Gut microbial network signatures of early colonizers in preterm neonates with extrauterine growth restriction.

BACKGROUND: Extrauterine growth restriction (EUGR) represents a prevalent condition observed in preterm neonates, which poses potential adverse implications for both neonatal development and long-term health outcomes. The manifestation of EUGR has been intricately associated with perturbations in microbial and metabolic profiles. This study aimed to investigate the characteristics of the gut microbial network in early colonizers among preterm neonates with EUGR. METHODS: Twenty-nine preterm infants participated in this study, comprising 14 subjects in the EUGR group and 15 in the normal growth (AGA) group. Meconium (D1) and fecal samples were collected at postnatal day 28 (D28) and 1 month after discharge (M1). Subsequently, total bacterial DNA was extracted and sequenced using the Illumina MiSeq system, targeting the V3-V4 hyper-variable regions of the 16S rRNA gene. RESULTS: The outcomes of principal coordinates analysis (PCoA) and examination of the microbial network structure revealed distinctive developmental trajectories in the gut microbiome during the initial three months of life among preterm neonates with and without EUGR. Significant differences in microbial community were observed at the D1 (P = 0.039) and M1 phases (P = 0.036) between the EUGR and AGA groups, while a comparable microbial community was noted at the D28 phase (P = 0.414). Moreover, relative to the AGA group, the EUGR group exhibited significantly lower relative abundances of bacteria associated with secretion of short-chain fatty acids, including Lactobacillus (P = 0.041) and Parabacteroides (P = 0.033) at the D1 phase, Bifidobacterium at the D28 phase, and genera Dysgonomonas (P = 0.042), Dialister (P = 0.02), Dorea (P = 0.042), and Fusobacterium (P = 0.017) at the M1 phase. CONCLUSION: Overall, the present findings offer crucial important insights into the distinctive gut microbial signatures exhibited by earlier colonizers in preterm neonates with EUGR. Further mechanistic studies are needed to establish whether these differences are the cause or a consequence of EUGR.

Music therapy and weight gain in preterm infants: Secondary analysis of the randomized controlled LongSTEP trial.

OBJECTIVES: This study assessed the association between MT and weight gain among preterm infants hospitalized in Neonatal Intensive Care Units. METHODS: Data collected during the international, randomized, Longitudinal Study of Music Therapy's Effectiveness for Premature Infants and their Caregivers (LongSTEP) study were compared between the MT group and the standard care (SC) group. Weights were recorded at birth, enrollment, and discharge. Weight percentiles, Z-scores, weight gain velocity, and extrauterine growth restriction (EUGR) were calculated. RESULTS: Among 201 preterm infants included, no significant differences in weight parameters (weight, weight percentiles, weight Z-scores; all p ≥ 0.23) were found between the MT group (n = 104) and the SC (n = 97) group at birth, enrollment, or discharge. No statistical differences in EUGR represented by change in Z-scores from birth to discharge were recorded between MT and SC (0.8 vs. 0.7). Among perinatal parameters, younger gestational age (p = 0.005) and male sex (p = 0.012) were associated with increased risk of EUGR at discharge. Antenatal steroid treatment, systemic infection, bronchopulmonary dysplasia, neurological morbidities, retinopathy of prematurity, necrotizing enterocolitis, parental factors (amount of skin-to-skin care, bonding, anxiety, and depression questionnaire scores), and type of enteral nutrition did not significantly influence weight gain parameters (all p > 0.05). CONCLUSIONS: In the LongSTEP study, MT for preterm infants and families was not associated with better weight parameters compared to the SC group. The degree of prematurity remains the main risk factor for unfavorable weight parameters.

Mortality and extrauterine growth restriction of necrotizing enterocolitis in very preterm infants with heart disease: a multi-center cohort study.

Congenital heart disease (CHD) and patent ductus arteriosus (PDA) are risk factors of necrotizing enterocolitis (NEC) in infants. However, it is unclear whether the prognosis of NEC is different between very preterm infants (VPIs) with and without heart diseases. This was an observational cohort study that enrolled VPIs (born between 24+0 and 31+6 weeks) admitted to 79 tertiary neonatal intensive care units (NICU) in the Chinese Neonatal Network (CHNN) between 2019 and 2021. The exposure was CHD or isolated PDA, and VPIs with NEC were divided into three groups: complicated with CHD, with isolated PDA, and without heart diseases. The primary outcomes were NEC-related adverse outcomes (death or extrauterine growth restriction (EUGR)). Logistic regression models were used to adjust potential confounders and calculate the odds ratios (ORs) and 95% confidential intervals (CIs) for each outcome. A total of 1335 VPIs with NEC were enrolled in this study, including 65 VPIs with CHD and 406 VPIs with isolated PDA. The VPIs with heart diseases had smaller gestational ages and lower body weights at birth, more antenatal steroids use, and requiring inotrope prior to the onset of NEC. While suffering from NEC, there was no significant increased risks in NEC-related death in VPIs with either CHD (adjusted OR [aOR]: 1.10; 95% CI: 0.41-2.50) or isolated PDA (aOR: 1.25; 95% CI 0.82-1.87), and increased risks in EUGR were identified in either survival VPIs with CHD (aOR: 2.35; 95% CI: 1.31-4.20) or isolated PDA (aOR: 1.53; 95% CI: 1.16-2.01) in survivors. The composite outcome (death or EUGR) was also more often observed in VPIs with either CHD (aOR: 2.07; 95% confidence interval [CI]: 1.20-3.60) or isolated PDA (aOR: 1.51; 95% CI: 1.17-1.94) than that without heart diseases. VPIs with either CHD or isolated PDA were associated with significantly prolonged duration of fasting, extended time to achieve full enteral feeding, and longer ventilation duration and hospitalization duration. Similar characteristics were also seen in VPIs with isolated PDA, with the exception that VPIs with CHD are more likely to undergo surgical intervention and maintain a prolonged fast after NEC.     Conclusion: In VPIs with NEC, CHD and isolated PDA are associated with an increased risk in worse outcomes. We recommend that VPIs with cardiac NEC be managed with aggressive treatment and nutrition strategies to prevent EUGR. What is Known: • CHD and PDA are risk factors for NEC in infants, which can lead to adverse outcomes such as death and EUGR. • NEC in infants with heart disease differs clinically from that in infants without heart disease and should be recognized as a separate disease process. What is New: • CHD and isolated PDA are associated with increased risks of EUGR in VPIs with NEC. • Risk factors associated with VPIs with cardiac NEC suggested these patients should be managed with aggressive treatment and nutrition strategies to adverse outcomes.

Extrauterine growth restriction in very-low-birthweight infants: prevalence and concordance according to Fenton, Olsen, and INTERGROWTH-21st growth charts in a multicenter Spanish cohort.

Multiple criteria and growth references have been proposed for extrauterine growth restriction (EUGR). We hypothesized that these may impact the diagnosis of EUGR. The objective was to evaluate the prevalence of EUGR with its different definitions and the concordance according to Fenton, Olsen, and INTERGROWTH-21st in very-low-birthweight (VLBW) infants. This is an observational, retrospective, and multicenter study including VLBW infants from the Spanish SEN1500 Network from 2011 to 2020. Patients with major congenital anomalies, embryopathies, and gestational age less than 24 weeks were excluded. EUGR prevalence was calculated at discharge with cross-sectional, longitudinal, "true" cross-sectional, and "true" longitudinal definitions. Concordance was assessed with Fleiss' kappa coefficient. 23582 VLBW infants from 77 NICUs were included. In total, 50.4% were men with a median of gestational age of 29 (4) weeks. The prevalence of EUGR (cross-sectional, longitudinal, and "true") was variable for weight, length, and head circumference. Overall, the prevalence was higher with Fenton and lower with Olsen (cross-sectional and "true" cross-sectional) and INTERGROWTH-21st (longitudinal and "true" longitudinal). Agreement among the charts by weight was good only for cross-sectional EUGR and moderate for longitudinal, "true" cross-sectional, and "true" longitudinal. Concordance was good or very good for EUGR by length and head circumference.Conclusions: The prevalence of EUGR with the most commonly used definitions was variable in the cohort. Agreement among growth charts was moderate for all the definitions of EUGR by weight except cross-sectional and good or very good for length and head circumference. The choice of reference chart can impact the establishment of the diagnosis of EUGR. What is known: • EUGR has been defined in the literature and daily practice considering weight, length and head circumference with multiple criteria (cross-sectional, longitudinal, and "true" definition) • Different growth charts have been used for EUGR diagnosis What is new: • Prevalence of EUGR is variable depending on the definition and growth chart used in our cohort of VLBW infants • For the most frequently EUGR criteria used, traditionally considering weight, concordance among Fenton, Olsen and INTERGROWTH-21st growth charts is only moderate for all the definitions of EUGR by weight except cross-sectional definition. Concordance among the charts is good or very good for the different criteria of EUGR by head circumference and length.

The role of nutrition in analysis of risk factors and short-term outcomes for late-onset necrotizing enterocolitis among very preterm infants: a nationwide, multicenter study in China.

BACKGROUND: Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease, primarily affects preterm newborns and occurs after 7 days of life (late-onset NEC, LO-NEC). Unfortunately, over the past several decades, not much progress has been made in its treatment or prevention. This study aimed to analyze the risk factors for LO-NEC, and the impact of LO-NEC on short-term outcomes in very preterm infants (VPIs) with a focus on nutrition and different onset times. METHOD: Clinical data of VPIs were retrospectively collected from 28 hospitals in seven different regions of China from September 2019 to December 2020. A total of 2509 enrolled VPIs were divided into 2 groups: the LO-NEC group and non-LO-NEC group. The LO-NEC group was divided into 2 subgroups based on the onset time: LO-NEC occurring between 8 ~ 14d group and LO-NEC occurring after 14d group. Clinical characteristics, nutritional status, and the short-term clinical outcomes were analyzed and compared among these groups. RESULTS: Compared with the non-LO-NEC group, the LO-NEC group had a higher proportion of anemia, blood transfusion, and invasive mechanical ventilation (IMV) treatments before NEC; the LO-NEC group infants had a longer fasting time, required longer duration to achieve the target total caloric intake (110 kcal/kg) and regain birthweight, and showed slower weight growth velocity; the cumulative dose of the medium-chain and long-chain triglyceride (MCT/LCT) emulsion intake in the first week after birth was higher and breastfeeding rate was lower. Additionally, similar results including a higher proportion of IMV, lower breastfeeding rate, more MCT/LCT emulsion intake, slower growth velocity were also found in the LO-NEC group occurring between 8 ~ 14d when compared to the LO-NEC group occurring after 14 d (all (P < 0.05). After adjustment for the confounding factors, high proportion of breastfeeding were identified as protective factors and long fasting time before NEC were identified as risk factors for LO-NEC; early feeding were identified as protective factors and low gestational age, grade III ~ IV neonatal respiratory distress syndrome (NRDS), high accumulation of the MCT/LCT emulsion in the first week were identified as risk factors for LO-NEC occurring between 8 ~ 14d. Logistic regression analysis showed that LO-NEC was a risk factor for late-onset sepsis, parenteral nutrition-associated cholestasis, metabolic bone disease of prematurity, and extrauterine growth retardation. CONCLUSION: Actively preventing premature birth, standardizing the treatment of grade III ~ IV NRDS, and optimizing enteral and parenteral nutrition strategies may help reduce the risk of LO-NEC, especially those occurring between 8 ~ 14d, which may further ameliorate the short-term clinical outcome of VPIs. TRIAL REGISTRATION: ChiCTR1900023418 (26/05/2019).

Extrauterine growth restriction and low energy intake during the early neonatal period of very low birth weight infants are associated with decreased lung function in childhood.

Premature birth, bronchopulmonary dysplasia or restrictive nutrition in the first weeks of postnatal life may have repercussions on lung development and affect long-term lung function outcomes. This prospective observational study is based on a cohort of 313 very low birth weight (VLBW) neonates, born between 1 January 2008 and 1 December 2016. The daily intake of calories, protein, fat and carbohydrates during the first week of life and evidence of inadequate weight gain (Δwt) until week 36 of gestational age (GA) were recorded. FEV1, FEF25-75 %, forced vital capacity (FVC) and the FEV1/FVC ratio were determined. The relations between these parameters were determined by regression analysis. Spirometric parameters were obtained for 141 children with a mean age of 9 years (95 % CI 7, 11); 69 of them (48·9 %) had presented wheezing episodes on more than three occasions. In addition, 60 (42·5 %) had a history of bronchopulmonary dysplasia. Of these, n 40 (66·6 %) had a history of wheezing. Significant association between protein/energy intake in the first week of life and the lung function parameters analysed was observed. Poor Δwt to GA week 36 was significantly associated with decreased mean pulmonary flow. Inadequate protein/energy intake in the first week of life of VLBW newborns and poor Δwt to week 36 of GA is associated with a significant worsening of lung function parameters.

Implementation of a Nutrition Care Bundle and Improved Weight Gain of Extremely Preterm Infants to 36 Weeks Postmenstrual Age.

OBJECTIVE: To evaluate the effect of a nutrition care bundle in improving growth in premature infants during neonatal hospitalization. STUDY DESIGN: This study was a retrospective analysis of prospectively collected data for 584 surviving infants with birth weight ≤1000 g and gestational age 24-29 weeks admitted to a single-center neonatal intensive care unit between July 3, 2005, and June 6, 2016. Participants were divided into 3 discrete epochs based on evolving nutrition practices during the study period: epoch 1, baseline, open-bay setting; epoch 2, improved lactation staffing, introduction of high-protein formula, single-family room setting; epoch 3, complete nutrition care bundle. Infants in each epoch were evaluated for the primary outcome of change in weight z-score between postnatal day 7 and 36 weeks postmenstrual age (PMA) or discharge if sooner. Univariate and multivariable regression analyses were conducted to evaluate the effect of clinical variables on outcome. RESULTS: Significant increases in weight z-score between day of life 7 and 36 weeks PMA were observed across the 3 epochs, which accounted for 31% (P < .0001) of the variance. Variables that were positive predictors of weight z-score change included birth weight z-score, cesarean delivery, and later epochs of nutritional support. Variables that were negative predictors of weight change included gestational age, postnatal steroids, and days on parenteral nutrition. CONCLUSIONS: Implementation of a nutrition care bundle was associated with improved weight gain in extremely low birth weight infants.

Risk factors of extrauterine growth restriction in very preterm infants with bronchopulmonary dysplasia: a multi-center study in China.

OBJECTIVE: Nutritional deficiency soon after birth is a risk factor of chronic lung disease (bronchopulmonary dysplasia, BPD). Afflicted infants are further prone to inadequate growth during hospitalization (extrauterine growth restriction, EUGR). This multi-center retrospective study investigated risk factors of EUGR, specifically in very preterm infants with BPD. METHOD: Data of infants with BPD who were born less than 32 weeks gestation (n = 1010) were collected from 7 regions of China. All infants were non-small for gestational age at birth. Infants were characterized as EUGR or non-EUGR at 36 weeks gestation or discharge, or stratified by gestational age or birthweight. Logistic regression analysis was applied. RESULTS: In 65.5% of the population, the BPD was mild. Infants with severe BPD (8.3%) had the highest rate of EUGR (72.6%, P < 0.001). Groups stratified by gestational age did not differ in rates of EUGR, but the birthweight of the EUGR group was significantly lower than that of the non-EUGR (P < 0.001). Birthweights of < 1000, 1000-1499, and ≥ 1500 g showed EUGR rates of 65.9%, 43.4%, and 23.8%, respectively (P < 0.001). Overall, the independent risk factors of EUGR were: moderate-to-severe BPD, gestational hypertension, cesarean section, cumulative fasting time, time required to achieve 110 kcal/kg/d, and hemodynamically significant patent ductus arteriosus (hsPDA). CONCLUSION: In very preterm infants with BPD, the lower the birthweight or the more severe the BPD, the greater the risk of EUGR. In those with hsPDA, or moderate-to-severe BPD, it is especially important to prevent EUGR through perinatal management, enteral nutrition, and nutritional strategies.

Assessment of early nutritional intake in preterm infants with bronchopulmonary dysplasia: a cohort study.

This cohort study evaluated the nutritional supply in 78 very preterm newborns, with 20.5% developing bronchopulmonary dysplasia (BPD). This work aimed to evaluate the nutritional intake and the calorie/protein ratio received in the first 4 weeks of life. Anthropometric measures at birth and term age, the weight at each of the first 4 weeks of life, and the feeding practices were registered. The mean gestational age and birth weight were lower in those who developed BPD. At term age, head circumference and length Z-scores were significantly lower in newborns with BPD, who started enteral feeding and reached full diet later, staying longer in parenteral nutrition. The protein rate received by all newborns was similar, whether developing BPD or not, but those who developed BPD received significantly lower fluid volume and calorie rates after the second week. The daily calorie/protein ratio (30 kcal/1-g protein) was reached by 88.7% of the newborns who did not develop BPD in the third week, with those who developed BPD receiving less than this ratio until the second week, persisting in 56.3% of them on the fourth week.Conclusion: A calorie/protein ratio below that recommended for growth was found in preterm newborns who developed BPD, and providing nutrition for these newborns remains a challenge. What is Known: • The importance of preterm newborn nutrition is well known. • Early nutritional support may avoid severe BPD. What is New: • Newborns who developed BPD received a calorie/protein ratio below that recommended for preterm newborns' growth during the first 2 weeks of life, lasting until the fourth week in most of these newborns.

Extrauterine growth restriction in extremely preterm infants based on the Intergrowth-21st Project Preterm Postnatal Follow-up Study growth charts and the Fenton growth charts.

Growth charts are essential for monitoring the postnatal growth of preterm infants. The preterm postnatal follow-up study (PPFS) of the Intergrowth-21st Project provides new growth standards based on a longitudinal study. This study was conducted to investigate the prevalence of extrautrine growth restriction (EUGR) and the associated factors of EUGR in preterm infants, using the PPFS charts and the Fenton charts. Data of 1,356 infants with gestational age (GA) less than 28 weeks from the Korean Neonatal Network were analysed. The prevalence of small for gestational age (SGA) of weight and length was higher with the Intergrowth charts than with the Fenton charts. EUGR in weight and length was more prevalent when using the Fenton charts. Multivariate analysis showed that low GA, high birthweight z score, male, treated patent ductus arteriosus (PDA), necrotizing enterocolitis, intraventricular haemorrhage and duration of parenteral nutrition (PN) were associated with EUGR in weight by the Intergrowth charts. High birthweight z score, treated PDA and PN duration were associated with EUGR defined by the Fenton charts.Conclusion: Compared to the Fenton charts, SGA was more defined and EUGR was less prevalent in extremely low gestational infants, while EUGR defined by the Intergrowth charts categorized infants with adverse clinical courses more elaborately. What is Known: • Preterm infants are at risk of postnatal growth restriction (PGR), although optimal postnatal growth is important for the long-term outcomes. • Growth charts are essential tools to monitor the postnatal growth of preterm infants. What is New: • PGR of weight and length were less defined with the Intergrowth charts than the Fenton charts. • PGR defined by the Intergrowth preterm postnatal follow-up study (PPFS) chart categorized preterm infants with morbidities more elaborately than the Fenton charts.

Somatic Growth of Enteral-Only Fed Extremely Low Birth Weight Infants in a Resource-Restricted Setting.

AIM: To determine the growth and prevalence of extrauterine growth restriction (EUGR) in extremely low birth weight (ELBW) infants receiving enteral-only nutrition in a resource-restricted (RR) environment. METHODS: Information on nutritional intake, provided largely from fortified breastmilk, was collected retrospectively for 72 ELBW (<1000 g) infants admitted to Tygerberg Hospital, Cape Town, South Africa over a 1 year period. Anthropometric data for the first 49 postnatal days were compared to gender-specific INTERGROWTH-21st standards. RESULTS: Full enteral feeds (150 ml/kg) were reached by Day 10-14 with energy >100 Kcal/kg/day from Day 10, and protein >3.5 mg/kg/day from Day 14, onwards. Growth velocity remained below 15 g/kg/day at Day 49. INTERGROWTH-21st Z-scores decreased from -0.8 ± 1.1 at birth to -2.4 ± 1.5 at Day 49. Adequate weight growth velocity (≥15 g/kg/day) was associated with maternal hypertension, completed antenatal steroids, caesarean section delivery and small for gestational age status. CONCLUSION: This is the first study to evaluate growth of ELBW infants in a RR setting where enteral-only nutrition, principally from fortified breastmilk, was the primary feeding option. The incidence of EUGR, although high, was similar to the incidence in well-resourced settings, where total parenteral nutrition is routinely provided. Lay summaryExtra-uterine growth restriction (EUGR) is high in extremely low birth weight infants receiving enteral-only nutrition. However, EUGR rates are similar to infants receiving parenteral nutrition. Despite developmental immaturity, it is possible for these infants to achieve fetal growth rates. More aggressive feeding and fortification strategies may be necessary and will need to be balanced against the risk and fear of necrotizing enterocolitis. Enteral-only feeding regimens, especially in resource-restricted environments, should be audited regularly to ensure provision of feeds with the most optimal protein, and protein to energy ratios possible.

Comorbidities in childhood associated with extrauterine growth restriction in preterm infants: a scoping review.

Extrauterine growth restriction (EUGR) is a frequent morbidity of preterm infants that can affect short- and long-term prognosis as it involves different EUGR-related alterations in growth and neurological development, as well as cardiometabolic risk. However, knowledge about the prognosis of EUGR is scarce. Thus, the objective of this study is to review the evidence regarding EUGR-related comorbidities in childhood by a systematic approach. This review was carried out using the Joanna Briggs Institute Reviewers' Manual Methodology and the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses)-Search Extension for scoping review. The MEDLINE and EMBASE databases were used to identify papers published until September 2017. Twenty-four publications were included and 19 examined cohort studies. EUGR is mainly associated with (1) lower weight, length, and head circumference measures in childhood; (2) poor neurodevelopment; and (3) alterations in cardiometabolic risk markers. The definition for EUGR and the populations studied differ among authors.Conclusion: EUGR is mainly associated with poor growth and neurodevelopment, as well as with cardiometabolic alterations in childhood. Evidence is based on observational studies with variability in the included populations due to the lack of consensus regarding the definition for EUGR. Finding a gold standard definition becomes paramount in order to select phenotypes at risk later in life. What is known? • EUGR is a frequent condition of preterm infants. Up to date little is known about the effect of the metabolic programming on prognosis. What is new? • The available evidence, which is based on observational studies with variability in the population and the existing different definitions for EUGR, do not enable appropriate data collection. EUGR is mainly associated with poor growth and neurodevelopment, as well as with cardiometabolic alterations in childhood.

Extrauterine growth restriction in very preterm infant: etiology, diagnosis, and 2-year follow-up.

In very-preterm small-for-gestational-age (SGA) infants, long-term postnatal growth is confused with extrauterine growth restriction (EUGR). We aimed to document EUGR in SGA infants and in non-SGA infants ("true-EUGR") and its relationship with fetal, maternal, and neonatal etiological factors. Four hundred seventy-nine very-preterm infants (< 32 weeks) born between 2003 and 2014 and attending the follow-up clinic were included. INTERGROWTH-21st preterm postnatal growth standards in conjunction with WHO Child Growth Standards were used to judge the postnatal growth patterns. EUGR was defined as weight < 10th percentile according to the sex at 36-34 weeks postmenstrual age, usually at discharge. Catch-up was evaluated at 2-2.5 years. Low-weight-for-age (wasting), low-length-for-age (stunting), and low-head-circumference-for-age were diagnosed if the z-scores were below - 2 SD. Logistic regression analysis estimated the association between the risk factors and EUGR, according to the SGA status at birth. Overall, EUGR occurred in 51% at 36-34 postmenstrual weeks and 21% at 2-2.5 years. However, among 411 non-SGA infants, "true-EUGR" rates were 43% and 15%, respectively.Conclusion: By 2-2.5 years of age, a "true-EUGR" of 15% can be expected and only the head circumference normalizes in SGA infants. Low birth weight, hyaline membrane disease, bronchopulmonary dysplasia, and male sex were associated with "true-EUGR." What is Known: • Fetal, neonatal, or postnatal charts have been considered to monitor the postnatal growth of preterm infants. • This selection influences the diagnosis of "extrauterine growth restriction" (EUGR) and the clinical strategies used. What is New: • Extrauterine growth restriction (EUGR) in small-for-gestational-age (SGA) infants can not be considered a true EUGR but a postnatal evolution of fetal growth restriction. • Preeclampsia, low gestational age, severe neonatal morbidity and male sex are independently associated with EUGR in non-SGA infants (named "true-EUGR"), which can be expected in 15% of very preterm infants by 2-2.5 years of age.

Notch3 signaling activation in smooth muscle cells promotes extrauterine growth restriction-induced pulmonary hypertension.

BACKGROUND AND AIMS: Early postnatal life is a critical developmental period that affects health of the whole life. Extrauterine growth restriction (EUGR) causes cardiovascular development problems and diseases, including pulmonary arterial hypertension (PAH). PAH is characterized by proliferation, migration, and anti-apoptosis of pulmonary artery smooth muscle cells (PASMCs). However, the role of PASMCs in EUGR has not been studied. Thus, we hypothesized that PASMCs dysfunction played a role in EUGR-induced pulmonary hypertension. METHODS AND RESULTS: Here we identified that postnatal nutritional restriction-induced EUGR rats exhibited an elevated mean pulmonary arterial pressure and vascular remodeling at 12 weeks old. PASMCs of EUGR rats showed increased cell proliferation and migration features. In EUGR-induced PAH rats, Notch3 signaling was activated. Relative mRNA and protein expression levels of Notch3 intracellular domain (Notch3 ICD), and Notch target gene Hey1 in PASMCs were upregulated. We further demonstrated that pharmacological inhibition of Notch3 activity by using a γ-secretase inhibitor DAPT, which blocked the cleavage of Notch proteins to ICD peptides, could effectively inhibit PASMC proliferation. Specifically knocked down of Notch3 in rat PASMCs by shRNA restored the abnormal PASMC phenotype in vitro. We found that administration of Notch signaling inhibitor DAPT could successfully reduce mean pulmonary arterial pressure in EUGR rats. CONCLUSIONS: The present study demonstrated that upregulation of Notch3 signaling in PASMCs was crucial for the development of EUGR-induced PAH. Blocking Notch3-Hey1 signaling pathway in PASMCs provides a potential therapeutic target for PAH.

Extrauterine growth restriction was associated with short stature and thinness in very low birthweight infants at around six years of age.

AIM: The effect that intrauterine or extrauterine growth restriction (EUGR) had on the build of very low birthweight (VLBW) infants was investigated before Japanese children started school. METHOD: Between 2005 and 2017, the National Hospital Organization, Saga, Japan, carried out preschool checks on 322 children born with a VLBW at approximately six years of age. Growth restriction was defined as being born small for gestational age (SGA) or EUGR if they were born at term. The prevalence of short stature, thinness and obesity was determined, and associations between SGA or EUGR and subsequent body build were investigated. RESULTS: In this study, 77 of 322 (23.9%) infants were SGA and 153 of 322 (47.5%) were EUGR: 14 of 77 (18.2%) SGA infants caught up in growth to the 169 non-EUGR infants, while 90 of 245 (36.7%) appropriate for gestational age infants subsequently demonstrated EUGR. There were 38 (11.8%) short stature, 38 (11.8%) thin and six (1.9%) obese subjects in the total cohort and growth hormone deficiencies in nine (2.8%) cases. We found significant associations between EUGR and both short stature and thinness. CONCLUSION: Extrauterine growth restriction was significantly associated with short stature and thinness in VLBW infants at around six years, irrespective of the degree of SGA.

Statewide Initiative to Reduce Postnatal Growth Restriction among Infants <31 Weeks of Gestation.

OBJECTIVE: To decrease the incidence of postnatal growth restriction, defined as discharge weight <10th percentile for postmenstrual age, among preterm infants cared for in New York State Regional Perinatal Centers. STUDY DESIGN: The quality improvement cohort consisted of infants <31 weeks of gestation admitted to a New York State Regional Perinatal Center within 48 hours of birth who survived to hospital discharge. Using quality improvement principles from the Institute for Healthcare Improvement and experience derived from successfully reducing central line-associated blood stream infections statewide, the New York State Perinatal Quality Collaborative sought to improve neonatal growth by adopting better nutritional practices identified through literature review and collaborative learning. New York State Regional Perinatal Center neonatologists were surveyed to characterize practice changes during the project. The primary outcome-the incidence of postnatal growth restriction-was compared across the study period from baseline (2010) to the final (2013) years of the project. Secondary outcomes included differences in z-score between birth and discharge weights and head circumferences. RESULTS: We achieved a 19% reduction, from 32.6% to 26.3%, in postnatal growth restriction before hospital discharge. Reductions in the difference in z-score between birth and discharge weights were significant, and differences in z-score between birth and discharge head circumference approached significance. In survey data, regional perinatal center neonatologists targeted change in initiation of feedings, earlier breast milk fortification, and evaluation of feeding tolerance. CONCLUSIONS: Statewide collaborative quality improvement can achieve significant improvement in neonatal growth outcomes that, in other studies, have been associated with improved neurodevelopment in later infancy.

Nonrandomised interventional study showed that early aggressive nutrition was effective in reducing postnatal growth restriction in preterm infants.

AIM: This study evaluated whether an early aggressive nutrition (EAN) strategy could limit extrauterine growth restriction (EUGR) in a cohort of preterm infants. METHODS: This prospective nonrandomised interventional study was carried out in the neonatal intensive care unit of an Italian hospital from January 2013 to December 2015. The prevalence of EUGR was assessed in 100 infants with a gestational age of ≤34 weeks, 50 after the introduction of an EAN regimen in October 2014 and 50 before. RESULTS: The prevalence of EUGR at discharge was significantly lower after the introduction of EAN than before for weight (34% vs. 66%), head circumference (22% vs. 42%) and length at discharge (20% vs. 48%). The Z-scores for all measurements were significantly higher after the introduction of EAN. In the EAN group, weight velocity was significantly higher and maximum weight loss and negative changes in the Z-scores from birth to discharge for weight were lower than in the pre-intervention controls. In extremely low birthweight subjects, the weight Z-score and weight velocity were significantly higher in the EAN group than the control group. CONCLUSION: The use of EAN at a very early age reduced EUGR and improved auxological outcomes in preterm infants.

Effect of Intra- and Extrauterine Growth on Long-Term Neurologic Outcomes of Very Preterm Infants.

OBJECTIVE: To determine whether extrauterine growth is associated with neurologic outcomes and if this association varies by prenatal growth profile. STUDY DESIGN: For 1493 preterms from the EPIPAGE (Étude Épidémiologique sur les Petits Âges Gestationnels [Epidemiological Study on Small Gestational Ages]) cohort, appropriate for gestational-age (AGA) was defined by birth weight >-2 SD and small for gestational-age (SGA) by birth weight ≤-2 SD. Extra-uterine growth was defined by weight gain or loss between birth and 6 months by z-score change. Growth following-the-curve (FTC) was defined as weight change -1 to +1 SD, catch-down-growth (CD) as weight loss ≥1 SD, and catch-up-growth (CU) as weight gain ≥1 SD. At 5 years, a complete medical examination (n = 1305) and cognitive evaluation with the Kauffman Assessment Battery for Children (n = 1130) were performed. Behavioral difficulties at 5 years and school performance at 8 years were assessed (n = 1095). RESULTS: Overall, 42.5% of preterms were AGA-FTC, 20.2% AGA-CD, 17.1% AGA-CU, 5.6% SGA-FTC, and 14.5% SGA-CU. Outcomes did not differ between CU and FTC preterm AGA infants. Risk of cerebral palsy was greater for AGA-CD compared with AGA-FTC (aOR 2.26 [95% CI 1.37-3.72]). As compared with children with SGA-CU, SGA-FTC children showed no significant increased risk of cognitive deficiency (aOR 1.41[0.94-2.12]) or school difficulties (aOR 1.60 [0.84-3.03]). Compared with AGA-FTC, SGA showed increased risk of cognitive deficiency (SGA-FTC aOR 2.19 [1.25-3.84]) and inattention-hyperactivity (SGA-CU aOR 1.65 [1.05-2.60]). CONCLUSION: Deficient postnatal growth was associated with poor neurologic outcome for AGA and SGA preterm infants. CU growth does not add additional benefits. Regardless of type of postnatal growth, SGA infants showed behavioral problems and cognitive deficiency.

Population-based study shows improved postnatal growth in preterm very-low-birthweight infants between 1995 and 2010.

AIM: To assess whether the postnatal growth of preterm very-low-birthweight (VLBW) infants, as determined by measures of postnatal growth failure (PNGF), improved during the period 1995-2010 and to evaluate postnatal growth by gestational age (GA) and intrauterine growth groups. METHODS: The study was based on the Israel national VLBW infant database and comprised 13 531 VLBW infants of 24-32 weeks' GA, discharged at a postmenstrual age of ≤40 weeks. Z-scores were determined for weight at birth and discharge. Severe and mild PNGF was defined as a decrease >2 and 1-2 z-scores, respectively. Three time periods were considered: 1995-2000, 2001-2005 and 2006-2010. Multinomial logistic regression was used to assess the independent effect of time period on PNGF. RESULTS: Severe PNGF decreased from 11.7% in 1995-2000 to 7.2% in 2001-2005 and 5.2% in 2006-2010. Infants born in 2006-2010 had sixfold lower odds for severe PNGF than babies born in 1995-2000 (adjusted odds ratio 0.17, 95% confidence interval 0.14-0.21) and

Variability in Definitions and Criteria of Extrauterine Growth Restriction and Its Association with Neurodevelopmental Outcomes in Preterm Infants: A Narrative Review.

Extrauterine growth restriction (EUGR) has been used in the literature and clinical practice to describe inadequate growth in preterm infants. Significant variability is seen in the criteria for EUGR, with no standard definition reached to date. Moreover, no consensus on the optimal timing for assessment or the ideal growth monitoring tool has been achieved, and an ongoing debate persists on the appropriate terminology to express poor postnatal growth. To ensure an adequate understanding of growth and early intervention in preterm infants at higher risk, it is critical to relate the diagnostic criteria of EUGR to the ability to predict adverse outcomes, such as neurodevelopmental outcomes. This narrative review was conducted to present evidence that evaluates neurodevelopmental outcomes in preterm infants with EUGR, comparing separately the different definitions of this concept by weight (cross-sectional, longitudinal and "true" EUGR). In this article, we highlight the challenges of comparing various published studies on the subject, even when subclassifying by the definition of EUGR, due to the significant variability on the criteria used for each definition and for the evaluation of neurodevelopmental outcomes in different papers. This heterogeneity compromises the obtention of a single firm conclusion on the relation between different definitions of EUGR and adverse neurodevelopmental outcomes.