Extrauterine Growth Research Articles

Preterm nutrition and neurodevelopmental outcomes

Survival of preterm infants has been steadily improving in recent years because of many recent advances in perinatal and neonatal medicine. Despite these advances, the growth of survivors does not reach the ideal target level of the normal fetus of the same gestational age. Postnatal weight gain is often not achieved because extrauterine growth has higher energy requirements than intrauterine growth, due to the intensive care environment, illness and inadequate nutrition. Although many other factors influence infant brain development, including family socioeconomic and educational background, the role of nutrition is considerable and fortunately, amenable to intervention. In the preterm neonate, the brain is the most metabolically demanding organ, consuming the largest proportions of energy and nutrient intake for its function and programmed growth and maturation. Weight gain, linear and head circumference growth are all markers of nutritional status and are independently associated with long-term neurodevelopment. Brain development is not only the result of nutrients intake, but in addition, of the interaction with growth factors which depend on adequate nutrient supply and overall health status. This explains why conditions such as sepsis, necrotizing enterocolitis and chronic lung disease alter the distribution and accretion of nutrients thereby suppressing growth factor synthesis. In this review, we will focus on the direct role of nutrition on neurodevelopment, emphasizing why it should be started without delay. The nutritional requirements of the preterm infant will be discussed, followed by the effects of general nutritional interventions and specific nutrients, as well as the role of nutritional supplements on neurodevelopment. The primordial role of human breast milk, breast milk fortifiers and human milk oligosaccharides will be discussed in detail. We will also examine the role of nutrition in preventing neonatal complications which can affect neurodevelopment in their own right.

Energy Expenditure, Protein Oxidation and Body Composition in a Cohort of Very Low Birth Weight Infants.

The nutritional management of preterm infants is a critical point of care, especially because of the increased risk of developing extrauterine growth restriction (EUGR), which is associated with worsened health outcomes. Energy requirements in preterm infants are simply estimated, so the measurement of resting energy expenditure (REE) should be a key point in the nutritional evaluation of preterm infants. Although predictive formulae are available, it is well known that they are imprecise. The aim of our study was the evaluation of REE and protein oxidation (Ox) in very low birth weight infants (VLBWI) and the association with the mode of feeding and with body composition at term corrected age. Methods: Indirect calorimetry and body composition were performed at term corrected age in stable very low birth weight infants. Urinary nitrogen was measured in spot urine samples to calculate Ox. Infants were categorized as prevalent human milk (HMF) or prevalent formula diet (PFF). Results: Fifty VLBWI (HMF: 23, PFF: 27) were evaluated at 36.48 ± 0.85 post-conceptional weeks. No significant differences were found in basic characteristics or nutritional intake in the groups at birth and at the assessment. No differences were found in the REE of HMF vs. PFF (59.69 ± 9.8 kcal/kg/day vs. 59.27 ± 13.15 kcal/kg/day, respectively). We found statistical differences in the protein-Ox of HMF vs. PFF (1.7 ± 0.92 g/kg/day vs. 2.8 ± 1.65 g/kg/day, respectively, p < 0.01), and HMF infants had a higher fat-free mass (kg) than PFF infants (2.05 ± 0.26 kg vs. 1.82 ± 0.35 kg, respectively, p < 0.01), measured with air displacement plethysmography. Conclusion: REE is similar in infants with a prevalent human milk diet and in infants fed with formula. The HMF infants showed a lower oxidation rate of proteins for energy purposes and a better quality of growth. A greater amount of protein in HMF is probably used for anabolism and fat-free mass deposition. Further studies are needed to confirm our hypothesis.

Intermittent bolus feeding does not enhance protein synthesis, myonuclear accretion, or lean growth more than continuous feeding in a premature piglet model

Extrauterine growth restriction often occurs in premature infants but may be mitigated by optimizing enteral feeding strategies. We show that intermittent bolus feeding does not increase skeletal muscle protein synthesis, myonuclear accretion, or lean growth more than continuous feeding in preterm pigs. This attenuated anabolic response of muscle to intermittent bolus feeding, compared with previous observations in pigs born at term, may contribute to deficits in lean mass that many premature infants exhibit into adulthood.

Neuropsychological Development and New Criteria for Extrauterine Growth Restriction in Very Low-Birth-Weight Children.

Background: Controversy between short-term neonatal growth of very low birth-weight preterm (VLBW) and neurodevelopment may be affected by criteria changes of extrauterine growth restriction (EUGR). Objective: to determine if new EUGR criteria imply modifications in the relationship between old criteria and results of neuropsychological tests in preterm children. Patients and methods: 87 VLBW at 5–7 years of age were studied. Neuropsychological assessment included RIST test (Reynolds Intellectual Sctreening Test) and NEPSY-II (NE neuro, PSY psycolgy assessment) tests. The relationships between these tests and the different growth parameters were analyzed. Results: RIST index was correlated with z-score Fenton’s weight (p = 0.004) and length (p = 0.003) and with z-score IGW-21’s (INTERGRWTH-21 Project) weight (p = 0.004) and length (p = 0.003) at neonatal discharge, but not with z-score difference between birth and neonatal discharge in weight, length, and HC for both. We did not find a statistically significant correlation between Fenton or IGW-21 z-scores and scalar data of NEPSY-II subtasks. Conclusion: In our series, neonatal growth influence on neuropsychological tests at the beginning of primary school does not seem robust, except for RIST test. New EUGR criteria do not improve the predictive ability of the old ones.

Effectiveness of prealbumin as an indicator of growth in neonates.

We designed this study to assess the effectiveness of prealbumin as an indicator of growth as well as a nutritional marker in neonates.Between March 2017 and June 2019, we measured serum prealbumin concentrations of 80 neonates in neonatal intensive care unit at birth, postnatal day 14 and 28, and classified them into 3 groups (early preterm, late preterm, and term infants). And we examined correlation among prealbumin levels, nutritional intake, and anthropometric measurements (weight, length, and head circumference) in neonates.Prealbumin measured on the 14th postnatal day in early preterm infants showed significant correlations with the length, weight, and head circumference z-scores. Prealbumin levels increased with time in the late preterm and term groups. At birth, prealbumin levels were the lowest in late preterm babies, implying that they are nutritionally deficient and need nutritional support. At postnatal day 28, the prealbumin levels of many preterm infants did not reach those seen in term babies at birth, suggesting the presence of extrauterine growth restriction.Prealbumin can be considered as an indicator of sufficient growth in early preterm infants.

Transgenerational inheritance of promoter methylation changes in extrauterine growth restriction-induced pulmonary arterial pressure disorders.

BackgroundThis study aimed to investigate the influence of extrauterine growth restriction (EUGR) on pulmonary arterial pressure (PAP) and the transgenerational inheritance of promoter methylation changes in pulmonary vascular endothelial cells (PVECs) of 2 consecutive generations under EUGR stress.MethodsAfter modeling, PAP values of F1 and F2 pups were investigated at 9-week-old. The methyl-DNA immune precipitation chip was used to analyze DNA methylation profiling. Differential enrichment peaks (DEPs) and regions of interest (ROIs) were identified, based on which Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and reactome pathway enrichments were analyzed.ResultsThe F1 male rats in the EUGR group had significantly increased PAP levels compared to the control group; however, this increase was not observed in female rats. Interestingly, in F2 female rats, the EUGR group had decreased PAP. In the X chromosome of the F1 males, there were 16 differential ROI genes in the F1 generation, while in F2 females, there were 86 differential ROI genes. Similarly, there were 105 DEPs in the F1 generation and 38 DEPs in the F2 generation. In combination with the 5 common ROIs and 14 common DEPs, 18 genes were regarded as the key candidate genes associated with hereditable PAP variation in the EUGR model. Enrichment analysis showed that synaptic and neurotransmitter relative pathways might be involved in the process of EUGR-induced PAH development. Among common DEPs, Smad1 and Serpine1 were also found in 102 PAH-associated genes in the MalaCards database.ConclusionsTogether, there is a transgenerational inheritance of promoter methylation changes in the X chromosome in EUGR-induced PAP disorders, which involves the participation of synaptic and neurotransmitter relative pathways. Also, attenuated methylation of Smad1 and Serpine1 in the promoter region may be a partial driver of PAH in later life.

Comparison of Fenton Versus Intergrowth-21 Growth Charts for Preterm Neonates

Background:Fenton charts from developed world are commonly used for growth assessment of preterm newborns. Recently prescribed Intergrowth-21 (IG-21) charts look more promising as they include mixed population from economically diverse nations.Objective:We compared IG-21 with Fenton charts for birth size classification and extrauterine growth in preterm infants.Study design:A prospective collection of growth parameters.Participants:Preterm newborns (&lt;37 weeks).Intervention:Weight (W), length (L), and head circumference (HC) were collected at weekly interval during the stay as well as follow-up.Outcomes:Growth of preterm newborns at birth and last follow-up was assessed using Fenton and IG-21 charts. Agreement between Fenton and IG-21 for percentiles and z-scores of growth parameters was assessed using Bland-Altman plot.Results:A total of 301 preterm newborns were enrolled in the study. Mean (standard deviation [SD]) gestational age at birth was 34.08 (1.84) weeks, while at last follow-up (N = 296) it was 37.62 (1.85) weeks. The mean (SD) of birth W, L, and HC were 1889.24 (418.9) g, 44.69 (3.03) cm, and 30.6 (1.84) cm, respectively, while for last follow-up, they were 2114.76 (397.7) g, 47.64 (2.97) cm, and 32.65 (1.7) cm, respectively. The agreement of z-score/percentile between the 2 growth charts was not good for all the anthropometric parameters. Overall, Fenton reported more intrauterine (42.9% vs 36.9%) and extrauterine (92.9% vs 73%) growth restriction as compared to IG-21.Conclusion:The agreement between the 2 charts was poor. More proportions of the preterm population were growth restricted using Fenton charts.

Effects of colostrum oral immunological nursingon the growth and development of very low birth weight infants

Objective To investigate the effect of colostrum oral immunological nursing on the growth and development of very low birth weight infants (VLBW). Methods Sixty-nine cases of VLBW were selected as the research objects, and randomly divided into treatment group (n=34) and control group (n=35). The control group was given routine nursing, and the treatment group was given colostrum oral immunotherapy related nursing within one week after birth. Results The duration of total intestinal feeding in the treatment group was significantly shorter, the body weight gain per week was significantly higher, and the body weight day of birth was significantly earlier than that in the control group (P Conclusion Colostrum oral immunity nursing can effectively shorten the time for VLBW to reach total enteral nutrition, reduce the incidence of NEC, sepsis and extrauterine growth restriction, and accelerate the growth rate of VLBW.

Evaluation of nutrition status of very preterm infants in neonatal intensive care units using different growth indicators.

Nutrition status of very preterm infants in the neonatal intensive care unit (NICU) is strongly associated with postnatal growth. This study aimed to develop indicators of nutrition status using growth data of very preterm infants during hospitalization. The data of 596 newborns from eight NICUs were retrospectively analyzed. Inclusion criteria were birth at <32 weeks' gestation, NICU admission ≤24 h after delivery, and length of hospital stay ≥28 days. Three indicators were evaluated: (indicator I) prevalence of extrauterine growth restriction (EUGR); (indicator II) z-score for change in weight from birth to discharge, adjusted for birth weight z-score and gestational age; and (indicator III) change in weight z-score from birth to discharge, adjusted for birth weight z-score, gestational age, and time to regain birth weight. Using data from NICU 1 as the reference for the latter two indicators, we established linear regression models of the adjusted change in weight z-score from birth to discharge. The difference between the observed value and the baseline value (calculated by the two models) served as the nutrition indices. The prevalence of EUGR differed significantly between the eight NICUs (P = .009). Statistically significant differences were found between the mean indices calculated by the other two models (all P < .05). Indicator III, change in weight z-score from birth to discharge (adjusted for birth weight z-score, gestational age, and time to regain birth weight), appears to be the most accurate for evaluating the quality of nutrition in the NICU.

Effect of intestinal microecology on postnatal weight gain in very preterm infants in intensive care units

ObjectiveTo study the effect of intestinal microecology on postnatal weight gain of very preterm infants in neonatal intensive care unit (NICU).MethodsVery preterm infants who met the inclusion criteria were enrolled. The subjects were divided into the extrauterine growth retardation (EUGR) group(defined as a body weight less than the 10th percentile of the corresponding gestational age or a weight loss between birth and a given time of > 2SD were considered EUGR) and normal growth group, and the growth was evaluated at 2 and 4 weeks after birth. Meanwhile, the stool samples were taken to perform16S ribosomal RNA (rRNA) high -throughput 16S rRNA sequencing of the intestinal microflora was performed on stool samples.ResultsA total of 22 infants were included. There was no significant difference in the alpha diversity indexes indices between the two groups at 2 weeks or 4 weeks after birth. The beta diversity analysis showed that the two groups had similar principal components of the intestinal microflora were similar between the two groups. Linear discriminant analysis (LDA) effect size (LEfSe) showed that 2 weeks after birth, the bacteria with an absolute LDA score (log10) higher than 4 included Streptococcaceae, Streptococcus, Bacteroidetes, Bacteroidales and Stenotrophomonas in the EUGR group and Enterococcaceae and Enterococcus in the control group. At the 4th week after birth, the bacteria with an absolute LDA score (log10) higher than 3 in the EUGR group includedwere Clostriaceae, Eubacteriaceae and Eubacterium. TheBy comparing the composition of the microbial community composition comparison showed, significant differences were found in the principal components of Enterococcus and Streptococcus on the family and genus levels at 2 weeks after birth. No Bifidobacterium was found in either group at 4 weeks after birth.ConclusionIntestinal microecology is different between infants with EUGR and those with normal growth. The diversity and richness of the intestinal microflora in preterm infants at the NICU are significantly insufficient and change dynamically with time, and the establishment of intestinal homeostasis is obviously delayed.

Evidence for Resolution of Endometrial Implants with Hormonal Therapy

Endometriosis affects 10% of reproductive-aged women, carrying considerable morbidity [1]. It is defined by extrauterine growth of functional endometrial tissue, most commonly in the peritoneal cavity. However, extrapelvic implants can be encountered in the thoracic cavity with signs/symptoms of pneumothorax, hemothorax, hemoptysis, and lung nodules [2,3].

Association between postnatal growth and neurodevelopmental impairment by sex at 2 years of corrected age in a multi-national cohort of very preterm children

Extra-uterine growth restriction (EUGR) is common among very preterm (VPT) infants and has been associated with impaired neurodevelopment. Some research suggests that adverse effects of EUGR may be more severe in boys. We investigated EUGR and neurodevelopment at 2 years of corrected age (CA) by sex in a VPT birth cohort. Data come from a population-based cohort of children born <32 weeks' gestation from 11 European countries and followed up at 2 years CA. Postnatal growth during the neonatal hospitalization was measured with: (1) birthweight and discharge-weight Z-score differences using Fenton charts (2) weight-gain velocity using Patel's model. Published cut-offs were used to define EUGR as none, moderate or severe. Neurodevelopmental impairment was assessed using a parent-report questionnaire, with standardized questions/instruments on motor function, vision, hearing and non-verbal cognition. We estimated relative risks (RR) adjusting for maternal and neonatal characteristics overall and by sex. Among 4197 infants, the prevalence of moderate to severe impairment at 2 years CA was 17.7%. Severe EUGR was associated with neurodevelopmental impairment in the overall sample and the interaction with sex was significant. For boys, adjusted RR were 1.57 (95% Confidence Intervals (CI): 1.18-2.09) for Fenton's delta Z-score and 1.50 (95% CI: 1.12-2.01) for Patel's weight-gain velocity, while for girls they were 0.97 (0.76-1.22) and 1.12 (0.90-1.40) respectively. EUGR was associated with poor neurodevelopment at 2 years among VPT boys but not girls. Understanding why boys are more susceptible to the effects of poor growth is needed to develop appropriate healthcare strategies.

Quality improvement initiative to decrease extrauterine growth restriction in preterm neonates.

Prevention of extrauterine growth restriction (EUGR) in preterm neonates is one of the biggest challenges to neonatologists. Lack of uniformity and inconsistency in nutrition practices are the most common causes. We started a quality improvement (QI) initiative with an intention to decrease the proportion of EUGR. We performed prospective nonrandomized QI from May 2018 to July 2019. Ninety-six neonates (born at <32 weeks and/or <1.2 kg) were compared with 111 historical controls. A continuous feedback loop was maintained, and changes were analyzed as plan-do-study-actcycle. Although EUGR was lower after the intervention (93.7% vs 87.5%), this change was not statistically significant. However, other measures of in-hospital neonatal growth showed improvement, including median discharge weight percentile from 1% to 3% (P = .003). Median difference in the z-score for weight from birth to discharge also improved significantly from -1.84 to -1.65 (P = .04). Babies in the intervention group regained birth weight earlier (P = .005) and had better growth velocity (P = .0005). The feeding was started early (P < .0001), and these babies reached full feeds (P < .0001) earlier than the control cohort. Although our QI initiative failed to achieve a significant reduction in EUGR, it did achieve a significant improvement in discharge weight percentile and difference in the z-score for weight at birth and during discharge from hospital. There was a significant improvement in growth velocity and an early regaining of birth weight. The implementation of written nutrition practice guidelines facilitated improved outcomes.

Extra-uterine growth restriction in preterm infants: Neurodevelopmental outcomes according to different definitions

Aim Extra-uterine Growth Restriction (EUGR) is common among preterm infants. Two types of EUGR definitions are still now available: cross-sectional definitions and longitudinal ones. In a cohort of very preterm infants, we aimed to evaluate which definition could better predict neurodevelopmental outcomes at 2 years of corrected age. We used Italian Neonatal Study Charts (INeS) growth charts and INTERGROWTH-21st (IG-21) standard charts and compared results. Method We restrospectively collected data from clinical charts of 324 preterm newborns with a gestational age ≤30 weeks born from 2012 to 2017. Then we compared forty-eight definitions (24 cross-sectional and 24 longitudinal) of EUGR, in term of neurodevelopmental outcomes at 2 years of corrected age. Results We included in the study 254 preterm infants, whose clinical information met the enrolment criteria. Nineteen out of 48 definitions of EUGR were significantly predictive both for Griffith's Development Quotient (GDQ) and Neurodevelopment Impairment (NDI). Among these, longitudinal definitions appeared to have a higher negative predictive value for NDI than cross-sectional ones. Furthermore, infants with EUGR appeared to have a lower cognitive score than their peers without EUGR. Interpretation A loss of Zs > 1 SDS in weight and head circumference, calculated from when physiological weight loss is over and identified as soon as possible rather than at discharge, better predicts neurodevelopmental outcomes of preterm infants.

Extrauterine Growth Restriction in Very Low Birth Weight Infants: Concordance Between Fenton 2013 and INTERGROWTH-21st Growth Charts.

Postnatal growth restriction has high prevalence in very low birth weight (VLBW) preterm neonates, and this could affect their long-term prognosis. Nowadays, there is no consensus on how to monitor growth in these neonates.Objective: This study aimed to compare prevalence of intra- and extrauterine growth restriction (IUGR and EUGR) in a sample of VLBW infants according to the Fenton 2013 charts and INTERGROWTH-21st (IW-21) standards and to analyze concordance between both in the different EUGR definitions criteria (cross-sectional, dynamic, and true).Patients and Methods: An observational retrospective study of 635 VLBW preterm was performed. The study was carried out in Central University Hospital of Asturias. Body measurements (weight, length, and head circumference) were collected at birth and at hospital discharge and expressed in z-scores for the two references (Fenton 2010 and IW-21). Kappa concordance was calculated.Results: Kappa concordance between Fenton and IW-21 was 0.887 for IUGR and 0.580 for static EUGR. Prevalence was higher according to Fenton in IUGR (36.5 vs. 35.1%), in static EUGR (73.8 vs. 59.3%), and in dynamic EUGR (44.3 vs. 29.3%). Despite observing low prevalence of EUGR when IW-21 was used to define EUGR, a statistical association between neonatal morbidity and diagnosis of EUGR was observed.Conclusion: The Fenton and IW-21 concordance for IUGR is good. IW-21 is more restrictive than Fenton in EUGR. Patients diagnosed by IW-21 as EUGR are more likely to have neonatal morbidity, especially if we use EUGR dynamic definition. In our study, we cannot conclude that one graph is better than the other.

Exosomes and their cargo are important regulators of cell function in endometriosis

Endometriosis is a chronic oestrogen-dependent gynaecological disorder characterized by non-menstrual pelvic pain, infertility and the extrauterine growth of endometrial-like glands and stroma. It has been noted that the eutopic endometrium of women with endometriosis is functionally distinct from that of women without endometriosis. Moreover, ectopic endometrial implants are functionally different from the eutopic endometrium of women with endometriosis. However, the mechanisms directing these differences are ill-defined. It is proposed here that small membrane-bound extracellular vesicles called exosomes are important vehicles in the protection and transport of signalling molecules central to the dysregulation of endometrial function in women with endometriosis. Therefore, a critical review of the literature linking exosomes and their cargo to the pathobiology of endometriosis was conducted. Circulating peritoneal fluid and endometrial cell exosomes contained long non-coding RNA, miRNA and proteins involved in histone modification, angiogenesis and immune modulation that differed significantly in women with endometriosis compared with controls. Moreover, experimental evidence supports a role for exosomes and their cargo in angiogenesis, neurogenesis, immune modulation and endometrial stromal cell invasion. It is therefore suggested that exosomes play an important role in the pathophysiology of endometriosis.

Regulation of Akt Signaling in Skeletal Muscle Is Altered by Prematurity in a Neonatal Piglet Model

Abstract Objectives Preterm birth is a risk factor for growth faltering. We recently showed in a neonatal piglet model of prematurity that premature birth decreases weight gain and skeletal muscle protein synthesis. This is associated with reduced insulin-induced activation of signaling components downstream of Akt but with no change in the activation of the IR/IRS-1/PI3K axis upstream of Akt. The aim of this study was to identify key regulatory molecules involved in Akt activation that are responsible for the differential response of skeletal muscle to insulin in preterm compared to term pigs. Methods Piglets were delivered by cesarean section 11 d (preterm/PT) or 2 d (term/T) before term birth and a jugular vein catheter was placed for delivery of total parenteral nutrition. On day 3, after 4 h fasting, piglets were fasted one additional h or fed an elemental diet (31.5 kcal/kg, 1.3 g/kg carbohydrate, 2.7 g/kg amino acids, and 1.6 g/kg lipid), similar in composition to sow milk, via oral gavage. Longissimus dorsi muscle was collected following euthanasia (fasted state or 60 min after feeding). Positive and negative regulators of Akt activity were determined by immunoprecipitation and immunoblotting assays. Results Akt1 and Akt2 phosphorylation were lower in PT than in T pigs (P &amp;lt; 0.05), whereas Akt3 phosphorylation was not affected by prematurity. The phosphorylation of Akt activators PDK1 and mTORC2, but not FAK, was lower in PT than in T pigs (P &amp;lt; 0.05). The abundance of Ubl4A, a positive regulator of Akt, was lower in PT than in T pigs (P &amp;lt; 0.05). The abundance Akt inhibitors PHLPP and SHIP2, but not PTEN and IP6K1, was significantly higher in PT than in T pigs (P &amp;lt; 0.05). Activation of the phosphatase PP2A was lower in PT than in T pigs (P &amp;lt; 0.05), but its activation was not affected by feeding. However, PP2A activation was inhibited by feeding in T pigs (P &amp;lt; 0.05). Conclusions These results showed that following preterm birth, the postprandial activation of positive regulators of Akt is reduced whereas the activation of negative regulators of Akt is enhanced. Our findings suggest that premature birth impairs the activation of Akt that is essential for channeling dietary nutrients for anabolism and likely contributes to the extrauterine growth faltering of prematurity. Funding Sources NIH and USDA.

Clinical characteristics and post-discharge follow-up analyses of 10 infants with congenital tuberculosis: A retrospective observational study.

ABSTRACTImportanceCongenital tuberculosis (TB) is a rare, potentially fatal disease. There is currently a lack of detailed clinical information available regarding this disease.ObjectiveThis retrospective study investigated the clinical manifestations, treatment, and long‐term prognosis of congenital TB.MethodsPatients were treated in Beijing Children’s Hospital, Capital Medical University (Beijing, China) between 2009 and 2018. Their demographic data, maternal and family histories, symptoms and signs, treatment information, and follow‐up data were retrospectively collected using the hospital’s electronic information system.ResultsTen infants with congenital TB were enrolled. The mean gestational age was 36.6 ± 2.2 weeks and mean birth weight was 2517 ± 487 g. All 10 patients exhibited fever, nine patients (90%) had anemia, and six patients (60%) had extrauterine growth retardation. On chest computed tomography scans, all 10 patients presented multiple pulmonary nodules and four patients (40%) had mediastinal adenopathy. Nine out of ten (90%) completed the T‐spot test, and eight of them (8/9, 89%) were positive. Anti‐TB treatment was initiated upon diagnostic confirmation. All patients (100%) received combined treatment with isoniazid (INH) and rifampicin (RIF). Eight of 10 patients (80%) received combined treatment with INH, RIF, and pyrazinamide. The survival rate was 100%. One patient was lost to follow‐up and four patients are currently continuing treatment. Three of nine patients (33%) achieved normal developmental milestones at 6 months of age.InterpretationEarly diagnosis based on maternal history, typical imaging results, and timely treatment can improve outcomes in infants with congenital TB.

Risk factors for metabolic bone disease of prematurity in very/extremely low birth weight infants: a multicenter investigation in China

OBJECTIVE To investigate the incidence rate and risk factors for metabolic bone disease of prematurity (MBDP) in very low birth weight/extremely low birth weight (VLBW/ELBW) infants. METHODS The medical data of 61 786 neonates from multiple centers of China between September 1, 2013 and August 31, 2016 were retrospectively investigated, including 504 VLBW/ELBW preterm infants who met the inclusion criteria. Among the 504 infants, 108 infants diagnosed with MBDP were enrolled as the MBDP group and the remaining 396 infants were enrolled as the non-MBDP group. The two groups were compared in terms of general information of mothers and preterm infants, major diseases during hospitalization, nutritional support strategies, and other treatment conditions. The multivariate logistic regression analysis was used to investigate the risk factors for MBDP. RESULTS The incidence rate of MBDP was 19.4% (88/452) in VLBW preterm infants and 38.5% (20/52) in ELBW preterm infants. The incidence rate of MBDP was 21.7% in preterm infants with a gestational age of < 32 weeks and 45.5% in those with a gestational age of < 28 weeks. The univariate analysis showed that compared with the non-MBDP group, the MBDP group had significantly lower gestational age and birth weight, a significantly longer length of hospital stay, and a significantly higher incidence rate of extrauterine growth retardation (P < 0.05). Compared with the non-MBDP group, the MBDP group had significantly higher incidence rates of neonatal sepsis, anemia, hypocalcemia, and retinopathy of prematurity (P < 0.05). The MBDP group had a significantly lower mean feeding speed, a significantly higher age when reaching total enteral feeding, and a significantly longer duration of parenteral nutrition (P < 0.05). The use rate of caffeine citrate in the MBDP group was significantly higher, but the use rate of erythropoietin was significantly lower than that in the non-MBDP group (P < 0.05). The multivariate logistic regression analysis showed that gestational age < 32 weeks, hypocalcemia, extrauterine growth retardation at discharge, and neonatal sepsis were risk factors for MBDP (P < 0.05). CONCLUSIONS A lower gestational age, hypocalcemia, extrauterine growth retardation at discharge, and neonatal sepsis may be associated an increased risk of MBDP in VLBW/ELBW preterm infants. It is necessary to strengthen perinatal healthcare, avoid premature delivery, improve the awareness of the prevention and treatment of MBDP among neonatal pediatricians, and adopt positive and reasonable nutrition strategies and comprehensive management measures for preterm infants.

Fortification of Breast Milk With Preterm Formula Powder vs Human Milk Fortifier in Preterm Neonates

Fortification of expressed breast milk (EBM) using commercially available human milk fortifiers (HMF) increases short-term weight and length in preterm very low-birth-weight (VLBW) neonates. However, the high cost and increased risk of feed intolerance limit their widespread use. Preterm formula powder fortification (PTF) might be a better alternative in resource-limited settings. To demonstrate that fortification of EBM by preterm formula powder is noninferior to fortification by HMF, in terms of short-term weight gain, in VLBW neonates. Open-label, noninferiority, randomized trial conducted from December 2017 to June 2019 at a level 3 neonatal unit in India. The trial enrolled preterm (born at or before 34 weeks of gestation) VLBW neonates receiving at least 100 mL/kg/d of feeds and consuming 75% of milk or more as EBM. Neonates were randomly assigned to receive fortification by either PTF or HMF. Calcium, phosphorus, iron, vitamin D, and multivitamins were supplemented in PTF and only vitamin D in the HMF group to meet the recommended dietary allowances. The primary outcome was the weight gain until discharge from the hospital or 40 weeks' postmenstrual age, whichever was earlier; the prespecified noninferiority margin was 2 g/kg/d. Secondary outcomes included morbidities such as necrotizing enterocolitis, feed intolerance, and extrauterine growth restriction (<10th percentile on the Fenton chart at 40 weeks' postmenstrual age). Of the 123 neonates enrolled, 60 and 63 were randomized to the PTF and HMF groups, respectively. The mean gestation (30.5 vs 29.9 weeks) and birth weight (1161 vs 1119 g) were comparable between the groups. There was no difference in the mean (SD) weight gain between the PTF and HMF groups (15.7 [3.9] vs 16.3 [4.0] g/kg/d; mean difference, -0.5 g/kg/d; 95% CI, -1.9 to 0.7). The lower bound of 95% CI did not cross the noninferiority margin. The incidence of feed intolerance was lower in the PTF group (1.4 vs 6.8 per 1000 patient-days; incidence rate ratio 0.19; 95% CI, 0.04 to 0.95), and fewer neonates required withholding of fortification for 24 hours or more (5% vs 22%; risk ratio, 0.22; 95% CI, 0.07 to 0.75). The incidence of necrotizing enterocolitis stage II or more (0 vs 5%) and extrauterine growth restriction (73% vs 81%) was comparable between the groups. Fortification with preterm formula powder is not inferior to fortification with human milk fortifiers in preterm neonates. Given the possible reduction in feed intolerance and lower costs, preterm formula might be a better option for fortification, especially in resource-restricted settings. Clinical Trial Registry, India Identifier: CTRI/2017/11/010593.