Ajay Sinha

Maternal gestational diabetes is associated with genome-wide DNA methylation variation in placenta and cord blood of exposed offspring

Exposure of a developing foetus to maternal gestational diabetes (GDM) has been shown to programme future risk of diabetes and obesity. Epigenetic variation in foetal tissue may have a mechanistic role in metabolic disease programming through interaction of the pregnancy environment with gene function. We aimed to identify genome-wide DNA methylation variation in cord blood and placenta from offspring born to mothers with and without GDM. Pregnant women of South Asian origin were studied and foetal tissues sampled at term delivery. The Illumina HumanMethylation450 BeadChip was used to assay genome-wide DNA methylation in placenta and cord blood from 27 GDM exposed and 21 unexposed offspring. We identified 1485 cord blood and 1708 placenta methylation variable positions (MVPs) achieving genome-wide significance (adjusted P-value <0.05) with methylation differences of >5%. MVPs were disproportionately located within first exons. A bioinformatic co-methylation algorithm was used to detect consistent directionality of methylation in 1000 bp window around each MVP was observed at 74% of placenta and 59% of cord blood MVPs. KEGG pathway analysis showed enrichment of pathways involved in endocytosis, MAPK signalling and extracellular triggers to intracellular metabolic processes. Replication studies should integrate genomics and transcriptomics with longitudinal sampling to elucidate stability, determine causality for translation into biomarker and prevention studies.

Doppler Flow Velocimetry in the Superior Mesenteric Artery on the First Day of Life in Preterm Infants and the Risk of Neonatal Necrotizing Enterocolitis

OBJECTIVE. The purpose of this work was to relate Doppler indices of splanchnic perfusion and vascular resistance to the risk of developing necrotizing enterocolitis. METHODS. We conducted a prospective cohort study with analysis of Doppler flow velocity waveforms of splanchnic vessels on the first day of life. Clinical management and diagnosis of necrotizing enterocolitis were performed blind to the Doppler results in a tertiary NICU on 64 eligible preterm neonates admitted for intensive care. We measured necrotizing enterocolitis using an objective diagnostic classification. RESULTS. When adjusted for gestational age at birth, the following indices of the Doppler flow velocity wave form in the superior mesenteric artery were significantly predictive of the risk of necrotizing enterocolitis: end-diastolic velocity, mean velocity, and pulsatility index. The association between necrotizing enterocolitis and Doppler velocimetry indicative of high vascular resistance was independent of a range of other factors and comorbidities (race, mode of delivery, umbilical arterial catheter, growth restriction, patent ductus arteriosus, jaundice, respiratory distress syndrome, mechanical ventilation, and hypotension). CONCLUSIONS. We concluded that neonates with high resistance patterns of blood flow velocity in the superior mesenteric artery on the first day of life are at increased risk of developing necrotizing enterocolitis.

A gestation- and postnatal age-based reference chart for assessing renal function in extremely premature infants

Objective:A single value of plasma creatinine cannot be used to define renal dysfunction in premature babies, as levels are influenced by gestation and postnatal age. The aim of this study was to create reference ranges for plasma creatinine in cohort of extremely premature infants.Study Design:Retrospective analysis of plasma creatinine levels in the first 8 weeks of life from 161 consecutively admitted premature infants 28 weeks gestation.Result:Babies were divided into three groups according to gestation. Peak (10th, 90th percentiles) creatinine levels were 132 (106,162) in 22 to 24 weeks gestational infants, 127 (89,151) in those from 25 to 26 weeks and 110 (87,134) in those from 27 to 28 weeks (P<0.001). Creatinine at birth was similar across the groups with levels increasing during the first few days. It decreases thereafter before reaching stable levels by 5 weeks of age.Conclusion:Gestation- and age-based reference charts should be used for interpretation of creatinine values in extremely premature babies.

Relationships between Maternal Ethnicity, Gestational Age, Birth Weight, Weight Gain, and Severe Retinopathy of Prematurity

OBJECTIVE To develop an algorithm that allows advanced identification of infants requiring treatment for retinopathy of prematurity (ROP). STUDY DESIGN A retrospective observational study was performed at 2 tertiary neonatal units serving a multiethnic population in the UK, using data on 929 infants eligible for ROP screening. The relationships between study variables and the risk of developing ROP requiring treatment were analyzed using multiple logistic regression. RESULTS After applying exclusion criteria, data from 589 infants were analyzed; of these, 57 required laser treatment. The proportion of treated infants was 5.9% of those born to black mothers, 9.39% of those born to white mothers, and 12.8% of those born to Asian mothers (P = .047). Multiple logistic regression showed that gestational age, birth weight, maternal ethnicity, and early weight gain were predictors for the development of ROP requiring treatment, with maternal ethnicity having greater predictive power compared with early weight gain. We developed an algorithm for predicting the development of ROP requiring treatment with sensitivity, specificity, and positive and negative predictive values of 100%, 65.7%, 23.8%, and 100%, respectively. CONCLUSION Gestational age, birth weight, early weight gain, and maternal ethnicity are important predictors for the development of ROP requiring treatment. In a multiethnic population, an algorithm to predict development of ROP requiring treatment should include maternal ethnicity. If confirmed through prospective studies, this algorithm could reduce the number of opthalmologic examinations performed for ROP screening.

Blood flow in the common carotid artery in term and preterm infants: reproducibility and relation to cardiac output

Aim: To assess the reproducibility of, and determine normative data for, flow volume measurements from the right common carotid artery (CCA) and its relation to left ventricular output (LVO) in stable term and preterm babies using Doppler ultrasound. Methods: Right CCA flow volume was measured using a near focus, high frequency transducer by obtaining intensity weighted mean velocity and right CCA diameter. LVO was determined using standard Doppler techniques. Reproducibility studies were performed on 30 newborn infants by two observers. Normative data were obtained from 40 spontaneously breathing preterm babies and 21 term babies. Results: The intraobserver coefficient of variation for CCA flow measurements was 10.5% for observer 1 and 15.4% for observer 2, whereas the interobserver coefficient of variation was 16.4%. In term and preterm infants, right CCA flow was about 20 ml/kg/min, accounting for 11% of cardiac output. Among the preterm infants, there was a positive correlation of right CCA flow with gestation (r  =  0.61, p<0.001), weight (r  =  0.64, p<0.001), and LVO (r  =  0.59, p<0.001). Right CCA diameter also increased with weight (r  =  0.63, p<0.001) and gestation (r  =  0.58, p<0.001). The proportion of LVO distributed to the right CCA did not increase with gestation, nor did the right CCA flow per kg body weight. Conclusions: It is possible to perform reproducible measurements of flow volume in the CCA of newborn infants. In stable, spontaneously breathing babies, both cardiac output and carotid flow increased with gestation and body weight. The proportion of cardiac output distributed to the right CCA remained relatively constant across gestation.

Outcomes of full-term infants with bilious vomiting: observational study of a retrieved cohort

Bilious vomiting in a neonate may be a sign of intestinal obstruction often resulting in transfer requests to surgical centres. The aim of this study was to assess the use of clinical findings at referral in predicting outcomes and to determine how often such patients have a time-critical surgical condition (eg, volvulus, where a delay in treatment is likely to compromise gut viability). Methods 4-year data and outcomes of all term newborns aged ≤7 days with bilious vomiting transferred by a regional transfer service were analysed. Specificity, sensitivity, likelihood ratios, correlations, prior and posterior probability of clinical findings in predicting newborns with surgical diagnosis were calculated. Results Of 163 neonates with bilious vomiting, 75 (46%) had a surgical diagnosis and 23 (14.1%) had a time-critical surgical condition. The diagnosis of a surgical condition in neonates with bilious vomiting was significantly associated with abdominal distension (χ2=5.17, p=0.023), abdominal tenderness (χ2=5.90, p=0.015) and abnormal abdominal X-ray findings (χ2=5.68, p=0.017) but not with palpation findings of a soft as compared with a tense abdomen (χ2=3.21, p=0.073). Abnormal abdominal X-ray, abdominal distension and tenderness had 97%, 74% and 62% sensitivity, respectively, with regard to association with an underlying surgical diagnosis. Normal abdominal X-ray reduced the posterior probability of surgical diagnosis from 50% to 16%. Overall, clinical findings at referral did not differentiate between infants with or without surgical or time-critical condition. Conclusions We recommend that term neonates with bilious vomiting referred for transfer are prioritised as time critical.

Reduced utility of serum IGF-1 levels in predicting retinopathy of prematurity reflects maternal ethnicity

Aims To validate known risk factors and identify a threshold level for serum insulin-like growth factor 1 (IGF-1) in the development of severe retinopathy of prematurity (ROP) in an ethnically diverse population at a tertiary neonatal unit, 2011–2013. Methods A prospective cohort masked study was conducted. Serum IGF-1 levels at 31, 32 and 33 weeks were measured and risk factor data collected including gestational age (GA), birth weight (BW), absolute weight gain (AWG) and maternal ethnicity. The eventual ROP outcome was divided into two groups: minimal ROP (Stages 0 and 1) and severe ROP (Stage 2 or worse including Type 1 ROP). Results 36 patients were recruited: 14 had minimal ROP and 22 severe ROP. Significant differences between the groups were found in GA, BW, AWG and IGF-1 at 32 and 33 weeks. There was minimal rise in IGF-1 in Stage 2 patients and/or black patients (p=0.0013) between 32 and 33 weeks but no pragmatic threshold level of IGF-1 that could distinguish between minimal or severe ROP. Conclusions There were significant differences in GA, BW, AWG and IGF-1 at 32 and 33 weeks between those babies with severe ROP and those with minimal ROP. However, there was no threshold level of IGF-1 at a time point between 31 and 33 weeks that can be used to exclude a large proportion of babies from screening. We also found ethnic differences in IGF-1 levels with infants born to black mothers having significantly lower IGF-1 levels at 32 and 33 weeks gestation. The determination of ROP risk using IGF-1 is a race-specific phenomenon.

Can early-onset nonoliguric hyperkalemia be predicted in extremely premature infants?

Hyperkalemia is common soon after birth in extremely premature infants and often occurs in the absence of oliguria or renal failure. Our objective was to examine the early biochemical indicators, clinical risk factors, and incidence of early-onset nonoliguric hyperkalemia in a cohort of extremely premature infants. We studied clinical and biochemical data from 154 consecutive premature infants < or = 28 weeks of gestation admitted to a tertiary neonatal unit over a 3-year period. Hyperkalemia (> 7 mmol/L) was found in 33 (21%) of patients during the first 4 days of life, with peak potassium levels occurring at 3 days of age. Hyperkalemic patients had similar birthweight, gestation, creatinine and sodium levels as normokalemic infants, but they had higher phosphate and urea levels, with lower calcium levels. The combination of a high phosphate (> 2.0 mmol/L) and a high potassium (> 5.6 mmol/L) within 6 hours of birth predicted later development of hyperkalemia, with a positive likelihood ratio of 8.3 (post-test probability, 70%). Potassium level of < 5.6 mmol/L at birth indicates subsequent hyperkalemia is unlikely (likelihood ratio, 0.25; post-test probability, 4%). Mildly elevated potassium and phosphate levels within 6 hours after birth may be useful in predicting the development of early-onset hyperkalemia.

Prevention of Late Onset Sepsis and Central-line Associated Blood Stream Infection in Preterm Infants.

Aim: Late onset sepsis (LOS) and central-line associated blood stream infection (CLA-BSI) contribute toward the mortality and morbidity in prematurely born infants. The aim of this study is to investigate the effects of hospital-wide and unit-based interventions on LOS and CLA-BSI in infants born at <32 weeks gestation. Methods: Intensive care, high dependency days and catheter days were obtained from the unit database and blood culture results from a microbiology laboratory database. Poisson regression was used to evaluate the effects of interventions on LOS and CLA-BSI. Results: Quarterly rates of LOS reduced from 26.1 to 2.9 per 1000 intensive care, high dependency days and CLA-BSI from 31.6 to 4.3 per 1000 catheter days between 2007 and 2012. Appointment of a hospital specialist vascular device nurse, a change in the mode of administration of vancomycin, standardization of the hospital skin and hub disinfection policy and the introduction of a venous infusion phlebitis scoring system were associated with a reduction of LOS to 55% (95% confidence interval: 40–74%) and CLA-BSI 45% (95% confidence interval: 33–61%) of pre-intervention levels. The standardization of the neonatal unit policy for skin disinfection and a move to a new building were associated with reductions of LOS to 64% (47–87%) and 54% (34–88%), respectively, and aseptic no touch technique for infusion access with CLA-BSI to 53% (37–75%) of pre-intervention levels. Conclusion: A multifaceted approach involving changes in antimicrobial and skin disinfection policy, training for aseptic no touch technique and surveillance resulted in sustained reduction in LOS and CLA-BSI rates.

Comparison of Passive and Servo-Controlled Active Cooling for Infants with Hypoxic-Ischemic Encephalopathy during Neonatal Transfers

Objective The recent availability of servo‐controlled cooling equipment on transport makes it possible to commence active cooling at the referral unit for infants with hypoxic‐ischemic encephalopathy. This study aimed to compare the temperature and transfer variables in passively and actively cooled babies. Study Design This is a retrospective cohort study comparing two groups—passively cooled (July 2011 to August 2012) versus actively cooled group (September 2012 to June 2013), following introduction of active hypothermia using servo‐controlled cooling mattress by the London Neonatal Transfer Service (NTS). Results Seventy‐six infants were passively cooled and 69 were actively cooled. There was a significant difference between the temperatures of the two groups at each point in the transfer episode: on arrival of NTS, during stabilization, during transfer, and at the receiving hospital. Median time to achieve target temperature was 30 (95% confidence interval [CI]: 23‐37) minutes in actively cooled, significantly shorter in comparison to 130 (95% CI: 83‐177) minutes in passively cooled babies. Of the 69 newborns, 62 (90%) had temperature within target range at receiving center in actively cooled group as compared with 30/76 (40%) in passively cooled group. Conclusion The use of active cooling during neonatal transfer achieves target temperature in a shorter period and maintains better temperature stability.