Use and Impact of Pessary, Cerclage, and Progesterone for the Secondary Prevention of Preterm Birth: Data from the German Neonatal Network.

BACKGROUND: To evaluate the use and effect of cervical stitch cerclage, pessary, and progesterone on pregnancy outcome in mothers of very low birth weight infants (VLBWI) born<32 weeks of gestation in the German Neonatal Network (GNN). METHODS: The GNN is a population-based cohort study enrolling VLBWI since 2009. We included 575 neonates from 424 mothers into our analysis, who were born between 2015 and 2019, after prenatal intervention with cerclage, pessary, progesterone or a combination between 20/0 to 25/0 weeks of gestation to prevent preterm birth. Median intervention-to-birth interval was the primary endpoint. RESULTS: 231 of 424 pregnant women had a cerclage only (54.5%), 76 women a pessary only (17.9%), and 27 were prescribed progesterone only (15.3%). The most common combination treatment (>1 intervention group) was cerclage plus progesterone (n=27), followed by cerclage plus pessary (n=13). The median intervention-to-birth interval for the whole cohort was 24 days (IQR 19.0 days). The earlier the intervention was started, the longer the intervention-to-birth interval lasted: When started at 20 weeks, the interval was 34 days in contrast to 11.5 days, when started at 25 weeks. The >1 group was born at a significantly higher median GA with 27.0 weeks (IQR 2.9 weeks) and a higher median birth weight of 980 g (IQR 394 g) accordingly. CONCLUSION: We propose that the earliest possible start of intervention leads to the most efficient pregnancy prolongation.

Erythrocyte transfusions are associated with retinopathy of prematurity in extremely low gestational age newborns.

AIM: Retinopathy of prematurity (ROP) is a major morbidity in preterm infants causing visual impairment including blindness. Prevention and timely treatment are critical. We investigated the potential role of red blood cell (RBC) transfusions as risk factor for ROP development. METHODS: Retrospective cohort study of data from 68 tertiary level neonatal intensive care units in Germany. Preterm infants born at 22 + 0 to 28 + 6 weeks of gestation between January 2009 and December 2021 were enrolled. RESULTS: We included n = 12 565 infants. Prevalence of any ROP was 49.2% with most infants being diagnosed with stage 1 (21.5%) and 2 disease (17.2%). ROP stage 3 was present in 10.2%, stage 4 in 0.3%, and ROP requiring treatment in 6.6%. Infants with ROP had significantly more frequently a history of RBC transfusions. Adjusting for confounders, RBC transfusions were associated with increased odds of ROP (OR 1.4, p < 0.001), ROP progression (OR 2.1, p < 0.01) and ROP requiring treatment (OR 3.6, p < 0.001). Restrictive transfusion approaches correlated with decreased (OR 0.7, p < 0.001), liberal regimes with increased odds (OR 1.2, p = 0.001). CONCLUSION: The present study confirmed an association of RBC transfusions and ROP. Our findings emphasise the need for anaemia prevention and critical re-evaluation of transfusion practices in preterm infants.

Increased Expression of Anaphylatoxin C5a-Receptor-1 in Neutrophils and Natural Killer Cells of Preterm Infants.

Preterm infants are susceptible to infection and their defense against pathogens relies largely on innate immunity. The role of the complement system for the immunological vulnerability of preterm infants is less understood. Anaphylatoxin C5a and its receptors C5aR1 and -2 are known to be involved in sepsis pathogenesis, with C5aR1 mainly exerting pro-inflammatory effects. Our explorative study aimed to determine age-dependent changes in the expression of C5aR1 and C5aR2 in neonatal immune cell subsets. Via flow cytometry, we analyzed the expression pattern of C5a receptors on immune cells isolated from peripheral blood of preterm infants (n = 32) compared to those of their mothers (n = 25). Term infants and healthy adults served as controls. Preterm infants had a higher intracellular expression of C5aR1 on neutrophils than control individuals. We also found a higher expression of C5aR1 on NK cells, particularly on the cytotoxic CD56dim subset and the CD56- subset. Immune phenotyping of other leukocyte subpopulations revealed no gestational-age-related differences for the expression of and C5aR2. Elevated expression of C5aR1 on neutrophils and NK cells in preterm infants may contribute to the phenomenon of "immunoparalysis" caused by complement activation or to sustained hyper-inflammatory states. Further functional analyses are needed to elucidate the underlying mechanisms.

Association of ApoE Genotypes and Recovery From Intracerebral Hemorrhage in Very Low Birth Weight Infants.

BACKGROUND AND PURPOSE: Associations of APOE genotypes with intracerebral hemorrhage (ICH) in preterm infants were previously described. In adults, APOE-ε4 genotype has been proposed as susceptibility factor for impaired recovery after cerebral insult. We here aim to determine APOE genotype-specific neurological consequences of neonatal ICH at school age. METHODS: In this multicenter observational cohort study, very low birth weight (<1500 g, <32 weeks gestational age) children were studied for cerebral palsy (CP) after ultrasound diagnosed ICH stratified by APOE genotype. Follow-up examination was done at the age of 5 to 6 years. Study personnel were blinded for perinatal information and complications. Participants were born between January 1, 2009 and December 31, 2013 and enrolled in the German Neonatal Network. Of 8022 infants primarily enrolled, 2467 children were invited for follow-up between January 1, 2014 and December 31, 2019. Univariate analyses and multivariate logistic regression models were used to assess the impact of APOE genotype (APOE-ε2, APOE-ε3, APOE-ε4) on CP after ICH. RESULTS: Two thousand two hundred fifteen children participated at follow-up, including 363 children with ultrasound diagnosed neonatal ICH. In univariate analyses of children with a history of ICH, APOE-ε3 carriers had lower frequencies of CP (n=33/250; 13.2 [95% CI, 9.4%-17.8%]), as compared to APOE-ε2 (n=15/63; 23.8 [14.6%-35.3%], P=0.037) and -ε4 carriers (n=31/107; 29.0 [21.0%-38.0%], P<0.001), respectively. Regression models revealed an association of APOE-ε4 genotype and CP development (odds ratio, 2.77 [1.44-5.32], P=0.002) after ICH. Notably, at low-grade ICH (grade I) APOE-ε4 expression resulted in an increased rate of CP (n=6/39; 15.4 [6.7-29.0]) in comparison to APOE-ε3 (n=2/105; 1.9 [0.4%-6.0%], P=0.002). CONCLUSIONS: APOE-ε4 carriers have an increased risk for long-term motor deficits after ICH. We assume an effect even after low-grade neonatal ICH, but more data are needed to clarify this issue.

Multi-centre randomised trial of invasive and less invasive surfactant delivery methods showed similar spirometry results at 5-9 years of age.

AIM: We explored whether subnormal forced expiratory volume within 1 s (FEV1 ) at 5-9 years of age was lower in children born preterm who received less invasive surfactant administration (LISA) rather than surfactant via an endotracheal tube. METHODS: The multi-centre, randomised Nonintubated Surfactant Application trial enrolled 211 preterm infants born at 23-26 weeks of gestation from 13 level III neonatal intensive care units from April 2009 to March 2012. They received surfactant via LISA (n = 107) or after conventional endotracheal intubation (n = 104). The follow-up assessments were carried out by a single team blinded to the group assignments. The main outcome was FEV1 < 80% of predicted values. RESULTS: Spirometry was successful in 102/121 children. The other children died or were lost to follow-up. Median FEV1 was 93% (interquartile range 80%-113%) of predicted values in the LISA group and 86% (interquartile range 77-102%) in the control group (p = 0.685). Rates of FEV1 < 80% were 11/57 (19%) and 15/45 (33%), respectively, which was an absolute risk reduction of 14% (95% confidence interval -3.1% to 31.2%, p = 0.235). There were no differences in other outcome measures. CONCLUSION: The proportion of children aged 5-9 years with subnormal FEV1 was not significantly different between the groups.

Extremely and very preterm-born children <1500 g show different weight development in childhood compared to their peers.

AIM: To develop reference growth charts for body mass index (BMI), weight, length and head circumference in children born extremely preterm (EPT) or very preterm (VPT) with a birth weight <1500 g. METHODS: We analysed EPT and VPT children from the German Neonatal Network born between 2009 and 2013 without chronic diseases or medications influencing growth. These data of EPT and VPT datasets were split into a training dataset and a validation dataset. In the validation dataset, data from 385 EPT and 491 VPT children from birth to age 6 years were analysed to calculate growth charts. RESULTS: The percentiles of length of EPT and VPT children were comparable to German reference percentiles. The BMI peak in infancy was attenuated, and BMI was lower in all the EPT and VPT children analysed. From 2 years until 6 years of age, head circumference was lower in EPT and VPT boys and girls. CONCLUSION: Deficits in height described in EPT cohorts born during the 1980 s and 1990 s were not seen in our cohort. However, EPT and VPT born children showed growth patterns that differed from national reference curves for BMI. The growth charts provided here can be used to judge the growth of EPT and VPT born children.

Aminoglycosides were associated with higher rates of surgical patent ductus arteriosus closure in preterm infants.

AIM: In animal studies, aminoglycosides induced ductus arteriosus relaxation in a dose-dependent fashion. We tested the hypothesis that antibiotic treatment of preterm infants with aminoglycosides is associated with higher rates of surgical patent ductus arteriosus (PDA) closure. METHODS: Preterm infants (birthweight <1000 grams or gestational age <29 weeks) enrolled in 62 German neonatal intensive care units (NICUs) were analysed. NICUs were stratified according to the use of aminoglycosides as first-line antibiotics. RESULTS: Baseline data were not different when NICUs using aminoglycosides (n = 9965 infants) were compared to NICUs using other antibiotics (n = 1948 infants). Rates of surgical PDA closure were 5.9% for NICUs using aminoglycosides; 6.2% for units using gentamicin; and 5.0% for NICUs using tobramycin compared to 4.1% in NICUs using other antibiotics (P < .001, P < .001 and P = .140, respectively, Fisher's exact test). Indomethacin and ibuprofen use was more common in NICUs using aminoglycosides (41% vs 33%, P < .001, Fisher's exact test). Gentamicin trough levels were higher in NICUs with surgical closure rates above the mean (median 2.0 µg/mL, inter-quartile range 0.8-4.0 µg/mL vs 1.2 µg/mL, IQR 0.8-1.7, P < .001, Mann-Whitney U test). CONCLUSION: First-line antibiotic treatment of preterm infants with aminoglycosides was associated with higher rates of surgical PDA closure.

Developmental outcome of extremely preterm infants is improved after less invasive surfactant application: Developmental outcome after LISA.

AIM: The aim of this study was to evaluate neurocognitive outcome at 24 months of corrected age after less invasive surfactant application (LISA) in preterm infants born at 23-26 weeks of gestational age. METHODS: Surviving participants of a LISA trial conducted in 13 German level III neonatal intensive care units were reviewed for assessment of developmental outcome, hearing and vision problems, growth and rehospitalisation days. Maternal depression, breastfeeding rates and socio-economic factors were evaluated as potentially confounding factors. RESULTS: In total, 156/182 infants took part in the study, 78 had received surfactant via LISA and 78 via endotracheal intubation. 22% of LISA infants compared to 42% of intubated infants had a psychomotor development index (PDI) <70 (0.012). A significant difference in mental development index (MDI) was observed in the stratum of more mature infants (25 and 26 weeks of GA). For this group, MDI < 70 was observed in 4% of LISA infants vs 21% of intubated infants (P = 0.008). CONCLUSION: At 24 months of age, the LISA-treated infants scored less often PDI < 70 and had similar results in MDI. Infants born at 25 and 26 weeks treated with LISA had lower rates of severe disability. LISA is safe and may be superior.

Vancomycin-induced ototoxicity in very-low-birthweight infants.

BACKGROUND: Vancomycin is an extensively used anti-infective drug in neonatal ICUs. However, exposure-toxicity relationships have not been clearly defined. OBJECTIVES: To evaluate the risk profile for hearing deficits in vancomycin-exposed very-low-birthweight infants (VLBWI). METHODS: In a large cohort study of the German Neonatal Network (GNN; n = 16 967 VLBWI) we assessed the association of vancomycin treatment and pathological hearing tests at discharge and at 5 year follow-up. We performed audits on vancomycin exposure, drug levels, dose adjustments and exposure to other ototoxic drugs in a subgroup of 1042 vancomycin-treated VLBWI. RESULTS: In the GNN cohort, 28% (n = 4739) were exposed to IV vancomycin therapy. In multivariable logistic regression analysis, vancomycin exposure proved to be independently associated with pathological hearing test at discharge (OR 1.18, 95% CI 1.03-1.34, P = 0.016). Among vancomycin-treated infants, a cumulative vancomycin dose above the upper quartile (>314 mg/kg bodyweight) was associated with pathological hearing test at discharge (OR 2.1, 95% CI 1.21-3.64, P = 0.009), whereas a vancomycin cumulative dose below the upper quartile was associated with a reduced risk of pathological tone audiometry results at 5 years of age (OR 0.29, 95% CI 0.1-0.8, P = 0.02, n = 147). CONCLUSIONS: Vancomycin exposure in VLBWI is associated with an increased, dose-dependent risk of pathological hearing test results at discharge and at 5 years of age. Prospective studies on long-term hearing impairment are needed.

Less invasive surfactant administration: best practices and unanswered questions.

PURPOSE OF REVIEW: The purpose of this review is to describe current concepts in the field of Less Invasive Surfactant Administration (LISA). The use of continuous positive airway pressure (CPAP) has become standard for the treatment of premature infants with respiratory problems throughout the world. However, if CPAP fails, technologies like LISA are needed that can combine surfactant delivery and spontaneous breathing with the support of noninvasive modes of ventilation. RECENT FINDINGS: LISA with thin catheters has been in use in Germany for more than 15 years. In the last 5 years, there was substantial interest in this method around the world. Randomized studies and recent metaanalyses indicate that the LISA technique helps to avoid mechanical ventilation especially in emerging respiratory distress syndrome (RDS). LISA is also associated with improved outcomes of preterm infants, specifically in the prevention of bronchopulmonary dysplasia (BPD) and intracranial hemorrhage (ICH). By now, a variety of different LISA catheters, devices and techniques have been described. However, most of the technologies are still connected with the unpleasant experience of laryngoscopy for the affected infants, so that the search for even less invasive techniques, for example, surfactant application by nebulization, goes on. SUMMARY: Maintenance of spontaneous breathing with support by the LISA technique holds big promise in the care of preterm infants. Patient comfort and lower complication rates are strong arguments to further investigate and promote the LISA approach. Open questions include exact indications for different patient groups, the usefulness of devices/catheters that have recently been built for the LISA technique and -- perhaps most urgently -- the issue of analgesia/sedation during the procedure. Studies on long-term outcome after LISA are under way.

Two-year outcome data suggest that less invasive surfactant administration (LISA) is safe. Results from the follow-up of the randomized controlled AMV (avoid mechanical ventilation) study.

Less invasive surfactant administration (LISA) is a method to deliver surfactant to spontaneously breathing premature infants via a thin catheter. Here we report the two-year outcome from the AMV (avoid mechanical ventilation) study, the first randomized controlled trial on this mode of surfactant delivery. No statistically significant differences in weight, length or neurodevelopmental outcome (Bayley II scores) were found between the LISA intervention group (n = 95) and the control group (n = 84) that received standard treatment.Conclusion: No differences in outcome were observed at 2 years. LISA seems safe in that aspect. What is Known: • LISA is a method that is in increasing use for surfactant delivery to spontaneously breathing infants. LISA reduces the need for mechanical ventilation. What is New: • Outcome data at 2 years from the first randomized study with LISA raise no safety concerns in comparison to a group of infants that received standard treatment.

The effect of less invasive surfactant administration on cerebral oxygenation in preterm infants.

AIM: To determine the regional cerebral tissue oxygenation saturation (rcSO2 ) in a group of infants requiring less invasive surfactant administration (LISA) as compared to infants with continuous positive airway pressure (CPAP) only. METHODS: In preterm infants with a gestational age 26 0/7-31 6/7 weeks, we conducted an observational study using near-infrared spectroscopy (NIRS) in the first 120 hours of life. RESULTS: We analysed the data of 22 infants who never received surfactant (CPAP), 22 infants had LISA and CPAP (LISA) and 6 infants received surfactant via endotracheal tube (ETT). Four infants had both surfactant application modes including six LISA applications. In total, there were 32 successful LISA applications but 44 attempts; 13/44 (30%) of LISA attempts resulted in a 20% decrease of rcSO2 . During the first 120 hours of life, rcSO2 values of CPAP were similar to those of infants in the LISA group, that is median rcSO2 values 90% vs 85%, respectively (P = .126). Episodes with rcSO2 values <65% were 0.4% in the CPAP group as compared to 4.8% in the LISA group (P < .001). CONCLUSION: Our observational data indicate that rcSO2 values of infants in the LISA group were similar to the CPAP group.

Mannose-binding lectin and mannose-binding protein-associated serine protease 2 levels and infection in very-low-birth-weight infants.

OBJECTIVE: The aim of this study was to explore the role of the lectin pathway in neonatal sepsis through the study of MBL and MASP2 levels and their relationship with infection in a cohort of very-low-birth-weight infants (VLBWI). METHODS: MBL and MASP2 were measured in plasma samples of n = 89 VLBWI using ELISA and correlated with clinical parameters. MBL plasma levels were aligned with genotyping data of mbl2 exon 1 polymorphisms, rs1800450, rs1800451, and rs5030737. RESULTS: MBL levels were clearly determined by MBL genotype, i.e., AA individuals had tenfold higher MBL levels than AO individuals. MBL and MASP2 levels did not correlate with gestational age, apart from MASP2 levels on day 7. During the first 21 days of life, we noted a gradual increase in both MBL and MASP2 levels. On day 7 of life, MASP2 levels in infants developing late-onset sepsis measured before the onset of symptoms were found to be lower, as compared to non-LOS infants. CONCLUSIONS: In our cohort of VLBWI, MBL levels were genetically determined, but not associated with gestational age or sepsis in the first 21 days of life. Lower MASP2 levels on day 7 may indicate increased risk for late-onset infection.

Necrotizing enterocolitis and high intestinal iron uptake due to genetic variants.

BackgroundIntestinal iron is a nutritional compound, which is essential for enteric microbiota. We evaluated the hypothesis that polymorphisms, which are known modifiers of intestinal iron uptake in adults, are associated with necrotizing enterocolitis (NEC) in preterm infants.MethodsPreterm infants (birth weight below 1,500 g) were studied. Single-nucleotide polymorphisms with known effects on serum iron levels (rs1800562, rs1799945, and rs855791) were determined using PCR. The effects of polymorphisms on NEC surgery were tested by Mendelian randomization. Outcome data were compared with χ2-test, Fisher's exact test, t-test, and Cochran-Armitage test for trend and multiple logistic regression analysis.ResultsComplete genotyping data were available for 11,166 infants. High serum iron levels due to rs855791 genotype were associated with a significantly reduced risk of NEC surgery (odds ratio (OR) 0.265; 95% confidence interval (CI) 0.11-0.65; adjusted P=0.011). Carriers of the rs855791 A-allele not receiving prophylactic probiotics had a higher risk of NEC surgery (OR 1.12, 95% CI 1.08-1.70, nominal P=0.002). Prophylactic treatment with probiotics was associated with a reduced risk of NEC surgery in carriers of the rs855791 A-Allele. No differences were found with regard to other short- or long-term outcome data.ConclusionPolymorphisms inducing lower intestinal iron uptake like the rs855791 A-allele might be an underestimated risk factor for NEC.

Treatment and outcome data of very low birth weight infants treated with less invasive surfactant administration in comparison to intubation and mechanical ventilation in the clinical setting of a cross-sectional observational multicenter study.

The aim of this study was to contribute further to existing randomized controlled trials and meta-analyses showing advantages in the outcome of less invasive surfactant administration (LISA)-treated infants and add new aspects concerning treatment and outcome data collected in the routine clinical setting. Four hundred seven very low birth weight infants who received surfactant via either LISA or intubation methods were enrolled in the observational cross-sectional multicenter study. To compare infants in terms of surfactant administration, we used an exact matching procedure (the same gestational age, severe perinatal depression (pH < 7.10), birth weight < 10th percentile, antenatal steroid treatment, and the same gender). To check for robustness, we performed repeated matching. LISA-treated infants required significantly less mechanical ventilation during hospital stay (p < 0.001) and days with supplemental oxygen (p = 0.03). Analgesics and sedatives were used less often during the stay (p < 0.001). Infants treated with LISA had significantly lower rates of bronchopulmonary dysplasia (p = 0.003). LISA failure infants were identified as more likely to be small for gestational age and more immature. CONCLUSION: Our study complements former results with advantages for LISA-treated infants in mechanical ventilation and bronchopulmonary dysplasia in the clinical routine. TRIAL REGISTRATION: DRKS00004589 What is Known: • According to existing literature, LISA-treated infants seem to have some favors in terms of treatment and outcome data. Observational studies in routine clinical setting are missing. What is New: • Data of 407 VLBW infants collected in routine clinical setting showed that LISA-treated infants needed less mechanical ventilation and fewer days with supplemental oxygen and less analgesics and sedatives. A reduced risk of BPD could be showed. SGA infants seem to have higher risks of LISA failure.

Prevalence of Congenital CMV Infection and Antiviral Therapy in Very-Low-Birth-Weight Infants: Observations of the German Neonatal Network.

BACKGROUND: To determine the prevalence of congenital CMV infection (cCMV) in very-low-birth-weight infants (VLBWI) and to evaluate epidemiological characteristics of VLBWI with antiviral therapy (AT). METHODS: CMV-specific PCR in umbilical cord tissue was performed (n=3330). Univariate analyses and logistic regression models were used to identify associations with outcome. RESULTS: 22/3330 VLBWI received AT (0.66%). 4 of these (0.12%) were PCR positive, with 2 VLBWI showing pathological screening for hearing loss. VLBWI with AT and negative PCR had significantly reduced mean birth weight (BW) and higher rates of small-for-gestational-age (SGA). Clinical sepsis, bronchopulmonary dysplasia (BPD), use of reserve antibiotics (RA) and treatment for retinopathy of prematurity were significantly increased. We further observed a higher need of transfusion of red blood cells (RBC), fresh frozen plasma and platelets. Logistic regression (controlled for gender, gestational age, SGA and BW) showed associations for AT and BPD (OR 3.4 [1.2-10.1], p=0.024), RA (OR 20.4 [4.2-98.9], p≤0.001), transfusions of RBC (OR 11.9 [1.3-105.7], p=0.026) and platelets (OR 8.7 [2.9-26.4], p≤0.001). DISCUSSION: All VLBWI with positive PCR received AT. We hypothesize from our data by assuming a postnatal aquired CMV infection in VLBWI with AT and negative PCR that VLBWI born SGA have a different risk profile. CONCLUSION: Further prospective studies concerning postnatal transmission should take VLBWI born SGA into account and should study the impact of infection on short- and long-term complications in this supposed vulnerable group.

Does Breastmilk Influence the Development of Bronchopulmonary Dysplasia?

OBJECTIVE: To assess whether breastmilk feeding is associated with a reduced risk of bronchopulmonary dysplasia (BPD). Secondary outcome measures analyzed were retinopathy of prematurity (ROP) and necrotizing enterocolitis (NEC). STUDY DESIGN: In an ongoing multicenter cohort study, the data of 1433 very low birth weight infants born before 32 weeks of gestation and discharged in 2013 were analyzed. We compared growth and neonatal complications of infants who received breastmilk exclusively (N = 223) with those who received formula feedings exclusively (N = 239). Logistic regression models were estimated for BPD, ROP, and NEC using nutrition as an independent variable. The Firth logistic regression model and Lasso were used for sensitivity analyses. RESULTS: Exclusively breastmilk-fed infants gained less weight compared with formula-fed infants. SDS for weight decreased between birth and discharge (median (Q1-Q3): formula -0.9 (-1.4 to [-0.5]) vs breastmilk -1.1 (-1.7 to [-0.6])). Exclusive formula feeding of very low birth weight infants was associated with increased risks of BPD (OR 2.6) as well as NEC (OR 12.6) and ROP (OR 1.80) after controlling for known risk factors. CONCLUSIONS: Exclusive breastmilk feeding was associated with lower growth rates and a reduced risk of BPD as well as NEC and ROP.

FUT 2 polymorphism and outcome in very-low-birth-weight infants.

BACKGROUND: To determine whether the secretor gene fucosyltransferase (FUT)2 polymorphism G428A is predictive for adverse outcomes in a large cohort of very-low-birth weight (VLBW) infants. METHODS: We prospectively enrolled 2,406 VLBW infants from the population-based multicenter cohort of the German Neonatal network cohort (2009-2011). The secretor genotype (rs601338) was assessed from DNA samples extracted from buccal swabs. Primary study outcomes were clinical sepsis, blood-culture confirmed sepsis, intracerebral hemorrhage (ICH), necrotizing enterocolitis (NEC) or focal intestinal perforation requiring surgery, and death. RESULTS: Based on the assumption of a recessive genetic model, AA individuals had a higher incidence of ICH (AA: 19.0% vs. GG/AG: 14.9%, P = 0.04) which was not significant in the additive genetic model (multivariable logistic regression analysis; allele carriers: 365 cases, 1,685 controls; OR: 1.2; 95% CI: 0.99-1.4; P = 0.06). Other outcomes were not influenced by FUT2 genotype in either genetic model. CONCLUSION: This large-scale multicenter study did not confirm previously reported associations between FUT2 genotype and adverse outcomes in preterm infants.

About the power of biostatistics in sibling analysis-comparison of empirical and simulated data.

The determination of potential sibship is a common task in routine kinship analysis, but often the putative parents are not available for analysis anymore. Then, a sibling analysis has to be conducted investigating only the potential siblings, thus reducing the power of the conclusion. In an attempt to determine meaningfulness of biostatistical calculations, 346 dizygotic twin pairs, 30 confirmed half siblings, and 112 unrelated people (to generate 6216 pair comparisons) were studied, all genetically typed using at least the Powerplex® 16 STRs. From every pair, the probabilities for a full sibship (identical parents) and half sibship (different fathers) were calculated using a commercially available computer program. Additionally, we simulated marker data for one million pairs of full sibs, half sibs, and unrelated persons each. Ninety-five percent of full sibling pairs demonstrated a likelihood ratio (LR) > 9 (W-value > 90 %) and less than 4% of these showed a LR < 3 (W-value < 75%) for full sibship after analysis of 15 STRs. The results for half siblings are less unambiguous. Here, only 57% achieved a LR > 9 and 23% a LR < 3. Regarding the unrelated pairs, more than 90% had a LR < 1/9 and only 2% reached a LR > 9. All in all, our results show that 15 to 20 STRs have sufficient power for analyses in kinship. Moreover, our data provide a statistical basis for the determination of the information content of a LR/W-value in a sibship case. Investigating an identical number of full siblings and unrelated pairs, it could be shown that 92% of pairs with a LR > 9 for full sibship probability really are full siblings. So, setting a cutoff level for full sibship at LR > 9, less than 10% of pairs will be wrongly assumed as full siblings even though they are unrelated.