Machine learning for understanding and predicting neurodevelopmental outcomes in premature infants: a systematic review

BACKGROUND: Machine learning has been attracting increasing attention for use in healthcare applications, including neonatal medicine. One application for this tool is in understanding and predicting neurodevelopmental outcomes in preterm infants. In this study, we have carried out a systematic review to identify findings and challenges to date. METHODS: This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Four databases were searched in February 2022, with articles then screened in a non-blinded manner by two authors. RESULTS: The literature search returned 278 studies, with 11 meeting the eligibility criteria for inclusion. Convolutional neural networks were the most common machine learning approach, with most studies seeking to predict neurodevelopmental outcomes from images and connectomes describing brain structure and function. Studies to date also sought to identify features predictive of outcomes; however, results varied greatly. CONCLUSIONS: Initial studies in this field have achieved promising results; however, many machine learning techniques remain to be explored, and the consensus is yet to be reached on which clinical and brain features are most predictive of neurodevelopmental outcomes

Cystatin C: a more reliable biomarker of renal function in young infants? A longitudinal cohort study

Aim: We carried out a longitudinal cohort study to measure serial CysC (Cystatin C) in a cohort of neonates born preterm until the age of 2 years. We hypothesised that CysC levels are independent of body weight and would not vary with gestational age. Methods: This prospective cohort study was conducted from August 2014 until October 2016, and follow-up was completed in October 2018. Preterm infants at less than 28 weeks of gestation (extremely preterm infants) were recruited and followed up until the age of 24 months. Blood samples for measurement of CysC were collected at regular intervals. Results: We recruited 58 preterm neonates with mean gestation was 26.2 (1.5) weeks, and a mean birth weight was 917 (140) g. One-way analysis of variance (ANOVA) did not show any significant difference in CysC levels between 28, 32 and 37 weeks' gestation (P = .09) despite a significant increase in body weight (P < .001). The mean CysC level was higher in the neonatal period and subsequently plateaued by 24 months. Conclusion: Serum CysC level is independent of body weight and not influenced by postnatal age nor by gender

Vascular endothelial growth factor-A levels in term neonates

Vascular endothelial growth factor-A (VEGF-A) plays an integral role in physiological and pathophysiological angiogenesis and has increasingly been implicated in the development of retinopathy of prematurity (ROP) in preterm infants. Application of intravitreal anti-VEGF is frequently used to treat ROP with little consideration given to the role of VEGF-A in neonatal growth and development. Previous studies have demonstrated systemic anti-VEGF persistence, reduced peripheral VEGF levels following treatment, and possible diagnostic and prognostic uses for VEGF-A determination. This study seeks to determine a normal range for serum VEGF-A (sVEGF-A) in healthy,term infants. The sVEGF-A levels were obtained from 32 neonates born at term infants (16 males and 16 females) using an enzyme-linked immunosorbent assay. No significant correlations were found between sVEGF-A levels and time of sample collection, birth weight, or gender. The median sVEGF-A level was 976 (394–1635) pg/mL (95% confidence interval for median: 496–1,318 pg/mL). This preliminary study determines a normal range for the sVEGF-A level in healthy, term neonates. This normal range will provide a tool to assist in the diagnosis, prognosis, and monitoring of treatment of infants with ROP

Sex differences in the outcome of very low birth weight premature infants born in a regional Australian Neonatal Intensive Care Unit

Background: Advancements in neonatal care have improved survival for premature and very low birth weight (VLBW) infants. Despite this, differences have been reported when comparing males and females. While the previously described concept of the "male disadvantage" asserts that there is a higher risk of mortality and morbidity for male infants, many studies have also found no sex differences in outcomes. Aim: The objective of this study is to determine if the sex of VLBW premature infants is associated with survival and neurodevelopmental outcome in a regional Australian Neonatal Intensive Care Unit (NICU). Methods: A retrospective cohort study was conducted for infants born at < 37 weeks gestation with VLBW (< 1,500 g) admitted to The Townsville Hospital NICU between 2010 and 2015. Comparisons for survival and neurodevelopment between males and females were made with Chi-square, Fisher's exact test and the Independent t-test. Multivariate logistic regression analysis was performed for the outcomes of death before NICU discharge and developmental delay assessed by the Bayley Scales of Infant and Toddler Development, the 3rd Edition. Results: Data were collected for 430 infants. Fifty-three infants died before NICU discharge, with no sex difference in survival. Follow-up assessment was completed for 84 infants from the original cohort and demonstrated no sex differences in neurodevelopmental outcome. Male infants had a significantly higher prevalence of chronic lung disease (p = 0.009). Neither the logistic regression model for death by NICU discharge nor for neurodevelopmental delay identified sex as a significant predictor of outcome. Conclusions: Male and female VLBW premature infants did not differ in survival or neurodevelopmental outcome at this center

Female preterm indigenous Australian infants have lower renal volumes than males: a predisposing factor for end-stage renal disease?

Aim: Indigenous Australians have an increased risk of developing chronic kidney disease (CKD). Indigenous women have a higher rate of CKD than men. In a cohort of Indigenous and non-Indigenous preterm neonates, we assessed total renal volume (TRV) (a proxy indicator for nephron number). We hypothesized that there would be no difference in renal volume between these two groups at term corrected (37 weeks gestation). Methods: Normally grown preterm neonates less than 32 weeks of gestation were recruited and at term corrected dates, the neonates underwent renal ultrasonography (TRV measurements), urine microalbumin-creatinine ratio and serum analysis for Cystatin C measurement for estimated glomerular filtration rate (eGFR) calculation. Results: One hundred and five neonates (38 Indigenous; 67 non-Indige-nous) were recruited. Indigenous neonates were significantly more prema-ture and of lower birth weight. At term corrected age, Indigenous neonates had a significantly smaller TRV (18.5 (4.2) vs 21.4 (5.1) cm3; P = 0.027) despite no significant difference in body weight. Despite having a smaller TRV, there was no significant difference in eGFR between Indigenous and Non-indigenous neonates (47.8 [43.2–50.4] vs 46.2 [42.6–53.3] ml/min per 1.73 m2; P = 0.986). These infants achieve similar eGFR through hyperfiltra-tion, which likely increases their future risk of CKD. There was no differ-ence in microalbumin-creatinine ratio. Female Indigenous neonates, however, had significantly smaller TRV compared with Indigenous male neonates (15.9 (3.6) vs 20.6 (3.6) cm3; P = 0.006), despite no difference in eGFR, birth weight, gestational age, and weight at term corrected. Conclusion: The difference in TRV is likely to be an important risk factor for the difference in morbidity and mortality from renal disease reported between male and female Indigenous adults

Kidney growth following preterm birth: evaluation with renal parenchyma ultrasonography

Background: Preterm birth impairs nephrogenesis, leading to a reduced nephron endowment which is inextricably linked to hypertension and chronic kidney disease in adults. The aim of this study was to compare nephron endowment between preterm infants to that of intrauterine fetuses at the same gestational age (GA) using a novel indirect ultrasound measurement of the renal parenchymal thickness. We hypothesized that extrauterine and intrauterine renal parenchymal thickness would differ based on altered renal growth environments. Methods: In this observational study, appropriately grown preterm infants (birth weight of between the 5th and 95th percentile) born <32 weeks, admitted to the neonatal department were eligible to participate. Renal parenchymal thickness of the infants was measured at 32- and 37-weeks postmenstrual age (PMA). These measurements were compared to the intrauterine renal parenchymal thickness of appropriately grown fetuses (control). Results: At 32-weeks PMA, the preterm infants had a significantly thinner renal parenchyma compared to fetuses at 32-weeks GA suggesting they had less nephrons, however by 37-weeks there was no significant difference in renal parenchymal thickness. Conclusions: We propose that the differences in the extrauterine growth of the renal parenchyma in preterm infants may be due to a reduced number of nephrons and compensatory hyperfiltration. Impact: This article provides insight into the effects of prematurity on nephrogenesis by comparing extrauterine renal parenchymal growth of born preterm infants to the ideal intrauterine fetal growth. Renal parenchyma thickness measurement using ultrasonography is a novel non-invasive measurement of renal development for the determination of nephron endowment. Differences in the renal parenchymal thickness of the preterm infants may be due to a deficit in nephron number and compensatory hyperfiltration

The use of nitric oxide in premature neonates: a 15-year retrospective chart review

Aim: We aim to describe some characteristics of premature neonates which may predict response to inhaled nitric oxide (iNO). Methods: Neonates < 37 weeks without congenital abnormalities who received a single episode of iNO between January 2002 to December 2016 were included in this retrospective chart review. For the purposes of this study, we defined a response to iNO as being any reduction in fraction of inhaled oxygen (FiO2) at the time of iNO weaning. Results: 52 infants with a 57.7% overall survival were included. There was no significant difference in survival between gender or birth weight groups. Responders were found to be of older gestational age (p = 0.045), had a longer duration of iNO treatment (p = 0.004), longer time to weaning (p = 0.014) and earlier initiation of treatment (p = 0.010). Infants < 1,000 g were less likely to respond to iNO therapy (p = 0.006) and had a higher FiO2 at weaning (p = 0.037). Gender had no effect on response to iNO therapy (p = 0.176). Infants with preterm premature rupture of membranes (PPROM) were treated for longer prior to weaning (p = 0.025), treated for longer overall (p = 0.005) and had a lower FiO2 at weaning (p = 0.018). There was no significant correlation between methaemoglobin level and duration of iNO (R = -0.08; p = 0.57). Conclusions: We found that premature infants with birth weight > 1,000 g and older gestational age were more likely to respond to iNO therapy. Our findings also suggest that infants with PPROM may benefit from the use of iNO for respiratory distress. As a result, these findings support the individualized use of iNO in select premature infants whose premorbid characteristics deem them more likely to have a positive response

Fetal renal parenchyma: evaluation of a novel ultrasound measurement to assess kidney development

Introduction: Abnormal fetal growth can adversely impact renal development and is associated with increased risks of developing hypertension and chronic kidney disease later in life. A non-invasive, sensitive method of assessing normal and abnormal fetal kidney development is required. We hypothesise that the fetal renal parenchymal thickness could be used to evaluate the development of the fetal kidneys and provide an indirect estimate of fetal nephron number. This study uses antenatal ultrasound to assess fetal renal parenchymal growth and blood flow to determine if these are affected by abnormal fetal growth. Methods: A longitudinal, observational study was conducted at the Townsville Hospital, Townsville, Australia between May 2017 to December 2018. Mixed risk women with an accurately dated, singleton pregnancy underwent a pregnancy ultrasound scan at least every four weeks between 16 and 40 weeks gestation. Renal parenchymal thickness and echogenicity, renal volume, fetal growth biometries, amniotic fluid measurements, renal artery Doppler and other fetal Dopplers were assessed in appropriately grown, fetal growth restriction or large for gestational age fetuses. Results: 155 participants were recruited, with 7 participants excluded due to fetal abnormalities. Mixed effects modelling was used so that variations between gestational ages within fetuses and between fetuses was considered. A reference graph was developed for normal fetal renal parenchymal growth. In growth restricted fetuses the renal parenchymal thickness was found to be significantly less when compared to the parenchymal thickness of appropriately grown fetuses. Conclusions: Measurement of the renal parenchymal thickness is an innovative method to evaluate the development of the fetal kidneys. This new chart of fetal renal parenchymal thickness may be useful for the diagnosis of nephropathologies and the identification of infants at risk of kidney disease. Fetal growth restriction was found to adversely affect the renal parenchymal growth. This suggests growth restricted fetuses are born with fewer nephrons and are therefore likely to be more susceptible to hypertension and early onset kidney disease later in life

International Communications

Introduction: Disorders of fetal growth, such as intrauterine growth restriction (IUGR) and large for gestational age (LGA), have been found to have a profound effect on the development of the fetal kidney. Abnormal kidney development is associated with hypertension and chronic kidney disease later in life. This study will use a novel ultrasound measurement to assess the renal parenchymal growth and kidney arterial blood flow in the fetus to evaluate the development of the fetal kidneys and provide an indirect estimate of nephron number. Measurements in normally grown, IUGR and LGA fetuses will be compared to determine if changes in renal parenchymal growth can be detected in utero. Methods and analysis: This longitudinal, prospective, observational study will be conducted over 12 months in the Ultrasound Department of the Townsville Hospital, Australia. The study will compare fetal renal parenchymal thickness (RPT) and renal artery Doppler flow between IUGR fetuses and appropriately grown fetuses, and LGA fetuses and appropriately grown fetuses between 16 and 40 weeks. The fetal RPT to renal volume ratio will also be compared, and correlations between RPT, renal parenchymal echogenicity, fetal Doppler indices and amniotic fluid levels will be analysed. Ethics and dissemination: This study was approved by the Townsville Health District Human Research Ethics Committee. The study results will form part of a thesis and will be published in peer-reviewed journals and disseminated at international conferences

Extra uterine development of preterm kidneys

Objective: We carried out a study to determine the impact of prematurity on renal development. The primary outcomes measured were nephrinuria and albuminuria; renal volume and glomerular filtration rate were the secondary outcomes. Methods: Preterm neonates born at less than 28 weeks of gestation, with birth weight between 10th and 90th centile (appropriate for gestational age), were recruited and underwent assessments at 28, 32 and 37 weeks postmenstrual age (PMA). Results: Fifty-three premature neonates and 31 term neonates (control) were recruited. The median gestational age of the premature neonates was 26.4 [24.7–27.4] weeks, with a mean birth weight of 886 (179) g. The mean gestational age of term neonates was 39.1 (1.2) weeks and the mean birth weight was 3406 (406) g. The median age of the term neonates was 6.5 [3.0–12.5] days. The total kidney volume (TKV) almost doubled from 10.3 (2.9) cm3 at 28 weeks PMA to 19.2 (3.7) cm3 at 37 weeks PMA (P = 0.0001). TKV at 37 weeks PMA was significantly smaller compared to term neonates (19.2 (3.7) vs 26.3 (7.0) cm3; P = 0.0001). However, there was no significant difference in estimated glomerular filtration rate (eGFR) between premature neonates (at 37 weeks PMA) and term neonates (control) (43.5 [39.7–48.9] vs. 42.0 [38.2–50.0] mL/min/1.73 m2; P = 0.75). There was a statistically significant decline in nephrin-creatinine ratio and albumin-creatinine ratio from 32 to 37 weeks PMA. Conclusions: Despite having a smaller renal volume (and fewer nephrons), extremely premature neonates achieve similar eGFRs at corrected term as term-born neonates, likely through single nephron hyperfiltration. Extremely premature neonates also show evidence of glomerular injury