Bedside application of the Neonatal Facial Coding System in pain assessment of premature neonates

Assessment of infant pain is a pressing concern, especially within the context of neonatal intensive care where infants may be exposed to prolonged and repeated pain during lengthy hospitalization. In the present study the feasibility of carrying out the complete Neonatal Facial Coding System (NFCS) in real time at bedside, specifically reliability, construct and concurrent validity, was evaluated in a tertiary level Neonatal Intensive Care Unit (NICU). Heel lance was used as a model of procedural pain, and observed with n = 40 infants at 32 weeks gestational age. Infant sleep/wake state, NFCS facial activity and specific hand movements were coded during baseline, unwrap, swab, heel lance, squeezing and recovery events. Heart rate was recorded continuously and digitally sampled using a custom designed computer system. Repeated measures analysis of variance (ANOVA) showed statistically significant differences across events for facial activity (P <0.0001) and heart rate (P <0.0001). Planned comparisons showed facial activity unchanged during baseline, swab and unwrap, then increased significantly during heel lance (P <0.0001), increased further during squeezing (P <0.003), then decreased during recovery (P <0.0001). Systematic shifts in sleep/wake state were apparent. Rise in facial activity was consistent with increased heart rate, except that facial activity more closely paralleled initiation of the invasive event. Thus facial display was more specific to tissue damage compared with heart rate. Inter-observer reliability was high. Construct validity of the NFCS at bedside was demonstrated as invasive procedures were distinguished from tactile. While bedside coding of behavior does not permit raters to be blind to events, mechanical recording of heart rate allowed for an independent source of concurrent validation for bedside application of the NFCS scale.

Neonatal facial and cry responses to invasive and non-invasive procedures

Evaluation of pain in neonates is difficult due to their limited means of communication. The aim was to determine whether behavioural reactions of cry and facial activity provoked by an invasive procedure could be discriminated from responses to non-invasive tactile events. Thirty-six healthy full-term infants (mean age 2.2 h) received 3 procedures in counterbalanced order: intramuscular injection, application of triple dye to the umbilical stub, and rubbing thigh with alcohol. Significant effects of procedure were found for total face activity and latency to face movement. A cluster of facial actions comprised of brow bulging, eyes squeezed shut, deepening of the naso-labial furrow and open mouth was associated most frequently with the invasive procedure. Comparisons between the 2 non-invasive procedures showed more facial activity to thigh swabbing and least to application of triple dye to the umbilical cord. Acoustic analysis of cry showed statistically significant differences across procedures only for latency to cry and cry duration for the group as a whole. However, babies who cried to two procedures showed higher pitch and greater intensity to the injection. There were no significant differences in melody, dysphonation, or jitter. Methodological difficulties for investigators in this area were examined, including criteria for the selection of cries for analysis, and the logical and statistical challenges of contrasting cries induced by different conditions when some babies do not always cry. It was concluded that facial expression, in combination with short latency to onset of cry and long duration of first cry cycle typifies reaction to acute invasive procedures.

The impact of body mass index on maternal and neonatal outcomes: a retrospective study in a UK obstetric population, 2004-2011

Objective: To assess the prevalence of overweight and obesity, and the impact of body mass index (BMI) on maternal and neonatal outcomes, in a UK obstetric population.
Design: Retrospective study.
Setting: A tertiary referral unit in Northern Ireland.
Population: A total of 30 298 singleton pregnancies over an 8-year period, 2004–2011.
Methods: Women were categorised according to World Health Organization classification: underweight (BMI < 18.50 kg/m2); normal weight (BMI 18.50–24.99 kg/m2; reference group); overweight (BMI 25.00–29.99 kg/m2); obese class I (BMI 30.00–34.99 kg/m2); obese class II (BMI 35–39.99 kg/m2); and obese class III (BMI = 40 kg/m2). Maternal and neonatal outcomes were examined using logistic regression, adjusted for confounding variables.
Main outcome measures: Maternal and neonatal outcomes.
Results: Compared with women of normal weight, women who were overweight or obese class I were at significantly increased risk of hypertensive disorders of pregnancy (OR 1.9, 99% CI 1.7–2.3; OR 3.5, 99% CI 2.9–4.2); gestational diabetes mellitus (OR 1.7, 99% CI 1.3–2.3; OR 3.7, 99% CI 2.8–5.0); induction of labour (OR 1.2, 99% CI 1.1–1.3; OR 1.3, 99% CI 1.2–1.5); caesarean section (OR 1.4, 99% CI 1.3–1.5; OR 1.8, 99% CI 1.6–2.0); postpartum haemorrhage (OR 1.4, 99% CI 1.3–1.5; OR 1.8, 1.6–2.0); and macrosomia (OR 1.5, 99% CI 1.3–1.6; OR 1.9, 99% CI 1.6–2.2), with the risks increasing for obese classes II and III. Women in obese class III were at increased risk of preterm delivery (OR 1.6, 99% CI 1.1–2.5), stillbirth (OR 3.0, 99% CI 1.0–9.3), postnatal stay > 5 days (OR 2.1, 99% CI 1.5–3.1), and infant requiring admission to a neonatal unit (OR 1.6, 99% CI 1.0–2.6).
Conclusions: By categorising women into overweight and obesity subclassifications (classes I –III), this study clearly demonstrates an increasing risk of adverse outcomes across BMI categories, with women who are overweight also at significant risk.
Keywords Body mass index, maternal and neonatal outcomes,obesity, pregnancy

Hyperglycemia and adverse pregnancy outcome study:Neonatal glycemia

OBJECTIVE: The goal was to describe the temporal pattern of neonatal plasma glucose levels and associations with maternal glucose levels, cord serum C-peptide levels, and neonatal size and adiposity. METHODS: A total of 17 094 mothers and infants were included in the Hyperglycemia and Adverse Pregnancy Outcome Study (15 centers in 9 countries). Mothers underwent a 75-g, 2-hour, oral glucose tolerance test (OGTT) at 24 to 32 weeks of gestation. Cord blood and neonatal blood samples were collected. Biochemical neonatal hypoglycemia was defined as glucose levels of 90th percentile. CONCLUSIONS: Mean neonatal plasma glucose concentrations varied little in the first 5 hours after birth, which suggests normal postnatal adjustment. Biochemical and clinical hypoglycemia were weakly related to maternal OGTT glucose measurements but were strongly associated with elevated cord serum C-peptide levels. Larger and/or fatter infants were more likely to develop hypoglycemia and hyperinsulinemia. These relationships suggest physiologic relationships between maternal glycemia and fetal insulin production. Copyright © 2010 by the American Academy of Pediatrics.

Hyperglycemia and adverse pregnancy outcome (HAPO) study:Associations with neonatal anthropometrics

OBJECTIVE-To examine associations of neonatal adiposity with maternal glucose levels and cord serum C-peptide in a multicenter multinational study, the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, thereby assessing the Pederson hypothesis linking maternal glycemia and fetal hyperinsulinemia to neonatal adiposity. RESEARCH DESIGN AND METHODS-Eligible pregnant women underwent a standard 75-g oral glucose tolerance test between 24 and 32 weeks gestation (as close to 28 weeks as possible). Neonatal anthropometrics and cord serum C-peptide were measured. Associations of maternal glucose and cord serum C-peptide with neonatal adiposity (sum of skin folds >90th percentile or percent body fat >90th percentile) were assessed using multiple logistic regression analyses, with adjustment for potential confounders, including maternal age, parity, BMI, mean arterial pressure, height, gestational age at delivery, and the baby's sex. RESULTS-Among 23,316 HAPO Study participants with glucose levels blinded to caregivers, cord serum C-peptide results were available for 19,885 babies and skin fold measurements for 19,389. For measures of neonatal adiposity, there were strong statistically significant gradients across increasing levels of maternal glucose and cord serum C-peptide, which persisted after adjustment for potential confounders. In fully adjusted continuous variable models, odds ratios ranged from 1.35 to 1.44 for the two measures of adiposity for fasting, 1-h, and 2-h plasma glucose higher by 1 SD. CONCLUSIONS-These findings confirm the link between maternal glucose and neonatal adiposity and suggest that the relationship is mediated by fetal insulin production and that the Pedersen hypothesis describes a basic biological relationship influencing fetal growth. © 2009 by the American Diabetes Association.

Maternal Vitamin D Status in Type 1 Diabetic Pregnancy: Impact on Neonatal Vitamin D Status and Association with Maternal Glycaemic Control

Objective: The first aim of this study was to assess 25-hydroxy vitamin D (25OHD) concentrations in women with type 1 diabetes (T1DM) during pregnancy, post-delivery and also foetal (cord blood) 25OHD concentrations and to examine relationships between these. The second aim of the study was to investigate potential interactions between maternal body mass index (BMI) and foetal vitamin D status. A further study aim was to examine potential relationships between maternal 25OHD and glycosylated haemoglobin (HbA_1c) throughout pregnancy.

Research Design and Methods: This was an observational study of 52 pregnant controls without diabetes and 65 pregnant women with T1DM in a university teaching hospital. Maternal serum 25OHD was measured serially throughout the pregnancy and post-delivery. Cord blood 25OHD was measured at delivery. 25OHD was measured by liquid chromatography tandem mass spectrometry (LC-MS/MS).

Results: Vitamin D deficiency (25OHD <25 nmol/L) was apparent in both the T1DM subjects and controls at all 3 pregnancy trimesters. Vitamin D levels in all cord blood were <50 nmol/L. Maternal 25OHD correlated positively with cord 25OHD at all 3 trimesters in the T1DM group (p= 0.02; p<0.001; p<0.001). 25OHD levels within cord blood were significantly lower for women with diabetes classified as obese vs. normal weight at booking [normal weight BMI <25 kg/m² vs. obese BMI >30 kg/m² (nmol/L±SD); 19.93±11.15 vs. 13.73±4.74, p= 0.026]. In the T1DM group, HbA_1c at booking was significantly negatively correlated with maternal 25OHD at all 3 trimesters (p= 0.004; p = 0.001; p= 0.05).

Conclusion: In T1DM pregnancy, low vitamin D levels persist throughout gestation and post-delivery. Cord blood vitamin D levels correlate with those of the mother, and are significantly lower in obese women than in their normal weight counterparts. Maternal vitamin D levels exhibit a significant negative relationship with HbA_1c levels, supporting a potential role for this vitamin in maintaining glycaemic control. 

The sympathetic release test: a test used to assess thermoregulation and autonomic control of blood flow

When a subject is heated, the stimulation of temperature-sensitive nerve endings in the skin, and the raising of the central body temperature, results in the reflex release of sympathetic vasoconstrictor tone in the skin of the extremities, causing a measurable temperature increase at the site of release. In the sympathetic release test, the subject is gently heated by placing the feet and calves in a commercially available foot warming pouch or immersing the feet and calves in warm water and wrapping the subject in blankets. Skin blood flow is estimated from measurements of skin temperature in the fingers. Normally skin temperature of the fingers is 65-75 degrees F in cool conditions (environmental temperature: 59-68 degrees F) and rises to 85-95 degrees F during body heating. Deviations in this pattern may mean that there is abnormal sympathetic vasoconstrictor control of skin blood flow. Abnormal skin blood flow can substantially impair an individual's ability to thermoregulate and has important clinical implications. During whole body heating, the skin temperature from three different skin sites is monitored and oral temperature is monitored as an index of core temperature. Students determine the fingertip temperature at which the reflex release of sympathetic activity occurs and its maximal attainment, which reflects the vasodilating capacity of this cutaneous vascular bed. Students should interpret typical sample data for certain clinical conditions (Raynaud's disease, peripheral vascular disease, and postsympathectomy) and explain why there may be altered skin blood flow in these disorders.

Neonatal Pain-Related Stress and NFKBIA Genotype Are Associated with Altered Cortisol Levels in Preterm Boys at School Age

Neonatal pain-related stress is associated with elevated salivary cortisol levels to age 18 months in children born very preterm, compared to full-term, suggesting early programming effects. Importantly, interactions between immune/inflammatory and neuroendocrine systems may underlie programming effects. We examined whether cortisol changes persist to school age, and if common genetic variants in the promoter region of the NFKBIA gene involved in regulation of immune and inflammatory responses, modify the association between early experience and later life stress as indexed by hair cortisol levels, which provide an integrated index of endogenous HPA axis activity. Cortisol was assayed in hair samples from 128 children (83 born preterm =32 weeks gestation and 45 born full-term) without major sensory, motor or cognitive impairments at age 7 years. We found that hair cortisol levels were lower in preterm compared to term-born children. Downregulation of the HPA axis in preterm children without major impairment, seen years after neonatal stress terminated, suggests persistent alteration of stress system programming. Importantly, the etiology was gender-specific such that in preterm boys but not girls, specifically those with the minor allele for NFKBIA rs2233409, lower hair cortisol was associated with greater neonatal pain (number of skin-breaking procedures from birth to term), independent of medical confounders. Moreover, the minor allele (CT or TT) of NFKBIA rs2233409 was associated with higher secretion of inflammatory cytokines, supporting the hypothesis that neonatal pain-related stress may act as a proinflammatory stimulus that induces long-term immune cell activation. These findings are the first evidence that a long-term association between early pain-related stress and cortisol may be mediated by a genetic variants that regulate the activity of NF-?B, suggesting possible involvement of stress/inflammatory mechanisms in HPA programming in boys born very preterm. © 2013 Grunau et al.

Risk assessment of neonatal excipient exposure:Lessons from food safety and other areas

Newborn babies can require significant amounts of medication containing excipients intended to improve the drug formulation. Most medicines given to neonates have been developed for adults or older children and contain excipients thought to be safe in these age groups. Many excipients have been used widely in neonates without obvious adverse effects. Some excipients may be toxic in high amounts in which case they need careful risk assessment. Alternatively, it is conceivable that ill-founded fears about excipients mean that potentially useful medicines are not made available to newborn babies. Choices about excipient exposure can occur at several stages throughout the lifecycle of a medicine, from product development through to clinical use. Making these choices requires a scalable approach to analysing the overall risk. In this contribution we examine these issues.

Neonatal intensive care and late preterm infants:Health and family functioning at three years

Background: Late preterm infants (LPIs), born at 34 + 0 to 36 + 6 weeks of gestation contribute a significant proportion of all neonatal intensive care (NIC) admissions and are regarded as being at risk of adverse outcomes compared to term-born infants.

Aim: To explore the health outcomes and family functioning of LPIs who required neonatal intensive care, at three years of age.

Study design and subjects: This cohort study included 225 children born late preterm, between 1 January and 31 December 2006 in Northern Ireland. Children admitted for NIC (study group, n = 103) were compared with children who did not require NIC or who required special care only for up to three days (comparison group, n = 122).

Outcome measures
Health outcomes were measured using the Health Status Questionnaire, health service usage by parent report and family functioning using the PedsQL™ Family Impact Module.

Results: LPIs who required NIC revealed similar health outcomes at three years in comparison to those who did not. Despite this, more parents of LPIs who required NIC reported visiting their GP and medical specialists during their child's third year of life. Differences in family functioning were also observed with mothers of LPIs who required NIC reporting, significantly lower levels of social and physical functioning, increased difficulties with communication and increased levels of worry.

Conclusions: LPIs were observed to have similar health outcomes at three years of age regardless of NIC requirement. The increase in GP and medical specialist visits and family functioning difficulties observed among those infants who required NIC merits further investigation.

Abbreviations: LPI, late preterm infant; NIC, neonatal intensive care; HSQ, Health Status Questionnaire; GP, general practitioner

Behavioural outcomes at 3 years of age among late preterm infants admitted to neonatal intensive care: a cohort study

Objective: Examine the behavioural outcomes at age 3 years of late preterm infants (LPIs) who were admitted to neonatal intensive care (NIC) in comparison with LPIs who were not admitted.
Method: This cohort study prospectively recruited 225 children born late preterm (34–36+6 weeks gestation) in 2006 in Northern Ireland, now aged 3 years. Two groups were compared: LPIs who received NIC (study; n=103) and LPIs who did not receive NIC (control; n=122). Parents/guardians completed the Child Behaviour Checklist/1½-5. Descriptive maternal and infant data were also collected.
Results: As expected LPI children admitted to NIC had higher medical risk than the non-admitted comparison group (increased caesarean section, born at earlier gestation, lower birth weight and an episode of resuscitation at birth). LPIs admitted to NIC scored higher on the Child Behaviour Checklist/1½-5 compared with those who were not admitted indicating more behavioural problems; this was statistically significant for the Aggressive Behaviour Subscale (z=−2.36) and the Externalising Problems Scale (z=−2.42). The group difference on the Externalising Problems Scale was no longer significant after controlling for gender, gestational age and deprivation score.
Conclusions: This study provides valuable data on the behaviour at age 3 years of LPIs admitted to NIC compared with LPIs not admitted to NIC. Further research would be beneficial to explore medical and psychosocial explanations for observed differences between groups using large prospective cohort studies.