sildenafil-citrate and Birth-Weight

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

The number of studies associating the use of sildenafil in gestation is increasing. This drug inhibits phosphodiesterase type 5 (PDE5), an enzyme responsible for degradation of nitric oxide, and its efficacy is greater in the placental territory, as the maternal side of the placenta have more PDE5 than other sites. For this reason, promising results have been observed related to the prevention of preeclampsia and intrauterine growth restriction and to improvement of maternal-fetal morbidity in cases of placental insufficiency.. To evaluate the benefits of using sildenafil in pregnancy.. MEDLINE, ClinicalTrials.gov, Embase, LILACS and Cochrane databases were searched through September 2018. There was no restriction in language or year of publication. This study was registered in PROSPERO (CRD42017060288).. Randomized clinical trials which used sildenafil for treatment or prevention of obstetric diseases compared with placebo were selected.. The results were obtained using the inverse variance method for continuous variables and Man-Whitney for categorical variables.. Among a population of 598 pregnant women from the seven clinical trials included, 139 had pre-eclampsia, 275 had intrauterine growth restriction, and 184 had oligohydramnios. A significant increase of 222.58 grams [27.75 to 417.41] was observed in the fetal weight at birth of patients taking sildenafil. The other outcomes did not show any statistical significance. This may be due to the small number of patients used in each study and the great heterogeneity between the groups.. Sildenafil could be associated with increasing fetal weight at birth in placental insufficiency despite the limitations of this meta-analysis, even though more studies in this field are needed to introduce this drug into obstetric clinical practice.

Topics: Birth Weight; Delivery, Obstetric; Female; Fetus; Gestational Age; Headache; Humans; Infant; Infant Mortality; Labor, Obstetric; Pregnancy; Pregnancy Outcome; Publication Bias; Risk; Sildenafil Citrate; Umbilical Arteries

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

The survival of great number of extremely premature newborn babies is associated with increased risk of damage of the newborn lung and development of chronic lung disease/Broncopulmonary dysplasia. The lower the gestational age and weight, the greater the frequency of BPD. The disease leads to impairment of the normal alveolization and vascularization of the premature lung. There are new theories for the pathogenesis of BPD and new staging of the disease. These changes lead to new therapeutic strategies.

Topics: Antihypertensive Agents; Birth Weight; Bronchodilator Agents; Bronchopulmonary Dysplasia; Epoprostenol; Female; Gestational Age; Humans; Infant, Newborn; Lung; Milrinone; Nitric Oxide; Pregnancy; Sildenafil Citrate; Vasodilator 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

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

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

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

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

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

Pulmonary hypertension (PH) affects 1 in 6 infants with a birthweight <1,000 g (extremely low birthweight; ELBW) and is frequently associated with bronchopulmonary dysplasia (BPD). If untreated, the mortality rates of the disease are high.. The aim of this study was to characterize risk factors for PH in ELBW infants and to describe the timing of onset of the disease by setting up a screening program.. ELBW infants treated at the Department of Neonatology (level III neonatal intensive care unit at the University of Cologne Medical Centre, Germany) between January 2010 and March 2015 were included. Echocardiography screening for PH was performed either before discharge or if BPD was diagnosed. Additionally, infants had at least 1 echocardiographic scan after discharge. Survival with PH, age at diagnosis of PH, and risk factors associated with PH were assessed.. In total, 34/188 (18%) infants had PH. Of these, 14 (41%) were identified after discharge. Another 11 (32%) were diagnosed with PH without suffering from moderate or severe BPD. The risk factors for diagnosis of PH were moderate (odds ratio, OR 4 [2-8]) or severe BPD (OR 13 [2-71]), prolonged rupture of membranes >7 days (OR 5 [1-19]), and birthweight below the 3rd percentile (OR 3 [1-9]). All infants with PH before discharge and 50% diagnosed after discharge were treated with sildenafil (2.0 mg/kg/day). PH resolved and sildenafil was discontinued in all patients after a median duration of 13 months (IQR 8-20).. An echocardiographic screening program may help to identify infants with PH. Examinations should include all ELBW infants irrespective of the presence of BPD and be continued after discharge.

Topics: Birth Weight; Bronchopulmonary Dysplasia; Echocardiography; Female; Germany; Gestational Age; Humans; Hypertension, Pulmonary; Infant; Infant, Extremely Low Birth Weight; Infant, Newborn; Intensive Care Units, Neonatal; Logistic Models; Male; Risk Factors; Severity of Illness Index; Sildenafil Citrate

A retrospective analysis of the records of all the patients of pulmonary arterial hypertension with pregnancy at AIIMS, New Delhi, India, to study maternal and perinatal outcome and to compare outcome between severe and mild pulmonary arterial hypertension.. A retrospective analysis was carried out of 30 pregnancies in women with pulmonary arterial hypertension (PAH) who delivered at ≥ 28 weeks of gestation from July 2006 through July 2012 at a tertiary care center in India. Pulmonary artery blood pressure (PABP) during the first trimester of pregnancy or before pregnancy was considered to define PABP as severe or mild, with severe cases having systolic PABP >50 mmHg on echocardiography.. Out of 30 patients, 14 patients had severe PAH and 16 patients had mild PAH. Women with severe PAH had a significantly higher incidence of preterm delivery (11 vs. 3, P < 0.05), small for gestational age infants (10 vs. 2, P < 0.05) and cardiac complications (6 vs. 1, P < 0.05) compared to women with mild PAH. There was maternal mortality in a patient with Eisenmenger syndrome. In women with severe PAH and mild PAH, PABP increased in later pregnancy from 63.14 ± 7.6 to 71.57 ± 7.9 mmHg (P < 0.05) and from 40.37 ± 3.6 to 41.69 ± 4.1 mmHg (P < 0.05), respectively.. Pregnancy in women with severe PAH is associated with higher maternal morbidity and adverse fetal outcome compared to pregnancy in women with mild PAH.

Topics: Adult; Arrhythmias, Cardiac; Arterial Pressure; Birth Weight; Cesarean Section; Echocardiography; Eisenmenger Complex; Familial Primary Pulmonary Hypertension; Female; Gestational Age; Heart Failure; Humans; Hypertension, Pulmonary; India; Infant, Newborn; Infant, Small for Gestational Age; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Pregnancy Trimester, First; Pregnancy Trimester, Third; Premature Birth; Purines; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Sulfones; Vasodilator Agents; Young Adult

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

To describe the pharmacokinetics and exposure of oral sildenafil (SIL) in neonates (2-5 kg) with pulmonary hypertension (PH).. We included 11 neonates (body weight 2-5 kg, postnatal age 2-121 days) who received SIL and extracorporeal membrane oxygenation (ECMO) treatment for PH. SIL capsules were given via a nasogastric tube. Blood samples were collected via a pre-existing arterial line to quantify SIL and metabolite plasma levels (219 samples). Non-linear mixed effects modelling was used to describe SIL and desmethylsildenafil (DMS) pharmacokinetics.. A one-compartment model was suitable for SIL and DMS. Interpatient and intrapatient variability for clearance at 100% bioavailability were 87% and 27% (SIL) and 62% and 26% (DMS). Patient weight, postnatal age and post-ECMO time did not explain variability. Concomitant fluconazole use was associated with a 47% reduction in SIL clearance. The exposure expressed as average plasma concentration area under the curve over 24 h (AUC(24 (SIL+DMS))) ranged from 625 to 13 579 ng/h/ml. An oral dose of 4.2 mg/kg/24 h would lead to a median AUC(24 (SIL+DMS)) of 2650 ng/h/ml equivalent to 20 mg three times a day in adults. Interpatient variability was large, with a simulated AUC(24 (SIL+DMS)) range (10th and 90th percentiles) of 1000-8000 ng/h/ml.. SIL pharmacokinetics are highly variable in post-ECMO neonates and infants. In a median patient, the current dose regimen of 0.5-2.0 mg/kg four times a day leads to an exposure comparable to the recommended adult dose of 20 mg four times a day. Careful dose titration, based on efficacy and the occurrence of hypotension, remains necessary. Follow-up research should include appropriate pharmacodynamic endpoints, with a population pharmacokinetic/pharmacodynamic analysis to assign a suitable exposure window or target concentration.

Topics: Antihypertensive Agents; Area Under Curve; Biological Availability; Birth Weight; Capsules; Extracorporeal Membrane Oxygenation; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Intubation, Gastrointestinal; Off-Label Use; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Sildenafil is a phosphodiesterase type 5 inhibitor used as a therapeutic adjunct in critically ill neonates with persistent pulmonary hypertension. Sildenafil is associated with several ocular complications in adults and is suspected to exacerbate retinopathy of prematurity (ROP). The risk of ocular complication in sildenafil-treated newborns, not otherwise at risk for the development of ROP, is unknown.. Twenty-two neonates with birth gestational age greater than 34 weeks and birth weight over 2,100 g who received oral sildenafil for more than 2 weeks were assessed by a pediatric ophthalmologist for potential ocular complications.. Four patients had ocular findings: 2 had bacterial conjunctivitis; 1 had optic nerve hypoplasia, choroidal coloboma, and nystagmus; 1 had previously suffered from a hypotensive episode and had a documented cortical injury accompanied by bilateral optic disk atrophy and nystagmus. All cases seemed unrelated to sildenafil use and improved despite continued use of the drug.. Our results do not support the need for a routine ophthalmologic examination in term and near-term neonates receiving sildenafil.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Birth Weight; Eye; Female; Gestational Age; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Assessment; Sildenafil Citrate; Sulfones