The Use of a Novel Donkey Milk-Derived Human Milk Fortified in the Neonatal Period Had No Effect on the Frequency of Allergic Manifestations During the First Years of Life: The "Fortilat Trial" Follow-Up.

Background: Since human milk contents does not meet the high need of very low birth weight infants, fortification of breast milk is a standard practice for this population. As donkey milk has been long considered for children allergic to cow's milk proteins due to its low allergic properties, a new donkey milk-derived fortifier (DF) has been recently evaluated as a valid alternative to bovine milk-derived fortifier (BF). It seems to improve feeding tolerance when compared with standard BF, with similar neurodevelopmental and auxological outcome at 18 months of age. The aim of this study is to evaluate the development of allergic manifestations occurring in the population of the "Fortilat Trial" at 6-8 years of age. Methods: Allergic manifestations were assessed by an ad hoc questionnaire administered to families. The occurrence of asthma, allergic rhinitis and oculorhinitis, rashes and atopic dermatitis, food allergies, accesses to an emergency department for allergic reactions, and the need of antihistamine have been investigated. Results: In total, 113 infants were enrolled in the study (BF arm: n = 60, DF arm: n = 53). No difference in risk was observed between the two groups for all the considered outcomes. In conclusion, our data suggest that DF does not impact the development of allergic manifestations in the first years of life. Clinical Trial Registration number: ISRCT N70022881.

Two-stage learning-based prediction of bronchopulmonary dysplasia in very low birth weight infants: a nationwide cohort study.

Introduction: The aim of this study is to develop an enhanced machine learning-based prediction models for bronchopulmonary dysplasia (BPD) and its severity through a two-stage approach integrated with the duration of respiratory support (RSd) using prenatal and early postnatal variables from a nationwide very low birth weight (VLBW) infant cohort. Methods: We included 16,384 VLBW infants admitted to the neonatal intensive care unit (NICU) of the Korean Neonatal Network (KNN), a nationwide VLBW infant registry (2013-2020). Overall, 45 prenatal and early perinatal clinical variables were selected. A multilayer perceptron (MLP)-based network analysis, which was recently introduced to predict diseases in preterm infants, was used for modeling and a stepwise approach. Additionally, we applied a complementary MLP network and established new BPD prediction models (PMbpd). The performances of the models were compared using the area under the receiver operating characteristic curve (AUROC) values. The Shapley method was used to determine the contribution of each variable. Results: We included 11,177 VLBW infants (3,724 without BPD (BPD 0), 3,383 with mild BPD (BPD 1), 1,375 with moderate BPD (BPD 2), and 2,695 with severe BPD (BPD 3) cases). Compared to conventional machine learning (ML) models, our PMbpd and two-stage PMbpd with RSd (TS-PMbpd) model outperformed both binary (0 vs. 1,2,3; 0,1 vs. 2,3; 0,1,2 vs. 3) and each severity (0 vs. 1 vs. 2 vs. 3) prediction (AUROC = 0.895 and 0.897, 0.824 and 0.825, 0.828 and 0.823, 0.783, and 0.786, respectively). GA, birth weight, and patent ductus arteriosus (PDA) treatment were significant variables for the occurrence of BPD. Birth weight, low blood pressure, and intraventricular hemorrhage were significant for BPD ≥2, birth weight, low blood pressure, and PDA ligation for BPD ≥3. GA, birth weight, and pulmonary hypertension were the principal variables that predicted BPD severity in VLBW infants. Conclusions: We developed a new two-stage ML model reflecting crucial BPD indicators (RSd) and found significant clinical variables for the early prediction of BPD and its severity with high predictive accuracy. Our model can be used as an adjunctive predictive model in the practical NICU field.

A Timely Administration of Antenatal Steroids Is Highly Protective Against Intraventricular Hemorrhage: An Observational Multicenter Cohort Study of Very Low Birth Weight Infants.

Aim: The aim of the study is to evaluate the influence of the timing of antenatal steroids (ANSs) on neonatal outcome of very low birth weight infants (VLBWI) born before 30 weeks of gestation in the German Neonatal Network. Methods: The German Neonatal Network is a large population-based cohort study enrolling VLBWIs since 2009. We included 672 neonates, who were born between January 1, 2009 and December 31, 2019 in our analysis in 10 selected centers. Infants were divided into four subgroups based on the interval between the first steroid administration and preterm birth: (I) two doses of betamethasone, ANS-birth interval: >24 h to 7 days, n = 187, (II) only one dose of betamethasone, ANS-birth interval 0-24 h, n = 70, (III) two doses of betamethasone, ANS-birth interval >7 days, n = 177, and (IV) no antenatal steroids, n = 238. Descriptive statistics and logistic regression analyses were performed for the main neonatal outcome parameters. Group IV (no ANS) was used as a reference. Results: An ANS-birth interval of 24 h to 7 days after the first dose was associated with a reduced risk for intraventricular hemorrhage (OR 0.17; 95% CI 0.09-0.31, p < 0.001) and mechanical ventilation (OR 0.37; 95% CI 0.23-0.61, p < 0.001), whereas the group of infants that only received a single dose of steroids reflected a subgroup at high risk for adverse neonatal outcomes; an ANS-birth interval of >7 days was still associated with a lower risk for intraventricular hemorrhage (OR 0.43; 95% CI 0.25-0.72, p = 0.002) and the need for mechanical ventilation (OR 0.43; 95% CI 0.27-0.71, p = 0.001). Conclusion: Our observational data indicate that an ANS-birth interval of 24 h to 7 days is strongly associated with a reduced risk of intraventricular hemorrhage in VLBWIs. Further research is needed to improve the prediction of preterm birth in order to achieve a timely administration of antenatal steroids that may improve neonatal outcomes such as intraventricular hemorrhage.

Development and verification of a risk prediction model for bronchopulmonary dysplasia in very low birth weight infants.

BACKGROUND: To analyze the risk factors of bronchopulmonary dysplasia (BPD) of very low birth weight infants (VLBWIs), and to develop and verify a risk prediction model of BPD. METHODS: The data of 611 VLBWIs from the neonatal intensive care unit (NICU) of a tertiary grade A hospital in Suzhou from January 2017 to September 2019 were collected. The data was randomly divided into the modeling set (451 cases) and the validation set (160 cases). Binary logistic regression was used to analyze the data, and the model was examined by a receiver operating characteristic (ROC) curve. The grouped data was used to verify the sensitivity and specificity of the model. RESULTS: The study found that neonatal asphyxia, the positive rate of sputum culture, neonatal sepsis, neonatal respiratory distress syndrome (NRDS), blood transfusions (≥3), patent ductus arteriosus (PDA), the time of invasive mechanical ventilation, the duration of oxygen therapy, and the time of parenteral nutrition were the independent risk factors of BPD, while 1 min Apgar score was a protective factor. The model formula was Z=neonatal asphyxia * 1.229 + the positive rate of sputum culture * 1.265 + neonatal sepsis * 1.677 + NRDS * 1.848 + blood transfusions (≥3) * 1.455 + PDA * 1.835 - 1 min Apgar score * 0.25 + the time of invasive mechanical ventilation * 0.123 + the duration of oxygen therapy * 0.09 + the time of parenteral nutrition * 0.057 - 8.077. The area under the ROC curve of this model was 0.965 (95% CI: 0.946-0.983), with a sensitivity of 93.7% and a specificity of 91.3%. Verification of this prediction model showed a sensitivity of 92.9% and a specificity of 76%, demonstrating that the effects of this model were satisfactory. CONCLUSIONS: The risk prediction model had a good predictive effect for the risk of BPD in VLBWIs, and can provide a reference for preventive treatment and nursing intervention.

Neonatal Outcome After Preeclampsia and HELLP Syndrome: A Population-Based Cohort Study in Germany.

Aim: To analyze short term outcomes of very low birth weight infants (VLBWI) born preterm after maternal preeclampsia and HELLP syndrome within the German Neonatal Network. Methods: The German Neonatal Network is a large population-based cohort study enrolling VLBWI since 2009. Two thousand six hundred and fifty two infants below 32 weeks of gestation born after maternal preeclampsia or HELLP syndrome and 13,383 infants born prematurely for other causes between 2009 and 2018 were included in our analysis. Descriptive statistics and multinomial regression models including preeclampsia and HELLP syndrome were performed for short-term outcome measures such as intracerebral hemorrhage, necrotizing enterocolitis requiring surgery, bronchopulmonary dysplasia, retinopathy of prematurity, periventricular leukomalacia, persistent ductus arteriosus requiring surgery, blood culture positive sepsis and death. Results: After adjustment for confounding variables, preterm birth due to preeclampsia or HELLP syndrome was associated with a reduced risk for intracerebral hemorrhage (OR 0.73, 95% CI 0.60-0.89), necrotizing enterocolitis requiring surgery (OR 0.35 95% CI 0.15-0.82), periventricular leukomalacia (OR 0.61 95% CI 0.40-0.92), and death (OR 0.72 95% CI 0.55-0.96) as compared to other causes of preterm birth. Conclusions: The indication for preterm birth has an impact on neonatal outcome in preterm infants born below 32 weeks. This notion should be included when counseling the families.

Target Body Temperature in Very Low Birth Weight Infants: Clinical Consensus in Place of Scientific Evidence.

Background: Although thermal care is part of the daily routine in Neonatal Intensive Care Units (NICUs), scientific evidence on what is the appropriate body temperature for very low birth weight infants (VLBWI) is largely lacking. Aim: To find out to what extent the standards of thermal care vary among high-level NICUs, especially with respect to the target body temperature in VLBWI. Methods: An online survey with 21 questions on thermal care in three categories of VLBWI was sent to 149 NICUs in Germany, Switzerland, and Austria. Results and discussion: Out of 112 (75%) returned questionnaires, 87 (58%) were included into analysis. A significant increase in incubator settings (air temperature/relative humidity) with decreasing gestational age and birth weight was reported, according to common textbook recommendations. However, a uniform target body temperature of 36.99 ± 0.19°C was chosen for all VLBWI categories. Likewise, the cut-off points for hypo- and hyperthermia were defined very similarly and showed low inter-center variability. This is a remarkable finding in view of the fact that the body temperature of mammalian fetuses in utero is 0.5-1.0°C higher than that of the mother. Conclusion: Despite lacking scientific evidence, there is a tacit consensus among high-level NICUs that 37.0°C is the appropriate body temperature in VLBWI, regardless of gestational age and birth weight. As this is below the intrauterine "breeding temperature" of the fetus, further research on this topic is warranted.

Nutritional Support of Very Low Birth Weight Infants in a Tertiary Center in a Developing Country.

BACKGROUND: Very low birth weight infants (VLBWIs) are at high risk for nutritional deficiency. Enteral feeding is usually challenged by increased risk of necrotizing enterocolitis (NEC). The nutritional needs of VLBWIs are usually dependent on parenteral nutrition during early postnatal life. This study aimed to evaluate the nutritional service of VLBWIs at Jordan University Hospital. METHODS: This was a prospective follow-up study of VLBWIs with birth weight ≤ 1,500 g. Data were extracted from medical charts and laboratory database. RESULTS: In total, 43 VLBWIs met our inclusion criteria; of them, 21% were extremely low birth weight infants (ELBWIs). The mean gestational age was 29 weeks, and the mean birth weight was 1,218 g. The mean age of starting feeds was 3 days. Mean full feed age is 2 weeks. The most common side effect of total parenteral nutrition (TPN) was hypertriglyceridemia (35%). CONCLUSIONS: Nutritional care of VLBWIs is well established in our center. Initiating fortification earlier and working to increase mother's own breast milk supply is vital to improve growth in low resource setting.

Early standard development assessment characteristics in very low birth weight infants later classified with autism spectrum disorder.

BACKGROUND: The prevalence of autism spectrum disorder (ASD) symptoms is high among very low birth weight infants (VLBWIs). Early diagnosis of ASD is crucial, because early intervention for ASD is effective. OBJECTIVE: To evaluate early standard development assessment characteristics in VLBWIs later classified with ASD. METHODS: Thirty-five VLBWIs later diagnosed with ASD were compared with 169 children with typical development who were admitted to the neonatal intensive care unit at Nagano Children's Hospital between 2001 and 2005. We retrospectively evaluated developmental quotient (DQ) using the Kyoto Scale of Psychological Development (KSPD) at 6 and 18months post-term age (PTA) and 3year chronological age. RESULTS: KSPD DQ was significantly lower in ASD infants than in typical development infants at all ages. Postural-motor DQs of ASD infants at 18months PTA and 3year chronological age showed some increase compared to that at 6months PTA. CONCLUSION: Early recognition of ASD using standardized development assessment tools in VLBWIs might be possible.

Preoperative left ventricular internal dimension in end-diastole as earlier identification of early patent ductus arteriosus operation and postoperative intensive care in very low birth weight infants.

Patent ductus arteriosus (PDA) is common in premature infants. In very low birth weight infants (VLBWI), PDA requires surgical therapy in many cases. It is unclear to know at-risk infants showing cardio-dysfunction after PDA surgery. The purpose of this study was to identify at-risk infants showing cardio-dysfunction after surgery for patent ductus arteriosus (PDA). We examined the relationship between left ventricular (LV) performance before and after PDA ligation in a retrospective observational cohort study. We studied 64 preterm neonates with symptomatic PDA before and after surgical ligation. Echocardiographic examinations were performed pre- and postoperatively. M-mode measurements included left ventricular internal dimension in end-diastole (LVIDd) and LV fractional shortening (FS). All cases showed decreased LVFS after PDA closure. Most cases (49/64, 77%) showed postoperative FS decreased to below normal (<28%). Preoperative relative LVIDd was significantly larger in abnormal FS infants (137 ± 18%) than in normal FS infants (118 ± 11%; p<0.01). A cut-off value of preoperative relative LVIDd (absolute LVIDd/normal value) for predicting postoperative cardio-dysfunction was 127.4% (sensitivity, 0.735; specificity, 0.933; area under curve, 0.817). Determination of preoperative LVIDd might facilitate earlier identification of infants needing early PDA surgery and postoperative intensive care.