Behavioural problems at the age of eleven years in preterm-born children with or without fetal brain sparing: A prospective cohort study

Background

In severe intrauterine growth restriction (IUGR) due to placental insufficiency a haemodynamic adaptation occurs, resulting in preferential blood flow to the fetal brain (brain sparing). With Doppler ultrasound an increased ratio between the umbilical and the cerebral artery pulsatility index (U/C ratio) can be demonstrated. IUGR is associated with impaired neurodevelopmental outcome.

Objective

Evaluation of the effect of fetal brain sparing on behavioural problems at eleven years in premature born children.

Methods

Prospective cohort study in premature children born in 1989, with a gestational age of 26 0/7 to 33 0/7 weeks. An U/C ratio > 0.72 was defined as brain sparing. Behavioural problems were assessed with the parent-reported Child Behaviour Check List (CBCL) and the Teacher's Report Form (TRF). T scores > 60 for total problem score and subscales of internalizing and externalizing behaviour, were considered abnormal.

Results

Ninety-eight of the 116 survivors were assessed, of which 31 with antenatally established fetal brain sparing. According to the CBCL-total problem score 23.3% of the premature born babies in the brain sparing group had behavioural problems compared with 22.8% of those without brain sparing. According to the TRF-total problem score the percentages were 21.4% and 20.0%, respectively. Logistic regression analysis failed to show a significant association of U/C ratio with behavioural problems. In this model oxygen dependency at 28 days, IQ < 85 at five years, cranial ultrasound abnormalities, fetal growth ratio < 0.80, Apgar scores < 7 after 5 min and birth weight < p10 contributed significantly.

Conclusion

In this cohort brain sparing itself has no significant association with behavioural problems at eleven years.     

Fructose in fetal cord blood and its relationship with maternal and 48-hour-newborn blood concentrations

Background

Studies have suggested that different non-glucose sugars and sugar alcohols play a role in placental and fetal metabolism. However, the role of fructose in the fetal and newborn metabolism is unclear and studies are scarce.

Aim

Our objective was to investigate the presence of fructose in umbilical cord blood in full-term gestation and its relationship with maternal and 48-hour-old- newborn blood concentrations, to evaluate fructose production by the fetus and newborn infant.

Methods

Blood fructose and glucose concentrations were determined by HPLC in 26 paired samples of maternal blood, umbilical cord vein, and peripheral newborn blood at 48 h after birth. ANOVA, the Friedman Analysis of Variance on Ranks and the Pearson correlation with p < 0.05 were used.

Results

Fructose concentration in umbilical cord blood was higher than maternal blood (p = 0.024), suggesting endogenous fructose production by the fetal-placental unit via the sorbitol pathway. Fructose concentrations were higher in newborns at 48 h after birth than in the fetal umbilical cord blood (p = 0.004), suggesting that fructose production is a continuous process from fetus to newborn.

Conclusions

Fructose production by the sorbitol pathway, present in the fetus and newborn, is an alternative pathway in glucose metabolism probably used to maintain redox balance in the fetus. We suggest that endogenous fructose, similar to dietary ingested fructose, under physiological conditions produces the backbone for triacylglycerol and lipid synthesis in the fetus and newborn. Therefore the route for metabolizing fructose is already present in the early steps of human development.     

General movements in the perinatal period and its relation to echogenicity changes in the brain

Background

In preterm born infants abnormal general movements (GMs) generally normalize before three months post term, but may persist when perinatal brain injury is present.

Aims

To assess the continuity of GM quality from fetal to early neonatal period and its relation to brain echogenicity changes.

Study design

Prospective study examining GMs and three vulnerable brain areas before and 7 days after birth. The quality of GMs was classified as normal or abnormal by Gestalt-perception. The brain was examined for moderate echogenicity changes (periventricular: brighter than choroid plexus, intraventricular: filling equal or more than 50% of the ventricle, and locally increased basal ganglia/thalami).

Subjects

94 fetuses from pregnancies complicated by preterm hypertensive disorders or labour at a gestational age between 26 and 34 weeks.

Outcomes measures

Correlations of fetal GMs, echogenicity changes, and clinical parameters (e.g. gestational age, parity, hypertensive disorders or preterm labour, oligohydramnios and fetal growth restriction) with neonatal GMs.

Results

Fetal GMs were abnormal in 64%, normalizing in 68% within 7 days after birth. Fetal GMs were significantly related to postnatal GMs (p = 0.045). Moderate fetal brain echogenicity changes and clinical parameters were not significantly related to neonatal GM.

Conclusions

In this population of pregnancies compromised by hypertensive disorders or preterm labour fetal GMs correlated with neonatal GMs. Presence of moderate echogenicity changes in the fetal brain was not related to neonatal GMs.     

Oxidative stress after antenatal betamethasone: Acute downregulation of glutathione peroxidase-3

Background

Human and experimental data show that antenatal exposure to glucocorticoids (GC) temporarily reduces fetal well-being and impairs the fetal response to hypoxemia.

Aims

We tested the hypothesis that antenatal betamethasone provokes transient oxidative stress, which may be triggered directly by the GC or indirectly by metabolic signals such as increased glucose and free fatty acid (FFA) concentrations.

Study design

Prospective (single center, 18 months) cohort study in newborns < 34 weeks gestational age at birth.

Methods

We studied 105 newborns and measured oxidative damage to lipids [malondialdehyde (MDA)] and proteins (protein carbonyls), as well as glutathione peroxidase-3 (GPx3), an important antioxidant enzyme, in umbilical vein (UV) plasma. In addition, we measured umbilical artery and UV blood gases, and metabolic indices (plasma glucose, FFA and insulin) in UV.

Results

MDA but not protein carbonyl concentrations was inversely related to time elapsed since the first or last betamethasone administration (p = 0.006); MDA remained elevated by 69-96% for at least 72 h after the last betamethasone. By contrast, GPx3 concentrations were repressed in newborns who received betamethasone ≤ 24 h before birth. GPx3 and MDA concentrations were correlated (r = − 0.38, p < 0.001). Labor, GA, sex, size at birth, blood gases or metabolic indices did not explain the effects of betamethasone on MDA and GPx3.

Conclusions

Antenatal GC elicit a rapid suppression of the GPx3 antioxidant defense system which may contribute to a longer-lasting but also transient rise in lipid oxidative damage.     

Perinatal cerebral insults alter auditory event-related potentials

Background

Auditory event-related potentials (AERPs) can be used as indices of neural information processing. Altered AERPs have been reported in children and young adults with frontal lobe infarction.

Aim

To test the hypothesis that perinatal brain injury affects cortical auditory processing.

Methods

We assessed AERPs at term, 6 and 12 months of age in preterm infants [n = 9, median gestational age (GA) 27.9, range 23.9-30.0 wk], term infants with perinatal intracerebral hemorrhage (ICH) [n = 5, GA 40.3, range 37.4-42.3 wk], and term infants with perinatal asphyxia [n = 4, GA 39.4, range 37.9-40.3 wk]. Healthy preterm (n = 16) and term infants (n = 22) served as controls. A harmonic tone of 500-Hz frequency was used as standard and of 750-Hz as deviant stimulus. Mean AERP amplitudes were calculated over 100 ms periods from 50 to 350 ms. The developmental outcome was followed until 2 years of age.

Results

The term ICH (p = 0.012) and asphyxia (p = 0.0016) group had smaller or more negative responses to the deviant, resulting in smaller or more negative MMR amplitudes than those of the controls. The preterm ICH group did not differ significantly from their preterm born controls. MMR varied in all patient groups and was not associated with adverse outcome.

Conclusion

AERP alterations suggest that perinatal cerebral insults affect cortical auditory processing.     

Reduced cerebellar diameter in very preterm infants with abnormal general movements

Background

Abnormal General Movements (GMs) early in life are predictive of later neuromotor deficits and are related to white matter abnormalities on magnetic resonance imaging (MRI). However, other structural correlates of abnormal GMs have not been defined.

Aims

The objective of this study was to explore brain-metrics (linear brain measurements on MRI representative of 3-D brain volumes) at term as a predictor of abnormal GMs at 1 and 3 months' corrected age in preterm infants. It was hypothesized that abnormal GMs would be related to reduced brain-metrics in primary motor areas, namely the cerebellum and parietal lobes.

Study design

Eighty three preterm infants (< 30 weeks' gestational age) were scanned at term-equivalent age. MRI was assessed for white matter abnormality and brain-metrics in six predefined brain regions (i.e. bifrontal, biparietal, lateral ventricles and transverse cerebellar diameters, and inter-hemispheric distance).

Outcome measures

At 1 and 3 months' corrected age infants' GMs were assessed from video-taped footage and rated as normal or abnormal using standardized methodology.

Results

At 1 month, 63% (n = 52) of infants had abnormal GMs with no association between any of the brain-metrics and abnormal GMs. At 3 months, 23% (n = 18) of infants had abnormal GMs (absent fidgety movements n = 18; abnormal fidgety movements n = 0). Reduced bifrontal, biparietal, and cerebellar transverse diameters, along with an increase in lateral ventricle sizes were associated with an increased risk of abnormal GMs at 3 months' corrected age. After controlling for white matter abnormality and grade III/IV intraventricular haemorrhage, only the cerebellar transverse diameter was predictive of abnormal GMs at 3 months.

Conclusions

Reduced cerebellar diameter at term equivalent age is related to abnormal GMs at 3 months' corrected age, independent of white matter abnormality and intraventricular haemorrhage.     

Patterns in sleep-wakefulness in three-month old infants exposed to methadone or buprenorphine

Background

Infants exposed to opioides in-utero frequently demonstrate withdrawal symptoms in the neonatal period and have difficulties with state regulation.

Aim

This study examines sleep-wakefulness-distress patterns as indicators of regulatory mechanisms at 3 months of age.

Participants

A national infant cohort (N = 35) born to women in high-dose maintenance treatment during pregnancy and a comparison group (N = 36) of low-risk infants born in the same period.

Outcome measures

Distributions and frequencies of sleep, wakefulness and distress measured in hours and episodes on sleep charts recorded by the mothers in the two groups.

Results

Women in maintenance treatment were monitored closely during pregnancy to avoid illicit drug use and to be prepared for motherhood. They were also offered residential treatment before pregnancy and after the child was born. There were no statistical differences between the two groups in any of the 10 measures reflecting diurnal and nocturnal rhythmicity at 3 months despite of neonatal abstinence syndrome in 47% of the exposed infants and significant differences in infant characteristics with respect to birth weight, gestational age and maternal characteristics.

Conclusions

Follow-up procedures combining drug monitoring and counseling during pregnancy and in the first months after birth enhance the development of state regulation in terms of sleep-wakefulness patterns.     

Movements and postures of infants aged 3 to 5 months: to what extent is their optimality related to perinatal events and to the neurological outcome?

Background

The quality of spontaneous general movements (GMs), assessed in the individual infant, has emerged as one of the most reliable and valid predictors especially of severe neurological impairments.

Aims

To implement a more detailed assessment of GMs and co-existing movements and postural patterns in a rehabilitation clinic, and to examine to what extend is the optimality of movements and postures of infants aged 3 to 5 months related to perinatal events and the neurological outcome.

Study design

Prospective study of 41 infants (15 boys and 26 girls; 11 infants born preterm) admitted to the Department of Paediatric Neurology and Rehabilitation of the St. Joseph's Hospital in Kyoto (Japan).

Outcome measures

Clinical, neurological and psychological status at age 5.

Results

Motor optimality at age 3 to 5 months correlated positively with neonatal optimality (r = 0.48, p < 0.01), especially regarding factors associated with hypoxic events. A non-optimal motor performance (lowest possible scores) predicted cerebral palsy with 100% accuracy. Other adverse outcomes such as developmental delays, developmental coordination disorders, pervasive developmental disorder or attention deficit hyperactivity disorder turned out not to be associated with early motor performance. In 13% of cases absence of fidgety movements proved to be false positives, but their normal appearance along with a smooth concurrent motor performance was solely found in infants with a normal neurological development.

Conclusion

Assessing the quality of motor performance at age 3 to 5 months considerably improves our ability to identify infants at risk for maldevelopment.     

Response of the foetal pupil to vibro-acoustic stimulation: a foetal attention test

Background

The iris regulates the intensity of light that stimulates the retina. The pupils dilate also in response to mental activities as sign of attention. We hypothesized that the response of the foetal pupil to vibro-acoustic stimulation (VAS) reflects foetal attention.

Aims

To determine whether the changes in the foetal pupil produced by vibroacoustic stimulation is a sign of foetal attention.

Study design

We studied sonographically the pupils and iris of 151 foetuses between 27 and 41 weeks of gestation, using maximum ultrasonic zoom.

Subjects

160 human foetuses between the 27th and the 41st week of gestation.

Outcome measures

The diameters of the pupil and iris were compared before and after VAS.

Results

At baseline, the pupils were miotic. We observed a response to VAS, manifest as a prominent pupillary dilatation in all foetuses. At all gestational ages, the percent increase in pupillary diameter was ≥ 57% (mean 87%; range: 57-135%).

Conclusions

VAS dilated the foetal pupil. Sonographic assessment of the foetal pupil provided important insights in the development of foetal neurological functions.     

CPAP combined with inhaled nitric oxide for treatment of lung hypoplasia and persistent foetal circulation due to prolonged PPROM

Background

Second trimester preterm premature rupture of the membranes (PPROM) before 24 weeks of gestation is associated with a high morbidity and mortality rate.

Aim

To demonstrate the efficacy of early continuous positive airway pressure (CPAP) combined with inhaled nitric oxide (iNO) for treatment of preterm infants with lung hypoplasia and persistent foetal circulation (PFC) due to very early PPROM and prolonged severe oligohydramnios.

Methods

Seven infants with prolonged PPROM, lung hypoplasia, respiratory distress and persistent foetal circulation were intubated in the delivery room for subsequent surfactant and iNO application. As our new treatment strategy was to keep the period of mechanical ventilation as short as possible, all infants were switched on nasal CPAP combined with iNO within the first 24 hours.

Results

Mean gestational age at PPROM was 19 + 6 weeks (range 14 + 2 to 23 + 6 weeks) and the average latency period between rupture of membranes and delivery was 10 + 3 weeks (7 + 3 to 16 + 4 weeks). Infants were born at 30 + 3 weeks of gestation (28 + 3 to 33 + 1 weeks) with an average birth weight of 1468 g (884 to 2200 g). In all neonates CPAP combined with iNO reversed PFC and 6 patients stabilised without the need for reintubation and mechanical ventilation. One infant had to be reintubated following 12 hours of CPAP combined with iNO due to respiratory insufficiency. All seven infants survived to discharge.

Conclusion

CPAP combined with iNO might be a promising approach for therapy of preterm infants with lung hypoplasia and persistent foetal circulation due to very early PPROM.     

Leptin determination in colostrum and early human milk from mothers of preterm and term infants

Background

Leptin is involved in the regulation of food intake and energy expenditure and is therefore important for growth and brain development. Analytical methods used for leptin measurement in human milk differ widely in the literature and yield varying results.

Aims

To compare different preparation methods for the analysis of leptin in human milk and to investigate the leptin levels in colostrum and mature human milk from mothers of preterm or term infants.

Methods

Mothers delivering a preterm (n = 37) or a term infant (n = 40) were recruited for a prospective study and were ask to collect breast milk on the 3rd and 28th day of lactation. Leptin, protein and fat concentrations were analysed. Clinical data of mother and child were recorded prospectively.

Results

Skim milk was most appropriate for leptin analysis. Human milk leptin concentrations did not differ between preterm and term human milk. In term milk, leptin concentration on day 28 was lower than on day 3 (p < 0.05). Milk leptin levels on the 3rd and 28th day were positively correlated with mothers' body mass index, but not with fat content in milk.

Conclusion

Skim milk was the most stabile preparation for leptin analysis. Preterm and term human milk contain leptin in equal concentrations. Human milk leptin depends on mothers' body mass index.     

Breastfeeding is not associated with left cardiac structures and blood pressure during the first two years of life. The Generation R Study

Background

Shorter duration of breastfeeding in infancy has been suggested to be associated with an increased risk of cardiovascular disease in adulthood. Early cardiovascular adaptations due to breastfeeding may explain these associations.

Aim

To investigate whether breastfeeding affects left cardiac structures and blood pressure development in early childhood.

Study design

Prospective cohort study from fetal life until the age of two years.

Subjects

Information about the duration and exclusivity of breastfeeding was collected by questionnaires at the ages of 2, 6 and 12 months in 933 children.

Outcome measures

Left cardiac structures (left atrial diameter, aortic root diameter and left ventricular mass), fractional shortening and blood pressure at the ages of 1.5, 6 and 24 months.

Results

No differences in cardiac structures, fractional shortening and blood pressure were observed between breastfed and non-breastfed children. Duration and exclusivity of breastfeeding were not consistently associated with any cardiac structure, fractional shortening, or blood pressure until the age of 24 months. Also, there was no association of breastfeeding with cardiac growth between 6 months and 24 months. All analyses were adjusted for child age and sex. Additional adjustment for child anthropometrics, maternal age, anthropometrics, family history, maternal cardiovascular risk factors, pregnancy or delivery complications, parity, socio-economic status, smoking status and alcohol consumption during pregnancy did not materially change the effect estimates.

Conclusions

Our results do not support the hypothesis that early postnatal cardiovascular adaptations underlie the previously shown associations between breastfeeding and cardiovascular disease in adulthood. Further studies are needed to investigate whether and at what age the associations appear.     

Cardiovascular and metabolic outcome in 6-8 year old offspring of women with type 1 diabetes with near-optimal glycaemic control during pregnancy

Background

High maternal glucose concentrations during diabetic pregnancy may lead to health problems in the offspring later in life. We showed in a previous nationwide study on pregnancy outcome in type 1 diabetic women that prepregnancy care was good and a near-optimal glycaemic control during pregnancy was achieved (mean HbA1c 6.2%).

Aims

We investigated to what extent current care and treatment of pregnant women with type 1 diabetes were related to cardiovascular and metabolic disturbances in the offspring at school age. Additionally, we studied the influence of level of maternal glycaemic control, preterm birth and neonatal macrosomia (birth weight > p90).

Study design

Observational cohort study.

Subjects

6-8 year old offspring of women with type 1 diabetes (ODM, n = 213) and a control group of children of non-diabetic women (n = 79).

Outcome measures

BMI, blood pressure, parameters of fasting glucose regulation and lipid metabolism, components of the metabolic syndrome (overweight, hypertension, impaired fasting glucose, dyslipidaemia).

Results

Parameters of fasting glucose regulation and lipid metabolism and the frequency of components of the metabolic syndrome did not significantly differ between ODM and controls. Systolic blood pressure was slightly higher in ODM. The influence of level of maternal glycaemic control, preterm birth and neonatal macrosomia on outcome in ODM was limited.

Conclusions

Current care and treatment of pregnant women with type 1 diabetes result in cardiovascular and metabolic outcome in the offspring at 6-8 years of age that is comparable to that in children of non-diabetic women. Further follow-up should substantiate these results at later age.     

Small and large foetuses: Identification and estimation of foetal weight at delivery from third-trimester ultrasound data

Background

The estimation of foetal weight (EFW) at delivery is crucial to assess the risk of foetal and neonatal morbidity and mortality, most notably when the foetus is small or large.

Aim

To accurately predict the EFW at delivery of small foetuses (birth weight [BW] ≤ 2500 g) and large foetuses (BW ≥ 4000 g) identified with third-trimester ultrasound data.

Methods

We included 1309 foetuses whose age and weight at birth were known and for whom standard data were available from third-trimester ultrasound scans. Small and large foetuses were identified by extrapolation to full term of the estimated foetal weight obtained using Hadlock's equation. We built two regression models for predicting the birth weights of small and large foetuses, respectively. The results obtained with these models were compared to those obtained with Hadlock's equation.

Results

Third-trimester sonograms were obtained at 33.6 ± 1.3 weeks gestational age [WGA] and birth occurred at 38.7 ± 1.2 WGA. EFW of small foetuses predicted using the regression model showed significantly less systematic bias than the Hadlock estimate (2.3% vs. 7.2%, respectively), whereas random errors were similar. EFW of large foetuses predicted using the regression model showed significantly less random error than the Hadlock estimate (6.2% vs. 10.1%, respectively), whereas systematic bias was similar. Data from an independent validation sample indicate that our regression models are accurate.

Conclusions

To apply distinct models for accurately predicting the EFWs at delivery of small and large foetuses should prevent adverse events related to newborn size.     

A patient care system for early 3.0 Tesla magnetic resonance imaging of very low birth weight infants

Background

Very low birth weight (VLBW) infants (weight < 1500 g) are increasingly cared for without prolonged periods of positive pressure ventilation (PPV).

Aims

To develop a system for 3.0 T magnetic resonance (MR) image acquisition from VLBW infants who are not receiving PPV, and to test the clinical stability of a consecutive cohort of such infants.

Design

Seventy VLBW infants whose median weight at image acquisition was 940 g (590-1490) underwent brain MR imaging with the developed care system as participants in research. Twenty infants (29%) received nasal continuous positive airway pressure (nCPAP), 28 (40%) received supplemental oxygen by nasal cannulae, and 22 (31%) breathed spontaneously in air during the MR examination.

Results

There were no significant adverse events. Seventy-six percent had none or transient self-correcting oxygen desaturations. Desaturations that required interruption of the scan for assessment were less common among infants receiving nCPAP (2/20) or breathing spontaneously in air (2/22), compared with those receiving nasal cannulae oxygen (13/28), p = 0.003. Sixty-four (91%) infants had an axillary temperature ≥ 36 °C at completion of the scan (lowest 35.7 °C), There was no relationship between weight (p = 0.167) or use of nCPAP (p = 0.453) and axillary temperature < 36 °C. No infant became hyperthermic.

Conclusion

VLBW infants who do not require ventilation by endotracheal tube can be imaged successfully and safely at 3.0 T, including those receiving nCPAP from a customised system.     

Maternal vitamin B-12 and folate status during pregnancy and excessive infant crying

Background

The etiology of excessive infant crying is largely unknown. We hypothesize that excessive infant crying may have an early nutritional origin during fetal development.

Aims

This study is the first to explore whether (1) maternal vitamin B-12 and folate status during pregnancy are associated with excessive infant crying, and (2) whether and how maternal psychological well-being during pregnancy affects these associations.

Study design

Women were approached around the 12th pregnancy week to complete a questionnaire (n = 8266) and to donate a blood sample (n = 4389); vitamin B-12 and folate concentrations were determined in serum. Infant crying behavior was measured through a postpartum questionnaire (± 3 months; n = 5218).

Subjects

Pregnant women living in Amsterdam and their newborn child.

Outcome measures

Excessive infant crying, defined as crying ≥ 3 h/day on average in the past week.

Results

Multiple logistic regression analysis was performed for 2921 (vitamin B-12) and 2622 (folate) women.Vitamin B-12 concentration (categorized into quintiles) was associated with excessive infant crying after adjustment for maternal age, parity, ethnicity, education, maternal smoking and psychological problems (OR[95%CI]: Q1 = 3.31[1.48-7.41]; Q2 = 2.50[1.08-5.77]; Q3 = 2.59[1.12-6.00]; Q4 = 2.77[1.20-6.40]; Q5 = reference). Stratified analysis suggested a stronger association among women with high levels of psychological problems during pregnancy. Folate concentration was not associated with excessive infant crying.

Conclusions

First evidence is provided for an early nutritional origin in excessive infant crying. A low maternal vitamin B-12 status during pregnancy could, in theory, affect infant crying behavior through two potential mechanisms: the methionine-homocysteine metabolism and/or the maturation of the sleep-wake rhythm.     

Episodes of hypocarbia and early-onset sepsis are risk factors for cystic periventricular leukomalacia in the preterm infant

Background

Septic episodes in preterm infants recently have been reported to be associated with periventricular leukomalacia (PVL). The role of hypocarbia as an independent risk factor for PVL in clinical studies raises many questions without conclusive answers.

Aims

To evaluate risk factors for cystic PVL focussing on the influence of hypocarbia.

Study design

Retrospective single centre case-control study.

Subjects

Preterm infants 24 to 35 weeks of gestational age and matched (1:2 for gender, birth year, gestational age and birth weight) controls.

Outcome measures

Multivariate analysis of perinatal factors being associated with cystic PVL diagnosed by serial ultrasound examinations.

Results

Univariate analysis of risk factors revealed lower 5 and 10 min Apgar scores, and higher rates of neonatal seizures, early-onset sepsis, neonatal steroids, respiratory distress syndrome with surfactant replacement therapy, and episodes of hypocarbia significantly being associated with PVL. Multivariate analysis using a logistic regression model revealed early-onset sepsis and hypocarbia being significantly associated with PVL (p = .022 and .024, respectively). Lowest PaCO₂ values did not differ as did not the duration of hypocarbia, but the onset of hypocarbia was significantly later in PVL cases compared to controls (mean 26 vs. 15 h, p = .033). Neurodevelopmental follow-up at a median time of 46 months was poor showing 88% of the cases having an adverse neurological outcome.

Conclusion

We found early-onset sepsis and episodes of hypocarbia within the first days of life being independently associated with PVL.     

Hyperbilirubinemia in infants with Gram-negative sepsis does not affect mortality

Background

Sepsis is associated with an increased production of oxidant species and a decrease in endogenous antioxidant defenses. Mortality is high, especially when endotoxins are involved, e.g., in infants with Gram-negative sepsis. Yet, chronic as well as acute unconjugated hyperbilirubinemia has been shown to protect against endotoxin-induced shock in vivo in rats and in mice. We hypothesized that hyperbilirubinemia in infants with Gram-negative sepsis improves survival and/or mitigates the inflammatory response.

Objective

To assess the relationships between serum bilirubin concentrations on the one hand, and leukocyte count, C-reactive protein and survival on the other hand, in infants with Gram-negative sepsis.

Methods

Retrospectively, we retrieved clinical and biochemical data from infants less than 90 days of age with a blood culture-proven Gram-negative sepsis between January 1998 and December 2005.

Results

We identified 92 infants with Gram-negative sepsis in the indicated period. Median gestational age was 29 (24-42) weeks. 22 Patients died. Preceding sepsis, median total serum bilirubin concentrations were below 150 μmol/L. Median concentrations of conjugated bilirubin concentrations increased (+ 63%, p < 0.05), and median concentrations of unconjugated bilirubin decreased (− 36%, p < 0.05) in infants with Gram-negative sepsis. Median total bilirubin concentrations before and during sepsis were not significantly different between survivors and non-survivors. Changes in bilirubin concentrations were not significantly correlated with changes in either white blood cell count or C-reactive protein.

Conclusion

Present data do not support the concept that bilirubin positively affects survival or the inflammatory response in infants with Gram-negative sepsis.     

Effect of ibuprofen on bilirubin-albumin binding in vitro at concentrations observed during treatment of patent ductus arteriosus

Background

In vitro studies have shown that ibuprofen (IBU) may interfere with bilirubin-albumin binding at concentrations of 100 µg/mL and above.

Objectives

The present study evaluates the in vitro bilirubin displacement over the range of IBU plasma concentrations observed in vivo during curative treatment of patent ductus arteriosus in preterm infants.

Methods

Considering that individual plasma concentrations obtained during the clinical development of IBU in preterm infants were ranging between 10 and 70 µg/mL and exceptionally above 100 µg/mL, we used the modified peroxidase method to determine total and unbound bilirubin concentrations without IBU and with IBU over this specific concentration range.

Results

Total bilirubin and albumin concentrations were respectively 6.6 mg/dL and 2.87 g/dL in pooled newborn plasma. No displacement of bilirubin from its albumin binding sites by IBU was observed over a range of concentrations from 10 to 100 µg/mL. Only a concentration of 200 µg/mL significantly increased the unbound bilirubin by 1.5-fold (p = 0.0008).

Conclusions

This in vitro study confirms displacement of bilirubin by a high IBU concentration of 200 µg/mL, however it retrieves no significant displacement over a range of concentrations up to and including 100 µg/mL, i.e. within the range of in vivo concentrations at the recommended dose regimen.