Cardiorespiratory Events Following the Second Routine Immunization in Preterm Infants: Risk Assessment and Monitoring Recommendations.

Due to frequent cardiorespiratory events (CREs) in response to the first routine immunization (rIM), current guidelines recommend readmitting and monitoring extremely preterm infants after the second rIM, though evidence on CREs in response to the second rIM is weak. In a prospective observational study, preterm infants with an increase in CREs after the first rIM were monitored for CREs before and after the second rIM. Seventy-one infants with a median gestational age of 26.4 weeks and a median weight of 820 g at birth were investigated at a median postnatal age of 94 days. All but seven infants showed an increase in CREs after the second rIM. The frequency of hypoxemias (p < 0.0001), apneas (p = 0.0003) and cardiorespiratory events requiring tactile stimulation (CRE-ts) (p = 0.0034) increased significantly. The 25 infants (35%) presenting with CRE-ts were significantly more likely to have been continuously hospitalized since birth (p = 0.001) and to receive analeptic therapy at the first rIM (p = 0.002) or some kind of respiratory support at the first (p = 0.005) and second rIM (p < 0.0001). At a postmenstruational age of 43.5 weeks, CRE-ts ceased. Our data support the recommendation to monitor infants who fulfil the above-mentioned criteria during the second rIM up to a postmenstruational age of 44 weeks.

Does the enteral feeding advancement affect short-term outcomes in very low birth weight infants?

BACKGROUND AND OBJECTIVES: Controversy exists regarding the optimal enteral feeding regimen of very low birth weight infants (VLBW). Rapid advancement of enteral feeding has been associated with an increased rate of necrotizing enterocolitis. In contrast, delaying enteral feeding may have unfavorable effects on nutrition, growth, and neurodevelopment. The aim is to compare the short-term outcomes of VLBW infants in tertiary care centers according to their enteral feeding advancement. PATIENTS AND METHODS: We prospectively studied the influence of center-specific enteral feeding advancement in 1430 VLBW infants recruited from 13 tertiary neonatal intensive care units in Germany on short-term outcome parameters. The centers were post hoc stratified to "rapid advancement to full enteral feeds" (median duration of advancement to full enteral feeds < or =12.5 days; 6 centers), that is, rapid advancement (RA), or "slow advancement to full enteral feeds" (median duration of advancement to full enteral feeds >12.5 days; 7 centers), that is, slow advancement (SA). RESULTS: VLBW infants born in centers with SA (n = 713) had a significantly higher rate of sepsis compared with VLBW infants born in centers with RA (n = 717), which was particularly evident for late-onset sepsis (14.0% vs 20.4%; P = 0.002). Furthermore, more central venous lines (48.6% vs 31.1%, P < 0.001) and antibiotics (92.4% vs 77.7%, P < 0.001) were used in centers with SA. CONCLUSIONS: Center differences in enteral feeding advancement occur and may have a significant impact on short-term outcomes such as nosocomial sepsis. Large, multicenter, prospective trials are required to further elucidate the optimal feeding strategy for VLBW infants.

Very low birth weight infants as a model to study genetic influences on neonatal weight gain.

In a cohort of 829 preterm infants (birth weight below 1500 g) we identified 13 monozygotic, 10 same-sex dizygotic, and 12 same-sex matched singleton pairs. The difference in daily weight gain within pairs was significantly lower in monozygotic twins compared with dizygotic twins or matched singleton pairs. Our data support a strong genetic influence on postnatal growth in preterm infants. Therefore, weight gain of preterm infants may be an interesting model to study polymorphic variants of genes regulating neonatal resorption, metabolism, or energy expenditure, and their influence on weight gain in preterm infants.

Outcome of extremely low birth weight survivors at school age: the influence of perinatal parameters on neurodevelopment.

Extremely low birth weight (ELBW) is associated with impaired neurodevelopmental outcome in infancy. Information on the long-term cognitive and neurological consequences of ELBW is scarce. We aimed to identify the perinatal and neonatal factors of ELBW infants associated with adverse cognitive and neurological outcome at school age. A regional cohort of 135 ELBW infants born between 1993 and 1998 was prospectively evaluated at 3, 6, 12, and 18 months postmenstrual age and at yearly intervals up to age 10 years. The comprehensive follow-up programme for high-risk infants included neurological examinations and psychometric evaluations. According to the overall results of these tests, children were classified as either being normal or having minor or major impairment. At a mean age of 8.4 (SD: 1.6) years, 43% of children had survived without any impairment. Minor impairment was diagnosed in 39% and major impairment in 18% of assessed children. The proportion of disabled school children rose with decreasing gestational age. The following neonatal complications were significant risk factors for developing major or minor impairment at school age: an increase in head circumference < 6 mm per week (OR 4.0, 95% CI: 1.1-14.8), parenteral nutrition > or = 6 weeks (OR 2.5, 95% CI: 1.1-6.0), and mechanical ventilation > 14 days (OR 2.3, 95% CI: 1.0-5.1). High-grade intraventricular haemorrhage (IVH) and/or PVL (OR 13.3, 95% CI: 4.0-44.9), neonatal seizures (OR 5.2, 95% CI: 1.2-22.4) and bowel perforation, and/or necrotizing enterocolitis (OR 4.4, 95% CI: 1.1-17.0) were significant risk factors for developing major impairment. In spite of the relatively large proportion of normal children, ELBW remains an important risk factor for neurodevelopmental impairment at school age. Thus, measures to prevent complications such as necrotizing enterocolitis, cerebral haemorrhage, and undernutrition remain important goals for neonatal intensive care.

Neurodevelopmental outcome in extremely low birth weight infants: what is the minimum age for reliable developmental prognosis?

AIM: We present a longitudinal study on the neurodevelopmental outcome in preterm infants with extremely low birth weight <1000 g (ELBW) to answer the question at which age a developmental prognosis can be given. METHODS: A group of 129 ELBW, median birth weight: 794 g (SD 123 g), gestational age: 27.0 weeks (SD 2.0 weeks), born between 1993 and 1998, were followed up to the age between 6 and 10 years (mean 8.5 years [SD 1.7 years]) and evaluated by neurodevelopmental and psychometric tests. The status of children without cerebral palsy was ranked into categories of major, minor and no developmental impairments. RESULTS: At the time of the last follow-up examination 17% of the children showed a major impairment including 9% cerebral palsy, 42% a minor impairment and 41% were normally developed. The longitudinal analysis of cases without cerebral palsy reveals that an assessment 'at term' can only give the correct developmental prognosis in 49% of the cases. At the corrected age of 12 months the prognosis is correct in 59% of the cases, whereas at the corrected age of 3 years 70% proves to be right. Diagnosis of cerebral palsy could be confirmed at the corrected age of 2 years with sufficient reliability. CONCLUSION: The neurodevelopmental evaluation of former preterm infants with a birth weight <1000 g demands a follow-up period of at least 6 years in order to make reliable statements. We are doubtful that follow-up testing completed prior to this age can yield reliable results.

Genetic polymorphisms of hemostasis genes and primary outcome of very low birth weight infants.

BACKGROUND: Recent investigations have reported an influence of thrombophilic mutations and antithrombotic risk factors with development of intraventricular hemorrhage. It was our objective for this study to investigate the impact of genetic polymorphisms of hemostasis genes on the primary outcome measures of sepsis, bronchopulmonary dysplasia, intraventricular hemorrhage, and periventricular leukomalacia in a large cohort of very low birth weight infants. METHODS: There were 586 very low birth weight infants enrolled prospectively in a multicenter trial between September 2003 and July 2005, and an additional 595 very low birth weight infants, who had been recruited in a previous prospective trial, were studied. DNA samples were taken by buccal swab, and genotypes of factor V Leiden mutation, prothrombin G20210A mutation, the factor VII-323 del/ins polymorphism, and the factor XIII-Val34Leu polymorphisms were determined by polymerase chain reaction and restriction enzyme digestion. RESULTS: In contrast to data published previously, the frequency of intraventricular hemorrhage or periventricular leukomalacia was not significantly influenced by any of the genetic variants tested. Carriers of the factor XIII-Val34Leu polymorphism, however, had a higher sepsis rate and a longer period of hospital care compared with noncarriers. The factor VII-323 del/ins polymorphism was found to be a potential protective factor against bronchopulmonary dysplasia. CONCLUSIONS: We could not confirm previously reported associations of hemostasis gene variants and development of intraventricular hemorrhage in very low birth weight infants. To better understand gene-disease associations in very low birth weight infants, the prospective development of large-scale cohorts with well-defined phenotypes and corresponding DNA samples is essential.

Polymorphisms of haemostasis genes as risk factors for preterm delivery.

Clinical trials evaluating the potential benefit of anticoagulant treatment in pregnant women with inherited thrombophilia are based on the observation that a genetic predisposition to thrombosis is associated with frequent abortions and preterm birth. It was the aim of our study to delineate the impact of genetic polymorphisms with prothrombotic and antithrombotic effects on the occurrence of preterm birth in a large cohort of very-low-birth-weight (VLBW)-infants and their mothers. We examined the factor V Leiden and the prothrombin G20210A mutation, the factor VII 121del/ins and the factor XIII Val34Leu polymorphism in preterm very-low-birth-weight (VLBW, n=593) and term-born-infants (n=278) and their mothers (n=785). The primary outcome was preterm vs.term birth. From all polymorphisms tested, the maternal factor VII-121del/ins polymorphism (26.2 vs. 17.6 %; p=0.009) and the infant's factor VII-121del/ins polymorphism (29.0 vs. 20.0 %; p=0.009) were more frequent in singleton VLBW and their mothers compared to term infants and their mothers. Furthermore, the frequency of the factor XIII-Val34Leu polymorphism was significantly lower in singleton VLBW than in term infant controls (5.1 vs. 9.6%, p=0.025). In a multivariate regression analysis, previous preterm delivery (OR=3.8, 95% CI: 1.7-8.4), the maternal carrier status of the factor-VII-121del/ins polymorphism (OR=1.7, 95% CI: 1.12-2.5, p=0.007) and the lower frequency of infant's factor-XIII-Val34Leu polymorphism (OR=0.53; 95% CI: 0.29-0.96; p=0.038) were found to be independently associated with preterm delivery. InVLBW mothers with pathological CTG as cause of preterm delivery, the frequency of factor V Leiden mutation was significantly increased compared to VLBW mothers without pathological CTG (14.1 vs. 6.1%, p=0.01). The investigated haemostasis gene polymorphisms have a much lower impact on subsequent preterm delivery than known risk factors such as previous preterm birth. The reported association of the factor-VII-121del/ins polymorphism on preterm delivery and its clinical relevance needs to be further elucidated.

Mutations of genes involved in the innate immune system as predictors of sepsis in very low birth weight infants.

Mutations of genes involved in the innate immune system have been reported to be associated with an increased sepsis rate in adults. We determined the -159T mutation of the CD14 gene, the 896G mutation of the toll-like receptor 4 gene, the 3020insC mutation of the NOD2 gene (NOD2-3020insC), the IL-6 174G/C promoter polymorphism (IL6-174G/C), and the mannose-binding lectin genotype and their association to the subsequent development of neonatal sepsis in a large cohort of very low birth weight (VLBW) infants. Fifty (14%) of 356 VLBW infants developed blood culture-proven sepsis during their stay in the hospital. VLBW infants carrying the NOD2-3020insC allele (n =15) and the IL6-174G allele (n =121) had a significantly higher rate of blood culture-proven sepsis (33% and 19.8%, respectively) than VLBW infants without these genotypes (p = 0.046 and 0.035, respectively). In a multivariate logistic regression analysis, gestational age less than 28 wk (odds ratio, 3.2; 95% confidence interval, 1.7-6.0; p < 0.001) and the homozygous IL6-174G allele (odds ratio, 1.9; 95% confidence interval, 1.0-3.9; p = 0.039) were predictive for the development of sepsis, whereas the NOD2-3020insC allele was only of borderline significance (odds ratio, 3.2; 95% confidence interval, 1.0-10.4; p = 0.052). VLBW infants with repeated episodes of sepsis had higher frequencies of the NOD2-3020insC and IL6-174G allele. The increased sepsis rate of homozygous IL6-174G carriers was especially related to an increase in Gram-positive infections, and was not observed in VLBW infants who received prophylaxis with teicoplanin (frequency of Gram-positive sepsis in homozygous IL6-174G carriers without prophylaxis 16.5% versus 2.4% in homozygous IL6-174G carriers with prophylaxis; p = 0.033).

Early treatment with erythropoietin beta ameliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g.

OBJECTIVE: To investigate whether recombinant erythropoietin (rhEPO) reduces the need for transfusion in extremely low birth weight (ELBW) infants (birth weight 500-999 g) and to determine the optimal time for treatment. METHODS: In a blinded multicenter trial, 219 ELBW infants were randomized on day 3 to one of 3 groups: early rhEPO group (rhEPO from the first week for 9 weeks, n = 74), late rhEPO group (rhEPO from the fourth week for 6 weeks, n = 74), or control group (no rhEPO, n = 71). All infants received enteral iron (3-9 mg/kg/day) from the first week. The rhEPO beta dose was 750 IU/kg/week. Success was defined as no transfusion and hematocrit levels never below 30%. RESULTS: Success rate was 13% in the early rhEPO group, 11% in the late rhEPO group, and 4% in the control group (P =.026 for early rhEPO versus control group). Median transfusion volume was 0.4 versus 0.5 versus 0.7 mL/kg/day (P =.02) and median donor exposure was 1.0 versus 1.0 versus 2.0 (P =.05) in the early rhEPO group, the late rhEPO group, and the control group, respectively. Infection risk was not increased and weight gain was not delayed with rhEPO beta. CONCLUSION: Early rhEPO beta treatment effectively reduces the need for transfusion in ELBW infants.

The effect of the Val34Leu polymorphism in the factor XIII gene in infants with a birth weight below 1500 g.

OBJECTIVES: The 34Leu polymorphism of the factor XIII gene is associated with a low rate of brain infarction and a higher incidence of primary intracerebral hemorrhage in adults. We evaluated the effect of the polymorphism on the subsequent development of isolated intracranial hemorrhage and white matter disease in preterm infants with a birth weight <1500 g (very low birth weight [VLBW] infants). STUDY DESIGN: We studied 531 VLBW infants and 301 control infants born at term. The factor XIII 34Leu polymorphism was detected by polymerase chain reaction and restriction enzyme digestion. RESULTS: Allele frequencies were not different from term and VLBW infants (Val/Val, 53.1% and 57.8%; Val/Leu, 38.8% and 37.6%; Leu/Leu, 8.0% and 4.5%, respectively). VLBW infants carrying the Leu/Val or Leu/Leu allele had a significant reduced risk of the development of white matter disease (3.6% vs 10.4% in infants without the polymorphism, P =.003). In a multivariate logistic regression analysis, only gestational age <28 weeks (odds ratio, 3.8; 95% confidence interval, 1.9-7.5; P <.001), and the factor XIII 34Leu allele (odds ratio, 0.3; 95% confidence interval, 0.1-0.7; P =.005) had significant prognostic value in predicting subsequent white matter disease. However, VLBW infants who carried the factor XIII 34Leu allele also had a moderately increased risk of the subsequent development of isolated intraventricular hemorrhage (14.3% vs 10.1% in infants without the mutation, P =.17). CONCLUSIONS: VLBW infants carrying the factor XIII 34Leu polymorphism had a decreased risk for white matter disorders.