Angiotensin II receptor blocker induced fetopathy: 7 cases.

BACKGROUND: During a period of 12 months 7 newborns with a partially severe fetopathy caused most probably by maternal sartan-intake in pregnancy were treated in 5 German teaching hospitals. Sartans antagonize the effect of angiotensin II at the AT1-receptor and are used to treat arterial hypertension. METHOD: We presented 2 cases at the yearly GNPI meeting 2010 and we were informed about similar cases in other German teaching hospitals which we brought together in this publication. RESULTS: In the presented cases, maternal sartan intake was noticed at different times in pregnancy and was in part discontinued some weeks before delivery. In all pregnancies oligohydramnios was present and fetal kidneys displayed a hyperechogenic structure on ultrasound. The newborns' postnatal course varied: oligohydramnios sequence with lung hypoplasia, arterial hypotension and renal insufficiency were the predominant problems of the first days of life. The majority (4/7) of infants did not survive this period, in other cases there was a complete (1/7) recovery of renal function whereas others survived with renal impairment (2/7), in part requiring chronic dialysis. Further distinctive features seen frequently were disturbances of cranial ossification and flaccid paralysis of hands and feet with deviations as well as sensorineural hearing loss. CONCLUSION: These case reports again underline the hazardousness of maternal sartan intake with potential fatal outcome for the newborn. Though the use of sartans in pregnancy is contraindicated and several case reports of sartan induced fetopathies exist, the risk of sartan treatment generally seems to be underestimated.

Surfactant without intubation in preterm infants with respiratory distress: first multi-center data.

BACKGROUND: Recently in a report of a single center a method has been described to apply surfactant via a thin endotracheal catheter to very low birth weight infants spontaneously breathing with nasal continuous positive airway pressure. We now analyzed available multicenter data. PATIENTS AND METHODS: In a multicenter study investigating genetic risk factors, clinical and outcome data and data of antenatal and postnatal treatment of infants with a birth weight below 1,500 g were prospectively recorded. The measures of infants treated with the new method of surfactant application were compared to those of infants who received standard care. The analysis was restricted to infants with a gestational age below 31 weeks (n=1,541). RESULTS: 319 infants were treated with the new method and 1,222 with standard care. The need for mechanical ventilation during the first 72 h (29% vs. 53%, p<0.001), the rate of bronchopulmonary dysplasia defined as oxygen at 36 weeks of postmenstrual age (10.9 % vs. 17.5%, p=0.004) and the rate of death or bronchopulmonary dysplasia were significantly lower in the treatment group than in the standard care group. Surfactant, theophyllin, caffeine and doxapram were significantly more often and analgetics, catecholamines and dexamethasone were significantly less frequently used in the treatment group. CONCLUSIONS: A new method of surfactant application was associated with a lower prevalence of mechanical ventilation and better pulmonary outcome. A prospective controlled trial is required to determine whether this approach is superior to standard care.

Polymorphisms in the Renin-Angiotensin system and outcome of very-low-birthweight infants.

BACKGROUND: The insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE-ins/del) and the angiotensin II type 1 receptor 1166A/C polymorphism (ATR1166A/C) were reported to be associated with several unfavorable outcome parameters in preterm infants like bronchopulmonary dysplasia, persistent ductus arteriosus and impaired insulin sensitivity. OBJECTIVE: To confirm the above-mentioned associations in a large cohort of very-low-birthweight (VLBW) infants. METHOD: Clinical data of VLBW infants were prospectively recorded. The ACE-ins/del polymorphism and the ATR1166A/C polymorphism were determined by polymerase chain reaction in 1,209 and 1,168 infants, respectively. RESULTS: There was no significant association between ACE-ins/del or ATR1166A/C genotype and outcome parameters (death, intraventricular hemorrhage, sepsis, bronchopulmonary dysplasia, ventilation, supplemental oxygen at discharge, postnatal treatment with insulin, surgery for intestinal perforation/necrotizing enterocolitis/retinopathy of prematurity/persistent ductus arteriosus. CONCLUSION: Both known functional polymorphisms of the renin-angiotensin system do not seem to be associated with the outcome of VLBW infants.

Very low birth weight infants have only few adverse events after timely immunization.

INTRODUCTION: Premature infants should be vaccinated at the appropriate vaccinating age, without correcting for their gestational week and regardless of their weight. Uncertainty with regard to possible severe adverse events exists among physicians. METHODS: In all, 473 patients with a birth weight under 1500 g were included in a prospective observational study for adverse events that included cardiorespiratory events, local reactions and fever. Three vaccination combinations were used at different time periods. RESULTS: The median birth weight was 910 (375 to 1495) g. Gestational week at birth was 27.6 (22.6 to 34.3). At the time of vaccination, the gestational week was 37.4 (31.5 to 48.3). The frequency of adverse events for local reactions/fever was 2.8% and for apnea/bradycardia it was 10.8%. Apnea appeared significantly more often in children who were younger at the time of immunization. This is in concordance with the fact that they were also younger at birth. If apnea appeared, the chance of the development of bradycardia had an odds ratio of 6.4 (3.2:13.0). Children with higher-grade hemorrhages and/or with periventricular leukomalacia did not experience more adverse events, except fever. CONCLUSION: Timely vaccination of premature infants with a birth weight under 1500 g is safe, but the occurrence of cardiorespiratory events is related to earlier gestational week.

[Newborn metabolic screening]. / Analyse der Zeitabläufe des Neugeborenenscreenings.

BACKGROUND: Guidelines for neonatal screening for inborn errors of metabolism published by the Federal Joint Committee of physicians and health insurances in Germany include preanalytical specifications, e. g. blood collection at 36 to 72 hours of life and rapid sample transportation which is necessary with respect to those target diseases of the German program that might lead to very early metabolic decompensation. METHODS AND RESULTS: Analysis of 149 854 data sets containing all necessary informations out of a total of 173 221 screening samples sent to our laboratory from April 2006 to the end of March 2007 showed significant discrepancies between the requested and the actual times recorded for blood collection. 11.5 % of samples were drawn later than required. Looking at outpatients only, 43 % of the samples were taken after 72 hours. Sample shipping was delayed in several hospitals and private practises, especially on weekends. This was the reason why 31.2 % of all samples could not be reported on within 72 hours after blood collection as required. In addition the quality of 914 samples (0.52 %) was insufficient so that a repeat sample had to be analysed. CONCLUSION: In the future, as a rule, every baby should have his/her blood taken around the 48th hour, in any case between the 36th and 72nd hour of life. Moreover, sample shipping needs to be optimised in order to guarantee early diagnosis of inborn errors of metabolism. Also, more attention has to be paid to the quality of blood samples.

Prevalence of two tumor necrosis factor gene polymorphisms in premature infants with early onset sepsis.

BACKGROUND: Tumor necrosis factor (TNF) is a central mediator of sepsis. The NcoI polymorphism within the TNF locus has been described as a prognostic marker for mortality in adult patients with sepsis. OBJECTIVES: The aim of our study was to investigate the genotype and allele distribution of 2 TNF gene polymorphisms in preterm infants <32 weeks of gestational age, who developed early-onset sepsis. METHODS: A double-blinded retrospective cohort study was carried out on stored Guthrie blood spot cards with group A including 67 premature infants <32 weeks of gestational age with proven early-onset sepsis and group B including 102 healthy newborn infants (>32 + 0 weeks of gestation). The genotype andallele distribution of the study population were also compared to reference groups of healthy adult volunteers (n = 252 for TNF-beta NcoI and n = 233 for -308 TNF-alpha promoter). Polymorphisms of the TNF-alpha promoter -308 region and the NcoI site of the TNF-beta gene were assessed using PCR followed by melting curve analysis or NcoI digestion. The groups were compared by estimation of Hardy-Weinberg equilibrium. RESULTS: The overall allele frequency and genotype distribution of the -308 TNF-alpha and NcoI polymorphism of the TNF-beta gene were comparable to the values found in the controls. CONCLUSION: The study results suggest that none of the analyzed TNF gene polymorphisms may serve as a prognostic marker for preterm infants at high risk of sepsis.

Interleukin-6-174-genotype, sepsis and cerebral injury in very low birth weight infants.

We investigated the association between the interleukin 6 (IL-6)-174-genotype and unfavorable outcomes in preterm infants since it has been reported that the IL-6-174GG-genotype is associated with increased susceptibility to sepsis, and the IL-6-174CC-genotype is more common in preterm infants with severe intraventricular hemorrhage (IVH). We studied 1206 preterm infants with a birth weight below 1500 g. In contrast to previously published data, the frequency of IVH grade IV, periventricular leukomalacia, ventricular-peritoneal-shunting or death was not different between infants with different IL-6-genotypes: IL-6-174GG (n = 430) 8%, IL-6-174GC (n = 605) 9% and IL-6-174CC (n = 167) 12% (P = 0.2 for IL-6-174CC vs GG + GC). Furthermore, we were not able to confirm previously reported association between sepsis and the IL-6-174GG-genotype. Blood-culture-proven sepsis occurred in 19% of IL-6-174GG-carriers (n = 157), 26% of IL-6-174GC-carriers (n = 193) and 27% of infants carrying the IL-6-174CC-genotype (n = 67). We were not able to confirm previously reported associations between sepsis, cerebral injury and the IL-6-174-genotype in VLBW-infants.

Polymorphisms of genes involved in innate immunity: association with preterm delivery.

An altered inflammatory activity due to functionally relevant polymorphisms of the innate immune system may influence pathways leading to labour and, therefore, impact on the frequency of preterm birth. We examined five polymorphisms of the innate immune system in a large cohort of preterm very-low-birth-weight (VLBW, n = 909) and term-born infants (n = 491) and their mothers (n = 747). The primary outcome was preterm versus term birth. Frequencies of polymorphisms in mothers of term-born infants versus mothers of VLBW infants and term infants versus preterm VLBW infants (singletons) are given. Homozygous CD14-159T: 18.5 versus 21.8% (mothers) and 19.6 versus 21.2% (infants). Homozygous interleukin IL-6-174G: 28.8 versus 38% (P = 0.018, mothers) and 30 versus 32.7% (infants). Homozygous or heterozygous nuclear oligomerization domain NOD2-3020insC: 6.9 versus 6.1% (mothers) and 5.7 versus 5.1% (infants). Heterozygous or homozygous toll-like-receptor TLR2-Arg753Gln: 6.9 versus 6.1% (mothers) and 5.7 versus 5.1% (infants). Homozygous or heterozygous TLR4-896G: 8.1 versus 11.5% (mothers) and 11.6 versus 10.5% (infants). Although the homozygous maternal IL-6-174G genotype was found to be independently associated with preterm delivery in multivariate regression analysis, the incidence of intrauterine infection was not significantly increased in mothers of preterm VLBW-infants, carrying this or other polymorphisms of the innate immune system. The overall influence of the investigated polymorphisms on the development of preterm delivery seems moderate, since only the maternal IL6-174G genotype was associated with preterm birth and none of the polymorphisms were associated with intrauterine infection as the cause of preterm birth.

[Strategies for the diagnosis and treatment of prenatal toxoplasmosis - a survey]. / Strategien zur Diagnostik und Behandlung der pränatalen.

Today, a decreasing number of infants with prenatal toxoplasmosis present with clinical signs of severe, generalised infection and cerebral involvement. The favourable clinical outcome - mild or subclinical infection - is considered to be an effect of early maternofetal treatment with spiramycin and pyrimethamine/sulfadiazine (PS). However, a Cochrane Review and a recently published European multicentre study on congenital toxoplasmosis did not only question this positive effect but also the efficiency of a postnatal long-term therapy. Both studies caused much confusion among neonatologists and paediatricians. The new setting requires an update of the diagnostic possibilities and different therapeutic strategies for prenatal toxoplasmosis. Only few prospective studies are available to compare the efficiency of different drug regimens in infected infants. However, clinical data demonstrate that the available therapeutics are not curative and cannot prevent late sequelae. Follow-up studies in pregnant women and their offspring show that prenatal parasite detection does not predict an unfavourable clinical outcome when treatment is initiated early after diagnosis. In Germany, prenatal screening is not obligatory. In case of primary maternal infection, materno-fetal therapy is recommended. A combination therapy consisting of PS is considered more effective than a spiramycin monotherapy. Treatment is recommended for all infected newborns with different strategies for infants with or without clinical symptoms. The treatment strategies of different European countries are discussed. This paper provides recommendations for the diagnosis and treatment of newborn toxoplasmosis and materno-fetal infection as well as recommendations for the clinical management of infected neonates and their follow-up, including drug monitoring.

[Heart failure caused by myocardial hypertrophy in diabetic fetopathy]. / Herzinsuffizienz infolge Myokardhypertrophie bei diabetischer Fetopathie.

Diabetic fetopathy is still a common clinical problem correlated with a high morbidity of the neonate. These children are often macrosome, suffer from respiratory distress syndrome due to delayed lung maturity, acidosis, hypoglycaemia, electrolyte-imbalances and polycythaemia. We describe a male neonate with diabetic fetopathy as a result of gestational diabetes of the mother. In addition to the symptoms described above, our patient clinically presented with severe hypertrophy of the right ventricle associated with intrauterine heart failure. The boy was born with serious prenatal asphyxia which made initial neonatal intensive care treatment necessary. The hypertrophic cardiomyopathy normalized within 6 weeks after birth without further treatment. Different causes of a hypertrophic cardiomyopathy (infections, metabolic disorders, neurologic affections, syndromes) could be ruled out, so that the diabetic fetopathy was the most probable cause for the condition. If we are looking at the heart only, this case-report suggests a good prognosis of septumhypertrophy as well as right ventricular hypertrophy in patients with diabetic fetopathy. The case also elucidates that not only the diabetes type I can entail serious fetal damage but also gestational diabetes can. Therefore, in suspect mothers screening for gestational diabetes should be expanded to oral glucose tolerance testing.

[Pre- and postnatal diagnosis and treatment of hydrops fetalis--an interdisciplinary problem]. / Prä- und postnatale Diagnostik und Behandlung des Hydrops fetalis--ein interdisziplinäres Problem.

Hydrops fetalis (HF) is diagnosed prenatally in one out of 600 pregnancies, thirty percent of these fetuses will die in utero. Post partum, one out of approximately 25,000 newborn infants is affected. With the introduction of Rhesus immunoprophylaxis only fifty percent of the cases with HF are caused by Rhesus hemolytic disease. There is a large variety of non-immunological reasons such as cardiac defects (hypoplastic left healt syndrome, atrio-ventricular canal), arrhythmias, cytomegalovirus- or parvovirus infection (9% HF), twin-to-twin transfusion syndrome (15-30% HF) or chromosomal abnormalities (28-45% HF). However, in one third of the non immunological cases of HF the etiology remains unclear. Early diagnosis by ultrasound scan faces both the obstetrician and the neonatologist with the problem of differential diagnosis as well as therapeutic options, respectively. Various diagnostic procedures such as fetal echocardiography, karyotyping, molecular genetic techniques and sophisticated serological testings will help to classify the etiology and to determine the pre- and postnatal management. Nevertheless, neonatal mortality still varies between 50 and 95%.

High-versus low-dose erythropoietin in extremely low birth weight infants. The European Multicenter rhEPO Study Group.

OBJECTIVE: To investigate whether a weekly 1500 IU/kg dose of recombinant human erythropoietin (rhEPO) is more effective than a dose of 750 IU/kg/week in preventing anemia and reducing the transfusion need in infants with birth weights less than 1000 gm. STUDY DESIGN: In a randomized, double-blind, multicenter trial, 184 infants with birth weights between 500 and 999 gm were treated with either rhEPO 750 (low-dose group) or 1500 IU/kg/week (high-dose group) from day 3 of life until 37 weeks' corrected age. RESULTS: Thirty-two percent of the infants in each group did not receive any transfusion during the treatment period. The total volume of erythrocytes received was similar in each group. The success rate, defined as no transfusion needed and hematocrit value 0.30 L/L or greater, was 27.6% in the low-dose and 29.5% in the high-dose group (p = 0.96). CONCLUSION: Doubling the rhEPO dose of 750 IU/kg/week is not indicated in infants with birth weights less than 1000 gm.

Hydrops fetalis: manifestation in lysosomal storage diseases including Farber disease.

UNLABELLED: The authors describe a case of disseminated lipogranulomatosis (Farber disease) presenting as nonimmune hydrops fetalis. This is the tenth lysosomal storage disease which can show this clinical manifestation. The literature is reviewed for all hydrops cases associated with lysosomal storage diseases. CONCLUSION: Although rare, the lysosomal storage diseases collectively are significant causes of nonimmune hydrops and appropriate investigations are required in all cases of unexplained hydrops fetalis.

[Disseminated lipogranulomatosis (Farber disease) with hydrops fetalis]. / Disseminierte Lipogranulomatose (M. Farber) mit Hydrops fetalis.

We report on a female preterm infant of 29 weeks' gestation with severe hydrops fetalis who died 3 days post natum as a result of disseminated intravascular coagulation. Autopsy findings included anasarca, bilateral pleural effusions, ascites and hepatosplenomegaly as well as multiple, up to pinhead sized, white granulomas on the surface of liver, spleen and lungs. Microscopy revealed storage macrophages of the reticuloendothelial system, especially in liver, spleen and bone marrow, the lymphatic organs, the salivary glands, the thyroid gland and the suprarenal medulla. Cerebrum, heart, kidneys, intestines and placenta were not afflicted. Atrophy of the lymphatic compartments in the spleen, lymph nodes and thymus, as well as disorder of the liver texture, are presumably a secondary result. The diagnosis of Farber's disease was established biochemically by the demonstration of ceramide depositions in the spleen, and in fibroblast cultures in situ by the accumulation of ceramide released from loaded radioactive glucosylceramide. Ultrastructurally, corresponding storage lysosomes were found in macrophages. To our knowledge this is the first account of Farber's disease in a preterm infant with hydrops fetalis.

Influence of clinical and ventilatory parameters on morphology of bronchopulmonary dysplasia.

Our aim was to assess multiple factors which contribute to bronchopulmonary dysplasia (BPD) in prematurely born neonates. Specific morphologic features might relate to cumulative oxygen dose, barotrauma, prematurity, infection, and persistent ductus arteriosus (PDA). Seventy-two patients dying from BPD as defined by the histopathologic criteria of Stocker were analyzed retrospectively. Median (range) gestational age was 28 (25-35) weeks, and median survival was 16 (5-386) days. The infants were ventilated for 15 (15-149) days with a mean inspired oxygen fraction (FiO2) of 0.78. The cumulative oxygen dose and mean airway pressures were determined. The presence of neonatal infection, PDA, and interstitial lung emphysema (ILE) was assessed. Baseline lung disease was estimated as proposed by Palta. At autopsy, the degree of hyaline membranes, epithelial cell necrosis, emphysema, atelectasis, interstitial cell proliferation, and lung fibrosis was scored semiquantitatively (0 to 3+). The influence of neonatal infection, PDA, gestational age, survival, oxygen dose, or barotrauma on morphological findings was examined by multivariate analysis. We found "acute" BPD in 22, "reparative" in 34 and long-standing-"healed" in 16 cases. ILE within the first week was associated with interstitial cell proliferation and lung fibrosis in infants surviving more than 28 days. Initial barotrauma contributes to lung fibrosis in infants with BPD.

Diminished cord blood lymphocyte L-selectin expression in neonatal bacterial infection.

L-Selectin, a leukocyte surface glycoprotein involved in white blood cell extravasation, is rapidly down-regulated after leukocyte activation. We prospectively determined lymphocyte L-selectin expression in freshly obtained cord blood samples of 98 neonates (gestational age 25-42 weeks). In eight infants with bacterial infection, the mean percentage of L-selectin(high) lymphocytes was 32.5% (SD 20.1%), compared to 60.1% (SD 18.7%) in the control group (P < 0.01). A percentage of L-selectin(high) lymphocytes of less than 42% had a sensitivity of 75% and a specificity of 82% in identifying infected newborns. Cord blood lymphocyte L-selectin expression was independent of gestational age, birth weight, umbilical artery pH, hematocrit, white blood cell count, absolute neutrophil count, C-reactive protein level, or maternal fever before delivery while there was a weak correlation with the newborn's immature/total ratio and platelet count. To our knowledge, this is the first report demonstrating downregulation of human lymphocyte L-selectin expression following activation of the immune system in vivo.

Accelerated lung maturation following maternal steroid treatment in infants born before 30 weeks gestation.

A meta-analysis was performed of 9 controlled trials of maternal beta-/dexamethasone treatment in which the incidence of RDS in infants born before 30 weeks gestation was reported. A significant decrease could be shown in 250 immature infants. The number of cases was to small for analysis of lower gestational ages or for the demonstration of a reduction in mortality. In a separate study of 135 infants born before 30 weeks gestation tracheal aspirate phospholipid analysis was performed using thin layer chromatography. 64 of them had been exposed prenatally to steroids. Significantly more of these infants had a mature L/S ratio > or = 2.7 (p < 0.02) and prenatal glucocorticoid treatment was associated with a markedly increased survival rate (odds ratio 2.4, p < 0.02). We conclude from the meta-analysis of the literature and from the findings of our study, that accelerated lung maturation follows prenatal steroid treatment with a reduction in RDS-incidence even in very immature fetuses. Consequently it would be appropriate to administer glucocorticoids combined with tocolysis since this has been shown to be beneficial for those women threatening to deliver prematurely at less than 30 weeks gestation.