Hypophosphataemia and late-onset sepsis in extremely preterm neonates: A case-control study.

AIM: Late-onset sepsis (LOS) is common in extreme prematurity. These infants are at risk of refeeding syndrome-associated hypophosphataemia. Our objective was to investigate whether hypophosphataemia predisposes to LOS in extremely premature neonates. METHODS: A retrospective case-control study of neonates born before 29 weeks' gestation in an Australian NICU from 2016 to 2020. Cases developed LOS or localised infection. Two controls, matched within 2 gestational weeks and 90 calendar days, were selected per case. RESULTS: Amongst 48 cases and 93 controls, cases were smaller at birth (767 g vs. 901 g, P = 0.01), but were otherwise comparable. Hypophosphataemia was more common in cases (26% vs. 15%, P = 0.18). Increased intravenous protein intake in the first week was protective against LOS (OR = 0.9, 95% CI 0.76-1.00, P = 0.04); median 2.1 g/kg/day in cases, 2.3 g/kg/day in controls. CONCLUSIONS: Hypophosphataemia as part of refeeding syndrome is prevalent and under-recognised in extremely premature neonates. We did not find an association between hypophosphataemia and LOS. Low intravenous protein may be an independent risk factor for infection.

Hypothermia in preterm infants admitted to low-resource neonatal units in northern Nigeria: an observational study of occurrence and risk factors.

BACKGROUND: Hypothermia is an important cause of morbidity and mortality among preterm and low-birth-weight neonates. In resource-constrained settings, limited referral infrastructure and technologies for temperature control potentiate preterm hypothermia. While there is some documentation on point-of-admission hypothermia from single center studies, there are limited multicenter studies on the occurrence of hypothermia among preterm infants in resource-limited-settings. Therefore, we conducted a multicenter study to determine the prevalence and risk factors for hypothermia at the time of admission and during the first 72 h after admission in northern Nigeria. METHOD: We carried out a prospective cohort study on preterm infants admitted to four referral hospitals in northern Nigerian between August 2020 and July 2021. We documented temperature measurements at admission and the lowest and highest temperatures in the first 72 h after admission. We also collected individual baby-level data on sociodemographic and perinatal history data. We used the World Health Organization classification of hypothermia to classify the babies' temperatures into mild, moderate, and severe hypothermia. Poisson regression analysis was used to identify risk factors for moderate-severe hypothermia. RESULTS: Of the 933 preterm infants enrolled, 682 (72.9%) had hypothermia at admission although the prevalence of hypothermia varied across the four hospitals. During the first 24 h after admission, 7 out of every 10 babies developed hypothermia. By 72 h after admission, between 10 and 40% of preterm infants across the 4 hospitals had at least one episode of moderate hypothermia. Gestational age (OR = 0.86; CI = 0.82-0.91), birth weight (OR = 8.11; CI = 2.87-22.91), presence of a skilled birth attendant at delivery (OR = 0.53; CI = 0.29-0.95), place of delivery (OR = 1.94 CI = 1.13-3.33) and resuscitation at birth (OR = 1.79; CI = 1.27-2.53) were significant risk factors associated with hypothermia. CONCLUSION: The prevalence of admission hypothermia in preterm infants is high and hypothermia is associated with low-birth-weight, place of delivery and presence of skilled birth attendant. The prevalence of hypothermia while in care is also high and this has important implications for patient safety and quality of patient care. Referral services for preterm infants need to be developed while hospitals need to be better equipped to maintain the temperatures of admitted small and sick newborns.

The performance of the practices associated with the occurrence of severe intraventricular hemorrhage in the very premature infants: data analysis from the Chinese neonatal network.

BACKGROUND: The occurrence of severe intraventricular hemorrhage (sIVH) was high in the very preterm infants (VPIs) in China. The management strategies significantly contributed to the occurrence of sIVH in VPIs. However, the status of the perinatal strategies associated with sIVH for VPIs was rarely described across the multiple neonatal intensive care units (NICUs) in China. We aim to investigate the characteristics of the perinatal strategies associated with sIVH for VPIs across the multiple NICUs in China. METHODS: This was a retrospective analysis of data from a prospective cohort of Chinese Neonatal Network (CHNN) dataset, enrolling infants born at 24+0-31+6 from 2019 to 2021. Eleven perinatal practices performed within the first 3 days of life were investigated including antenatal corticosteroids use, antenatal magnesium sulphate therapy, intubation at birth, placental transfusion, need for advanced resuscitation, initial inhaled gas of 100% FiO2 in delivery room, initial invasive respiratory support, surfactant and caffeine administration, early enteral feeding, and inotropes use. The performances of these practices across the multiple NICUs were investigated using the standard deviations of differences between expected probabilities and observations. The occurrence of sIVH were compared among the NICUs. RESULTS: A total of 24,226 infants from 55 NICUs with a mean (SD) gestational age of 29.5 (1.76) and mean (SD) birthweight of 1.31(0.32) were included. sIVH was detected in 5.1% of VPIs. The rate of the antenatal corticosteroids, MgSO4 therapy, and caffeine was 80.0%, 56.4%, and 31.5%, respectively. We observed significant relationships between sIVH and intubation at birth (AOR 1.52, 95% CI 1.13 to 1.75) and initial invasive respiratory support (AOR 2.47, 95% CI 2.15 to 2.83). The lower occurrence of sIVH (4.8%) was observed corresponding with the highest utility of standard antenatal care, the lowest utility of invasive practices, and early enteral feeding administration. CONCLUSIONS: The current evidence-based practices were not performed in each VPI as expected among the studied Chinese NICUs. The higher utility of the invasive practices could be related to the occurrence of sIVH.

RBC transfusion and necrotizing enterocolitis in very preterm infants: a multicenter observational study.

The causal relationship between Packed red blood cell (RBC) transfusion and necrotizing enterocolitis (NEC) remains uncertain. This study aims to provide an exploration of transfusion and NEC in very preterm infants. Using data from the Chinese Neonatal Network cohort study between 2019 and 2021, the analysis focused on very preterm infants (with a birth weight of < 1500 g or a gestational age of < 32 weeks) who developed NEC after receiving transfusions. The time interval between the prior transfusion and NEC was analyzed. An uneven distribution of the time interval implies an association of transfusion and NEC. Additionally, multivariable logistic analysis was conducted to detect the prognosis of defined transfusion-associated NEC(TANEC). Of the 16,494 infants received RBC transfusions, NEC was noted in 1281 (7.7%) cases, including 409 occurred after transfusion. Notably, 36.4% (149/409) of post-transfusion NEC occurred within 2 days after transfusion. The time interval distribution showed a non-normal pattern (Shapiro-Wilk test, W = 0.513, P < 0.001), indicating a possible link between transfusion and NEC. TANEC was defined as NEC occurred within 2 days after transfusion. Infants with TANEC had a higher incidence of death (adjusted OR 1.69; 95% CI 1.08 to 2.64), severe bronchopulmonary dysplasia (adjusted OR 2.03; 95% CI 1.41 to 2.91) and late-onset sepsis (adjusted OR 2.06; 95% CI 1.37 to 3.09) compared with infants without NEC after transfusion. Unevenly high number of NEC cases after RBC transfusions implies transfusion is associated with NEC. TANEC is associated with a poor prognosis. Further research is warranted to enhance our understanding of TANEC.

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.

Morbidity and trends in length of hospitalisation of very and extremely preterm infants born between 2008 and 2021 in the Netherlands: a cohort study.

OBJECTIVES: This study investigated changes in the length of stay (LoS) at a level III/IV neonatal intensive care unit (NICU) and level II neonatology departments until discharge home for very preterm infants and identified factors influencing these trends. DESIGN: Retrospective cohort study based on data recorded in the Netherlands Perinatal Registry between 2008 and 2021. SETTING: A single level III/IV NICU and multiple level II neonatology departments in the Netherlands. PARTICIPANTS: NICU-admitted infants (n=2646) with a gestational age (GA) <32 weeks. MAIN OUTCOME MEASURES: LoS at the NICU and overall LoS until discharge home. RESULTS: The results showed an increase of 5.1 days (95% CI 2.2 to 8, p<0.001) in overall LoS in period 3 after accounting for confounding variables. This increase was primarily driven by extended LoS at level II hospitals, while LoS at the NICU remained stable. The study also indicated a strong association between severe complications of preterm birth and LoS. Treatment of infants with a lower GA and more (severe) complications (such as severe retinopathy of prematurity) during the more recent periods may have increased LoS. CONCLUSION: The findings of this study highlight the increasing overall LoS for very preterm infants. LoS of very preterm infants is presumably influenced by the occurrence of complications of preterm birth, which are more frequent in infants at a lower gestational age.

Association of different doses of antenatal corticosteroids exposure with early major outcomes and early weight loss percentage in extremely preterm infants or extremely low birthweight infants: a multicentre cohort study.

OBJECTIVES: To determine the dose-dependent associations between antenatal corticosteroids (ANS) exposure and the rates of major morbidities, and the early weight loss percentage (EWLP) in hospital among extremely preterm infants (EPI) or extremely low birthweight infants (ELBWI). METHODS: A multicentre, retrospective cohort study of EPI or ELBWI born between 2017 and 2018 was conducted. Infants were classified into no ANS, partial ANS and complete ANS exposure group; three subgroups were generated by gestational age and birth weight. Multiple logistic regression and multiple linear regression were performed. RESULTS: There were 725 infants included from 32 centres. Among no ANS, partial ANS and complete ANS exposure, there were significant differences in the proportions of bronchopulmonary dysplasia (BPD) (24.5%, 25.4% and 16.1%), necrotising enterocolitis (NEC) (6.7%, 2.0% and 2.0%) and death (29.6%, 18.5% and 13.5%), and insignificant differences in the proportions of intraventricular haemorrhage (IVH) (12.5%, 13.2% and 12.2%), and extrauterine growth restriction (EUGR) (50.0%, 56.6% and 59.5%). In the logistic regression, compared with no ANS exposure, complete ANS reduced the risk of BPD (OR 0.58, 95% CI 0.37 to 0.91), NEC (OR 0.21, 95% CI 0.08 to 0.57) and death (OR 0.36, 95% CI 0.23 to 0.56), and partial ANS reduced the risk of NEC (OR 0.23, 95% CI 0.07 to 0.72) and death (OR 0.54, 95% CI 0.34 to 0.87). Compared with partial ANS exposure, complete ANS decreased the risk of BPD (OR 0.58, 95% CI 0.37 to 0.91). There were insignificant associations between ANS exposure and IVH, EUGR. In the multiple linear regression, partial and complete ANS exposure increased EWLP only in the ≥28 weeks (w) and <1000 g subgroup (p<0.05). CONCLUSIONS: Different doses of ANS (dexamethasone) exposure were protectively associated with BPD, NEC, death in hospital, but not EUGR at discharge among EPI or ELBWI. Beneficial dose-dependent associations between ANS (dexamethasone) exposure and BPD existed. ANS exposure increased EWLP only in the ≥28 w and<1000 g subgroup. ANS administration, especially complete ANS, is encouraged before preterm birth. TRIAL REGISTRATION NUMBER: NCT06082414.

Early skin-to-skin contact and the risk of intraventricular haemorrhage and sepsis in preterm infants.

AIM: This study aimed to investigate the risks of intraventricular haemorrhage (IVH) or sepsis in extremely and very preterm infants exposed to early skin-to-skin contact (SSC). METHODS: Data from the Swedish Neonatal Quality Register from 2015 to 2021 were extracted to compare the proportions of infants exposed and not exposed to SSC on day 0 and/or 1 in life that developed IVH or sepsis. RESULTS: A total of 2514 infants, 1005 extremely preterm and 1509 very preterm, were included. This amounted to 69% of all extremely and very preterm infants born during the study period. The proportion of infants with IVH exposed and not exposed to early SSC was 11% and 27%, an adjusted odds ratio (aOR) of 0.67 (95%CI 0.52-0.86, p = 0.002). The proportion of infants with sepsis exposed and not exposed to early SSC was 16% and 30%, an aOR of 0.94 (95%CI 0.75-1.2, p = 0.60). For extremely preterm infants, the proportion with sepsis when exposed and not exposed to early SSC was 29% and 44%, an aOR of 0.65 (95%CI 0.46-0.92, p = 0.015). CONCLUSION: In the current setting, the risk of IVH or sepsis is not increased when an extremely or very preterm infant is exposed to early SSC.

Actual electrolyte intake during the first week of life and morbidity in very-low-birthweight infants.

AIM: To describe sodium and potassium intake, their sources and plasma concentrations, and the association between intake and morbidity in very-low-birthweight (VLBW, <1500 g) infants during the first week of life. METHODS: This retrospective cohort study comprised 951 VLBW infants born at <32 weeks. Infants were divided into three groups according to gestational age: 23-26 (n = 275), 27-29 (n = 433) and 30-31 (n = 243) weeks. Data on fluid management and laboratory findings were acquired from an electronic patient information system. RESULTS: The median sodium intake was highest in the 23-26 week group, peaking at 6.4 mmol/kg/day. A significant proportion of sodium derived from intravascular flushes; it reached 27% on day 1 in the 23-26 week group. High cumulative sodium intake in the first postnatal week was associated with weight gain from birth to day 8 in the 23-26 week group. High intake of sodium associated with an increased risk of surgically ligated patent ductus arteriosus (PDA), bronchopulmonary dysplasia and intraventricular haemorrhage, whereas low intake of potassium associated with an increased risk of PDA. CONCLUSION: Sodium intake in the most premature infants exceeded recommendations during the first postnatal week. Saline flushes accounted for a significant proportion of the sodium load.

Risk factors for acute kidney injury in very-low birth weight newborns: a systematic review with meta-analysis.

This study aims to analyze the main risk factors for acute kidney injury in the subgroup of very-low birth weight newborns, using the diagnosing criteria of the Kidney Disease Improving Global Outcomes (KDIGO) or the Acute Kidney Injury Network (AKIN). A systematic review of the literature was performed on the EMBASE® and PubMed® platforms. Studies that evaluated the risk factors for developing AKI in VLBW newborns were included. For the meta-analysis, we only included the risk factors that were associated with AKI in the univariate analysis of at least two studies. After an initial screening, abstract readings, and full-text readings, 10 articles were included in the systematic review and 9 in the meta-analysis. The incidence of AKI varied from 11.6 to 55.8%. All the studies have performed multivariate analysis, and the risk factors that appeared most were PDA and hemodynamic instability (use of inotropes or hypotension), sepsis, and invasive mechanical ventilation. After the meta-analysis, only cesarian delivery did not show an increased risk of AKI, all the other variables remained as important risk factors. Moreover, in our meta-analysis, we found a pooled increased risk of death in newborns with AKI almost 7 times.  Conclusion: AKI in VLBW has several risk factors and must be seen as a multifactorial disease. The most common risk factors were PDA, hemodynamic instability, sepsis, and invasive mechanical ventilation. What is known: • Acute kidney injury is associated with worst outcomes in all ages. It´s prevention can help diminish mortality. What is new: • A synthesis of the main risk factors associated with AKI in very low birth weight newborns.

Timing of Red Blood Cell Transfusions and Occurrence of Necrotizing Enterocolitis: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Observational studies often report that anemia and red blood cell (RBC) transfusions are associated with a higher risk of necrotizing enterocolitis (NEC) among extremely low-birthweight (ELBW) infants. Objective: To evaluate whether there is a temporal association between 72-hour hazard periods of exposure to RBC transfusions and NEC among ELBW infants randomized to either higher or lower hemoglobin transfusion thresholds. Design, Setting, and Participants: This post hoc secondary analysis of 1690 ELBW infants who survived to postnatal day 10 enrolled in the Transfusion of Prematures (TOP) randomized multicenter trial between December 1, 2012, and April 12, 2017, was performed between June 2021 and July 2023. Exposures: First, the distribution of RBC transfusions and the occurrence of NEC up to postnatal day 60 were examined. Second, 72-hour posttransfusion periods were categorized as hazard periods and the pretransfusion periods of variable duration as control periods. Then, the risk of NEC in posttransfusion hazard periods was compared with that in pretransfusion control periods, stratifying the risk based on randomization group (higher or lower hemoglobin transfusion threshold group). Main Outcomes and Measures: The primary outcome was incidence of NEC stage 2 or 3. Secondary outcomes included the incidence rates of NEC within five 10-day intervals, taking into account the number of days at risk. Results: Of 1824 ELBW infants randomized during the TOP trial, 1690 were included in the present analysis (mean [SD] gestational age, 26.0 [1.5] weeks; 899 infants [53.2%] were female). After categorizing 4947 hazard periods and 5813 control periods, we identified 133 NEC cases. Fifty-nine of these cases (44.4%) occurred during hazard periods. Baseline and clinical characteristics of infants with NEC during hazard periods did not differ from those of infants with NEC during control periods. The risk of NEC was 11.9 per 1000 posttransfusion hazard periods and 12.7 per 1000 control periods (adjusted risk ratio, 0.95; 95% CI, 0.68-1.32; P = .74). This risk did not differ significantly between randomization groups, but the incidence rate of NEC per 1000 days peaked between postnatal days 20 and 29 in the lower hemoglobin transfusion threshold group. Conclusions and Relevance: The findings of this post hoc analysis suggest that, among ELBW infants with the hemoglobin ranges occurring in the TOP trial, exposure to RBC transfusions was not temporally associated with a higher risk of NEC during 72-hour posttransfusion hazard periods. Given that the incidence rate of NEC peaked between postnatal days 20 and 29 among infants with lower hemoglobin values, a more in-depth examination of this at-risk period using larger data sets is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01702805.

No differences were observed in the prevention of necrotizing enterocolitis and late-onset sepsis among preterm infants who received either single-species or multi-species probiotics.

BACKGROUND: Probiotic prophylaxis has been suggested to reduce the incidence of necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) in very preterm newborns. However, choosing the optimal probiotic is difficult due to variations in strain-specific effects and interactions facilitated by the use of combination species. AIMS: To compare clinical outcomes of very preterm infants receiving multi or single-species probiotics. STUDY DESIGN: Retrospective, single-center, cohort study. SUBJECTS: Very preterm infants (<32 weeks' gestation) born between 2019 and 2022 at a tertiary perinatal center received either a multi-species (Lactobacillus rhamnosus 45 %, Lactobacillus casei 15 %, Lactobacillus acidophilus 15 %, Bifidobacterium infantis 15 %, Bifidobacterium bifidum 10 %; n = 228) or a single-species (Bifidobacterium breve BR03 and B632; n = 227) probiotic formulation. MAIN OUTCOME MEASURES: NEC, LOS, and mortality. RESULTS: The overall incidence of NEC and LOS was 3.1 % and 13.8 %, respectively. There were no differences between the multi-species and single-species probiotic groups in the rate of NEC (3.5 % vs 2.6 %; p = 0.787), LOS (15.4 % vs 12.3 %; p = 0.416), mortality (0.9 % vs 1.8 %; p = 0.449), or composite outcome (NEC, LOS and/or death; 16.7 % vs 12.8 %; p = 0.290). CONCLUSION: The clinical outcomes of very preterm newborns receiving multi vs. single-species probiotic formulations were similar in our study. In view of the sample size and low baseline rate of NEC in our unit, further trials are warranted to investigate the effects of specific probiotics for prevention of serious neonatal morbidities.

Necrotizing enterocolitis in premature infants at different gestation ages.

OBJECTIVE: Aim: To compare X-ray signs in different gestational and body weight groups of patients with NEC. PATIENTS AND METHODS: Materials and Methods: We conducted a retrospective study, enrolling 52 preterm newborns with symptoms of NEC regardless of onset time, who underwent treatment at Neonatal Intensive Care Units in Municipal Non-commercial enterprise "City Children Hospital №2", Odesa. The patients were split into 3 clinical groups: very preterm newborns (VPN), moderately preterm newborns (MPN), and moderately preterm newborns with intrauterine growth restriction (MPN+IUGR). RESULTS: Results: In the VPN group NEC was diagnosed at stage II (58,82±12,30) % and III (41,18±12,30) % by Bell MJ, р>0,05. In the group MPN+IUGR, NEC stage II (33,33±14,21) % and stage III (66,66 ±14,21) %, р>0,05, were equally observed. In the MPN group, NEC was diagnosed at stage I (41,67±10,28) % and II (58,33±10,28) %, р>0,05, without prevalence of any. Also only localized forms were observed. In VPN, we observed localized forms in most cases, while diffuse forms were diagnosed in (11,76±8,05) % cases, р<0,05. In the MPN+IUGR group, we found diffuse form of the NEC in half of the cases - (50,00±15,08) %. In the VPN and MPN+IUGR groups, NEC developed at 13,23±0,39 and 14,33±1,19 days, respectively. However, in MPN without IUGR, NEC developed at 17,75±0,55 days, significantly later than in the MPN+IUGR group, р<0,05. CONCLUSION: Conclusions: We have described distinct features of NEC in MPN with IUGR. Compared to MPN without IUGR, NEC had more severe course and earlier manifestation in such neonates.

Delineating morbidity patterns in preterm infants at near-term age using a data-driven approach.

BACKGROUND: Long-term survival after premature birth is significantly determined by development of morbidities, primarily affecting the cardio-respiratory or central nervous system. Existing studies are limited to pairwise morbidity associations, thereby lacking a holistic understanding of morbidity co-occurrence and respective risk profiles. METHODS: Our study, for the first time, aimed at delineating and characterizing morbidity profiles at near-term age and investigated the most prevalent morbidities in preterm infants: bronchopulmonary dysplasia (BPD), pulmonary hypertension (PH), mild cardiac defects, perinatal brain pathology and retinopathy of prematurity (ROP). For analysis, we employed two independent, prospective cohorts, comprising a total of 530 very preterm infants: AIRR ("Attention to Infants at Respiratory Risks") and NEuroSIS ("Neonatal European Study of Inhaled Steroids"). Using a data-driven strategy, we successfully characterized morbidity profiles of preterm infants in a stepwise approach and (1) quantified pairwise morbidity correlations, (2) assessed the discriminatory power of BPD (complemented by imaging-based structural and functional lung phenotyping) in relation to these morbidities, (3) investigated collective co-occurrence patterns, and (4) identified infant subgroups who share similar morbidity profiles using machine learning techniques. RESULTS: First, we showed that, in line with pathophysiologic understanding, BPD and ROP have the highest pairwise correlation, followed by BPD and PH as well as BPD and mild cardiac defects. Second, we revealed that BPD exhibits only limited capacity in discriminating morbidity occurrence, despite its prevalence and clinical indication as a driver of comorbidities. Further, we demonstrated that structural and functional lung phenotyping did not exhibit higher association with morbidity severity than BPD. Lastly, we identified patient clusters that share similar morbidity patterns using machine learning in AIRR (n=6 clusters) and NEuroSIS (n=8 clusters). CONCLUSIONS: By capturing correlations as well as more complex morbidity relations, we provided a comprehensive characterization of morbidity profiles at discharge, linked to shared disease pathophysiology. Future studies could benefit from identifying risk profiles to thereby develop personalized monitoring strategies. TRIAL REGISTRATION: AIRR: DRKS.de, DRKS00004600, 28/01/2013. NEuroSIS: ClinicalTrials.gov, NCT01035190, 18/12/2009.

Incidence of metabolic bone disease in neonates under 32 gestational weeks at the Hospital Universitario de Santander in Colombia. / Incidencia de enfermedad metabólica ósea en neonatos con menos de 32 semanas de gestación en el Hospital Universitario de Santander en Colombia

INTRODUCTION: Metabolic bone disease of premature infants is a rare complication characterized by a lower mineral content in bone tissue. OBJECTIVE: To establish the incidence of metabolic bone disease in premature infants and to determine associated risk factors. MATERIALS AND METHOD: We conducted a descriptive prospective cohort study for one year in all newborns under 32 gestational weeks, or 1,500 g, at the Hospital Universitario de Santander to determine the incidence of metabolic bone disease. We collected demographic data and prenatal histories of the selected patients, and later, we measured serum alkaline phosphatase and serum phosphorus at the third week of birth, having as reference values for diagnosis less than 5.6 mg/dl for the first one and more than 500 UI/L for the second one. We applied statistical tools for data analysis, such as average proportions, dispersion, distribution and association measures, and binomial regression. RESULTS: From a total of 58 patients, 7 had a diagnosis of metabolic bone disease, with an incidence of 12%. The weight was reported as an independent variable for the development of the disease, being significant in children under 1,160 g, as well as prolonged parenteral nutrition for more than 24 days. When performing the multivariate analysis, low weight and short time of parenteral nutrition appeared as risk factors; in the same way, maternal age below 22 years is associated with a higher relative risk, even more than a newborn weight inferior to 1,160 g. CONCLUSION: Establishing an early intervention in patients with metabolic bone disease enhancing risk factors, such as low weight and prolonged parenteral nutrition, is critical to prevent severe complications.

Introducción. La enfermedad metabólica ósea de neonatos prematuros es una complicación poco común que se caracteriza por una disminución del contenido mineral en el hueso. Objetivo. Establecer la incidencia de la enfermedad metabólica ósea en neonatos prematuros y los factores de riesgo asociados. Materiales y métodos. Durante un año, se realizó un estudio prospectivo de cohorte, descriptivo, con todos los neonatos nacidos con menos de 32 semanas de gestación o un peso menor de 1.500 g en el Hospital Universitario de Santander. Se recolectaron datos demográficos y antecedentes prenatales de los pacientes seleccionados. A la tercera semana de nacimiento, se midieron la fosfatasa alcalina y el fósforo sérico, tomando como valores de referencia diagnóstica aquellos inferiores a 5,6 mg/dl para el primero y aquellos mayores de 500 UI/L para la segunda. Para el análisis de la información, se emplearon herramientas estadísticas, como proporciones de promedios, medidas de dispersión, distribución y asociación, y regresión binomial. Resultados. De un total de 58 pacientes, 7 tuvieron diagnóstico de enfermedad metabólica ósea, con una incidencia del 12 %. De las variables estudiadas, el peso se reportó como una variable independiente para el desarrollo de la enfermedad, significativa en aquellos neonatos con peso menor de 1.160 g, al igual que la nutrición parenteral prolongada por más de 24 días. Al hacer el análisis multivariado, La edad materna menor de 22 años representó un riesgo relativo mayor, en comparación con un peso inferior a 1.160 g. Conclusión. Se estableció la importancia de una intervención temprana en pacientes con factores de riesgo para enfermedad metabólica ósea, como bajo peso (menor de 1.160 g) y nutrición parenteral prolongada (mayor de 24 días), con el fin de prevenir complicaciones graves.

Neurodevelopmental outcomes of preterm with necrotizing enterocolitis: a systematic review and meta-analysis.

While neonatal necrotising enterocolitis (NEC) is associated with high mortality rates in newborns, survivors can face long-term sequelae. However, the relationship between NEC and neurodevelopmental impairment (NDI) in preterm infants remains unclear. To explore the relationship between neonatal NEC and neurodevelopmental outcomes in preterm infants, we searched PubMed, EMBASE, and the Cochrane Library from their inception to February 2024 for relevant studies. Studies included were cohort or case-control studies reporting neurodevelopmental outcomes of NEC in preterm infants. Two independent investigators extracted data regarding brain damage and neurodevelopmental outcomes in these infants at a corrected age exceeding 12 months. Odds ratios (ORs) were pooled using a random effects model. We included 15 cohort studies and 18 case-control studies, encompassing 60,346 infants. Meta-analysis of unadjusted and adjusted ORs demonstrated a significant association between NEC and increased odds of NDI (OR 2.15, 95% CI 1.9-2.44; aOR 1.89, 95% CI 1.46-2.46). Regarding brain injury, pooled crude ORs indicated an association of NEC with severe intraventricular haemorrhage (IVH) (OR 1.42, 95% CI 1.06-1.92) and periventricular leucomalacia (PVL) (OR 2.55, 95% CI 1.76-3.69). When compared with conservatively treated NEC, surgical NEC potentially carries a higher risk of NDI (OR 1.78, 95% CI 1.09-2.93) and severe IVH (OR 1.57, 95% CI 1.20-2.06). However, the risk of PVL did not show a significant difference (OR 1.60, 95% CI 0.47-5.40). CONCLUSIONS:  Our meta-analysis provides evidence suggesting an association between NEC and NDI. Additionally, the severity of intestinal lesions appears to correlate with a higher risk of NDI. Further high-quality studies with comprehensive adjustments for potential confounding factors are required to definitively establish whether the association with NDI is causal. WHAT IS KNOWN: • NEC is a serious intestinal disease in the neonatal period with a high mortality rate, and surviving children may have digestive system sequelae. • Compared with non-NEC preterm infants, the reported incidences of brain injury and neurodevelopmental disorders in NEC preterm infants are not the same. WHAT IS NEW: • The risk of neonatal brain injury and neurodevelopmental disorders in preterm infants with NEC is higher than that in non-NEC infants, and the risk of NDI in surgical NEC infants is higher than that in the conservative treatment group. • NEC may increase the risk of motor, cognitive, language development delays, and attention deficits in children.

Long-term outcomes of very low birth weight infants with intraventricular hemorrhage: a nationwide population study from 2011 to 2019.

BACKGROUND: Advancements in neonatal care have increased preterm infant survival but paradoxically raised intraventricular hemorrhage (IVH) rates. This study explores IVH prevalence and long-term outcomes of very low birth weight (VLBW) infants in Korea over a decade. METHODS: Using Korean National Health Insurance data (NHIS, 2010-2019), we identified 3372 VLBW infants with IVH among 4,129,808 live births. Health-related claims data, encompassing diagnostic codes, diagnostic test costs, and administered procedures were sourced from the NHIS database. The results of the developmental assessments  are categorized into four groups based on standard deviation (SD) scores. Neonatal characteristics and complications were compared among the groups. Logistic regression models were employed to identify significant changes in the incidence of complications and to calculate odds ratios with corresponding 95% confidence intervals for each risk factor associated with mortality and morbidity in IVH. Long-term growth and development were compared between the two groups (years 2010-2013 and 2014-2017). RESULTS: IVH prevalence was 12% in VLBW and 16% in extremely low birth weight (ELBW) infants. Over the past decade, IVH rates increased significantly in ELBW infants (P = 0.0113), while mortality decreased (P = 0.0225). Major improvements in certain neurodevelopmental outcomes and reductions in early morbidities have been observed among VLBW infants with IVH. Ten percent of the population received surgical treatments such as external ventricular drainage (EVD) or a ventriculoperitoneal (VP) shunt, with the choice of treatment methods remaining consistent over time. The IVH with surgical intervention group exhibited higher incidences of delayed development, cerebral palsy, seizure disorder, and growth failure (height, weight, and head circumference) up to 72 months of age (P < 0.0001). Surgical treatments were also significantly associated with abnormal developmental screening test results. CONCLUSIONS: The neurodevelopmental outcomes of infants with IVH, especially those subjected to surgical treatments, continue to be a matter of concern. It is imperative to prioritize specialized care for patients receiving surgical treatments and closely monitor their growth and development after discharge to improve developmental prognosis. Supplementary file2 (MP4 77987 kb).

Apnea, Intermittent Hypoxemia, and Bradycardia Events Predict Late-Onset Sepsis in Infants Born Extremely Preterm.

OBJECTIVE: The objective of this study was to examine the association of cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, with late-onset sepsis for extremely preterm infants (<29 weeks of gestational age) on vs off invasive mechanical ventilation. STUDY DESIGN: This is a retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in 5 level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean gestational age: 26.4 weeks, SD 1.71). Monitoring data were available and analyzed for 719 infants (47 512 patient-days); of whom, 109 had 123 sepsis events. Using continuous monitoring data, we quantified apnea, periodic breathing, bradycardia, and IH. We analyzed the relationships between these daily measures and late-onset sepsis (positive blood culture >72 hours after birth and ≥5-day antibiotics). RESULTS: For infants not on a ventilator, apnea, periodic breathing, and bradycardia increased before sepsis diagnosis. During times on a ventilator, increased sepsis risk was associated with longer events with oxygen saturation <80% (IH80) and more bradycardia events before sepsis. IH events were associated with higher sepsis risk but did not dynamically increase before sepsis, regardless of ventilator status. A multivariable model including postmenstrual age, cardiorespiratory variables (apnea, periodic breathing, IH80, and bradycardia), and ventilator status predicted sepsis with an area under the receiver operator characteristic curve of 0.783. CONCLUSION: We identified cardiorespiratory signatures of late-onset sepsis. Longer IH events were associated with increased sepsis risk but did not change temporally near diagnosis. Increases in bradycardia, apnea, and periodic breathing preceded the clinical diagnosis of sepsis.

Respiratory distress syndrome is associated with increased morbidity and mortality in late preterm births.

BACKGROUND: Respiratory distress syndrome is strongly associated with prematurity, including late preterm births. Respiratory distress syndrome has been shown to be associated with certain neonatal morbidities and mortality, but these associations are not well described among late preterm births. OBJECTIVE: We sought to determine the association between respiratory distress syndrome and adverse neonatal outcomes among late preterm (34-36 weeks) born singleton neonates. STUDY DESIGN: This is a retrospective cohort study using California's linked vital statistics and patient discharge data (2008-2019). We included singleton, nonanomalous births with a gestational age of 34-36 weeks. Outcomes of interest were interventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, neonatal sepsis, length of hospital stay, neonatal death, and infant death. Chi-square and multivariable Poisson regression analyses were used to examine the association of respiratory distress syndrome with outcomes at each gestational age. Adjusted risk ratio and 95% confidence interval values were estimated. RESULTS: A total of 242,827 births were included, of which 11,312 (4.7%) had respiratory distress syndrome. We found that among neonates with respiratory distress syndrome, necrotizing enterocolitis was higher at 35 weeks (adjusted risk ratio, 3.97 [95% confidence interval, 1.88-8.41]) and 36 weeks (adjusted risk ratio, 4.53 [95% confidence interval, 1.45-14.13]). Intraventricular hemorrhage, retinopathy of prematurity, neonatal sepsis, and length of hospital stay were significantly higher at 34-36 weeks of gestation in neonates with respiratory distress syndrome. Neonatal death was significantly higher among neonates with respiratory distress syndrome at 35 weeks (adjusted risk ratio, 3.04 [95% confidence interval, 1.58-5.85]) and 36 weeks (adjusted risk ratio, 3.25; 95% confidence interval, 1.59-6.68). In addition, infant death was significantly higher at 35 weeks (adjusted risk ratio, 2.27 [95% confidence interval, 1.43-3.61]) and 36 weeks (adjusted risk ratio, 2.60 [95% confidence interval, 1.58-4.28]). CONCLUSION: We found that respiratory distress syndrome was associated with intraventricular hemorrhage, retinopathy of prematurity, and sepsis at 34-36 weeks of gestation, whereas respiratory distress syndrome was associated with neonatal death, infant death, and necrotizing enterocolitis at 35 and 36 weeks. Clinicians should keep these outcomes in mind when making decisions about delivery timing, the potential benefits of antenatal steroids in pregnancies in the late preterm period, and the management of respiratory distress syndrome in late preterm neonates.

The Incidence of Necrotizing Enterocolitis and Late-Onset Sepsis during the COVID-19 Pandemic in Sweden: A Population-Based Cohort Study.

INTRODUCTION: The effect of the pandemic restrictions in the NICUs is not well studied. Necrotizing enterocolitis (NEC) is characterized by intestinal inflammation and bacterial invasion. This study aimed to investigate whether the incidence of NEC has changed during the COVID-19 pandemic in Sweden and whether it was associated with a change in the frequency of extremely preterm births. METHODS: Data were retrieved from the Swedish Neonatal Quality Register (SNQ) for infants registered between January 2017 and December 2021 born below a gestational age of 35 weeks. The registry completeness is 98-99%. The diagnosis of NEC was the primary outcome. Generalized linear model analysis was used to calculate the risk ratio for NEC. RESULTS: Totally 13,239 infants were included. 235 (1.8%) infants developed NEC, out of which 91 required surgical treatment. 8,967 infants were born before COVID-19 pandemic and 4,272 during. Median gestational age at birth was 32.8 weeks in both periods. The incidence of NEC was significantly lower during COVID-19 pandemic compared to the prior period (1.43 vs. 1.94%, p 0.037), but not the incidence of surgical NEC. The crude risk ratio of developing NEC during COVID-19 pandemic was 0.74 (95% CI: 0.55-0.98). The incidence of late-onset sepsis with positive culture was also declined during COVID-19 (3.21 vs. 4.15%, p value 0.008). CONCLUSION: While we found significant reduction in the incidence of NEC and culture-positive late-onset sepsis during the COVID-19 pandemic, the number of extremely preterm births was unchanged.