University of Dundee
ButterflyEuthyroid Collaboration

Programme of research: optimising neurodevelopment

Introduction to programme of research

Premature infants are at risk of cerebral handicap and an adverse neurodevelopmental outcome is the major unsolved consequence of the compromised pregnancy. There are about 7000 extreme preterm infants (< 30 weeks gestation) born per annum in the UK; 25% will have neurological abnormalities, 9% visual and 11% hearing impairments. The group as a whole has a reduction in IQ of 10 points and 50% will require specialist school support.

Neurodevelopmental outcome is affected by many factors which have their origin during fetal life and early infancy. These factors could be described according to their origin as medical or environmental-social. Medical factors include disturbances of homeostasis such as hypoglycaemia, hyperbilirubinaemia, transient hypothyroxinaemia, hypoxia, periventricular leucomalacia, intraventricular haemorrhage, postnatal dexamethasone, and serious infections such as meningitis. Environmental-social factors include heredity, exposure to lead, malnutrition, type of infant feeding, socio-economic status and parental IQ.

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Research aims

The overall research aim that has directed our programme of work since the 1980s, and which will take it forward for the next 20 years, is to optimise neurodevelopmental outcome of infants through the development of a range of preventative therapies.

The programme started, and is continuing, with the understanding of human fetal and infant metabolism and how it is influenced by genetic and molecular regulation. Our current focus is on iodothyronine and glucose metabolism in term and preterm infants and the consequences of developmental and genetic deficiencies for brain function.

The conditions we are investigating currently are transient hypothyroxinaemia, transient hypothyroidism and neonatal hypoglycaemia as these are potentially modifiable conditions.

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Current specific research areas

Thyroid hormone metabolism

Thyroid hormones are required for development of the human brain, but data on local regulation of thyroid hormones are limited. In a series of publications we describe the ontogenic changes in T4, T3, and rT3 and the activities of the types I, II, and III iodothyronine deiodinases (D1, D2, and D3) in different brain regions in normal fetuses (13–20 weeks postmenstrual age) and in premature infants (24–42 weeks postmenstrual age). D1 activity is undetectable. The developmental changes in the levels of the iodothyronines and D2 and D3 activities show spatial and temporal specificity. T3 increases in the cortex between 13 and 20 weeks postmenstrual age to levels higher than adults; this finding was unexpected given the low circulating T3. Considerable D2 activity was found in the cortex, which correlated positively with T4 (r = +0.65). Cortex D3 activity was very low, as was D3 activity in germinal eminence and choroid plexus. In contrast, cerebellar T3 was very low and increased only after midgestation. D3 activity in the cerebellum was the highest (64 fmol/min mg) of the regions studied, and decreased after midgestation. Other regions with high D3 activities (midbrain, basal ganglia, brain stem, spinal cord, and hippocampus) also had low T3 until D3 started decreasing after midgestation. D3 was correlated with T3 (r = -0.682) and rT3:T3 ratio (r = +0.812) and rT3/T4 (r = +0.889).

Our data support the hypothesis that T3 is required by the human cerebral cortex before midgestation at a time when the mother is the only source of T4. D2 and D3 play important roles in the local bioavailability of T3. T3 is produced from T4 by D2, and D3 protects brain regions from excessive T3 until differentiation is required.

(This abstract is abridged from a paper published by Kester MHA et al. Iodothyronine levels in the human developing brain: major regulatory roles of iodothyronine deiodinases in different areas. J Clin Endocrinol Metab 2004;89:3117-3128.)

pathways

Slide based on an original by Professor Michael Coughtrie, University of Dundee

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Transient hypothyroxinaemia and preterm infant brain development

The overall aim of this work is to fully understand the metabolism and interconversion of iodothyronines during human development. This will allow us to identify critical steps in this process which are amenable to clinical intervention in the treatment of the hypothyroxinaemia associated with prematurity and thus to develop improved preventative therapies for common disorders associated with this abnormal thyroid function such as respiratory distress syndrome and long-term neurodevelopmental deficit.

The major aim of our collaboration is to develop a pre-therapeutic screening programme that can identify infants at risk of transient hypothyroxinaemia and to devise preventative therapies, which are based on our knowledge of the regulation of thyroid hormone metabolising enzymes and supply of iodine during development.

We are in a unique position, with a varied combination of clinical and scientific expertise, to allow us to develop new therapeutic approaches based on a knowledge of human metabolism in early life.

This following paper has been reproduced with the kind permission of Thyroid International and Merck: Thyroid International 2; 2005)

http://www.thyrolink.com/servlet/PB/menu/1271750/index.html

Introduction

Thyroid hormones are required for the normal development of the brain. In term infants (37-42 weeks gestation) serum thyroxine (T4) levels characteristically increase postnatally whereas in infants born prematurely, especially some extreme preterm infants (<30 weeks gestation) serum T4 levels may decrease transiently resulting in a period of hypothyroxinaemia (1-3).

Transient hypothyroxinaemia in preterm infants was thought to be without long-term sequelae (4). However more recent studies have linked low T4 levels in preterm infants with later neurodevelopmental deficits in cognitive (5-7) and motor function (7) and low plasma triiodothyronine (T3) with reductions in IQ at 8 years of age (8). These associations persist after adjustment for perinatal illness (7,8). In addition hypothyroxinaemia is associated with an increase in perinatal mortality and morbidity (9), prolonged oxygen supplementation and mechanical ventilation (10), an increased incidence of intraventricular haemorrhage (11) and cerebral white matter damage (12).

Trials of thyroid hormone supplementation

Are low serum T3 and or T4 levels in preterm infants causative per se of acute morbidity and mortality in the newborn period and later neurodevelopmental deficit or simply an epiphenomenon of severe illness? This critical question has been previously stated (13) and subsequent research has resulted in a number of studies of thyroid hormone supplementation. Nine studies up to 2001 were identified in a Cochrane Review that compared thyroid hormone treatment to controls (14). Three of the studies were randomized (15-17) and one quasi-randomized study (18) met the inclusion criteria. The preterm infants recruited were < 32 weeks gestation but the studies were relatively small in size (except van Wassenaer et al (17) with 200 infants) and used different timing, dose and durations of treatment. Meta-analysis of five studies found no significant difference in mortality to discharge in infants who received thyroid hormone treatment compared to controls (14). The severity of respiratory disease was not reduced in infants receiving thyroxine (16,17) but in one small quasi-randomized study using triiodothyronine (18) the inspired oxygen fraction was reduced. However, in a subsequent randomized study this was not sustained (19). Meta-analysis of two studies (16,17) found no significant difference in the developmental scores of the Bayley Mental and Psychomotor Development Indices or the incidence of cerebral palsy (14). This neutral effect of T4 supplementation suggests that there are other factors associated with acute illness in preterm infants, which are having significant negative impacts on brain development and subsequent neurodevelopmental outcome.

In the van Wassenaer et al study (17) infants <30 weeks gestation were recruited; in subgroup analysis by gestational age there was a significant difference at 24 months in the Bayley Mental Development Index (18 points higher) in the thyroxine treated group born at 25–26 weeks gestation compared with the placebo group, but a significantly lower mental development index (10 points) in thyroxine treated infants of 27–29 weeks gestation. These results suggest that thyroxine supplementation might be detrimental to some infants but advantageous to the most premature. Further appropriate clinical trials of thyroxine substitution in extreme preterm infants have been suggested (20). Because the purpose of thyroxine substitution in extreme preterm infants is to remedy hypothyroxinaemia selection of entrants to clinical trials is important. Selection should not be made solely on the basis of gestational age, as has been the case in the majority of studies to date, but on whether the infants are hypothyroxinaemic and could thus potentially benefit from thyroid hormone supplementation. The definition of what constitutes hypothyroxinaemia in preterm infants is however problematic.

Definitions of transient hypothyroxinaemia

Transient hypothyroxinaemia is the most common thyroid dysfunction in preterm infants but there is no consensus about its definition and specifically what constitutes a ‘low’ plasma T4 level. Transient hypothyroxinaemia has been defined variously as blood T4 levels of 3.0 (6) or 2.6 (7) standard deviations below the mean of their (non-stratified) preterm populations, or simply as cut-off values such as <40 nmol/l for serum T4 (21) or 6 µg/dl for blood T4 (22). Other researchers have used only a plasma T3 level <0.3 nmol/l as an outcome measure (8), or simply present data in standard deviations without using a definition of what constitutes transient hypothyroxinaemia (5). None of these studies use thyroid hormone values adjusted for gestational age.

Preterm infant cord and postnatal thyroid hormone sera levels differ from those of the term infant and adult values (1,23-25); differing across the range of prematurity (23-36 weeks gestation) (e.g.3,19,27-29). Longitudinal studies within gestationally restricted groups vary in the range and nature of the serum parameters analysed (16,19,30,31). Thyroid hormone reference ranges for preterm infants have been derived from plasma levels taken opportunistically during the first weeks of life in populations of gestationally restricted age groups (e.g. 3, 32), but there are problems with the assumptions supporting this approach. Firstly, the response of the hypothalamic-pituitary-thyroid axis is attenuated in preterm infants at birth for an unknown postnatal duration (33). In addition non-thyroidal illnesses such as respiratory distress syndrome can also influence plasma thyroid hormone levels (e.g. 24,29,34-36). These points raise the question of whether existing reference ranges are appropriate for assessing postnatal serum thyroid levels in preterm populations, especially for the brain, which is particularly sensitive to an inadequacy of thyroid hormone.

The structural and functional maturation of early human brain follows an inherent developmental pattern (37) and the brain of the post-natal preterm infant appears to develop using the same fixed agenda of maturation as the comparable fetus in-utero (37,38). To achieve optimal brain development in preterm infants, it is not unreasonable to assume that thyroid hormone requirements are similar to the equivalent fetus in-utero. Yet, with the exception of the extreme preterm infant, the postnatal milieu exposes the developing brain to higher levels of FT4 than in the fetus of equivalent gestational age. The validation of the adequacy of postnatal thyroid hormone levels should ideally be neurodevelopmental outcome of preterm infants, and such studies have begun (16). In the meantime, other ways of informing the description of appropriate postnatal thyroid hormone levels need to be explored.

An alternative to neurodevelopmental outcome studies of preterm infants is the determination of the correlation of iodothyronine levels in sera and brain regions with development. T3 levels and thyroid hormone receptor concentrations increase in the human brain until mid-gestation (39-42); but only one study has defined temporal and regional iodothyronine levels in a limited number of preterm infant brains (42). As yet no study has correlated brain and serum iodothyronine levels in the human fetus or infant and such studies are unlikely to be forthcoming in the near future.

In the meantime until such studies are available we have suggested that for preterm infants the appropriate ranges for postnatal serum T4 and FT4 are cord levels corrected to an equivalent gestational age had the fetuses remained in utero (43,44). Sera levels from in utero cordocentesis samples of normal fetuses progressing to a term delivery would be optimal but numbers to date are limited (45-47); and given this restriction another option would be to use cord levels of thyroid hormones that are adjusted for the significant prenatal and intrapartum factors.

Aetiology of transient hypothyroxinaemia

The aetiology of transient hypothyroxinaemia is not clear and may have contributions from the withdrawal of maternal-placental thyroxine transfer (48,49), hypothalamic-pituitary-thyroid immaturity (33, 50), developmental constraints on the synthesis (43,45,51) and peripheral metabolism of iodothyronines (9,42,52), iodine deficiency (53,54), and non-thyroidal illness (9,29,35,44). These various factors which may contribute to transient hypothyroxinaemia are important to consider as preventative measures or alternative therapies to thyroid hormone supplementation may become apparent.

Maternal-placental thyroxine transfer

During the first trimester at a time prior to the development of an effective fetal hypothalamic–pituitary-thyroid the fetus is critically dependent on T4 transfer from the mother (48). The anatomical development of the fetal hypothalamic-pituitary-thyroid axis continues throughout gestation but we have no evidence of the extent of the maternal contribution to the fetus as a normal pregnancy progresses, particularly in the critical weeks between 23 and 30 weeks gestation when transient hypothyroxinaemia is problematic. There is evidence that substantial amounts of T4 are transferred from the mother to the fetus during late gestation in severe congenital hypothyroidism, occurring as a result of a total organification defect (49).

Hypothalamic-pituitary-thyroid immaturity

The response of the hypothalamic-pituitary-thyroid axis can be studied immediately post birth as cooling and other birth stresses are natural stimulants of hypothalamic TRH production. Following delivery in term infants there is a marked postnatal surge of serum TSH levels to approximately 70 mU/l at 30 min postnatal age (55). This surge stimulates T3 and T4 secretion and increases serum T3 and T4 levels which peak at between 24-36 h (56). In preterm infants, the postnatal TSH peak is lower and gestationally age related (33,55) such that in the most extreme preterm infants (23-27 weeks gestation) the mean peak TSH level increases to a mean of only 8 mU/l (33). Subsequent hormonal responses in infants >28 weeks gestation are reminiscent of term infants (1,35,55,57) as both T4 and T3 increase postnatally and above cord values. In more extreme preterm infants, T4 and T3 show no increments at 24 h (33); comparison with other studies with more mature preterm infants (9,28,29) suggests that the postnatal thyroidal axis responsiveness to birth shows a severely attenuated or a failed response in infants <27 weeks gestation and so critically defines this 23-27 week group as distinct from more mature preterm infants.

Iodine deficiency

The immediate neonatal requirements for thyroxine, and hence iodine are high (58) as the calculated intra-thyroidal reserve pool of thyroid hormone is small (59). Renewal of the intra-thyroidal T4 pool requires an appropriate and rapid supply of iodine, but the concentration of iodine and thyroglobulin in the thyroid gland of preterm infants is low (60-62) and does not increase until 42 weeks postmenstrual age (62). The iodine content of thyroglobulin in the thyroid gland appears to be related to maternal iodine status (62) and potential reserves of iodine in some preterm infants may be lower in iodine deficient mothers. The recommended enteral intake of iodine for preterm infants based on balance studies is 30 mg/kg/day (31,63) and increasing the enteral intake further to 40-50 mg iodine/kg/day in more mature preterm infants does not alter serum iodothyronine levels (64).

The fetal thyroid is extremely sensitive to the inhibitory effect of iodine (65) and iodine contamination is a major cause of transient neonatal hypothyroidism (66). This can follow the application of maternal vaginal povidone-iodine solutions during the last trimester or in labour (65,67) or postnatal injection of iodinated contrast dyes to visualise parenteral feeding lines (68) or the topical application of povidone-iodine solution as an antiseptic to the skin of the newborn (69). These latter risk factors are more common in preterm infants (66,68,69) and in response many neonatal intensive care units currently do not use povidine-iodine antiseptics, or non-radiopaque parenteral feeding lines. In the 1980’s when clinical exposure to exogenous and often excess iodine was common, the American Society for Clinical Nutrition reduced the recommended iodine intake in parenteral nutrition regimens to 1µg/kg/day (70). Commercially available parenteral solutions for infants still reflect these recommendations. However, in the absence of other iodine sources preterm infants who are dependent on parenteral nutrition are now vulnerable to iodine insufficiency (54). A clinical trial of iodine supplementation in preterm infants who are parenterally fed is now necessary to determine the contribution of iodine insufficiency to the aetiology of transient hypothyroxinaemia.

Non - thyroidal illness

The response to critical illness is complex and may involve changes in hypothalamic-pituitary function and alterations in peripheral thyroid hormone metabolism including plasma membrane transport and tissue iodothyronine deiodinase expression (71). In adults a decrease in serum T3 and an increase in rT3 levels are characteristic of the fasting state, and the most common changes in nonthyroidal illness in response to a variety of acute and chronic illnesses (71). With increasing severity of illness serum T4 levels decrease as well as those of T3 (72). Critical illness and thyroid hormone status in preterm infants have been studied for 30 years; in particular the effects of respiratory distress syndrome and more recently intraventricular haemorrhage. But preterm infants can have other non-thyroidal illnesses, or drug treatments, or inadequate caloric intakes, often occurring at the same time, which may also affect serum thyroid hormone levels.

The Score for Neonatal Acute Physiology (SNAP) is an established physiologic severity index for neonatal care involving 26 scored parameters (73) and correlates inversely with a single blood T4 level at 5 postnatal days in very low birthweight infants (74). The majority of the SNAP parameters are dependent on a range of blood investigations and to avoid unnecessary phlebotomy we have used a routinely applied scoring system as a surrogate marker of illness severity. The scoring system used was that of The British Association of Perinatal Medicine, which was initially devised to quantify resources required by UK neonatal intensive care units such as nursing staffing numbers, expertise and equipment; with severity of illness being related to the amount of resource required (75). The application of the British Association of Perinatal Medicine scoring system allows systematic categorization of a large sample of preterm infants by a uniform set of parameters describing illness severity.

Respiratory distress syndrome is characteristically most severe in the few days after birth and is associated with reductions in plasma T4 levels (29,30,34-36,76,77). In very low birth weight infants low serum T4 levels during the first week of life are associated with intraventricular haemorrhage but not thereafter at 2-4 weeks postnatal age (11,79). In our most recent studies where we have used the British Association of Perinatal Medicine Score as a surrogate marker of severity of illness and extended observations up to 28 postnatal days in infant groups from 23 to 34 weeks gestation the majority of postnatal T4 levels in all our preterm groups with less severe illness are within or above cord values of equivalent gestational age (44). In contrast, all postnatal T4 levels in all preterm groups with the severest illnesses are well below the equivalent gestational age values (44). Illness severity in preterm infants appears therefore to be an important determinant of low serum T4 levels. This is consistent with adult data as serum T4 levels are decreased in nonthyroidal illnesses in proportion to the severity and probably the duration of the illness, with T4 levels inversely related to mortality (72,80-84). Adult patients with mild to moderate illness, or acute short-term trauma, such as cardiac bypass surgery (83), or short-term fast (84), show no decrease in serum T4 levels.

Maintaining serum FT4 levels in extreme preterm infants may be a priority for sustaining postnatal brain development and neurodevelopmental outcome (85). In all preterm groups the majority of postnatal FT4 levels are within or above the cord values of equivalent gestational age (43), irrespective of severity of illness (44), leading us to conclude that lowered serum FT4 levels are not a pathognomonic feature of transient hypothyroxinaemia in preterm infants, in contrast to previous studies (23,29,30).

T3 levels are consistently lower in our most severely ill infants (44) as in preterm infants with severe respiratory distress syndrome (29,36), and in those who die compared to those who survive (9). In all our preterm groups all postnatal T3 levels are within or above the equivalent gestational age values irrespective of severity of illness. Some preterm infants are therefore exposed postnatally to higher T3 levels than if they had remained in-utero; this is particularly evident in the preterm infants with less severe illness (44). The preterm brain is likely to be protected from these relatively elevated T3 levels, as the systemic T3 contribution to the developing brain is negligible (86).

Our preterm infant groups do not mirror exactly the decrease in serum T3 and concomitant rise of rT3 that is characteristic of adult nonthyroidal illness (44). rT3 levels remain unchanged with illness in all our gestational age groups; a finding consistent with previous infant studies (9,29,35). However, rT3 is not invariably increased in adult ill health. For example, patients with acute and chronic renal failure have decreased T4 and T3 levels but normal rT3 levels (although relative to T4, rT3 is increased), even with superimposed critical illness (37). The molecular bases for these variations in rT3 response are not entirely known but in nonthyroidal illnesses hepatic type I iodothyronine deiodinase (D1) activity is reduced in tissues from sick and starved animals, which may contribute to the increased rT3 levels (80). In deceased intensive care patients hepatic D1 is decreased, and liver and skeletal muscle D3 activities are increased (88). It is not known if similar responses occur in the peripheral tissues of preterm infants, but if such alterations exist in the expression of D2 and D3 activities in the developing human brain these could have adverse consequences.

TSH levels in adults with nonthyroidal illness are usually within the normal range but some may be increased as levels rise during the recovery phase (89,90). TSH levels in our infant groups are similar with postnatal age and severity of illness and this is consistent with a neutral effect of illness on TSH levels in most previous infant studies (36,91,92).

In summary serum T4 and T3 levels are substantially reduced in infants with severe illness, irrespective of gestational age, yet TSH remains unchanged.

Conclusion

Disability is common among extreme preterm infants who survive (93). In a large population based UK study of developmental assessment at 30 months in infants <25 weeks gestation at birth, 49% were disabled, including 23% who met the criteria for severe disability (94). The causative factors in these infants for their disabilities or developmental delays may be complex and multiple. The role of thyroid hormone status as a contributory factor remains unclear and we are still left with the question:

Are low serum T4 levels, particularly those associated with severe illness in preterm infants, causative per se of later neurodevelopmental deficits or simply an epiphenomenon of illness?

There are clearly a number of ways future investigations could proceed to resolve this question and some suggestions have been embedded in this article, and elsewhere by others and by us. It may be that rather than a direct approach to simply correcting hypothyroxinaemia by hormone replacement a more oblique approach may be necessary to maintain the thyroid hormone status in these infants. For example respiratory distress syndrome and intraventricular haemorrhage in preterm infants are associated with reductions in serum T4 and T3 levels but these infants suffer from other illnesses, which have not yet been assessed in terms of their contribution to hypothyroxinaemia. A systematic, comprehensive and sufficiently powered study of the various illnesses common to preterm infants and their influence on thyroid hormone levels is now required to highlight where preventative measures in reducing the incidence or severity of such illnesses could have most benefit to preserve thyroid hormone status. Within such a study prescribed drugs which influence the hypothalamic-pituitary-thyroid axis such as dopamine (95) and nutritional status (96) should also be included.

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This paper is reproduced with the permission of Merck KGaA, Darnstadt, Germany; and first appeared in Thyroid International 2; 2005

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Glucose homeostasis

Glucose is an essential primary fuel for the brain but it can utilise lactate, ketones, or certain amino acids. In term infants prolonged or recurrent neonatal hypoglycaemia may lead to permanent neurological damage (1-4). In growth retarded preterm infants hypoglycaemia is strongly correlated with abnormal neurodevelopment and reduced brain growth (4). In preterm infants hypoglycaemia of even a moderate degree can lead to an adverse neurodevelopmental outcome (5). This pioneering work was completed 20 years ago but only recorded glycaemic status to a maximum of the first month of life and did not acknowledge the persistence of asymptomatic hypoglycaemia beyond this early period. Asymptomatic hypoglycaemia, which suggests that alternative metabolic substrates may be available for brain metabolism, has in general been associated with a more favourable prognosis (6). However, acute cerebral dysfunction (auditory and somatosensory evoked potentials) occurs in the majority of children when blood glucose levels fall below 2.6 mmol/l, and when 50% are asymptomatic (7); the definition of what constitutes hypoglycaemic blood glucose levels in infants remains contentious but evidence to support a higher level than 2.6 mmol/litre is lacking.

The fetus receives a constant supply of trans-placental glucose. Post-delivery blood glucose levels fall and thereafter stabilisation is dependent on the activation of hepatic glycogenolysis and gluconeogenesis in response to changes in insulin, cortisol, glucagon, and catecholamines. Over the first few days of life blood glucose levels stabilise with increases in enteral intake and continued maturation of hepatic gluconeogenesis. Transient disturbances in neonatal glucose homeostasis are common during this time, especially where metabolic reserves are low as in prematurity and intra-uterine growth retardation or, where expenditure of energy is high as seen for example with sepsis, birth asphyxia and hypothermia. Preterm infants have lower hepatic glycogen reserves, lower activities of key gluconeogenic enzymes, an initially limited hormonal response and, even where regimens of postnatal care were similar to those of term infants (i.e. oral milk feeds), blood glucose values were lower and the postnatal rise was slower.

Hypoglycaemia is very common in preterm infants in the first hour of extrauterine life (9). For the first few postnatal days, blood glucose levels are routinely measured and corrected until they are apparently stable and normoglycaemic (9). At this time, many infants are fed parenterally and/or by continuous or frequent bolus nasogastric milk feeds (usually hourly). Thereafter, it is not normal practice to routinely measure blood glucose concentrations if blood glucose levels are consistently >2.6 mmol/litre and thereafter most infants will advance to an increased reliance on enteral nutrition, and a progression from hourly through to 4 hourly feeds. The efficacy of this practice has not been systematically evaluated.

We have a long term research interest in the developmental regulation of glucose homeostasis in the human fetus and infant (e.g. 10). Hepatic glucose production by glycogenolysis and gluconeogenesis is essential to maintain blood glucose levels, and the glucose-6-phosphatase system catalyses the terminal step of both pathways. We have shown that developmental delays in the postnatal up-regulation of hepatic glucose-6-phosphatase enzyme activity in preterm infants dying from the range of complications of prematurity are common in postmortem liver samples up to 360 days postpartum (11). In contrast, the glucose-6-phosphatase activity in term infants rises rapidly after birth reaching adult values by about 3 days postpartum. The suboptimal glucose-6-phosphatase activity described in preterm infants who died has implications for surviving preterm infants and potentially places them at risk of hypoglycaemia. This prompted our further clinical work with the hypothesis that some preterm infants would have significant hypoglycaemia outwith the neonatal period.

Our first clinical pilot studies indicated a relationship between blood glucose levels and hepatic glucose-6-phosphatase enzyme activity (12). Our further clinical studies in preterm infants have identified failures of developmental regulation of glucose homeostasis. First, preterm infants about to be discharged home are at risk of hypoglycaemia if a feed is delayed (13,14). In 5-9% of infants the hypoglycaemia was severe and around 11% had milder hypoglycaemia which self–corrected. Cortisol, corticotrophin and epinephrine levels were appropriately higher in the infants with severe hypoglycaemia, but insulin, glucagon and human growth hormone levels did not differ from normoglycaemic infants (13, 14). Metabolic screening failed to reveal any of the known inborn errors of metabolism. Infants who were hypoglycaemic at the time of discharge home had experienced significantly more episodes of hypoglycaemia in the early newborn period which suggests a persistent problem which, in some infants, had extended to 3 months postnatal age (15, 16). Secondly, also in preterm infants prior to discharge home, 30% had an inadequate glycaemic response to glucagon provocation (17). They also had relative fasting hyperglycaemia, hyperinsulinaemia, increased insulin:glucagon ratios and a lower insulin sensitivity index when compared to infants with an adequate response. Such hormonal dysfunctions in preterm infants may contribute to failures in postnatal expression of hepatic enzymes (13) and dysfunctional glucose regulation. Further evidence that preterm infants have different mechanisms for glycaemic control, in comparison to adults, is their paradoxical reaction to insulin therapy, stress and infection in which they show increased hepatic glucose-6-phosphatse enzyme activity (15, 16).

The aetiology of neurodisability in preterm infants is multifactorial but the contribution and importance is unknown of asymptomatic hypoglycaemia that is still present at the time of discharge home. We aim to investigate the relationship between asymptomatic hypoglycaemia at time of discharge and neurodevelopment adjusted for the known contributory causes of neurodisability in preterm infants. neurodevelopment of preterm infants.

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