Gastroesophageal endoscopic findings and gastrointestinal symptoms in preterm neonates with and without perinatal indomethacin exposure.

BACKGROUND: The aim of this study was to investigate whether perinatal indomethacin treatment has effects on the development of esophageal and gastric lesions in preterm infants and to evaluate other potential etiologic factors behind these lesions. METHODS: Sixty-nine infants were born at less than 33 weeks' gestation. Forty-five of these infants underwent treatment with perinatal indomethacin (study group) and 24 did not (control group). All underwent upper gastrointestinal tract endoscopy and biopsy during the neonatal period. The correlation between gastrointestinal symptoms, abnormal endoscopic findings, and the factors correlating with the development of esophageal and gastric mucosal lesions was evaluated. RESULTS: Abnormal endoscopic findings were equally common in the study group (77.8%) and in controls (83.3%). There was no dependence between gastrointestinal symptoms and endoscopic findings because only 15 infants (21.7%) were symptomatic before endoscopy. The interval between endoscopy and the last perinatal indomethacin dose correlated significantly with abnormal esophageal findings and gastric mucosal lesions. Shorter duration of enteral feeding before endoscopy correlated with greater risk of abnormal esophageal findings. Older gestational age and need of ventilator treatment at the time of endoscopy remained the risk factors associated with abnormal gastric findings. CONCLUSIONS: Esophageal and gastric lesions diagnosed by endoscopy correlate poorly with the gastrointestinal symptoms of patients. Short duration of enteral feeding seems to be correlated with an increased risk of esophageal mucosal lesions, increasing gestational age and ventilator treatment with gastric mucosal lesions, and perinatal indomethacin with esophageal and gastric mucosal lesions in preterm infants. Ventilator-treated preterm infants not receiving enteral nutrition and patients with indomethacin exposure might benefit from ulcer prophylaxis.

Enamel defects in primary and permanent teeth of children born prematurely.

The objective of this study was to determine the prevalence of enamel defects in both primary and permanent dentitions of the same preterm children, and to elucidate the role of early dietary mineral and vitamin D intake in the etiology of the enamel defects. The status of the primary and permanent teeth was evaluated in 32 preterm children and in 64 control children. The prevalence of enamel defects in children born preterm was clearly higher as compared with controls in both the primary (78% vs 20%, P<0.001) and permanent (83% vs 36%, P<0.001) dentitions. Neither the mineral supplementation used nor a vitamin D dose of 1000 IU/day, as compared with a lower dose of 500 IU/day, reduced the prevalence of enamel defects in the primary or permanent dentitions. Further studies are needed to clarify whether achieving near optimum intra-uterine mineral retention would lower the prevalence of subsequent enamel defects in infants born prematurely.

Maturation of primary and permanent teeth in preterm infants.

AIMS: To elucidate the development of primary and permanent teeth and to interpret the effect of different calcium, phosphorus, and vitamin D supplementation in the neonatal period on dental maturation in preterm children. METHODS: Preterm infants were randomised to four groups to receive a vitamin D dose of 500 or 1000 IU/day and calcium and phosphorus supplemented or unsupplemented breast milk. The maturity of the primary and permanent teeth was recorded in 30 preterm children. Sixty children aged 2 years and 60 children aged 9-11 years served as controls. Bone mineral content/density was assessed in the preterm infants. RESULTS: The median (range) corrected teething age was 7 (2-16) months in preterm infants and 6 (2-12) months in controls (p = 0.43). The median (range) number of erupted teeth at 2 years of age was 16 (11-19) in preterm infants and 16 (12-20) in controls (p = 0.16). Maturation of the permanent teeth in the preterm infants was not delayed compared with the controls (mean Demirjian SDS 0.16 v 0.49, p = 0.14). Early dietary intake of either mineral or vitamin D did not affect maturation of the primary dentition in preterm children. Children receiving the higher vitamin D dose in the neonatal period had more mature permanent dentition than those receiving the lower dose, but mineral intake did not affect maturation of the permanent teeth. Dental maturation did not correlate with bone mineral status. CONCLUSIONS: This is the first longitudinal study to follow primary and permanent tooth maturation in the same preterm children. Premature birth has no appreciable late sequelae in tooth maturation.

Bone isoenzyme of serum alkaline phosphatase and serum inorganic phosphate in metabolic bone disease of prematurity.

UNLABELLED: We wanted to improve detection of low bone mineral density in preterm infants by combining serum measurements of total alkaline phosphatase, its bone-type isoenzyme and serum inorganic phosphate in a prospective design. The subjects were 43 preterm infants. Total and bone isoenzyme activity of alkaline phosphatase was determined at 3 wk chronological age and at 3 and 6 mo corrected age. The main outcome measure, apparent bone mineral density (BMAD) at the distal forearm and forearm shaft, was assessed by dual energy X-ray absorptiometry at 3 and 6 mo corrected age. An apparent density below 95 mg/cm3 at 3 mo corrected age was considered to indicate bone disease, based on the distribution of BMAD values of children with non-complicated courses of prematurity. At 3 mo corrected age, total alkaline phosphatase activities exceeding 900 IU/l revealed low bone mineral density with 88% sensitivity and 71% specificity. Measurements of bone isoenzyme activity did not improve diagnostic performance. Serum inorganic phosphate levels below 1.8 mmol/l reflected low bone density with high specificity (96%), but the sensitivity was only 50%. CONCLUSION: A combination of the criteria "serum total alkaline phosphatase activity above 900 IU/l" and "serum inorganic phosphate concentrations below 1.8 mmol/l" yielded a sensitivity of 100% at a specificity of 70%. This was the best available screening method for low bone mineral density in preterms.

The long-term effect of early mineral, vitamin D, and breast milk intake on bone mineral status in 9- to 11-year-old children born prematurely.

BACKGROUND: Although the short-term benefits of mineral supplementation in preterm infants has been established, the long-term benefits are less clear. The purpose of the study was to evaluate effects of early-life mineral, vitamin D, and breast milk intake on bone mineral status in children 9 to 11 years of age who were born prematurely. METHODS: Seventy preterm infants born 1985 through 1987 were randomized into four groups: to receive a vitamin D dose of 500 or 1000 IU/day and calcium- and phosphorus-supplemented or unsupplemented breast milk. At 3 months of age, radial bone mineral content was determined by single-photon absorptiometry and vitamin D metabolites were assessed. At 9 to 11 years of age, the bone mineral status of the radius and lumbar spine was assessed using dual energy x-ray absorptiometry. RESULTS: At the age of 3 months, the preterm infants with diets supplemented with minerals had 36% higher bone mineral content than the preterm infants whose diet was not supplemented with minerals. At the age of 9 to 11 years, in contrast, bone mineral status was comparable among the groups, irrespective of different mineral supplementation during the neonatal period. Interestingly, the lumbar bone mineral apparent density was positively related to lactation in mineral-supplemented children. There was neither short-term nor long-term benefit to bone mineral status of a vitamin D dose of 1000 IU/day compared with 500 IU/day. CONCLUSIONS: The short-term benefit to bone mineral density in preterm infants of mineral supplementation of the early diet is obvious, but, in the long term, the effects seem to disappear. The results also imply that a relatively long period of breast-feeding may be needed to optimize long-term bone mineral acquisition in the lumbar spine.

Randomised controlled trial of vitamin D supplementation on bone density and biochemical indices in preterm infants.

AIMS: To test the hypothesis that a vitamin D dose of 200 IU/kg, maximum 400 IU/day, given to preterm infants will maintain normal vitamin D status and will result in as high a bone mineral density as that attained with the recommended dose of 960 IU/day. METHODS: Thirty nine infants of fewer than 33 weeks of gestational age were randomly allocated to receive vitamin D 200 IU/kg of body weight/day up to a maximum of 400 IU/day or 960 IU/day until 3 months old. Vitamin D metabolites, bone mineral content and density were determined by dual energy x-ray absorptiometry, and plasma ionised calcium, plasma alkaline phosphatase, and intact parahormone measurements were used to evaluate outcomes. RESULTS: The 25 hydroxy vitamin D concentrations tended to be higher in infants receiving 960 IU/day, but the differences did not reach significance at any age. There was no difference between the infants receiving low or high vitamin D dose in bone mineral content nor in bone mineral density at 3 and 6 months corrected age, even after taking potential risk factors into account. CONCLUSIONS: A vitamin D dose of 200 IU/kg of body weight/day up to a maximum of 400 IU/day maintains normal vitamin D status and as good a bone mineral accretion as the previously recommended higher dose of 960 IU/day. Vitamin D is a potent hormone which affects organs other than bone and should not be given in excess to preterm infants.

Dual energy x-ray absorptiometry of the forearm in preterm and term infants: evaluation of the methodology.

The objective of this study was to evaluate the performance of dual energy x-ray absorptiometry (DXA) in forearm measurements of preterm and newborn term infants. The accuracy and linearity of DXA in measuring low mineral content levels (ranging from 30 to 300 mg) was assessed using bone-simulating K2HPO4 phantoms. For in vivo precision, DXA was performed twice on left forearms of four new-born term babies, 21 preterm infants at corrected age 3 mo, and 20 at corrected age 6 mo. Bone mineral content (BMC in mg) and areal bone mineral density (BMD in mg/cm2) at distal forearm and forearm shaft were measured. A special software program allowing a free adjustment of the bone detection threshold was used in the analysis of the scan data. The threshold level affected the overall ability of analysis to detect bone tissue and altered significantly the BMC and BMD values too. Given absolute success in detecting low amounts of bone mineral (BMC > 100 mg), the lowest bone detection threshold evaluated (0.040 g/cm2) became the preferable choice. The relationships between the actual and measured data were highly linear (r was 0.94 for BMC and 0.97 for BMD) but showed underestimation (corresponding slopes were 0.66 and 0.64). In vivo precision expressed as 95% limits of agreement was approximately +/-45 mg for BMC and +/-16 mg/cm2 for BMD. We conclude that DXA provides adequate reliability for in vivo determinations of BMC and areal BMD in the distal and shaft sites of forearm in term and preterm infants and thus strongly supports the clinical utility of DXA in the diagnosis and monitoring of metabolic disease of prematurity. Movements during scanning are typical of pediatric measurements and may decrease the precision considerably. Therefore, every effort must be made to prevent movement artefacts. In addition, special attention must be paid to keeping the analysis procedures consistent.

A randomized, controlled study of prophylactic ranitidine in preventing stress-induced gastric mucosal lesions in neonatal intensive care unit patients.

OBJECTIVE: To assess endoscopically the effect of prophylactic short-term ranitidine treatment in the prevention of stress-induced gastric lesions in neonatal intensive care unit (ICU) patients. DESIGN: Prospective, randomized study. SETTING: Department of Neonatal Intensive Care, University Hospital of Tampere. PATIENTS: Fifty-three infants were enrolled in a randomized, controlled study. Forty-eight (90%) of these patients underwent endoscopic examination and were evaluated. INTERVENTIONS: A histamine-2-receptor blocker, ranitidine, was given prophylactically after birth for 4 days to infants mechanically ventilated and treated in the neonatal ICU. The gastric mucosa was both visually and histologically evaluated after 3 to 6 days, and the outcome of the infants was registered. MEASUREMENTS AND MAIN RESULTS: In the 23 infants prophylactically treated with ranitidine, the gastric mucosa was visually classified as normal in 14 (61%) infants as compared with five (20%) of 25 controls (p < .004). Histologic lesions showed parallel results (57% vs. 16%, p < .004). Eight gastric ulcers were diagnosed endoscopically in the control group vs. none in the treatment group. The ulcers were all clinically "silent" at the time of endoscopy. According to logistic regression modeling, the decreased risk for gastric mucosal lesions in infants receiving prophylactic ranitidine was 0.03 (95% confidence interval 0.003 to 0.178). Surfactant treatment for infant respiratory distress syndrome also decreased the risk for stress-induced gastric mucosal lesions (odds ratio 0.083; 95% confidence interval 0.009 to 0.788), whereas other variables (birth weight, gestational age, Apgar scores, cord blood pH, and duration of intubation) had no significant effect. No side effects could be attributed to the ranitidine treatment. CONCLUSION: We conclude that short-term prophylactic ranitidine treatment prevents gastric mucosal lesions in newborn infants under stress.

Prenatal dexamethasone treatment in conjunction with rescue therapy of human surfactant: a randomized placebo-controlled multicenter study.

OBJECTIVES: A placebo-controlled, randomized, double-blind study was performed to determine whether prenatal dexamethasone (DEX) treatment improves the outcome of the preterm infant when exogenous surfactant is available. METHODS: 157 pregnant women at five hospitals with threatened preterm delivery and with lengths of gestation < 32 weeks received either DEX (dose 6 mg four times at 12-hour intervals) or placebo (PL). Prenatal treatment was not repeated. Preterm infants received rescue therapy of human surfactant (maximum four doses) if they required ventilatory support and at least 40% oxygen for the treatment of respiratory distress syndrome (RDS). RESULTS: Enrolled pregnant women delivered 188 live-born neonates, of whom 79 (DEX 41 and PL 38 neonates) were born 1 to 14 days after the prenatal treatment. Neonates born within 1 to 14 days after the initial DEX treatment had a lower incidence of RDS (DEX, 44%; PL, 79%; P < .01), lower requirements of surfactant (DEX, 22%; PL, 53%; P < .01), shorter duration of ventilatory support (DEX, 2.0 days; PL, 5.3 days; P < .05) and oxygen therapy (DEX, 2.0 days; PL, 7.0 days; P < .01), and a higher neonatal survival without ventilatory support (P < .05) than PL-treated neonates. DEX-treated neonates had higher mean blood pressure than PL-treated neonates during the first 3 days after birth. Among all neonates treated with DEX, there was a lower incidence of intraventricular hemorrhage or periventricular leucomalacia (DEX, 13%; PL, 33%; P < .01). Reduction in the incidence of intraventricular hemorrhage or periventricular leucomalacia in DEX-treated neonates was particularly associated with exogenous human surfactant therapy (DEX+surfactant 10%; PL+surfactant 48%; P < .01). CONCLUSIONS: Prenatal DEX treatment combined with exogenous human surfactant therapy in preterm infants decreases pulmonary morbidity and cerebral complications, and increases survival without severe morbidity.

High prevalence of asymptomatic esophageal and gastric lesions in preterm infants in intensive care.

OBJECTIVE: To establish the prevalence of upper gastrointestinal mucosal lesions in full-term and preterm infants under stress. DESIGN: A prospective, cohort study. SETTING: Neonatal intensive care unit at a university teaching hospital. PATIENTS: Seventeen (14 preterm, 3 term; median gestational age 29.7 wks; median birth weight 1230 g) consecutive, unselected infants treated in intensive care. INTERVENTIONS: Gastroscopy, using a prototype fiberoptic gastroscope designed for newborns, was performed for the first time at the age of 3 to 7 days. Biopsy specimens were taken when possible. Ranitidine treatment and follow-up endoscopies were performed in selected patients. Blood pressure, heart rate, oxygen saturation by pulse oximeter, and the general condition of the infants were monitored at 1-min intervals during the endoscopy. Central nervous system ultrasonography examination was repeatedly performed before and after the procedure. MEASUREMENTS AND MAIN RESULTS: At the time of first endoscopy, 15 of 17 infants were asymptomatic for gastrointestinal tract problems, one had melena, and one hematemesis. Upper gastrointestinal endoscopy revealed pathology in 16 (94%) infants, macroscopic esophagitis in six infants, hemorrhagic gastritis in nine infants, and gastritis with ulcers in six infants. Microscopically, the lesions were also clear. A peculiar finding was acute gastritis with cystic gland deformation ("cystic gastritis") seen in five of the infants under stress; one of these infants also had intestinal metaplasia in the gastric mucosa. Seven infants were treated with ranitidine without side-effects. Follow-up endoscopies demonstrated normalization of the lesions in five of six infants studied. The procedure, including biopsies, seemed to be safe, even for very low-birth weight infants. CONCLUSIONS: Gastric mucosal lesions are highly prevalent in preterm infants in intensive care before any symptoms occur. Further research on preterm infants under stress is needed in order to determine the risk factors and optimal treatment for the esophageal and gastric mucosal lesions described here.

Dexamethasone treatment in preterm infants at risk for bronchopulmonary dysplasia.

A randomised double blind placebo controlled study was conducted to determine whether a one week course of dexamethasone could reduce the severity of bronchopulmonary dysplasia in preterm infants without compromising their adrenal function. Forty one infants with a mean birth weight of 880 g and a gestational age of 27 weeks who were ventilator dependent at 10 days of age were enrolled. At the age of 28 days pulmonary outcome was significantly better in the girls treated with dexamethasone but not in all infants. There was no difference between the groups in the long term outcome, except for a shorter duration of supplemental oxygen in dexamethasone treated female infants. After the one week dexamethasone treatment there was a significant but short lived suppression of the basal cortisol concentrations and the adrenal response to corticotrophin (ACTH). No serious side effects were observed. It is concluded that early one week dexamethasone treatment improves short term pulmonary outcome in premature infants, but there is no clear evidence of long term benefits.

Hyperbilirubinemia, hypocarbia and periventricular leukomalacia in preterm infants: relationship to cerebral palsy.

This study comprised 103 preterm infants with a gestational age less than 33 weeks who were born in Tampere University Hospital and who were followed up to two years of age. Sixty-four perinatal variables were compared to ultrasound findings in the neonatal period and neurologic handicap at the age of two years. Duration of hypocarbia (PCO2 < or = 30 mmHg) during the first 72 h and hyperbilirubinemia (the mean level of serum total bilirubin) at three days of age were independently and significantly related to periventricular leukomalacia, but not directly to cerebral palsy. The only perinatal variables related independently and significantly to cerebral palsy at two years of age were periventricular leukomalacia and ventriculomegaly. According to these results, periventricular leukomalacia was the main predictor of cerebral palsy in preterm infants. In addition to hypocarbia, hyperbilirubinemia may also be involved in the pathogenesis of extensive (severe cystic) periventricular leukomalacia.

Coincident maternal meiotic nondisjunction of chromosomes X and 21 without evidence of autosomal asynapsis.

A family in which the proband showed phenotypic signs of both the Turner and Down syndromes was studied cytogenetically and with restriction fragment length polymorphisms. The proband's karyotype was 46,X,+21, showing double aneuploidy without any signs of mosaicism. The single X and one chromosome 21 were of paternal origin while two chromosome 21 were of maternal origin. The nondisjunction of chromosome 21 took place in maternal meiosis II. If it is assumed that the absence of mosaicism renders postzygotic mitotic loss of the X chromosome unlikely, then the X chromosome would have been lost in maternal meiosis I or II. Recombination had occurred between the nondisjoined chromosomes 21. We conclude that double nondisjunction took place in one patient and that asynapsis was not a prerequisite for the autosomal nondisjunction.

Neonatal septicaemia in Finland 1981-85. Predominance of group B streptococcal infections with very early onset.

A survey of blood culture-confirmed neonatal septicaemia was carried out in seven delivery hospitals in 1981-85, for a second successive five-year period. The total number of cases was 377, to compare with 410 in the previous five-year period. Group B streptococcus (GBS) was throughout the major pathogen (29%), followed by Staphylococcus aureus (15%) and Escherichia coli (14%), while Staphylococcus epidermidis (10%) has emerged as a significant new causative agent. Septicaemia with very early onset was predominant: 49% of the cases had onset within the first 24 hours; in the majority the symptoms were present from birth. GBS was responsible for 49% of the cases detected in the first 24 hours of life. The overall mortality was 20% as compared to 23% in the previous five-year period, whereas in the very early onset septicaemia mortality was now 18%, down from the preceding 30%. Despite the modest progress, GBS septicaemia with very early onset remains a significant problem, and effective preventive measures are needed.

Possible etiological factors in extensive periventricular leukomalacia of preterm infants.

During a twelve-month period five cases of extensive periventricular leukomalacia (PVL) in preterm infants with a gestational age of 31-32 weeks were diagnosed by routine ultrasound screening of preterm infants. The perinatal courses and later development of these infants were compared with 12 other infants with a comparable gestational age born during the same time period. PVL babies were delivered more often by the vaginal route (p = 0.0034), and their mean highest serum total bilirubin value was significantly higher (p = 0.0054) than that of the control infants. The mean value of the highest blood pH during the first 72 hours of life was also significantly higher (p = 0.0311) in PVL babies than in control babies. On the basis of these results we speculate that in addition to ischaemia in the periventricular area, bilirubin toxicity may play an additional role in the severe damage seen in extensive periventricular leukomalacia.

Visual evoked potentials in high-risk infants.

Flash VEPs were recorded in 109 high-risk infants, and the result were compared with the clinical outcome of the infants at the age of one year. 87 of the infants (80%) had a normal outcome and also seemed to have normal VEP maturation. This material was used as a reference for infants with abnormal outcome. Altogether, 20 infants (18%) had abnormal VEPs. In most of these repeated VEPs were recorded. In 70 cases the first VEP was recorded at an age of less than three months. Among these 57 children had normal outcome, with abnormal VEPs in 8 cases (14%). 13 infants who had an abnormal outcome had abnormal VEPs in 7 cases (54%). 7 infants of them had poor outcome, and they had abnormal VEPs in 6 cases (86%). The difference between normal and abnormal outcome was statistically significant. The present results indicate that it is possible to predict the poor outcome but not the moderate abnormality by VEP. The absence of VEP or its abnormal wave form were the most important parameters to predict the prognosis. Our present opinion is that VEPs should be recorded selectively, e.g. according to the findings in ultrasound examination, at least twice, the first time as soon as possible after birth and the second time at the age of two months.