Small for gestational age-cognitive performance from infancy to adulthood: an observational study.

OBJECTIVE: To determine whether cognitive performance from infancy to adulthood is affected by being born small for gestational age (SGA), and if this depends on the SGA reference used. Furthermore, to determine SGA's effect while considering the effects of very preterm/very low birthweight (VP/VLBW), socio-economic status (SES) and parent-infant relationship. DESIGN, SETTING AND POPULATION: A total of 414 participants (197 term-born, 217 VP/VLBW) of the Bavarian Longitudinal Study. METHODS: Small for gestational age was classified using neonatal or fetal growth references. SES and the parent-infant relationship were assessed before the infant was 5 months old. MAIN OUTCOME MEASURES: Developmental (DQ) and intelligence (IQ) tests assessed cognitive performance on six occasions, from 5 months to 26 years of age. RESULTS: The fetal reference classified more infants as SGA (<10th centile) than the neonatal reference (n = 138, 33% versus n = 75, 18%). Using linear mixed models, SGA was associated with IQ -8 points lower than appropriate for gestational age, regardless of reference used (95% CI -13.66 to -0.64 and 95% CI -13.75 to -1.98). This difference narrowed minimally into adulthood. Being VP/VLBW was associated with IQ -16 (95% CI -21.01 to -10.04) points lower than term-born participants. Low SES was associated with IQ -14 (95% CI -18.55 to -9.06) points lower than high SES. A poor parent-infant relationship was associated with IQ -10 points lower than those with a good relationship (95% CI -13.91 to -6.47). CONCLUSIONS: Small for gestational age is associated with lower IQ throughout development, independent of VP/VLBW birth, low SES or poor parent-child relationship. Social factors effects on IQ comparable to those of SGA and should be considered for interventions. TWEETABLE ABSTRACT: Small for gestational age is associated with lower cognitive performance from infancy to adulthood.

[Stillbirths in Germany: Retrospective Analysis of 168 Cases between 2003 and 2011]. / Totgeburten in Deutschland: Retrospektive Datenanalyse von 168 Fällen zwischen 2003 und 2011.

BACKGROUND: The decline in the incidence of stillbirths in Germany has remained static in recent years. This study aims to analyse the current situation of data documentation and examination of stillbirths. Furthermore, possible stillbirth prevention strategies should be developed. METHODS: Searches in the international peer-reviewed literature, retrospective data collection of 168 stillbirths in 8 hospitals, (in the area of Bonn) with subsequent statistical evaluation (descriptive statistics, t-test and binominal test) were undertaken. RESULTS: This study shows considerable deficits in data documentation, interdisciplinary communication and postmortal examination. Only in 51.8% (87/168) of the cases was a certain or uncertain cause of death found (42.3% placental, 1.2% foetal, 3.6% chromosomal, 4.8% umbilical cord abnormalities). Severe foetal growth restriction (<5(th) percentile) was observed in 29.2%; 44.9% (22/49) of them died at the age of ≥36+0 weeks of gestation. CONCLUSION: The first step to reduce the rate of stillbirths in Germany is to increase the identified causes of foetal death: Therefore, an interdisciplinary case report form was compiled to improve data collection and interdisciplinary collaboration. To standardise and complete postmortal management, an algorithm was created. The long-term aim is the development of a central data register for statistical analysis, to identify goals of research and to organise conferences with interdisciplinary reports of diagnostic findings.

Poor attention rather than hyperactivity/impulsivity predicts academic achievement in very preterm and full-term adolescents.

BACKGROUND: Very preterm (VP) children are at particular risk for attention deficit/hyperactivity disorder (ADHD) of the inattentive subtype. It is unknown whether the neurodevelopmental pathways to academic underachievement are the same as in the general population. This study investigated whether middle childhood attention or hyperactivity/impulsivity problems are better predictors of VP adolescents' academic achievement. METHOD: In a geographically defined prospective whole-population sample of VP (<32 weeks gestation) and/or very low birth weight (<1500 g birth weight) (VLBW/VP; n = 281) and full-term control children (n = 286) in South Germany, ADHD subtypes were assessed at 6 years 3 months and 8 years 5 months using multiple data sources. Academic achievement was assessed at 13 years of age. RESULTS: Compared with full-term controls, VLBW/VP children were at higher risk for ADHD inattentive subtype [6 years 3 months: odds ratio (OR) 2.8, p < 0.001; 8 years 5 months: OR 1.7, p = 0.020] but not for ADHD hyperactive-impulsive subtype (6 years 3 months: OR 1.4, p = 0.396; 8 years 5 months: OR 0.9, p = 0.820). Childhood attention measures predicted academic achievement in VLBW/VP and also full-term adolescents, whereas hyperactive/impulsive behaviour did not. CONCLUSIONS: Attention is an important prerequisite for learning and predicts long-term academic underachievement. As ADHD inattentive subtype and cognitive impairments are frequent in VLBW/VP children, their study may help to identify the neurofunctional pathways from early brain development and dysfunction to attention problems and academic underachievement.

Previable preterm premature rupture of membranes: 117 cases with neonatal outcomes in light of current research.

BACKGROUND: ppPROM < 24 + 0 weeks of gestation complicates < 1 % of all pregnancies but is responsible for significant maternal and neonatal morbidity. It is associated with 18-20% of perinatal deaths. OBJECTIVE: To evaluate neonatal outcome after expectant management in ppPROM in order to obtain evidence-based information for purposes of future counselling. METHODS: A single-centre, retrospective cohort study of 117 neonates born 1994 to 2012 after ppPROM < 24 weeks of gestation with a latency period > 24 hours and admission to the NICU of the Department of Neonatology, University of Bonn. Data of pregnancy characteristics and neonatal outcome were collected. The results were compared to those found in the literature. RESULTS: The mean gestational age at ppPROM was 20.45±2,9 weeks (range 11 + 2 -22 + 6) with a mean latency period of 44.7±34.8 days (range 1-135). Mean gestational age at birth was 26.77±3.22 weeks (range 22 + 2-35 + 3). 117 newborns were admitted to the NICU, the overall survival rate at discharge was 72.6% (85/117). Non-survivors had a significantly lower gestational age and higher rates of intra-amniotic infections. The most common neonatal morbidities were RDS (76.1%), BPD (22.2%), pulmonary hypoplasia (PH) (14.5%), neonatal sepsis (37.6%), IVH (34.1% all grades, 17.9% grades III/IV), NEC (8.5%) and musculoskeletal deformities (13.7%). Mild growth restriction as a new complication of ppPROM was observed. CONCLUSIONS: Neonatal morbidity after expectant management is similar to that described for infants without ppPROM, but carries a higher risk of pulmonary hypoplasia and mild growth restriction.

Familial translocation t(6;20)(p21;p13) resulting in partial trisomy 6p and partial monosomy 20p: report of a new case and review of the literature.

Carriers of completely balanced chromosomal translocations have all necessary genetic information. Nevertheless, because of the possibility of maldistribution during gametogenesis, they are at increased risk for infertility, miscarriage, stillbirth or having a child with congenital anomalies including mental retardation. As postnatal clinical reports are infrequent, prediction of clinical course for specific unbalanced karyotypes diagnosed during pregnancy remains difficult. Here, we report the 6th case of partial trisomy 6p and partial monosomy 20p due to an unbalanced adjacent-1 segregation of the rare familial translocation t(6;20)(p21;p13). We give a thorough clinical description of the present case, demonstrating broad phenotypic overlap with the 5 previously published cases reviewed here, providing important data on postnatal outcome.

Rational diagnostic strategies for Lyme borreliosis in children and adolescents: recommendations by the Committee for Infectious Diseases and Vaccinations of the German Academy for Pediatrics and Adolescent Health.

The varying clinical manifestations of Lyme borreliosis, transmitted by Ixodes ricinus and caused by Borrelia burgdorferi, frequently pose diagnostic problems. Diagnostic strategies vary between early and late disease manifestations and usually include serological methods. Erythema migrans is pathognomonic and does not require any further laboratory investigations. In contrast, the diagnosis of neuroborreliosis requires the assessment of serum and cerebrospinal fluid. Lyme arthritis is diagnosed in the presence of newly recognized arthritis and high-titer serum IgG antibodies against B. burgdorferi. The committee concludes the following recommendations: Borrelial serology should only be ordered in case of well-founded clinical suspicion for Lyme borreliosis, i.e., manifestations compatible with the diagnosis. Tests for borrelial genomic sequences in ticks or lymphocyte proliferation assays should not be ordered. When results of such tests or of serological investigations that were not indicated are available, they should not influence therapeutic decisions. Laboratories should be cautious when interpreting results of serological tests and abstain from giving therapeutic recommendations and from proposing retesting after some time without intimate knowledge of patient's history and disease manifestations.

Successful management of an MRSA outbreak in a neonatal intensive care unit.

We report an MRSA outbreak in our 25-bed tertiary neonatal intensive care unit (NICU), which was successfully contained. Methods include a retrospective review of patient files, microbiology records and meeting protocols. During the seven months of outbreak, 27 patients and seven health care workers (HCWs) had positive cultures for MRSA. The outbreak was caused by the epidemic Rhine-Hessen strain; cultured isolates were monoclonal. After a sharp increase of the number of new MRSA-cases the installation of an outbreak management team (OMT) and implementation of comprehensive measures (extensive screening and decolonization strategy including orally applied vancomycin, isolation wards, intensive disinfection regimen) successfully terminated the outbreak within one month. Ten (53%) of 19 patients with completed follow-up and all of the HCWs were decolonized successfully. Gastrointestinal colonization was present in 15 of 27 (56%) neonates, and was associated with poor decolonization success (30% vs. 78% in absence of gastrointestinal colonization). A comprehensive outbreak management can terminate an outbreak in a NICU setting within a short time. Thorough screening of nares, throat and especially stool is necessary for correct cohorting. Gastrointestinal decolonization in neonates seems difficult.

Clinical characteristics of viral intestinal infection in preterm and term neonates.

The clinical presentation of the viral enteric pathogens in newborn infants has not been adequately examined. The aim of this study was to evaluate the clinical characteristics of viral intestinal infections in newborn infants. Clinical data of all term and preterm infants admitted to our tertiary neonatal intensive care unit from 1998 to 2007 with clinical signs of gastroenteritis (GE) or necrotizing enterocolitis (NEC) were retrospectively reviewed and compared between infants with different viral enteric pathogens in stool specimens. In 34 infants with signs of GE or NEC, enteropathogenic viruses were found in stool specimens. Rotavirus was detected in 12 cases, of which two infants had NEC. Compared with infants with rotavirus or norovirus, infants with astrovirus more frequently suffered from NEC (p<0.05). In addition, an acute systemic inflammatory response was significantly more common in patients with astrovirus infection (astrovirus vs. rotavirus and astrovirus vs. norovirus, p < 0.01 and p < 0.05, respectively). Of eight children infected with norovirus, one infant had a systemic acute inflammatory response and NEC. This study demonstrates that in newborn infants, intestinal rotavirus, norovirus, and astrovirus infections may be associated with severe illness such as hemorrhagic enteritis resulting in bloody diarrhea or even NEC.

ARDS as presenting symptom in an infant with CD40L deficiency (Hyper-IgM syndrome Type 1).

We report on a 4 month old male infant with respiratory syncytial virus (RSV) infection leading to acute respiratory distress syndrome (ARDS). A diagnostic algorithm including extended infectiological and immunological work-up revealed absence of CD40-ligand. ARDS was treated successfully with a complex respiratory therapy plus intravenous immunoglobulin substitution. Molecular analysis detected mutations in the CD40L gene (Hyper-IgM syndrome Type 1). The case underlines the importance of an extended diagnostic work-up in an uncommonly severe course of respiratory infection in early infancy.

Oral valganciclovir for symptomatic congenital cytomegalovirus infection in an extremely low birth weight infant.

Cytomegalovirus (CMV) infection is the most important congenital viral infection. Intravenous (i.v.) Ganciclovir (GCV) improved outcome in term infants with symptomatic congenital CMV infection. We present data on oral valganciclovir (VGCV) in an extremely low birth weight infant. A male preterm infant was delivered at 28 weeks of gestation because of abnormal fetal perfusion with severe intrauterine growth retardation. The infant developed hepatitis and a severe thrombocytopenia. Serology revealed a positive CMV IgM in maternal serum 3 days after delivery and CMV DNA was detected in plasma and urine samples of the infants. Treatment with i.v. GCV was started at day 4 of life for 35 days and continued with oral VGCV for further 6 weeks. Plasma GCV levels were 1.68 ng ml(-1) (peak) and 0.92 ng ml(-1) (trough) on day 10 of oral treatment. Clinical signs resolved and virus load decreased slowly during therapy. At discharge brain stem-evoked audiometry was normal. Oral treatment with VGCV in an extremely low birth weight preterm infant with congenital CMV infection resulted in adequate GCV plasma levels, reduced effectively the CMV viral load and was well tolerated without apparent adverse effects.

The association of children's mathematic abilities with both adults' cognitive abilities and intrinsic fronto-parietal networks is altered in preterm-born individuals.

Mathematic abilities in childhood are highly predictive for long-term neurocognitive outcomes. Preterm-born individuals have an increased risk for both persistent cognitive impairments and long-term changes in macroscopic brain organization. We hypothesized that the association of childhood mathematic abilities with both adulthood general cognitive abilities and associated fronto-parietal intrinsic networks is altered after preterm delivery. 72 preterm- and 71 term-born individuals underwent standardized mathematic and IQ testing at 8 years and resting-state fMRI and full-scale IQ testing at 26 years of age. Outcome measure for intrinsic networks was intrinsic functional connectivity (iFC). Controlling for IQ at age eight, mathematic abilities in childhood were significantly stronger positively associated with adults' IQ in preterm compared with term-born individuals. In preterm-born individuals, the association of children's mathematic abilities and adults' fronto-parietal iFC was altered. Likewise, fronto-parietal iFC was distinctively linked with preterm- and term-born adults' IQ. Results provide evidence that preterm birth alters the link of mathematic abilities in childhood and general cognitive abilities and fronto-parietal intrinsic networks in adulthood. Data suggest a distinct functional role of intrinsic fronto-parietal networks for preterm individuals with respect to mathematic abilities and that these networks together with associated children's mathematic abilities may represent potential neurocognitive targets for early intervention.

Analysis of the stepwise clinical introduction of experimental percutaneous fetoscopic surgical techniques for upcoming minimally invasive fetal cardiac interventions.

BACKGROUND: This study assessed the feasibility and safety of surgical techniques developed in sheep for fetoscopic fetal cardiac interventions during three selected less complex procedures for noncardiac fetal conditions in humans. On the basis of this assessment, the implications for the clinical introduction of minimally invasive fetoscopic fetal cardiac interventions in the near future are discussed. METHODS: The authors performed 16 percutaneous fetoscopic procedures in 13 human fetuses at between 19 + 2 and 34 + 6 weeks of gestation, then analyzed various parameters of surgical relevance for minimally invasive fetoscopic fetal cardiac interventions. Each of the three noncardiac malformations posed typical surgical challenges that will be critical for the technical success of minimally invasive fetoscopic cardiac interventions. RESULTS: Overall technical success was achieved in 14 of the 16 procedures. Percutaneous fetoscopic surgery did not result in any untoward effects and was well tolerated by all but two pregnant women: one with bleeding complication and one with mild postoperative pulmonary edema. No fetal complications or injuries from the various percutaneous fetoscopic surgical approaches were observed. CONCLUSIONS: The author's experience with surgical techniques introduced for percutaneous fetoscopic fetal cardiac intervention in selected noncardiac fetal lesions has led them to believe the time has come for the clinical introduction of fetoscopic fetal cardiac interventions. After an adequate learning curve supervised by committees of human research, the overall outcome and quality of postnatal life for the unborn patients ultimately will determine whether fetoscopic or other fetal cardiac interventions will be better therapeutic alternatives to currently available postnatal procedures.

Extensive and interrelated subcortical white and gray matter alterations in preterm-born adults.

Preterm birth is a leading cause for impaired neurocognitive development with an increased risk for persistent cognitive deficits in adulthood. In newborns, preterm birth is associated with interrelated white matter (WM) alterations and deep gray matter (GM) loss; however, little is known about the persistence and relevance of these subcortical brain changes. We tested the hypothesis that the pattern of correspondent subcortical WM and GM changes is present in preterm-born adults and has a brain-injury-like nature, i.e., it predicts lowered general cognitive performance. Eighty-five preterm-born and 69 matched term-born adults were assessed by diffusion- and T1-weighted MRI and cognitive testing. Main outcome measures were fractional anisotropy of water diffusion for WM property, GM volume for GM property, and full-scale IQ for cognitive performance. In preterm-born adults, reduced fractional anisotropy was widely distributed ranging from cerebellum to brainstem to hemispheres. GM volume was reduced in the thalamus, striatum, temporal cortices, and increased in the cingulate cortices. Fractional anisotropy reductions were specifically associated with GM loss in thalamus and striatum, with correlation patterns for both regions extensively overlapping in the WM of brainstem and hemispheres. For overlap regions, fractional anisotropy was positively related with both gestational age and full-scale IQ. Results provide evidence for extensive, interrelated, and adverse WM and GM subcortical changes in preterm-born adults. Data suggest persistent brain-injury-like changes of subcortical-cortical connectivity after preterm delivery.

Response to diphtheria and tetanus booster vaccination in pediatric renal transplant recipients.

BACKGROUND: Although inactivated vaccines are recommended for immunocompromized patients, efficacy and safety of diphtheria and tetanus immunization in renal transplant recipients have received little attention so far. The aim of the study was to investigate the response to a standard diphtheria and tetanus booster vaccination in pediatric renal transplant recipients. METHODS: Forty-two children, median age 13.2 years (range, 7.8-18.9 years) with complete primary immunization 9.2 years (0.9-15.4 years) before transplantation were enrolled. Immunosuppression consisted of cyclosporine plus prednisolone in 15 (36%), cyclosporine, azathioprine, and prednisolone in 24 (57%), and tacrolimus plus prednisolone in 3 (7%). Antibodies were measured by enzyme-linked immunosorbent assay before and 1, 6, and 12 months after vaccination. RESULTS: Before vaccination, protective antibody concentrations exceeding 0.1 IU/ml against diphtheria were found in 16 children (38%). Thirty-eight (90%) had protective antibody concentrations against tetanus. After booster immunization, the protection rate against diphtheria rose to 95% at 1 month with a decline to 93% at 6 and 76% at 12 months. Protection against tetanus was complete after vaccination and persisted over the observation. Antibody concentrations were comparable to those reported for healthy children. Statistical analysis showed no influence of allograft function, immunosuppressive regimen, previous cytotoxic therapy, or time between primary immunization and end-stage renal failure on antibody response. Immunization was well tolerated and kidney function remained unaffected in patients with stable allograft function. CONCLUSIONS: Diphtheria and tetanus vaccination can be performed effectively and safely in renal transplant recipients as generally recommended.

Interleukin-6: a sensitive parameter for the early diagnosis of neonatal bacterial infection.

OBJECTIVE: Early recognition is important for the successful treatment and outcome of neonatal infections. As interleukin-6 (Il-6) plays a critical role in the induction of C-reactive protein (CRP) synthesis in the liver, it was hypothesized that this cytokine could be detected earlier in blood than the CRP during the course of bacterial infection. DESIGN: In a prospective study of 298 newborns who were admitted to the nursery unit, CRP levels, blood cell count with differential, and Il-6 levels were determined at the time of admission and 24 hours after admission. Seventy-six newborns were excluded from the study because of incomplete or incorrect blood sampling. RESULTS: The remaining 222 newborns were assigned to one of five groups: 11 newborns with blood culture-positive sepsis (sensitivity of Il-6 on admission 73%), 15 newborns with clinical sepsis (sensitivity of Il-6 on admission 87%), 41 newborns with infection (sensitivity of Il-6 on admission 68%), and 54 newborns without clinical and laboratory evidence of infection (specificity 78%). The remaining 101 newborns were defined as a mixed group because the diagnosis of neonatal infection could not clearly be made. Seventy-five percent of infected newborns had negative Il-6 levels 24 hours after admission. Of the 18 infected newborns with negative Il-6 levels on admission, 10 newborns had elevated CRP levels, suggesting that Il-6 was already negative because of the short half-life of Il-6. Sensitivity of Il-6 in CRP-negative newborns on admission was 100% in newborns with blood culture-positive and clinical sepsis. Il-6 was more sensitive than CRP in infected newborns on admission (73% vs 58%). CONCLUSION: Il-6 is a sensitive parameter for diagnosing neonatal bacterial infection. The combination of CRP and Il-6 seems to be the ideal tool for the early diagnosis of neonatal infection.

In vitro studies on clonal growth of chondrocytes in thanatophoric dysplasia.

Thanatophoric dysplasia (TD) is characterized by a disorganized growth plate with markedly reduced proliferative and hypertrophic cartilage zones. Therefore, we studied in vitro the proliferation rates of articular chondrocytes from five TD patients and age-matched controls in response to bFGF, IGF-I, IGF-II, and TGF-beta 1. In human fetal controls bFGF was the most potent growth factor. Clonal growth the articular chondrocytes in response to bFGF was reduced in two of five TD patients and slightly below the range of controls in a third case. Stimulation of chondrocyte proliferation by IGF I and II was reduced in the patient whose response to bFGF was most markedly impaired. The effect of TGF-beta 1 ranged from normal to slightly elevated values in TD fetuses. These results indicate heterogeneity of the underlying defects in TD. Low proliferative responses of chondrocytes to bFGF and IGF-I/II are likely to play a key role in the pathogenesis of some cases. In two of five patients studied, the mechanisms of bFGF and IGF-signal transduction are candidates for the primary molecular defect.

Yunis-Varon syndrome: evidence for a lysosomal storage disease.

We present clinical and neuropathological findings in a female infant with Yunis-Varon syndrome (YVS) comprising absence of thumbs and halluces, aphalangia of fingers and toes, hypoplasia of clavicles, severely undermineralized skeleton (especially skull), microcephaly, and multiple nonskeletal anomalies. The patient also had a Dandy-Walker malformation, hydrocephalus, and hypertension, which were not reported previously in YVS. The infant excreted an abnormal unidentified oligosaccharide. The patient died at day 108 with severe neurological impairment. Autopsy showed prominent intraneuronal inclusions with vacuolar degeneration, mainly in the thalamic, dentate nuclei, cerebellar cortex, and inferior olivary nuclei. No storage phenomena were observed in other tissues. These findings strongly suggest that a lysosomal storage disorder is involved in the pathogenesis of Yunis-Varon syndrome.

Antiretroviral therapy in sporadic adult amyotrophic lateral sclerosis.

Clinical and experimental findings in idiopathic amyothrophic lateral sclerosis (ALS) would be compatible with a retroviral involvement. In 35 adult patients with non-familial ALS we observed elevated circulating immune complexes, a decrease in IgG3 isotype and enzyme-linked sorbent assay (ELISA) serum antibodies against human spuma retrovirus (HSRV), confirmed by specific human foamy virus immunoblots. All 35 were negative for IgM or relevant IgG anti-ganglioside antibodies. We treated 12 HIV-negative, immune-complex-positive ALS patients with 500 mg d-1 zidovudine p.o. over 2-10 months and found reductions of serum creatine kinase and circulating immune complexes from two days to two weeks after the beginning of medication.