Leveraging Predictive Pharmacometrics-Based Algorithms to Enhance Perinatal Care—Application to Neonatal Jaundice

The field of medicine is undergoing a fundamental change, transforming towards a modern data-driven patient-oriented approach. This paradigm shift also affects perinatal medicine as predictive algorithms and artificial intelligence are applied to enhance and individualize maternal, neonatal and perinatal care. Here, we introduce a pharmacometrics-based mathematical-statistical computer program (PMX-based algorithm) focusing on hyperbilirubinemia, a medical condition affecting half of all newborns. Independent datasets from two different centers consisting of total serum bilirubin measurements were utilized for model development (342 neonates, 1,478 bilirubin measurements) and validation (1,101 neonates, 3,081 bilirubin measurements), respectively. The mathematical-statistical structure of the PMX-based algorithm is a differential equation in the context of non-linear mixed effects modeling, together with Empirical Bayesian Estimation to predict bilirubin kinetics for a new patient. Several clinically relevant prediction scenarios were validated, i.e., prediction up to 24 h based on one bilirubin measurement, and prediction up to 48 h based on two bilirubin measurements. The PMX-based algorithm can be applied in two different clinical scenarios. First, bilirubin kinetics can be predicted up to 24 h based on one single bilirubin measurement with a median relative (absolute) prediction difference of 8.5% (median absolute prediction difference 17.4 mu mol/l), and sensitivity and specificity of 95.7 and 96.3%, respectively. Second, bilirubin kinetics can be predicted up to 48 h based on two bilirubin measurements with a median relative (absolute) prediction difference of 9.2% (median absolute prediction difference 21.5 mu mol/l), and sensitivity and specificity of 93.0 and 92.1%, respectively. In contrast to currently available nomogram-based static bilirubin stratification, the PMX-based algorithm presented here is a dynamic approach predicting individual bilirubin kinetics up to 48 h, an intelligent, predictive algorithm that can be incorporated in a clinical decision support tool. Such clinical decision support tools have the potential to benefit perinatal medicine facilitating personalized care of mothers and their born and unborn infants

Enhanced early prediction of clinically relevant neonatal hyperbilirubinemia with machine learning

BACKGROUND: Machine learning models may enhance the early detection of clinically relevant hyperbilirubinemia based on patient information available in every hospital. METHODS: We conducted a longitudinal study on preterm and term born neonates with serial measurements of total serum bilirubin in the first two weeks of life. An ensemble, that combines a logistic regression with a random forest classifier, was trained to discriminate between the two classes phototherapy treatment vs. no treatment. RESULTS: Of 362 neonates included in this study, 98 had a phototherapy treatment, which our model was able to predict up to 48 h in advance with an area under the ROC-curve of 95.20%. From a set of 44 variables, including potential laboratory and clinical confounders, a subset of just four (bilirubin, weight, gestational age, hours since birth) suffices for a strong predictive performance. The resulting early phototherapy prediction tool (EPPT) is provided as an open web application. CONCLUSION: Early detection of clinically relevant hyperbilirubinemia can be enhanced by the application of machine learning. Existing guidelines can be further improved to optimize timing of bilirubin measurements to avoid toxic hyperbilirubinemia in high-risk patients while minimizing unneeded measurements in neonates who are at low risk

Serum Neurofilament Levels in Children With Febrile Seizures and in Controls

Objective Neuroaxonal damage is reflected by serum neurofilament light chain (sNfL) values in a variety of acute and degenerative diseases of the brain. The aim of this study was to investigate the impact of febrile and epileptic seizures on sNfL, serum copeptin, and prolactin levels in children compared with children with febrile infections without convulsions. Methods A prospective cross-sectional study was performed in children aging 6 months to 5 years presenting with fever (controls,n= 61), febrile seizures (FS,n= 78), or epileptic seizures (ES,n= 16) at our emergency department. sNfL, copeptin, and prolactin were measured within a few hours after the event in addition to standard clinical, neurophysiological, and laboratory assessment. All children were followed up for at least 1 year after presentation concerning recurrent seizures. Results Serum copeptin values were on average 4.1-fold higher in FS and 3.2-fold higher in ES compared with controls (bothp< 0.01). Serum prolactin values were on average 1.3-fold higher in FS compared with controls ( p< 0.01) and without difference between ES and controls. There was no significant difference of mean sNfL values (95% CI) between all three groups, FS 21.7 pg/ml (19.6-23.9), ES 17.7 pg/ml (13.8-21.6), and controls 23.4 pg/ml (19.2-27.4). In multivariable analysis, age was the most important predictor of sNfL, followed by sex and C reactive protein. Neither the duration of seizures nor the time elapsed from seizure onset to blood sampling had an impact on sNfL. None of the three biomarkers were related to recurrent seizures. Significance Serum neurofilament light is not elevated during short recovery time after FS when compared with children presenting febrile infections without seizures. We demonstrate an age-dependent decrease of sNfL from early childhood until school age. In contrast to sNfL levels, copeptin and prolactin serum levels are elevated after FS

Serum neurofilament light chain (sNfL) values in a large cross-sectional population of children with asymptomatic to moderate COVID-19

Background Serum neurofilament light chain (sNfL) is an established biomarker of neuro-axonal damage in multiple neurological disorders. Raised sNfL levels have been reported in adults infected with pandemic coronavirus disease 2019 (COVID-19). Levels in children infected with COVID-19 have not as yet been reported. Objective To evaluate whether sNfL is elevated in children contracting COVID-19. Methods Between May 22 and July 22, 2020, a network of outpatient pediatricians in Bavaria, Germany, the Coronavirus antibody screening in children from Bavaria study network (CoKiBa), recruited healthy children into a cross-sectional study from two sources: an ongoing prevention program for 1–14 years, and referrals of 1–17 years consulting a pediatrician for possible infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We determined sNfL levels by single molecule array immunoassay and SARS-CoV-2 antibody status by two independent quantitative methods. Results Of the 2652 included children, 148 (5.6%) were SARS-CoV-2 antibody positive with asymptomatic to moderate COVID-19 infection. Neurological symptoms—headache, dizziness, muscle aches, or loss of smell and taste—were present in 47/148 cases (31.8%). Mean sNfL levels were 5.5 pg/ml (SD 2.9) in the total cohort, 5.1 (SD 2.1) pg/ml in the children with SARS-CoV-2 antibodies, and 5.5 (SD 3.0) pg/ml in those without. Multivariate regression analysis revealed age—but neither antibody status, antibody levels, nor clinical severity—as an independent predictor of sNfL. Follow-up of children with pediatric multisystem inflammatory syndrome (n = 14) showed no association with sNfL. Conclusions In this population study, children with asymptomatic to moderate COVID-19 showed no neurochemical evidence of neuronal damage

Safety and Short-term Outcomes of High-Dose Erythropoietin in Preterm Infants With Intraventricular Hemorrhage

IMPORTANCE Intraventricular hemorrhage (IVH) is a major cause of neonatal morbidity and mortality in preterm infants without a specific medical treatment to date. OBJECTIVE To assess the safety and short-term outcomes of high-dose erythropoietin in preterm infants with IVH. DESIGN, SETTING, AND PARTICIPANTS Between April 1, 2014, and August 3, 2018, a randomized double-blind clinical trial enrolled 121 preterm infants (gestational age <32 weeks or birth weight <1500 g) aged 8 or less days with moderate to severe IVH identified by cerebral ultrasonography from 8 Swiss and Austrian tertiary neonatal units. Statistical analyses were performed between October 1, 2019, and September 12, 2022. INTERVENTIONS Infants received intravenous high-dose erythropoietin (2000 units/kg body weight) or placebo at 4time points between weeks land 4 of life. MAIN OUTCOMES AND MEASURES Secondary outcomes included (1) mortality and morbidity rates and (2) brain magnetic resonance imaging findings at term-equivalent age (TEA). The primary outcome was the composite intelligence quotient at 5 years of age (not available before 2023). RESULTS Sixty infants (48% male [n = 29]) were randomly assigned to receive erythropoietin, and 61 infants (61% male [n = 37]) were randomly assigned to receive placebo. The median birth weight was 832 g (IQR, 687-990 g) in the erythropoietin group and 870 g (IQR, 680-1110 g) in the placebo group. Median gestation was 26.1 weeks (IQR, 24.8-27.3 weeks) in the erythropoietin group and 27.0 weeks (24.9-28.1weeks) in the placebo group. The 2 groups had similar baseline characteristics and morbidities. Up to TEA, 10 newborns died (16.7%) in the erythropoietin group, and 5 newborns (8.2%) died in the placebo group (adjusted odds ratio, 2.24 [95% CI, 0.74-7.66]; P = .15). Infants receivingerythropoietin had higher mean hematocrit levels. Conventional magnetic resonance imaging at TEA for 100 infants showed no significant differences in global or regional brain injury scores. CONCLUSIONS AND RELEVANCE This preliminary report of a randomized clinical trial found no evidence that high-dose erythropoietin in preterm infants with IVH affects brain injury scores on conventional magnetic resonance imaging at TEA. Higher mortality in the erythropoietin group was not significant but should be reassessed based on future results from similar trials