Advertisement

Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial

Published:January 21, 2020DOI:https://doi.org/10.1016/j.ajog.2020.01.025

      Background and objective

      Sildenafil citrate is a vasodilator used in erectile dysfunction and pulmonary hypertension. We tested whether it reduces emergency operative births for fetal compromise and improves fetal or uteroplacental perfusion in labor in a phase 2 double-blind randomized controlled trial.

      Study Design

      Women at term in early labor or undergoing scheduled induction of labor at Mater Mother’s Hospital, Brisbane, Australia, were randomly allocated 50 mg of sildenafil citrate orally 8 hourly up to 150 mg or placebo. Intrapartum fetal monitoring followed Royal Australian and New Zealand College of Obstetricians and Gynaecologists guidelines. Primary outcomes were (1) emergency operative birth (by cesarean delivery or instrumental vaginal birth) for intrapartum fetal compromise and (2) mean indices of fetal and uteroplacental perfusion using Doppler ultrasound. Analysis was by intention-to-treat. Trial Registration Number: ANZCTRN12615000319572

      Results

      Between September 2015 and January 2019, 300 women were randomized equally to sildenafil citrate or placebo. Sildenafil citrate reduced the risk of emergency operative birth by 51% (18% vs 36.7%; relative risk, 0.49, 95% confidence interval, 0.33–0.73, P=.0004, number needed to treat = 5 [3–11]). There was no difference in indices of fetal and uteroplacental perfusion, but these were ascertained in only 71 women. Sildenafil citrate reduced the risk of meconium-stained liquor or pathologic fetal heart rate patterns by 43% (25.3% vs 44.7%; relative risk, 0.57, 95% confidence interval, 0.41–0.79, P=.0005), but its effects on fetal scalp sampling rates (2.0% vs 6.7%; relative risk, 0.30, 95% confidence interval, 0.08–1.07, P=.06) and adverse neonatal outcome (20.7% vs 21.3%; relative risk, 0.97, 95% confidence interval, 0.62–1.50, P=.89) were inconclusive. Only 3.6% of maternal levels of sildenafil citrate or its metabolite were detected in cord blood. No differences in maternal adverse events were seen.

      Conclusion

      Sildenafil citrate reduced operative birth for intrapartum fetal compromise, but much larger phase 3 trials of its effects on mother and child are needed before it can be routinely recommended.

      Key words

      Click Supplemental Materials and Video under article title in Contents at ajog.org
      Most cases of intrapartum fetal compromise, or nonreassuring fetal status (“fetal distress”) in labor, reflect inadequate placental perfusion between contractions or preexisting placental impairment that limits metabolic exchange with the fetus.
      • Bakker P.C.
      • Kurver P.H.
      • Kuik D.J.
      • Van Geijn H.P.
      Elevated uterine activity increases the risk of fetal acidosis at birth.
      • Simpson K.R.
      • James D.C.
      Effects of oxytocin-induced uterine hyperstimulation during labor on fetal oxygen status and fetal heart rate patterns.
      • Ayres-de-Campos D.
      • Arulkumaran S.
      FIGO Intrapartum Fetal Monitoring Expert Consensus Panel. FIGO consensus guidelines on intrapartum fetal monitoring: physiology of fetal oxygenation and the main goals of intrapartum fetal monitoring.
      • Turner J.M.
      • Mitchell M.D.
      • Kumar S.
      The physiology of intrapartum fetal compromise at term.
      In term pregnancies, uterine blood flow can fall by 60% during contractions.
      • Janbu T.
      • Nesheim B.I.
      Uterine artery blood velocities during contractions in pregnancy and labour related to intrauterine pressure.
      Reduced uteroplacental blood flow diminishes placental function by causing placental hypoxia and trophoblast apoptosis and precipitates fetal decompensation, provoking fetal distress.
      • Cindrova-Davies T.
      • Yung H.W.
      • Johns J.
      • et al.
      Oxidative stress, gene expression, and protein changes induced in the human placenta during labor.
      ,
      • Mizuuchi M.
      • Cindrova-Davies T.
      • Olovsson M.
      • Charnock-Jones D.S.
      • Burton G.J.
      • Yung H.W.
      Placental endoplasmic reticulum stress negatively regulates transcription of placental growth factor via ATF4 and ATF6beta: implications for the pathophysiology of human pregnancy complications.

      Why was this study conducted?

      There are currently no proven interventions that reduce the risk of intrapartum fetal compromise and birth asphyxia. We tested the biologically plausible hypothesis that, through its vasodilatory action and by improving uteroplacental perfusion, sildenafil citrate in labor would reduce the risk of emergency operative birth for intrapartum fetal compromise.

      Key Findings

      Compared with placebo, sildenafil citrate significantly reduced the risk of emergency operative birth by 51%, meconium-stained liquor and pathologic fetal heart rate patterns by 43%. There were no differences in maternal or neonatal adverse outcomes.

      What does this add to what is known?

      This is the first clinical trial assessing the effect of sildenafil citrate on intervention rates for fetal compromise in term labor. Oral sildenafil citrate significantly reduced emergency operative birth for fetal compromise and appeared safe for women and neonates. However, there was insufficient power to ascertain its effect on perinatal outcomes.
      Fetal distress due to hypoxia is a global challenge. It is a key contributor to 23% of emergency cesarean deliveries (CDs) in Australia,
      • Hilder L.
      • Zhichao Z.
      • Parker M.
      • Jahan S.
      • Chambers G.
      Australia’s mothers and babies 2012. Perinatal statistics series no. 30. Cat. no. PER 69.
      27% in the United States,
      • Boyle A.
      • Reddy U.M.
      • Landy H.J.
      • Huang C.C.
      • Driggers R.W.
      • Laughon S.K.
      Primary cesarean delivery in the United States.
      and 22% in the United Kingdom.
      • Bragg F.
      • Cromwell D.A.
      • Edozien L.C.
      • et al.
      Variation in rates of caesarean section among English NHS trusts after accounting for maternal and clinical risk: cross sectional study.
      In low- and middle-income countries, it is a major cause of perinatal deaths,
      • Lawn J.
      • Shibuya K.
      • Stein C.
      No cry at birth: global estimates of intrapartum stillbirths and intrapartum-related neonatal deaths.
      hypoxic ischemic encephalopathy, and cerebral palsy.
      • Lawn J.E.
      • Blencowe H.
      • Oza S.
      • et al.
      Every Newborn: progress, priorities, and potential beyond survival.
      In high-income countries, 1 in 5 cases of cerebral palsy is attributed to birth asphyxia.
      • Badawi N.
      • Keogh J.M.
      Causal pathways in cerebral palsy.
      Most of these outcomes occur without previous risk factors.
      • Low J.A.
      • Pickersgill H.
      • Killen H.
      • Derrick E.J.
      The prediction and prevention of intrapartum fetal asphyxia in term pregnancies.
      ,
      • Flenady V.
      • Koopmans L.
      • Middleton P.
      • et al.
      Major risk factors for stillbirth in high-income countries: a systematic review and meta-analysis.
      Globally, the burden of disability-adjusted life years due to neonatal encephalopathy, birth asphyxia, and birth trauma compares with that of congenital malformations, type II diabetes, or HIV/AIDS.
      Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.
      Despite significant investment in intrapartum fetal monitoring, no interventions are proven to reduce the development of intrapartum fetal compromise,
      • Nunes I.
      • Ayres-de-Campos D.
      • Ugwumadu A.
      • et al.
      Central fetal monitoring with and without computer analysis: a randomized controlled trial.
      • Brocklehurst P.
      • Field D.
      • Greene K.
      • et al.
      Computerised interpretation of fetal heart rate during labour (INFANT): a randomised controlled trial.
      • Alfirevic Z.
      • Devane D.
      • Gyte G.M.
      • Cuthbert A.
      Continuous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) for fetal assessment during labour.
      • Neilson J.P.
      Fetal electrocardiogram (ECG) for fetal monitoring during labour.
      and the only options to achieve safe outcomes when fetal distress occurs are emergency operative birth by CD or by instrumental vaginal birth with forceps or vacuum. However, emergency CD is linked with postnatal depression,
      • Tonei V.
      Mother's mental health after childbirth: does the delivery method matter?.
      • Prado D.S.
      • Mendes R.B.
      • Gurgel R.Q.
      • Barreto I.D.C.
      • Cipolotti R.
      • Gurgel R.Q.
      The influence of mode of delivery on neonatal and maternal short and long-term outcomes.
      • Dekel S.
      • Ein-Dor T.
      • Berman Z.
      • Barsoumian I.S.
      • Agarwal S.
      • Pitman R.K.
      Delivery mode is associated with maternal mental health following childbirth.
      breastfeeding difficulties,
      • Hobbs A.J.
      • Mannion C.A.
      • McDonald S.W.
      • Brockway M.
      • Tough S.C.
      The impact of caesarean section on breastfeeding initiation, duration and difficulties in the first four months postpartum.
      and—in subsequent pregnancies, uterine rupture, abnormal placentation, ectopic pregnancy, stillbirth, and preterm birth.
      • Sandall J.
      • Tribe R.M.
      • Avery L.
      • et al.
      Short-term and long-term effects of caesarean section on the health of women and children.
      Instrumental birth can cause birth trauma,
      • O'Mahony F.
      • Hofmeyr G.J.
      • Menon V.
      Choice of instruments for assisted vaginal delivery.
      including severe perineal laceration with long-term fecal or urinary incontinence and sexual dysfunction,
      ACOG Practice Bulletin No
      198: Prevention and Management of Obstetric Lacerations at Vaginal Delivery.
      and neonatal intracranial bleeding.
      • O'Mahony F.
      • Hofmeyr G.J.
      • Menon V.
      Choice of instruments for assisted vaginal delivery.
      ,
      • Aberg K.
      • Norman M.
      • Pettersson K.
      • Jarnbert-Pettersson H.
      • Ekeus C.
      Protracted vacuum extraction and neonatal intracranial hemorrhage among infants born at term: a nationwide case-control study.
      Safe, affordable strategies to reduce emergency operative birth are an urgent global priority.
      Stemming the global caesarean section epidemic.
      Sildenafil citrate is a phosphodiesterase type-5 inhibitor that blocks inactivation of cyclic guanosine monophosphate, mainly in vascular smooth muscle cells, and thus increases bioavailability of nitric oxide. This accounts for its vasodilatory properties, which are more pronounced in pelvic vasculature. It increases fetal and uteroplacental blood flow
      • Groom K.M.
      • David A.L.
      The role of aspirin, heparin, and other interventions in the prevention and treatment of fetal growth restriction.
      • Dastjerdi M.V.
      • Hosseini S.
      • Bayani L.
      Sildenafil citrate and uteroplacental perfusion in fetal growth restriction.
      • Hale S.A.
      • Jones C.W.
      • Osol G.
      • Schonberg A.
      • Badger G.J.
      • Bernstein I.M.
      Sildenafil increases uterine blood flow in nonpregnant nulliparous women.
      and reverses vasoconstriction in uterine and spiral arteries.
      • Wareing M.
      • Myers J.E.
      • O'Hara M.
      • Baker P.N.
      Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction.
      ,
      • Samangaya R.A.
      • Wareing M.
      • Skillern L.
      • Baker P.N.
      Phosphodiesterase inhibitor effect on small artery function in preeclampsia.
      It has been prescribed for more than 64 million men for erectile dysfunction
      • Patole S.K.
      • Kumaran V.
      • Travadi J.N.
      • Brooks J.M.
      • Doherty D.A.
      Does patent ductus arteriosus affect feed tolerance in preterm neonates?.
      and is safe, affordable, and available over the counter in the United Kingdom
      • Patole S.K.
      • Muller R.
      Does carboxymethylcellulose have a role in reducing time to full enteral feeds in preterm neonates?.
      and New Zealand.
      • Brooks J.M.
      • Travadi J.N.
      • Patole S.K.
      • Doherty D.A.
      • Simmer K.
      Is surgical ligation of patent ductus arteriosus necessary? The Western Australian experience of conservative management.
      It is effective in adult and newborn pulmonary hypertension.
      • Kelly L.E.
      • Ohlsson A.
      • Shah P.S.
      Sildenafil for pulmonary hypertension in neonates.
      ,
      • Barnes H.
      • Brown Z.
      • Burns A.
      • Williams T.
      Phosphodiesterase 5 inhibitors for pulmonary hypertension.
      In our systematic review of 16 pregnancy studies, maternal side effects were mild and self-limiting—mainly headache or flushing with no long-term adverse outcomes.
      • Dunn L.
      • Greer R.
      • Flenady V.
      • Kumar S.
      Sildenafil in pregnancy: a systematic review of maternal tolerance and obstetric and perinatal outcomes.
      Sildenafil citrate also has been assessed as an antenatal treatment for severe, early-onset fetal growth restriction in several related trials coordinated by the STRIDER (Sildenafil TheRapy In Dismal prognosis Early-onset intrauterine growth Restriction) Consortium.
      • Groom K.M.
      • McCowan L.M.
      • Mackay L.K.
      • et al.
      STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction.
      We therefore tested the biologically plausible hypothesis that, through its vasodilatory effect and by improving uterine and placental perfusion in labor, sildenafil citrate reduces the rate of emergency CD or instrumental vaginal birth for intrapartum fetal distress.

      Materials and Methods

      Study overview

      We conducted the RIDSTRESS (“Reducing the Incidence of Fetal Distress with Sildenafil Citrate”) trial at the Mater Mother’s Hospital in Brisbane, Australia, from September 2015 to January 2019. This double-blind, placebo-controlled, pragmatic phase 2 randomized controlled trial was registered with the Australia New Zealand Clinical Trials Registry (ANZCTRN12615000319572).
      All versions of the protocol were submitted for approval to the local Human Research Ethics Committee (HREC; HREC/15/MHS/33) and research governance office (RG-15-088). Version 2.0 of the study protocol (Original) was published
      • Dunn L.
      • Flenady V.
      • Kumar S.
      Reducing the risk of fetal distress with sildenafil study (RIDSTRESS): a double-blind randomised control trial.
      ,
      • Kumar S.
      Correction to: Dunn L, Flenady V, Kumar S. Reducing the risk of fetal distress with sildenafil study (RIDSTRESS): a double blind randomised control trial.
      and is available alongside 6.1 (Final) with this article (Supplemental Materials and Methods). The HREC and the independent data and safety monitoring committee (DSMC) emphasized the safety of participants in this first-ever trial of sildenafil citrate in labor at term. The protocol therefore mandated that the DSMC rigorously monitor all adverse events and undertake interim analyses after the first 200 participants and then after each subsequent 100 were enrolled, but no formal stopping rule was proposed. The trial was conducted according to the Declaration of Helsinki
      World Medical Association Declaration of Helsinki
      Ethical principles for medical research involving human subjects.
      and Good Clinical Practice Guidelines.
      • Bhuiyan P.
      • Rege N.
      ICH Harmonised Tripartite Guideline: guideline for good clinical practice.

      Participants

      Women aged 18–50 years of age with a single, structurally normal, cephalic presenting fetus were eligible if they planned vaginal birth at term (≥37 weeks of gestation). A researcher provided detailed oral and written information. Women were randomized if admitted in early labor when the cervix was dilated less than 4 cm or if undergoing planned induction of labor. We excluded women with preeclampsia, more than 1 previous CD, a fetus known to be small for gestational age, women taking antihypertensive medication, and those with a contraindication to sildenafil citrate treatment such as hypersensitivity to sildenafil citrate, to an ingredient in its formulation, to nitrates or nitrites or to Riociguat.
      Sildenafil citrate, 2018 (vol 2019).

      Randomization and treatment

      We originally planned to screen all women after randomization using Doppler ultrasound to show that sildenafil citrate reduced the rate of emergency operative delivery from 36% to 18% in the 10% of women whose fetuses had a cerebroplacental ratio below the 10th centile on Doppler ultrasound. This would have required enrollment and screening of 1012 women per group.
      • Dunn L.
      • Flenady V.
      • Kumar S.
      Reducing the risk of fetal distress with sildenafil study (RIDSTRESS): a double-blind randomised control trial.
      ,
      • Kumar S.
      Correction to: Dunn L, Flenady V, Kumar S. Reducing the risk of fetal distress with sildenafil study (RIDSTRESS): a double blind randomised control trial.
      However, because it proved infeasible to perform Doppler ultrasound in all women after randomization, we sought HREC approval to amend the sample size while remaining blinded to outcomes. The revised sample size calculation was based on data in all deliveries showing that the incidence of emergency operative delivery (CD or instrumental vaginal birth) for fetal compromise at the Mater Mother’s Hospital was 18.9%.
      • Bligh L.N.
      • Alsolai A.A.
      • Greer R.M.
      • Kumar S.
      Prelabor screening for intrapartum fetal compromise in low-risk pregnancies at term: cerebroplacental ratio and placental growth factor.
      If sildenafil halved the rate to 9.45%, a total sample size of 288 women per group (>90% power, alpha of 0.05) would be required. Assuming a 10% drop out rate, a sample of 320 women per group was needed, resulting in protocol version 6.1 (Supplemental Materials and Methods). The revised sample size maintained the 50% reduction in primary outcome specified in the first sample size calculation.
      After recruitment, women were randomly assigned using a computer-generated sequence in a 1:1 ratio to receive either sildenafil citrate or placebo in variable blocks of up to 6 (Stata Statistical Software, release 14; StataCorp LP, College Station, TX). Each participant’s study identification number was recorded in the clinical notes and subsequently in their electronic health records. The hospital pharmacy prepared sequentially ordered packs labeled with individual study identification numbers containing identical capsules of sildenafil citrate or placebo. These were stored in a locked drug cabinet in the birth suite. The midwife caring for the woman then cross referenced the appropriate study pack with the study identification number recorded in the clinical notes and administered the trial capsules as specified in the protocol. Women, clinicians, and investigators were unaware of allocation. Whenever possible, a researcher performed an ultrasound scan to measure indices of fetal and uteroplacental perfusion before and 2–4 hours after the initial dose of study medication. Maternal venous blood samples were obtained 2–4 hours after first dose of study medication for measurement of sildenafil citrate and its active metabolite (N-desmethyl sildenafil).
      Depending on the Modified Bishop’s Score, induction of labor was performed with balloon catheters (Cook’s cervical-ripening balloon catheter) or vaginal prostaglandin gel. In women with a favorable cervix, artificial rupture of membranes was performed followed by an oxytocin infusion. Women received the first dose of trial medication after transfer to the birth suite. Sildenafil citrate was given orally as a 50-mg dose 8 hourly to a maximum of 3 doses. Blood pressure was monitored 15–30 minutes after each dose. Fetal heart rate monitoring was performed in all cases. Heart rate abnormalities were classified using Royal Australian and New Zealand College of Obstetricians and Gynecologists guidelines
      RANZCOG
      Intrapartum Fetal Surveillance, Clinical Guidelines 3.1.
      (Supplemental Materials and Methods). A pathologic fetal heart rate pattern was defined as having one or more of the features in Box 1.
      Box 1Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) definition of pathological Fetal Heart Rate patterns
      Prolonged bradycardia (<100 bpm for >5 minutes)

      Absent baseline variability <3 bpm

      Sinusoidal pattern

      Complicated variable decelerations with reduced or absent baseline variability

      Late decelerations with reduced or absent baseline variability
      When clinically indicated, fetal scalp blood samples for lactate levels were obtained by the treating obstetric team. Levels of 4.2–4.7 mmol/L were considered borderline and repeated in 30 minutes. Levels ≥4.8 mmol/L mandated immediate birth. Cord arterial blood gases were performed immediately after birth. Umbilical cord venous blood was collected to analyze levels of sildenafil citrate and N-desmethyl-sildenafil.

      Trial outcomes

      The primary outcomes were (1) rates of operative birth (by CD or instrumental vaginal birth) for intrapartum fetal compromise and (2) mean indices of fetal and uteroplacental perfusion, ie, umbilical artery (UA) pulsatility index (PI), middle cerebral artery (MCA) PI, and uterine artery PI, measured in the absence of fetal breathing movements and uterine contractions. The mean of 3 measurements was recorded. The cerebroplacental ratio was calculated by dividing the MCA PI by the UA PI.
      Prespecified secondary outcomes or comparisons were (1) a composite of pathologic intrapartum fetal heart rate abnormalities or meconium-stained liquor; (2) need for intrapartum fetal blood sampling because of concerns of fetal well-being; (3) concentration of sildenafil citrate and N-desmethyl-sildenafil in maternal and cord blood (measured only in the sildenafil citrate group); and (4) a composite of adverse neonatal outcomes—admission to the neonatal intensive care unit (NICU), or Apgar score <7 at 5 minutes or cord pH <7.1 or initial lactate >6 mmol/L or neonatal encephalopathy (Sarnat stage 2 or 3).
      • Sarnat H.B.
      • Sarnat M.S.
      Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study.
      Subsidiary intrapartum and neonatal outcomes included mode of birth (CD, instrumental, or spontaneous vaginal birth), indication for operative birth, length of labor (from time partograph commenced to delivery of the infant), fetal heart rate abnormalities, meconium-stained liquor, postpartum hemorrhage (blood loss >500 mL), maternal intensive care unit admission, cord blood pH and lactate levels, Apgar score at 5 minutes and, if admission to the NICU occurred, length of stay, respiratory illness (transient tachypnoea of the newborn or pneumothorax), or neonatal encephalopathy. Failed induction of labor was defined as lack of significant cervical dilatation after 12 hours of oxytocin infusion.
      Newborns were screened for major cardiopulmonary disease and pulmonary hypertension by measuring oxygen saturation by pulse oximetry within 8 hours of birth. We recorded adverse events, serious adverse events, and maternal symptoms potentially related to sildenafil citrate administration (nausea, vomiting, flushing, hypotension, blurred vision, visual loss, headache, dyspepsia, diarrhea, and tremor).
      As poorly grown fetuses are particularly vulnerable to intrapartum fetal compromise, in post-hoc analyses in 30 women with infants with birth weights below the 10th centile for the study cohort, we reported the effects of sildenafil citrate on clinical outcomes including operative birth for fetal compromise, mode of birth, pathologic fetal heart rate patterns, and composite neonatal outcome.
      Sildenafil and N-desmethyl-sildenafil levels were measured using liquid chromatography-mass spectrometry. This assay is linear over 1–600 ng/mL for sildenafil citrate and 1–300 ng/mL for desmethyl-sildenafil with intra- and interassay accuracies of 92.8%–103.2%, and intra- and inter-assay variation not exceeding 15%.
      • Russo F.M.
      • Conings S.
      • Allegaert K.
      • et al.
      Sildenafil crosses the placenta at therapeutic levels in a dually perfused human cotyledon model.

      Statistical analysis

      The revised sample size of 320 women per group aimed to detect a 50% reduction in the incidence of operative birth for intrapartum fetal compromise from 18.9%
      • Bligh L.N.
      • Alsolai A.A.
      • Greer R.M.
      • Kumar S.
      Prelabor screening for intrapartum fetal compromise in low-risk pregnancies at term: cerebroplacental ratio and placental growth factor.
      to 9.45% at 90% power and 2-sided alpha of 0.05, allowing for 10% drop-outs. We did not estimate the sample needed to detect differences in fetal or uteroplacental perfusion.
      The primary analysis was performed by intention-to-treat. A per-protocol analysis excluded participants who did not receive their allocated study medication. (Supplemental Table 1) Quantitative data are presented as mean (standard deviation) or median (interquartile range). Differences between study groups were compared with the Student t test, Wilcoxon rank-sum test, χ2 test, or Fisher exact test as appropriate. The effects of sildenafil citrate were assessed using generalized linear modeling and expressed as relative risk (RR), 95% confidence intervals (95% CIs), and number needed to treat (NNT) for benefit. Ultrasound Doppler indices for MCA, UA, and cerebroplacental ratio were converted to z scores using gestation-specific centiles.
      • Flatley C.
      • Kumar S.
      • Greer R.M.
      Reference centiles for the middle cerebral artery and umbilical artery pulsatility index and cerebro-placental ratio from a low-risk population—a Generalised Additive Model for Location, Shape and Scale (GAMLSS) approach.
      A P value of <.05 was deemed statistically significant.
      • Perneger T.V.
      What's wrong with Bonferroni adjustments.
      In addition to the analyses planned in the protocol, we retrospectively used Benjamini–Hochberg–Simes
      • Benjamini Y.
      • Hochberg Y.
      Controlling the false discovery rate: a practical and powerful approach to multiple testing.
      ,
      • Simes R.J.
      An Improved Bonferroni procedure for multiple tests of significance.
      critical P values to account for multiple testing of the 3 prespecified secondary outcomes, controlling for a 5% false-discovery rate (Supplemental Table 2). Stata S/E Statistical Software, release 15.0 (StataCorp LP) was used for analysis.
      The DSMC conducted 3 interim analyses, during which the Trial Steering Committee remained blinded. The first was preplanned in the protocol, after enrolling 200 participants. The second was unplanned, after 241 participants, when the Dutch STRIDER trial of maternal oral sildenafil citrate for severe early fetal growth restriction was reported.
      • Ganzevoort W.
      • Gluud C.
      • Lim K.
      • Mol B.
      • Groom K.
      The STRIDER trials: ongoing research.
      ,
      • Groom K.
      • Ganzevoort W.
      • Alfirevic Z.
      • Lim K.
      • Papageorghiou A.
      STRIDER Consortium
      Clinicians should stop prescribing sildenafil for fetal growth restriction (FGR): comment from the STRIDER Consortium.
      The DSMC advised continuing enrollment after both interim analyses. After the third, which was prespecified in the protocol, the DSMC unblinded the Trial Steering Committee and advised them of a significant difference in the primary outcome between study groups. The Trial Steering Committee then stopped the trial (Supplemental Table 3).

      Results

      Of the 1043 women screened for eligibility, 554 were deemed eligible: 300 consented and were randomized, 150 to sildenafil citrate and 150 to placebo (Figure 1). Of these, 32 received no study medication—13 (8.7%) in the sildenafil citrate group and 19 (12.7%) in the placebo group, mainly because they withdrew consent or delivered before the first dose. Baseline demographics and adherence to protocol were similar between groups. Paired maternal and cord blood samples for sildenafil citrate levels were obtained from 19 women in the sildenafil citrate group (Table 1).
      Figure thumbnail gr1
      Figure 1Flow chart of the study population
      Turner et al. Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial. Am J Obstet Gynecol 2020.
      Table 1Participant demographics
      Sildenafil (N=150)Placebo (N=150)
      Maternal age, y30 (25–33)30 (27–34)
      Prepregnancy body mass index, kg/m226.8 (6.6)26.7 (6.7)
      Ethnicity
       White86 (57.3)89 (59.3)
       Indigenous4 (2.7)0
       Asian16 (10.7)16 (10.7)
       Indian26 (17.3)31 (20.7)
       Other18 (12.0)14 (9.3)
      Smoking during pregnancy14 (9.3)11 (7.3)
      Alcohol during pregnancy5 (3.3)8 (5.3)
      Nulliparous87 (58.0)96 (64.0)
      Previous cesarean delivery4 (2.7)7 (4.7)
      Diabetes mellitus
       Gestational39 (26.0)36 (24.0)
       Type 12 (1.3)1 (0.7)
       Type 21 (0.7)2 (1.3)
      Onset of labor
       Spontaneous19 (12.8)15 (10.0)
       Induction of labor128 (85.9)134 (89.3)
       Cesarean delivery before induction of labor2 (1.3)1 (0.7)
      Method of induction of labor
       Prostaglandin E228 (19.9)37 (25.5)
       Cervical balloon77 (53.4)78 (52.4)
       Artificial rupture of membranes and oxytocin infusion23 (17.1)19 (12.1)
      Indications for induction of labor
      Fetal24 (18.8)30 (22.4)
       Decreased fetal movements12 (9.4)19 (14.3)
       Growth concerns6 (4.7)1 (0.8)
       Suspected large for gestational age6 (4.7)10 (7.5)
      Maternal62 (48.4)61 (45.6)
       Diabetes mellitus37 (28.9)33 (24.6)
       Intrahepatic cholestasis of pregnancy3 (2.3)5 (3.7)
       Advanced maternal age12 (9.4)11 (8.2)
       Social/other10 (7.8)12 (9.0)
      Obstetric42 (32.8)43 (32.1)
       Spontaneous rupture of membranes9 (7.0)6 (4.5)
       Previous obstetric history7 (5.8)5 (3.7)
       Post dates26 (20.3)32 (23.9)
      Epidural use99 (66.0)114 (76.0)
      Number of trial medication capsules administered
       179 (52.7)74 (49.3)
       246 (30.7)48 (32.0)
       312 (8.0)9 (6.0)
      Ultrasound scans performed
       Pretreatment143 (95.3)143 (95.3)
       Posttreatment34 (22.7)37 (24.7)
      Interval between first treatment dose and posttreatment ultrasound scan (minutes)120 (96–174)115 (90–132.5)
      Paired maternal and cord blood samples obtained
      Only samples from participants in the sildenafil citrate group were analyzed.
      19
      Data presented as % (n), mean (standard deviation), or median (interquartile range) as appropriate.
      Turner et al. Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial. Am J Obstet Gynecol 2020.
      a Only samples from participants in the sildenafil citrate group were analyzed.
      Sildenafil citrate reduced the risk of operative birth for intrapartum fetal compromise by 51.0% (18.0% vs 36.7%; RR, 0.49, 95% CI, 0.33–0.73, P=.0004; NNT = 5, 95% CI, 3–11) (Table 2). There was no difference in indices of fetal and uteroplacental perfusion, but these were measured in only 71 women as expert sonography was often unavailable (Table 3).
      Table 2Primary and secondary outcomes by intention to treat
      OutcomeSildenafil (N=150) N (%)Placebo (N=150)

      N (%)
      P valueRelative risk (95% CI)Number needed to treat
      Primary outcomes
       Operative birth for intrapartum fetal compromise27 (18.0)55 (36.7).00040.49 (0.33–0.73)5 (3–11)
       Measures of fetal and uteroplacental perfusion
      Only measured in 71 women
      See Table 3
      Secondary outcomes
       Meconium-stained liquor or pathologic fetal heart rate pattern38 (25.3)67 (44.7).00050.57 (0.41–0.79)5 (4–12)
       Fetal blood sampling3 (2.0)10 (6.7).060.30 (0.08–1.07)n/a
       Cord blood levels of sildenafil citrate and N-desmethyl sildenafil in sildenafil treated groupSee Table 4
      Composite adverse neonatal outcome
      Composite neonatal adverse outcome: admission to neonatal intensive care unit or Apgar score <7 at 5 minutes, or cord pH <7.1 or initial lactate ≥6 mmol/L or neonatal encephalopathy.
      31 (20.7)32 (21.3)0.890.97 (0.62–1.50)n/a
      Data presented as % (n), mean (standard deviation), or median (interquartile range).
      CI, confidence interval.
      Turner et al. Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial. Am J Obstet Gynecol 2020.
      a Only measured in 71 women
      b Composite neonatal adverse outcome: admission to neonatal intensive care unit or Apgar score <7 at 5 minutes, or cord pH <7.1 or initial lactate ≥6 mmol/L or neonatal encephalopathy.
      Table 3Indices of fetal and uteroplacental perfusion measured by Doppler ultrasound in 71 women
      Scan measurePretreatment ultrasoundPosttreatment ultrasoundDifference between pre- and posttreatment ultrasound scan
      SildenafilPlaceboSildenafilPlaceboSildenafilPlaceboP value
      n343734373437
      MCA PI z score
      Difference reported as absolute difference
      0.18 (–0.50 to 0.47)0.37 (-0.84 to 1.10)–0.10 (–0.73 to 0.60)0.02 (–0.65 to 0.80)–0.07 (–0.74 to 0.88)–0.25 (–0.90 to 0.62).53
      UA PI z score
      Difference reported as absolute difference
      0.19 (–0.96 to 0.84)0.32 (–0.27 to 1.04)–0.08 (–0.63 to 0.77)0.36 (–0.51 to 0.90)–0.13 (–0.57 to 0.30)0.14 (–0.47 to 0.41).67
      CPR z score
      Difference reported as absolute difference
      –0.43 (-0.62 to 0.30)–0.07 (–0.92 to 0.55)–0.45 (–0.75 to 0.18)–0.46 (–1.2 to 0.47)–0.16 (–0.52 to 0.39)–0.28 (–0.82 to 0.36).24
      UtA PI
      Difference between scans reported as percentage change.
      0.74 (0.59–1.62)0.81 (0.66–1.01)0.92 (0.69–1.4)0.95 (0.74–1.29)13.8 (–3.1 to 40.2)10.8 (–16.8 to 30.6).97
      CPR, cerebroplacental ratio; MCA, middle cerebral artery; PI, pulsatility index; UA, umbilical artery; UtA, uterine artery.
      Turner et al. Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial. Am J Obstet Gynecol 2020.
      a Difference reported as absolute difference
      b Difference between scans reported as percentage change.
      For the prespecified secondary outcomes, sildenafil citrate reduced the risk of meconium-stained liquor or pathologic fetal heart rate patterns by 58% (25.3% vs 44.7%; RR, 0.57, 0.41–0.79, P=.0005; NNT=5, 95% CI, 4–12) but its effects on fetal blood sampling rates (2.0% vs 6.7%; RR, 0.30, 0.08–1.07, P=.06) and the composite adverse neonatal outcome (20.7% vs 21.3%; RR, 0.97, 0.62–1.50, P=.89) were inconclusive (Table 2). Median sildenafil citrate and N-desmethyl sildenafil levels in cord blood were 0 ng/mL (range, 0–24.5) and 0 ng/mL (range, 0–22.3), respectively. The median fetal/maternal concentration ratio of sildenafil citrate was 3.6% (range, 2.6–6.3) for 13 infants in whose cord blood sildenafil citrate could be detected (Table 4).
      Table 4Maternal and cord blood levels of SC and NDS
      Data reported as mean (standard deviation) or median (interquartile range) as appropriate
      ,
      Only measured in 19 women who had paired maternal and umbilical cord venous samples
      MaternalUmbilical cord
      Interval between SC treatment and blood sample, h2.6 (1.1)
      Interval between final SC dose to cord blood collection, h4.95 (2.7)
      SC, ng/mL29.3 (17.8–50.0)0 (0–11.4)
      Range = 0–24.5 ng/mL
      NDS, ng/mL86.8 (50.5–140)0 (0–0)
      Range = 0–22.3 ng/mL
      SC maternal blood levels/umbilical cord levels ratio, %3.6 (2.6–6.3)
      Calculated in those with cord blood SC or NDS levels >0, n=13.
      NDS maternal blood levels/umbilical cord levels ratio, %1.9 (0.9–2.1)
      Calculated in those with cord blood SC or NDS levels >0, n=13.
      NDS, N-desmethyl sildenafil; SC, sildenafil citrate.
      Turner et al. Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial. Am J Obstet Gynecol 2020.
      a Data reported as mean (standard deviation) or median (interquartile range) as appropriate
      b Only measured in 19 women who had paired maternal and umbilical cord venous samples
      c Range = 0–24.5 ng/mL
      d Range = 0–22.3 ng/mL
      e Calculated in those with cord blood SC or NDS levels >0, n=13.
      Sildenafil citrate was associated with a substantial reduction in emergency CD (10.0% vs 20.0%; RR, 0.50, 95% CI, 0.28–0.89, P=.02) and in instrumental vaginal birth for fetal compromise (8.0% vs 16.7%; RR, 0.48, 95% CI, 0.25–0.93, P=.02). It also resulted in a significant reduction of pathologic fetal heart rate patterns (15.4% vs 32.0%; RR, 0.48, 95% CI, 0.31–0.75, P=.0009) and a nonsignificant reduction in meconium-stained liquor (12.7% vs 20.0%; RR, 0.63, 95% CI, 0.37–1.07, P=.09) (Table 5). Although there was no difference in total length of labor, sildenafil citrate was associated with a shorter second stage (36 [13–107.5] minutes vs 65.5 [24-126] minutes, P=.02). No differences were seen in the proportions of women receiving oxytocin to augment uterine activity, the interval between starting oxytocin infusion and birth, or maternal or perinatal adverse outcomes (Tables 5 and 6). No infant failed the newborn oxygen saturation screening test. Two cases of hypoxic ischemic encephalopathy occurred, one in the sildenafil citrate group and one in the placebo group (Supplemental Table 4). Per-protocol and intention-to-treat analyses were similar (Supplemental Table 1).
      Table 5Subsidiary intrapartum and neonatal outcomes by intention to treat
      OutcomeSildenafil (N=150)Placebo (N=150)Relative risk (95% CI)
      Spontaneous vaginal birth81 (54.0)65 (43.3)1.25 (0.99–1.58)
      All instrumental delivery22 (14.7)35 (23.3)0.63 (0.39–1.02)
       Instrumental for intrapartum fetal compromise12 (8.0)25 (16.7)0.48 (0.25–0.92)
       Instrumental for failure to progress10 (6.7)10 (6.7)1.00 (0.43–2.33)
      All emergency cesarean delivery47 (31.3)50 (33.3)0.94 (0.68–1.30)
       Cesarean delivery for intrapartum fetal compromise15 (10.0)30 (20.0)0.50 (0.28–0.89)
       Cesarean delivery for failure to progress23 (15.3)15 (10.0)1.53 (0.83–2.82)
       Cesarean delivery for other indications9 (6.0)5 (3.3)1.80 (0.62–5.25)
      Meconium-stained liquor19 (12.7)30 (20.0)0.63 (0.37–1.07)
      Pathologic fetal heart rate pattern23 (15.4)48 (32.0)0.48 (0.31–0.75)
      Length of labor, minutes284.5 (145.5–490.5)323 (184.5–448)
       First stage197 (120–385)230 (114–318)
       Second stage36 (13–107.5)65.5 (24–126)
      Oxytocin infusion127 (85.2)123 (82.0)
      Length of oxytocin infusion, h
      Time from commencement of oxytocin infusion until birth.
      7.4 (4.5–12.4)7.8 (5.2–12.5)
      Estimated blood loss, mL300 (200–500)350 (200–450)
      Postpartum hemorrhage44 (29.3)38 (25.5)1.15 (0.79–1.67)
       Blood loss >1000 mL10 (6.7)9 (6.0)1.11 (0.46–2.66)
      Maternal intensive care unit admission2 (1.3)0
      Gestational age, wk39.5 (1.3)39.5 (1.3)
      Male infant77 (51.3)81 (54.0)
      Birthweight, g3474.5 (3138–3780)3432 (3178–3763)
      5-minute Apgar score <72 (1.3)3 (2.0)0.67 (0.11–3.93)
      Cord artery pH <7.16 (4.0)5 (3.3)1.20 (0.37–3.85)
      Cord lactate ≥6 mmol/L23 (15.3)22 (14.7)1.05 (0.61–1.79)
      Neonatal intensive care unit admission >24 h5 (3.3)3 (2.0)1.67 (0.41–6.85)
      Pneumothorax1 (0.7)3 (2.0)0.33 (0.04–3.17)
      Transient tachypnea of the newborn4 (2.7)4 (2.7)1.00 (0.25–3.92)
      Hypoxic ischemic encephalopathy1 (0.7)1 (0.7)1.00 (0.06–15.8)
      Data presented as n (%), mean (standard deviation), or median (interquartile range) as appropriate. Postpartum hemorrhage defined as >500 mL estimated blood loss.
      CI, confidence interval.
      Turner et al. Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial. Am J Obstet Gynecol 2020.
      a Time from commencement of oxytocin infusion until birth.
      Table 6Adverse and serious adverse events
      Sildenafil (N=150)Placebo (N=150)
      Serious adverse events7 (4.7)7 (4.7)
       Maternal death00
       Stillbirth/neonatal death00
       Maternal ICU admission2 (1.3)
      Both were for observation after PPH and discharged after 24 hours. One woman experienced a cesarean angle tear that was difficult to secure and had a 4-L blood loss
      0
       Severe maternal hypotension
      Defined as blood pressure <80/50 on 3 occasions requiring medical intervention.
      00
       PPH >1500 mL2 (1.3)4 (2.7)
       Persistent visual disturbances requiring urgent ophthalmology review00
       Admission to NICU >24 h5 (3.3)3 (2.0)
       Cord arterial pH <7.01 (0.7)0
       HIE/neonatal seizures1 (0.7)1 (0.7)
      Adverse events/adverse drug reactions92 (61.3)90 (60.0)
       Dizziness3 (2.0)2 (1.3)
       Flushing1 (0.7)2 (1.3)
       Dyspepsia00
       Dyspnea00
       Epistaxis00
       Diarrhea00
       Tremor00
       Headache1 (0.7)2 (1.3)
       Myalgia00
       Paraesthesia00
       Edema00
       Visual changes01 (0.7)
       Vaginal itch00
       Nausea and vomiting24 (16.0)19 (12.7)
       Intrapartum antiemetic use47 (31.3)42 (28.0)
       PPH ≤1500 mL41 (27.7)33 (22.6)
       Anemia00
       Bronchitis00
       Skin rash00
       Intrapartum pyrexia7 (4.7)10 (6.7)
       Placental abruption2 (1.3)1 (0.7)
       Uterine rupture00
       Cord prolapse01 (0.7)
       Maternal collapse00
       New-onset preeclampsia developing intra or postpartum01 (0.7)
       Cord arterial pH 7.0–7.14 (2.7)5 (3.3)
      Data presented as % (n).
      HIE, hypoxic ischemic encephalopathy; ICU, intensive care unit; NICU, neonatal intensive care unit; PPH, postpartum hemorrhage.
      Turner et al. Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial. Am J Obstet Gynecol 2020.
      a Both were for observation after PPH and discharged after 24 hours. One woman experienced a cesarean angle tear that was difficult to secure and had a 4-L blood loss
      b Defined as blood pressure <80/50 on 3 occasions requiring medical intervention.
      Among infants with birthweights below the 10th centile for the cohort, sildenafil citrate was associated with a nonsignificantly lower risk of CD or instrumental birth for intrapartum fetal compromise, one half the rate of CD for any reason (P=.049), and twice the rate of spontaneous vaginal birth (P=.02) (Table 7).
      Table 7Post-hoc subgroup analysis in 30 women with infants weighing <10th centile (<2913 g) for the study cohort
      Sildenafil (n=17)Placebo (n=13)RR (95% CI)
      Operative birth for intrapartum fetal compromise2 (11.8)5 (38.5)0.31 (0.07–1.33)
      All cesarean delivery2 (11.8)6 (46.2)0.25 (0.06–1.06)
       Cesarean delivery for intrapartum fetal compromise5.9 (1)4 (30.8)0.19 (0.02–1.51)
       Cesarean delivery for failure to progress1 (5.9)2 (15.4)0.38 (0.04–3.77)
       Cesarean delivery for other indications00NA
      All instrumental1 (5.9)2 (15.4)0.38 (0.04–3.77)
       Instrumental for intrapartum fetal compromise1 (5.9)1 (7.7)0.76 (0.05–11.11)
       Instrumental for failure to progress01 (7.7)NA
      Spontaneous vaginal birth14 (82.4)5 (38.5)2.14 (1.04–4.41)
      Fetal blood sample performed01 (7.7)NA
      Pathological fetal heart rate pattern or meconium-stained liquor4 (23.5)5 (38.5)0.61 (0.20–1.84)
       Pathologic fetal heart rate pattern3 (17.7)4 (30.8)0.57 (0.15–2.13)
       Meconium-stained liquor1 (5.9)1 (7.7)0.76 (0.05–11.11)
      Composite adverse neonatal outcome
      Composite adverse neonatal outcome: admission to neonatal intensive care unit or Apgar score <7 at 5 minutes or cord pH<7.1 or initial lactate ≥6 mmol/L or neonatal encephalopathy.
      3 (17.7)2 (15.4)1.15 (0.22–5.90)
      Data presented as % (n), mean (standard deviation), or median (interquartile range) as appropriate.
      CI, confidence interval; NA, not available; RR, risk ratio.
      Turner et al. Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial. Am J Obstet Gynecol 2020.
      a Composite adverse neonatal outcome: admission to neonatal intensive care unit or Apgar score <7 at 5 minutes or cord pH<7.1 or initial lactate ≥6 mmol/L or neonatal encephalopathy.

      Discussion

      Principal findings and results in context

      Our results support the hypothesis that sildenafil citrate reduces operative birth by emergency CD or instrumental vaginal birth for intrapartum fetal compromise at term. Compared with placebo, up to three 50-mg doses of sildenafil citrate in labor reduced the risk of this primary outcome by 51.0% (NNT 5 [3–11]; P=.0004]. Sildenafil citrate also reduced the risk of meconium-stained liquor or pathologic fetal heart rate patterns, a composite indicator of fetal compromise, by 47% (NNT 5 [4–12]; P=.0005). Maternal and neonatal safety profiles were similar between groups. There was no clinically important difference between groups in the coprimary outcome of fetal and uteroplacental perfusion, but this analysis included only 71 women, limiting power. Our ultrasound findings are, however, consistent with data from the STRIDER trials, which found no significant difference in fetal (MCA and UA) and maternal (uterine artery) Doppler indices in women receiving sildenafil citrate.
      • Sharp A.
      • Cornforth C.
      • Jackson R.
      • et al.
      Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial.
      ,
      • Sharp A.
      • Cornforth C.
      • Jackson R.
      • et al.
      Mortality in the UK STRIDER trial of sildenafil therapy for the treatment of severe early-onset fetal growth restriction.
      Reassuringly, concentrations of sildenafil citrate and N-desmethyl sildenafil were low in cord blood samples in our study and significantly lower than in neonates given sildenafil citrate for pulmonary hypertension.
      • Kelly L.E.
      • Ohlsson A.
      • Shah P.S.
      Sildenafil for pulmonary hypertension in neonates.
      ,
      • Hill K.D.
      • Sampson M.R.
      • Li J.S.
      • Tunks R.D.
      • Schulman S.R.
      • Cohen-Wolkowiez M.
      Pharmacokinetics of intravenous sildenafil in children with palliated single ventricle heart defects: effect of elevated hepatic pressures.
      ,
      • Thakkar N.
      • Gonzalez D.
      • Cohen-Wolkowiez M.
      • et al.
      An opportunistic study evaluating pharmacokinetics of sildenafil for the treatment of pulmonary hypertension in infants.
      Although fetal compromise in labor has many causes, it often results from subclinical placental impairment with inability to match fetal metabolic demands.
      • Maltepe E.
      • Fisher S.J.
      Placenta: the forgotten organ.
      ,
      • Fisher S.J.
      Why is placentation abnormal in preeclampsia?.
      Because small-for-gestational age fetuses are often more vulnerable to intrapartum hypoxia,
      • Madden J.V.
      • Flatley C.J.
      • Kumar S.
      Term small-for-gestational-age infants from low-risk women are at significantly greater risk of adverse neonatal outcomes.
      we undertook post-hoc exploratory analyses among 30 infants with birth weights below the tenth centile (2913 g) for the study cohort. These showed no evidence of harm and suggested that sildenafil citrate may reduce the overall CD rate and increase spontaneous vaginal birth. However, these results, and the association between sildenafil citrate and a shorter second stage of labor, should be interpreted with caution because they were not adjusted for multiplicity and should be regarded only as hypothesis-generating.
      Our study was temporarily halted to undertake an unplanned safety analysis after the Dutch STRIDER trial stopped in July 2018, owing to a statistically nonsignificant increase in neonatal death (P=.46) and an increase in persistent pulmonary hypertension of the newborn of 27% in the sildenafil citrate group compared with 5% in the control group (P=.0014).
      • Ganzevoort W.
      • Gluud C.
      • Lim K.
      • Mol B.
      • Groom K.
      The STRIDER trials: ongoing research.
      ,
      • Groom K.
      • Ganzevoort W.
      • Alfirevic Z.
      • Lim K.
      • Papageorghiou A.
      STRIDER Consortium
      Clinicians should stop prescribing sildenafil for fetal growth restriction (FGR): comment from the STRIDER Consortium.
      Although a subsequent meta-analysis of 329 women in 3 STRIDER trials showed no significant difference in either outcome,
      • Sharp A.
      • Cornforth C.
      • Jackson R.
      • et al.
      Mortality in the UK STRIDER trial of sildenafil therapy for the treatment of severe early-onset fetal growth restriction.
      investigators advised that pending an individual participant data meta-analysis,
      • Ganzevoort W.
      • Gluud C.
      • Lim K.
      • Mol B.
      • Groom K.
      The STRIDER trials: ongoing research.
      sildenafil citrate should not be prescribed for fetal growth restriction outside clinical trials.
      • Groom K.
      • Ganzevoort W.
      • Alfirevic Z.
      • Lim K.
      • Papageorghiou A.
      STRIDER Consortium
      Clinicians should stop prescribing sildenafil for fetal growth restriction (FGR): comment from the STRIDER Consortium.
      The repurposing of sildenafil citrate in RIDSTRESS is very different from its use in the STRIDER trials, which compared 75 mg of oral maternal sildenafil citrate daily vs placebo for severe early fetal growth restriction, in cumulative doses of up to 5000 mg or more.

      Strengths and limitations

      Our study had several strengths. Operational and performance bias were minimized because this was a double-blind, placebo-controlled trial in which investigators remained blinded to study allocation and final outcomes until the end of the study. Our trial was also at low risk of other types of bias, as indicated by applying the Cochrane Handbook tool
      • Higgins J.P.
      • Green S.
      Cochrane handbook for systematic reviews of interventions.
      (Supplemental Table 5). The finding that sildenafil citrate substantially reduced the primary outcome of emergency operative birth for intrapartum fetal compromise with a 2-sided P value of .0004 (Table 2) equates to a deviation of more than 4 standard deviations from the null hypothesis, which is extremely unlikely to represent a type I error. Further, the finding that sildenafil citrate substantially reduced the prespecified secondary composite outcome of meconium-stained liquor or abnormal fetal heart rate pattern (P=.0005; Table 2), which is both a measure of fetal compromise and a clinical indication for emergency operative delivery, makes it even more unlikely that these might be chance effects and that the null hypothesis for the primary outcome was incorrectly rejected.
      Our study also had limitations. In both groups, more women than expected had induction of labor for various indications. Some of these indications are recognized as being of greater risk for intrapartum fetal compromise. Nevertheless, in this placebo-controlled study, randomization would have tended to distribute these women equally across both study arms. Furthermore, although induction of labor reduces overall rates of CD,
      • Middleton P.
      • Shepherd E.
      • Crowther C.A.
      Induction of labour for improving birth outcomes for women at or beyond term.
      ,
      • Grobman W.A.
      • Rice M.M.
      • Reddy U.M.
      • et al.
      Labor induction versus expectant management in low-risk nulliparous women.
      we found in another study that it was associated with twice the adjusted odds of CD for intrapartum fetal compromise (adjusted odds ratio, 2.25; 95% CI, 2.08–2.44, P<.001).
      • Mendis R.
      • Flatley C.
      • Kumar S.
      Maternal demographic factors associated with emergency caesarean section for non-reassuring foetal status.
      In addition, despite the recognized significant inter- and intraobserver differences in interpreting fetal heart rate patterns by clinicians, and variability in deciding the need for emergency operative birth,
      • Ayres-de-Campos D.
      • Bernardes J.
      • Costa-Pereira A.
      • Pereira-Leite L.
      Inconsistencies in classification by experts of cardiotocograms and subsequent clinical decision.
      bias was unlikely, as caregivers were blinded. We also recognize that fetuses who develop intrapartum compromise are not necessarily hypoxic. Furthermore, paired ultrasound scans were only performed in 23.7% (37/300) of participants and maternal and cord blood analyses for sildenafil citrate and N-desmethyl sildenafil levels were done in only 12.7% (19/150) of women in the sildenafil citrate group.
      No adjustment was made for multiplicity among the coprimary and secondary outcome measures of intrapartum fetal compromise. However, after using the Benjamini–Hochberg–Simes procedure to control in retrospect for false discovery and even after using the more stringent Bonferroni correction to adjust for all 8 prespecified outcomes,
      • Benjamini Y.
      • Hochberg Y.
      Controlling the false discovery rate: a practical and powerful approach to multiple testing.
      ,
      • Simes R.J.
      An Improved Bonferroni procedure for multiple tests of significance.
      our conclusions did not change (Supplemental Materials and Methods, Supplemental Table 2) Lastly, no formal stopping rule was prespecified in the study protocol. However, the DSMC statistician has advised that, had a commonly used formal threshold of P=.001 for nominal significance been used at the first 2 interim analyses, as recommended by Geller and Pocock,
      • Geller N.L.
      • Pocock S.J.
      Interim analyses in randomized clinical trials: ramifications and guidelines for practitioners.
      the DSMC would not have advised earlier termination of the study. Thus, no adjustment has been made to account for interim analyses and the final P value of .0004 for the primary outcome represents a statistically robust result.

      Clinical and research implications

      Our trial heralds the possibility of a simple and affordable pharmacologic intervention to reduce intrapartum fetal compromise arising from inadequate placental perfusion and deteriorating function in labor. However, sildenafil citrate will not prevent other causes of fetal compromise such as cord prolapse, placental abruption, or uterine rupture, which are all strongly associated with severe hypoxic injury, neonatal encephalopathy, and cerebral palsy.
      • Hankins G.D.
      • Speer M.
      Defining the pathogenesis and pathophysiology of neonatal encephalopathy and cerebral palsy.
      In addition, accurate identification of women that might benefit from this treatment is also important to enable more targeted therapy, given that current methods for prenatal identification of at-risk fetuses have limited prognostic utility.
      • Flatley C.
      • Gibbons K.S.
      • Hurst C.
      • Kumar S.
      Development of a cross-validated model for predicting emergency cesarean for intrapartum fetal compromise at term.
      • Akolekar R.
      • Ciobanu A.
      • Zingler E.
      • Syngelaki A.
      • Nicolaides K.H.
      Routine assessment of cerebroplacental ratio at 35-37 weeks' gestation in the prediction of adverse perinatal outcome.
      • Kalafat E.
      • Morales-Rosello J.
      • Thilaganathan B.
      • Tahera F.
      • Khalil A.
      Risk of operative delivery for intrapartum fetal compromise in small-for-gestational-age fetuses at term: an internally validated prediction model.
      Furthermore, as with the use of aspirin in obstetrics,
      • Duley L.
      • Meher S.
      • Hunter K.E.
      • Seidler A.L.
      • Askie L.M.
      Antiplatelet agents for preventing pre-eclampsia and its complications.
      ,
      • Turner J.M.
      • Robertson N.T.
      • Hartel G.
      • Kumar S.
      The impact of low-dose aspirin on adverse perinatal outcomes: a meta-analysis and meta-regression.
      the impact of sildenafil citrate on key outcomes like intrapartum stillbirth, perinatal or neonatal mortality, neonatal morbidity, and childhood disability remains unknown. Trials to improve stillbirth or neonatal mortality will require tens of thousands of participants with international collaboration, as envisaged by the ALPHA Collaboration
      • Tarnow-Mordi W.
      • Cruz M.
      • Morris J.M.
      • Mol B.W.
      RCT evidence should drive clinical practice: A day without randomisation is a day without progress.
      • Fogarty M.
      • Osborn D.A.
      • Askie L.
      • et al.
      Delayed vs early umbilical cord clamping for preterm infants: a systematic review and meta-analysis.
      • Tarnow-Mordi W.O.
      • Kirby A.
      Current recommendations and practice of oxygen therapy in preterm infants.
      (Table 8).
      Table 8Sample sizes to show moderate, clinically important 10% or 20% reductions in relative risk of key outcomes like mortality, severe morbidity or disability
      Event rate in control group

      (C)
      Event rate in treated group

      (T)
      Risk difference

      (C – T =Δ)
      Relative risk (or risk ratio)

      (RR = T/C)
      Relative risk reduction

      (1 – RR)
      Number needed to benefit or harm

      (100/ Δ)
      Total sample to show effect in a 2-arm comparison with 90% power, 2P=.05 and nonadherence to protocol due to
      0% dropout or crossover (perfect protocol adherence)10% drop-out5% crossover in each group10% crossover in each group
      20%16%4%0.80.2253868425547766044
      20%18%2%0.90.15016,16617,78319,96025,260
      10%8%2%0.80.2508598945810,61613,436
      10%9%1%0.90.110036,13639,75044,61456,464
      5%4%1%0.80.210018,05819,86422,29428,216
      5%4.5%0.5%0.90.120076,07683,68493,922118,870
      Turner et al. Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial. Am J Obstet Gynecol 2020.
      How can we progress to trials with sufficient power to demonstrate moderate but important differences in perinatal mortality? The next step is to undertake several concurrent trials with the same protocol, each funded by relevant national or international agencies, which might each have 80% to 90% power to detect a 35% reduction in relative risk of a composite neonatal outcome (such as intrapartum stillbirth, neonatal death, Apgar score ≤3 at 5 minutes, moderate/severe neonatal encephalopathy receiving cooling, umbilical cord artery pH <7.0, prolonged respiratory support or admission to a NICU, persistent pulmonary hypertension, or meconium aspiration) from 7% to 4.55%. It is critically important that all such trials be overseen by a single international DSMC, guided by an agreed charter,
      Damocles Study Group, NHS Health Technology Assessment Programme
      A proposed charter for clinical trial data monitoring committees: helping them to do their job well.
      so that all trials could be terminated early if an answer emerges beyond reasonable doubt, for example, when accumulating data from all trials showed a moderate reduction or increase in perinatal mortality of 10% or more, associated with a P value of less than .001.
      • Geller N.L.
      • Pocock S.J.
      Interim analyses in randomized clinical trials: ramifications and guidelines for practitioners.

      Conclusion

      Despite its promising results, this phase 2 trial was underpowered to evaluate the effects of sildenafil citrate on maternal and neonatal outcomes. Much larger numbers are therefore urgently needed in phase 3 trials, endorsed by key stakeholders.
      • Cook J.A.
      • Julious S.A.
      • Sones W.
      • et al.
      DELTA2 guidance on choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial.
      Trials to improve stillbirth or neonatal mortality will require tens of thousands of participants in aggregate with international collaboration. This could be achieved by concurrent, nationally funded trials with similar or identical protocols overseen by a single international DSMC, to ensure that enrollment stops as soon as an answer emerges beyond reasonable doubt. Preventing intrapartum hypoxia and mitigating the immediate and longer-term sequelae of birth asphyxia are urgent health challenges, because the need to improve birth outcomes is a critically important global priority.
      Stemming the global caesarean section epidemic.
      ,
      • Yoshida S.
      • Rudan I.
      • Lawn J.E.
      • et al.
      Newborn health research priorities beyond 2015.
      ,
      • Spong C.Y.
      Improving birth outcomes key to improving global health.

      Acknowledgments

      The authors acknowledge the support of the Mater Foundation, staff of the Mater Mother’s Hospital, the women who participated in this trial, Dr Francesca Russo and Professor Jan DePrest from the Department of Biomedical Sciences, Katholieke Universiteit, Leuven, for measurement of blood sildenafil citrate levels, the Interdisciplinary Maternal Perinatal Australasian Collaborative Trials (IMPACT) Network and members of the Data Safety and Monitoring Committee (Dr Chris Flatley, [trial statistician], Associate Professor Treasure McGuire [pharmacist and Chair], Associate Professor Robert Cincotta [obstetrician], Professor David Tudehope [neonatologist]). The decision to invite Dr Flatley to become a coauthor to ensure the accuracy of statistical reporting was made only after his role in the Data and Safety Monitoring Committee had ended, when all interim analyses had been completed, and the trial had terminated. Statistical advice from Ms Adrienne Kirby, Professor John Simes, and Professor Anthony Keech is also gratefully acknowledged. The Trial Steering Committee comprised Dr J. Turner, Prof V. Flenady, Dr L. Dunn, and Prof S. Kumar. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author (S.K.) had full access to all the data in the study and had final responsibility for the decision to submit.

      Supplementary Data

      References

        • Bakker P.C.
        • Kurver P.H.
        • Kuik D.J.
        • Van Geijn H.P.
        Elevated uterine activity increases the risk of fetal acidosis at birth.
        Am J Obstet Gynecol. 2007; 196: 313e1-313e6
        • Simpson K.R.
        • James D.C.
        Effects of oxytocin-induced uterine hyperstimulation during labor on fetal oxygen status and fetal heart rate patterns.
        Am J Obstet Gynecol. 2008; 199: 34 e1-34 e5
        • Ayres-de-Campos D.
        • Arulkumaran S.
        FIGO Intrapartum Fetal Monitoring Expert Consensus Panel. FIGO consensus guidelines on intrapartum fetal monitoring: physiology of fetal oxygenation and the main goals of intrapartum fetal monitoring.
        Int J Gynaecol Obstet. 2015; 131: 5-8
        • Turner J.M.
        • Mitchell M.D.
        • Kumar S.
        The physiology of intrapartum fetal compromise at term.
        Am J Obstet Gynecol. 2020; 222: 17-26
        • Janbu T.
        • Nesheim B.I.
        Uterine artery blood velocities during contractions in pregnancy and labour related to intrauterine pressure.
        Br J Obstet Gynaecol. 1987; 94: 1150-1155
        • Cindrova-Davies T.
        • Yung H.W.
        • Johns J.
        • et al.
        Oxidative stress, gene expression, and protein changes induced in the human placenta during labor.
        Am J Pathol. 2007; 171: 1168-1179
        • Mizuuchi M.
        • Cindrova-Davies T.
        • Olovsson M.
        • Charnock-Jones D.S.
        • Burton G.J.
        • Yung H.W.
        Placental endoplasmic reticulum stress negatively regulates transcription of placental growth factor via ATF4 and ATF6beta: implications for the pathophysiology of human pregnancy complications.
        J Pathol. 2016; 238: 550-561
        • Hilder L.
        • Zhichao Z.
        • Parker M.
        • Jahan S.
        • Chambers G.
        Australia’s mothers and babies 2012. Perinatal statistics series no. 30. Cat. no. PER 69.
        AIHW, Canberra2014
        • Boyle A.
        • Reddy U.M.
        • Landy H.J.
        • Huang C.C.
        • Driggers R.W.
        • Laughon S.K.
        Primary cesarean delivery in the United States.
        Obstet Gynecol. 2013; 122: 33-40
        • Bragg F.
        • Cromwell D.A.
        • Edozien L.C.
        • et al.
        Variation in rates of caesarean section among English NHS trusts after accounting for maternal and clinical risk: cross sectional study.
        BMJ. 2010; 341: c5065
        • Lawn J.
        • Shibuya K.
        • Stein C.
        No cry at birth: global estimates of intrapartum stillbirths and intrapartum-related neonatal deaths.
        Bull World Health Organ. 2005; 83: 409-417
        • Lawn J.E.
        • Blencowe H.
        • Oza S.
        • et al.
        Every Newborn: progress, priorities, and potential beyond survival.
        Lancet. 2014; 384: 189-205
        • Badawi N.
        • Keogh J.M.
        Causal pathways in cerebral palsy.
        J Paediatr Child Health. 2013; 49: 5-8
        • Low J.A.
        • Pickersgill H.
        • Killen H.
        • Derrick E.J.
        The prediction and prevention of intrapartum fetal asphyxia in term pregnancies.
        Am J Obstet Gynecol. 2001; 184: 724-730
        • Flenady V.
        • Koopmans L.
        • Middleton P.
        • et al.
        Major risk factors for stillbirth in high-income countries: a systematic review and meta-analysis.
        Lancet. 2011; 377: 1331-1340
      1. Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.
        Lancet. 2018; 392: 1859-1922
        • Nunes I.
        • Ayres-de-Campos D.
        • Ugwumadu A.
        • et al.
        Central fetal monitoring with and without computer analysis: a randomized controlled trial.
        Obstet Gynecol. 2017; 129: 83-90
        • Brocklehurst P.
        • Field D.
        • Greene K.
        • et al.
        Computerised interpretation of fetal heart rate during labour (INFANT): a randomised controlled trial.
        Lancet. 2017; 389: 1719-1729
        • Alfirevic Z.
        • Devane D.
        • Gyte G.M.
        • Cuthbert A.
        Continuous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) for fetal assessment during labour.
        Cochrane Database Syst Rev. 2017; 2: CD006066
        • Neilson J.P.
        Fetal electrocardiogram (ECG) for fetal monitoring during labour.
        Cochrane Database Syst Rev. 2015; : CD000116
        • Tonei V.
        Mother's mental health after childbirth: does the delivery method matter?.
        J Health Econ. 2019; 63: 182-196
        • Prado D.S.
        • Mendes R.B.
        • Gurgel R.Q.
        • Barreto I.D.C.
        • Cipolotti R.
        • Gurgel R.Q.
        The influence of mode of delivery on neonatal and maternal short and long-term outcomes.
        Rev Saude Publica. 2018; 52: 95
        • Dekel S.
        • Ein-Dor T.
        • Berman Z.
        • Barsoumian I.S.
        • Agarwal S.
        • Pitman R.K.
        Delivery mode is associated with maternal mental health following childbirth.
        Arch Womens Ment Health. 2019; 22: 817-824
        • Hobbs A.J.
        • Mannion C.A.
        • McDonald S.W.
        • Brockway M.
        • Tough S.C.
        The impact of caesarean section on breastfeeding initiation, duration and difficulties in the first four months postpartum.
        BMC Pregnancy Childbirth. 2016; 16: 90
        • Sandall J.
        • Tribe R.M.
        • Avery L.
        • et al.
        Short-term and long-term effects of caesarean section on the health of women and children.
        Lancet. 2018; 392: 1349-1357
        • O'Mahony F.
        • Hofmeyr G.J.
        • Menon V.
        Choice of instruments for assisted vaginal delivery.
        Cochrane Database Syst Rev. 2010; : CD005455
        • ACOG Practice Bulletin No
        198: Prevention and Management of Obstetric Lacerations at Vaginal Delivery.
        Obstet Gynecol. 2018; 132: e87-e102
        • Aberg K.
        • Norman M.
        • Pettersson K.
        • Jarnbert-Pettersson H.
        • Ekeus C.
        Protracted vacuum extraction and neonatal intracranial hemorrhage among infants born at term: a nationwide case-control study.
        Acta Obstet Gynecol Scand. 2019; 98: 523-532
      2. Stemming the global caesarean section epidemic.
        Lancet. 2018; 392: 1279
        • Groom K.M.
        • David A.L.
        The role of aspirin, heparin, and other interventions in the prevention and treatment of fetal growth restriction.
        Am J Obstet Gynecol. 2018; 218: S829-S840
        • Dastjerdi M.V.
        • Hosseini S.
        • Bayani L.
        Sildenafil citrate and uteroplacental perfusion in fetal growth restriction.
        J Res Med Sci. 2012; 17: 632-636
        • Hale S.A.
        • Jones C.W.
        • Osol G.
        • Schonberg A.
        • Badger G.J.
        • Bernstein I.M.
        Sildenafil increases uterine blood flow in nonpregnant nulliparous women.
        Reprod Sci. 2010; 17: 358-365
        • Wareing M.
        • Myers J.E.
        • O'Hara M.
        • Baker P.N.
        Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction.
        J Clin Endocrinol Metab. 2005; 90: 2550-2555
        • Samangaya R.A.
        • Wareing M.
        • Skillern L.
        • Baker P.N.
        Phosphodiesterase inhibitor effect on small artery function in preeclampsia.
        Hypertens Pregnancy. 2011; 30: 144-152
        • Patole S.K.
        • Kumaran V.
        • Travadi J.N.
        • Brooks J.M.
        • Doherty D.A.
        Does patent ductus arteriosus affect feed tolerance in preterm neonates?.
        Arch Dis Child Fetal Neonatal Ed. 2007; 92: F53-F55
        • Patole S.K.
        • Muller R.
        Does carboxymethylcellulose have a role in reducing time to full enteral feeds in preterm neonates?.
        Int J Clin Pract. 2005; 59: 544-548
        • Brooks J.M.
        • Travadi J.N.
        • Patole S.K.
        • Doherty D.A.
        • Simmer K.
        Is surgical ligation of patent ductus arteriosus necessary? The Western Australian experience of conservative management.
        Arch Dis Child Fetal Neonatal Ed. 2005; 90: F235-F239
        • Kelly L.E.
        • Ohlsson A.
        • Shah P.S.
        Sildenafil for pulmonary hypertension in neonates.
        Cochrane Database Syst Rev. 2017; 8: CD005494
        • Barnes H.
        • Brown Z.
        • Burns A.
        • Williams T.
        Phosphodiesterase 5 inhibitors for pulmonary hypertension.
        Cochrane Database Syst Rev. 2019; 1: CD012621
        • Dunn L.
        • Greer R.
        • Flenady V.
        • Kumar S.
        Sildenafil in pregnancy: a systematic review of maternal tolerance and obstetric and perinatal outcomes.
        Fetal Diagn Ther. 2017; 41: 81-88
        • Groom K.M.
        • McCowan L.M.
        • Mackay L.K.
        • et al.
        STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction.
        BJOG. 2019; 126: 997-1006
        • Dunn L.
        • Flenady V.
        • Kumar S.
        Reducing the risk of fetal distress with sildenafil study (RIDSTRESS): a double-blind randomised control trial.
        J Transl Med. 2016; 14: 15
        • Kumar S.
        Correction to: Dunn L, Flenady V, Kumar S. Reducing the risk of fetal distress with sildenafil study (RIDSTRESS): a double blind randomised control trial.
        J Transl Med. 2016; 14 (see erratum: Annex 5, Web Supplementary Appendix): 15
        • World Medical Association Declaration of Helsinki
        Ethical principles for medical research involving human subjects.
        J Bull World Health Organ. 2001; 79: 373
        • Bhuiyan P.
        • Rege N.
        ICH Harmonised Tripartite Guideline: guideline for good clinical practice.
        J Postgrad Med. 2001; 47
      3. Sildenafil citrate, 2018 (vol 2019).
        (Available at:) (Accessed February 18, 2019)
        • Bligh L.N.
        • Alsolai A.A.
        • Greer R.M.
        • Kumar S.
        Prelabor screening for intrapartum fetal compromise in low-risk pregnancies at term: cerebroplacental ratio and placental growth factor.
        Ultrasound Obstet Gynecol. 2018; 52: 750-756
        • RANZCOG
        Intrapartum Fetal Surveillance, Clinical Guidelines 3.1.
        RANZCOG, Melbourne, Australia2014
        • Sarnat H.B.
        • Sarnat M.S.
        Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study.
        Arch Neurol. 1976; 33: 696-705
        • Russo F.M.
        • Conings S.
        • Allegaert K.
        • et al.
        Sildenafil crosses the placenta at therapeutic levels in a dually perfused human cotyledon model.
        Am J Obstet Gynecol. 2018; 219: 619 e1-619 e10
        • Flatley C.
        • Kumar S.
        • Greer R.M.
        Reference centiles for the middle cerebral artery and umbilical artery pulsatility index and cerebro-placental ratio from a low-risk population—a Generalised Additive Model for Location, Shape and Scale (GAMLSS) approach.
        J Maternal-Fetal Neonatal Med. 2019; 32: 2338-2345
        • Perneger T.V.
        What's wrong with Bonferroni adjustments.
        BMJ. 1998; 316: 1236-1238
        • Benjamini Y.
        • Hochberg Y.
        Controlling the false discovery rate: a practical and powerful approach to multiple testing.
        J Roy Stat Soc Ser B (Method). 1995; 57: 289-300
        • Simes R.J.
        An Improved Bonferroni procedure for multiple tests of significance.
        Biometrika. 1986; 73: 751-754
        • Ganzevoort W.
        • Gluud C.
        • Lim K.
        • Mol B.
        • Groom K.
        The STRIDER trials: ongoing research.
        Lancet Child Adolesc Health. 2018; 2: e3
        • Groom K.
        • Ganzevoort W.
        • Alfirevic Z.
        • Lim K.
        • Papageorghiou A.
        • STRIDER Consortium
        Clinicians should stop prescribing sildenafil for fetal growth restriction (FGR): comment from the STRIDER Consortium.
        Ultrasound Obstet Gynecol. 2018; 52: 295-296
        • 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
        • Sharp A.
        • Cornforth C.
        • Jackson R.
        • et al.
        Mortality in the UK STRIDER trial of sildenafil therapy for the treatment of severe early-onset fetal growth restriction.
        Lancet Child Adolesc Health. 2019; 3: e2-e3
        • Hill K.D.
        • Sampson M.R.
        • Li J.S.
        • Tunks R.D.
        • Schulman S.R.
        • Cohen-Wolkowiez M.
        Pharmacokinetics of intravenous sildenafil in children with palliated single ventricle heart defects: effect of elevated hepatic pressures.
        Cardiol Young. 2016; 26: 354-362
        • Thakkar N.
        • Gonzalez D.
        • Cohen-Wolkowiez M.
        • et al.
        An opportunistic study evaluating pharmacokinetics of sildenafil for the treatment of pulmonary hypertension in infants.
        J Perinatol. 2016; 36: 744-747
        • Maltepe E.
        • Fisher S.J.
        Placenta: the forgotten organ.
        Annu Rev Cell Dev Biol. 2015; 31: 523-552
        • Fisher S.J.
        Why is placentation abnormal in preeclampsia?.
        Am J Obstet Gynecol. 2015; 213: S115-S122
        • Madden J.V.
        • Flatley C.J.
        • Kumar S.
        Term small-for-gestational-age infants from low-risk women are at significantly greater risk of adverse neonatal outcomes.
        Am J Obstet Gynecol. 2018; 218: 525.e1-525.e9
        • Higgins J.P.
        • Green S.
        Cochrane handbook for systematic reviews of interventions.
        The Cochrane Collaboration, 2011 (Available at:) (Accessed June 26, 2019)
        • Middleton P.
        • Shepherd E.
        • Crowther C.A.
        Induction of labour for improving birth outcomes for women at or beyond term.
        Cochrane Database Syst Rev. 2018; 5: CD004945
        • Grobman W.A.
        • Rice M.M.
        • Reddy U.M.
        • et al.
        Labor induction versus expectant management in low-risk nulliparous women.
        N Engl J Med. 2018; 379: 513-523
        • Mendis R.
        • Flatley C.
        • Kumar S.
        Maternal demographic factors associated with emergency caesarean section for non-reassuring foetal status.
        J Perinat Med. 2018; 46: 641-647
        • Ayres-de-Campos D.
        • Bernardes J.
        • Costa-Pereira A.
        • Pereira-Leite L.
        Inconsistencies in classification by experts of cardiotocograms and subsequent clinical decision.
        Br J Obstet Gynaecol. 1999; 106: 1307-1310
        • Geller N.L.
        • Pocock S.J.
        Interim analyses in randomized clinical trials: ramifications and guidelines for practitioners.
        Biometrics. 1987; 43: 213-223
        • Hankins G.D.
        • Speer M.
        Defining the pathogenesis and pathophysiology of neonatal encephalopathy and cerebral palsy.
        Obstet Gynecol. 2003; 102: 628-636
        • Flatley C.
        • Gibbons K.S.
        • Hurst C.
        • Kumar S.
        Development of a cross-validated model for predicting emergency cesarean for intrapartum fetal compromise at term.
        Int J Gynaecol Obstet. 2020; 148: 41-47
        • Akolekar R.
        • Ciobanu A.
        • Zingler E.
        • Syngelaki A.
        • Nicolaides K.H.
        Routine assessment of cerebroplacental ratio at 35-37 weeks' gestation in the prediction of adverse perinatal outcome.
        Am J Obstet Gynecol. 2019; 221: 65 e1-65 e18
        • Kalafat E.
        • Morales-Rosello J.
        • Thilaganathan B.
        • Tahera F.
        • Khalil A.
        Risk of operative delivery for intrapartum fetal compromise in small-for-gestational-age fetuses at term: an internally validated prediction model.
        Am J Obstet Gynecol. 2018; 218: 134 e1-134 e8
        • Duley L.
        • Meher S.
        • Hunter K.E.
        • Seidler A.L.
        • Askie L.M.
        Antiplatelet agents for preventing pre-eclampsia and its complications.
        Cochrane Database Syst Rev. 2019; 2019
        • Turner J.M.
        • Robertson N.T.
        • Hartel G.
        • Kumar S.
        The impact of low-dose aspirin on adverse perinatal outcomes: a meta-analysis and meta-regression.
        Ultrasound Obstet Gynecol. 2020; 55: 157-169
        • Tarnow-Mordi W.
        • Cruz M.
        • Morris J.M.
        • Mol B.W.
        RCT evidence should drive clinical practice: A day without randomisation is a day without progress.
        BJOG. 2017; 124: 613
        • Fogarty M.
        • Osborn D.A.
        • Askie L.
        • et al.
        Delayed vs early umbilical cord clamping for preterm infants: a systematic review and meta-analysis.
        Am J Obstet Gynecol. 2018; 218: 1-18
        • Tarnow-Mordi W.O.
        • Kirby A.
        Current recommendations and practice of oxygen therapy in preterm infants.
        Clin Perinatol. 2019; 46: 621-636
        • Damocles Study Group, NHS Health Technology Assessment Programme
        A proposed charter for clinical trial data monitoring committees: helping them to do their job well.
        Lancet. 2005; 365: 711-722
        • Cook J.A.
        • Julious S.A.
        • Sones W.
        • et al.
        DELTA2 guidance on choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial.
        BMJ. 2018; 363k3750
        • Yoshida S.
        • Rudan I.
        • Lawn J.E.
        • et al.
        Newborn health research priorities beyond 2015.
        Lancet. 2014; 384: e27-e29
        • Spong C.Y.
        Improving birth outcomes key to improving global health.
        JAMA. 2016; 316: 395-396