Severe Early-onset Fetal Growth Restriction Research Articles

Prediction of perinatal mortality in early-onset fetal growth restriction: A post hoc analysis of the Dutch STRIDER trial to predict perinatal mortality in early-onset fetal growth restriction

ObjectiveEarly-onset fetal growth restriction affects about 0.3% of pregnancies, posing high perinatal risks due to placental insufficiency. Early-onset fetal growth restriction often coincides with early-onset pre-eclampsia, associated with significant mortality and morbidity. Clinical management varies among clinicians, with emphasis on intensive monitoring and timely delivery. Our objective was to improve clinical prediction of perinatal mortality in early-onset fetal growth restriction for parental counseling. Study designThis was a secondary analysis of prospective cohort data from the Dutch STRIDER trial. The study included 215 pregnant women diagnosed with severe early-onset fetal growth restriction between 20 + 0 and 29 + 6 weeks of gestation, from tertiary and secondary antenatal care centers in The Netherlands. Maternal and fetal characteristics were collected at inclusion, including sonographic and laboratory measurements. Analysis was performed using univariable and multivariable binary logistic regression to create a prediction model for perinatal mortality. The main outcome measures were fetal demise and neonatal mortality up to discharge. Results215 Participants were included for this analysis. Perinatal mortality occurred in 84 (39 %) cases; 51 (24 %) were fetal and 33 (15 %) neonatal. Fetal abdominal circumference, gestational age at diagnosis, estimated fetal weight Multiple of Median, absent or reversed end-diastolic flow of the umbilical artery, umbilical artery pulsatility index Multiple of Median, non-Caucasian ethnicity, male sex, placental growth factor level and uterine artery pulsatility index were independent predictors of perinatal mortality. Randomization allocation (sildenafil or placebo) had no predictive value for mortality. The prediction model including gestational age at diagnosis, estimated fetal weight Multiple of Median and umbilical artery pulsatility index Multiple of Median showed an area under the receiver operating characteristic curve of 0.840 (P < 0.01). Placental growth factor was measured in a subset of patients and was an independent prognostic factor and performed significantly better within the predictive model, however it did not improve the predictive value of the model. ConclusionsPrediction of perinatal mortality in early-onset fetal growth restriction is feasible with commonly available tests and measurements and could support decision making in management of pregnancy. However, implementation in practice requires further studies.

Neurodevelopmental outcomes at 2 years in children who received sildenafil therapy in utero: The STRIDER randomised controlled trial.

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

Prenatal Features of MIRAGE Syndrome-Case Report and Review of the Literature.

MIRAGE syndrome is a recently described congenital condition characterized genetically by heterozygous gain-of-function missense mutations in the growth repressor sterile alpha domain containing 9 (SAMD9) located on the arm of chromosome 7 (7q21.2). The syndrome is rare and is usually diagnosed in newborns and children with myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy, hence the acronym MIRAGE. The aims of this paper are (1) to present fetal ultrasound features in a case where MIRAGE syndrome was diagnosed prenatally and (2) to review the existing literature records on prenatal manifestations of MIRAGE syndrome. In our case, the fetus had severe early fetal growth restriction (FGR) with normal Doppler studies, atypical genitalia, oligohydramnios, and hyperechogenic bowel at the routine mid-gestation anomaly scan. Amniocentesis excluded infections and numeric or structural chromosomal abnormalities while whole exome sequencing (WES) of the fetal genetic material identified the specific mutation. Targeted testing in parents was negative, suggesting the "de novo" mutation in the fetus. We could not identify other specific case reports in the literature on the prenatal diagnosis of MIRAGE syndrome. In cases reported in the literature where the diagnosis of MIRAGE syndrome was achieved postnatally, there are mentions related to the marked FGR on prenatal ultrasound. Severe early-onset FGR with no other apparent cause seems to be a central prenatal feature in these babies, and WES should be offered, especially if there are other structural abnormalities. Prenatal diagnosis of MIRAGE syndrome is possible, allowing for reproductive choices, improved counseling of parents, and better preparation of neonatal care.

Rate of deterioration of umbilical artery Doppler indices in fetuses with severe early-onset fetal growth restriction

ObjectiveTo examine risk factors for the development of absent or reversed end-diastolic velocity (A/REDV) and the time intervals of deterioration from normal UA EDV by S/D, PI or RI to decreased and A/REDV in fetuses with early-onset severe FGR. Study DesignRetrospective cohort study performed from 2005 to 2020. All singleton pregnancies with severe (estimated fetal weight [EFW] or abdominal circumference [AC] below the 3rd percentile) and early-onset (diagnosed between 20 0/7 to 31 6/7 weeks of gestation) were included. Fetal genetic or structural anomalies, suspected congenital infections, A/REDV at diagnosis, poor pregnancy dating and absence of follow-up ultrasounds were excluded. EFW, AC and Doppler indices were reviewed longitudinally from diagnosis to delivery. To examine risk factors for A/REDV, we performed backward stepwise logistic regression and calculated odds ratio with 95% confidence interval (CI). Kaplan-Meier curves were compared using log-rank test. ResultsA total of 985 patients met the inclusion criteria and 79 (8%) progressed to A/REDV. Factors associated with development of A/REDV included gestational age at diagnosis (AOR 4.88 [2.55 – 9.37, 95% CI] at 20 0/7 to 23 6/7 weeks and AOR 1.56 [0.86-2.82, 95%CI] at 24 0/7 to 27 6/7 weeks compared to 28 0/7 to 31 6/7 weeks) and presence of chronic hypertension (CHTN) with AOR 2.37 (1.33 – 4.23, 95% CI). Rates of progression from diagnosis of FGR with normal UA Doppler to A/REDV were significant after 4 weeks from diagnosis (5.84% [4.50 – 7.57, 95% CI]). Regarding the Doppler indices, the progression from normal values to abnormal indices was similar in 1 and 2 weeks however the progression from normal to abnormal S/D ratio compared to PI or RI were higher at 4 and 6 weeks. Deterioration from abnormal indices to A/REDV was shorter with abnormal RI and PI when compared to S/D ratio at 2, 4 and 6 weeks after diagnosis and at 6 weeks, respectively. ConclusionEarlier gestational age at diagnosis and CHTN are considered risk factors for Doppler deterioration and development of A/REDV in the UA. With normal Doppler indices, significant deterioration and progression to A/REDV is unlikely until 4 weeks after diagnosis. Abnormal S/D ratio seems to be appear first. However, abnormal PI or RI was associated with A/REDV.

1068 Pregnancy Outcomes in Severe Early-Onset Fetal Growth Restriction: Results from the Multicenter PERIMETER Study

1068 Pregnancy Outcomes in Severe Early-Onset Fetal Growth Restriction: Results from the Multicenter PERIMETER Study

Systemic Oxidative Stress in Severe Early-Onset Fetal Growth Restriction Associates with Concomitant Pre-Eclampsia, Not with Severity of Fetal Growth Restriction.

Placental insufficiency is an important mechanism underlying early-onset fetal growth restriction (eoFGR). Reduced placental function causes impaired metabolic and gaseous exchange. This unfavorable placental environment is among other processes characterized by increased oxidative stress. Systemic free thiols (FT) are known for their reactive oxygen species scavenging capacity, and higher plasma levels of FT are associated with a better outcome in a multitude of ischemic and inflammatory diseases. We aimed to investigate the relationships between systemic FT levels and maternal and perinatal clinical characteristics and outcomes. In a post hoc analysis of the Dutch Strider study, a cohort of women with eoFGR, we investigated the association between the maternal redox status (FT) levels at study inclusion, placental biomarkers, and maternal and neonatal outcomes in 108 patients. FT were significantly lower in pregnancies complicated with eoFGR with concurrent maternal hypertensive disorders (pregnancy-induced hypertension; ρ = -0.281 p = 0.004, pre-eclampsia; ρ = -0.505 p = 0.000). In addition, lower FT levels were significantly associated with higher systolic (ρ = -0.348 p = 0.001) and diastolic blood pressure (ρ = -0.266 p = 0.014), but not with the severity of eoFGR. FT levels were inversely associated with sFlt (ρ = -0.366, p < 0.001). A strong relation between systemic FT levels and PlGF levels was observed in women with pre-eclampsia at delivery (ρ = 0.452, p = 0.002), which was not found in women without hypertensive disorders (ρ = 0.008, p = 0.958). In women with pregnancies complicated with eoFGR, FT levels reflect the severity of maternal disease related to the underlying placental insufficiency rather than the severity of the placental dysfunction as reflected in eoFGR or perinatal outcomes.

Neonatal outcomes following early fetal growth restriction: a subgroup analysis of the EVERREST study

ObjectiveTo quantify the risks of mortality, morbidity and postnatal characteristics associated with extreme preterm fetal growth restriction (EP-FGR).DesignThe EVERREST (Does vascular endothelial growth factor gene therapy safely improve outcome in...

Dysregulation of integrin αvβ3 and α5β1 impedes migration of placental endothelial cells in fetal growth restriction.

Placentas from pregnancies complicated by severe early-onset fetal growth restriction (FGR) exhibit diminished vascular development mediated by impaired angiogenesis, but underlying mechanisms remain unknown. In this study, we show that FGR endothelial cells demonstrate inherently reduced migratory capacity despite the presence of fibronectin, a matrix protein abundant in placental stroma that displays abnormal organization in FGR placentas. Thus, we hypothesized that aberrant endothelial-fibronectin interactions in FGR are a key mechanism underlying impaired FGR endothelial migration. Using human fetoplacental endothelial cells isolated from uncomplicated term control and FGR pregnancies, we assessed integrin α5β1 and αvβ3 regulation during cell migration. We show that endothelial integrin α5β1 and αvβ3 interactions with fibronectin are required for migration and that FGR endothelial cells responded differentially to integrin inhibition, indicating integrin dysregulation in FGR. Whole-cell expression was not different between groups. However, there were significantly more integrins in focal adhesions and reduced intracellular trafficking in FGR. These newly identified changes in FGR endothelial cellular processes represent previously unidentified mechanisms contributing to persistent angiogenic deficiencies in FGR.

Effectiveness of pentoxifylline in severe early-onset fetal growth restriction: A randomized double-blinded clinical trial

ObjectiveManagement of pregnancy complicated by severe early-onset fetal growth restriction (FGR) is one of the most challenging obstetrical issues. So far, there has not been a proven option for the treatment or improvement of this condition. Improper immune response during placentation leads to inadequate trophoblast invasion and impaired utero-placental perfusion. Pentoxifylline improves the endothelial function and induces vasodilation by reducing the inflammatory-mediated cytokines. We have evaluated the effect of Pentoxifylline on fetal-placental perfusion, neonatal outcome, and the level of oxidative stress markers before and after the intervention in the setting of severe early-onset FGR. Materials and methodsThis study is a pilot randomized clinical trial on 40 pregnant women who had developed early-onset growth restricted fetus. Pentoxifylline and placebo were given with a dose of 400 mg per os two times daily until delivery. Serial ultrasound examination regarding fetal weight, amniotic fluid and also utero-placenta-fetal Doppler's were done. For the assessment of serum Antioxidant level, blood sampling was done once at the beginning of the study and again, at least, three weeks after the investigation. After delivery, umbilical-cord blood gas analysis, APGAR score at 1 and 5 min, NICU admission, and neonatal death were recorded and compared between the two groups. ResultsUtero-placenta-fetal Doppler's in the Pentoxifylline group did not significantly change compared to the control group. Fetal weight gain was significantly higher in the Pentoxifylline group before (996.33 ± 317.41) and after (1616.89 ± 527.90) treatment (P = 0.002). Total serum antioxidant capacity significantly increased in the Pentoxifylline group (p < 0.036). Average 5 min Apgar score was significantly higher (P < 0.036) and the percentage of babies admitted to NICU was significantly lower (P < 0.030) in the treated group. ConclusionUsing Pentoxifylline in pregnancy affected by FGR might show promising effects. In this study, Pentoxifylline improved the neonatal outcome, increased fetal weight gain, and reduced neonatal mortality by decreasing the level of oxidative stress markers and cutting down the inflammatory cascade.

Neonatal pulmonary hypertension after severe early-onset fetal growth restriction: post hoc reflections on the Dutch STRIDER study

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).Conclusion: 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.What is Known:• In the Dutch STRIDER trial, persistent pulmonary hypertension in the neonate (PPHN) was more frequent among infants after antenatal sildenafil exposure versus placebo.What is New:• 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.

Outcomes of pregnancies complicated by severe early-onset fetal growth restriction

Outcomes of pregnancies complicated by severe early-onset fetal growth restriction

VP28.07: Impact of confined placental mosaicism on outcome of pregnancy

To assess the incidence of confined placental mosaicism (CPM) on CVS and amniocentesis in our population and to study the impact of CPM on the outcome of pregnancies with a structurally normal fetus at mid trimester anomaly scan and the association of abnormal first trimester serum biochemistry with CPM. This is a single centre study where all pregnancies that had an invasive procedure ie CVS or amniocentesis before 20 weeks of gestation from January 2011 till December 2020 were considered. The study included pregnancies that had mosaic pattern on CVS or amniocentesis. The incidence of CPM on CVS and amniocentesis was calculated. Fetal ultrasound in all trimesters, maternal serum biochemistry in the first trimester, presence of fetal growth restriction (FGR) and postnatal outcome were obtained. During the study period, of the 2081 Amniocentesis procedures 1 (0.05%) had CPM with tetraploidy mosaic confirmed by postnatal karyotype with normal outcome. Of 1144 CVS procedures performed 10/1144 (0.9%) were detected to have a mosaic pattern. 5/10 mosaic pattern obtained in pregnancies with fetal structural abnormalities were terminated before amniocentesis could be performed. 5/10 (0.44%) had structurally normal fetuses and hence Amniocentesis could be performed to confirm CPM. Of the four where first trimester serum biochemistry was available, three (75%) cases had low maternal serum PAPP-A (< 0.3). 2 of 5 cases had Trisomy 18, one had Trisomy 16 and one had Trisomy 21 mosaic pattern, all of which had normal antenatal and postnatal outcomes. 1/5 pregnancies had Trisomy 16 mosaic pattern which was found to have severe early onset FGR at 18 weeks and was terminated. Hence, 1/5 pregnancies with CPM had poor fetal outcome. The incidence of CPM in our study was about 0.44% on CVS and that on amniocentesis 0.05%. FGR was the only antenatal complication. We did not observe any maternal complications. Low maternal serum PAPP-A levels may indicate a higher possibility of obtaining a mosaic pattern on a CVS.

Maternal serum concentrations of proteins linked to angiogenesis and cardiovascular disease are associated with placental histomorphometry in severe early-onset fetal growth restriction, with effect modification by fetal sex and aspirin use.

Maternal serum concentrations of proteins linked to angiogenesis and cardiovascular disease are associated with placental histomorphometry in severe early-onset fetal growth restriction, with effect modification by fetal sex and aspirin use.

Severe early-onset fetal growth restriction: What do we tell the prospective parents?

Fetal growth restriction (FGR) is a common complication of pregnancy, associated withhigher risk of perinatal mortality and adverse health and developmental outcomes for surviving infants. True FGR relates to a pathological restriction of fetal growth resulting from complex interactions between maternal, placental, fetal, and environmental factors. Early-onset FGR (onset <32weeks' gestation) is often first suspected at routine mid-trimester sonographic assessment of fetal morphology, or identified aspart of the placental syndrome, commonly maternal pre-eclampsia. Prenatal investigations may identify the cause of FGR. Timing of delivery is guided by serial sonographic surveillance of fetal growth and well-being and maternal condition, balancing the risk of stillbirth with the benefits of advancing gestation. This is particularly pertinent to severe early-onset FGR, a leading iatrogenic cause of very preterm birth. Prognosis is largely determined by the severity of FGR and its causes, gestation at birth, and birthweight. Pregnancy termination may be considered. Antenatal careand delivery in a tertiary center, provided by a multi-disciplinary team with expertise in managing high-risk pregnancies, are imperative to optimizing outcomes.

502 Progression rate of umbilical artery doppler indices in severe early-onset fetal growth restriction

Umbilical Artery (UA) Doppler is an essential component of fetal surveillance in fetal growth restriction (FGR). Although the Pulsatility Index (PI) is commonly used as the primary index for UA Doppler assessment, S/D ratio is still widely used in many centers. We sought to statistically compare the three UA Doppler Indices and to assess rate of progression in a large cohort of fetuses with severe early-onset FGR. Retrospective longitudinal cohort of singleton pregnancies with severe early-onset FGR from 2005 to 2020. S/D ratio, PI and Resistance Index (RI) were evaluated according to SMFM guidelines for each ultrasound and longitudinally until delivery. Abnormal Doppler was defined at greater than 95% for gestational age for all indices. Kaplan-Meier survival curve was used to examine the cumulative Doppler abnormalities. A total of 1,730 pregnancies were included in the analysis. The median gestational age was 28.4 weeks (IQR 26.4; 30.4) and median EFW at diagnosis was 929 grams (IQR 687; 1,197). At initial diagnosis, the S/D ratio was abnormal in 535/1730 (30.9%), PI in 383/1730 (22.1%) and RI in 274/1730 (15.8%). When UA Doppler was normal at initial diagnosis, time to abnormality in 25% of the cohort was 6, 8 and 9 weeks and in 50% of the cohort was 13,14 and 13 weeks for S/D, PI and RI respectively (Table 1). Relationship between PI and S/D ratio is demonstrated in Figure 1. In severe early-onset FGR, S/D ratio is more commonly abnormal than PI or RI. The rate of UA Doppler deterioration for the three indices is slower than previously described. The PI index most significantly impacts the rate of UA Doppler progression over time when compared to other Indices.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction

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.

Antenatal sildenafil citrate treatment increases offspring blood pressure in the placental-specific Igf2 knockout mouse model of FGR.

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 (P < 0.05) and reduced glucose sensitivity in both WT (P < 0.01) and P0 (P < 0.05) female offspring compared with controls. Antenatal SC treatment increased systolic blood pressure in both male (WT vs. WT-SC: 117 ± 2 vs. 140 ± 3 mmHg, P < 0.0001; P0 vs. P0-SC: 113 ± 3 vs. 140 ± 4 mmHg, P < 0.0001; means ± SE) and female (WT vs. WT-SC: 121 ± 2 vs. 140 ± 2 mmHg, P < 0.0001; P0 vs. P0-SC: 117 ± 2 vs. 144 ± 4 mmHg, P < 0.0001) offspring at 8 and 13 wk of age. Increased systolic blood pressure was not attributed to altered mesenteric artery function. In utero exposure to SC may result in metabolic dysfunction and elevated blood pressure in later life.NEW & NOTEWORTHY Sildenafil citrate (SC) is currently used to treat fetal growth restriction (FGR). We demonstrate that SC is ineffective at treating FGR, and leads to a substantial increase systolic blood pressure and alterations in glucose homeostasis in offspring. We therefore urge caution and suggest that further studies are required to assess the safety and efficacy of SC in utero, in addition to the implications on long-term health.

Early‐onset fetal growth restriction: A systematic review on mortality and morbidity

IntroductionSevere early‐onset fetal growth restriction is an obstetric condition with significant risks of perinatal mortality, major and minor neonatal morbidity, and long‐term health sequelae. The prognosis of a fetus is influenced by the extent of prematurity and fetal weight. Clinical care is individually adjusted. In literature, survival rates vary and studies often only include live‐born neonates with missing rates of antenatal death. This systematic review aims to summarize the literature on mortality and morbidity.Material and methodsA broad literature search was conducted in OVID MEDLINE from 2000 to 26 April 2019 to identify studies on fetal growth restriction and perinatal death. Studies were excluded when all included children were born before 2000 because (neonatal) health care has considerably improved since this period. Studies were included that described fetal growth restriction diagnosed before 32 weeks of gestation and antenatal mortality and neonatal mortality and/or morbidity as outcome. Quality of evidence was rated with the GRADE instrument.ResultsOf the 2604 publications identified, 25 studies, reporting 2895 pregnancies, were included in the systematic review. Overall risk of bias in most studies was judged as low. The quality of evidence was generally rated as very low to moderate, except for 3 large well‐designed randomized controlled trials. When combining all data on mortality, in 355 of 2895 pregnancies (12%) the fetus died antenatally, 192 died in the neonatal period (8% of live‐born neonates) and 2347 (81% of all pregnancies) children survived. Of the neonatal morbidities recorded, respiratory distress syndrome (34% of the live‐born neonates), retinopathy of prematurity (13%) and sepsis (30%) were most common. Of 476 children that underwent neurodevelopmental assessment, 58 (12% of surviving children, 9% of all pregnancies) suffered from cognitive impairment and/or cerebral palsy.ConclusionsWhen combining the data of 25 included studies, survival in fetal growth restriction pregnancies, diagnosed before 32 weeks of gestation, was 81%. Neurodevelopmental impairment was assessed in a minority of surviving children. Individual prognostic counseling on the basis of these results is hampered by differences in patient and pregnancy characteristics within the included patient groups.

A prediction model for short-term neonatal outcomes in severe early-onset fetal growth restriction

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

Pregnant women\u2019s experiences and perceptions of participating in the EVERREST prospective study; a qualitative study

BackgroundThe EVERREST Prospective Study is a multicentre observational cohort study of pregnancies affected by severe early-onset fetal growth restriction. The study recruits women with singleton pregnancies where the estimated fetal weight is less than the 3rd centile and below 600 g, between 20 + 0 and 26 + 6 weeks of pregnancy, in the absence of a known chromosomal, structural or infective cause.MethodThe reported study was retrospective descriptive qualitative interview study of women who had participated in the EVERREST Prospective Study. The aim of this study was to explore the experiences and perceptions of pregnant women taking part in research during a pregnancy affected by severe early-onset fetal growth restriction. Audio-recorded semi-structured telephone interviews were conducted with a purposive sample of 12 women, at least 1 year after delivery of their baby. Two of these pregnancies had ended in stillbirth and one in neonatal death, reflecting the outcomes seen in the EVERREST Prospective Study. Participants gave informed consent, were 16 years or older and were interviewed in English. A topic guide was used to ensure a consistent approach. Questions focused on pregnancy experiences, involvement with the EVERREST study and potential involvement in future research. Recordings were transcribed verbatim for thematic analysis using NVivo10.ResultsFour broad themes were identified; ‘before joining the EVERREST Prospective Study’, ‘participating in research’, ‘information and support’ and ‘looking back and looking forwards’. Each broad theme incorporated several subthemes. All participants recalled their reaction to being told their baby was smaller than expected. The way this news was given had a lasting impact. A range of benefits of participation in the EVERREST Prospective Study were described and the participants were positive about the way it was conducted. As a consequence, they were receptive to participating in future research. However, the findings suggest that research teams should be sensitive when approaching families at a difficult time or when they are already participating in other research.ConclusionsThis study highlights the willingness of pregnant women to participate in research and identifies strategies for researchers to engage participants.