Abstract Introduction Our aim was to assess maternal and perinatal morbidity associated with induction of labor (IOL) and elective cesarean section (ECS) in uncomplicated twin pregnancies delivered >36 weeks' gestation. Material and Methods A retrospective review of all twin pregnancies, irrespective of chorionicity, that underwent ECS and IOL at the Liverpool Women's Hospital (LWH) over a 10‐year period. Results Three hundred and eighty‐two women underwent IOL and 326 had ECS between January 2010 and December 2020 at LWH. 71.2% ( n = 272) achieved vaginal delivery of both babies in the IOL group, 4.2% ( n = 16) required CS for the second twin. There was no difference in blood loss >1500 mLs (7.4% vs. 6.8%, RR 0.92 (0.54–1.58), p = 0.77). Admission of one or both twins to the neonatal unit was higher following IOL than ECS (13.5% vs. 10%, RR 1.35 (1.01–1.81), p = 0.04 and 5.1% vs. 2.9%, RR 1.75 (1.03–2.97), p = 0.04, respectively). There was no impact of chorionicity on outcomes. Conclusions Existing consensus on mode of delivery of twins at term suggests both IOL and ECS are safe options. We found an association between increased neonatal admissions following IOL compared to ECS, which has also been observed in line with previous epidemiological studies. Our study broadens our knowledge and strengthens the case that this should be discussed when counseling women about intended mode of birth.

Objective To determine if the Pregnolia System (PS) for cervical stiffness (CS) assessment is feasible for an induction of labour (IOL) cohort and to inform definitive study design for IOL outcome prediction.Design Single-centre, prospective, observational, feasibility study.Setting Liverpool Women's Hospital (Liverpool, UK) IOL suite.Population 100 nulliparous, term pregnant women with intact membranes undergoing IOL.Methods Participants underwent a CS assessment using the PS and routine Bishop Score (BS) before IOL commenced. Participants completed an acceptability questionnaire. Decision for IOL was as per clinical team and unit policy. Clinical outcomes were collected from electronic records after delivery.Main Outcome Measures Feasibility outcomes; recruitment rate, acceptability profile and assessment tool fidelity in this cohort. Clinical outcomes; exploring associations between Pregnolia System CS results and IOL outcomes of interest.Results Recruitment was good at 68% (100/148). Reliability analysis of completed CS assessments showed internal consistency to be excellent (Cronbach's Alpha 0.967). The PS assessment had a lower discomfort score compared to Bishop Score assessment (mean difference 3.73). Exploratory clinical outcome analysis revealed both cervical assessment tools had poor diagnostic capability for vaginal delivery following IOL (PS AUC 0.466 95% CI 0.340, 0.593, BS AUC 0.621 95% CI 0.497-0.745).Conclusion This novel study confirms the feasibility of the PS for pre-induction cervical assessment. However, it could not determine the clinical utility in this cohort due to the study design for feasibility outcomes.

Antenatal intracranial hemorrhage (ICH) is an uncommon but serious finding, particularly in the setting of fetal growth restriction (FGR). This report describes a case of severe early-onset FGR complicated by extensive fetal ICH, highlighting the sonographic findings and pathophysiological relationship between the two conditions. A 28-week growth-restricted fetus with reversed umbilical artery end-diastolic flow and reduced fetal movements underwent detailed sonographic evaluation, including Doppler studies of the umbilical artery, middle cerebral artery (MCA), and ductus venosus. Sonography of the fetal cranial structures demonstrated progressive supratentorial and infratentorial hemorrhages, later confirmed by postmortem magnetic resonance imaging and examination. FGR is a recognized risk factor for antenatal ICH, likely related to chronic hypoxia and altered cerebrovascular autoregulation. The presence of cerebral hyperechogenicity, ventriculomegaly, or elevated MCA peak systolic velocity in a growth-restricted fetus should prompt targeted sonography of the fetal cranial structures and Doppler evaluation.

INTRODUCTION:Induction of labour is a common intervention. The prostaglandin dinoprostone is often used, but there is increasing evidence that misoprostol may be more effective without compromising safety. This review compares the efficacy and safety of vaginal misoprostol and vaginal dinoprostone. METHODS:Electronic databases were searched for randomised controlled trials comparing singleton, term inductions with vaginal dinoprostone or vaginal misoprostol. The primary outcome was vaginal births within 24 h. Secondary outcomes included induction to birth interval, mode of birth, oxytocin augmentation, uterine hyperstimulation, fetal distress and adverse maternal and neonatal outcomes. A sub-group analysis by misoprostol dosage (25 and ≥ 50 μg) was planned. A random effects meta-analysis was performed and risk of bias assessed using Cochrane Risk of Bias 2 tool. RESULTS:44 papers reported 7040 participants induced with vaginal misoprostol and 6604 with vaginal dinoprostone. Participants given vaginal misoprostol were 48% (OR 1.48 95% CI 1.20, 1.84) more likely to achieve vaginal birth within 24 h, although heterogeneity was high. The rates of caesarean section, and adverse maternal or neonatal outcomes were comparable. In the vaginal misoprostol group, fewer patients required oxytocin (OR 0.51 95% CI 0.40, 0.65) and time to birth was reduced (-230 min (95% CI -286 to -175, I2 57.6%)). These findings were consistent in the subgroup analysis, although uterine hyperstimulation with fetal heart rate changes was reduced in the 25-μg group. CONCLUSION:Vaginal misoprostol is more effective for achieving vaginal birth in 24 h, reducing time to birth and oxytocin use when compared to vaginal dinoprostone. It does not seem to increase caesarean birth and has a similar side-effect profile. At lower doses (25-μg), it is likely to be similarly effective with a lower incidence of uterine hyperstimulation. This information can be used to support discussions around choice of induction agent.

(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:Spontaneous vaginal births are often the presumed choice, representing 45% of UK births. However, information about benefits and risks is inconsistently given, impacting decision-making and experience. A Core Information Set (CIS) is an agreed set of information points discussed prior to a decision. We aimed to develop a CIS for vaginal birth. DESIGN:A Delphi study was used to create the CIS. Information points were identified from a literature search, patient leaflets, interviews, and a survey. These informed a two-round Delphi survey, where stakeholders rated item importance. Items rated critically important by ≥ 80% of parents or professionals, and of limited importance by < 15%, progressed to consensus meetings, where 20 parents and professionals discussed retained items. The final CIS was populated with an engagement group ensuring accessibility. SETTING:The study took place in the UK, with participants recruited online. POPULATION:Pregnant and postnatal women, birth partners, healthcare professionals, medicolegal professionals, and representatives from relevant organizations. MAIN OUTCOME:A CIS for vaginal birth. RESULTS:77 information items were identified. In round 1 (631 participants) of the Delphi Survey, 84.5% were from the patient group and 15.5% from the professional group; in round 2 (228 participants), 74.3% were from the patient group and 25.7% from the professional group. 29 items met the criteria for consensus discussion. The final CIS includes 19 information points addressing: labour process, pain relief, labour complications, procedures or interventions during labour, experiences after birth, outcomes for the baby and labour environment. CONCLUSIONS:This CIS can facilitate discussions and support informed decision-making about vaginal birth.

OBJECTIVE:To determine the feasibility of a trial investigating the optimal timing for the birth of women with a suspected late preterm and term SGA baby using either angiogenic biomarker-led care or standard care. DESIGN:A mixed methods study including a randomised feasibility trial, interviews, questionnaires and economic analysis. SETTING:Two tertiary maternity hospitals in the UK. POPULATION:Women with suspected SGA pregnancies between 32+0 weeks gestation and 37+6 weeks gestation. METHODS:Women were randomised in a 3:1 ratio to biomarker-led care versus standard care. Biomarker tests were either revealed, with birth delayed until 40 weeks if normal (sFlt-1/PlGF < 38 pg/mL) and considered from 37 weeks if abnormal (sFlt-1/PlGF ≥ 38 pg/mL), or concealed alongside standard care. MAIN OUTCOME MEASURES:Primary outcome was the feasibility of the study measured through the recruitment rate and adherence. Secondary outcomes were the qualitative, proof-of-concept and economic analyses. RESULTS:Out of 128 women invited to participate 78 women were recruited giving a recruitment rate of 60.1% (95% confidence interval 52%-69%). Sixty-seven of the 78 women consented to randomisation. Sixteen parents and 12 clinicians were interviewed. Fourty parents completed a questionnaire. Participants, partners and clinicians viewed the study as acceptable but experienced challenges in participation and delivering the study. There were no significant adverse events or differences in neonatal outcomes. Collection of health economics data was feasible. CONCLUSIONS:The clinical, qualitative and economic results support the acceptability of utilising sFlt-1/PlGF to refine SGA management after 32+0 weeks but the feasibility is less certain.

Linked article: This is a mini commentary on Bray et al., pp. 61–70 in this issue. To view this article, visit https://doi.org/10.1111/1471‐0528.18266 .

AbstractBreast milk iodine concentration (BMIC) is a promising indicator of iodine status in lactating women. However, there are limited data on its usefulness to reflect maternal iodine deficiency. Therefore, the aim of our study was to assess iodine concentration in breast milk and urine samples in exclusively breast-feeding women. Eligible pregnant women undergoing routine antenatal care in a large hospital in Shaanxi Province, China, were followed up from the third trimester of pregnancy until the first week of lactation. Urine samples (20 ml) were collected during pregnancy and lactation. Iodine concentration in samples was measured based on Sandell–Kolthoff reaction. Breast milk samples (5 ml) were provided during lactation. A receiver operating curve (ROC) was constructed to determine the diagnostic performance of BMIC. An iodine-specific FFQ was completed twice during pregnancy and lactation. A total of 200 women completed the study. The overall median BMIC was 89 μg/l, indicating iodine sufficiency (i.e. BMIC reference range between 60 and 465 μg/l). Women reported similar median urinary iodine concentration (UIC) during pregnancy and lactation (112 and 113 μg/l, respectively), but their iodine status differed – mild-to-moderate iodine deficiency during pregnancy and iodine sufficiency during lactation. The ROC for BMIC using UIC as a reference standard was 0·755 (95 % CI: 0·644, 0·866). In conclusion, this study demonstrated that women were iodine sufficient in the first week of lactation as assessed by UIC, which was consistent with BMIC. These findings suggested that BMIC is a useful biomarker to assess iodine status in lactating women.

OBJECTIVES:As part of the FERN feasibility study, this qualitative research aimed to explore parents' and clinicians' views on the acceptability, feasibility and design of a randomised controlled trial (RCT) of active intervention versus expectant management in monochorionic (MC) diamniotic twin pregnancies with early-onset (prior to 24 weeks) selective fetal growth restriction (sFGR). Interventions could include laser treatment or selective termination which could lead to the death or serious disability of one or both twins. DESIGN:Qualitative semi-structured interviews with parents and clinicians. Data were analysed using reflexive thematic analysis and considered against the Principles of Biomedical Ethics. PARTICIPANTS AND SETTING:We interviewed 19 UK parents experiencing (six mothers, two partners) or had recently experienced (eight mothers, three partners) early-onset sFGR in MC twin pregnancy and 14 specialist clinicians from the UK and Europe. RESULTS:Participants viewed the proposed RCT as 'ethically murky' because they believed that the management of sFGR in MC twin pregnancy should be individualised according to the type and severity of sFGR. Clinicians prioritised the gestational age, size, decrease in growth velocity, access to the placental vessels and acceptability of intervention for parents. Discussions and decision-making about selective termination appeared to cause long-term harm (maleficence). The most important outcome for parents and clinicians was 'live birth'. For clinicians, this was the live birth of at least one twin. For parents, this meant the live birth of both twins, even if this meant that their babies had neurodevelopmental impairment or disabilities. CONCLUSIONS:All three pregnancy management approaches for sFGR in MC twin pregnancy carry risks and benefits, and the ultimate goal for parents is to receive individualised care to achieve the best possible outcome for both twins. An RCT was not acceptable to parents or clinicians or seen as ethically appropriate. Alternative study designs should be considered to answer this important research question.

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.

Objectives: Cardiovascular disease is the leading cause of female death worldwide. The link between future cardiovascular events and a history of hypertensive disease in pregnancy or gestational diabetes (GDM) has been well established. Less well understood is the impact on future cardiovascular risk when gestational hypertension (GH) and GDM have occurred together. We assessed the association of GDM and GH with future cardiovascular events both alone and in combination. Study design: All female patients discharged from French hospitals in 2013 with 5 years of subsequent and complete follow-up were identified. They were grouped depending on their history of GDM, history of GH, history of both or history of neither. After propensity score matching, patients with GDM and/or GH were matched 1:1 with patients with no GDM or GH. Hazard ratios (HR) for cardiovascular events during follow-up were adjusted by age at baseline. Results: Women with a history of GH had an increased risk of cardiovascular death (HR 5.46, 95 % confidence interval [CI] 1.93-15.49). Women with a history of GDM had no significant difference in the risk of cardiovascular events such as myocardial infarction (HR 0.88, 95 %CI 0.38-2.03) and cardiovascular death (HR 1.25, 95 %CI 0.47-3.36) during the 5 year follow up. Those with a history of both GDM and GH had a significantly increased risk of myocardial infarction (HR 23.33, 95 %CI 4.84-112.39). Conclusion: Women with a history of both GH and GDM are at a 23-fold increased risk of myocardial infarction within the first 5 years of their postnatal lives.

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.

There has been a scarcity of evidence about iodine nutrition knowledge among women during pregnancy and lactation. The aim of this study was to determine women’s iodine knowledge and the relationship between knowledge and iodine status during pregnancy and lactation. Women were recruited from a hospital in the western part of China in the third trimester of pregnancy and followed until the end of the first week of lactation. The women’s iodine status was measured by their urinary iodine concentration (UIC) and an iodine-specific, validated food frequency questionnaire (FFQ). Iodine nutrition knowledge was assessed using an iodine nutrition knowledge questionnaire. A total of 200 women (mean age of 29.0 ± 4.2 years) completed the whole study. The majority of the women did not consume enough iodine during both pregnancy and lactation (231.89 vs. 237.26 µg/day). The overall mean iodine knowledge scores in our sample of women during pregnancy and lactation were 4.77 and 4.87, indicating low iodine knowledge. The use of iodized salt and a higher education level were significantly associated with an increased iodine knowledge score. In conclusion, this study reported poor iodine nutrition knowledge in women, highlighting a public health concern. Therefore, the iodine knowledge of women should be improved, possibly via maternal health campaigns to avoid the consequences of iodine deficiency disorders in newborns.

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).