Fetal Growth Restriction Infants Research Articles

Vascular responsiveness to low-dose dexamethasone in extremely premature infants: negative influence of fetal growth restriction.

Dexamethasone is frequently prescribed for preterm infants to wean from respiratory support and/or to facilitate extubation. This pre-/postintervention prospective study ascertained the impact on clinical (respiratory support) and echocardiographic parameters after dexamethasone therapy in preterm fetal growth restriction (FGR) infants compared with appropriate for gestational age (AGA) infants. Echocardiography was performed within 24 h before the start and after completion of 10-day therapy. Parameters assessed included those reflecting pulmonary vascular resistance and right ventricular output. Seventeen FGR infants (birth gestation and birth weight, 25.2 ± 1.1 wk and 497 ± 92 g, respectively) were compared with 22 AGA infants (gestation and birth weight, 24.5 ± 0.8 and 663 ± 100 g, respectively). Baseline respiratory severity score (mean airway pressure × fractional inspired oxygen) was comparable between the groups, (median [interquartile range] FGR, 10 [6, 13] vs. AGA, 8 ± 2.8, P = 0.08). Pre-dexamethasone parameters of pulmonary vascular resistance (FGR, 0.19 ± 0.03 vs. AGA, 0.2 ± 0.03, P = 0.16) and right ventricular output (FGR, 171 ± 20 vs. 174 ± 17 mL/kg/min, P = 0.6) were statistically comparable. At post-dexamethasone assessments, the decrease in the respiratory severity score was significantly greater in AGA infants (median [interquartile range] FGR, 10 [6, 13] to 9 [2.6, 13.5], P = 0.009 vs. AGA, 8 ± 2.8 to 3 ± 1, P < 0.0001). Improvement in measures of pulmonary vascular resistance (ratio of time to peak velocity to right ventricular ejection time) was greater in AGA infants (FGR, 0.19 ± 0.03 to 0.2 ± 0.03, P = 0.13 vs. AGA 0.2 ± 0.03 to 0.25 ± 0.03, P < 0.0001). The improvement in right ventricular output was significantly greater in AGA infants (171 ± 20 to 190 ± 21, P = 0.014 vs. 174 ± 17 to 203 ± 22, P < 0.0001). This highlights differential cardiorespiratory responsiveness to dexamethasone in extremely preterm FGR infants, which may reflect the in utero maladaptive state.NEW & NOTEWORTHY Dexamethasone (DEX) is frequently used in preterm infants dependent on ventilator support. Differences in vascular structure and function that may have developed prenatally arising from the chronic intrauterine hypoxemia in FGR infants may adversely affect responsiveness. The clinical efficacy of DEX was significantly less in FGR (birth weight < 10th centile) infants, compared with appropriate for gestational age (AGA) infants. Echocardiography showed significantly less improvement in pulmonary vascular resistance in FGR, compared with AGA infants.

Long-term neurological outcomes of offspring misdiagnosed with fetal growth restriction.

Fetal growth restriction (FGR) is a major determinant of adverse short- and long-term perinatal outcomes. The current definition of FGR (estimated fetal weight measurement < 10th percentile) may lead, at times, to a false diagnosis of fetuses that are eventually born appropriate for gestational age (AGA). Our objective was to investigate the potential association between a misdiagnosis of antepartum fetal growth restriction and long-term neurological outcomes in offspring. A population-based cohort analysis was performed including deliveries between the years 1991-2020 in a tertiary medical center. We compared neurological hospitalization during childhood among AGA infants falsely diagnosed as FGR versus AGA infants without a false FGR diagnosis. A Kaplan-Meier survival curve was used to assess cumulative morbidity and a Cox proportional hazards model was employed to control for confounders. During the study period, 324,620 AGA infants met the inclusion criteria; 3249 of them were falsely classified as FGR. These offspring had higher rates of hospitalizations due to various neurological conditions, as compared to those without an FGR diagnosis (OR 1.431, 95% CI 1.278-1.608; P < 0.001). In addition, cumulative hospitalization incidence was elevated in the FGR group (log-rank P-value < 0.001). When controlling for confounders, a false FGR diagnosis remained independently associated with long-term neurological morbidities (adjusted HR 1.086, 95% CI 1.003-1.177, P = 0.043). Misdiagnosis of FGR in the antepartum period is associated with an increased risk for offspring long-term neurological morbidities.

Impact of early-onset fetal growth restriction on the neurodevelopmental outcome of very preterm infants at 24 months: a retrospective cohort study

BackgroundThe association between fetal growth restriction (FGR) and childhood neurodevelopmental delay is unclear and the evidence available to the present date shows conflicting results. Our aim was to analyse the impact of early-onset FGR on the neurodevelopmental outcome at 24 months of corrected age in very preterm infants.MethodsRetrospective cohort study of very preterm infants (≤ 32 weeks’ gestation) admitted to a neonatal intensive care unit between 1 January 2013–31 December 2019. The control group comprised appropriate for gestational age (AGA) newborns. Griffiths III Mental Development Scale was performed at 24 months of corrected age.Results132 infants were included: 44 FGR and 88 AGA. Mean Global Development Quotient (GDQ) was lower for FGR infants (p = 0.004) even after adjusting for maternal and perinatal factors (βadjusted -16.703; p = 0.009). The average scores for the neurodevelopmental domains were highest for personal-social-emotional skills (107.02 ± 16.34), followed by eye/hand coordination (105.61 ± 14.20) and foundation of learning skills (102.23 ± 13.74) and were lowest for gross motor (97.90 ± 11.88) and language/communication skills (96.39 ± 18.88). FGR had a significant negative impact on all domains except for gross motor skills. After adjustment, FGR continued to have a significant adverse impact on language/communication (βadjusted -21.924; p = 0.013), eye/hand coordination (βadjusted -15.446; p = 0.015) and foundation of learning skills (βadjusted -15.211; p = 0.013).ConclusionsIn very preterm infants, FGR was associated with a significantly increased risk of poor neurodevelopmental outcome at 24 months of corrected age compared to age-matched AGA infants.

Growth Pattern of Preterm Neonates with Fetal Growth Restriction: A Prospective Cohort Study.

To compare the growth of preterm neonates with fetal growth restriction (FGR) and preterm neonates born appropriate-for-gestational-age (AGA) from birth to 12-18 mo of corrected age (CA). In this prospective cohort study, 85 preterm neonates with FGR and 85 gestation- and gender-matched AGA neonates were followed up from birth till 12-18 mo corrected age. Anthropometric indices were compared at specific time points and the risk factors for underweight status were analyzed. Mean gestational age of the cohort was 32.8 ± 2.1 wk. Mean birth weight was 1414 ± 248g in the FGR and 1806 ± 416g in AGA neonates. At 12-18 mo of corrected age, a significantly greater proportion of FGR infants were wasted (24.3% vs. 7.2%, P = 0.005). A greater proportion of FGR infants were underweight (27% vs. 17.4%, P = 0.11), stunted (41.9% vs. 36.2%, P = 0.30), and microcephalic (27% vs. 23.1%, P = 0.36), although the differences were not statistically significant. Significant catch-up growth from 40 wk postmenstrual age (PMA) to 12-18 mo corrected age in weight (52.8% vs. 13.1%, P <0.001) and length (37.9% vs. 8.7%, P <0.001) was observed in the FGR neonates. The z-score of weight for age at 3 mo (adjusted OR 0.65, 95% CI: 0.52-0.8; P <0.001), the median time to full feeds (aOR: 1.10, 95% CI: 1.04-1.15; P = 0.001), and hypothyroidism (aOR 2.44, 95% CI: 1.46-4.08; P = 0.001), were independent predictors of underweight status at 12-18 mo. At 12-18 mo of corrected age, a significantly greater proportion of preterm FGR neonates were wasted compared to AGA ones. The former also exhibited significantly greater catch-up growth than the latter.

The left ventricle in well newborns versus those with perinatal asphyxia, haemodynamically significant ductus arteriosus or fetal growth restriction.

Hemodynamic changes accompanying the initial breaths at the time of birth are especially important for a smooth transition of fetal to neonatal circulation. Understanding the normal transitional physiology and the clinical impact of adverse adaptation is important for delineating pathology so as to guide physiologically relevant therapies. Disorders such as severe perinatal asphyxia, hemodynamically significant patent ductus arteriosus (and its surgical ligation) and utero-placental insufficiency underlying fetal growth restriction, can adversely affect left ventricular (LV) function. The left ventricle is the predominant chamber involved in systemic perfusion during postnatal life. Cardiac output is closely linked to afterload; the latter is determined by arterial properties such as stiffness and compliance. This article outlines normal transition in term and preterm infants. It also highlights the adverse impact of three not uncommon neonatal disorders on LV function. Perinatal asphyxia leads to a reduced LV output, superior vena cava and coronary artery blood flow and an increase in the troponin level. Multiple haemodynamic changes are observed in the premature infant with a large patent ductus arteriosus. They need careful analysis to determine when ligation should proceed. Ligation itself generally results in a dramatic increase in afterload which may lead to a reduction in LV contractility and the need for ionotropic support. Fetal growth restricted infants have a higher systolic pressure, a somewhat hypertrophied heart arising from an increased arterial wall thickness/stiffness and systemic peripheral resistance. Point of care ultrasound (POCUS) helps differentiate normal transition and that resulting from neonatal disorders. It may be increasingly utilized in guiding management.

Measuring gut perfusion and blood flow in neonates using ultrasound Doppler of the superior mesenteric artery: a narrative review.

The gut is a relatively silent organ in utero but takes on a major role after birth for the absorption and digestion of feed for adequate nutrition and growth. The neonatal circulation undergoes a transition period after birth, and gut perfusion increases rapidly to satisfy the oxygen demand and consumption. If this process is compromised at any stage, preterm and fetal growth restricted infants are at particular risk of gut tissue injury secondary to hypoxia, leading to necrotizing enterocolitis. Feeding can also be a challenge in these high-risk groups due to gut dysmotility. Superior mesenteric artery (SMA) Doppler is a safe, bedside investigation that could rapidly aid clinicians with feeding strategies and in monitoring high-risk infants. This article aims to establish normal patterns of gut blood flow velocity in neonates using SMA Doppler and reviews how it might be used clinically in pathologic states.

Classification and Special Nutritional Needs of SGA Infants and Neonates of Multiple Pregnancies.

Data regarding the nutritional management of preterm small for gestational age (SGA) infants are scarce. In the recent report of ESPGHAN, the recommended energy for very preterm infants during hospitalization has been increased, yet this may not fit the needs of all preterm infants. It is important to distinguish fetal growth-restricted (FGR) infants from constitutional SGA infants, as well as preterm SGA from preterm AGA infants, since they may have different nutritional needs. Preterm FGR infants, and specifically infants < 29 weeks' gestation, accumulate nutrient deficits due to intrauterine malnutrition, prematurity, morbidities, delayed initiation of feeding, and feeding intolerance. Therefore, these infants may need more aggressive nutrition for optimal catch-up growth and neurologic development. However, a balance should be kept between optimal and excessive catch-up growth, since the combination of intrauterine malnutrition and excessive postnatal growth has been linked with later adverse metabolic consequences. Furthermore, multiple gestation is often complicated by FGR and prematurity. There is controversy in the definition of FGR in multiple gestations, and it should be noted that FGR in multiple gestation usually differs etiologically from FGR in singletons. The aim of this review is to summarize existing knowledge regarding the nutritional needs of preterm FGR and FGR infants of multiple gestation.

Intracranial ultrasound abnormalities and mortality in preterm infants with and without fetal growth restriction stratified by fetal Doppler study results.

To evaluate whether fetal growth restriction (FGR) with or without abnormal Dopplers is associated with intracranial abnormalities and death in premature infants. Premature infants with and without FGR born between 2016 and 2019 were included. Primary outcome was death, severe intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL). Groups were compared using standard bivariate testing and multivariable regression. Among 168 FGR and 560 non-FGR infants, FGR infants with abnormal Dopplers had an increased incidence of death, severe IVH or PVL compared to non-FGR infants (13% (16/123) vs. 7% (41/560); p = 0.03) while FGR infants with normal Dopplers had a nonsignificant decrease. In a logistic regression model, FGR with abnormal Dopplers was associated with more than three times higher odds of death, severe IVH or PVL (OR 3.2, 95% CI 1.54,6.49; p < 0.001). Growth-restricted infants with abnormal Dopplers had an increased risk of death, intracranial abnormalities, and prematurity-related morbidities.

Cranial Ultrasound Abnormalities in Small for Gestational Age or Growth-Restricted Infants Born over 32 Weeks Gestation: A Systematic Review and Meta-Analysis.

To perform a systematic review and meta-analysis of existing literature to evaluate the incidence of cranial ultrasound abnormalities (CUAs) amongst moderate to late preterm (MLPT) and term infants, affected by fetal growth restriction (FGR) or those classified as small for gestational age (SGA). A systematic review methodology was performed, and Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement was utilised. Descriptive and observational studies reporting cranial ultrasound outcomes on FGR/SGA MLPT and term infants were included. Primary outcomes reported was incidence of CUAs in MLPT and term infants affected by FGR or SGA, with secondary outcomes including brain structure development and growth, and cerebral artery Dopplers. A random-effects model meta-analysis was performed. Risk of Bias was assessed using the Newcastle-Ottawa scale for case-control and cohort studies, and Joanna Briggs Institute Critical Appraisal Checklist for studies reporting prevalence data. GRADE was used to assess for certainty of evidence. Out of a total of 2085 studies identified through the search, seventeen were deemed to be relevant and included. Nine studies assessed CUAs in MLPT FGR/SGA infants, seven studies assessed CUAs in late preterm and term FGR/SGA infants, and one study assessed CUAs in both MLPT and term FGR/SGA infants. The incidence of CUAs in MLPT, and late preterm to term FGR/SGA infants ranged from 0.4 to 33% and 0 to 70%, respectively. A meta-analysis of 7 studies involving 168,136 infants showed an increased risk of any CUA in FGR infants compared to appropriate for gestational age (AGA) infants (RR 1.96, [95% CI 1.26-3.04], I2 = 68%). The certainty of evidence was very low due to non-randomised studies, methodological limitations, and heterogeneity. Another meta-analysis looking at 4 studies with 167,060 infants showed an increased risk of intraventricular haemorrhage in FGR/SGA infants compared to AGA infants (RR 2.40, [95% CI 2.03-2.84], I2 = 0%). This was also of low certainty. The incidence of CUAs in MLPT and term growth-restricted infants varied widely between studies. Findings from the meta-analyses suggest the risk of CUAs and IVH may indeed be increased in these FGR/SGA infants when compared with infants not affected by FGR, however the evidence is of low to very low certainty. Further specific cohort studies are needed to fully evaluate the benefits and prognostic value of cranial ultrasonography to ascertain the need for, and timing of a cranial ultrasound screening protocol in this infant population, along with follow-up studies to ascertain the significance of CUAs identified.

Myocardial perfusion and function dichotomy in growth restricted preterm infants.

Compared to preterm appropriate for gestational age (AGA) fetuses, fetuses with fetal growth restriction (FGR) have earlier visualisation of coronary artery blood flow (CABF) but impaired cardiac function. This dichotomy remains uncharacterised during postnatal life. This study compared CABF and cardiac function in preterm FGR infants, against AGA infants during the postnatal period. FGR was defined as birthweight < 10th centile for gestation and sex with absent/reversed antenatal umbilical artery Doppler. Diastolic CABF was measured in the left anterior descending coronary artery. Twenty-eight FGR infants were compared with 26 AGA infants (gestation and birthweight, 29.7 ± 1.3 vs 29.9 ± 1 weeks, P = 0.6 and 918 ± 174 vs 1398 ± 263g, P < 0.001, respectively). Echocardiography was performed in the second week of life. FGR infants had higher CABF (velocity time integral, 2.4 ± 0.9 vs 1.6 ± 0.8 cm, P = 0.002). Diastolic function was impaired (↑ trans-mitral E/A ratio in FGR infants; 0.84 ± 0.05 vs 0.79 ± 0.03, P = 0.0002) while the systolic function was also affected (mean velocity of circumferential fibre shortening [mVCFc], 1.9 ± 0.3 vs 2.7 ± 0.5 circ/s, P < 0.001). Indexing CABF to cardiac function noted significant differences between the groups (CABF: E/A [FGR vs AGA], 2.9 ± 1.1 vs 2.1 ± 1, P = 0.01 and CABF: mVCFc [FGR vs AGA], 1.3 ± 0.5 vs 0.6 ± 0.3, P < 0.001). Diastolic blood pressure (BP) was significantly higher, and CABF to diastolic BP ratio trended higher in FGR infants (30 ± 2 vs 25 ± 3 mmHg, P < 0.001 and 0.08 ± 0.03 vs 0.06 ± 0.03, P = 0.059, respectively). Greater CABF in FGR infants did not translate into better cardiac function. This dichotomy may be a persistent response to fetal hypoxaemia (fetal programming) and/or reflection of altered cardiac architecture.

Blood-Brain Barrier Disintegration in Growth-Restricted Fetuses with Brain Sparing Effect.

The endothelial cells of the blood-brain barrier adhere closely, which is provided by tight junctions (TJs). The aim of the study was to assess the damage to the endothelial TJs in pregnancy, complicated by fetal growth restriction (FGR) and circulatory centralization (brain-sparing effect, BS). The serum concentrations of NR1 subunit of the N-methyl-D-aspartate receptor (NR1), nucleoside diphosphate kinase A (NME1), S100 calcium-binding protein B (S100B), occludin (OCLN), claudin-5 (CLN5), and zonula occludens protein – 1 (zo-1), and the placental expressions of OCLN, claudin-4 (CLN4), CLN5, and zo-1 were assessed with ELISA. The significantly higher serum NME1 concentrations and the serum CLN5/zo-1 index were observed in FGR pregnancy with BS, as compared to the FGR group without BS. The FGR newborns with BS were about 20 times more likely to develop an intraventricular hemorrhage (IVH) than the FGR infants without BS. The cerebroplacental ratio (CPR) allowed to predict the IVH in growth-restricted fetuses. The significantly lower placental CLN4 expression was observed in the FGR group with BS and who postnatally developed an IVH, as compared to the growth-restricted infants with BS without IVH signs. Pregnancy complicated by FGR and BS is associated with the destabilization of the fetal blood-brain barrier. The IVH in newborns is reflected in the inhibition of the placental CLN4 expression, which may be a useful marker in the prediction of an IVH among growth-restricted fetuses.

Prediction of late-onset fetal growth restriction by umbilical artery velocities at 37 weeks of gestation: a cross-sectional study

ObjectiveTo explore the predictive capacity of umbilical artery (UA) velocities at 37 weeks of gestation in identifying fetal growth restriction (FGR).DesignCross-sectional study.Setting and participantsWe retrospectively recruited 569 fetuses in the...

Deficient neural encoding of speech sounds in term neonates born after fetal growth restriction.

Infants born after fetal growth restriction (FGR)-an obstetric condition defined as the failure to achieve the genetic growth potential-are prone to neurodevelopmental delays, with language being one of the major affected areas. Yet, while verbal comprehension and expressive language impairments have been observed in FGR infants, children and even adults, specific related impairments at birth, such as in the ability to encode the sounds of speech, necessary for language acquisition, remain to be disclosed. Here, we used the frequency-following response (FFR), a brain potential correlate of the neural phase locking to complex auditory stimuli, to explore the encoding of speech sounds in FGR neonates. Fifty-three neonates born with FGR and 48 controls born with weight adequate-for-gestational age (AGA) were recruited. The FFR was recorded to the consonant-vowel stimulus (/da/) during sleep and quantified as the spectral amplitude to the fundamental frequency of the syllable and its signal-to-noise ratio (SNR). The outcome was available in 45 AGA and 51 FGR neonates, yielding no differences for spectral amplitudes. However, SNR was strongly attenuated in the FGR group compared to the AGA group at the vowel region of the stimulus. These findings suggest that FGR population present a deficit in the neural pitch tracking of speech sounds already present at birth. Our results pave the way for future research on the potential clinical use of the FFR in this population, so that if confirmed, a disrupted FFR recorded at birth may help deriving FGR neonates at risk for postnatal follow-ups.

Increased incidence of chronic lung disease and respiratory sequelae in growth restricted versus appropriately grown preterms

Background: Fetal growth restriction (FGR) affects 5–10% term gestational age pregnancies. When accompanied by prematurity, FGR infants have significantly greater risk of perinatal morbidity and/or mortality compared to non-growth restricted preterm infants. Aim: Current study aimed to ascertain the incidence FGR among premature infants and its association with respiratory morbidity. Methods: Institution database for preterm infants of 23–31+6 weeks of gestation was accessed. FGR infants were compared with gestation/sex matched appropriately grown infants. Results: During the period 2016–2018, 973 infants between 23 and 31+6 weeks gestation were admitted amongst whom, 206 (27%) were FGR. Between 28 and 31+6 weeks gestation, approximately 1/3rd were FGR. Gestation and birth weight of the FGR and appropriately grown cohorts were 30.2±0.2 versus 30.1±0.2 weeks (p=0.8) and 1132±43 versus 1499±54 g (p&lt;0.0001), respectively. While antenatal steroids, surfactant, mechanical ventilation, sepsis, and ductal therapy were comparable, respiratory outcomes were significantly worse in the FGR cohort (duration of respiratory support: 37±10 vs. 23±5 days [p=0.016], home oxygen: 24 [11.6%] vs. 8 [3.8%]; [p=0.005] and chronic lung disease [CLD]: 53 [25.7%] vs. 28 [13.6%], [p=0.002], respectively). The odds ratio (95% confidence intervals) for developing CLD and for home oxygen when born FGR were 2.2 (1.3–3.6) and 3.2 (1.4–7.4), respectively. Conclusions: In spite of comparable postnatal variables, FGR infants had significantly greater respiratory morbidity.

Fetal growth restriction: underdiagnosed condition with non-optimal screening

Background Fetal Growth restriction (FGR) is the pathological failure of a fetus to reach its biologically determined growth potential. Detection of FGR fetuses is a universally agreed key objective of antenatal care. Antenatal detection of FGR has undeniable benefits, juggling between intensive fetal surveillance and optimized timing of delivery; it reduces adverse perinatal outcomes by up to four-fold. However, FGR is still widely underdiagnosed. We aimed to identify the prevalence of FGR diagnosis in our wards and study the impact of the 2013 published French guidelines on the detection rate of FGR. The secondary objective aimed to highlight the factors of suboptimal screening in the population of non-diagnosed FGR fetuses and emphasize the screening method that led to antenatal diagnosis of FGR. Materials and methods We conducted a retrospective study at a single tertiary maternity center in Lyon-France, the Femme Mère Enfant Hospital, including the exhaustive population of FGR born after 24 + 0 weeks of gestation from 1 January 2011 to 31 December 2017. FGR was defined combining the neonatal and antenatal consensus-based definitions for early and late FGR in absence of congenital anomalies, excluding small for gestational age fetuses. For all FGR fetuses, we compared the antenatal detection rate of FGR during 2011–2013 to 2015–2017, since the French guidelines were published in December 2013. When FGR fetuses underwent an antenatal diagnosis of FGR, we retrospectively collected the characteristics that led to the diagnosis. When fetuses were not diagnosed as FGR, we retrospectively reviewed the implementation of the recommended screening method, enabling to evaluate whether screening was optimal or not. Statistical analysis was performed in July 2018, and statistical significance was regarded as a p-value <.05. Results Over the seven-year period, and among 31,052 newborns, 1020 (3.3%) infants were identified as FGR and met the inclusion criteria. The detection rate of FGR was similar before and after publication of the French Guidelines related to FGR in 2013. Indeed, 50.8% (201/395) FGR were diagnosed between 2011 and 2013 versus 52.6% (245/465) between 2015 and 2017 (p = .59). In the population of non-diagnosed FGR infants, screening was suboptimal in 80%. Symphysis-fundal height (SFH) was not measured in 10.7%, with no difference before and after 2014 (7.3 versus 11.8% p = .11). Ultrasound examination for fetal biometry had not been prescribed in spite of abnormal SFH in 47.7% of undiagnosed FGR infants. Diagnosis has been missed in 11.5% of infants because of misinterpretation of the estimated fetal weight’s centile. Conclusion FGR is widely underdiagnosed. However, the limited performances can partially be explained by the regular misuse of screening method in clinical practice. Despite the systematic third trimester ultrasound screening, the detection rate of FGR was similar to the one reported in the medical literature. The timing of routine third trimester ultrasound in low-risk women may be rethought.

Infant outcome after active management of early-onset fetal growth restriction with absent or reversed umbilical artery blood flow.

ABSTRACTObjectiveTo describe the short‐ and long‐term outcomes of infants with early‐onset fetal growth restriction (FGR) and umbilical artery absent or reversed end‐diastolic flow (AREDF), delivered before 30 weeks' gestation and managed proactively.MethodsThis was a retrospective cohort study of fetuses delivered for fetal indication before 30 completed weeks' gestation that had early‐onset FGR (defined as estimated fetal weight more than 2 SD below the mean) with AREDF in the umbilical artery (FGR group), at the level‐3 perinatal unit in Lund, Sweden, between 1998 and 2015. Perinatal outcome and neurodevelopment at ≥ 2 years of age in surviving infants were compared with those of a group of infants without small‐for‐gestational‐age birth weight or any known fetal Doppler changes delivered before 30 weeks in Lund during the corresponding time period (non‐FGR group). In the FGR group, the main indication for delivery was the Doppler finding of AREDF in the umbilical artery.ResultsThere were 139 fetuses (of which 26% were a twin/triplet) in the FGR group and 946 fetuses (of which 28% were a twin/triplet) in the non‐FGR group. The FGR infants had a median birth weight of 630 g (range, 340–1165 g) and gestational age at birth of 187 days (range, 164–209 days), as compared with 950 g (range, 470–2194 g) and 185 days (range, 154–209 days), respectively, in the non‐FGR group. The rate of fetal mortality did not differ between the two groups (5.0% and 5.4% in the FGR and non‐FGR groups, respectively). All seven intrauterine deaths in the FGR group occurred before 26 weeks' gestation. In the FGR group compared with the non‐FGR group, severe intraventricular hemorrhage was less frequent and bronchopulmonary dysplasia and septicemia were more frequent (P = 0.008, P < 0.001 and P = 0.017, respectively). In the FGR group, the survival rate at 2 years (83% of liveborn infants) and the rate of cerebral palsy (7%) did not differ significantly from those in the non‐FGR group (82% and 8%, respectively). The rate of survival without neurodevelopmental impairment was higher in the non‐FGR group (83%) than in the FGR group (62%) (P < 0.001), as well as in infants in the FGR group delivered at or after 26 weeks (72%) compared with those delivered before 26 weeks (40%) (P = 0.003). Within the FGR group, outcomes were similar between twins and singletons and, in those who survived beyond 2 years, outcomes were similar between fetuses with absent and those with reversed end‐diastolic flow in the umbilical artery.ConclusionsInfants delivered very preterm after severe FGR with AREDF in the umbilical artery had a similar rate of survival as did non‐FGR infants of corresponding gestational age; however, they were at higher risk of neurodevelopmental impairment, the risk being most pronounced following birth before 26 weeks. Gestational age remains an important factor associated with the prognosis of early‐onset FGR; nevertheless, the present results support the hypothesis, which should be tested prospectively, that fetuses with early‐onset FGR and umbilical artery AREDF may benefit from early intervention rather than expectant management, and that umbilical artery Doppler findings could be incorporated into clinical protocols for cases very early in gestation. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Subtle impairment of neurodevelopment in infants with late fetal growth restriction

Introduction Children with late fetal growth restriction (FGR) are at high risk of being born small for gestational age (SGA). These categories of newborns are at increased risk for neurodevelopment impairment. The general movements assessment, in particular at fidgety age, has been used to predict neurological dysfunctions. This study aimed to evaluate growth recovery, presence of fidgety movements at 3 months, and neurodevelopmental outcome at 2 years of age in term late FGR infants and adequate for gestational age (AGA) controls. Methods Prospective clinical evaluation. At 3 months auxological parameters (AP) and neurological examination were evaluated while at 24 months neurodevelopment outcome by Griffiths Mental Development Scales (GMDS-R) was evaluated. Results 38 late FGR and 20 AGA controls completed the study. Despite a significant catch up, at 3 months 13% of late FGR presented at least one auxological parameter <3° percentile. Moreover, 23.7% of late FGR infants did not show fidgety movements compared to 100% AGA controls (p < .001). Cranial circumference at birth resulted a positive predictive factor for FMs (p = .039). At 2 years of age, a difference statistically significant between late FGR and AGA was detected in GMDS-R. Conclusion Independently from growth recovery, fidgety movements resulted less expressed in late FGR infants, and at 2 years of age the neurodevelopmental assessment revealed differences in each domain of evaluation between late FGR and AGA infants, although within normal ranges.

Assessing pulmonary circulation in severe bronchopulmonary dysplasia using functional echocardiography

Pulmonary hypertension (PH) is common in infants with severe bronchopulmonary dysplasia (BPD) and increases the risk of death. The objectives of this preliminary study were to compare responses of pulmonary circulation parameters to 100% oxygen (O2) and inhaled nitric oxide (iNO) in infants with BPD and PH using echocardiography. Responses between fetal growth restriction (FGR) and appropriate for gestational age infants were compared. Ten infants <28 weeks GA at birth were assessed at ≥36 weeks corrected gestation. Baseline echocardiography1 was performed which was repeated (echocardiography2) after 30 minutes of O2. After a gap of 2–3 hours, iNO was administered for 15 minutes and echocardiography3 was performed, followed by iNO weaning. The gestation and birthweight of the cohort were 25.9 ± 1.6 weeks and 612 ± 175 g. Assessments were performed at 38.7 ± 1.4 weeks corrected gestational age. Baseline time to peak velocity: right ventricular ejection time (TPV/RVETc) increased from 0.24 ± 0.02 to 0.27 ± 0.02 (O2, p = .01) and 0.31 ± 0.03 (iNO, p < .001), indicating a decrease in pulmonary vascular resistance [PVR]. Baseline tricuspid annular plane systolic excursion (TAPSE) increased from 8.1 ± 0.6 mm to 9.3 ± 0.7 mm (O2, p = .01) and 10.5 ± 1.1 mm (iNO, p = .0004), indicating improved ventricular systolic performance. Percentage change for all parameters was greater with iNO. Significant correlations between cardiac performance and PVR were noted. FGR infants noted higher baseline PVR (TPV/RVETc, 0.21 ± 0.02 vs. 0.25 ± 0.01, p = .002), lower ventricular performance (TAPSE, 7 ± 1.2 mm vs. 8.6 ± 6 mm, p = .003), and lower percentage change with O2 and iNO. A reactive component of pulmonary circulation provides real‐time physiological information, which could rationalize treatment decisions.

Neurodevelopmental Outcome of Preterm Newborns with Abnormal Umbilical Artery Doppler - A Prospective Cohort Study.

To assess the neurodevelopmental outcome of preterm neonates with absent/reversed end diastolic flow (A/REDF) in umbilical artery Doppler at 1year of corrected age. A cohort of 70 preterm newborns with fetal growth restriction (FGR), defined as estimated fetal weight (EFW) <10th centile, confirmed by birthweight <10th centile, along with A/REDF in the umbilical artery Doppler was followed up till 1year of corrected age (CA). An equal number of gestation and gender matched preterm newborns with birthweight >10th centile [appropriate for gestational age (AGA)] and normal antenatal ultrasound were taken as controls. Primary outcome was a composite of death or major neurodevelopmental disability (NDD) at 1year of corrected age. Matched analysis was performed. A total of 140 newborns were enrolled, of which, 20 expired and 8 were lost to follow-up. The primary outcome (death/major NDD) occurred in 26.8% of the FGR (A/REDF) newborns as compared to 9.3% of their AGA counterparts (RR-2.83, p = 0.02, 95% CI:1.11-7.18). Mean motor quotient in Development Assessment Scale for Indian Infants (DASII) at 1year of corrected age was significantly lower in FGR (A/REDF) infants (91 ± 13.6 vs. 96.3 ± 7.1, p < 0.05). Multiple other co-morbidities were also significantly more among these newborns. Preterm newborns with FGR and A/REDF are at significantly increased risk of death/major NDD at 1year of corrected age.

Human placental uptake of glutamine and glutamate is reduced in fetal growth restriction

Fetal growth restriction (FGR) is a significant risk factor for stillbirth, neonatal complications and adulthood morbidity. Compared with those of appropriate weight for gestational age (AGA), FGR babies have smaller placentas with reduced activity of amino acid transporter systems A and L, thought to contribute to poor fetal growth. The amino acids glutamine and glutamate are essential for normal placental function and fetal development; whether transport of these is altered in FGR is unknown. We hypothesised that FGR is associated with reduced placental glutamine and glutamate transporter activity and expression, and propose the mammalian target of rapamycin (mTOR) signaling pathway as a candidate mechanism. FGR infants [individualised birth weight ratio (IBR) < 5th centile] had lighter placentas, reduced initial rate uptake of 14C-glutamine and 14C-glutamate (per mg placental protein) but higher expression of key transporter proteins (glutamine: LAT1, LAT2, SNAT5, glutamate: EAAT1) versus AGA [IBR 20th–80th]. In further experiments, in vitro exposure to rapamycin inhibited placental glutamine and glutamate uptake (24 h, uncomplicated pregnancies) indicating a role of mTOR in regulating placental transport of these amino acids. These data support our hypothesis and suggest that abnormal glutamine and glutamate transporter activity is part of the spectrum of placental dysfunction in FGR.