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In the newborn preterm infant a combination of inadequate reserves and increased loss of essential minerals is common and frequently compounded by difficulties in obtaining an intake sufficient to replace losses and restore reserves. Deficiencies in calcium and phosphate and disturbed balance between them are frequently encountered, and may lead to significant impairment of bone deposition. Osteopenia of prematurity – also known as neonatal rickets, rickets of prematurity or neonatal metabolic bone disease – is a common and important concern in neonatology, and effective management is hindered by difficulties in accurately assessing calcium and phosphate status and the ‘quality’ of bone deposition. It is well known that preterm infants are at risk of reduced bone mineral content (BMC) and subsequent bone disease and that many factors may contribute to this. The majority of calcium and phosphate accretion and bone mineralisation occur in the third trimester of pregnancy and from 24 weeks of gestation onwards, it has been estimated that the fetus in utero gains about 30 g in weight each day, and this daily requirement includes 310 mg of calcium and 170 mg phosphorus.1 It has been shown that BMC and bone mineral density (BMD) correlate positively with gestational age, birth weight, body area and length.2 Mineral deposition may be affected before an infant is born as a number of prenatal factors, particularly placental function, have been shown to play a part in the development of osteopenia. The placenta converts vitamin D to 1,25-dihydrocholecalciferol which enables phosphate to be transported across the placenta.3 A reduced ability to do so explains the higher incidence of postnatal rickets that may be seen in infants with intrauterine growth restriction suggesting that chronic injury to the placenta may limit the ability to transfer phosphate.4 Poor mineralisation may also occur in …

Due to the presence of fetal haemoglobin and the patency of anatomical shunts the fetal circulation is perfectly adapted to intrauterine life, utilizing the placenta as the organ of gas exchange. Immediate adaptation must occur at birth as the lungs take over this role. Initially the pulmonary vascular resistance is high but pulmonary blood flow progressively increases in the newborn due to vasodilatation as a consequence of increased oxygenation and activation of pulmonary stretch receptors. Changes in the pulmonary vasculature are mediated through a number of vasoactive substances, including nitric oxide. Increased pulmonary blood flow leads to an increase in left atrial pressure with subsequent closure of the foramen ovale. In some babies this normal adaptation fails and persistent fetal circulation may develop, leading to the symptoms of persistent pulmonary hypertension of the newborn. The mainstay of treatment is to maximize oxygenation by use of an appropriate ventilatory strategy and to maintain blood pH within normal range using inotropic support as indicated to sustain an adequate systemic blood pressure. Nitric oxide has proved to be an extremely effective treatment for this condition in some cases but ECMO may be required as a rescue therapy. Persistent pulmonary hypertension of the newborn still carries a 10–20% mortality rate despite modern intervention.

Over the last two decades survival has significantly increased for infants who have been born prematurely. Although long term neurodevelopmental, educational and behavioural problems are common, and are increasingly so with decreasing gestational age at birth, a limited amount of long term data suggest that quality of later life is good and a high proportion of these infants go on to lead lives that are fulfilling both to themselves and to society. The short and long term costs of providing care for this group of infants are high, but the great majority of these costs are incurred by infants who are not extremely preterm. It is not uncommon to hear a proposition that care should not be offered to the most immature infants and in at least one country in Western Europe there appears to be a clear national policy to this end. This review discusses the implications for society of such decisions.

BackgroundMany infants born prematurely experience growth failure following delivery, with subsequent catch-up growth. Traditionally catch-up was thought to be complete in the first few years of life. Most studies have focused on groups of infants defined by birth weight, for example MethodologyThis UK based prospective longitudinal cohort study recruited 204 preterm children born at a tertiary neonatal unit during 1994 and 50 matched controls. Growth parameters have been assessed annually until the completion of growth.ResultsThere was no significant difference in the final height SD score (SDS) of children born at term (n=30) and those born prematurely and AGA (n=70) (0.45 term vs 0.22 preterm). Catch-up growth however, continued throughout the whole of childhood. When the difference between final height SDS and mid-parental height SDS were compared, there were again no significant differences (0.13 term vs 0.03 preterm).ConclusionsThose born prematurely with an AGA achieve a comparable adult height to children born at term, however, catch-up growth continues for much longer than traditionally thought.

In adults, the Carter method allows the separation of the lumbar spine bone mineral content (BMC) into its constituents; bone volume (BV) and volumetric density (bone mineral apparent density [BMAD]). However, this method is not widely used in pediatric studies and does not account for the effects of body habitus on bone mass. The aims of this study were to modify the Carter method for use in children by developing an approach that adjusts separately for age and body height, and to test whether lumbar spine bone mass is normal in children born who were born preterm. Twenty-five preterm-born children were matched to a term-born child. Lumbar spine bone mass was measured using dual-energy X-ray absorptiometry. The BV and BMAD were calculated. Z-scores based on age and height were calculated. The preterm group had reduced absolute height, weight, BMC, BV, and BMAD, and reduced height, weight, and BMC for their age. The BMC was appropriate for height. The BV was appropriate for age. The BMAD was reduced for age but appropriate for height. In preterm children, the major abnormality at the lumbar spine is a decrease in volumetric density; however, this decrease is proportional with their reduced stature, and we speculate that there is no reduction in the strength of the lumbar spine.

Measurement of newborn babies is widely regarded as being too inaccurate to justify its regular practice. It is common for infants to be weighed at birth and for no other measurements to be made. Although such assumptions are superficially correct, it is possible to train people to perform accurate measurements and for improved performance to be sustained. Accurate sequential measurements are possible and provide more information than single measurements. Detailed measurements show that postnatal growth may change rapidly and dramatically, particularly in preterm infants. Postnatal growth impairment is common in such infants and may be sustained. Limited evidence suggests that there may be a significant reduction in final stature. Preliminary data also suggest that many preterm infants may also show evidence of alterations in biochemical and physiological variables consistent with early programming and the potential for altered disease susceptibility in adult life.

Objective. To evaluate the outcome for all infants born before 26 weeks of gestation in the United Kingdom and the Republic of Ireland. This report is of survival and complications up until discharge from hospital. Methodology. A prospective observational study of all births between March 1, 1995 and December 31, 1995 from 20 to 25 weeks of gestation. Results. A total of 4004 births were recorded, and 811 infants were admitted for intensive care. Overall survival was 39% (n 5 314). Male sex, no reported chorioamnio- nitis, no antenatal steroids, persistent bradycardia at 5 minutes, hypothermia, and high Clinical Risk Index for Babies (CRIB) score were all independently associated with death. Of the survivors, 17% had parenchymal cysts and/or hydrocephalus, 14% received treatment for reti- nopathy of prematurity (ROP), and 51% needed supple- mentary oxygen at the expected date of delivery. Failure to administer antenatal steroids and postnatal transfer for intensive care within 24 hours of birth were predic- tive of major scan abnormality; lower gestation was pre- dictive of severe ROP, while being born to a black mother was protective. Being of lower gestation, male sex, tocolysis, low maternal age, neonatal hypothermia, a high CRIB score, and surfactant therapy were all predic- tive of oxygen dependency. Intensive care was provided in 137 units, only 8 of which had >5 survivors. There was no difference in survival between institutions when di- vided into quintiles based on their numbers of extremely preterm births or admissions. Conclusions. This study provides outcome data for this geographically defined cohort; survival and neonatal morbidity are consistent with previous data from the United Kingdom and facilitate comparison with other geographically based data. Pediatrics 2000;106:659 - 671; ex- tremely preterm infant, survival, cerebral ultrasound scan, intraventricular hemorrhage, parenchymal cysts, hydro- cephalus, retinopathy of prematurity, chronic lung disease. ABBREVIATIONS. PMA, postmenstrual age; NNU, neonatal unit; LMP, last menstrual period; EDD, expected date of delivery; ROP, retinopathy of prematurity; CI, confidence interval; HR, heart rate; CRIB, Clinical Risk Index for Babies; RDS, respiratory distress syndrome; IQR, interquartile range; PROM, prolonged rupture of membranes .24 hours; Fio2, fraction of inspired oxygen; PDA, patent ductus arteriosus. T he care of the fetus considered to be at the threshold of viability raises some of the most difficult clinical problems for obstetricians and pediatricians. Advice given to parents needs to be based on reliable contemporary information drawn from appropriate populations. The number of these infants born in an individual unit is small and con- clusions based on their outcome are unreliable. Pub- lished reports derive from a range of populations including those from single tertiary centers with se- lected patients and others based on geographically defined areas. Furthermore, survival and morbidity are defined differently in different studies and show wide variation. For example, since 1990, for infants born at 25 weeks of gestational age, published rates of survival range from 35% to 79% 1,2 and published rates of severe disability range from 12% to 35%. 3,4 The EPICure study was designed to describe sur- vival and health problems for all infants born before 26 completed weeks of gestational age in the United Kingdom and the Republic of Ireland. In this article we describe the progress of these infants during their initial admission for intensive care.

Background Small studies show that many children born as extremely preterm infants have neurologic and developmental disabilities. We evaluated all children who were born at 25 or fewer completed weeks of gestation in the United Kingdom and Ireland from March through December 1995 at the time when they reached a median age of 30 months. Methods Each child underwent a formal assessment by an independent examiner. Development was evaluated with use of the Bayley Scales of Infant Development, and neurologic function was assessed by a standardized examination. Disability and severe disability were defined by predetermined criteria. Results At a median age of 30 months, corrected for gestational age, 283 (92 percent) of the 308 surviving children were formally assessed. The mean (±SD) scores on the Bayley Mental and Psychomotor Developmental Indexes, referenced to a population mean of 100, were 84±12 and 87±13, respectively. Fifty-three children (19 percent) had severely delayed development (with scores more t...

Growth velocity is higher in late intra-uterine and early post-natal life than at any time thereafter, and accurate measurements are essential for appropriate monitoring. The accuracy with which such measurements are made and recorded is frequently questionable, however, and short- and medium-term changes in growth may be difficult to interpret in the light of normal variations in the pattern of growth. Infants who are small at birth must be accurately classified because intra-uterine growth retardation and small for gestational age have different implications for both causation and outcome. Prediction of expected growth on the basis of mid-parental height is essential but frequently omitted. Post-natal growth impairment is common in pre-term infants and is often rapid in onset. Poor growth may continue for many months, and catch-up may be incomplete. Early growth failure may have a significant influence on subsequent morbidity and mortality.

Concentrations of circulating antioxidants may be important in the aetiology of disease in premature infants. Blood samples were taken from 49 premature infants within two hours of birth. Plasma ascorbic acid, caeruloplasmin, and the ability of plasma to prevent lipid peroxidation in vitro were measured. Plasma ascorbic acid concentrations at birth ranged from 26.3 to 185.4 mumol/l. Plasma antioxidant activity at birth (microliter plasma required to inhibit lipid peroxidation) showed a strong negative correlation with plasma ascorbic acid and the plasma ascorbic acid to caeruloplasmin ratio. After correcting for gestational age and birth weight, plasma antioxidant activity at birth remained a significant predictor of mortality. Such plasma antioxidant activity is partly determined by the ferroxidase activity of caeruloplasmin. This may be modulated by high concentrations of ascorbic acid which may inhibit the antioxidant activity of plasma and thereby influence outcome.

Knemometry has been used to measure lower leg growth during 32 nine day courses of dexamethasone in 26 babies ranging from 24 to 32 weeks' gestation at birth. Mean leg length velocity was 0.37 mm/day in the 10 days before steroids. Administration of dexamethasone was associated with a decrease in velocity in all babies, and in 15 leg shortening was documented. Mean leg length velocity during steroid treatment was -0.003 mm/day. After the course of dexamethasone was completed there was an immediate increase in leg length velocity to a mean of 0.52 mm/day over the first 10 days then falling to a value similar to the growth velocity observed before treatment. Leg length had reached the value predicted by growth before steroids about 30 days after dexamethasone. The reduction in leg length velocity occurred despite a significant increase in energy intake and decrease in oxygen requirements.

The characteristics of a knemometer designed for accurate lower leg measurement in babies were assessed. Repeated measurement of a 100 mm Perspex rod gave a mean length of 99.993 mm and a mean SD of 0.058. When used to measure leg length, technical error of the measurement technique was 0.31 with a mean leg length of 98.49 mm (coefficient of variation 0.31%). Leg lengths measured at birth in 324 babies from 23 to 42 weeks' gestation gave an estimated in utero leg length velocity of 0.43 mm/day (95% confidence interval 0.41 to 0.45). Assessment of interobserver variation showed poor agreement in absolute values of leg length, although similar estimates of leg length velocity could be obtained. The neonatal knemometer allows measurements to be made in situations where conventional growth measurements are not possible. It is believed that knemometry has an important role in accurate evaluation of factors that can influence short term bone growth.

Preterm birth currently occurs in approximately 12% of pregnancies and appears to be increasing despite improvements in obstetric care. Improvements in neonatal care have led to increased survival, particularly at extreme prematurity, but survival may be associated with significant morbidity. This may be acute, reflecting the difficulties in supporting an individual in a hostile extrauterine environment to which they should not be exposed, or chronic, reflecting disturbances to fragile, immature body systems. Brain, lungs, intestines and eyes are particularly vulnerable and damage may be severe. For some infants the consequences of this damage may be permanent disability and impairment. Despite this, the limited information currently available suggests that adult outcomes may be comparable with those for infants born at term.

We determined the contributions of IGF-I, IGFBP-3 and leptin to growth in extremely premature infants over the first two years. Weight (Wt), crown-to heel length (CHL), plasma IGF-I, IGFBP-3 and leptin were measured in infants (gestation 24-33 wk) at birth (n = 54), expected date of delivery (EDD) and 6, 12 and 24 mo post-EDD (n = 29). Area under the curve (AUC) for hormone levels was calculated over 4 periods: birth-EDD, EDD-200 d, EDD-350 d and EDD-700 d. IGFBP-3, but not IGF-I or leptin, on day 1 correlated with birth Wt SD scores (SDS) (r = 0.46, p = 0.002) and CHL SDS (r = 0.41, p = 0.01). Wt SDS at EDD correlated with AUC IGF-I, IGFBP-3 and leptin (birth-EDD), but leptin was the best predictor in multiple regression (r = 0.65, p < 0.0001). Wt at EDD + 700 d correlated with AUC leptin (EDD-700 d) (r = 0.62, p = 0.002). CHL SDS at EDD correlated with AUC IGFBP-3 and leptin (birth-EDD), but IGFBP-3 was the best predictor (r = 0.55, p < 0.0001). CHL at EDD + 700 d correlated with AUC IGF-I and IGFBP-3 (EDD-700 d), but IGFBP-3 was the best predictor (r = 0.47, p = 0.01). Wt and CHL at birth were associated with IGFBP-3 levels in these infants. Wt at EDD and EDD + 700 d was predicted by concurrent leptin output while linear growth at EDD and EDD + 700 d was predicted by IGFBP-3 output.

Aims: To describe perinatal factors associated with later morbidity among extremely preterm children at 30 months of age corrected for prematurity. Population: Of 308 surviving children born at ⩽25 weeks gestation in the United Kingdom and Ireland from March to December 1995, 283 (92%) were evaluated at 30 months of age corrected for prematurity. Methods: Cerebral palsy, severe motor disability, and Bayley scores were used as dependent variables in sequential multiple regression analyses to identify factors associated with adverse outcomes. Results: Adverse outcomes were consistently more common in boys. Factors related to perinatal illness, ultrasound evidence of brain injury, and treatment (particularly postnatal steroids) were associated with adverse motor outcomes (cerebral palsy, disability or Bayley psychomotor development index). Increasing duration of postnatal steroid treatment was associated with poor motor outcomes. A score was developed for severe motor disability with good negative predictive value. In contrast, mental development was associated with a broader range of factors: ethnic group, maternal educational level, the use of antenatal steroids, and prolonged rupture of membranes in addition to chronic lung disease. Conclusion: Male sex is a pervasive risk factor for poor outcome at extremely low gestations. Avoidable or effective treatment factors are identified, which may indicate the potential for improving outcome.

Aim: To define growth outcomes of a geographically defined population of extremely preterm babies. Population: The EPICure study identified all surviving children in the United Kingdom and Ireland born at ⩽ 25 weeks 6 days gestation between March and December 1995. Of 308 survivors, 283 (92%) were evaluated at 30 months of age corrected for prematurity. Methods: Growth was measured as part of a medical and full neurodevelopmental assessment. Growth parameters were evaluated in relation to other 30 month outcomes and perinatal variables. Results: The children were smaller in each of the five growth measures compared with published population norms: mean (SD) standard deviation scores were −1.19 (1.32) for weight, −1.40 (1.37) for head circumference, −0.70 (1.19) for height, −1.00 (1.38) for body mass index, and −0.75 (0.95) for mid-upper arm circumference. Despite being of average size at birth, children were significantly lighter with smaller head circumferences at the expected date of delivery, compared with population norms, and only weight showed later catch up, by 0.5 SD. Poorer growth was found in children whose parents reported feeding problems and with longer duration of oxygen dependency, as a marker for neonatal respiratory illness. Although severe motor disability was associated with smaller head circumference, overall there was no relation between Bayley scores and head growth. Conclusions: Poor growth in early childhood is common in extremely preterm children, particularly when prolonged courses of systemic steroids have been given for chronic lung disease. Improving early growth must be a priority for clinical care.

A significant number of infants are born prematurely each year, many of whom will develop respiratory disease and require ventilation. A substantial number of these infants will die and many of the survivors will subsequently develop chronic inflammatory lung disease. Administration of corticosteroids to women prior to a premature delivery is associated with a significant reduction in mortality and in the incidence of respiratory distress syndrome and intracranial haemorrhage in their infants once born. Postnatal administration of corticosteroids to the infant who develops chronic lung disease has been widely practised for many years. Recent meta-analyses have suggested that benefit may be limited. Treatment is also associated with a range of different side-effects but it has been assumed that the cost-benefit ratio favoured treatment. Recent evidence of permanent and highly significant long-term adverse effects has questioned the validity of this judgement.

We describe the clinical presentation and pathological features of an unusual case of tracheal agenesis. The axial derivatives of the primitive foregut between the larynx and stomach were represented by a single structure featuring sequential segmentation into regions showing exclusively tracheal or esophageal differentiation in a pattern that is not easily classified by existing nosologic systems nor explained by the conventional hypothesis of dysontogenesis.

Accurate measurements of both healthy and premature neonates are possible but rarely performed. Routine anthropometry is often not performed at all or with large measurement errors due to inadequate training of personnel or inappropriate equipment. Sick neonates are often considered unsuitable for anthropometry and growth is wrongly equated with weight gain. Gain in length may be disturbed by poor health and permanent extrauterine growth retardation and changes in body proportions induced in some survivors of neonatal intensive care. Drug treatments may have profound effects on length gain and the relationship of length to weight.

1. Non-protein-bound iron has been implicated in the aetiology of chronic lung disease of prematurity. 2. The modification of a method for the measurement of non-transferrin-bound iron in small volumes of plasma and bronchoalveolar lavage fluid from preterm babies is described. 3. The assay runs with a good degree of precision and a lower limit of detection of 0.02 μmol/l. 4. Non-transferrin-bound iron was detected in 50% of plasma samples and 11% of bronchoalveolar lavage fluid samples collected over the first week of life from babies born prematurely.

High concentrations of total vitamin C have been measured in the plasma of premature infants. At these concentrations ascorbic acid inhibited the ferroxidase activity of caeruloplasmin measured directly in vitro. The degree of inhibition was dependent on the ratio of ascorbic acid: caeruloplasmin. Values for the ratio of vitamin C: caeruloplasmin measured in premature babies would be predicted to inhibit ferroxidase activity by up to at least 80%. Ferroxidase activity measured in the plasma of premature babies increased from birth but was significantly lower than in plasma collected from adults (

A study was conducted to investigate the relationship between vitamin C intake and the rate of tyrosine catabolism in premature babies. A 13C tyrosine breath test was developed for the measurement of tyrosine catabolism. Premature babies were randomly allocated to receive a daily intake of vitamin C which ranged from 8 to 100 mg/kg body weight, for 5 days. Tyrosine catabolism was measured at the beginning and the end of this period. Daily intakes of vitamin C of 20 mg/kg or more elicited a greater increase in tyrosine catabolism over 5 days than 8 mg/kg/day. The magnitude of the difference, in terms of percentage of tyrosine metabolised, was, however, small and of doubtful biological significance. Vitamin C intakes above 20 mg/kg/day had no further measurable effect on the catabolism of tyrosine.

A second male twin was born at 36 weeks’ gestation by emergency caesarian section owing to failure to progress following spontaneous onset of labour. He was difficult to deliver because of a transverse lie. He developed respiratory distress shortly after birth, requiring oxygen and antibiotics, and became lethargic, hypothermic (temperature 36.1°C) and tachycardic (174 …

To describe the trends in birthweight and their association with socioeconomic status in a 10 year birth cohort in Sheffield.Data for all live singleton births were extracted from the Sheffield Child Development Study (SCDS) database for 1985-94. Enumeration districts (EDs), derived from postcodes, were ranked into deciles by Townsend Deprivation Index (TDI), based on the 1991 census. Birthweight by 500 g group and mean birthweights for the city and by ED decile were calculated by year. chi2 analyses for linear trend were calculated. The proportion of variance in birthweight explained by ED decile and raw TDI score was estimated by year. Absolute risk difference of birthweight3500 g for the most compared with the least deprived deciles and proportion of births3500 g statistically "attributable" to social inequality were calculated.The mean birthweight for all births increased by 34 g between 1985 and 1994. This difference is largely accounted for by a positive trend in births/=3500 g and a negative trend in births of 3000-3499 g. Similar trends were noted across all ED deciles. Around 10% of the variance in birthweight was explained by area deprivation level. Absolute risk difference for births3500 g was 12.5% for the 10 years (range 8.3-18.4). The proportion of births3500 g statistically "attributable" to social inequality for the 10 year period was 9.6% (range 4.3-15.5).Despite an overall increase in mean birthweight, large social differences persisted during the study period. An average of 350 births a year were not in the group (/=3500 g) bestowing most health advantage throughout the life course, as a result of social inequality.

To evaluate the effect of disturbance in early growth on subsequent stature we have made detailed measurements of weight, length and lower leg length in the early postnatal period and at 8 months corrected age in 33 babies who received intensive care. Mean leg length SD score decreased by 1.22 (p = 0.0001, paired t test) between birth and 36 weeks postconceptual age. Both length and weight at 8 months most closely correlated with length or mean leg length at 36 weeks (r = 0.762 & 0.703, p = 0.0001 for length; r = 0.556 & 0.511, p = 0.0017 & 0.003 for weight). Correlation with any measure of early weight was less strong. Using stepwise linear regression leg length velocity in the first eight weeks of life was most strongly associated with length at eight months (adjusted r squared = 0.3, F = 10.4, p =

Impairment of growth in BPD is well described but the amount by which growth is disturbed and the stage at which impairment occurs is unclear. We have compared lower leg growth, measured by knemometry, and weight gain, in 16 babies who needed home oxygen, 22 babies who needed oxygen for more than 28 days but were discharged in air and 24 babies who needed supplementary oxygen for less than 28 days All groups exhibited an initial weight loss followed by steady weight gain, with no apparent difference in weight gain for the two oxygen dependent groups. Changes in leg length are shown in the figure. Comparison of leg length velocities demonstrated differences in the three groups between 0-13 days (p=0,12); 14-27 days (p=0.0001) and 28-41 davs (p=0.006). A significant impairment of growth in the early postnatal period is seen in those babies who will develop moderate and severe BPD. This may occur despite apparently similar weight gains

In 1951 Silverman reported significant growth disturbance in premature infants who received ACTH for the treatment of retinopathy. Despite the dramatic response that was demonstrated the effects of steroids on growth in this age group remain poorly understood. We have used the neonatal knemometer to assess bone growth in 26 babies who received a total of 32 nine day courses of dexamethasone for the treatment of chronic lung disease. Growth of the lower leg and weight gain were assessed for 10 days before, during and 30 days after the course. There was a decrease in leg length velocity in all subjects during steroid administration and actual limb shrinkage occurred in 15. There was then catch-up growth to the estimated pre-steroid length by 30 days. Oxygen requirements fell and calorific intake rose during steroid treatment Dexamethasone has a profound effect on cartilage and bone growth even in the preterm neonate. The long term consequences of this effect are no clearer today than they were for Silverman more than 40 years ago.