Perinatal risk factors of adverse outcome in very preterm children: a role of initial treatment of respiratory insufficiency?

AIM: To investigate risk factors of adverse outcome in a cohort of very preterm children treated mainly with nasal continuous positive airway pressure (CPAP) during the neonatal course. METHODS: In Denmark, preterm children are treated with nasal CPAP as a first approach to respiratory support. A national prospective study of all infants with a birthweight below 1000 g or a gestational age below 28 wk born in 1994-1995 was initiated to evaluate this approach. Of the 269 surviving children 164 (61%) were not treated with mechanical ventilation in the neonatal period. A follow-up of the children at 5 y of age was conducted. Data from the neonatal period and the 5-y follow-up were analysed. RESULTS: In multivariate analyses including 250 children, a severely abnormal neonatal brain ultrasound scan was predictive of cerebral palsy (OR = 19.9, CI 95%: 6.1-64.8) and intellectual disability (OR = 6.2, CI 95%: 2.3-16.5). A high Clinical Risk Index for Babies (CRIB) score (OR = 2.4, CI 95%: 1.1-5.5) and chronic lung disease (OR = 2.8, CI 95%: 1.2-6.9) were predictive of intellectual disability. In univariate analyses mechanical ventilation was associated with cerebral palsy (OR=4.3, CI 95%: 1.7-10.8) and intellectual disability (OR = 2.2, CI 95%: 1.2-4.2), but the associations became insignificant in multivariate analyses including chronic lung disease and a severely abnormal ultrasound scan. CONCLUSION: The associations between neonatal risk factors and adverse outcome in our cohort were very similar to those found in other cohorts with another initial treatment of respiratory insufficiency. We found no significant adverse effects of mechanical ventilation beyond what could be explained by associations with chronic lung disease and IVH 3-4/PVL.

Feasibility of neonatal screening for toxoplasma infection in the absence of prenatal treatment. Danish Congenital Toxoplasmosis Study Group .

BACKGROUND: The best method for prevention and control of congenital toxoplasma infection is uncertain. Prenatal screening is done in Austria and France, but the effect of treatment during pregnancy is not well documented. The aim of our study was to find out the maternofetal transmission rate and outcome in infants born to mothers who were not treated during pregnancy. METHODS: We analysed 89873 eluates from phenylketonuria (PKU) cards from neonates and paired first-trimester serum samples from the mothers for specific IgG antibodies to Toxoplasma gondii. Children born to mothers who seroconverted during pregnancy were followed-up clinically and serologically to 12 months of age. In addition, 21144 PKU cards were analysed for toxoplasma-specific IgM antibodies during the last 12 months of the study. FINDINGS: In 24989 (27.8%) cases both the PKU eluate and the first-trimester samples were IgG positive, which indicates previous maternal infection. 139 of the 64884 seronegative women acquired toxoplasma infection during pregnancy and gave birth to 141 infants (two sets of twins). 27 of these children were diagnosed with congenital toxoplasma infection. The transmission rate was 19.4% (95% CI 13.2-27.0). Clinical signs and symptoms were found in four (15%) of the 27 children. The additional analysis for toxoplasma-specific IgM antibodies from the PKU card identified seven of nine children with congenital toxoplasma infection. The false-positive rate for the IgM test was 0.19 per 1000, and no false-negatives were found. INTERPRETATION: The risks of transmission of infection and of disease in the infant are low in an area with a low risk of toxoplasma infection. A neonatal screening programme based on detection of toxoplasma-specific IgM antibodies alone will identify between 70% and 80% of cases of congenital toxoplasmosis.

A novel variant of lysosomal acid lipase (Leu336-->Pro) associated with acid lipase deficiency and cholesterol ester storage disease.

Cholesterol ester storage disease (CESD) is associated with premature atherosclerosis, hepatomegaly, elevated LDL cholesterol levels, and in most cases, low HDL cholesterol levels. Previous studies have shown a G-->A mutation at the 3' splice junction of exon 8 (E8SJM) of the gene encoding lysosomal acid lipase (LAL) in two kindreds with CESD. In a Canadian-Norwegian kindred with this disease, we show this mutation in conjunction with an as yet unknown T-->C transition in exon 10 predicting a Leu336-->Pro (L336P) replacement and an A-->C transversion in exon 2 predicting a T-6P replacement in the prepeptide. Identification of the L336P rather than the T-6P replacement as the second defect underlying CESD in our patient is deduced from three lines of evidence. First, the E8SJM allele is located in cis with the mutation predicting the T-6P-encoding allele but in trans with the L336P-encoding allele; second, the L336P but not the T-6P replacement cosegregates with low LAL activity in the family; third, the T-6P replacement was found in 6 of 28 alleles from subjects with normal lysosomal acid lipase activity, suggesting that this variant represents a frequent nonfunctional polymorphism. Since the residual LAL activity is higher and the clinical phenotype based on plasma lipid values and severity of hepatosplenomegaly is milder in this case than in a previously studied case who was homozygous for the E8SJM allele, we conclude that the L336P variant appears to be associated with a phenotypically mild form of CESD.

[Surfactant treatment of newborn infants with respiratory distress syndrome primarily treated with nasal continuous positive air pressure. A pilot study]. / Surfaktantbehandling af nyfødte med respiratorisk distress-syndrom primaert behandlet med nasalt kontinuerligt positivt luftvejstryk. En pilotundersøgelse.

In this pilot study, Curosurf (200 mg/kg) was administrated to 34 patients with the respiratory distress syndrome in nasal-CPAP therapy with FiO2 requirements greater than 0.60 and/or TcPCO2 greater than 8 kPa. The surfactant was instilled during a short period of intubation or in a few cases via an intratracheal catheter (Ch. 6). The age of the patients on surfactant treatment ranged from two to 72 hours. Eighteen patients could be maintained on nasal-CPAP after treatment with Curosurf and only a few complications were seen in these infants. The other 16 patients subsequently required artificial ventilation and had a higher incidence of pulmonary and extrapulmonary complications. On the basis of these observations, we plan a randomized trial to investigate whether, administration of surfactant reduces the need for ventilator treatment and improves the odds for uneventful recovery in this category of patients.

[Early nasal continuous positive respiratory pressure therapy of infants with a birth weight less than or equal to 1500g. Survival and duration of treatment]. / Tidlig nasal kontinuerlig positiv luftvejstryksbehandling af børn med fødselsvaegt less than or equal to 1.500 g. Overlevelse og behandlingsvarighed.

Survival and the therapeutic regime for 103 infants with birth weights (FV) less than or equal to 1,500 g admitted to the neonatal department of a county hospital were calculated and described. The total survival was 78 (76%) but the survival for infants with birth weights 1,001 g-1,500 g was 90% and for infants with birth weights 500 g-1,000 g was 50%. The therapeutic regime consisted of early supportive respiratory treatment in the form of nasal continuous positive airway pressure (N-CPAP) and O2, most frequently initiated during the first hour of life. Eight infants did not require supportive respiratory treatment. Nine infants required respirator treatment. Treatment with N-CPAP was frequently prolonged (several weeks) but it was associated with few side effects whereas O2 treatment was frequently brief (few days). It is concluded that this form of therapeutic regime for infants with birth weights of 1,000-1,500 g appears to result in the same survival as more intensive therapeutic regimes while the mortality for infants with birth weights under 1,000 g is still very high.

Fatty acid composition of subcutaneous adipose tissue in mother-infant pairs.

The fatty acid composition of microsamples from 10 AGA term, 8 SGA term, 7 AGA preterm and 4 SGA preterm, 2-4 day old infants and their mothers were analyzed. In AGA preterm newborns the mean percent of palmitic and stearic acid was lower and the mean percent of linoleic acid was higher than in AGA term infants indicating that there is an increase in fatty acids derived by synthesis from glucose throughout gestation. SGA infants had relative amounts of palmitic and stearic acid similar to what was found in AGA term infants. This indicates that the enzymes involved in synthesis of fatty acids from glucose are intact in intrauterine growth retardation (IUGR). The absolute amount of adipose tissue and fatty acids, however, is smaller in SGA infants due to a reduced availability of glucose in IUGR gestation. No differences were found in the fatty acid composition of subcutaneous adipose tissue from the mothers in the 4 groups. All mothers had a lower mean percent of palmitic and stearic acid and a higher mean percent of oleic and linoleic acid than their infants, ensuring a transplacental gradient to the fetus of this latter essential fatty acid. The fatty acid composition of plasma free fatty acids generally reflected the composition of the subcutaneous adipose tissue in the infants.

Detection and exclusion of carriers of ornithine transcarbamylase deficiency by RFLP analysis.

By examining a restriction fragment length polymorphism (RFLP) detected by a gene specific DNA probe of ornithine transcarbamylase (OTC), we have been able to follow the segregation of the defective gene in a family with OTC deficiency. We have identified three sisters of the proband as carriers, and excluded a fourth as a carrier.

Fatty acid changes in plasma lipids and lymphocyte phospholipids after infusion of intralipid to newborn infants.

The fatty acid composition of the major plasma lipids and blood lymphocyte phospholipids was studied in four patients before and after 1 month of parenteral nutrition including 2 to 3 g/kg/day of Intralipid fat and in four matched controls before and after 1 month of breast-feeding. After treatment with Intralipid the concentration of polyunsaturated fatty acids including linoleic acid increased in all plasma lipids. The total concentration of polyunsaturated fatty acids in lymphocyte phospholipids did not change. The increase of linoleic acid and decrease of arachidonic acid in lymphocyte phospholipids were not statistically significant. In control infants the concentration of polyunsaturated fatty acids including linoleic and arachidonic acid in lymphocyte phospholipids increased after 1 month of breast-feeding to almost the same values as in the patients. The study indicates that at least in lymphocytes the incorporation of polyunsaturated fatty acids is actively regulated. The present way of administering Intralipid does not seem to cause any abnormal fatty acid pattern of the plasma and lymphocyte lipids. The use of intravenous fat emulsion with high content of linoleic acid in term newborns should thus not be expected to result in changes of the physical-chemical properties of membranes and membrane dysfunction.

Changes in plasma lipoproteins from first day to third week of life in healthy breast-fed infants. II. Fatty acid composition of lipoprotein triglyceride- and cholesterol esters.

The fatty acid composition of plasma lipoprotein-triglyceride (TG) and -cholesterol ester (CE) was studied in seven healthy breast-fed infants three times during the first day and on the third, sixth and twenty-first days of life. The major finding was a two-fold increase in the linoleic acid weight percent of plasma lipoprotein-TG and -CE between the first and third weeks of life. This increase could best be explained by the ingestion of breast-milk rich in linoleic acid.

Hyperlipemia among 1407 Danish children whose fathers have died from ischemic heart disease before age 45.

1407 children whose fathers had died from ischemic heart disease before age 45 were investigated. 15% had hypercholesterolemia and 8% hypertriglyceridemia at visit 1. At visit 2 and 3 this number of children with hyperlipemia fell to a minimum of 3% and 1.4%, resp. which is around 10 times higher than in a reference population. 1.8% of the children had familial hypercholesterolemia (FH) which is 10-15 times higher than in a reference population. These findings indicate that serum lipids should always be measured in children from such coronary heart risk families, and a decision made whether or not their permanent hyperlipemia should be treated.

Effect on serum calcium of a alpha-hydroxy-vitamin D3 supplementation in infants of low birth weight, infants with perinatal asphyxia, and infants of diabetic mothers.

Thirty infants of low birth weight, 35 infants with perinatal asphyxia, and 16 infants of diabetic mothers were investigated for early neonatal hypocalcaemia. The infants were randomized into a group prophylactically given 1 alpha-hydroxy-vitamin D3, 0.05 or 0.10 micrograms/kg i.v. on the first 3 days of life, and an untreated control group. In infants of low birth weight and infants of diabetic mothers there were no differences in serum ion-Ca concentrations on days 2, 3, 5, and 7 between the treated and untreated groups. In infants with perinatal asphyxia, however, serum ion-Ca concentrations on days 5 and 7 were significantly higher in the treated than in the untreated group, while on days 2 and 3 the differences were not statistically significant. The hypocalcaemia in asphyctic infants was not correlated to bicarbonate treatment, but infants with severe signs of asphyxia had lower serum ion-Ca concentrations than infants with only mild or no signs. Hypocalcaemia in asphyctic infants might be explained by a decreased concentration of 1 alpha, 25-dihydroxy-vitamin D3 following reduced 1 alpha-hydroxylation in the kidney as a consequence of anoxia during perinatal asphyxia.

Serum indomethacin concentrations after intravenous administration to preterm infants with patent ductus arteriosus.

Six preterm infants with PDA received 14 treatments with indomethacin 0.2 mg/kg intravenously. Auscultatory and echocardiographic assessment indicated closure of the duct in 2, partial closure in 2, and no effect in 2 infants. The mean serum concentration of indomethacin was: 15 min after the first injection 1 314 ng/ml, after 1 hour 970 ng/ml, after 6 hours 718 ng/ml, and after 24 hours 388 ng/ml. The mean half-life of indomethacin in the serum was 20 hours (range 9-50 hours). Side effects in all infants were hyponatraemia, decreased urinary output, decreased urinary sodium excretion, and weight gain. One infant had transient thrombocytopenia and gastrointestinal haemorrhage. By intravenous administration of indomethacin in a dose of 0.2 mg/kg to preterm infants a sufficiently high serum concentration is obtained shortly after the injection. To maintain a high serum concentration for a longer period it is recommended to give a second dose of 0.2 mg/kg after 6 hours and if necessary a third dose of 0.1 mg/kg 24 hours after the first dose.

Free fatty acids, glycerol and triglycerides during the first 24 hours in infants with a birth weight less than or equal to 2700 grams.

The influence of birth weight and gestational age on the concentrations of free fatty acids, glycerol and triglycerides during the first 24 hours of life were studied in 86 healthy newborn infants with BW less than or equal to 2700 g. Very low FFA values were found in the first 6 hours in infants with GA less than or equal to 34 weeks, whereas FFA increased from the second hour in infants with higher GA. All infants had peak values at 12 h. Significant correlations were found between FFA and GA, most pronounced in the second hour after birth. No differences were seen between AGA and SGA infants of similar GA. High glycerol concentrations were found from the second hour in all infants irrespective of GA and BW. Triglyceride concentrations 24 hours after birth were not influenced by GA or BW. Triglyceride concentrations 24 hours after birth were not influenced by GA or BW. The finding of intact lipolysis but low FFA releases in the first hours in infants with GA less than or equal to 34 weeks could not be explained by differences in rectal temperature, blood glucose or caloric intake.

Volume of blood removed for analytical purposes during hospitalization of low-birthweight infants.

Iatrogenic hazards may be induced by blood sampling in very-low-birthweight neonates. We report the number and types of analyses performed on 20 neonates with a birthweight below 1500 g during their first four weeks of hospitalization. Blood was sampled one to 13 times per infant per day on 382 of the 435 total days of hospitalization. The average blood loss was 7 to 51 mL per kilogram of body weight per four weeks--that is, from 5 to 45% of the calculated total blood volume. Of the blood removed, about 25% was in excess of the need for analytical procedures. Of the analyses, 40% were for acid-base, sodium, and potassium analyses--analyses for which transcutaneous methodology has been or is being developed. We conclude that because of the risks for low-birthweight neonates, procedures for blood sampling and analysis should periodically be reviewed, so as to minimize the number of samplings and the amount of blood removed.