff’s availability and access to patients. Out of the 75 babies who were discharged alive from the neonatal unit, 61 babies (81.3%) were included in the follow-up phase. Of those not followed up, 1 baby died (placebo), 3 declined follow-up and 10 were uncontactable. By the nature of follow-up participants were not randomised by treatment leaving 32 mothers who had received sildenafil and 29 had received placebo. There was no difference in the sex, birthweight, gestation at delivery (median 29.2 weeks vs. 29.9 weeks), mode of delivery, or oxygen usage. The physical characteristics of the population available for follow-up showed no difference in height or weight. Head circumference was slightly larger in those treated with sildenafil (49.25, 46.43–50.26) versus placebo (47.18, 44.71–48.95). There was no difference between systolic and diastolic BP between those children treated with sildenafil or placebo. Median values were appropriate for children aged 2 years. The Bayley assessment showed no significant differences in cognitive, language (including receptive and expressive language), or motor (including fine and gross motor) subscales between children of sildenafil-and placebo-treated mothers. Total scores were somewhat lower than expected across all three domains compared with standard population norms (i.e. 100, SD = 15); however, the difference was neither clinically nor statistically significant. There was no difference between the sildenafil and placebo groups for the presence of CP reported by parents. Functional assessment with the BRIEF-P demonstrated no difference in adjusted T-scores between sildenafil and placebo for any of the assessed domains. Likewise, the median total CBCL scores and adjusted T-scores also showed no difference between babies whose mothers were treated with sildenafil versus placebo for any of the assessed domains. The HSCS scores are shown as a total score by domain and as individual components. There was no difference between infants who had received sildenafil to those who had received placebo for any of the domains assessed. It was not possible to record the HEMPEL assessments and as such neurology could not be assessed. Unfortunately, no children were able to tolerate the NICOM (Non-invasive Cardiac Output Monitor)cardiovascular test, leaving BP as the sole assessment of infant cardiovascular status. Conclusions The results of the STRIDER study demonstrated that sildenafil did not result in prolongation of pregnancy, improvements in fetal growth, or perinatal outcome when administered to pregnant women with a severely-growth restricted fetus. These results have subsequently been confirmed in a number of other studies. Our study demonstrated a lack of benefit on any neurodevelopmental, emotional or behavioural assessment from treatment with sildenafil. This study represents the first study to report to the impact of antenatal treatment of women with severe early-onset FGR on their infants’ well-being at 2 years of age. Along with the findings of no benefit on prolongation of pregnancy or perinatal outcome this study it confirms the ineffectiveness of this treatment to improve outcomes in babies with severe early-onset FGR. Further to this lack of benefit there were concerns raised during the Dutch STRIDER trial of increased perinatal mortality in the sildenafil group. Further assessment deemed this excess mortality to be predominantly due to persistent pulmonary hypertension of the neonates (PPHN), which has been proposed to be a pathophysiological mechanism of ‘rebound’ vasoconstriction after cessation of sildenafil. Both the UK and the New Zealand/Australia STRIDER Trials reviewed their data using the same criteria for PPHN as the Dutch STRIDER trial and did not find an increased mortality. The international STRIDER studies are committed to combine the study data in a prospective individual participant data (IPD) meta-analysis to look for any possible long-term effect of sildenafil, particularly on neurodevelopmental and cardiovascular outcome. On current evidence, the researchers do not believe that there is likely to be any beneficial effect on fetal growth, perinatal outcomes or neurodevelopment in this patient group and would advise that further use of sildenafil in this population should be stopped. Prior to any further studies using PDE5 inhibitors to treat FGR being performed, pharmacokinetic and pharmacodynamic experiments specific to pregnancy should be performed to establish an efficacious therapeutic dose. Therefore, the STRIDER study showed no beneficial effect for any perinatal outcome for mother or baby from treatment with 25 mg sildenafil TDS for severe early-onset FGR. The follow-up study confirmed that there was no beneficial effect from maternal treatment with sildenafil on behavioural assessment performed at 2 years of age in the surviving infants. There was also no effect on infant BP from treatment with sildenafil. Trial registration This trial is registered as ISRCTN39133303. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/62/109) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 18. See the NIHR Funding and Awards website for further award information.

Introduction Selective fetal growth restriction (sFGR) in monochorionic twin pregnancy, defined as an estimated fetal weight (EFW) of one twin <10th centile and EFW discordance ≥25%, is associated with stillbirth and neurodisability for both twins. The condition poses unique management difficulties: on the one hand, continuation of the pregnancy carries a risk of death of the smaller twin, with a high risk of co-twin demise (40%) or co-twin neurological sequelae (30%). On the other, early delivery to prevent the death of the smaller twin may expose the larger twin to prematurity, with the associated risks of long-term physical, emotional and financial costs from neurodisability, such as cerebral palsy.When there is severe and early sFGR, before viability, delivery is not an option. In this scenario, there are currently three main management options: (1) expectant management, (2) selective termination of the smaller twin and (3) placental laser photocoagulation of interconnecting vessels. These management options have never been investigated in a randomised controlled trial (RCT). The best management option is unknown, and there are many challenges for a potential RCT. These include the rarity of the condition resulting in a small number of eligible pregnancies, uncertainty about whether pregnant women will agree to participate in such a trial and whether they will agree to be randomised to expectant management or active fetal intervention, and the challenges of robust and long-term outcome measures. Therefore, the main objective of the FERN study is to assess the feasibility of conducting an RCT of active intervention vs expectant management in monochorionic twin pregnancies with early-onset (prior to 24 weeks) sFGR.Methods and analysis The FERN study is a prospective mixed-methods feasibility study. The primary objective is to recommend whether an RCT of intervention vs expectant management of sFGR in monochorionic twin pregnancy is feasible by exploring women’s preference, clinician’s preference, current practice and equipoise and numbers of cases. To achieve this, we propose three distinct work packages (WPs). WP1: A Prospective UK Multicentre Study, WP2A: a Qualitative Study Exploring Parents’ and Clinicians’ Views and WP3: a Consensus Development to Determine Feasibility of a Trial. Eligible pregnancies will be recruited to WP1 and WP2, which will run concurrently. The results of these two WPs will be used in WP3 to develop consensus on a future definitive study. The duration of the study will be 53 months, composed of 10 months of setup, 39 months of recruitment, 42 months of data collection, and 5 months of data analysis, report writing and recommendations. The pragmatic sample size for WP1 is 100 monochorionic twin pregnancies with sFGR. For WP2, interviews will be conducted until data saturation and sample variance are achieved, that is, when no new major themes are being discovered. Based on previous similar pilot studies, this is anticipated to be approximately 15–25 interviews in both the parent and clinician groups. Engagement of at least 50 UK clinicians is planned for WP3.Ethics and dissemination This study has received ethical approval from the Health Research Authority (HRA) South West—Cornwall and Plymouth Ethics Committee (REC reference 20/SW/0156, IRAS ID 286337). All participating sites will undergo site-specific approvals for assessment of capacity and capability by the HRA. The results of this study will be published in peer-reviewed journals and presented at national and international conferences. The results from the FERN project will be used to inform future studies.Trial registration number This study is included in the ISRCTN Registry (ISRCTN16879394) and the NIHR Central Portfolio Management System (CPMS), CRN: Reproductive Health and Childbirth Specialty (UKCRN reference 47201).

Objective: To assess feasibility for a definitive randomized controlled trial (RCT) comparing three treatments for short cervix in a population at high risk for spontaneous preterm birth (sPTB) over a 1-year period.Design: Three arm, open label feasibility randomized clinical study.Methods: Women with singleton pregnancy with risk factors for sPTB (history of sPTB or prelabor premature rupture of membranes (PPROM) <34 weeks or significant cervical surgery), and short cervix on transvaginal ultrasound scan detected between 16+0 and 24+6 weeks gestation were randomized to receive either cervical cerclage, vaginal pessary, or vaginal progesterone 200 mg nocte. Pregnancy outcomes and treatment costs were collected from hospital records, NHS Reference costs, and British National Formulary costs.Main outcome measures: Feasibility targets were defined as (i) at least 55% of eligible women randomized; (ii) maximum 5% failure to adhere to the protocol per arm; (iii) maximum 5% loss to short-term follow-up.Results: Of 417 women screened between October 2015 and 2016, 25 (6%) were eligible for trial inclusion, of whom 18 (72%) agreed to participate at the rate 0.75 participants/site/month. Adherence to protocol was 100% in pessary and cerclage arms and 80% in vaginal progesterone arm (95% CI 24–100%). No participants were lost to follow up. Cost of interventions accounted for 6% (95% CI 2–10%) of overall health care expenditure.Conclusions: A definitive clinical trial comparing treatments for prevention of sPTB in high-risk women with short cervix is feasible but will be challenging due to small numbers of eligible participants.

We aimed to determine whether children with neonatal Hypoxic Ischaemic Encephalopathy (HIE) treated with therapeutic hypothermia (TH) differ from their peers on measures of fine motor skills, executive function, language and general cognitive abilities, factors that are important for school readiness. We compared school readiness in 31children with HIE treated with TH (without Cerebral Palsy; mean age 5 years 4 months) with 20 typically developing children without HIE (mean age 5 years 6 months). Children with HIE scored significantly lower than typically developing children on fine motor skills, executive functions, memory and language. While general cognitive abilities and attainment were in the normal range, our findings suggest those scores mask specific underlying difficulties identified by more focussed assessments. Children with HIE treated with TH may not be as ‘school ready’ as their typically developing classmates and may benefit from long-term follow-up until starting school.

We aimed to determine whether children with neonatal Hypoxic Ischaemic Encephalopathy (HIE) treated with therapeutic hypothermia (TH) differ from their peers on measures of fine motor skills, executive function, language and general cognitive abilities, factors that are important for school readiness.

Aims: The Patient-Reported Outcomes Measurement Information System (PROMIS) has demonstrated faster administration, lower burden of data capture and reduced floor and ceiling effects compared to traditional Patient Reported Outcomes Measurements (PROMs). We investigated the suitability of PROMIS Mobility score in assessing physical function in the sequelae of childhood hip disease. Methods: In all, 266 adolscents (aged ≥ 12 years) and adults were identified with a prior diagnosis of childhood hip disease (either Perthes’ disease (n = 232 (87.2%)) or Slipped Capital Femoral Epiphysis (n = 34 (12.8%)) with a mean age of 27.73 years (SD 12.24). Participants completed the PROMIS Mobility Computer Adaptive Test, the Non-Arthritic Hip Score (NAHS), EuroQol five-dimension five-level questionnaire, and the Numeric Pain Rating Scale. We investigated the correlation between the PROMIS Mobility and other tools to assess use in this population and any clustering of outcome scores. Results: There was a strong correlation between the PROMIS Mobility and other established PROMs; NAHS (rs = 0.79; p < 0.001). There was notable clustering in PROMIS at the upper end of the distribution score (42.5%), with less seen in the NAHS (20.3%). However, the clustering was broadly similar between PROMIS Mobility and the comparable domains of the NAHS; function (53.6%), and activity (35.0%). Conclusion: PROMIS Mobility strongly correlated with other tools demonstrating convergent construct validity. There was clustering of physical function scores at the upper end of the distributions, which may reflect truncation of the data caused by participants having excellent outcomes. There were elements of disease not captured within PROMIS Mobility alone, and difficulties in differentiating those with the highest levels of function. Cite this article: Bone Jt Open 2021;2(12):1089–1095.

Background Stillbirth remains a major concern across the globe and in some high-resource countries, such as the UK; efforts to reduce the rate have achieved only modest reductions. One third of stillborn babies are small for gestational age (SGA), and these pregnancies are also at risk of neonatal adverse outcomes and lifelong health problems, especially when delivered preterm. Current UK clinical guidance advocates regular monitoring and early term delivery of the SGA fetus; however, the most appropriate regimen for surveillance of these babies remains unclear and often leads to increased intervention for a large number of these women. This pilot trial will determine the feasibility of a large-scale trial refining the risk of adverse pregnancy outcome in SGA pregnancies using biomarkers of placental function sFlt-1/PlGF, identifying and intervening in only those deemed at highest risk of stillbirth. Methods PLANES is a randomised controlled feasibility study of women with an SGA fetus that will be conducted at two tertiary care hospitals in the UK. Once identified on ultrasound, women will be randomised into two groups in a 3:1 ratio in favour of sFlt-1/PlGF ratio led management vs standard care. Women with an SGA fetus and a normal sFlt-1/PlGF ratio will have a repeat ultrasound and sFlt-1/PlGF ratio every 2 weeks with planned birth delayed until 40 weeks. In those women with an SGA fetus and an abnormal sFlt-1/PlGF ratio, we will offer birth from 37 weeks or sooner if there are other concerning features on ultrasound. Women assigned to standard care will have an sFlt-1/PlGF ratio taken, but the results will be concealed from the clinical team, and the woman’s pregnancy will be managed as per the local NHS hospital policy. This integrated mixed method study will also involve a health economic analysis and a perspective work package exploring trial feasibility through interviews and questionnaires with participants, their partners, and clinicians. Discussion Our aim is to determine feasibility through the assessment of our ability to recruit and retain participants to the study. Results from this pilot study will inform the design of a future large randomised controlled trial that will be adequately powered for adverse pregnancy outcome. Such a study would provide the evidence needed to guide future management of the SGA fetus. Trial registration ISRCTN58254381 . Registered on 4 July 2019

ABSTRACTObjectivesFetal growth restriction (FGR) is associated with maternal cardiovascular changes. Sildenafil, a phosphodiesterase type‐5 inhibitor, potentiates the actions of nitric oxide, and it has been suggested that it alters maternal hemodynamics, potentially improving placental perfusion. Recently, the Dutch STRIDER trial was stopped prematurely owing to excess neonatal mortality secondary to pulmonary hypertension. The main aim of this study was to investigate the effect of sildenafil on maternal hemodynamics in pregnancies with severe early‐onset FGR.MethodsThis was a cardiovascular substudy within a UK multicenter, placebo‐controlled trial, in which 135 women with a singleton pregnancy and severe early‐onset FGR (defined as a combination of estimated fetal weight or abdominal circumference below the 10th centile and absent/reversed end‐diastolic flow in the umbilical artery on Doppler velocimetry, diagnosed between 22 + 0 and 29 + 6 weeks' gestation) were assigned randomly to receive either 25 mg sildenafil three times daily or placebo until 32 + 0 weeks' gestation or delivery. Maternal blood pressure (BP), heart rate (HR), augmentation index, pulse wave velocity (PWV), cardiac output, stroke volume (SV) and total peripheral resistance were recorded before randomization, 1–2 h and 48–72 h post‐randomization, and 24–48 h postnatally. For continuous data, analysis was performed using repeated measures ANOVA methods including terms for timepoint, treatment allocation and their interaction.ResultsIncluded were 134 women assigned randomly to sildenafil (n = 69) or placebo (n = 65) who had maternal BP and HR recorded at baseline. At 1–2 h post‐randomization, compared with baseline values, sildenafil increased maternal HR by 4 bpm more than did placebo (mean difference, 5.00 bpm (95% CI, 1.00–12.00 bpm) vs 1.25 bpm (95% CI, –5.38 to 7.88 bpm); P = 0.004) and reduced systolic BP by 1 mmHg more (mean difference, –4.13 mmHg (95% CI, –9.94 to 1.44 mmHg) vs –2.75 mmHg (95% CI, –7.50 to 5.25 mmHg); P = 0.048). Even after adjusting for maternal mean arterial pressure, sildenafil reduced aortic PWV by 0.60 m/s more than did placebo (mean difference, –0.90 m/s (95% CI, –1.31 to –0.51 m/s) vs –0.26 m/s (95% CI, –0.75 to 0.59 m/s); P = 0.001). Sildenafil was associated with a non‐significantly greater decrease in SV index after 1–2 h post‐randomization than was placebo (mean difference, –5.50 mL/m2 (95% CI, –11.00 to –0.50 mL/m2) vs 0.00 mL/m2 (95% CI, –5.00 to 4.00 mL/m2); P = 0.056).ConclusionsSildenafil in a dose of 25 mg three times daily increases HR, reduces BP and reduces arterial stiffness in pregnancies complicated by severe early‐onset FGR. These changes are short term, modest and consistent with the anticipated vasodilatory effect. They have no short‐ or long‐term clinical impact on the mother. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Background: Severe early-onset fetal growth restriction (FGR) predisposes to fetal death, neonatal death, neonatal morbidity and neurodisability. The use of placental biomarkers has been proposed for risk stratification in pre-eclampsia, but they could be equally useful in fetal growth restriction in aiding management. Objective: To determine the efficacy of angiogenic biomarkers at predicting adverse pregnancy outcome in severe early-onset fetal growth restriction. Study design: This is a secondary analysis of the multicentre, placebo-controlled STRIDER UK randomised controlled trial of singleton pregnancies with severe early-onset fetal growth restriction. Women with FGR pregnancies between 22(+0) and 29(+6) weeks of gestation were randomly assigned to receive either sildenafil 25 mg three times daily or placebo until 32(+0) weeks' gestation or delivery. We developed prediction models based upon maternal demographics (age, parity, blood pressure, preeclampsia, gestational hypertension), fetal biometric (estimated fetal weight) and Doppler measurements (Middle Cerebral Artery (MCA), Umbilical Artery (UA)) and maternal angiogenic biomarkers [placental growth factor (PIGF), soluble endoglin (sEng), soluble fms-like tyrosine kinase 1 (sFlt-1) and sFlt-1 :PIGF ratio) using both univariate and multivariate analysis. Results: A complete data set was available for 105 of 135 randomised women. Multivariate regression analysis identified estimated fetal weight (EFW) and sFlt-1:PlGF as independent predictors of livebirth (EFW OR: 1.01 (1.008,1.021); p < 0.001 and lower sFlt-1:PIGF ratio OR: 0.53 (0.284, 0.994); p = 0.048) and overall survival (ERN OR: 1.01 (1.006,1.015); p < 0.001 and lower sFlt-1/PlGF ratio OR: 0.51 (0.286, 0.904); p = 0.021). EFW was a consistent predictor for all outcomes other than gestation at delivery. sFlt-1:PlGF ratio was a consistent predictor for all outcomes other than neonatal morbidity. Conclusions: In severe early-onset FGR pregnancies livebirth and overall survival can be predicted using a model involving EFW and sFlt-1:PlGF ratio. This model require validation in a larger cohort but may allow informed decision making about pregnancy management, especially in previable cases. (C) 2019 Published by Elsevier B.V.

Severe early-onset fetal growth restriction (FGR) is an untreatable condition associated with substantial mortality and morbidity for the fetus and neonate. There has been growing interest in novel therapies such as nitric oxide donors and promotors to improve placental function and outcomes for these high-risk pregnancies. The UK STRIDER trial 1 Sharp A Cornforth C Jackson R et al. Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial. Lancet Child Adolesc Health. 2018; 2: 93-102 Summary Full Text Full Text PDF PubMed Scopus (117) Google Scholar was designed to test the effectiveness of sildenafil (25 mg three times a day) versus placebo at prolonging gestation in severe early-onset FGR. Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trialSildenafil did not prolong pregnancy or improve pregnancy outcomes in severe early-onset fetal growth restriction and therefore it should not be prescribed for this indication outside of research studies with explicit participants' consent. Full-Text PDF Open Access

The STRIDER is an international consortium of five randomised trials of the use of sildenafil to treat fetal growth restriction. We describe the scientific rationale and processes undertaken to take advantage of such a joint approach to studying new interventions in pregnancy. We also describe the challenges faced during recruitment and the further challenges faced after initial publication. We discuss concerns about fetal wellbeing identified in the Netherlands STRIDER trial and the implications of this on other studies and the wider maternity research community.

Fetal growth restriction (FGR) is associated with maternal cardiovascular changes. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates the actions of nitric oxide and could alter maternal haemodynamics. The main aim of this study was to investigate the effect of sildenafil on maternal haemodynamics in pregnancies complicated by severe early-onset FGR. In this multicentre, placebo-controlled trial, we randomly assigned 135 women with singleton pregnancies and severe early-onset FGR (defined as a combination of estimated fetal weight or abdominal circumference below 10th centile and absent/reversed end diastolic flow in the umbilical artery on Doppler velocimetry diagnosed between 22+0 and 29+6 weeks' gestation) to either sildenafil 25 mg three times daily or placebo until 32+0 weeks' gestation or delivery. The maternal blood pressure (BP), heart rate (HR), augmentation index, pulse wave velocity (PWV), cardiac output, stroke volume (SV) and total peripheral resistance were recorded before, one hour after, and 48–72 h post-randomisation, and postnatally. Sildenafil increased maternal HR by 4 bpm more than placebo did [5 bpm (95%CI:1,12) vs 1 (−5,8); P = 0.004] and reduced systolic BP by 1 mmHg more than placebo [−4 mmHg (−9,1) vs −3 mmHg (−8,5); P = 0.048]. Even after adjusting for maternal BP, sildenafil reduced aortic PWV by 0.6 m/s more than placebo [−0.90 m/s (−1.31,−0.51) vs −0.26 (−0.75,0.59); P = 0.001]. Sildenafil was associated with a non-significant decrease in the SV index [−5.5 m/m[b]/beat (−11,−0.5) vs 0 (−0.5,4); P = 0.056]. Sildenafil increases HR, reduces BP and reduces arterial stiffness in pregnancies complicated by FGR. These changes are modest and their clinical impact on mother and baby, both short- and long-term, remains uncertain.

Ultrasound in Obstetrics & GynecologyVolume 52, Issue S1 p. 125-125 AbstractFree Access Abstract withdrawn First published: 15 October 2018 https://doi.org/10.1002/uog.19576AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume52, IssueS1Special Issue: Abstracts of the 28th World Congress on Ultrasound in Obstetrics and Gynecology, 20–24 October 2018, SingaporeOctober 2018Pages 125-125 RelatedInformation

BACKGROUND:Severe early-onset fetal growth restriction can lead to a range of adverse outcomes including fetal or neonatal death, neurodisability, and lifelong risks to the health of the affected child. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates the actions of nitric oxide, which leads to vasodilatation of the uterine vessels and might improve fetal growth in utero. METHODS:We did this superiority, placebo-controlled randomised trial in 19 fetal medicine units in the UK. We used random computer allocation (1:1) to assign women with singleton pregnancies between 22 weeks and 0 days' gestation and 29 weeks and 6 days' gestation and severe early-onset fetal growth restriction to receive either sildenafil 25 mg three times daily or placebo until 32 weeks and 0 days' gestation or delivery. We stratified women by site and by their gestational age at randomisation (before week 26 and 0 days or at week 26 and 0 days or later). We defined fetal growth restriction as a combination of estimated fetal weight or abdominal circumference below tenth percentile and absent or reversed end-diastolic blood flow in the umbilical artery on Doppler velocimetry. The primary outcome was the time from randomisation to delivery, measured in days. This study is registered with BioMed Central, number ISRCTN 39133303. FINDINGS:Between Nov 21, 2014, and July 6, 2016, we recruited 135 women and randomly assigned 70 women to sildenafil and 65 women to placebo. We found no difference in the median randomisation to delivery interval between women assigned to sildenafil (17 days [IQR 7-24]) and women assigned to placebo (18 days [8-28]; p=0·23). Livebirths (relative risk [RR] 1·06, 95% CI 0·84 to 1·33; p=0·62), fetal deaths (0·89, 0·54 to 1·45; p=0·64), neonatal deaths (1·33, 0·54 to 3·28; p=0·53), and birthweight (-14 g,-100 to 126; p=0·81) did not differ between groups. No differences were found for any other secondary outcomes. Eight serious adverse events were reported during the course of the study (six in the placebo group and two in the sildenafil group); none of these were attributed to sildenafil. INTERPRETATION:Sildenafil did not prolong pregnancy or improve pregnancy outcomes in severe early-onset fetal growth restriction and therefore it should not be prescribed for this indication outside of research studies with explicit participants' consent. FUNDING:National Institute for Health Research and Medical Research Council.

Being small for gestational age (SGA) has been established as a risk factor for Attention Deficit Hyperactivity Disorder (ADHD). Likewise, several molecular genetic studies have found a link between DAT1 and ADHD. This study investigated whether SGA moderates the effect of dopamine transporter gene variants on the risk of ADHD. A total of 546 children of European descent were genotyped at age 11 for seven DAT1 SNPs (rs6347, rs11564774, rs40184, rs1042098, rs2702, rs8179029 and rs3863145). The Strengths and Difficulties Questionnaire was used to measure symptoms of ADHD at ages 3.5, 7 and 11. We found significant gene-environment interactions between birth weight and DAT1 SNPs (rs6347, rs40184, rs1042098, rs3863145) on ADHD symptoms at 3.5 years only. Results suggest that genotypic variation of DAT1 may confer a relative protective effect against ADHD in SGA individuals. This study supports the idea that being born SGA moderates the effect of the DAT1 gene on ADHD symptoms in the preschool years and may help to explain some of the heterogeneity in ADHD outcomes.