Quantifying noxious-evoked baseline sensitivity in neonates to optimise analgesic trials.

Despite the high burden of pain experienced by hospitalised neonates, there are few analgesics with proven efficacy. Testing analgesics in neonates is experimentally and ethically challenging and minimising the number of neonates required to demonstrate efficacy is essential. EEG (electroencephalography)-derived measures of noxious-evoked brain activity can be used to assess analgesic efficacy; however, as variability exists in neonate's responses to painful procedures, large sample sizes are often required. Here, we present an experimental paradigm to account for individual differences in noxious-evoked baseline sensitivity which can be used to improve the design of analgesic trials in neonates. The paradigm is developed and tested across four observational studies using clinical, experimental, and simulated data (92 neonates). We provide evidence of the efficacy of gentle brushing and paracetamol, substantiating the need for randomised controlled trials of these interventions. This work provides an important step towards safe, cost-effective clinical trials of analgesics in neonates.

Hospitalized newborns often undergo medical procedures, like blood tests, without pain relief. This can cause the baby to experience short-term distress that may have negative consequences later in life. However, testing the effects of pain relief in newborns is challenging because, unlike adults, they cannot report how much pain they are experiencing. One way to overcome this is to record the brain activity of newborns during a painful procedure and to see how these signals are modified following pain relief. Randomized controlled trials are the gold standard for these kinds of medical assessments, but require a high number of participants to account for individual differences in how babies respond to pain. Finding ways to reduce the size of pain control studies could lead to faster development of pain relief methods. Here, Cobo, Hartley et al. demonstrate a way to reduce the number of newborns needed to test potential pain-relieving interventions. In the experiments, the brain activity of nine babies was measured after a gentle poke and after a painful clinically required procedure. Cobo, Hartley et al. found that the babies' response to the gentle poke correlated with their response to pain. Further data analysis revealed that this information can be used to predict the variability in pain experienced by different newborns, reducing the number of participants needed for pain relief trials. Next, Cobo, Hartley et al. used this new approach in two pilot tests. One showed that gently stroking an infant's leg before blood is drawn from their heel reduced their brains' response to pain. The second showed that giving a baby the painkiller paracetamol lessened the brain's response to immunisation. The new approach identified by Cobo, Hartley et al. may enable smaller studies that can more quickly identify ways to reduce pain in babies. Furthermore, this work suggests that gentle brushing and paracetamol could provide pain relief for newborns undergoing hospital acute procedures. However, more formal clinical trials are needed to test the effectiveness of these two strategies.

Selenium-associated DNA methylation modifications in placenta and neurobehavioral development of newborns: An epigenome-wide study of two U.S. birth cohorts.

BACKGROUND/AIM: Selenium (Se) levels in pregnancy have been linked to neurobehavioral development of the offspring. DNA methylation is a potential mechanism underlying the impacts of environmental exposures on fetal development; however, very few studies have been done elucidating the role of DNA methylation linking prenatal Se and child neurobehavior. We aimed to investigate the associations between placental Se concentration and epigenome-wide DNA methylation in two U.S. cohorts, and to assess the association between Se-related DNA methylation modifications and newborns' neurobehavior. METHODS: We measured placental Se concentrations in 343 newborns enrolled in the New Hampshire Birth Cohort Study and in 141 newborns in the Rhode Island Child Health Study. Genome-wide placental DNA methylation was measured by HumanMethylation450 BeadChip, and newborn neurobehavioral development was assessed by the NICU Network Neurobehavioral Scales (NNNS). We meta-analyzed the associations between placental Se concentration and DNA methylation in each cohort, adjusting for covariates. We also fit multiple linear regression and ordinal logistic regression for methylation and newborn NNNS summary scores. RESULTS: We identified five Se-related differentially methylated CpG sites. Among them was cg09674502 (GFI1), where selenium concentration was positively associated with methylation (ß-coefficient = 1.11, FDR-adjusted p-value = 0.045), and where we observed that a one percent methylation level increase was associated with a 15% reduced odds of higher muscle tone in the arms, legs and trunk of newborns, (OR [95% Confidence Interval, CI] = 0.85 [0.77, 0.95]). We also observed for each interquartile range (IQR) increase in selenium concentration in the placenta, there was 1.76 times greater odds of higher hypotonicity (OR [95% CI] = 1.76 [1.12, 2.82]). CONCLUSIONS: Placental selenium concentration was inversely associated with muscle tone of newborns, and hypermethylation of GFI1 could be a potential mechanism underlying this association.

The effect of vitamin B12 supplementation in Nepalese infants on growth and development: study protocol for a randomized controlled trial.

BACKGROUND: Vitamin B12 deficiency is one of the most common micronutrient deficiencies and is associated with poor cognitive development and growth. Vitamin B12 is crucial for normal cell division and differentiation, and it is necessary for the development and myelination of the central nervous system. The aim of the present study is to measure the effect of daily supplementation of vitamin B12 on the neurodevelopment and growth of young children in Nepal. METHODS/DESIGN: We are conducting an individually randomized, double-blind, placebo-controlled trial with 600 marginally stunted children 6-11 months old (length for age less than -1 z-score). Children are randomized to receive a lipid-based paste containing vitamin B12 or placebo daily for 12 months. The main outcomes are changes in growth (z-scores) and in neurodevelopment measured by the Bayley Scales of Infant and Toddler Development, Third Edition, from baseline until the end of the study. DISCUSSION: If vitamin B12 supplementation benefits early child development and growth, this will have consequences for dietary recommendations for malnourished children worldwide. TRIAL REGISTRATIONS: ClinicalTrials.gov Identifier: NCT02272842 . Registered on 21 October 2014. Universal Trial Number: U1111-1161-5187. Registered on 8 September 2014.

Role of chelation in the treatment of lead poisoning: discussion of the Treatment of Lead-Exposed Children Trial (TLC).

Lead exposure in children is one component leading to cognitive impairment. The Treatment of Lead-Exposed Children Trial (1994-2004) studied the effect of succimer in treating low levels of lead exposure (20-44 mcg/dL) in children 12 to 33 months old. While succimer was effective in reducing blood lead concentrations in the short term, treatment of blood lead levels did not result in any detectable improvement in a wide variety of measurements of cognitive or behavioral function. Furthermore, blood lead concentrations were not distinguishable between chelated and non-chelated individuals at 1 year. The most important treatment strategy is identification and termination of major sources of lead exposure.

Meta-analysis of long-chain polyunsaturated fatty acid supplementation of formula and infant cognition.

BACKGROUND AND OBJECTIVE: Infant formula is supplemented with long-chain polyunsaturated fatty acids (LCPUFAs) because they are hypothesized to improve cognition. Several randomized controlled clinical trials have examined the effect of LCPUFA supplementation of infant formula on cognitive development. We conducted this meta-analysis to examine the efficacy of LCPUFA supplementation of infant formula on early cognitive development. METHODS: Two authors searched PubMed, PsychInfo, and Scopus for randomized controlled clinical trials assessing the efficacy of LCPUFA supplementation of infant formulas on cognition. Our analysis was restricted to randomized controlled clinical trials that examined the effect of LCPUFA supplementation on infant cognition using Bayley Scales of Infant Development. Our primary outcome was the weighted mean difference in Bayley Scales of Infant Development score between infants fed formula supplemented with LCPUFA compared with unsupplemented formula. We conducted secondary subgroup analyses and meta-regression to examine the effects of study sample, LCPUFA dose, and trial methodologic quality on measured efficacy of supplementation. RESULTS: Twelve trials involving 1802 infants met our inclusion criteria. Our meta-analysis demonstrated no significant effect of LCPUFA supplementation of formula on infant cognition. There was no significant heterogeneity or publication bias between trials. Secondary analysis failed to show any significant effect of LCPUFA dosing or prematurity status on supplementation efficacy. CONCLUSIONS: LCPUFA supplementation of infant formulas failed to show any significant effect on improving early infant cognition. Further research is needed to determine if LCPUFA supplementation of infant formula has benefits for later cognitive development or other measures of neurodevelopment.

Allergic disease in the first year of life is associated with differences in subsequent neurodevelopment and behaviour.

BACKGROUND: Recent trials suggest a link between neuropsychological function, atopy and allergic disease particularly in early childhood; however the nature of this association remains unclear. AIMS: To investigate the relationship between early allergic disease and sensitisation at 12 months of age and neurodevelopmental outcomes at 18 months. STUDY DESIGN: Linear or binary logistic regression analysis was used to determine whether allergic diseases or sensitization at 12 months of age was a significant predictor of neurodevelopmental test scores at the 18 months. SUBJECTS: Infants with a maternal history of allergic disease (n=324). OUTCOME MEASURES: Allergic outcomes at 12 months of age included allergen sensitisation, eczema, IgE-mediated and food allergy, and neurodevelopmental outcomes at 18 included the Bayley Scales of Infant Toddler Development III Edition, the Achenbach Child Behaviour Checklist and the Macarthur Scales of Infant Toddler Development. RESULTS: Children with any diagnosed allergic disease at 12 months had evidence of reduced motor scores (p=.016), and this was most apparent for a diagnosis of eczema (p=.007). Non-IgE mediated food allergy was significantly positively associated with problem Internalising Behaviours (p=.010), along with a trend for effects on the Social-Emotional composite score for IgE-Mediated food allergies (p=.052). Allergic sensitisation was not independently associated with any effects on neurodevelopmental outcomes. CONCLUSION: This study provides evidence that an allergic phenotype in infancy is associated with effects on neurodevelopment. Further research is required to investigate the nature of this relationship.

The effect of nutritional supplementation on physical activity and exploratory behavior of Mexican infants aged 8-12 months.

BACKGROUND/OBJECTIVES: Physical activity and exploration in infancy affect physical and cognitive development. Nutritional supplementation improves activity in severely malnourished infants, but the evidence in mild-to-moderately malnourished and nutritionally at-risk infants is equivocal. We tested the effect of multiple-micronutrient supplementation on physical activity and exploration in Mexican infants. SUBJECTS/METHODS: Using a quasi experimental design, we analyzed data from a supplementation study that lacked a placebo-control group. We compared infants between 8 and 12 months measured at baseline who had received no supplementation (comparison group, n=78), with infants 8-12 months measured after 4 months of daily supplementation (treatment group, n=109). The treatment consisted of three supplement types: micronutrient powder, syrup (each containing only micronutrients) and a milk-based, fortified-food supplement (FFS; containing micronutrients and macronutrients). We formed the micronutrient-only group (MM) by combining the micronutrient powder and syrup groups. We measured activity and exploration by direct observation and used cluster analysis to form and characterize activity and exploration clusters. We performed logistic regression with activity or exploration cluster as the outcome variable and treatment versus comparison and MM or FFS versus comparison as the predictor variables. RESULTS: Treatment versus comparison increased the odds of being in the high activity (odds ratio (OR)=2.35, P<0.05) and high exploration (OR=1.87, P<0.05) cluster. MM increased the odds of being in the high activity (OR=2.64, P<0.05) cluster and FFS increased the odds (OR=3.16, P<0.05) of being in the high exploration cluster. CONCLUSIONS: Nutritional supplementation benefited activity and exploration in this sample of Mexican infants.

Feeding preterm infants milk with a higher dose of docosahexaenoic acid than that used in current practice does not influence language or behavior in early childhood: a follow-up study of a randomized controlled trial.

BACKGROUND: The visual and mental development of preterm infants improved after feeding them milk enriched with docosahexaenoic acid (DHA) in amounts matching the fetal accretion rate. OBJECTIVE: The objective was to evaluate whether feeding preterm infants milk with a higher DHA content than that used in current practice influences language or behavior in early childhood. DESIGN: This was a follow-up study in a subgroup of infants enrolled in the DINO (Docosahexaenoic acid for the Improvement in Neurodevelopmental Outcome) trial. In a double-blind randomized controlled trial, infants born at <33 wk of gestation were fed milk containing 1% of total fatty acids as DHA (higher-DHA group) or approximately 0.3% DHA (control group) until reaching full-term equivalent age. The longer-term effects of the intervention on language, behavior, and temperament were measured by using the MacArthur Communicative Development Inventory (MCDI) at 26-mo corrected age, the Strengths and Difficulties Questionnaire (SDQ), and the Short Temperament Scale for Children (STSC) between 3- and 5-y corrected age. RESULTS: Mean (+/-SD) MCDI scores did not differ significantly (adjusted P = 0.8) between the higher-DHA group (308 +/- 179, n = 60) and the control group (316 +/- 192, n = 67) per the Vocabulary Production subscale. Composite scores on the SDQ and STSC did not differ between the higher-DHA group and the control group [SDQ Total Difficulties: higher-DHA group (10.3 +/- 6.0, n = 61), control group (9.5 +/- 5.5, n = 64), adjusted P = 0.5; STSC score: higher-DHA group (3.1 +/- 0.7, n = 61), control group (3.0 +/- 0.7, n = 64), adjusted P = 0.3]. CONCLUSIONS: Feeding preterm infants milk containing 3 times the standard amount of DHA did not result in any clinically meaningful change to language development or behavior when assessed in early childhood. Whether longer-term effects of dietary DHA supplementation can be detected remains to be assessed. This trial was registered with the Australia and New Zealand Clinical Trial Registry at www.anzctr.org.au as 12606000327583.

Delayed neurobehavioral development in children born to pregnant women with mild hypothyroxinemia during the first month of gestation: the importance of early iodine supplementation.

BACKGROUND: Maternal hypothyroxinemia, due to gestational iodine deficiency, causes neurological dysfunctions in the progeny. Our aim was to determine the effects of delayed iodine supplementation (200 microg KI per day) to mildly hypothyroxinemic pregnant women at the beginning of gestation (i.e., having circulating free thyroxine [FT(4)] within the 0th-10th percentile interval and normal thyrotropin [TSH]) on the neurobehavioral development of their children. METHODS: Using the Brunet-Lézine scale, we evaluated the neurocognitive performance at 18 months of age in three groups of children. Group 1 included children of women with FT(4) above the 20th percentile at 4-6 gestational weeks and at full-term. Group 2 included children of mildly hypothyroxinemic women diagnosed during the first 12-14 gestational weeks and with FT(4) above the 20th percentile at full-term. Group 3 included children born to mildly hypothyroxinemic women at full-term, without iodine supplementation during gestation. Women of all groups were iodine supplemented from the day of enrollment until the end of lactation. RESULTS: Before iodine supplementation, 33.0% of the women (114 out of 345) were hypothyroxinemic, with FT(4) below normal in 28 of them (8.1%). None were found to be hypothyroxinemic at full-term after supplementation. The mean (+/-SD) developmental quotient of children was 101.8 +/- 9.7 in group 1 (n = 13) vs. 87.5 +/- 8.9 in group 3 (n = 19; p < 0.001) and 92.2 +/- 5.4 in group 2 (n = 12; p < 0.05). The difference between groups 2 and 3 was not statistically significant. Delayed neurobehavioral performance was observed in 36.8% and 25.0% of children in groups 3 and 2, respectively, compared with no children in group 1. Differences (p < 0.001) were found on gross and fine motor coordination and socialization quotients. No statistically significant differences were found on language quotients. CONCLUSIONS: A delay of 6-10 weeks in iodine supplementation of hypothyroxinemic mothers at the beginning of gestation increases the risk of neurodevelopmental delay in the progeny. Public health programs should address the growing problem of iodine deficiency among women of gestational age in developing and industrialized nations.

Early infant diet and the omega 3 fatty acid DHA: effects on resting cardiovascular activity and behavioral development during the first half-year of life.

This investigation evaluated variations in resting heart rate (HR) measures during the first half year of life in healthy, full-term infants who were either breast-fed (BF), or fed formula with (milk-based: MF; soy-based: SF) or without (soy-based: SF(-)) commercially supplemented DHA (decosahexaenoic acid). In infants fed the DHA-deficient diet, higher HR and lower values for heart rate variability measures were observed, indicating decreased parasympathetic tone in this group. These effects, appearing at 4 months and continuing for the remainder of the study period, are consistent with suggestions that the 3-5-month postnatal interval may be an important period in the development of cardiovascular regulation. The absence of these effects in SF infants receiving the DHA-supplemented formula suggests that neither soy protein nor the associated phytochemicals in soy formula contribute to these effects to any appreciable extent. In general, the results do not indicate differences in any of the study variables attributable to soy formula per se.

Lavender bath oil reduces stress and crying and enhances sleep in very young infants.

Very young infants were given a bath with or without lavender-scented bath oil. The mothers in the lavender bath oil group were more relaxed, smiled and touched their infants more during the bath. Their infants looked at them a greater percentage of the bath time and cried less and spent more time in deep sleep after bath. The cortisol levels of this group of mothers and infants significantly decreased, confirming the behavioral data showing increased relaxation of the mothers and their infants. These findings support a body of research showing the relaxing and sleep-inducing properties of lavender aroma.

Effects of selective serotonin reuptake inhibitors and venlafaxine during pregnancy in term and preterm neonates.

OBJECTIVES: Our goals were to (a) describe neonatal behavioral signs in a group of newborns exposed in utero to selective serotonin reuptake inhibitors or venlafaxine at the time of delivery, (b) compare the rate of neonatal behavioral signs, prematurity, and admission to specialized neonatal care between a group of exposed and unexposed newborns, and (c) compare the effects in exposed preterm and term newborns. PATIENTS AND METHODS: This was a retrospective cohort study including mothers taking selective serotonin reuptake inhibitors or venlafaxine during the third trimester and mothers who were not taking any antidepressants, psychotropic agents, or benzodiazepines at the time of delivery of their newborns. Neonatal behavioral signs included central nervous, respiratory, and digestive systems, as well as hypoglycemia and the need for phototherapy. RESULTS: Seventy-six mothers taking antidepressants and 90 untreated mothers and their newborns were analyzed. Smoking, alcohol intake, and substance abuse were more frequent among treated mothers. In infants in the exposed group, signs involving the central nervous and the respiratory systems were often observed (63.2% and 40.8%, respectively). These signs appeared during the first day of life, with a median duration of 3 days for exposed newborns. The signs resolved in 75% of cases within 3 to 5 days for term and premature newborns, respectively. All exposed premature newborns presented behavioral manifestations compared with 69.1% of term exposed newborns. Median length of stay was almost 4 times longer for exposed premature newborns than for those who were unexposed (14.5 vs 3.7 days). CONCLUSIONS: Neonatal behavioral signs were frequently found in exposed newborns, but symptoms were transient and self-limited. Premature infants could be more susceptible to the effects of selective serotonin reuptake inhibitors and venlafaxine.

[SSRI during pregnancy and risk of fetal neurotoxicity. Follow precautions and look for other therapeutic alternatives]. / SSRI under graviditet och risk för fetal neurotoxicitet. Föij försiktighetsprincipen och sök andra behandlingsalternativ.

Fetal exposure to SSRI are associated to transient toxic symptoms of the neonates, likely to be an expression of excess serotonin activity in the CNS. The neonatal toxicity of SSRI raise the issue of behavioural teratogenicity due to fetal exposure to SSRIs. The current body of knowledge concerning SSRIs exposure during fetal CNS development, through interference with the neurotransmittors serotonin and GABA, and behavioural teratogenicity is still inadequate. Subtle long-term effects have been reported. While awaiting new findings, physicians are advised to look for alternatives to SSRIs whenever possible during the second and third trimester.

Neurobehavioral effects of treatment for opiate withdrawal.

A partially randomised, controlled trial was performed to test the hypothesis that opiate exposed infants treated with diluted tincture of opium (DTO) and phenobarbital would have better neurobehavioral scores than infants treated with DTO alone. Compared with those treated with DTO alone (n = 15), infants treated with DTO and phenobarbital (n = 17) were more interactive, had smoother movements, were easier to handle, and less stressed. Dual treatment results in improved neurobehavioral organisation during the first three weeks of life, which may indicate a more rapid recovery from opiate withdrawal.

Iron and zinc supplementation promote motor development and exploratory behavior among Bangladeshi infants.

BACKGROUND: Iron and zinc deficiency are prevalent during infancy in low-income countries. OBJECTIVES: The objectives were to examine whether a weekly supplement of iron, zinc, iron+zinc, or a micronutrient mix (MM) of 16 vitamins and minerals would alter infant development and behavior. DESIGN: The participants were 221 infants from rural Bangladesh at risk of micronutrient deficiencies. Development and behavior were evaluated at 6 and 12 mo of age by using the Bayley Scales of Infant Development II and the Home Observation Measurement of Environment (HOME) scale. In this double-blind trial, the infants were randomly assigned to 1 of 5 treatment conditions: iron (20 mg), zinc (20 mg), iron+zinc, MM (16 vitamins and minerals, including iron and zinc), or riboflavin weekly from 6 to 12 mo. Multivariate analyses were conducted to examine the change in development and behavior for each supplementation group, with control for maternal education, HOME score, months breastfed, anemia, growth at 6 mo, and change in growth from 6 to 12 mo. RESULTS: Iron and zinc administered together and with other micronutrients had a beneficial effect on infant motor development. Iron and zinc administered individually and in combination had a beneficial effect on orientation-engagement. Two-thirds of the infants were mildly anemic, no treatment effects on hemoglobin concentration were observed, and hemoglobin was not associated with measures of development or behavior. CONCLUSION: The beneficial effects of weekly iron and zinc supplementation on motor development and orientation-engagement suggest that infants benefit from these minerals when administered together.

Use of herbal agents by breastfeeding women may affect infants.

Breastfeeding women increasingly are taking herbal medications. Physicians dealing with women wishing to breastfeed should ask specifically about use of herbal and non-traditional medications. Important questions include why the herbals are being used, what benefits the patient is attempting to achieve, and whether it is truly critical to take the herbal agent during the time of breastfeeding. There are often other medications with known safety profiles during breastfeeding that can be used instead. If the herbal medication is not critical to a woman's health, it can often be deferred during the time of breastfeeding, the safest way to avoid any potential complications. To be able to discuss these issues with mothers who are planning to breastfeed, the clinician must become aware of which herbal medications are in use and understand their potential side effects. The more knowledge the health professional has regarding complementary medicine, the more trust the patient will have in discussing these issues and working with the physician to minimize any dangers to the breastfeeding infant.

Vitamin B-6 content of breast milk and neonatal behavioral functioning.

OBJECTIVE: To determine if vitamin B-6 intakes of mothers influence the B-6 vitamer content of transition milk and if correlations exist between the vitamin B-6 content of the milk and the infants' neurobehavioral functioning. DESIGN: Transition milk samples were collected from mothers 8 to 11 days after delivery for B-6 vitamer analysis. Neurobehavioral functioning of the neonates was determined at that time. A 24-hour recall was used in estimating vitamin B-6 intakes of the mothers. SUBJECTS: A convenience sample of low-income, lactating women (n = 25) who had normal pregnancies. MAIN OUTCOME MEASURES: B-6 vitamers were measured in the mothers' transition milk samples. Neurobehavioral functioning was assessed using the Brazelton Neonatal Behavioral Assessment Scale (NBAS), and the Center for Epidemiologic Studies Depression Scale was used to evaluate maternal depression. STATISTICAL ANALYSES PERFORMED: Pearson correlation coefficients were used to assess if statistically significant relationships existed between variables. The Mann-Whitney test was used to determine if median group values were significantly different. RESULTS: The major B-6 vitamer in transition milk was pyridoxal. Mothers with vitamin B-6 intake greater than the median value had a significantly higher median pyridoxal level in their breast milk than did the mothers with intakes below the median value. All except one mother had a dietary vitamin B-6 intake that exceeded the Recommended Dietary Allowance. Infant scores on habituation (r = .94, P < .05) and autonomic stability (r = .34, P < .05) subscales of the NBAS were positively correlated with milk pyridoxal values. APPLICATIONS/CONCLUSIONS: Vitamin B-6 is important for normal behavioral functioning of infants. The mothers' vitamin B-6 intake affects vitamin B-6 levels of breast milk and the need for consuming recommended levels of vitamin B-6 should be emphasized to all pregnant and lactating mothers.