Intravenous antibiotics in preterm infants have a negative effect upon microbiome development throughout preterm life.

BACKGROUND: Intestinal dysbiosis is implicated in the origins of necrotising enterocolitis and late-onset sepsis in preterm babies. However, the effect of modulators of bacterial growth (e.g. antibiotics) upon the developing microbiome is not well-characterised. In this prospectively-recruited, retrospectively-classified, case-control study, high-throughput 16S rRNA gene sequencing was combined with contemporaneous clinical data collection, to assess the within-subject relationship between antibiotic administration and microbiome development, in comparison to preterm infants with minimal antibiotic exposure. RESULTS: During courses of antibiotics, diversity progression fell in comparison to that seen outside periods of antibiotic use (-0.71units/week vs. + 0.63units/week, p < 0.01); Enterobacteriaceae relative abundance progression conversely rose (+ 10.6%/week vs. -8.9%/week, p < 0.01). After antibiotic cessation, diversity progression remained suppressed (+ 0.2units/week, p = 0.02). CONCLUSIONS: Antibiotic use has an acute and longer-lasting impact on the developing preterm intestinal microbiome. This has clinical implications with regard to the contribution of antibiotic use to evolving dysbiosis, and affects the interpretation of existing microbiome studies where this effect modulator is rarely accounted for.

Perinatal outcomes for extremely preterm babies in relation to place of birth in England: the EPICure 2 study.

BACKGROUND: Expertise and resources may be important determinants of outcome for extremely preterm babies. We evaluated the effect of place of birth and perinatal transfer on survival and neonatal morbidity within a prospective cohort of births between 22 and 26 weeks of gestation in England during 2006. METHODS: We studied the whole population of 2460 births where the fetus was alive at the admission of the mother to hospital for delivery. Outcomes to discharge were compared between level 3 (most intensive) and level 2 maternity services, with and without transfers, and by activity level of level 3 neonatal unit; ORs were adjusted for gestation at birth and birthweight for gestation (adjusted ORs (aOR)). FINDINGS: Of this national birth cohort, 56% were born in maternity services with level 3 and 34% with level 2 neonatal units; 10% were born in a setting without ongoing intensive care facilities (level 1). When compared with level 2 settings, risk of death in level 3 services was reduced (aOR 0.73 (95% CI 0.59 to 0.90)), but the proportion surviving without neonatal morbidity was similar (aOR 1.27 (0.93 to 1.74)). Analysis by intended hospital of birth confirmed reduced mortality in level 3 services. Following antenatal transfer into a level 3 setting, there were fewer intrapartum or labour ward deaths, and overall mortality was higher for those remaining in level 2 services (aOR 1.44 (1.09 to 1.90)). Among level 3 services, those with higher activity had fewer deaths overall (aOR 0.68 (0.52 to 0.89)). INTERPRETATION: Despite national policy, only 56% of births between 22 and 26 weeks of gestation occurred in maternity services with a level 3 neonatal facility. Survival was significantly enhanced following birth in level 3 services, particularly those with high activity; this was not at the cost of increased neonatal morbidity.

The nutrient intakes of mothers of low birth weight babies - a comparison of ethnic groups in East London, UK.

The objective of this paper was to compare the nutrient intakes of mothers of different ethnic origins after they had given birth to a low birth weight (LBW) baby (< 2.5 kg). A total of 165 participants from East London, UK completed a prospective 7-day diet diary using household measures, between 8 and 12 weeks post-partum. The data were originally collected as baseline data prior to two separate nutrition intervention studies and were combined and re-interrogated for the purpose of this paper. Folate and iron intakes were low in all ethnic groups compared to the Reference Nutrient Intakes (RNI). Half did not meet the RNI for folate and 88% did not meet the RNI for iron. Nearly a quarter of the group did not achieve the Lower Reference Nutrient Intake (LRNI) for iron. The mean vitamin D and calcium intakes were significantly different between the ethnic groups (P = 0.007, P = 0.001, respectively). African women had the highest vitamin D intakes (4.72 microg d(-1)) and Caucasians and Asians the lowest (2.4 microg d(-1)). Caucasians had the highest calcium intakes (780 mg d(-1)) and Africans the lowest (565 mg d(-1)). Over two-thirds of African, Asian and African-Caribbean women did not meet the RNI for calcium. Thirty-one per cent of Africans did not meet the LRNI for calcium. Our data show a high prevalence of inadequate nutrition among women who deliver LBW babies with differences in nutrient intake between ethnic groups. This information can be used to target specific appropriate dietary advice to ethnic minorities for the prevention or repetition of LBW.

Measuring intramucosal pH in very low birth weight infants.

Maintenance of adequate perfusion is essential for health of the intestinal mucosa. Methods available to assess intestinal perfusion provide information on mesenteric blood flow, which may differ from mucosal flow. Intramucosal pH (pH(i)) is influenced by tissue oxygenation and perfusion. Gastric pH(i) can be measured using the technique of tonometry. A prospective observational clinical study was performed to examine relationships between measured gastric pH(i) and mucosal CO(2) (mCO(2)), and acid-base balance, gastrointestinal complications (necrotizing enterocolitis and perforation), and death in infants <1500 g birth weight. A nasogastric tonometry catheter (size 5F) was inserted into the stomach of infants, and pH(i) was calculated from mCO(2) levels measured using saline tonometry. Measurements were performed at 3, 12, 24, and 48 h, then daily until arterial access was unavailable. Two hundred eleven sets of measurements were performed on 38 infants [birth weight (mean +/-SD), 863 +/- 241 g; gestation, 26.5 +/- 1.8 wk; and median Clinical Risk Index for Babies score, 8.0 (interquartile range, 5.0-10.75)]. Mean pH(i) was 7.27 (95% confidence interval, 7.26-7.28) and mean mCO(2) was 47.0 mm Hg (95% confidence interval, 45.7-48.3 mm Hg). pH(i) and mCO(2) correlated significantly with arterial pH (pH(a)), arterial PCO(2) (PaCO(2)), and arterial base excess. There were no significant relationships between pH(a) and pH gap (pH(a)-pH(i)) or CO(2) gap (mCO(2)-PaCO(2)). Recurrent low pH(i) (<7.2 on more than one occasion) and an mCO(2)/PaCO(2) ratio of > or =1.29 were significantly associated with an increase in gastrointestinal complications. There were no statistically significant associations with death. In conclusion, changes in pH gap and CO(2) gap can occur without alteration in pH(a). Abnormalities in pH(i) might predict gastrointestinal complications in infants <1500 g.

Inter-pregnancy folate and iron status of women in an inner-city population.

The purpose of the present study was to evaluate whether micronutrient supplementation improved the nutritional status of women with poor diets during the inter-pregnancy interval. Fifty-five women who had given birth to a low birth weight baby (<2.5 kg), and who planned to have a further pregnancy, were recruited to a prospective randomised study in East London, UK. Of the fifty-five mothers recruited, forty-four (78 %) met fewer than four of sixteen dietary reference values according to the information provided in a 7 d diet diary, and were categorised as having an 'inadequate' diet. Half of the mothers in the 'inadequate'-diet group were randomly assigned to receive a micronutrient and a single cell oil supplement containing docosahexaenoic acid. All participants received dietary advice based on analysis of their diet diaries, and general lifestyle advice on preparing for pregnancy. Mothers had a blood sample taken at 3 and 9 months post-partum to measure their folate, Fe stores and fatty acid status. Mean serum and erythrocyte folate levels increased significantly between 3 and 9 months post-partum in both the adequate-diet group and the supplemented group. At 9 months post-partum, over half of the unsupplemented, inadequate-diet group remained severely deficient in folate (serum folate <230 nmol/l) and had low serum ferritin levels (<15 microg/l). The high prevalence of inadequate diets in this inner-city population and the low motivation of women to participate in a nutrition programme suggests that consideration should be given to the provision of free folate and Fe supplements to all women in this and similar populations, or at least to women who have delivered a low birth weight baby, who plan further pregnancies.

Maturation of electroretinograms and visual evoked potentials in preterm infants.

Electroretinograms (ERGs) and visual evoked potentials (VEPs) to flash stimulation were recorded from 51 infants (gestational age 26 to 42 weeks; post-conceptional age (PCA) 31 to 47 weeks) to give cross-sectional data on the maturation of these responses. Sequential recordings were taken from a separate group of 24 preterm infants (gestational age 28 to 33 weeks) to give longitudinal data. There was a significant decrease in ERG a-wave latency and increase in a-b amplitude with increasing PCA in both groups. For the VEPs there was a significant decrease in latency of the early negative component (N1) and the major positive component (P2). Comparison between recordings made on preterm infants with those from term infants at an equivalent PCA suggested faster maturation of VEPs in the extra-uterine environment, but no difference in maturation of the ERG.

Analysis of tidal breathing parameters in infancy: how variable is TPTEF:TE?

During recent years there has been increasing interest in the measurement of tidal breathing parameters, such as the time to reach peak tidal expiratory flow as a proportion of total expiratory time (TPTEF:TE), and their application to population-based studies of the determinants of early respiratory morbidity. However, little is known about factors influencing the within and between-subject variability of these parameters. This study examines the influence of sedation on TPTEF:TE, estimates the optimal number of breaths and breath epochs required to measure TPTEF:TE, and assesses short-term repeatability of this parameter during the first year of life, taking account of age-related differences. Measurements were made in 266 healthy infants and young children (1 d to 19 mo old). Mean (SD) TPTEF:TE fell from 0.49 (0.11) in the first 2 wk of life to 0.34 (0.09) by 5 to 8 wk, remaining similar thereafter. Sedation with triclofos sodium (75 mg/kg) had no significant effect on TPTEF:TE, which was 0.33 (0.10) in 23 unsedated 6-wk-old infants and 0.32 (0.08) in 49 sedated infants of similar age and weight (95% CI for the difference: -0.05, 0.04). At least 10 breaths in each of two separate epochs from each infant were required to provide a representative estimate of TPTEF:TE. The mean (SD) difference between repeat measurements made 5 to 108 min apart was 0.02 (0.08) in 34 infants younger than 6 wk of age (95% limits of agreement: -0.15, 0.18) and -0.01 (0.04) (95% limits of agreement -0.09, 0.08) in 30 infants 6 wk and older.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of respiratory function in Afro-Caribbean and Caucasian infants.

Race is recognized as an important determinant of lung function in children and adults, but limited data exist for infants. Accurate interpretation of lung function tests during the neonatal period may depend on appropriate values for predicting normality. The aim of this study was to compare tidal breathing parameters, Hering-Breuer reflex (HBR) activity, and total respiratory compliance (Crs) in healthy newborn caucasian (white) and Afro-Caribbean (black) infants, to determine whether separate reference values were required for these two ethnic groups. Respiratory function was measured in 33 healthy black infants, 18 of whom were premature, and 33 healthy white infants matched for sex, gestational age, weight, postnatal age, and maternal smoking during pregnancy. There were no significant paired differences between black and white infants with respect to minute ventilation, respiratory frequency, the ratio of time to reach peak expiratory flow to total expiratory time, or HBR activity. Values of Crs were similar in black and white full-term infants (37.5 (SD 9.0) versus 35.0 (6.3) ml.kPa-1, respectively) suggesting that, in the immediate newborn period, separate reference values are not necessary for these parameters. However, Crs was somewhat lower in black than white preterm infants (26.0(5.2) versus 29.5(7.2) ml.kPa-1, this difference reaching statistical significance if results were expressed in relation to body weight (95% confidence interval of within-pair differences -4.0 to -0.02 ml.kPa-1 x kg-1; p < 0.05). We conclude that no separate reference values for tidal breathing, Hering-Breuer reflex activity or total respiratory compliance are required for white and black babies in the immediate newborn period.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of respiratory function in Afro-Caribbean and Caucasian infants

Race is recognized as an important determinant of lung function in children and adults, but limited data exist for infants. Accurate interpretation of lung function tests during the neonatal period may depend on appropriate values for predicting normality. The aim of this study was to compare tidal breathing parameters, Hering-Breuer reflex (HBR) activity, and total respiratory compliance (Crs) in healthy newborn caucasian (white) and Afro-Caribbean (black) infants, to determine whether separate reference values were required for these two ethnic groups. Respiratory function was measured in 33 healthy black infants, 18 of whom were premature, and 33 healthy white infants matched for sex, gestational age, weight, postnatal age, and maternal smoking during pregnancy. There were no significant paired differences between black and white infants with respect to minute ventilation, respiratory frequency, the ratio of time to reach peak expiatory flow to total expiratory time, or HBR activity. Values of Crs were similar in black and white full-term infants (37.5 (SD 9.0) versus 35.0 (6.3) ml.kPa-1, respectively) suggesting that, in the immediate newborn period, separate reference values are not necessary for these parameters. However, Crs was somewhat lower in black than white preterm infants (26.0(5.2) ml.kPa-1, this difference reaching statistical significance if results were expressed in relation to body weight (95 percent confidence interval of within-pair differences -4.0 to -0.02 ml.kPa-1 x Kg-1; p< 0.05). We conclude that no separate reference values for tidal breathing, Herin-Breuer reflex activity or total respiratory compliance are required for white and black babies in the immediate newborn period. (AU Truncated at 250 words)

Assessment of passive respiratory compliance in healthy preterm infants: a critical evaluation.

The airway occlusion techniques for assessing passive respiratory mechanics have become well established methods in fullterm neonates and older infants. The single breath technique (SBT) is frequently used for assessing lung function in intubated infants on neonatal intensive care units. However, less is known about the reliability of these quick and noninvasive techniques in healthy preterm infants. The aim of this study was to evaluate these methods in healthy unintubated preterm infants to facilitate both establishment of reference values and more meaningful interpretation of lung function assessments in the neonatal unit. Forty-seven studies were attempted in 31 healthy preterm infants (gestational age 29-36 weeks; body weight 1.88 +/- 0.28 kg; mean +/- SD) during the first 2 weeks of life, using both the multiple occlusion technique (MOT) and the SBT. Whereas technically acceptable respiratory system compliance (Crs) data from either the MOT or the SBT were obtained on 37 occasions in 25 infants, satisfactory results from both techniques were achieved only on 22 occasions. In these infants mean +/- SD Crs was 28.1 +/- 5.2 mL kPa-1 when assessed by MOT and 29.1 +/- 6.0 mL kPa-1 when using the SBT. The mean difference between technically satisfactory paired Crs values obtained with MOT and SBT was less than 5% (range, +28 to -18%). By contrast, in infants in whom data were invalidated as a result of expiratory airflow braking, failure to relax or instability of the end-expiratory level, gross discrepancies occurred between the techniques.(ABSTRACT TRUNCATED AT 250 WORDS)

Long chain polyunsaturated fatty acids and fetal growth.

Long chain polyunsaturated fatty acid composition of plasma choline phosphoglycerides has been measured at birth in 22 preterm infants. Positive correlations were found between both n-6 and n-3 fatty acids and measurements of growth and maturation. 20:4(n-6) and the sum of 20:3(n-6) + 20:4(n-6) correlated most strongly with weight and head circumference, while 22:6(n-3) showed strongest correlation with length of gestation. These findings are of relevance to understanding the role of nutrition in fetal growth and in establishing the group of infants most at risk of postnatal deficiency of essential fatty acids.

Factors affecting long-chain polyunsaturated fatty acid composition of plasma choline phosphoglycerides in preterm infants.

Long-chain polyunsaturated fatty acid (LCPUFA) composition of choline phosphoglycerides was measured in the plasma of 22 preterm infants at birth and at expected date of delivery (EDD). In a subgroup of 10 infants, data were also collected at regular intervals between birth and EDD. Levels at birth showed a positive correlation between arachidonic acid (AA) and birth weight, p less than 0.01, and between docosahexaenoic acid (DHA) and gestational age, p less than 0.01. Percentage compositions of both AA and DHA fell rapidly between preterm birth and expected date of delivery, at a time when they would remain high in utero. For AA, the mean value fell from 16.52 to 7.18%, and for DHA from 4.49 to 2.63%. Levels of DHA fell less in babies fed breast milk than in those fed formula milk, p less than 0.05, and levels of AA fell less in those requiring a large number of blood transfusions, p less than 0.05. The level of DHA fell more in those infants with intrauterine growth retardation, p less than 0.05. Although these nutrients share common metabolic pathways for their synthesis, they appear to be affected by different factors in both the fetus and the preterm infant. Low levels at this time may adversely affect brain and retinal development.

Tumour necrosis factor in the bronchoalveolar secretions of infants with the respiratory distress syndrome and the effect of dexamethasone treatment.

BACKGROUND: Tumour necrosis factor alpha may contribute to the lung damage that occurs in the adult respiratory distress syndrome. Whether it occurs in the lungs of preterm infants with respiratory distress syndrome is unknown. METHODS: Tumour necrosis factor alpha concentrations in the bronchopulmonary secretions of 28 ventilated preterm infants were determined by the enzyme linked immunosorbent assay. RESULTS: Concentrations were low in the first three days of life, being undetectable in nine of the 20 infants whose bronchopulmonary secretions were sampled. From day 4 concentrations were increased and detectable in all but two of 14 infants. Similar concentrations were found in samples taken on days 8-20 and 21-40. Greater mean concentrations occurred in those infants requiring oxygen for a long time. In six infants who received dexamethasone treatment for prolonged ventilator dependency treatment was associated with a reduction in tumour necrosis factor alpha concentrations. CONCLUSIONS: Tumour necrosis factor may contribute to the neonatal respiratory distress syndrome, as suggested for the adult respiratory distress syndrome. The therapeutic effects of dexamethasone treatment in neonatal respiratory distress syndrome may be mediated, at least in part, by reduced production of pulmonary tumour necrosis factor.

Persistence of the Hering-Breuer reflex beyond the neonatal period.

There is conflicting evidence regarding the persistence of the Hering-Breuer reflex (HBR) beyond the 1st wk of life. This study was designed to assess the influence of postnatal age on the HBR. The airway occlusion technique was used to assess changes in respiratory timing during stimulation of the HBR in healthy full-term unsedated infants measured shortly after birth and at 6-8 wk of life. The strength of the HBR was assessed from the relative change in expiratory time (TE) after end-inspiratory occlusion compared with resting TE during spontaneous breathing. Paired studies were performed in 31 infants at approximately 2 days and 6 wk of age. There was a significant increase in TE during each occlusion in every infant irrespective of age at measurement. No maturational changes were observed. The increase in TE after end-inspiratory occlusion was 91.9 +/- 31.6% (SD) (range 38-158%) at approximately 2 days and 89.8 +/- 30.7% (range 44-175%) at approximately 6 wk. We conclude that the activity of the HBR during tidal breathing persists beyond the neonatal period and that there is no statistically significant change in its strength during the first 2 mo life in healthy infants during natural sleep.

Influence of sedation on the Hering-Breuer inflation reflex in healthy infants.

The airway occlusion technique for measuring passive respiratory mechanics in infants relies on an ability to evoke the Hering-Breuer inflation reflex (HBR). However, the persistence of this reflex beyond the early newborn period remains controversial. We have recently demonstrated that there is no change in the strength of this reflex during the first two months of life in healthy infants during natural sleep. Measurements beyond this immediate newborn period are difficult without sedation, but it is unclear whether sedation itself may influence this reflex. To investigate the influence of sedation, the HBR was measured in 66 healthy, full-term infants aged 4-8 weeks. Thirty-three infants were measured during natural sleep, and 33 after triclofos sodium sedation (75 mg.kg-1). The strength of the HBR was assessed from the change in expiratory time (TE) following brief end-inspiratory airway occlusion, as compared to TE during spontaneous breathing. The mean increase in TE following occlusion was 89.45% (SD, 29.8; range, 44-175) in infants sleeping naturally, and 92.42% (SD, 31.2; range, 34-179) in sedated infants. Using unpaired t tests, no statistically significant difference was found between groups (P = 0.7516). We conclude that the strength of the HBR in healthy infants is not influenced by sedation with triclofos sodium, in doses normally used for lung function testing.

Blood resistivity and its implications for the calculation of cardiac output by the thoracic electrical impedance technique.

A relationship has been established between the haematocrit and the resistivity of whole blood at 37 degrees C for neonates and adults not suffering from renal failure. Values of resistivity obtained in this way were substituted into Kubicek's equation for stroke volume by the electrical impedance technique, the signal pick-up electrodes being placed in standard positions. The calculated cardiac outputs were then compared with those obtained simultaneously from other techniques such as the dye dilution method for adults and the measurement of pulmonary effective capillary blood flow by rebreathing nitrous oxide in neonates. It was found that the impedance method overrestimates under these circumstances, and other workers have shown that this is likely to be due to a contribution from the right heart. A haemotocrit-dependent correction factor has been employed in the case of neonates to align the impedance and nitrous oxide results.