sildenafil-citrate and Fetal-Growth-Retardation

An increase in vascular resistance of uterine vessels is associated with intrauterine growth restriction (IUGR). Sildenafil citrate, a phosphodiesterase-5 inhibitor that stabilizes cyclic guanosine monophosphate (cGMP) and increases nitric oxide levels, improves placental perfusion by dilation of spiral arteries and is beneficial in managing IUGR. This study aims to determine the effectiveness of sildenafil citrate in improving perinatal outcomes in IUGR pregnancies.. Meta-analysis was performed on data extracted from all studies specific to sildenafil citrate in IUGR management, searching relevant articles on PubMed, Medline, Google Scholar, Embase, and Cochrane databases. Publications identified by the manual search, based on references in reviews, were also included. Dichotomous results were presented as risk ratio (95% confidence interval), while continuous results were expressed as mean difference (MD); samples represented by the random effects model.. Nine trials were included where the sildenafil citrate effect was compared with a placebo or no intervention. A significant increase in birth weight [SMD (95% CI), 0.69 (0.31, 1.07)] was seen in IUGR pregnancies managed with sildenafil. However, gestational age (SMD (95% CI), 0.44 (-0.05, 0.94], fetal death rate [RR (95% CI), 0.56 (0.17, 1.79)] in IUGR pregnancies was not changed by sildenafil. Neonatal death [RR (95% CI), 0.93 (0.47, 1.86)] and neonatal intensive care unit (NICU) admissions [RR (95% CI), 0.76 (0.50, 1.17)] were not significantly different between sildenafil and control groups.. Sildenafil citrate increases birth weight and prolonged pregnancies but did not affect stillbirth rate, neonatal death, and NICU admission.. The study was registered in PROSPERO on September 18, 2021 (CRD42021271992).

Topics: Birth Weight; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Perinatal Death; Placenta; Pregnancy; Sildenafil Citrate

Fetal growth restriction (FGR) is a condition of poor growth of the fetus in utero. One of the causes of FGR is placental insufficiency. Severe early-onset FGR at < 32 weeks of gestation occurs in an estimated 0.4% of pregnancies. This extreme phenotype is associated with a high risk of fetal death, neonatal mortality, and neonatal morbidity. Currently, there is no causal treatment, and management is focused on indicated preterm birth to prevent fetal death. Interest has risen in interventions that aim to improve placental function by administration of pharmacological agents affecting the nitric oxide pathway causing vasodilatation.. The objective of this systematic review and aggregate data meta-analysis is to assess the beneficial and harmful effects of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or different drugs affecting this pathway against each other, in pregnant women with severe early-onset FGR.. We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 July 2022), and reference lists of retrieved studies.. We considered all randomised controlled comparisons of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or another drug affecting this pathway in pregnant women with severe early-onset FGR of placental origin, for inclusion in this review.. We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis.. We included a total of eight studies (679 women) in this review, all of which contributed to the data and analysis. The identified studies report on five different comparisons: sildenafil compared with placebo or no therapy, tadalafil compared with placebo or no therapy, L-arginine compared with placebo or no therapy, nitroglycerin compared with placebo or no therapy and sildenafil compared with nitroglycerin. The risk of bias of included studies was judged as low or unclear. In two studies the intervention was not blinded. The certainty of evidence for our primary outcomes was judged as moderate for the intervention sildenafil and low for tadalafil and nitroglycerine (due to low number of participants and low number of events). For the intervention L-arginine, our primary outcomes were not reported. Sildenafil citrate compared to placebo or no therapy (5 studies, 516 women) Five studies (Canada, Australia and New Zealand, the Netherlands, the UK and Brazil) involving 516 pregnant women with FGR were included. We assessed the certainty of the evidence as moderate. Compared with placebo or no therapy, sildenafil probably has little or no effect on all-cause mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.80 to 1.27, 5 studies, 516 women); may reduce fetal mortality (RR 0.82, 95% CI 0.60 to 1.12, 5 studies, 516 women), and increase neonatal mortality (RR 1.45, 95% CI 0.90 to 2.33, 5 studies, 397 women), although the results are uncertain for fetal and neonatal mortality as 95% confidence intervals are wide crossing the line of no effect. Tadalafil compared with placebo or no therapy (1 study, 87 women) One study (Japan) involving 87 pregnant women with FGR was included. We assessed the certainty of the evidence as low. Compared with placebo or no therapy, tadalafil may have little or no effect on all-cause mortality (risk ratio 0.20, 95% CI 0.02 to 1.60, one study, 87 women); fetal mortality (RR 0.11, 95% CI 0.01 to 1.96, one study, 87 women); and neonatal mortality (RR 0.89, 95% CI 0.06 to 13.70, one study, 83 women). L-Arginine compared with placebo or no therapy (1 study, 43 women) One study (France) involving 43 pregnant women with FGR was included. This study did not assess our primary outcomes. Nitroglycerin compared to placebo or no therapy (1 studies, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due. Interventions affecting the nitric oxide pathway probably do not seem to influence all-cause (fetal and neonatal) mortality in pregnant women carrying a baby with FGR, although more evidence is needed. The certainty of this evidence is moderate for sildenafil and low for tadalafil and nitroglycerin. For sildenafil a fair amount of data are available from randomised clinical trials, but with low numbers of participants. Therefore, the certainty of evidence is moderate. For the other interventions investigated in this review there are insufficient data, meaning we do not know whether these interventions improve perinatal and maternal outcomes in pregnant women with FGR.

Topics: Female; Fetal Death; Fetal Growth Retardation; Humans; Infant, Newborn; Nitric Oxide; Nitroglycerin; Placenta; Pregnancy; Premature Birth; Sildenafil Citrate; Tadalafil

The efficacy and safety profile of phosphodiesterase-5 inhibitors (PDE-5i) in pregnancy are unclear from the few relatively small diverse studies that have used them.. To assess the safety profile and clinical outcomes of PDE-5i use in pregnancy.. We searched Embase, PubMed, CENTRAL, Prospero and Google Scholar to identify randomised controlled trials (RCTs) reporting the use of any PDE-5i in pregnancy up to September 2021.. RCTs reporting obstetric or perinatal outcomes or maternal adverse outcomes in women taking PDE5i in pregnancy.. Risk ratios (RR), 95% confidence intervals (95% CI) and 95% prediction intervals were calculated and pooled for analysis.. We identified 1324 citations, of which 10 studies including 1090 participants met the inclusion criteria. Only tadalafil and sildenafil were reported as used in pregnancy. Two studies using tadalafil and eight sildenafil. Nine of ten studies were assessed at having of low risk of bias. PDE-5i use was associated with an increased risk of headaches (RR 1.41, 95% CI 0.97-2.05), flushing (RR 2.59, 95% CI 0.69-9.90) and nasal bleeding (RR 10.53, 95% CI 1.36-81.3); an increase in vaginal birth when used for non-fetal growth restriction (FGR) indications (RR 1.24, 95% CI 1.00-1.55) and a reduction in risk of operative birth for intrapartum fetal compromise (RR 0.58, 95% CI 0.38-0.88). There was no evidence of any increase in risk of perinatal death (RR 0.89, 95% CI 0.56-1.43). However, use for the treatment of FGR increased the risk of persistent pulmonary hypertension of the newborn (PPHN) (RR 2.52, 95% CI 1.00-6.32).. This meta-analysis suggests PDE-5i use in pregnancy is associated with mild maternal side effects and lower risk of operative birth for intrapartum fetal distress. Prolonged use for the treatment of FGR may increase the risk of PPHN.. PDE-5i use in pregnancy is associated with mild maternal side effects, lower operative birth for intrapartum fetal distress and a possible increase in persistent pulmonary hypertension of the newborn when used for the treatment of fetal growth restriction.

Topics: Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Fetal Distress; Fetal Growth Retardation; Humans; Hypertension, Pulmonary; Infant, Newborn; Phosphodiesterase 5 Inhibitors; Pregnancy; Sildenafil Citrate; Tadalafil

To determine the efficacy and safety of sildenafil citrate to improve outcomes in pregnancies complicated by early-onset, dismal prognosis, fetal growth restriction (FGR). Eligibility: women ≥ 18 years, singleton, 18 + 0-27 + 6 weeks' gestation, estimated fetal weight < 700 g, low PLFG, and ≥ 1 of (i) abdominal circumference < 10th percentile for gestational age (GA); or (ii) reduced growth velocity and either abnormal uterine artery Doppler or prior early-onset FGR with adverse outcome. Ineligibility criteria included: planned termination or reversed umbilical artery end-diastolic flow. Eligibility confirmed by placental growth factor (PLGF) < 5 th percentile for GA measured post randomization. Women randomly received (1:1) either sildenafil 25 mg three times daily or matched placebo until either delivery or 31 + 6 weeks.. delivery GA. The trial stopped early when Dutch STRIDER signalled potential harm; despite distinct eligibility criteria and IRB and DSMB support to continue, because of futility. NCT02442492 [registered 13/05/2015].. Between May 2017 and June 2018, 21 (90 planned) women were randomised [10 sildenafil; 11 placebo (1 withdrawal)]. Baseline characteristics, PLGF levels, maternal and perinatal outcomes, and adverse events did not differ. Delivery GA: 26 + 6 weeks (sildenafil) vs 29 + 2 weeks (placebo); p = 0.200. Data will contribute to an individual participant data meta-analysis.

Topics: Canada; Female; Fetal Growth Retardation; Gestational Age; Humans; Placenta Growth Factor; Pregnancy; Randomized Controlled Trials as Topic; Sildenafil Citrate; Ultrasonography, Prenatal; Umbilical Arteries

Sildenafil, a phosphodiesterase 5 inhibitor with a vasodilatory and anti-remodeling effect, has been investigated concerning various conditions during pregnancy. Per indication, we herein review the rationale and the most relevant experimental and clinical studies, including systematic reviews and meta-analyses, when available. Indications for using sildenafil during the second and third trimester of pregnancy include maternal pulmonary hypertension, preeclampsia, preterm labor, fetal growth restriction, oligohydramnios, fetal distress, and congenital diaphragmatic hernia. For most indications, the rationale for administering prenatal sildenafil is based on limited, equivocal data from in vitro studies and rodent disease models. Clinical studies report mild maternal side effects and suggest good fetal tolerance and safety depending on the underlying pathology.

Topics: Female; Fetal Growth Retardation; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Pre-Eclampsia; Pregnancy; Sildenafil Citrate

Fetal growth restriction (FGR) is associated with an increased incidence of fetal and neonatal death, and of neonatal morbidity. Babies born following FGR also are at risk of a range of postnatal complications, which may contribute to an increased incidence of disease later in life. There currently are no effective clinical interventions which improve perinatal survival, intrauterine growth and later outcomes of the FGR baby. Postnatal interventions aimed at promoting or accelerating growth in FGR babies to improve outcome, particularly neurodevelopmental outcomes, may further increase the risk of metabolic dysregulation and, therefore, the risk of developing chronic disease in adulthood. An intrauterine intervention to improve nutrition and growth in the FGR fetus may have the potential to decrease mortality and improve long-term outcomes by delaying preterm delivery and mitigating the need for and risks of accelerated postnatal growth.

Topics: Blood Flow Velocity; Developmental Disabilities; Female; Fetal Development; Fetal Growth Retardation; Fetal Monitoring; Gestational Age; Humans; Insulin-Like Growth Factor I; Maternal Nutritional Physiological Phenomena; Perinatal Care; Placental Circulation; Pregnancy; Premature Birth; Sildenafil Citrate; Uterine Artery; Vasodilator Agents

Intrauterine growth restriction (IUGR) is associated with perinatal morbidity and mortality. Several clinical trials have reported L-arginine and sildenafil citrate had effect on intrauterine growth restriction fetuses. A meta-analysis of available randomized controlled trials (RCTs) was conducted to investigate the effects of L-arginine and sildenafil citrate on major clinical outcomes of IUGR fetuses.. Systematically searched Medline, Embase, the Cochrane Library, and Clinical Trials, references of retrieved articles, and conference proceedings from 1960 to 2015. We included randomized controlled trials assessing the effects of L-arginine and sildenafil citrate on IUGR. Outcomes analyzed were the birth weight, gestational age at labor, Apgar score at 1and 5 min, the ratio of NRDS, the ratio of ICH and neonatal death, etc.. Ten trials were included. Nine trials (576 patients) compared L-arginine with either placebo or no intervention. In the L-arginine treatment groups of the L-arginine trials, there was a significant increase in fetal birth weight (SMD 0.41, 95 % CI [0.24,0.58]), gestational age (SMD 0.30, 95 % CI [0.07,0.54]); L-arginine treatment group have a significant reduction in the ratio of neonatal respiratory distress syndrome (P = 0.009), intracranial hemorrhage of fetuses (P = 0.002), but the number of included studies and people on these outcomes are small. As only one trial (41 patients) compared sildenafil citrate with placebo, it was too small for reliable conclusions about possible differential effects could be drawn.. The results of this meta-analysis showed that L-arginine increased birth weight and prolonged gestational age at labor of IUGR fetuses. However, further large-scale RCTs are needed to adequately assess the effect of L-arginine and Sildenafil citrate on clinical outcomes, because the number of study may be small.

Topics: Apgar Score; Arginine; Birth Weight; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Phosphodiesterase 5 Inhibitors; Pregnancy; Pregnancy Outcome; Randomized Controlled Trials as Topic; Sildenafil Citrate; Treatment Outcome

In pregnancies complicated by early-onset extreme fetal growth restriction, there is a high risk of preterm birth and an overall dismal fetal prognosis. Sildenafil has been suggested to improve this prognosis. The first aim of this review is to assess whether sildenafil benefits or harms these babies. The second aim is to analyse if these effects are modified in a clinically meaningful way by factors related to the women or the trial protocol.. The STRIDER (Sildenafil Therapy In Dismal prognosis Early-onset intrauterine growth Restriction) Individual Participant Data (IPD) Study Group will conduct a prospective IPD and aggregate data systematic review with meta-analysis and trial sequential analysis. The STRIDER IPD Study Group started trial planning and funding applications in 2012. Three trials will be launched in 2014, recruiting for three years. Further trials are planned to commence in 2015.The primary outcome for babies is being alive at term gestation without evidence of serious adverse neonatal outcome. The latter is defined as severe central nervous system injury (severe intraventricular haemorrhage (grade 3 and 4) or cystic periventricular leukomalacia, demonstrated by ultrasound and/or magnetic resonance imaging) or other severe morbidity (bronchopulmonary dysplasia, retinopathy of prematurity requiring treatment, or necrotising enterocolitis requiring surgery). The secondary outcomes are improved fetal growth velocity assessed by ultrasound abdominal circumference measurements, gestational age and birth weight (centile) at delivery, and age-adequate performance on the two-year Bayley scales of infant and toddler development-III (composite cognitive score and composite motor score). Subgroup and sensitivity analyses in the IPD meta-analysis include assessment of the influence of several patient characteristics: an abnormal or normal serum level of placental growth factor, absent/reversed umbilical arterial end diastolic flow at commencement of treatment, and other patient characteristics available at baseline such as gestational age and estimated fetal weight. The secondary outcomes for mothers include co-incidence and severity of the maternal syndrome of pre-eclampsia, mortality, and other serious adverse events.. Trials are expected to start in 2013-2014 and end in 2016-2017. Data analyses of individual trials are expected to finish in 2019. Given the pre-planned and agreed IPD protocol, these results should be available in 2020.

Topics: Female; Fetal Growth Retardation; Humans; Phosphodiesterase 5 Inhibitors; Piperazines; Pregnancy; Purines; Sildenafil Citrate; Sulfones; Systematic Reviews as Topic

Pre-eclampsia and intrauterine growth restriction (IUGR) are responsible for approximately 15-20% of serious maternal and neonatal diseases. These complications are related to very early anomalies of the uteroplacental circulation, accompanied, at least secondarily, by thromboxane-prostacyclin-related imbalances. Studies have failed to show a beneficial effect of betamimetics and calcium channel blockers for the treatment of IUGR. Sildenafil citrate, a type 5-specific phosphodiesterase inhibitor, augments the vasodilatory effects of NO by preventing the degradation of cGMP There is a selective effect of Sildenafil on the uteroplacental circulation. Sildenafil improves uterine artery blood flow.

Topics: Female; Fetal Growth Retardation; Humans; Phosphodiesterase 5 Inhibitors; Piperazines; Pre-Eclampsia; Pregnancy; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil could be an alternative in the treatment of intrauterine growth retardation (IUGR) and premature delivery. In order to systematically review the reproductive-related effects of sildenafil, a search was made on PubMed and the Science Citation Index for studies evaluating the effects of sildenafil on uterine vessels or myometrium either in vitro or in experimental animal models as well as for any clinical trial or case reporting the outcome of pregnant women treated with sildenafil. The information was obtained from: three in vitro studies, five studies performed in experimental animal models, four studies on women with fertility and sterility disorders receiving 100 mg/day of sildenafil intravaginally, and two case reports of pregnant women who received sildenafil for the treatment of pulmonary hypertension. Incubation with sildenafil of different in vitro preparations resulted in vasodilator and uterine relaxant effects. No evidence of teratogenicity was observed in the studies performed in mice, rats and dogs. Sildenafil increased fetal weight in rats. In women, contradictory results on uterine blood flow and endometrial development were reported after the intravaginal administration of sildenafil. No adverse fetal outcomes were reported in the two pregnant women with pulmonary hypertension receiving sildenafil late in their pregnancy. In conclusion, there is still limited information about the efficacy of sildenafil for the treatment of IUGR and premature delivery. However, studies in experimental animal models and two human case reports have reported no deleterious effects on the mother or offspring.

Topics: Administration, Intravaginal; Animals; Disease Models, Animal; Female; Fetal Growth Retardation; Humans; Obstetric Labor, Premature; Piperazines; Pregnancy; Purines; Sildenafil Citrate; Sulfones; Tocolytic Agents

The aim was to reflect on the unexpected finding of persistent pulmonary hypertension of the neonate (PPHN) and pulmonary hypertension in infants born within the Dutch STRIDER trial, its definition and possible pathophysiological mechanisms. The trial randomly assigned pregnant women with severe early-onset fetal growth restriction to sildenafil 25 mg three times a day versus placebo. Sildenafil use did not reduce perinatal mortality and morbidity, but did result in a higher rate of neonatal pulmonary hypertension (PH). The current paper reflects on the used definition, prevalence, and possible pathophysiology of the data on pulmonary hypertension. Twenty infants were diagnosed with pulmonary hypertension (12% of 163 live born infants). Of these, 16 infants had PPHN shortly after birth, and four had pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia. Four infants with PPHN in the early neonatal period subsequently developed pulmonary hypertension associated with bronchopulmonary dysplasia in later life. Infants with pulmonary hypertension were at lower gestational age at delivery, had a lower birth weight and a higher rate of neonatal co-morbidity. The infants in the sildenafil group showed a significant increase in pulmonary hypertension compared to the placebo group (relative risk 3.67; 95% confidence interval 1.28 to 10.51, P = 0.02).. Pulmonary hypertension occurred more frequent among infants of mothers allocated to antenatal sildenafil compared with placebo. A possible pathophysiological mechanism could be a "rebound" vasoconstriction after cessation of sildenafil. Additional studies and data are necessary to understand the mechanism of action.. • In the Dutch STRIDER trial, persistent pulmonary hypertension in the neonate (PPHN) was more frequent among infants after antenatal sildenafil exposure versus placebo.. • The current analysis focuses on the distinction between PPHN and pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia and on timing of diagnosis and aims to identify the infants at risk for developing pulmonary hypertension. • The diagnosis pulmonary hypertension is complex, especially in infants born after severe early-onset fetal growth restriction. The research field could benefit from an unambiguous consensus definition and standardized screening in infants at risk is proposed.

Topics: Birth Weight; Female; Fetal Growth Retardation; Gestational Age; Humans; Hypertension, Pulmonary; Infant, Newborn; Pregnancy; Sildenafil Citrate

To compare the effect of sildenafil citrate (SC) and low molecular weight heparin (LMWH) on neonatal birth weight (BW) and the fetoplacental blood flow in pregnancies with FGR.. A parallel groups, randomized clinical trial was conducted at a university hospital, between June 2017 and September 2018, involving 100 pregnant women with placental mediated FGR between 28 and 35 weeks of gestation who were randomly assigned to receive either SC or LMWH started at FGR diagnosis till delivery.. The neonatal BW in LMWH group was higher than SC group (p < 0.000) with a longer time from randomization till delivery, LMWH group had significant improvement in Ut A PI, UA PI, and MCA PI compared with SC treated group with p values 0.005, <0.000001, and 0.014, respectively.. The neonatal BW, time from randomization to delivery, and fetoplacental blood flow indices were significantly better with LMWH use compared with SC.

Topics: Female; Fetal Growth Retardation; Heparin, Low-Molecular-Weight; Humans; Infant, Newborn; Placenta; Placental Circulation; Pregnancy; Sildenafil Citrate

Recently a drug trial in the Netherlands in which the efficacy of oral sildenafil was compared to placebo in women bearing children with fetal growth restriction was stopped early because of very harmful side effects to the babies. There were quite some unwanted and unscientific aspects related to this study and the manner in which the side effects were communicated to the patients and the community. These have not gained the attention they ought to have. We therefore made an analysis of the basic problems which aims to prevent that the trust in medical research will be weakened.

Topics: Ethics Committees, Research; Female; Fetal Growth Retardation; Humans; Netherlands; Pregnancy; Sildenafil Citrate; Ultrasonography, Doppler; Vasodilator Agents

Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes.. To determine whether sildenafil reduces perinatal mortality or major morbidity.. This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants.. Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo.. The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge.. Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008).. These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension.. ClinicalTrials.gov Identifier: NCT02277132.

Topics: Adult; Birth Weight; Double-Blind Method; Early Termination of Clinical Trials; Female; Fetal Growth Retardation; Gestational Age; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Newborn, Diseases; Intention to Treat Analysis; Male; Middle Cerebral Artery; Perinatal Mortality; Phosphodiesterase 5 Inhibitors; Placenta Diseases; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Pulsatile Flow; Sildenafil Citrate; Umbilical Arteries

Uterine contractions during labour can result in a 60 % decline in fetoplacental perfusion, predisposing the fetus to hypoxic brain injury. Sildenafil citrate (SC) has shown promise in increasing uteroplacental perfusion as well as reducing the risk of operative birth for intrapartum fetal compromise (IFC). The aim of this study was to investigate the effect of intrapartum SC administration on fetoplacental blood flow indices.. This was a subgroup analysis from an earlier Phase II double blind randomized controlled trial; assessing the effect of intrapartum SC administration (50 mg orally 8 -hly in labour) compared to placebo for the reduction of operative birth for IFC. An ultrasound scan measuring fetoplacental Doppler indices was performed prior to and 1-4 h after the administration of the first treatment dose.. Of the 300 women randomized to the main study, pre-treatment ultrasound scans were performed in 261 participants who received the study medication; paired pre- and post-treatment scans were performed in 70 (26.8 %). SC resulted in an increase in the middle cerebral artery pulsatility index (PI) z-score [+0.08 (1.35) vs.-0.12 (1.15)], a decline in the umbilical artery-PI z-score [-0.07 (0.96) vs. + 0.04 (1.25)] and an increase in the cerebroplacental ratio [MCA-PI/UA-PI] (CPR) z-score [+0.10 (1.13) vs.-0.26 (1.14)] although these failed to reach statistical significance. Amongst those with a pre-treatment CPR above the 5th centile, SC significantly reduced the risk of operative birth for IFC compared to placebo [logrank p = 0.02; hazards ratio 0.48, 95 % CI 0.29-0.77, p = 0.003].. Although the differences in Doppler indices pre- and post- SC treatment were non-significant, there was a clear trend towards a reduction in the UA PI, a corresponding increase in the MCA PI and a rise in post treatment CPR values suggesting potential improvement in fetoplacental Dopplers with intrapartum SC treatment. However this study was limited by the small sample size. The results of this hypothesis generating study suggest that it may be possible to stratify women that would most benefit from this intervention based upon their pre-labour CPR.

Topics: Female; Fetal Growth Retardation; Humans; Middle Cerebral Artery; Pregnancy; Pulsatile Flow; Sildenafil Citrate; Ultrasonography, Doppler; Ultrasonography, Prenatal; Umbilical Arteries

Topics: Administration, Oral; Adult; Birth Weight; Double-Blind Method; Egypt; Female; Fetal Growth Retardation; Fish Oils; Humans; Infant, Newborn; Middle Cerebral Artery; Placenta; Pregnancy; Pulsatile Flow; Sildenafil Citrate; Ultrasonography, Prenatal; Umbilical Arteries; Vasodilator Agents; Zinc

The objective of the Dutch Sildenafil therapy in dismal prognosis early onset fetal growth restriction (STRIDER) randomised clinical trial is to assess the beneficial and harmful effects of sildenafil versus placebo on fetal and neonatal mortality in pregnant women with severe early-onset fetal growth restriction. The objective of this detailed statistical analysis plan is to minimize the risks of selective reporting and data-driven analysis.. The setting is 10 tertiary care hospitals and one secondary care hospital in The Netherlands.. The participants will be 360 pregnant women with severe early-onset fetal growth restriction.. The intervention is sildenafil 25 mg or placebo orally three times a day.. The primary outcome is a composite of death or major neonatal morbidity assessed at hospital discharge. The secondary outcomes are neurodevelopmental impairment; mean scores of the Bayley III cognitive and motor assessment; the proportion of patients experiencing either preeclampsia or haemolysis, elevated liver enzymes, and low platelets syndrome; pulsatility index of uterine arteries, umbilical artery, and middle cerebral artery; birthweight; and gestational age at either delivery or intra-uterine death.. A detailed statistical analysis is presented, including pre-defined exploratory outcomes and planned subgroup analyses. One interim analysis after 180 patients had completed the study was planned and a strategy to minimise the risks of type I errors due to repetitive testing is presented. During review of this manuscript the interim analysis was performed by the Data Safety Monitoring Board and early stopping of the trial was recommended. Final analyses will be conducted independently by two statistically qualified persons following the present plan.. This pre-specified statistical analysis plan was written and submitted without knowledge of the unblinded data and updated after stopping of the trial at interim analysis.. ClinicalTrials.gov, NCT02277132 . Registered on 29 September 2014. Original protocol for the study: doi: https://doi.org/10.5281/zenodo.56148.

Topics: Administration, Oral; Data Interpretation, Statistical; Drug Administration Schedule; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Models, Statistical; Multicenter Studies as Topic; Netherlands; Phosphodiesterase 5 Inhibitors; Pregnancy; Randomized Controlled Trials as Topic; Sildenafil Citrate; Time Factors; Treatment Outcome

To assess the effect of maternal sildenafil therapy on fetal growth in pregnancies with early-onset fetal growth restriction.. A randomised placebo-controlled trial.. Thirteen maternal-fetal medicine units across New Zealand and Australia.. Women with singleton pregnancies affected by fetal growth restriction at 22. Women were randomised to oral administration of 25 mg sildenafil citrate or visually matching placebo three times daily until 32. The primary outcome was the proportion of pregnancies with an increase in fetal growth velocity. Secondary outcomes included live birth, survival to hospital discharge free of major neonatal morbidity and pre-eclampsia.. Sildenafil did not affect the proportion of pregnancies with an increase in fetal growth velocity; 32/61 (52.5%) sildenafil-treated, 39/57 (68.4%) placebo-treated [adjusted odds ratio (OR) 0.49, 95% CI 0.23-1.05] and had no effect on abdominal circumference Z-scores (P = 0.61). Sildenafil use was associated with a lower mean uterine artery pulsatility index after 48 hours of treatment (1.56 versus 1.81; P = 0.02). The live birth rate was 56/63 (88.9%) for sildenafil-treated and 47/59 (79.7%) for placebo-treated (adjusted OR 2.50, 95% CI 0.80-7.79); survival to hospital discharge free of major neonatal morbidity was 42/63 (66.7%) for sildenafil-treated and 33/59 (55.9%) for placebo-treated (adjusted OR 1.93, 95% CI 0.84-4.45); and new-onset pre-eclampsia was 9/51 (17.7%) for sildenafil-treated and 14/55 (25.5%) for placebo-treated (OR 0.67, 95% CI 0.26-1.75).. Maternal sildenafil use had no effect on fetal growth velocity. Prospectively planned meta-analyses will determine whether sildenafil exerts other effects on maternal and fetal/neonatal wellbeing.. Maternal sildenafil use has no beneficial effect on growth in early-onset FGR, but also no evidence of harm.

Topics: Adult; Australia; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Live Birth; New Zealand; Phosphodiesterase 5 Inhibitors; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Sildenafil Citrate; Treatment Outcome

To assess efficacy and tolerability of sildenafil citrate on utero-placental blood flow and fetal growth in pregnancies complicated by fetal growth restriction (FGR).. From March 2015, a randomized controlled trial of 54 patients at 24 weeks or more complicated by FGR and abnormal Doppler indices were randomly allocated 1:1 into an intervention arm (receive sildenafil citrate, 50 mg) or a control arm (receive placebo). The primary outcomes were changes occurred in the Doppler parameters 2 h following drug administration.. Baseline characteristics were similar between groups. Significant difference was observed in the Delta uterine and umbilical Doppler indices among sildenafil group as compared to placebo group (p < 0.001). Middle cerebral Doppler indices, however, decreased significantly after sildenafil, which could be the result of shifting more blood to improve the utero-placental perfusion. No difference regarding Delta cerebro-placental ratio among both groups (p = 0.979). Sildenafil was also associated with pregnancy prolongation (p = .0001), increased gestational age at delivery (p = .004), improved neonatal weight (p = .0001), and less admission to neonatal intensive care unit (p = .03). No adverse effects reported in both treatment arms.. Sildenafil citrate, by its vasodilator effect, can improve utero-placental blood flow in pregnancies complicated by FGR and abnormal Doppler.. gov Registry: NCT02362399.

Topics: Adult; Double-Blind Method; Female; Fetal Development; Fetal Growth Retardation; Humans; Placental Circulation; Pregnancy; Sildenafil Citrate; Ultrasonography, Doppler; Ultrasonography, Prenatal; Vasodilator Agents; Young Adult

Intrauterine growth restriction (IUGR) is one of the most serious complications of pregnancy. Up to date, there is no evidence of achieving antenatal treatment of IUGR with abnormal placentation. Although, Sildenafil citrate has shown promising results, there are no firm conclusion till now. The aim of our study is to evaluate the use of Sildenafil citrate in the treatment of IUGR cases associated with impaired placental circulation.. This was a prospective non-randomized study conducted at Mansoura university hospitals starting from March 2016 till October 2017. The studied population included singleton pregnancy and suffering from IUGR associated with impaired placental circulation.. This study included 50 pregnant women. Cases were divided into two groups. The first group received sildenafil citrate and the second control group did not receive sildenafil citrate. After 4 weeks after the 1st dose of Sildenafil significant decrease in umbilical artery Doppler indices. There was a statistically significant difference in the mean birth weight at delivery and neonatal admission to the newborn nursery in sildenafil group.. sildenafil citrate treatment may present a new hope towards better perinatal outcomes for pregnancies complicated by IUGR and impaired placental circulation that may help to decrease neonatal admission to the newborn nursery.

Topics: Adolescent; Adult; Birth Weight; Egypt; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Perinatal Death; Phosphodiesterase 5 Inhibitors; Placental Circulation; Pregnancy; Pregnancy Outcome; Prospective Studies; Sildenafil Citrate; Stillbirth; Ultrasonography, Prenatal; Umbilical Arteries; Young Adult

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

Topics: Birth Weight; Double-Blind Method; Female; Fetal Growth Retardation; Gestational Age; Humans; Phosphodiesterase 5 Inhibitors; Pregnancy; Pregnancy Outcome; Sildenafil Citrate; Umbilical Arteries

Severe, early-onset fetal growth restriction due to placental insufficiency is associated with a high risk of perinatal mortality and morbidity with long-lasting sequelae. Placental insufficiency is the result of abnormal formation and function of the placenta with inadequate remodelling of the maternal spiral arteries. There is currently no effective therapy available. Some evidence suggests sildenafil citrate may improve uteroplacental blood flow, fetal growth, and meaningful infant outcomes. The objective of the Sildenafil TheRapy In Dismal prognosis Early onset fetal growth Restriction (STRIDER) collaboration is to evaluate the effectiveness of sildenafil versus placebo in achieving healthy perinatal survival through the conduct of randomised clinical trials and systematic review including individual patient data meta-analysis.. Five national/bi-national multicentre randomised placebo-controlled trials have been launched. Women with a singleton pregnancy between 18 and 30 weeks with severe fetal growth restriction of likely placental origin, and where the likelihood of perinatal death/severe morbidity is estimated to be significant are included. Participants will receive either sildenafil 25 mg or matching placebo tablets orally three times daily from recruitment to 32 weeks gestation.. The STRIDER trials were conceived and designed through international collaboration. Although the individual trials have different primary outcomes for reasons of sample size and feasibility, all trials will collect a standard set of outcomes including survival without severe neonatal morbidity at time of hospital discharge. This is a summary of all the STRIDER trial protocols and provides an example of a prospectively planned international clinical research collaboration. All five individual trials will contribute to a pre-planned systematic review of the topic including individual patient data meta-analysis.. New Zealand and Australia: ACTRN12612000584831 . Registered 30/05/2012. Canada: NCT02442492 . Registered 05/05/2015. Ireland: CT 900/572/1 . Registered 15/07/2015. The Netherlands: NCT02277132 . Registered 29/09/2014. United Kingdom: ISRCTN39133303 . Registered 31/07/2014.

Topics: Adult; Australia; Canada; Clinical Protocols; Female; Fetal Growth Retardation; Gestational Age; Humans; International Cooperation; Ireland; Netherlands; New Zealand; Pregnancy; Pregnancy Outcome; Prognosis; Sildenafil Citrate; Treatment Outcome; United Kingdom; Vasodilator Agents; Young Adult

To evaluate the effects of transdermal nitroglycerin (GTN) and sildenafil citrate on Doppler velocity waveforms of the uterine (UtA), umbilical (UA) and fetal middle cerebral (MCA) arteries in pregnancies with intrauterine growth restriction (IUGR).. This was a prospective study of 35 singleton pregnancies (gestational age, 24-31 weeks) with IUGR and abnormal UtA and UA Doppler waveforms. We compared maternal arterial blood pressure and Z-scores of the pulsatility index (PI) of UtA, UA and fetal MCA before and after application of a transdermal GTN patch (average dose, 0.4 mg/h), oral sildenafil citrate (50 mg) or placebo. Statistical analysis was performed by ANOVA for paired samples.. There was a significant decrease in UtA-PI after application of GTN (21.0%) and sildenafil citrate (20.4%). A significant reduction in UA-PI was also observed for both GTN (19.1%) and sildenafil citrate (18.2%). There was no difference in UtA- and UA-PI when the GTN and sildenafil groups were compared. No changes in Doppler velocimetry were observed in the placebo group and no significant change in MCA-PI was observed in any group. Maternal arterial blood pressure decreased with administration of both GTN and sildenafil citrate in those with pre-eclampsia.. The use of transdermal GTN or sildenafil citrate in pregnancies with IUGR is associated with a significant reduction in both UtA and UA Doppler PI, as well as maternal arterial blood pressure. Neither drug affected the MCA-PI. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Topics: Administration, Cutaneous; Adult; Blood Flow Velocity; Double-Blind Method; Female; Fetal Growth Retardation; Humans; Middle Cerebral Artery; Nitroglycerin; Placental Insufficiency; Pregnancy; Prospective Studies; Pulsatile Flow; Sildenafil Citrate; Treatment Outcome; Ultrasonography, Prenatal; Umbilical Arteries; Uterine Artery; Vasodilator Agents; Young Adult

Topics: Female; Fetal Growth Retardation; Gestational Age; Humans; Pregnancy; Sildenafil Citrate

Topics: Fetal Growth Retardation; Humans; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

Topics: Fetal Growth Retardation; Humans; Sildenafil Citrate; Vasodilator Agents

Early onset fetal growth restriction secondary to placental insufficiency can lead to severe maternal and neonatal morbidity and mortality. Pre-clinical studies and a few small randomised clinical trials have suggested that phosphodiesterase type 5 (PDE-5) inhibitors may have protective effects against placental insufficiency in this context; however, robust evidence is lacking. The STRIDER Consortium conducted four randomised trials to investigate the use of a PDE-5 inhibitor, sildenafil, for the treatment of early onset fetal growth restriction. We present a protocol for the pre-planned systematic review with individual participant data meta-analysis, aggregate meta-analysis, and trial sequential analysis of these and other eligible trials. The main objective of this study will be to evaluate the effects of PDE-5 inhibitors on neonatal morbidity compared with placebo or no intervention among pregnancies with fetal growth restriction.. We will search the following electronic databases with no language or date restrictions: OVID MEDLINE, OVID EMBASE, the Cochrane Controlled Register of Trials (CENTRAL), and the clinical trial registers Clinicaltrials.gov and World Health Organisation International Clinical Trials Registry Platform (ICTRP). We will identify randomised trials of PDE-5 inhibitors in singleton pregnancies with growth restriction. Two reviewers will independently screen all citations, full-text articles, and abstract data. Our primary outcome will be infant survival without evidence of serious adverse neonatal outcome. Secondary outcomes will include gestational age at birth and birth weight z-scores. We will assess bias using the Cochrane Risk of Bias 2 tool. We will conduct aggregate meta-analysis using fixed and random effects models, Trial Sequential Analysis, and individual participant data meta-analysis using one- and two-stage approaches. The certainty of evidence will be assessed with GRADE.. This pre-defined protocol will minimise bias during analysis and interpretation of results, toward the goal of providing robust evidence regarding the use of PDE-5 inhibitors for the treatment of early onset fetal growth restriction.. PROSPERO (CRD42017069688).

Topics: Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Meta-Analysis as Topic; Phosphodiesterase 5 Inhibitors; Placenta; Pregnancy; Sildenafil Citrate; Systematic Reviews as Topic

Fetal growth restriction (FGR), where a fetus fails to reach its genetic growth potential, affects up to 8% of pregnancies and is a major risk factor for stillbirth and adulthood morbidity. There are currently no treatments for FGR, but candidate therapies include the phosphodiesterase-5 inhibitor sildenafil citrate (SC). Randomized clinical trials in women demonstrated no effect of SC on fetal growth in cases of severe early onset FGR; however, long-term health outcomes on the offspring are unknown. This study aimed to assess the effect of antenatal SC treatment on metabolic and cardiovascular health in offspring by assessing postnatal weight gain, glucose tolerance, systolic blood pressure, and resistance artery function in a mouse model of FGR, the placental-specific insulin-like growth factor 2 (PO) knockout mouse. SC was administered subcutaneously (10 mg/kg) daily from embryonic day (E)12.5. Antenatal SC treatment did not alter fetal weight or viability but increased postnatal weight gain in wild-type (WT) female offspring (

Topics: Animals; Birth Weight; Blood Pressure; Female; Fetal Growth Retardation; Glucose Tolerance Test; Insulin-Like Growth Factor II; Mice; Mice, Inbred C57BL; Mice, Knockout; Pregnancy; Prenatal Exposure Delayed Effects; Sildenafil Citrate; Splanchnic Circulation; Vascular Resistance; Vasodilator Agents; Weight Gain

Fetal growth restriction induces a haemodynamic response that aims to maintain blood flow to vital organs such as the brain, in the face of chronic hypoxaemia Maternal sildenafil treatment impairs the hypoxaemia-driven haemodynamic response and potentially compromises fetal development.. Inadequate substrate delivery to a fetus results in hypoxaemia and fetal growth restriction (FGR). In response, fetal cardiovascular adaptations redirect cardiac output to essential organs to maintain oxygen delivery and sustain development. However, FGR infants remain at risk for cardiovascular and neurological sequelae. Sildenafil citrate (SC) has been examined as a clinical therapy for FGR, but also crosses the placenta and may exert direct effects on the fetus. We investigated the effects of maternal SC administration on maternal and fetal cardiovascular physiology in growth-restricted fetal sheep. Fetal sheep (0.7 gestation) underwent sterile surgery to induce growth restriction by single umbilical artery ligation (SUAL) or sham surgery (control, AG). Fetal catheters and flow probes were implanted to measure carotid and femoral arterial blood flows. Ewes containing SUAL fetuses were randomized to receive either maternal administration of saline or SC (36 mg i.v. per day) beginning 4 days after surgery, and continuing for 20 days. Physiological recordings were obtained throughout the study. Antenatal SC treatment reduced body weight by 32% and oxygenation by 18% in SUAL compared to AG. SC did not alter maternal or fetal heart rate or blood pressure. Femoral blood flow and peripheral oxygen delivery were increased by 49% and 30% respectively in SUAL

Topics: Animals; Female; Fetal Development; Fetal Growth Retardation; Fetus; Hypoxia; Pregnancy; Sheep; Sildenafil Citrate

Topics: Female; Fetal Growth Retardation; Humans; Infant, Newborn; Phosphodiesterase 5 Inhibitors; Pregnancy; Randomized Controlled Trials as Topic; Sildenafil Citrate; United Kingdom

Topics: Fetal Growth Retardation; Humans; Sildenafil Citrate

Topics: Female; Fetal Growth Retardation; Humans; Pregnancy; Sildenafil Citrate

Fetal growth restriction (FGR) is associated with increased risk for cardiovascular and renal disorders in later life. Prenatal sildenafil improves birth weight in FGR animal models. Whether sildenafil treatment protects against long-term cardiovascular and renal disease in these offspring is unknown. The aim of this study is to test the hypothesis that prenatal sildenafil ameliorates cardiovascular and renal function in FGR offspring of Dahl salt-sensitive rats. Sildenafil citrate (60 mg/kg per day) or control gel diet (containing 0.3% salt) was administered from gestational day ten until birth. In male and female offspring, the mean arterial pressure was measured by telemetry in 1 subset from week 5 until week twenty. Echocardiographic parameters, glomerular filtration rate, and fractional electrolyte excretion were determined in another subset at week 9. Aortic and mesenteric artery rings were prepared to assess endothelial-dependent (acetylcholine) and -independent (sodium nitroprusside) vasorelaxation (week 10). The rise in mean arterial pressure per week was attenuated in treated versus untreated male offspring. Mesenteric arteries showed an increased endothelium-dependent relaxation and improved endothelium-independent relaxation in treated versus control male offspring. No differences in aortic relaxation, echocardiographic parameters or renal function were observed between groups. Prenatal sildenafil treatment subtly improves cardiovascular but not renal function in the offspring of this FGR rat model. Translationally, in utero treatment could be beneficial for cardiovascular programming in a sex-specific manner; however, caution is warranted since recent human trials have been halted because of potentially deleterious neonatal side effects when treating pregnancies complicated with severe FGR with sildenafil.

Topics: Animals; Cardiovascular System; Disease Models, Animal; Female; Fetal Development; Fetal Growth Retardation; Pregnancy; Pregnancy, Animal; Prenatal Care; Rats; Rats, Inbred Dahl; Sildenafil Citrate; Vasodilator Agents

Objective- The objective of this study was to investigate the effect of intravenous maternal sildenafil citrate (SC) administration on vascular function in growth-restricted fetal sheep. Approach and Results- Fetal growth restriction (FGR) results in cardiovascular adaptations that redistribute cardiac output to optimize suboptimal intrauterine conditions. These adaptations result in structural and functional cardiovascular changes, which may underlie postnatal neurological and cardiovascular sequelae. Evidence suggests SC, a potent vasodilator, may improve FGR. In contrast, recent clinical evidence suggests potential for adverse fetal consequence. Currently, there is limited data on SC effects in the developing fetus. We hypothesized that SC in utero would improve vascular development and function in an ovine model of FGR. Preterm lambs (0.6 gestation) underwent sterile surgery for single umbilical artery ligation or sham (control, appropriately grown) surgery to replicate FGR. Ewes received continuous intravenous SC (36 mg/24 h) or saline from surgery until 0.83 gestation. Fetuses were delivered and immediately euthanized for collection of femoral and middle cerebral artery vessels. Vessel function was assessed via in vitro wire myography. SC exacerbated growth restriction in growth-restricted fetuses and resulted in endothelial dysfunction in the cerebral and femoral vasculature, irrespective of growth status. Dysfunction in the cerebral circulation is endothelial, whereas smooth muscle in the periphery is the origin of the deficit. Conclusions- SC crosses the placenta and alters key fetal vascular development. Extensive studies are required to investigate the effects of SC on fetal development to address safety before additional use of SC as a treatment.

Topics: Acetylcholine; Animals; Birth Weight; Brain; Cardiac Output; Cerebrovascular Circulation; Female; Fetal Blood; Fetal Development; Fetal Growth Retardation; Guanylate Cyclase; Male; Muscle, Smooth, Vascular; Nitric Oxide; Nitroprusside; Organ Size; Placenta; Pregnancy; Prenatal Injuries; Sheep; Sildenafil Citrate; Vasodilation; Vasodilator Agents

Topics: Drug Interactions; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Infant, Small for Gestational Age; Multicenter Studies as Topic; Patient Safety; Perinatal Death; Phosphodiesterase 5 Inhibitors; Pregnancy; Randomized Controlled Trials as Topic; Research Design; Sildenafil Citrate; Vasodilator Agents

Topics: Fetal Growth Retardation; Humans; Sildenafil Citrate

Fetal growth restriction resulting from reduced placental blood perfusion is a major cause of neonatal morbidity and mortality. Aside from intense surveillance and early delivery, there is no treatment for fetal growth restriction. A potential treatment associated with placental vasoconstriction is the class of PDE5 (phosphodiesterase type 5) inhibitors such as sildenafil, which is known to cross the placenta. In contrast, tadalafil, a more potent and selective PDE5 inhibitor has not been studied in pregnancy or experimental models of fetal growth restriction. Therefore, we compared the efficacy of these 2 PDE5 inhibitors for reversing vasoconstriction in an ex vivo human placental model and evaluating molecular and physiological responses. Sildenafil and tadalafil were infused into the intervillous space in a preconstricted human placental dual cotyledon, dual perfusion assay for the comparison of arteriole pressures and molecular indicators of drug inhibition. Results indicate a decrease arterial pressure with sildenafil citrate compared with controls, whereas tadalafil showed no difference. PDE5 and endothelial nitric oxide synthase activity were altered with sildenafil but not tadalafil. Sildenafil citrate improved preconstricted placental arterial perfusion in a human placental model, whereas tadalafil showed no response. It is possible that tadalafil did not cross the human placental barrier or was degraded by trophoblasts. This study supports human clinical trials exploring sildenafil as a potential treatment for improving fetal blood flow in fetal growth restriction associated with vasoconstriction.

Topics: Arteries; Female; Fetal Growth Retardation; Humans; Perfusion; Phosphodiesterase 5 Inhibitors; Placenta; Pregnancy; Sildenafil Citrate; Tadalafil; Vasoconstriction

Topics: Early Termination of Clinical Trials; Female; Fetal Growth Retardation; Humans; Hypertension, Pulmonary; Infant, Newborn; Phosphodiesterase 5 Inhibitors; Placenta; Pregnancy; Randomized Controlled Trials as Topic; Sildenafil Citrate; Withholding Treatment

Topics: Back; Double-Blind Method; Fetal Growth Retardation; Humans; Sildenafil Citrate

Topics: Double-Blind Method; Fetal Growth Retardation; Humans; Hydrophobic and Hydrophilic Interactions; Sildenafil Citrate; Water

Topics: Double-Blind Method; Female; Fetal Growth Retardation; Humans; Pregnancy; Pregnancy Outcome; Sildenafil Citrate

Topics: Advisory Committees; Animals; Clinical Trials as Topic; Disease Models, Animal; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Pregnancy; Review Literature as Topic; Sildenafil Citrate

Topics: Animals; Fetal Growth Retardation; Publications; Sildenafil Citrate

The present study evaluated the effectiveness of sildenafil citrate (SC) to improve placental and fetal growth in a diet-induced rabbit model of intrauterine growth restriction (IUGR). Pregnant rabbits were fed either ad libitum (Group C) or restricted to 50% of dietary requirements (Group R) or restricted and treated with SC (Group SC). The treatment with SC improved placental development by increasing vascularity and vessel hypertrophy in the decidua. The assessment of feto-placental haemodynamics showed higher resistance and pulsatility indices at the middle cerebral artery (MCA) in fetuses treated with SC when compared with Group R, which had increased systolic peak and time-averaged mean velocities at the MCA. Furthermore, fetuses in the SC group had significantly higher biparietal and thoracic diameters and longer crown-rump lengths than fetuses in Group R. Hence, the SC group had a reduced IUGR rate and a higher kit size at birth compared with Group R. In conclusion, SC may provide potential benefits in pregnancies with placental insufficiency and IUGR, partially counteracting the negative effects of food restriction on placental development and fetal growth. However, the present study also found evidence of a possible blood overflow in the brain that warrants further investigation.

Topics: Animals; Caloric Restriction; Cerebrovascular Circulation; Crosses, Genetic; Decidua; Disease Models, Animal; Female; Fetal Development; Fetal Growth Retardation; Maternal Nutritional Physiological Phenomena; Phosphodiesterase 5 Inhibitors; Placenta; Placental Circulation; Placentation; Pregnancy; Pulsatile Flow; Rabbits; Random Allocation; Sildenafil Citrate; Vascular Resistance; Vasodilator Agents

Cardiovascular dysfunction at birth may underlie poor outcomes after fetal growth restriction (FGR) in neonates. We compared the cardiovascular transition between FGR and appropriately grown (AG) preterm lambs and examined possible mechanisms underlying any cardiovascular dysfunction in FGR lambs.. FGR was induced in ewes bearing twins at 0.7 gestation; the twin was used as an internal control (AG). At 0.8 gestation, lambs were delivered and either euthanized with their arteries isolated for in vitro wire myography, or ventilated for 2 h. At 60 min, inhaled nitric oxide (iNO) was administered in a subgroup for 30 min. Molecular assessment of the nitric oxide (NO) pathway within lung tissue was conducted.. FGR lambs had lower left ventricular output and cerebral blood flow (CBF) and higher systemic vascular resistance compared with AG lambs. INO administration to FGR lambs rapidly improved cardiovascular and systemic hemodynamics but resulted in decreased CBF in AG lambs. Isolated arteries from FGR lambs showed impaired sensitivity to NO donors, but enhanced vasodilation to Sildenafil and Sodium nitroprusside, and altered expression of components of the NO pathway.. Cardiovascular dysfunction at birth may underlie the increased morbidity and mortality observed in preterm FGR newborns. Impaired NO signaling likely underlies the abnormal vascular reactivity.

Topics: Administration, Inhalation; Animals; Animals, Newborn; Cerebrovascular Circulation; Disease Models, Animal; Echocardiography, Doppler; Female; Fetal Growth Retardation; Hemodynamics; Litter Size; Lung; Nitric Oxide; Nitric Oxide Synthase Type III; Nitroprusside; Oxygen; Sheep; Sheep, Domestic; Sildenafil Citrate; Time Factors; Vascular Resistance

Intrauterine growth restriction (IUGR) causes short- and long-term morbidity. Reduced placental perfusion is an important pathogenic component of IUGR; substances that enhance vasodilation in the uterine circulation, such as sildenafil citrate (sildenafil), may improve placental blood flow and fetal growth. This study aimed to examine the effects of sildenafil in the growth-restricted ovine fetus. Ewes carrying singleton pregnancies underwent insertion of vascular catheters, and then, they were randomized to receive uterine artery embolization (IUGR) or to a control group. Ewes in the IUGR group received a daily infusion of sildenafil (IUGR+SC; n=10) or vehicle (IUGR+V; n=8) for 21 days. The control group received no treatment (n=9). Umbilical artery blood flow was measured using Doppler ultrasound and the resistive index (RI) calculated. Fetal weight, biometry, and placental weight were obtained at postmortem after treatment completion. Umbilical artery RI in IUGR+V fell less than in controls; the RI of IUGR+SC was intermediate to that of the other 2 groups (mean±SEM for control versus IUGR+V versus IUGR+SC: ∆RI, 0.09±0.03 versus -0.01±0.02 versus 0.03±0.02; F(2, 22)=4.21; P=0.03). Compared with controls, lamb and placental weights were reduced in IUGR+V but not in IUGR+SC (control versus IUGR+V versus IUGR+SC: fetal weight, 4381±247 versus 3447±235 versus 3687±129 g; F(2, 24)=5.49; P=0.01 and placental weight: 559.7±35.0 versus 376.2±32.5 versus 475.2±42.5 g; F(2, 24)=4.64; P=0.01). Sildenafil may be a useful adjunct in the management of IUGR. An increase in placental weight and fall in fetal-placental resistance suggests that changes to growth are at least partly mediated by changes to placental growth rather than alterations in placental efficiency.

Topics: Animals; Blood Gas Analysis; Disease Models, Animal; Female; Fetal Development; Fetal Growth Retardation; Placental Circulation; Placentation; Pregnancy; Pregnancy, Animal; Random Allocation; Reference Values; Regional Blood Flow; Sheep; Sildenafil Citrate; Uterine Artery; Vascular Resistance

Preeclampsia (PE) and fetal growth restriction (FGR) are serious complications of pregnancy, associated with greatly increased risk of maternal and perinatal morbidity and mortality. These complications are difficult to diagnose and no curative treatments are available. We hypothesized that the metabolomic signature of two models of disease, catechol-O-methyl transferase (COMT(-/-)) and endothelial nitric oxide synthase (Nos3(-/-)) knockout mice, would be significantly different from control C57BL/6J mice. Further, we hypothesised that any differences in COMT(-/-) mice would be resolved following treatment with Sildenafil, a treatment which rescues fetal growth. Targeted, quantitative comparisons of serum metabolic profiles of pregnant Nos3(-/-), COMT(-/-) and C57BL/6J mice were made using a kit from BIOCRATES. Significant differences in 4 metabolites were observed between Nos3(-/-) and C57BL/6J mice (p < 0.05) and in 18 metabolites between C57BL/6J and COMT(-/-) mice (p < 0.05). Following treatment with Sildenafil, only 5 of the 18 previously identified differences in metabolites (p < 0.05) remained in COMT(-/-) mice. Metabolomic profiling of mouse models is possible, producing signatures that are clearly different from control animals. A potential new treatment, Sildenafil, is able to normalize the aberrant metabolomic profile in COMT(-/-) mice; as this treatment moves into clinical trials, this information may assist in assessing possible mechanisms of action.

Topics: Animals; Catechol O-Methyltransferase; Disease Models, Animal; Female; Fetal Growth Retardation; Metabolome; Metabolomics; Mice; Mice, Knockout; Pre-Eclampsia; Pregnancy; Sildenafil Citrate

Fetal growth restriction (FGR) affects 3-8% of human pregnancies. Mouse models have provided important etiological data on FGR; they permit the assessment of treatment strategies on the physiological function of both mother and her developing offspring. Our study aimed to 1) develop a method to assess vascular function in fetal mice and 2) as a proof of principle ascertain whether a high dose of sildenafil citrate (SC; Viagra) administered to the pregnant dam affected fetal vascular reactivity. We developed a wire myography methodology for evaluation of fetal vascular function in vitro using the placenta-specific insulin-like growth factor II (Igf2) knockout mouse (P0; a model of FGR). Vascular function was determined in abdominal aortas isolated from P0 and wild-type (WT) fetuses at embryonic day (E) 18.5 of gestation. A subset of dams received SC 0.8 mg/ml via drinking water from E12.5; data were compared with water-only controls. Using wire myography, we found that fetal aortic rings exhibited significant agonist-induced contraction, and endothelium-dependent and endothelium-independent relaxation. Sex-specific alterations in reactivity were noted in both strains. Maternal treatment with SC significantly attenuated endothelium-dependent and endothelium-independent relaxation of fetal aortic rings. Mouse fetal abdominal aortas reproducibly respond to vasoactive agents. Study of these vessels in mouse genetic models of pregnancy complications may 1) help to delineate early signs of abnormal vascular reactivity and 2) inform whether treatments given to the mother during pregnancy may impact upon fetal vascular function.

Topics: Animals; Aorta, Abdominal; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fetal Growth Retardation; Gestational Age; Insulin-Like Growth Factor II; Mice; Mice, Knockout; Phenotype; Phosphodiesterase 5 Inhibitors; Piperazines; Pregnancy; Purines; Sildenafil Citrate; Sulfones; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Fetal growth restriction (FGR) is defined as the inability of a fetus to achieve its genetic growth potential and is associated with a significantly increased risk of morbidity and mortality. Clinically, FGR is diagnosed as a fetus falling below the 5(th) centile of customised growth charts. Sildenafil citrate (SC, Viagra™), a potent and selective phosphodiesterase-5 inhibitor, corrects ex vivo placental vascular dysfunction in FGR, demonstrating potential as a therapy for this condition. However, many FGR cases present without an abnormal vascular phenotype, as assessed by Doppler measures of uterine/umbilical artery blood flow velocity. Thus, we hypothesized that SC would not increase fetal growth in a mouse model of FGR, the placental-specific Igf2 knockout mouse, which has altered placental exchange capacity but normal placental blood flow. Fetal weights were increased (by 8%) in P0 mice following maternal SC treatment (0.4 mg/ml) via drinking water. There was also a trend towards increased placental weight in treated P0 mice (P = 0.056). Additionally, 75% of the P0 fetal weights were below the 5(th) centile, the criterion used to define human FGR, of the non-treated WT fetal weights; this was reduced to 51% when dams were treated with SC. Umbilical artery and vein blood flow velocity measures confirmed the lack of an abnormal vascular phenotype in the P0 mouse; and were unaffected by SC treatment. (14)C-methylaminoisobutyric acid transfer (measured to assess effects on placental nutrient transporter activity) per g placenta was unaffected by SC, versus untreated, though total transfer was increased, commensurate with the trend towards larger placentas in this group. These data suggest that SC may improve fetal growth even in the absence of an abnormal placental blood flow, potentially affording use in multiple sub-populations of individuals presenting with FGR.

Topics: Animals; Blood Flow Velocity; Disease Models, Animal; Female; Fetal Development; Fetal Growth Retardation; Fetal Weight; Fetus; Humans; Insulin-Like Growth Factor II; Mice; Mice, Knockout; Phenotype; Phosphodiesterase Inhibitors; Piperazines; Placenta; Pregnancy; Purines; Sildenafil Citrate; Sulfones; Umbilical Arteries; Uterine Artery

Topics: Adult; Cesarean Section; Female; Fetal Growth Retardation; Humans; Piperazines; Pregnancy; Pregnancy Outcome; Pulsatile Flow; Purines; Sildenafil Citrate; Sulfones; Ultrasonography, Prenatal; Uterus; Vasodilator Agents

Preeclampsia and fetal growth restriction are responsible for the majority of maternal and perinatal morbidity and mortality associated with complicated pregnancies. Although their etiologies are complex and multifactorial, both are associated with increased uterine artery resistance. Sildenafil citrate is able to rescue the dysfunction observed ex vivo in uterine arteries of women with preeclampsia. The ability of sildenafil citrate to increase uterine artery vasodilation, thereby decreasing uterine artery resistance and, hence, ameliorated preeclampsia and fetal growth restriction, was tested in a mouse model of preeclampsia, the catechol-O-methyl transferase knockout mouse (COMT(-/-)). COMT(-/-) and C57BL/6J mice were treated (0.2 mg/mL in drinking water, n=6-12) from gestational day 12.5 to 18.5. Measures of pup growth, including body weight, crown/rump length, and abdominal circumference, were reduced in COMT(-/-) mice; this was normalized after treatment with Sildenafil. COMT(-/-) mice also demonstrated abnormal umbilical Doppler waveforms, including reverse arterial blood flow velocity. This was normalized after treatment with Sildenafil. Abnormal uterine artery Doppler waveforms were not demonstrated in COMT(-/-) mice, although ex vivo responses of uterine arteries to phenylephrine were increased; moreover, treatment with Sildenafil did improve ex vivo sensitivity to an endothelium-dependent vasodilator. The data presented here demonstrate that Sildenafil can rescue pup growth and improve abnormal umbilical Doppler waveforms, providing support for a potential new therapeutic strategy targeting fetal growth restriction.

Topics: Animals; Blood Flow Velocity; Catechol O-Methyltransferase; Disease Models, Animal; Female; Fetal Growth Retardation; Hypertension; Mice; Mice, Inbred C57BL; Mice, Knockout; Myometrium; Piperazines; Pre-Eclampsia; Pregnancy; Proteinuria; Purines; Sildenafil Citrate; Sulfones; Ultrasonography, Doppler; Umbilical Arteries; Vasodilation; Vasodilator Agents

To assess the effect of sildenafil citrate in a rat model of Nω-nitro-l-arginine methyl ester (L-NAME)-induced intrauterine growth restriction (IUGR).. An in vivo experimental study was conducted where 40 pregnant Sprague-Dawley rats were randomly assigned to receive either: (1) control, (2) L-NAME 50 mg/kg/d by gavage (days 14 to 19), (3) L-NAME and sildenafil 15 mg/kg/d by gavage, or (4) sildenafil (days 14 to 21). On day 21, a hysterotomy was performed and all fetuses (live and dead) were counted, examined, and weighed. The primary outcome measure was the difference in pup birth weight.. The median number of live pups per dam was 11.5 (range: 1 to 15), 13.5 (2 to 17), 13.5 (7 to 16), and 11.5 (4 to 17) in controls, L-NAME, sildenafil, and combined drug groups, respectively (p = 0.02). Rats treated with L-NAME had a significantly higher number of stillbirths compared with control (p = 0.013) and sildenafil (p = 0.008) groups. L-NAME reduced pup birth weight compared with controls (4.53 ± 1.49 versus 5.65 ± 1.63 g, p < 0.001); this effect was more pronounced in the L-NAME and sildenafil groups (3.37 ± 1.25 g, p < 0.001).. Our data indicate that sildenafil citrate does not ameliorate L-NAME-induced IUGR, and in the doses utilized in this study might even have a synergistic negative effect on pup birth weight.

Topics: Animals; Birth Weight; Disease Models, Animal; Female; Fetal Growth Retardation; NG-Nitroarginine Methyl Ester; Piperazines; Pre-Eclampsia; Pregnancy; Proteinuria; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil citrate therapy for severe early-onset intrauterine growth restriction. BJOG 2011;118:624-628. Currently, there is no effective therapy for severe early-onset intrauterine growth restriction (IUGR). Sildenafil citrate vasodilates the myometrial arteries isolated from women with IUGR-complicated pregnancies. Women were offered Sildenafil (25 mg three times daily until delivery) if their pregnancy was complicated by early-onset IUGR [abdominal circumference (AC)< 5th percentile] and either the gestational age was <25(+0) weeks or an estimate of the fetal weight was <600 g (excluding known fetal anomaly/syndrome and/or planned termination). Sildenafil treatment was associated with increased fetal AC growth [odds ratio, 12.9; 95% confidence interval (CI), 1.3, 126; compared with institutional Sildenafil-naive early-onset IUGR controls]. Randomised controlled trial data are required to determine whether Sildenafil improves perinatal outcomes for early-onset IUGR-complicated pregnancies.

Topics: Adult; Blood Flow Velocity; Case-Control Studies; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Perinatal Mortality; Piperazines; Placenta; Pregnancy; Pregnancy Outcome; Purines; Sildenafil Citrate; Sulfones; Uterus; Vasodilator Agents

Adequate placental blood flow is essential for the optimal delivery of nutrients from mother to fetus for conceptus growth. Restricted fetal development results from pathophysiological and environmental factors that alter utero-placental blood flow, placental function, and, therefore, nutrient availability in the fetus. To test this hypothesis, 0, 75, or 150 mg/d sildenafil citrate (Viagra) was administered subcutaneously from d 28 to 115 of gestation to either nutrient-restricted [50% of NRC requirements) or adequately-fed ewes (100% of NRC requirements). On d 115, maternal, fetal, and placental tissues and fluids were collected. Concentrations of total amino acids and polyamines in uterine venous and arterial sera, amniotic and allantoic fluids, and fetal umbilical venous serum were lower (P < 0.05) in nutrient-restricted ewes than in adequately fed ewes, as were the ratios of total amino acids in fetal umbilical venous serum to uterine arterial serum. Sildenafil citrate dose-dependently increased (P < 0.05) total amino acids and polyamines in amniotic fluid, allantoic fluid, and fetal serum without affecting values in maternal serum. Fetal weight was lower (P < 0.05) in nutrient-restricted ewes on d 115. Sildenafil citrate treatment dose-dependently increased (P < 0.05) fetal weight in both nutrient-restricted and adequately fed ewes. This study supports the hypothesis that long-term sildenafil citrate treatment enhances fetal growth, at least in part, by increasing the availability of amino acids in the conceptus. These findings may lead to the clinical use of sildenafil citrate in human pregnancies suspected to be at risk for intrauterine fetal growth retardation.

Topics: Amino Acids; Amniotic Fluid; Animal Nutritional Physiological Phenomena; Animals; Dietary Proteins; Disease Models, Animal; Dose-Response Relationship, Drug; Embryonic Development; Female; Fetal Growth Retardation; Fetal Weight; Fetus; Maternal Nutritional Physiological Phenomena; Piperazines; Placenta; Polyamines; Pregnancy; Prenatal Nutritional Physiological Phenomena; Purines; Sheep; Sildenafil Citrate; Sulfones; Umbilical Veins; Uterine Artery; Vasodilator Agents

The pathophysiology of pre-eclampsia is still unknown thus effective primary prevention is not possible at the stage. The present study was conducted to research the smooth muscle responses in the pre-eclampsia model with suramin treated rats and the effect of phosphodiesterase-5 (PDE5) inhibitor on these responses. Rats of three groups; control, suramin and suramin+sildenafil were given intraperitoneal injections of saline, suramin or sildenafil citrate. Suramin injections caused increased blood pressure, protein in urine and caused fetal growth retardation. The use of sildenafil citrate straightened significantly both blood pressure and average fetus weight, but did not reach to control values. At the end of pregnancy, thoracic aorta rings were exposed to contractile and relaxant agents. KCl contraction responses, sodium nitroprusside and papaverine relaxation responses were similar in three groups. Contraction responses of phenylephrine, increased significantly in suramin group. Relaxation responses of acethylcholine and bradykinin decreased in suramin group. The use of sildenafil citrate partially straightened both relaxation and contraction responses, but did not reach to control values. In all groups in the presence of L-nitromonomethylarginine (L-NAME), 1H-(1, 2, 4) oxadiazole (4, 3-a) guinoxalin-1-one (ODQ) and indomethacin decreased the relaxation responses of acetylcholine and bradykinin. The cyclic guanosine monophosphate (cGMP) content of thoracic aorta tissue was determined by radioimmunoassay technique. The content of cGMP in suramin group decreased and use of sildenafil citrate increased the cGMP content but did not reach to control values. We conclude that in pre-eclampsia, the increase of contraction responses, the decrease of relaxation responses and the decrease of cGMP content can depend on insufficiency about synthesis or release of relaxant factors which was released from the vessel endothelium. The results in this study show that in pre-eclampsia; PDE5 inhibitors enhance endothelial function and may be used for protection. Further studies are needed to clear the efficiency and safety of PDE5 inhibitors.

Topics: Animals; Aorta, Thoracic; Blood Pressure; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Fetal Development; Fetal Growth Retardation; Muscle, Smooth, Vascular; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pre-Eclampsia; Pregnancy; Proteinuria; Purines; Radioimmunoassay; Rats; Sildenafil Citrate; Sulfones; Suramin; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Fetal growth restriction (FGR) affects up to 8% of all pregnancies and has massive short-term (increased fetal morbidity and mortality) and long-term (increased incidence of cardiovascular disease in adulthood) health implications. Doppler waveform analysis of pregnancies complicated by FGR suggests compromised uteroplacental circulation and placental hypoperfusion. Our aim was to determine whether myometrial small artery function was aberrant in FGR and to assess whether sildenafil citrate could improve vasodilatation in FGR pregnancies.. Small arteries dissected from myometrial biopsies obtained at cesarean section from normal pregnant women (n = 27) or women whose pregnancies were complicated by FGR (n = 12) were mounted on wire myographs. Vessels were constricted (with arginine vasopressin or U46619) and relaxed (with bradykinin) before and after incubation with a phosphodiesterase-5 inhibitor, sildenafil citrate.. We demonstrated increased myometrial small artery vasoconstriction and decreased endothelium-dependent vasodilatation in vessels from women whose pregnancies were complicated by FGR. Sildenafil citrate significantly reduced vasoconstriction and significantly improved relaxation of FGR small arteries.. We conclude that sildenafil citrate improves endothelial function of myometrial vessels from women whose pregnancies are complicated by intrauterine growth restriction. Sildenafil citrate may offer a potential therapeutic strategy to improve uteroplacental blood flow in FGR pregnancies.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Arginine Vasopressin; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelium, Vascular; Female; Fetal Growth Retardation; Humans; Myometrium; Phosphodiesterase Inhibitors; Piperazines; Pregnancy; Purines; Sildenafil Citrate; Sulfones; Vasodilation