Neurodevelopmental Outcomes at 42 Months After Thyroxine Supplementation in Infants Below 28 Weeks' Gestation: A Randomized Controlled Trial.

Background: Infants below 28 weeks' gestation have low thyroid hormone plasma levels compared with more mature infants and this may contribute to their risk of developmental disability. We aimed at determining the effect of supplementation with levothyroxine (LT4) for extremely premature infants born below 28 weeks' gestations on neurodevelopmental outcomes at 42 months. Methods: An explanatory double-blind, randomized, placebo-controlled trial consecutively recruited 153 infants below 28 weeks' gestation from 5 neonatal units in the United Kingdom. Infants were either supplemented with LT4 started intravenously during the first 5 days after birth and then changed to oral LT4 when enteral feeds were fully established (8 µg/kg birthweight/day as a single daily dose) or given placebo until 32 weeks' corrected gestational age. Neurodevelopmental outcomes at 42 months (range 40-43) were evaluated in 59 of these infants (30 LT4-supplemented, 29 placebo) by using Bayley III Mental and Psychomotor Developmental Indices. Cognition outcomes was correlated with plasma free thyroxine (fT4) level at 36 weeks and diffusion tensor imaging (DTI) markers. Results: The LT4 supplemented group performed significantly better in motor, language, and cognitive function domains. The mean of the difference between each group (95% confidence intervals [CI], p-value) was motor domain 6.96 ([0.55-13.38], p = 0.034); language domain 8.93 ([0.16-17.70], p = 0.041); and cognition domain 6.35 ([0.14-12.55], p = 0.045). Neurodevelopmental outcome at 42 months had some associations with the trial's primary outcome (subarachnoid space width and motor outcome, p = 0.03), plasma fT4 level at 36 weeks (fT4 and cognition outcome, p = 0.01), and DTI at 36 weeks with cognition outcomes (p > 0.05). Conclusion: Our data suggest that early supplementation with LT4 may improve long-term neurodevelopment in infants born below 28 weeks' gestation, but larger trials are warranted as the current reported improvements shown are not strong enough to warrant a change in practice.

Do maternal factors influence neonatal thyroid status in the extreme premature infant?

BACKGROUND: In early pregnancy, maternal transfer of thyroxine (T4) significantly contributes to the foetal T4 requirements. Interruption of the maternal transfer of T4 may lead to inadequate T4 exposure, potentially leading to neurodevelopmental deficits. AIM: To determine if maternal factors are associated with the thyroid hormone status of extremely premature infants during the first five days of life. METHOD: This prospective study looked at 117 mothers and their extremely premature babies (born before 28 weeks' gestation). The relationship between neonatal thyroid hormone status and maternal factors (gestation, route of delivery, exogenous maternal glucocorticoid administration, maternal free T4 (FT4), presence or absence of maternal chorioamnionitis, maternal smoking status, maternal body mass index (BMI) index, maternal thyroid peroxidase antibody status (TPO) and maternal haemoglobin levels) were evaluated. Multiple linear regression was used to study independent factors affecting neonatal thyroid function. RESULTS: Mean gestational age was 25(+5) ± 1.3 weeks (range 22(+0) to 27(+6)). Neonatal FT4 strongly correlated with gestation, with a greater severity of hypothyroxinaemia associated with lower gestation (r = 0.6, p < 0.0001). Multiple regression found gestation to be the only independent factors affecting thyroid status (beta coefficient = 0.08, p = 0.01), and no maternal factors were found to be associated with neonatal thyroid status. CONCLUSION: Neonatal thyroid status in extreme preterm infants is independently affected by gestation and not maternal factors such as route of delivery, exogenous maternal glucocorticoid administration, third trimester maternal FT4, presence or absence of chorioamnionitis, smoking status, BMI, TPO status or haemoglobin levels. The severity of neonatal hypothyroxinaemia increases with lower gestational age.

A novel method of collection of saliva for estimation of steroid levels in extremely premature infants.

AIM: The major advantage of salivary cortisol sampling is that it is considerably less invasive than taking a blood sample. However, previous methods of obtaining saliva in premature infants have been poorly tolerated and inaccurate. We describe a simple, non-distressing technique for obtaining saliva samples to assess extremely premature infants' salivary cortisol status. METHODS: We prospectively obtained early morning saliva samples from extremely premature infants. Their gestational age ranged between 23 and 27 weeks. Saliva was obtained using four standard universal swabs by placing one swab at a time in the infant's mouth for 1-2 min. No salivary stimulants were used. RESULTS: There were 65 infants (36 males). Mean gestation was 25.3 ± 1.3 weeks. This technique had a success rate of 85% in obtaining a mean of 150 µL of saliva (range 50-350 µL) by trained staff. No adverse events were recorded. CONCLUSION: We describe a novel, safe, non-distressing and effective method of saliva collection for salivary cortisol measurement in extremely premature infants.

Peripheral oxygenation and management in the perinatal period.

The mechanisms for the adequate provision of oxygen to the peripheral tissues are complex. They involve control of the microcirculation and peripheral blood flow, the position of the oxygen dissociation curve including the proportion of fetal and adult haemoglobin, blood gases and viscosity. Systemic blood pressure appears to have little effect, at least in the non-shocked state. The adequate delivery of oxygen (DO(2)) depends on consumption (VO(2)), which is variable. The balance between VO(2) and DO(2) is given by fractional oxygen extraction (FOE=VO(2)/DO(2)). FOE varies from organ to organ and with levels of activity. Measurements of FOE for the whole body produce a range of about 0.15-0.33, i.e. the body consumes 15-33% of oxygen transported.

Cause of death in infants of women with pregestational diabetes mellitus and the relationship with glycemic control.

BACKGROUND: Perinatal mortality remains high among infants of mothers with type 1 and type 2 diabetes mellitus. Although high glucose levels have been implicated, the mechanism is not well understood. AIMS: 1) to identify the causes of stillbirth and neonatal death in infants of women with type 1 and type 2 diabetes; 2) to determine whether the causes of perinatal mortality are the same for women with type 1 and type 2 diabetes; and 3) to ascertain the relationship between perinatal mortality and maternal glycemic control. MATERIALS AND METHODS: The case notes of women with type 1 and type 2 diabetes mellitus who had a stillbirth or neonatal death were identified and examined by 2 reviewers independently. RESULTS: Ninety-three perinatal deaths were identified (59 women with type 1 diabetes; 34 women with type 2 diabetes). There were 73 stillbirths, 12 were early neonatal deaths, and 8 were late neonatal deaths. Eighteen deaths were attributed to congenital anomalies, 64 to antepartum asphyxia, 4 to intrapartum asphyxia, 3 to postnatal hyaline membrane disease, 2 to postnatal infection, 1 was unclassifiable, and 1 case had no details available. Median postmenstrual age at death was 34 weeks for both women with type 1 and type 2 diabetes. Congenital anomalies were less common in women with type 1 diabetes than those with type 2 diabetes (rate ratio, 0.37 [95% confidence interval, 0.15-0.95]). The relationship between preconceptional and maximal maternal glycosylated hemoglobin (HbA1c) concentrations and birth weight was curvilinear: at low HbA1c levels, the fetal weight was normal; when HbA1c levels were moderately raised, there was macrosomia; very high HbA1c levels were associated with severe intrauterine growth restriction. CONCLUSION: We describe a relationship between HbA1c and fetal weight. We consider that this provides evidence that hyperglycemia not only causes fetal macrosomia but also an angiopathy affecting the utero-placental blood vessels and consequent fetal hypoxia. These observations provide further evidence that good pre- and periconceptional glycemic control is likely to be of great importance in improving the outcome of pregnancies of women with diabetes.

Peripheral blood flow and oxygen extraction in the sick, newborn very low birth weight infant shortly after birth.

This study examined the relationship between blood pressure, peripheral blood flow (PBF), and peripheral fractional oxygen extraction (FOE). Variables that may influence PBF and peripheral FOE were also measured. Measurements of PBF by near infrared spectroscopy and fractional shortening by echocardiography were made within 12 h of birth in 24 infants less than 32 wk gestation. Blood gases, Hb, temperature, and blood pressure were also measured. PBF was significantly correlated with fractional shortening (r = 0.56, p = 0.005), Po2 (r = -0.5, p = 0.01), and peripheral temperature (r = 0.52, p = 0.01). Peripheral FOE was significantly correlated with fractional shortening (r = -0.48, p = 0.02), Po2 (r = 0.52, p = 0.02), and Pco2 (r = -0.53, p = 0.008), but not with peripheral temperature. There was no significant correlation between blood pressure and either PBF or peripheral FOE. These results indicate the importance of several physiologic variables, but not blood pressure, in determining peripheral tissue oxygen delivery in sick preterm infants receiving intensive care. It adds weight to the idea that blood pressure should not be considered a surrogate for peripheral blood flow and oxygen delivery.

The relationship between cardiac output, cerebral electrical activity, cerebral fractional oxygen extraction and peripheral blood flow in premature newborn infants.

Cardiac output is a determinant of systemic blood flow and its measurement may therefore be a useful indicator of abnormal hemodynamics and tissue oxygen delivery. The purpose of this study was to investigate in very premature newborn infants the relationships between cardiac output (left and right ventricular outputs), systemic blood pressure, peripheral blood flow (PBF) and two indicators of cerebral oxygen delivery (cerebral electrical activity and cerebral fractional oxygen extraction (CFOE)). This was a prospective observational study performed on 40 infants of less than 30 wk gestation. Digital electroencephalograms (EEGs) were recorded for one hour every day during the first four days after birth and subjected to qualitative and quantitative analysis. Left and right ventricular outputs, mean blood pressure (MBP), CFOE, PBF and arterial blood gases were measured at the same time. Within the ranges studied, there was no apparent relationship between left or right ventricular output (RVO), PBF and indicators of cerebral perfusion (cerebral electrical activity and CFOE). The EEG was normal in infants with low left and right ventricular outputs (<150 mL/kg/min) and MBP > 30 mm Hg. Infants with low cardiac output and normal MBP seem able to maintain cerebral perfusion, possibly through vasodilatation of the cerebral microvasculature.

Relationship between blood pressure, cerebral electrical activity, cerebral fractional oxygen extraction, and peripheral blood flow in very low birth weight newborn infants.

There is uncertainty about the level of systemic blood pressure required to maintain adequate cerebral oxygen delivery and organ integrity. This prospective, observational study on 35 very low birth weight infants aimed to determine the mean blood pressure (MBP) below which cerebral electrical activity, peripheral blood flow (PBF), and cerebral fractional oxygen extraction (CFOE) are abnormal. Digital EEG, recorded every day on the first 4 d after birth, were analyzed a) by automatic spectral analysis, b) by manual measurement of interburst interval, and c) qualitatively. CFOE and PBF measurements were performed using near-infrared spectroscopy and venous occlusion. MBP was measured using arterial catheters. The median (range) of MBP recorded was 32 mm Hg (16-46). The EEG became abnormal at MBP levels below 23 mm Hg: a) the relative power of the delta (0.5-3.5 Hz) frequency band was decreased, b) interburst intervals were prolonged, and c) all four qualitatively abnormal EEG (low amplitude and prolonged interburst intervals) from four different patients were recorded below this MBP level. The only abnormally high CFOE was measured at MBP of 20 mm Hg. PBF decreased at MBP levels between 23 and 33 mm Hg. None of the infants in this study developed cystic periventricular leukomalacia. One infant (MBP, 22 mm Hg) developed ventricular dilatation after intraventricular hemorrhage. The EEG and CFOE remained normal at MBP levels above 23 mm Hg. It would appear that cerebral perfusion is probably maintained at MBP levels above 23 mm Hg.

Blood pressure in the neonate.

The paper by Dannevig et al. in this issue of Acta Paediatrica carefully compares the agreement between blood pressure measurements made by three non-invasive blood pressure monitors with those made from an indwelling intra-arterial catheter. Non-invasive blood pressure monitoring is not particularly accurate for making measurements in neonates and generally overestimates the blood pressure as observed by others. Clinicians thus should be wary about using non-invasive blood pressure techniques as substitutes for monitoring by means of an intra-arterial catheter and transducer.

Cerebral fractional oxygen extraction is inversely correlated with oxygen delivery in the sick, newborn, preterm infant.

Cerebral blood flow (CBF) is known to be low in newborn infants, but this has not been shown to be damaging. The purpose of this study was to investigate the relationships between cerebral haemoglobin flow, blood flow, oxygen delivery, oxygen consumption, venous saturation, and fractional oxygen extraction (OEF) in newborn, preterm infants. Measurements were made by near-infrared spectroscopy in 13 very preterm, extremely low birth weight infants (median gestation 25 weeks) during the first 3 days after birth. There was a negative correlation between cerebral oxygen delivery and OEF (n=13, r=-0.5, P=0.03), which implies that when there is a reduction in cerebral oxygen delivery in sick preterm infants, increased cerebral oxygen extraction may be responsible for maintaining oxygen availability to the brain. During the first 3 days after birth CBF (n=13, r=0.7, P=0.01), oxygen delivery (n=13, r=0.5, P=0.03), and oxygen consumption (n=13, r=0.7, P=0.004) all increased. This increase in oxygen consumption indicates increased cerebral metabolic activity after birth, which is likely to be a normal adaptation to extrauterine life. The increases in blood flow and oxygen delivery may also be normal adaptations that facilitate this increase in metabolic activity. There was a decrease (P=0.04) in mean (+/-s.d.) cerebral OEF between day 1 (0.37+/-0.10) and day 2 (0.29+/-0.09), with no change between day 2 and day 3. Taking into account the negative correlation between OEF and oxygen delivery, this decrease in OEF may be because of increased oxygen delivery during this time.

Spectral analysis of electroencephalography in premature newborn infants: normal ranges.

Continuous EEG monitoring has not been used widely in neonatal intensive care, especially in the care of extremely premature infants, probably in part because of a lack of a reliable quantitative method. The purpose of this study was to quantify the EEG of the very premature infants just after birth by using spectral analysis and to describe the characteristics of the spectral signal when infants were clinically stable. Digital EEG recordings were performed on 53 infants who were < or =30 wk gestation for 75 min each day during the first 4 d after birth. Artefact was rejected manually after visual inspection of trace. The EEG was analyzed by manual measurement of interburst interval and automatically by spectral analysis using Fast Fourier Transformation. Spectral analysis generated the normal ranges of the relative power of the delta (0.5-3.5 Hz), theta (4-7.5 Hz), alpha (8-12.5 Hz), and beta (13-30 Hz) frequency bands, spectral edge frequency, and symmetry. The median (range) relative power of the delta band increased significantly from 68% (62-76%) on day 1 to 81% (72-89%) on day 4 (p=0.001). The interburst intervals became progressively shorter between days 1 [14s (10-25)] and 3 [8s (6-12)]; there were no significant differences between days 3 and 4. The relative power of the delta band seemed to be the most useful and repeatable spectral measurement for continuous long-term monitoring. However, automatic artefact rejection software needs to be developed before continuous quantitative EEG monitoring can be used in the neonatal intensive care environment.

Postnatal changes in cerebral oxygen extraction in the preterm infant are associated with intraventricular hemorrhage and hemorrhagic parenchymal infarction but not periventricular leukomalacia.

Fluctuations in cerebral hemodynamics have been implicated in the pathogenesis of acquired brain damage in babies born prematurely. This study examined the changes in cerebral fractional oxygen extraction (FOE) over the first 3 d after birth in 25 very-low-birth-weight preterm infants. Twelve infants had no major cerebral injury and 13 had acquired brain injury; cystic periventricular leukomalacia (PVL) was present in 4 and intraventricular hemorrhage (IVH) in 9, of whom 2 also had hemorrhagic parenchymal infarction (HPI). Normal values (median, 5(th)-95(th) centiles) for cerebral FOE in very-low-birth-weight infants with no cerebral injury were 0.38 (0.23-0.53) on d 1, 0.31 (0.18-0.45) on d 2, and 0.28 (0.17-0.38) on d 3. Infants who developed cystic PVL had no significant change in cerebral FOE during the first 3 d after birth. By contrast, cerebral FOE fluctuated in infants with IVH over the 3 d of measurement, decreasing from d 1 to d 2 (p = 0.03) and increasing from d 2 to d 3 (p = 0.02). The highest cerebral FOE values were seen in the two infants with HPI. The different patterns of change in cerebral FOE with HPI and cystic PVL provide additional evidence that the pathogenesis of these two conditions is different. Because high cerebral FOE is likely to be a consequence of low cerebral oxygen delivery, probably because of low cerebral blood flow, our results indicate that fluctuations in cerebral blood flow may occur when there is IVH or HPI.

Cerebral fractional oxygen extraction in very low birth weight infants is high when there is low left ventricular output and hypocarbia but is unaffected by hypotension.

This study examined the relationships between cerebral fractional oxygen extraction (FOE), mean arterial blood pressure (MABP), left ventricular output (LVO), blood gases, and other physiologic variables in 36 very-low-birth-weight preterm infants during the first 3 d after birth. There was a decrease in cerebral FOE (p = 0.008), and rises in LVO (p < 0.0001) and MABP (p = 0.02) during the 3 d. Between d 1 and 2, cerebral FOE decreased (p = 0.007) and LVO increased (p < 0.0001). There was no relationship between MABP and cerebral FOE. LVO correlated negatively with cerebral FOE on d 1 (p = 0.01), but not on d 2 (p = 0.07). On d 1, median pressure of arterial CO(2) was lower in infants with low LVO (<5(th) centile) and high cerebral FOE (>95(th) centile) than in infants with low LVO (<5(th) centile) but normal cerebral FOE (5(th)-95(th) centile) (p = 0.03). These findings suggest that cerebral FOE was increased only when LVO was low and there was hypocarbia. MABP had no demonstrable effect. It is likely that increased cerebral FOE is a normal physiologic response to maintain an adequate oxygen supply to the cerebral tissues when LVO is low and hypocarbia has caused vasoconstriction. It is possible that the cerebral hemispheres are low-priority vascular beds in the preterm infant, and that the high cerebral FOE is a result of reduced hemispheric blood flow to maintain MABP in the presence of low LVO.

An evaluation of a national scheme for continuing professional development (CPD) for career grade doctors: the Royal College of Paediatrics and Child Health's programme for paediatricians evaluated by focus group methodology.

OBJECTIVES: To evaluate a national continuing professional development (CPD) scheme through the views and experiences of its participants. METHODS: A qualitative focus group methodology was used. Forty-nine career grade paediatricians were allocated to nine focus groups according to their work settings, ages and posts. All groups discussed the following: (a) ease or difficulty of achieving CPD requirements; (b) whether a personal professional development plan (PDP) enabled the planning process for CPD; (c) whether CPD participation facilitated changes in practice, and (d) their views on the CPD system in operation at the time of the study. RESULTS: Taking part in CPD had a positive effect on participants' clinical practice and broadened their professional and academic base. The main difficulties in achieving CPD were variable financial support (especially for non-consultant staff) and pressure due to extra work accumulating during study leave. The quality of internal CPD meetings was inconsistent. A professional development plan was useful for planning CPD needs, but there was a conflict between the educational and training needs of the individual and the employing NHS Trusts. The scheme's guidelines were clear but there were reservations about its layout and the system of recording points. CONCLUSION: This study enabled discovery of the views of paediatricians participating in a national CPD scheme operated by the Royal College of Paediatrics and Child Health. Consequently, changes were made to the scheme's presentation (but not content) and process of recording points. Barriers to achieving CPD requirements were identified and are being monitored. Efforts to involve non-consultant career grade paediatricians have been increased.