Risk factors for neonatal hypoxic ischemic encephalopathy and therapeutic hypothermia: a matched case-control study.

BACKGROUND: Peripartum asphyxia is one of the main causes of neonatal morbidity and mortality. In moderate and severe cases of asphyxia, a condition called hypoxic-ischemic encephalopathy (HIE) and associated permanent neurological morbidities may follow. Due to the multifactorial etiology of asphyxia, it may be difficult prevent, but in term neonates, therapeutic cooling can be used to prevent or reduce permanent brain damage. The aim of this study was to assess the significance of different antenatal and delivery related risk factors for moderate and severe HIE and the need for therapeutic hypothermia. METHODS: We conducted a retrospective matched case-control study in Helsinki University area hospitals during 2013-2017. Newborn singletons with moderate or severe HIE and the need for therapeutic hypothermia were included. They were identified from the hospital database using ICD-codes P91.00, P91.01 and P91.02. For every newborn with the need for therapeutic hypothermia the consecutive term singleton newborn matched by gender, fetal presentation, delivery hospital, and the mode of delivery was selected as a control. Odds ratios (OR) between obstetric and delivery risk factors and the development of HIE were calculated. RESULTS: Eighty-eight cases with matched controls met the inclusion criteria during the study period. Maternal and infant characteristics among cases and controls were similar, but smoking was more common among cases (aOR 1.46, CI 1.14-1.64, p = 0.003). The incidence of preeclampsia, diabetes and intrauterine growth restriction in groups was equal. Induction of labour (aOR 3.08, CI 1.18-8.05, p = 0.02) and obstetric emergencies (aOR 3.51, CI 1.28-9.60, p = 0.015) were more common in the case group. No difference was detected in the duration of the second stage of labour or the delivery analgesia. CONCLUSIONS: Smoking, induction of labour and any obstetric emergency, especially shoulder dystocia, increase the risk for HIE and need for therapeutic hypothermia. The decisions upon induction of labour need to be carefully weighed, since maternal smoking and obstetric emergencies can hardly be controlled by the clinician.

Viral shedding, and distribution of cytomegalovirus glycoprotein H (UL75), glycoprotein B (UL55), and glycoprotein N (UL73) genotypes in congenital cytomegalovirus infection.

BACKGROUND: Children with congenital CMV infection (cCMV) shed virus in urine and saliva for prolonged periods of time. Outcome of cCMV varies from asymptomatic infection with no sequelae in most cases, to severe longterm morbidity. The factors associated with asymptomatic cCMV are not well defined. We evaluated the viral shedding in a cohort of infants with cCMV identified on newborn screening. In addition, we describe the distribution of viral genotypes in our cohort of asymptomatic infants and previous cohorts of cCMV children in the literature. METHODS: Study population consisted of 40 children with cCMV identified in screening of 19,868 infants, a prevalence of 2/1000. The viral shedding was evaluated at 3 and 18 months of age by real-time CMV-PCR of saliva and plasma, and CMV culture of urine. CMV positive saliva samples were analyzed for genotypes for CMV envelope glycoproteins gB (UL55), and gH (UL75) by genotype specific real-time PCR, and gN (UL73) by cloning and sequencing RESULTS: At 3 months age 40/40 saliva and urine samples, and 19/40 plasma samples were positive for CMV. At 18 months age all urine samples tested (33/33), 9/37 of saliva samples, and 2/34 plasma samples were positive for CMV. The genotype distribution did not differ from the published data CONCLUSIONS: The urinary virus shedding is more persistent than salivary shedding in children with cCMV. The genotype distribution was similar to previous literature and does not explain the low disease burden of cCMV in our population.

Amniotic Fluid Infection in Preterm Pregnancies with Intact Membranes.

Introduction. Intra-amniotic infection (IAI) is a major cause of preterm labor and adverse neonatal outcome. We evaluated amniotic fluid (AF) proteolytic cascade forming biomarkers in relation to microbial invasion of the amniotic cavity (MIAC) and IAI in preterm pregnancies with intact membranes. Material and Methods. Amniocentesis was made to 73 women with singleton pregnancies; 27 with suspected IAI; and 46 controls. AF biomarkers were divided into three cascades: Cascade 1: matrix metalloproteinase-8 (MMP-8), MMP-9, myeloperoxidase (MPO), and interleukin-6; Cascade 2: neutrophil elastase (HNE), elafin, and MMP-9; Cascade 3: MMP-2, tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), MMP-8/TIMP-1 molar ratio, and C-reactive protein (CRP). MMP-8 was measured by an immunoenzymometric assay and the others were measured by ELISA. Standard biochemical methods, molecular microbiology, and culture techniques were used. Results. MMP-8, MMP-9, MPO, elafin, and TIMP-1 concentrations were higher in IAI suspected cases compared to controls and also in IAI suspected cases with MIAC compared to those without MIAC when adjusted by gestational age at amniocentesis. All biomarkers except elafin and MMP-2 had the sensitivity of 100% with thresholds based on ROC-curve. Odd ratios of biomarkers for MIAC were 1.2-38 and 95% confidential intervals 1.0-353.6. Conclusions. Neutrophil based AF biomarkers were associated with IAI and MIAC.

Fetal left ventricular noncompaction cardiomyopathy and fatal outcome due to complete deficiency of mitochondrial trifunctional protein.

We report a fetal case with fatal outcome having a novel mutation in the HADHB gene, coding the beta-subunit of the mitochondrial trifunctional protein. Parents had a previous pregnancy loss due to fetal heart failure and hydrops. The next pregnancy led to left ventricular noncompaction and increasing pleural effusions after 29 gestational weeks. The fetus was small for gestational age, and long bones were abnormally short. The baby was born severely asphyxiated at 32 gestational weeks by cesarean section. Intensive care was withdrawn due to failure to thrive and suspicion of a severe mitochondrial disorder. Postmortem brain MRI suggested microcephaly with a simplified gyral pattern. The lateral cerebral ventricles were normal. Chromosome analysis was normal (46, XX). Fibroblasts cultured from a skin biopsy of the baby revealed the large homozygous deletion c.1109+243_1438-703del in the HADHB gene, and heterozygous mutations were detected in both parents. The deletion has not been reported earlier. CONCLUSION: It is important to differentiate systemic metabolic diseases from disorders that affect only the cardiac muscle. Trifunctional protein deficiency is a relatively rare disorder of the fatty acid ß-oxidation cycle. The mutation in the HADHB gene causes a systemic disease with early-onset cardiomyopathy. Understanding the molecular genetic defect of the patient allows appropriate genetic counseling of the family. WHAT IS KNOWN: • Mitochondrial disorders as a group are an important etiology for fetal cardiomyopathies including human trifunctional protein (TFP) disorders and several other mitochondrial diseases. WHAT IS NEW: • We report a fetal case with fatal outcome having a novel mitochondrial trifunctional protein mutation (c.1109+243_1438-703del in the HADHB gene).

Activation of T cells in preterm infants with respiratory distress syndrome.

BACKGROUND: Preterm infants with respiratory distress syndrome (RDS) present with systemic inflammation. The role of lymphocytes in RDS is less studied. Activation of lymphocytes could mediate chronic inflammation and development of bronchopulmonary dysplasia (BPD). OBJECTIVE: To evaluate whether T cells are activated in preterm infants with RDS and whether T cell activation is associated with the development of BPD. METHODS: Thirty-four infants with RDS [mean gestational age 27.1 (SD 2.0) weeks, birth weight 900 (216) g] were compared with 21 infants without RDS [32.6 (1.4) weeks, 1,697 (406) g]. From blood samples taken on postnatal days 1, 3, and 7, CD4 and CD8 cell counts and their expressions of co-stimulatory molecule CD54 and adhesion molecule CD62L were determined by flow cytometry. In activated cells, expression of CD54 is increased and CD62L is decreased. RESULTS: As compared with infants without RDS, infants with RDS had less CD4 and CD8 cells on day 3 (both p = 0.02). On day 1 and day 3, RDS was associated with increased CD54 expression on CD4 cells (p = 0.001; p = 0.03) and decreased CD62L expression on CD8 cells (both p = 0.02). Infants with RDS who developed BPD (n = 18) had higher CD54 expression on CD4 cells on day 3 (p = 0.01) and on CD8 cells on day 1 and day 3 (p = 0.01; p = 0.04) as compared with infants without BPD (n = 16). CONCLUSIONS: In preterm infants, RDS is associated with a lower T cell count and a higher proportion of activated cells. Increased proportion of activated T cells predicts the development of BPD. Systemic T cell activation could mediate inflammation and development of BPD.

Vascular endothelial growth factor and angiogenin levels during fetal development and in maternal diabetes.

We evaluated the concentrations of vascular endothelial growth factor (VEGF) and angiogenin in the umbilical cord blood from 14 fetuses with erythroblastosis or alloimmune thrombocytopenia and at birth from 28 preterm fetuses, from 42 healthy term fetuses, and from 24 term fetuses born to mothers with insulin-treated diabetes. A correlation appeared between VEGF and angiogenin levels (r = 0.44, p = 0.038). The gestational age correlated with both VEGF (r = 0.38, p = 0.0008) and angiogenin levels (r = 0.80, p = 0.0001). The concentration of VEGF was lower in fetuses born to mothers with insulin-treated diabetes than in the healthy term fetuses (p = 0.0028), but this difference was absent for angiogenin (p > 0.05). In conclusion, in umbilical cord plasma, a developmental increase was evident in concentrations of VEGF and angiogenin during the last trimester of gestation. That the umbilical cord VEGF level was lower in term fetuses born to mothers with diabetes than in term fetuses of healthy mothers may be associated with an aberrant fetal vascular development in diabetic pregnancies.

Early postnatal dexamethasone decreases hepatocyte growth factor in tracheal aspirate fluid from premature infants.

OBJECTIVE: To evaluate in preterm infants the effect of dexamethasone on hepatocyte growth factor (HGF), an epithelial cell mitogen, and on vascular endothelial growth factor (VEGF), an endothelial cell mitogen, in tracheal aspirate fluid (TAF). METHODS: Thirty preterm infants (birth weight: 1000-1500 g) with respiratory distress syndrome were randomized to receive dexamethasone or to serve as control subjects. Dexamethasone was started at the age of 12 to 24 hours at a dose of 0.5 mg/kg/d for 2 days and 0.25 mg/kg/d for the subsequent 2 days. HGF and VEGF levels were examined from TAF samples during the first postnatal week. For eliminating the effect of dilution, the concentration of the secretory component of immunoglobulin A was determined. Student t test, 1-way analysis of variance, chi2, and simple regression analysis were used for statistical analysis. RESULTS: Mean HGF concentrations were similar in the dexamethasone and control groups on days 1 to 2, but the dexamethasone group had a lower mean HGF concentration on days 3 to 4 and 5 to 7. In contrast, no differences existed in mean VEGF levels between the dexamethasone and control groups. CONCLUSIONS: In preterm infants who received early postnatal dexamethasone, reduced levels of HGF were seen in tracheal aspirates. This reduction may participate in the suppressive effects of dexamethasone on lung development.