Treatment of Severe Hyperglycemia in Extremely Preterm Infants Using Continuous Subcutaneous Insulin Therapy.

Background: Hyperglycemia in preterm infants is usually treated with adjustment of glucose intake and, if persistent, with continuous insulin infusion. However, hypoglycemia is a well-known complication of iv insulin treatment. The aim of our study was to evaluate the feasibility of continuous subcutaneous insulin infusion (CSII) in extremely preterm infants. Methods and material: Clinical data from 15 extemely premature infants (< 28 weeks of gestation) undergoing CSII treatment for severe hyperglycemia at the NICU were included. Blood glucose levels during CSII as well as the nutritional intake and insulin intake were sampled. Data were analyzed and compared to a control group of very preterm infants receiving iv insulin therapy. Results: Normoglycemia rates were best in the iv insulin-cohort (50.3%; 15.6%). Hypoglycemia was very rare in both groups (0.4%; 0.0%). CSII therapy might require higher insulin doses compared to continuous iv therapy. Discussion: Subcutaneous Insulin therapy in extremely preterm infants is feasible, regarding the prevention of hypoglycemia. However, dose control needs to be improved. Conclusion: The results justify further model validation and clinical trial research to explore a model-based protocol and the use of CSII.

Characteristics and special challenges of neonatal emergency transports.

BACKGROUND: As a rule, newborns do not require special medical care. If unexpected complications occur peripartum or postpartum, support from and transport to specialised neonatal hospitals might be needed. METHODS: In a retrospective study, all transport protocols of a supraregional paediatric­neonatological maximum care hospital in northwestern Germany from 01.10.2018 through 30.09.2021 were analysed. The particular focus was on transports of newborns (<7 days) and the leading symptoms that led to contact. RESULTS: A total of 299 patients were included (average age of 15.4 h, 61.6 % males). The average complete transport time was approximately 2 h. Five leading neonatal diseases (respiratory, infectious, asphyxia, cardiac, haematological) were found to represent the causes of >80 % of transfers. Respiratory adaptation disorders are the main reason for transferring a newborn to a centre, whereas asphyxia is the most severe condition. The various symptoms differ in their time of onset, a factor which must be taken into account in practice. Differences were also found between different types of hospitals: while a large proportion of transports were carried out from maternity hospitals (80.6 %), children transported from children's hospitals were generally more severely ill. DISCUSSION: Transfers of neonates, especially from maternity hospitals to neonatal intensive care units due to special neonatal diseases, are not rare. In times of increasingly scarce resources, the effective care of sick or at-risk neonates is essential. For low-population regions, this means professional cooperation between maximum care providers and smaller children's hospitals and maternity-only hospitals.

Model-based subcutaneous insulin for glycemic control of pre-term infants in the neonatal intensive care unit.

Hyperglycaemia is a common problem in neonatal intensive care units (NICUs). Achieving good control can result in better outcomes for patients. However, good control is difficult, where poor control and resulting hypoglycaemia reduces outcomes and confounds results. Clinically validated models can provide good control, and subcutaneous insulin delivery can provide more options for insulin therapy for clinicians. However, this combination has only been significantly utilised in adult outpatient diabetes, but could hold benefit for treating NICU infants. This research combines a well-validated NICU metabolic model with subcutaneous insulin kinetics models to assess the feasibility of a model-based approach. Clinical data from 12 very/extremely pre-mature infants was collected for an average study duration of 10.1 days. Blood glucose, interstitial and plasma insulin, as well as subcutaneous and local insulin were modelled, and patient-specific insulin sensitivity profiles were identified for each patient. Modelling error was low, where the cohort median [IQR] mean percentage error was 0.8 [0.3 3.4] %. For external validation, insulin sensitivity was compared to previous NICU cohorts using the same metabolic model, where overall levels of insulin sensitivity were similar. Overall, the combined system model accurately captured observed glucose and insulin dynamics, showing the potential for a model-based approach to glycaemic control using subcutaneous insulin in this cohort. The results justify further model validation and clinical trial research to explore a model-based protocol.

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.

The coagulation system of extremely preterm infants: influence of perinatal risk factors on coagulation.

OBJECTIVE: Little is known about the influence of preterm delivery and perinatal risk factors on development and expression of the coagulation system in extremely preterm infants. The objective of this study was to determine reference values for the components of the coagulation system at the first day of life in extremely preterm infants. STUDY DESIGN: Components of the coagulation system were examined retrospectively in 132 extremely preterm infants. Patients were grouped according to clinical criteria for preterm delivery: group A: maternal indication; group B: uteroplacental dysfunction; group C: systemic inflammation. RESULT: Levels of coagulation factors VII and X rose with increasing gestational age, whereas fibrinogen and coagulation factors II, V and VIII remained constant. Levels of factors V and VIII were higher than those of vitamin K-dependent factors. If preterm delivery was caused by placental disorder (group B) or chorioamnionitis (group C), levels of factor II, VIII and X were significantly lower, whereas factor V and VII levels did not differ. In group C fibrinogen levels in group C were higher compared with group A. CONCLUSION: Identification of perinatal risk factors may help to define patients at risk of bleeding disorders.

Fetal anemia of unknown cause--a diagnostic challenge.

PURPOSE: To assess the spectrum of underlying diseases in cases of fetal anemia in which the cause was unknown at the time of first and second transfusion or thereafter. MATERIALS AND METHODS: All patients who underwent intrauterine transfusion were identified in the perinatal databases of two tertiary referral centers for prenatal medicine and treatment between 2002 and June 2010. RESULTS: 82 fetuses received intrauterine transfusion in the study period. A total of 356 transfusions were performed in these patients. The causes of fetal anemia in our cohort were alloimmunization (32), parvovirus infection (23), feto-fetal transfusion syndrome (9), sacrococcygeal teratoma (2) and cytomegalovirus infection (1). In the remaining 15 cases, the cause of fetal anemia was unknown at the time of first and second transfusion, and could only be ascertained in the further course of pregnancy, in the postnatal period or was ultimately left in doubt. In all cases markedly elevated peak systolic velocities in the middle cerebral artery accurately predicted fetal anemia. The final diagnosis in these cases was fetomaternal hemorrhage (4), Blackfan-Diamond anemia (1), diffuse neonatal hemangiomatosis with chorangioma (1), kaposi-like hemangioendothelioma (1), elliptocytosis (1), neonatal hemochromatosis (1), mucopolysaccharidosis type VII (1) and in 5 cases the cause of fetal anemia remained unexplained. The latter 5 cases had an uneventful postnatal course and did not require further transfusions in infancy. CONCLUSION: In cases of fetal anemia with negative indirect Coombs test and TORCH serology, rare causes of anemia have to be considered. Fetal studies should therefore include reticulocyte count, parameters of hemolysis, peripheral blood smear and fetal liver function tests. Maternal studies should involve a search for fetal red cells using flow cytometry rather than Kleihauer-Betke test.

[Cerebral MRI of preterm neonates at term equivalent age at 3 Tesla: hints at white matter damage on T2- and diffusion weighted images]. / Erfahrungen mit der MRT des Hirns bei Frühgeborenen--Hinweise auf Schädigung der weißen Substanz in T2- und Diffusionswichtung bei 3 Tesla.

BACKGROUND: MRI of the brain is reported to be very sensitive in the detection of diffuse white matter damage in preterm neonates. AIM: To review 3 Tesla-MRI studies of 21 preterm neonates at term equivalent age with regard to safety and detection of white matter changes. PATIENTS: In 21 preterm neonates (9 female, 12 male, mean age 96 days) an MRI of the brain was performed for clinical reasons with oral sedation. All examinations could be performed at 3 Tesla without any complication. In 7 of 21 noncystic periventricular white matter lesions could be found and in 14 hyperintensity of white matter (DEHSI) was observed. ADC-values of the white matter were considerably higher than reported for healthy children in literature. CONCLUSION: MRI at 3 Tesla can be performed safely in oral sedation at term equivalent age at 3 Tesla. T2-weighted and diffusion-weighted imaging is very sensitive for white matter changes.

Pyridoxal phosphate-dependent neonatal epileptic encephalopathy.

Pyridox(am)ine-5'-phosphate oxidase converts pyridoxine phosphate and pyridoxamine phosphate to pyridoxal phosphate, a cofactor in many metabolic reactions, including neurotransmitter synthesis. A family with a mutation in the pyridox(am)ine-5'-phosphate oxidase gene presenting with neonatal seizures unresponsive to pyridoxine and anticonvulsant treatment but responsive to pyridoxal phosphate is described. Pyridoxal phosphate should be considered in neonatal epileptic encephalopathy unresponsive to pyridoxine.

[Current stage of fMRI applications in newborns and children during the first year of life]. / Gegenwärtiger Stand der funktionellen MRT bei Neugeborenen und Kindern im ersten Lebensjahr.

Currently, a paradigm shift towards expanded early use of cranial MRI in newborns at risk and infants in the first year of life can be observed in neonatology. Beyond clinical MRI applications, there is progressive use of functional MRI (fMRI) in this age group. On the one hand, fMRI allows monitoring of functional developmental processes depending on maturational stage; on the other hand, this technique may provide the basis for early detection of pathophysiological processes as a prerequisite for functionally guided therapeutic interventions. This article provides a comprehensive review of current fMRI applications in neonates and infants during the first year of life and focuses on the associated methodological issues (e. g. signal physiology, sedation, safety aspects).

Spectrum and outcome of prenatally diagnosed fetal tumors.

OBJECTIVE: To describe the spectrum of prenatally diagnosed fetal tumors, and the course and fetal outcome in affected pregnancies. METHODS: This was a retrospective study in two German tertiary referral centers of 84 fetuses with tumors diagnosed in the prenatal period. The tumors were classified according to their location and histology. RESULTS: The most common site of origin was the heart (20/84, 23.8%), followed by the face and neck region (19/84, 22.6%) and the abdomen (16/84, 19%). Lymphangiomas (21/84, 25%) and rhabdomyomas (19/84, 22.6%) comprised half of the tumor histology. Less frequently, teratomas (14/84, 16.6%) and hemangiomas (12/84, 14.2%) were seen. Complications included arrhythmia in cases with rhabdomyoma (8/19, 42%) and signs of heart failure in cases with hemangioma (4/12, 33%) and teratoma (4/14, 28.6%). The overall survival rate was 75%. Cases with either a histological diagnosis of teratoma or tumor located in the brain had the worst prognosis. CONCLUSION: The combination of sonographic features and their location allows reliable prediction of the histological type in the vast majority of fetal tumors. Malignancy, associated malformations and aneuploidy are observed infrequently. Knowledge of the presence of a fetal tumor facilitates close surveillance by a specialized team, which might lead to early recognition of problems and improve perinatal outcome.

Pyridoxal phosphate-dependent neonatal epileptic encephalopathy.

Pyridox(am)ine-5'-phosphate oxidase converts pyridoxine phosphate and pyridoxamine phosphate to pyridoxal phosphate, a cofactor in many metabolic reactions, including neurotransmitter synthesis. A family with a mutation in the pyridox(am)ine-5'-phosphate oxidase gene presenting with neonatal seizures unresponsive to pyridoxine and anticonvulsant treatment but responsive to pyridoxal phosphate is described. Pyridoxal phosphate should be considered in neonatal epileptic encephalopathy unresponsive to pyridoxine.

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.

Treatment resistant hyperemesis gravidarum in a patient with type 1 diabetes mellitus: neonatal withdrawal symptoms after successful antiemetic therapy with mirtazapine.

Here we present the case of a 30-year-old woman with type I diabetes mellitus, preeclampsia and treatment resistant persistent hyperemesis gravidarum in her 25th week of gestation who was successfully treated with the antidepressant mirtazapine (Remergil). Nausea and vomiting resolved within 5 days. After discharge from the hospital in 28 weeks of gestation and discontinuation of the medication on her own initiative a relapse occurred, once again with good response to mirtazapine. The drug was continued until birth. At 34 + 0 weeks a cesarean section was performed due to fetal growth restriction and deteriorating preeclampsia. During the second and fourth day postnatal age the child temporarily developed hyperarousal which could be explained by mirtazapine withdrawal.

First-trimester treatment of fetal anemia secondary to parvovirus B19 infection.

Here we report two cases of first-trimester parvovirus B19 (PV-B19) infection that were successfully treated by intrauterine blood transfusion into the umbilical vein. At 13 weeks' gestation both fetuses presented with increased nuchal translucency (NT) and cardiomegaly. In both cases pulsed Doppler ultrasound examination of the fetal middle cerebral artery (MCA) revealed increased peak systolic velocity (PSV), which led to a suspicion of fetal anemia. Maternal PV infection was confirmed by a positive polymerase chain reaction result. Each fetus received a 3-mL intravenous transfusion of packed red blood cells into the umbilical vein, using a 25-G spinal needle. Follow-up ultrasound and Doppler examination demonstrated fetal well-being, decline of the MCA-PSV and resolution of the NT. Case 1 was readmitted at 25 weeks' gestation with severe hydrops fetalis, and both mother and fetus still tested positive for PV-B19 DNA. Three more intrauterine blood transfusions were performed and the fetal hydrops resolved. In Case 2 no additional transfusions were needed. Both babies had a good neonatal outcome and uneventful follow-up. Our findings demonstrate that the MCA-PSV is helpful in establishing the diagnosis of first-trimester fetal anemia. Intravasal transfusion can be attempted as early as the first trimester.

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.

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.

Prenatal diagnosis and therapy of upper extremity vascular malformation causing high cardiac output and Kasabach-Merritt sequence: a report of two cases.

We present two cases of upper extremity vascular malformation causing a high output state in the prenatal period. One fetus responded well to transplacental digitalis treatment. Both newborns had a Kasabach-Meritt sequence including anemia and thrombocytopenia. Postpartum treatment included successful interventional occlusion of the main feeding arteries and subsequent surgical removal of the tumor.