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Artificial Intelligence (AI)-based methods allow for automatic assessment of pain intensity based on continuous monitoring and processing of subtle changes in sensory signals, including facial expression, body movements, and crying frequency. Currently, there is a large and growing need for expanding current AI-based approaches to the assessment of postoperative pain in the neonatal intensive care unit (NICU). In contrast to acute procedural pain in the clinic, the NICU has neonates emerging from postoperative sedation, usually intubated, and with variable energy reserves for manifesting forceful pain responses. Here, we present a novel multi-modal approach designed, developed, and validated for assessment of neonatal postoperative pain in the challenging NICU setting. Our approach includes a robust network capable of efficient reconstruction of missing modalities (e.g., obscured facial expression due to intubation) using an unsupervised spatio-temporal feature learning with a generative model for learning the joint features. Our approach generates the final pain score along with the intensity using an attentional cross-modal feature fusion. Using experimental dataset from postoperative neonates in the NICU, our pain assessment approach achieves superior performance (AUC 0.906, accuracy 0.820) as compared to the state-of-the-art approaches.

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This paper presents the first multimodal neonatal pain dataset that contains visual, vocal, and physiological responses following clinically required procedural and postoperative painful procedures. It was collected from 58 neonates (27-41 gestational age) during their hospitalization in the neonatal intensive care unit. The visual and vocal data were recorded using an inexpensive RGB camera while the physiological responses (vital signs and cortical activity) were recorded using portable bedside monitors. The recorded behavioral and physiological responses were scored by expert nurses using two validated pain scales to obtain the ground truth labels. In addition to behavioral and physiological responses, our dataset contains clinical information such as the neonate's age, gender, weight, pharmacological and non-pharmacological interventions, and previous painful procedures. The presented multimodal dataset can be used to develop artificial intelligence systems that monitor, assess, and predict neonatal pain based on the analysis of behavioral and physiological responses. It can also be used to advance the understanding of neonatal pain, which can lead to the development of effective pain prevention and treatment.

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BACKGROUND AND OBJECTIVES: Infants who begin life in the medicalized environment of the neonatal intensive care unit (NICU) do so under stressful conditions. Environmental exposures are often abrasive to vulnerable infants, while invasive and noninvasive lifesaving interventions provide additional pain and/or stress. The most commonly selected biomarker to measure stress is cortisol. The skin is the barrier between the external environment and communicates with our neurological, endocrine and immune regulatory networks. To examine if skin cortisol may be a reliable biomarker of stress, NICU stress exposure and repeated measurements of skin cortisol in very preterm infants were examined retrospectively during the first 6 weeks of life. The temporal relationship between skin cortisol and NICU stress exposure was also analyzed. MATERIALS AND METHODS: Participants included 82 preterm infants born weighing less than 1500 g, admitted to a level III NICU, with a mean gestational age of 28.5 weeks. Infants were studied from birth through 6 weeks of life. NICU stress data was collected using the Neonatal Infant Stressor Scale. Skin samples were collected using d-squame tape as soon after birth as possible and every two weeks thereafter. RESULTS: On average, infants experienced approximately 43 stressful events per day during the first 6 weeks of life in the NICU. Stress level and cortisol reactivity varied by gestation age. Higher stress resulted in higher cortisol for infant >28 weeks; lower stress scores were associated with higher stress for infants <28 weeks. Stress exposure during 7 days prior to cortisol sampling yielded the highest AUC for the 2 groups. A statistically significant interaction was identified between gestational age and stress exposure during the previous 7 days (p < 0.01). CONCLUSION: This is the first study to demonstrate skin cortisol as a preterm infant biomarker of chronic stress exposure. For infants with appropriate skin maturation, this non-invasive sampling method provides several benefits. Importantly, this method may be less intrusive and disruptive for preterm infants.

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OBJECTIVE: We assessed survival, hospital length of stay (LOS), and costs of medical care for infants with lethal congenital malformations, and also examined the relationship between medical and surgical therapies and survival. STUDY DESIGN: Retrospective cohort study including infants born 1998-2009 with lethal congenital malformations, identified using a longitudinally linked maternal/infant database. RESULTS: The cohort included 786 infants: trisomy 18 (T18, n = 350), trisomy 13 (T13, n = 206), anencephaly (n = 125), bilateral renal agenesis (n = 53), thanatophoric dysplasia/achondrogenesis/lethal osteogenesis imperfecta (n = 38), and infants > 1 of the birth defects (n = 14). Compared to infants without birth defects, infants with T18, T13, bilateral renal agenesis, and skeletal dysplasias had longer survival rates, higher inpatient medical costs, and longer LOS. CONCLUSION: Care practices and survival have changed over time for infants with T18, T13, bilateral renal agenesis, and skeletal dysplasias. This information will be useful for clinicians in counseling families and in shaping goals of care prenatally and postnatally.

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Bedside caregivers assess infants' pain at constant intervals by observing specific behavioral and physiological signs of pain. This standard has two main limitations. The first limitation is the intermittent assessment of pain, which might lead to missing pain when the infants are left unattended. Second, it is inconsistent since it depends on the observer's subjective judgment and differs between observers. Intermittent and inconsistent assessment can induce poor treatment and, therefore, cause serious long-term consequences. To mitigate these limitations, the current standard can be augmented by an automated system that monitors infants continuously and provides quantitative and consistent assessment of pain. Several automated methods have been introduced to assess infants' pain automatically based on analysis of behavioral or physiological pain indicators. This paper comprehensively reviews the automated approaches (i.e., approaches to feature extraction) for analyzing infants' pain and the current efforts in automatic pain recognition. In addition, it reviews the databases available to the research community and discusses the current limitations of the automated pain assessment.

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Infants' early exposure to painful procedures can have negative short and long-term effects on cognitive, neurological, and brain development. However, infants cannot express their subjective pain experience, as they do not communicate in any language. Facial expression is the most specific pain indicator, which has been effectively employed for automatic pain recognition. In this paper, dynamic pain facial expression representation and fusion scheme for automatic pain assessment in infants is proposed by combining temporal appearance facial features and temporal geometric facial features. We investigate the effects of various factors that influence pain reactivity in infants, such as individual variables of gestational age, gender, and race. Different automatic infant pain assessment models are constructed, depending on influence factors as well as facial profile view, which affect the model ability of pain recognition. It can be concluded that the profile-based infant pain assessment is feasible, as its performance is almost as good as that of the whole face. Moreover, gestational age is the most influencing factor for pain assessment, and it is necessary to construct specific models depending on it. This is mainly because of a lack of behavioral communication ability in infants with low gestational age, due to limited neurological development. To our best knowledge, this is the first study investigating infants' pain recognition, highlighting profile facial views and various individual variables.

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OBJECTIVE: To describe difference in cytokines, chemokines, and growth factors (CCGFs) and secretory immunoglobulin A (sIgA) in the breast milk of mothers who gave birth preterm and maternal or infant characteristics related to these immune components. DESIGN: A prospective, repeated-measures, one-group design. SETTING: Data were collected at an 82-bed NICU in West Central Florida. PARTICIPANTS: Seventy-six very-low-birth-weight infants weighing less than 1,500 g and their mothers. METHODS: Daily aliquots of breast milk from mothers of preterm infants were collected from the daily infants' feedings and pooled at the end of each week, and CCGFs and sIgA were measured weekly with MagPix multiplexing (Luminex, Austin, TX) and enzyme-linked immunosorbent assay. RESULTS: The CCGFs showed high individual variability, but the levels of most CCGFs and sIgA fell over time. Immune variables were generally greater in milk from mothers of infants smaller than 1,000 g. The breast milk of mothers of male preterm infants had significantly greater sIgA than the breast milk of mothers of female preterm infants. We found relationships between age, body mass index, parity, sIgA, and some of the CCGFs in the breast milk of women who gave birth preterm. CONCLUSION: Immune molecules declined in concentration over time in the breast milk of mothers who give birth preterm during the NICU stay, and maternal and infant factors appeared to play some role in the levels of these immune molecules. Further exploration of this relationship is warranted.

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OBJECTIVE: To describe longitudinal effects of feeding volume and type of milk on fecal calprotectin (f-CP) in very low-birth weight (VLBW) infants. STUDY DESIGN: Prospective data were collected across Neonatal Intensive Care Unit (NICU) admission for 6 weeks or until discharge in 75 VLBW neonates. The mean gestational age on entry into the study was 29 weeks. RESULTS: Seventy-four (99%) mothers provided expressed milk in varying amounts. Twenty-three mothers (31%) provided exclusive mother's own milk (MOM) throughout. Preterm infant formula (PIF) and pasteurized donor milk were added to feedings of remaining infants. Pooled MOM was analyzed weekly for levels of a panel of cytokines, chemokines, and growth factors, and secretory Immunoglobulin A (sIgA) so that the exact amount of exposure to the gut of these milk bioactives could be estimated. f-CP levels ranged from 160 to 350 µg/g stool. Total feeding volume was positively associated with f-CP, controlling for infant weight, and f-CP levels rose across time. Exclusive MOM feedings for the entire measurement period were associated with rising levels of f-CP, but mixed feedings (MOM with added PIF or pasteurized donor milk (PDM) did not show this increase over time. CONCLUSION: The presence of f-CP may represent a response to milk volumes and MOM, which represents normal development rather than always implicating pathological inflammation in the VLBW infant.

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The objective of this study was to implement and evaluate a quality improvement project (the golden hour pathway [GHP]) aimed at improving the quality and efficiency of care delivered to extremely low birth weight (ELBW) infants <28 weeks gestation and/or <1000 g birth weight during the first hour of life. Process improvement and patient data collected during the quality improvement cycles were compared with retrospective data for ELBW infants admitted to the study neonatal intensive care unit during the 2 years prior to GHP implementation. GHP implementation resulted in improvements compared with past internal performance in time to surfactant administration, time to administration of dextrose and amino acids, body temperature at admission, odds of developing chronic lung disease, and odds of developing retinopathy of prematurity. A standardized interdisciplinary approach to the care of ELBW infants in the first hour of life can lead to more efficient care delivery and contribute to improved outcomes.

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BACKGROUND: An increasing number of infants are diagnosed with neonatal abstinence syndrome (NAS). The study's primary objectives were to describe an academic medical center's level IV neonatal ICU's (NICU's) comprehensive outpatient NAS management effort, measure guideline compliance, and assess its safety. Secondary objectives were to describe the duration and cumulative methadone exposure, and to improve parent and provider knowledge of NAS. METHODS: The study included 22 infants having a gestational age of 35-41 weeks, diagnosed with NAS, and discharged for outpatient methadone management. Discharges spanned 10 months and included 3 improvement periods. The outpatient program includes comprehensive discharge planning, a focused electronic health record (EHR) template, management guidelines, and parent and provider education. RESULTS: Providers complied with using the outpatient management guideline and EHR template, and assessed weight, NAS symptoms, and methadone dose during appointments. Two infants required NAS-related hospital readmission in the study period. From improvement period 1 to period 3 there was no difference in total outpatient days on methadone (58, 53, 74 days, respectively) or cumulative methadone dose (2.7, 2.6, 3.1mg/kg, respectively). A downward trend pattern in cumulative methadone exposure was noted in improvement period 2. Pre- and postimplementation surveys revealed that after implementation, parents had better understanding of NAS before delivery (71% vs. 100%, p = 0.009), while providers had increased comfort with outpatient management (24% vs. 67%, p < 0.001) and educating parents (48% vs. 82%, p = 0.001). CONCLUSION: This preliminary study suggests that outpatient NAS management can be safe when a comprehensive management program is implemented and can result in provider compliance with the program.

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The revised version of the Score for Neonatal Acute Physiology (SNAP-II) has been used across all birth weights and gestational ages to measure the concept of severity of illness in critically ill neonates. The SNAP-II has been operationalized in various ways across research studies. This systematic review seeks to synthesize the available research regarding the utility of this instrument, specifically on the utility of measuring severity of illness sequentially and at later time points. A systematic review was performed and identified 35 research articles that met inclusion and exclusion criteria. The majority of the studies used the SNAP-II instrument as a measure of initial severity of illness on the first day of life. Six studies utilized the SNAP-II instrument to measure severity of illness at later time points and only 2 studies utilized the instrument to prospectively measure severity of illness. Evidence to support the use of the SNAP-II at later time points and prospectively is lacking and more evidence is needed.

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OBJECTIVE: To determine if systematic implementation of the Spatz Ten Steps for Promoting and Protecting Breastfeeding for Vulnerable Infants (Ten Steps) would result in an improvement in the percentage of infants receiving mother's own milk (MOM) at initiation of feedings and at hospital discharge. DESIGN: Continuous quality improvement (QI) process. SETTING: Urban, 82-bed, Level-III NICU. PATIENTS: Very- low-birth-weight (VLBW) infants weighing fewer than 1500 grams. INTERVENTION: The Ten Step method was implemented during a 3-year period. MEASUREMENTS: Process measurements included percentage of VLBW infants receiving MOM at initiation of feeds, number of mothers of VLBW infants with hospital-grade electric breast pump at hospital discharge, and number of mothers of VLBW infants initiating pumping within 6 hours of delivery. Outcome measurements included percentage of VLBW infants with any human milk at discharge to home and parent satisfaction with nurses' support of mother's efforts to breastfeed. Balancing measurements included percentage of VLBW infants at less than the third percentile for growth on the Fenton growth chart at discharge and receiving pasteurized donor milk (PDM). RESULTS: Significant improvements were achieved in the percentages of mothers expressing their milk within 6 hours of delivery, infants receiving MOM at initiation of feeds, and mothers with a hospital-grade pump at discharge. Improvements in these processes resulted in increased parent satisfaction with nurses' support of breastfeeding and a 3.1-fold greater odds of the VLBW infant receiving MOM at discharge in 2013 compared to 2010 (odds ratio [OR]= 3.01, 95% confidence interval [CI] [1.75, 5.17], p < .001). Despite an increase in the use of MOM, there was not a significant increase in VLBW infants discharged at less than the third percentile for growth, and initiation of PDM did not negatively affect the percentage of VLBW infants with any human milk at discharge. CONCLUSIONS: Implementation of the Ten Steps method using QI methodology resulted in significantly improved rates of use of MOM at initiation of feeds and at hospital discharge.

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The very low birth weight (VLBW) infant is at great risk for marked dysbiosis of the gut microbiome due to multiple factors, including physiological immaturity and prenatal/postnatal influences that disrupt the development of a normal gut flora. However, little is known about the developmental succession of the microbiota in preterm infants as they grow and mature. This review provides a synthesis of our understanding of the normal development of the infant gut microbiome and contrasts this with dysbiotic development in the VLBW infant. The role of human milk in normal gut microbial development is emphasized, along with the role of the gut microbiome in immune development and gastroenteric health. Current research provides evidence that the gut microbiome interacts extensively with many physiological systems and metabolic processes in the developing infant. However, to the best of our knowledge, there are currently no studies prospectively mapping the gut microbiome of VLBW infants through early childhood. This knowledge gap must be filled to inform a healthcare system that can provide for the growth, health, and development of VLBW infants. The paper concludes with speculation about how the VLBW infants' gut microbiome might function through host-microbe interactions to contribute to the sequelae of preterm birth, including its influence on growth, development, and general health of the infant host.

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BACKGROUND: There has been a recent increase in availability of banked donor milk for feeding of preterm infants. This milk is pooled from donations to milk banks from carefully screened lactating women. The milk is then pasteurized by the Holder method to remove all microbes. The processed milk is frozen, banked, and sold to neonatal intensive care units (NICUs). The nutrient bioavailability of banked donor milk has been described, but little is known about preservation of immune components such as cytokines, chemokines, and growth factors (CCGF). OBJECTIVE: The objective was to compare CCGF in banked donor milk with mother's own milk (MOM). METHODS: Aliquots (0.5 mL) were collected daily from MOM pumped by 45 mothers of NICU-admitted infants weighing < 1500 grams at birth. All daily aliquots of each mother's milk were pooled each week during 6 weeks of an infant's NICU stay or for as long as the mother provided MOM. The weekly pooled milk was measured for a panel of CCGF through multiplexing using magnetic beads and a MAGPIX instrument. Banked donor milk samples (n = 25) were handled and measured in the same way as MOM. RESULTS: Multiplex analysis revealed that there were levels of CCGF in banked donor milk samples comparable to values obtained from MOM after 6 weeks of lactation. CONCLUSION: These data suggest that many important CCGF are not destroyed by Holder pasteurization.

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BACKGROUND: Antenatal MgSO4 administration is used extensively as a tocolytic agent and to treat preeclampsia. Various effects on the fetus and newborn have been reported, and MgSO4 has well-documented vasoactive effects. OBJECTIVE: To determine if antenatal MgSO4 administration affects intestinal blood flow velocity in newborn preterm infants. METHODS: Peak, mean and end-diastolic velocities in the superior mesenteric artery were measured on day 1 of life. Maternal medical records were reviewed to identify infants whose mothers had been administered MgSO4 for preterm labor or preeclampsia within 24 h of delivery. RESULT: Fifty-six infants were studied: 27 were exposed and 29 were not exposed to antenatal MgSO4. Mean birth weight (1,371 ± 349 and 1,401 ± 469 g, respectively), gestational age (29.7 ± 2.0 and 30.0 ± 2.9 weeks, respectively) and infant hemodynamic and clinical variables (other than clinical indication for antenatal MgSO4 administration) were similar between groups. There were no significant differences between the exposed and unexposed groups in intestinal blood flow velocities. For the exposed group, however, there was a significant negative correlation between mean velocity and the number of hours from birth to the time superior mesenteric artery blood flow velocity measurements were made (p = 0.002); there was no correlation for the unexposed group (p = 0.852). CONCLUSION: Group mean values indicate that antenatal exposure to MgSO4 does not significantly affect intestinal blood flow velocity in newborn preterm infants. However, the significant negative relationship between mean blood flow velocity and time from birth to blood flow velocity measurement in exposed infants suggests that there may be measurable effects of MgSO4 exposure within the hours immediately after birth. Trials that prospectively evaluate the development of intestinal blood flow velocities are needed to further clarify potential effects of antenatal MgSO4 on the gastrointestinal tract of preterm infants.

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Neonates with congenital diaphragmatic hernia (CDH) often have other major malformations. Anatomic airway anomalies associated with CDH include congenital stenosis, pulmonary hypoplasia, and abnormal bronchial branching. We describe an infant with CDH who, after developing recurrent upper-lobe atelectasis, was found to have a right tracheal bronchus. This clinically significant anomaly can have important and potentially preventable adverse consequences.

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UNLABELLED: We investigated the effects of maternal docosahexanoic acid (DHA) supplementation on pups' auditory startle responses and the composition of brain myelin. METHODS: Timed-pregnant rats were fed throughout pregnancy and lactation diets that contained 0, 0.3, 0.7 or 3% of total fatty acids as DHA. Milk was collected from culled pups' stomachs on postnatal day (PND) 3, latency of the auditory startle reflex was measured on PND 15, and pups were killed and brains collected on PND 24. RESULTS: Higher levels of DHA in maternal diet were reflected in milk and in pups' myelin. The latency of the auditory startle response was significantly longer in offspring of dams fed higher levels of DHA. There was a positive correlation between the myelin content of DHA and the latency of the startle response (p = 0.044), and a negative correlation between the myelin content of DHA and the myelin content of cholesterol (p = 0.005). CONCLUSION: High levels of maternal DHA intake alter the lipid composition of rat pup myelin, and are associated with longer latencies of the auditory startle response--a myelin-dependent electrophysiologic response.

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BACKGROUND: Quantitative ultrasound measurement of the speed of sound (SOS) through bone has been investigated as a means of assessing bone status in preterm infants. Few studies report longitudinal measurements. OBJECTIVE: To assess longitudinal changes in bone SOS in preterm infants. METHODS: Sixty preterm infants with gestational ages of < 33 weeks and with birth weight appropriate for gestational age (AGA), and 48 healthy, term AGA infants were enrolled. SOS measurements of the tibia were made within the first week of life in the preterm infants, and within the first 72 hours of life in the term infants. During their hospital stay, weekly measurements of tibial SOS were made in 29 of the preterm infants, who were divided into three gestational age groups: Group 1: 24-26 weeks (n = 8), Group 2: 27-29 weeks (n = 9), and Group 3: 30-32 weeks (n = 12). RESULTS: The median SOS value for the 60 newborn preterm infants was significantly lower than that for the 48 newborn term infants (2,924 versus 3,036 m/sec, p < 0.001). At each time point, SOS values for each of the preterm infant gestational age groups were significantly lower than the term newborn infant SOS values. SOS values decreased significantly over time for the entire cohort of 29 preterm infants (p < 0.001), and for Groups 1 (p = 0.015) and 2 (p = 0.003). At several time points, there was a significant negative correlation between serum alkaline phosphatase levels and SOS values, and a significant positive correlation between serum phosphorus levels and SOS values. CONCLUSION: SOS measurements of the tibia decline during hospitalization in preterm infants, suggesting a progressive loss of bone strength. Longitudinal measurements of bone SOS in combination with serum alkaline phosphatase and serum phosphorus levels may identify infants at risk of developing osteopenia of prematurity.

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Metabolic bone disease of prematurity (MBDP) is a common and significant problem that often gives rise to osteopenia, fractures, osteomalacia, and osteoporosis. The purpose of our study is to establish normative data on bone status in premature and full-term infants to help future studies on MBDP. Bone status was prospectively determined as part of a multicenter study among newborns within 96 hours of life. The patients were divided into 2 groups: group 1 included those neonates 25-36 wk gestational age (premature), and group 2 neonates were born at 37-42 wk gestational age (full term). Demographic data were collected. The Omnisense 7000 Bone Sonometer (Sunlight Medical Ltd., Tel-Aviv, Israel) was used to determine the speed of sound (SOS) through the mid tibia, which reflects bone strength. A total of 235 patients were enrolled in this study. Group 1 (i.e., the premature infants) had a statistically lower age-adjusted SOS as compared with group 2 (i.e., the full-term infants) (analysis of variance; p=0.001). There was also a correlation between SOS and birth weight (r=0.3; p<001). This study represents the largest database of normative data for bone status measuring in preterm and term infants.

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OBJECTIVE: Quantitative ultrasound is increasingly used to assess bone status in adults and children; however, few studies have been carried out in neonates. Our objective was to determine if tibial bone speed of sound (SOS) correlates with gestational age and birth anthropometrics, and if bone SOS is related to maternal factors. STUDY DESIGN: We prospectively studied 95 preterm infants to assess factors related to bone status as measured by quantitative ultrasound. RESULTS: We found significant (p< or =0.001) positive correlations between SOS and gestational age, birth weight, length, head circumference and tibial length. There was no significant relationship between SOS and prenatal steroid use, gestational diabetes, pre-eclampsia, race or parity. CONCLUSIONS: Quantitative ultrasound is an easy to use and inexpensive tool for assessing bone status in preterm neonates. Tibial SOS correlated with gestational age and birth anthropometrics, and was not related by few maternal factors.

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