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INTRODUCTION Labor induction rates are increasing and, in Finland today, one of three labors is induced. Group B streptococcus (GBS) is a bacterium found in 10%-30% of pregnant women and it can be transmitted to the neonate during vaginal delivery. Although GBS is rarely harmful in the general population, it is the leading cause of severe neonatal infections such as sepsis, pneumonia, and meningitis. In addition, GBS can cause maternal morbidity. Labor induction in GBS-positive women has not yet been investigated but concerns of infectious morbidity associated with balloon catheters have been raised. MATERIAL AND METHODS A historical cohort study of 1959 women undergoing labor induction by balloon catheter in Helsinki University Hospital, Finland, between January 1, 2014 and December 31, 2017. Women with viable singleton term pregnancy in cephalic presentation, unfavorable cervix (Bishop score

Introduction Although the perinatal mortality of monochorionic twins has been reported to be higher, the role of chorionicity is debated and data from Finland are still lacking. To examine the effect of chorionicity on the main outcome measures, perinatal and neonatal mortality and neonatal morbidity of Finnish twins, a comprehensive population-based historical cohort study was performed at Helsinki University Hospitals. Material and methods All 1034 dichorionic and monochorionic-diamniotic twin pregnancies managed at Helsinki University Hospital area during 2006, 2010, 2014 and 2018 were collected from patient databases. Information on chorionicity was retrieved from ultrasound reports and all relevant clinical information from patient records. Differences in perinatal and neonatal mortality and neonatal morbidity were analyzed by performing group comparisons between the twins and chorionicity. The role of chorionicity was also assessed in logistic regression analyses. Results There were 1034 dichorionic-diamniotic (DCDA, n = 789, 76.3%, 95% confidence interval [CI] 73.6-78.9) and monochorionic-diamniotic (MCDA, n = 245, 23.7%, 95% CI 21.4-26.0) twin pregnancies during the studied years. Most (n = 580, 56.1%, 95% CI 52.8-59.2) twins were born at term, but 151 (61.6%, 95% CI 55.8-67.3) of MCDA twins were preterm and had lower birthweight and Apgar scores and higher risk of death of one twin. Perinatal and neonatal mortality did not differ between twins A and B, but the immediate outcome of twin B was worse, with lower arterial pH and Apgar scores and increased need of neonatal intensive care unit treatment. Conclusions Chorionicity contributes to the perinatal and neonatal outcome in favor of dichorionic twins. This disadvantage of MCDA twinning is likely explained by earlier gestational age at birth and inequal placental sharing. Irrespective of chorionicity, twin B faces more complications.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6±9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8–0.9 per week increase; p Conclusions Early gestational age at infection, maternal ventilatory supports and low birthweight are the main determinants of adverse perinatal outcomes in fetuses with maternal COVID-19 infection. Conversely, the risk of vertical transmission seems negligible.

WOS:000613461600006 PubMed ID: 32926494 Objectives To evaluate the maternal and perinatal outcomes of pregnancies affected by SARS-CoV-2 infection. Methods This was a multinational retrospective cohort study including women with a singleton pregnancy and laboratory-confirmed SARS-CoV-2 infection, conducted in 72 centers in 22 different countries in Europe, the USA, South America, Asia and Australia, between 1 February 2020 and 30 April 2020. Confirmed SARS-CoV-2 infection was defined as a positive result on real-time reverse-transcription polymerase chain reaction (RT-PCR) assay of nasopharyngeal swab specimens. The primary outcome was a composite measure of maternal mortality and morbidity, including admission to the intensive care unit (ICU), use of mechanical ventilation and death. Results In total, 388 women with a singleton pregnancy tested positive for SARS-CoV-2 on RT-PCR of a nasopharyngeal swab and were included in the study. Composite adverse maternal outcome was observed in 47/388 (12.1%) women; 43 (11.1%) women were admitted to the ICU, 36 (9.3%) required mechanical ventilation and three (0.8%) died. Of the 388 women included in the study, 122 (31.4%) were still pregnant at the time of data analysis. Among the other 266 women, six (19.4% of the 31 women with first-trimester infection) had miscarriage, three (1.1%) had termination of pregnancy, six (2.3%) had stillbirth and 251 (94.4%) delivered a liveborn infant. The rate of preterm birth before 37 weeks' gestation was 26.3% (70/266). Of the 251 liveborn infants, 69/251(27.5%) were admitted to the neonatal ICU, and there were five (2.0%) neonatal deaths. The overall rate of perinatal death was 4.1% (11/266). Only one (1/251, 0.4%) infant, born to a mother who tested positive during the third trimester, was found to be positive for SARS-CoV-2 on RT-PCR. Conclusions SARS-CoV-2 infection in pregnant women is associated with a 0.8% rate of maternal mortality, but an 11.1% rate of admission to the ICU. The risk of vertical transmission seems to be negligible. (C) 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Introduction To investigate the safety of balloon catheter for cervical ripening in women with term pre-labor rupture of membranes (PROM) and to compare the incidence of maternal and neonatal infections in women with PROM and women with intact membranes undergoing cervical ripening with a balloon catheter. Material and methods This retrospective cohort study of 1923 women with term singleton pregnancy and an unfavorable cervix undergoing cervical ripening with a balloon catheter was conducted in Helsinki University Hospital between January 2014 and December 2018. For each case of PROM, two controls were assigned. The main outcome measures were the rates of maternal and neonatal infections. Statistical analyses were performed by SPSS. Results In all, 641 (33.3%) women following PROM and 1282 (66.6%) women with intact amniotic membranes underwent labor induction. The rates of intrapartum infection (3.7% vs 7.7%; P = .001) and neonatal infection (1.7% vs 3.8%; P = .01) were not increased in women induced by balloon catheter following PROM. Intrapartum infections were associated with nulliparity (odds ratio [OR] 3.3, 95% confidence interval [CI] 1.6-6.5), history of previous cesarean section (OR 2.8, 95% CI 1.2-6.4), extended gestational age >= 41 weeks (OR 1.9, 95% CI 1.2-3.0) and an induction to delivery interval of 48 hours or more (OR 2.0, 95% CI 1.2-3.3). The risk of neonatal infection was associated with nulliparity (OR 3.3, 95% CI 1.4-8.0), gestational age >= 41 weeks (OR 1.9, 95% CI 1.09-3.36) and induction to delivery interval of 48 hours or more (OR 3.4, 95% CI 1.9-6.0). Conclusions Use of balloon catheter in women with term PROM appears safe and was not associated with increased maternal or neonatal infectious morbidity.

To investigate the trends and changes in the incidence and overall outcome of twin pregnancies in Finland, a retrospective study was conducted with emphasis on maternal complications, covering a 28-year study period.All 23,498 twin pregnancies with 46,363 live born and 633 stillborn children in Finland during 1987-2014 were included in the study. Data were collected from the national Medical Birth Register and the Care Register on Hospital Care (Finnish Institute for Health and Welfare, Finland) regarding the parturients' characteristics and incidences of several pregnancy and childbirth complications. The incidences of twin pregnancies and maternal complications during pregnancy and childbirth are the main outcome measures of the study. The results are expressed in percentages, means, medians, ranges and standard deviations (SD), when appropriate.Twins comprised 1.4% of all births in Finland in 1987-2014. Parturients' mean age has remained stable, but the share of over 35 year-old parturients is increasing. The incidences of pre-eclampsia, intrahepatic cholestasis of pregnancy, gestational diabetes and postpartum haemorrhage have risen during the study period. Almost half (44.9%) of twins were born preterm, almost half via Caesarean section (47.1%), and 27.7% of twin labours were induced.Several pregnancy complications increased during the study period. Advanced maternal age among twin parturients has risen, enhancing the risks for developing complications in a pregnancy already of a high-risk category, and predisposing to preterm delivery. National and international guidelines are necessary to improve the overall outcome of twin pregnancies.

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.

Background To establish the changes in perinatal morbidity and mortality in twin pregnancies in Finland, a retrospective register research was conducted. Our extensive data from a 28-year study period provide important information on the outcome of twin pregnancies in Finland that has previously not been reported to this extent. Methods All 23,498 twin pregnancies with 46,996 children born in Finland during 1987–2014 were included in the study. Data were gathered from the Medical Birth Register and the Hospital Discharge Register (Finnish Institute for Health and Welfare, Finland) regarding perinatal mortality (PNM) and morbidity. For statistical analysis, binomial regression analysis and crosstabs were performed. The results are expressed in means, percentages and ranges with comparison to singletons when appropriate. Odds ratios from binomial regression analysis are reported. A p-value Results There were 46,363 liveborn and 633 stillborn twins in Finland during 1987–2014. Perinatal mortality decreased markedly, from 45.1 to 6.5 per 1000 for twin A and from 54.1 to 11.9 per 1000 for twin B during the study period. Yet, the PNM difference between twin A and B remained. Early neonatal mortality did not differ between twins, but has decreased in both. Asphyxia, respiratory distress syndrome, need for antibiotics and Neonatal Intensive Care Unit (NICU) stay were markedly more common in twin B. Conclusions In Finland, PNM and early neonatal mortality in twins decreased significantly during 1987–2014 and are nowadays very low. However, twin B still faces more complications. The outline provided may be used to further improve the monitoring and thus perinatal outcome of twins, especially twin B.

Neonatal sepsis (NS) is a frequent problem in neonatal intensive care, especially in preterm and very low birthweight (VLBW) infants. The objective of the study was to characterize the cutaneous bacterial microbiome in VLBW infants treated in the neonatal intensive care unit (NICU). Non-invasive skin microbiome specimens were taken repeatedly from 12 VLBW infants during treatment in NICU starting on the first day of life. All infants received benzylpenicillin and netilmicin during the first 1-5 postnatal days. Samples were also collected from incubators. High cutaneous microbial diversity was present at birth in 11 of 12 of the infants, but the diversity decreased substantially after the first weeks of life in all infants regardless of their infection status. After the loss of diversity, one Staphylococcus operational taxonomic unit dominated the skin microbiome. Recovery of microbial diversity was seen in six of 12 neonates. The microbiome of incubators showed typical environmental bacterial genera. Maternal antibiotic treatment, the aetiology of the preterm birth or being born by C-section did not appear to affect the diversity of skin microbiota at birth, and no correlation was found between cutaneous microbiome and NS.

Background. Congenital cytomegalovirus (cCMV) infection is the most common congenital infection and causes significant morbidity. This study was undertaken to evaluate the benefits of screening newborns for cCMV and to understand the cCMV disease burden in Finland. Methods. Infants born in Helsinki area hospitals were screened for CMV by testing their saliva with a real-time polymerase chain reaction assay. The CMV-positive infants and matched controls were monitored to determine their neurodevelopmental, audiological, and ophthalmological outcomes at 18 months of age. Griffiths Mental Development Scales, otoacoustic emission and sound field audiometry, and ophthalmologic examination were performed. Results. Of the 19 868 infants screened, 40 had confirmed cCMV infection (prevalence, 2 in 1000 [95% confidence interval, 1.4-2.6 in 1000]). Four (10%) infants had symptomatic cCMV. Griffiths general quotients did not differ significantly between the CMV-positive (mean, 101.0) and control (mean, 101.6) infants (P = .557), nor did quotients for any of the Griffiths subscales (locomotion, personal-social, hearing and language, eye and hand, performance) (P = .173-.721). Four of 54 CMV-positive ears and 6 of 80 CMV-negative ears failed otoacoustic emission testing (P = 1.000). The mean minimal response levels over the frequencies 500 Hz to 4 kHz in the sound field audiometry did not differ between CMV-positive (mean, 34.31-dB hearing level) and control (mean, 32.73-dB hearing level) infants (P = .338). No CMV-related ophthalmologic findings were observed. Conclusions. The prevalence of cCMV was low, and outcomes at 18 months of age did not differ between the infected infants and healthy control infants. With such a low burden in Finland, universal newborn screening for cCMV seems unwarranted.

To establish the changes in perinatal morbidity and mortality in twin pregnancies in Finland, a retrospective register research was conducted. Our extensive data from a 28-year study period provide important information on the outcome of twin pregnancies in Finland that has previously not been reported to this extent.All 23,498 twin pregnancies with 46,996 children born in Finland during 1987-2014 were included in the study. Data were gathered from the Medical Birth Register and the Hospital Discharge Register (Finnish Institute for Health and Welfare, Finland) regarding perinatal mortality (PNM) and morbidity. For statistical analysis, binomial regression analysis and crosstabs were performed. The results are expressed in means, percentages and ranges with comparison to singletons when appropriate. Odds ratios from binomial regression analysis are reported. A p-value0.05 was considered statistically significant.There were 46,363 liveborn and 633 stillborn twins in Finland during 1987-2014. Perinatal mortality decreased markedly, from 45.1 to 6.5 per 1000 for twin A and from 54.1 to 11.9 per 1000 for twin B during the study period. Yet, the PNM difference between twin A and B remained. Early neonatal mortality did not differ between twins, but has decreased in both. Asphyxia, respiratory distress syndrome, need for antibiotics and Neonatal Intensive Care Unit (NICU) stay were markedly more common in twin B.In Finland, PNM and early neonatal mortality in twins decreased significantly during 1987-2014 and are nowadays very low. However, twin B still faces more complications. The outline provided may be used to further improve the monitoring and thus perinatal outcome of twins, especially twin B.

Objectives To describe labor outcomes in women with prolonged pregnancy and induction of labor with a Foley catheter, as compared with women with spontaneous onset of labor. Design Retrospective study. Setting Helsinki University Hospital. Sample 553 women with uncomplicated prolonged pregnancies between January 2011 and January 2012, divided into 303 women (54.8%) with Foley catheter induction and 250 (45.2%) with spontaneous labor. Methods Maternal and neonatal characteristics of women with uncomplicated singleton pregnancy of ≥41+5 weeks of gestation were analyzed. Main outcome measures Cesarean delivery rates, maternal and neonatal morbidity. Results The cesarean delivery rate was 30.7% (n = 93/303) in women with labor induction and 4.8% (12/250) in women with spontaneous onset of labor (p

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.

Meconium drug testing is a non-invasive method to detect prenatal drug exposure, which can cause severe problems for the infant, indicating the need for follow-up measures to ensure the welfare of the child. Meconium samples for drug testing were collected from 143 infants as part of routine clinical work among addicted mothers. The drug testing findings were combined with medical records including clinical background and follow-up data. The substances screened for included medicinal opioids, 6-monoacetylmorphine (a metabolite of heroin), amphetamines and tetrahydrocannabinolic acid. At least one of the 13 target drugs was detected in 57 (40%) meconium samples. In 21 cases, the findings were unexpected on the basis of clinical data or denied by the mother. Medicinal opioids, especially the opioid substitution treatment drugs buprenorphine and methadone, comprised the majority of the findings of both admitted and unexpected drug misuse. Meconium drug testing methods should target not just traditional illicit drugs but also prescription drugs with misuse potential. Copyright © 2013 John Wiley & Sons, Ltd.

Background: Induction of labour is associated with increased risk for caesarean delivery among nulliparous women. The aims of this study were to evaluate the risk factors for caesarean delivery and to investigate the risk of maternal and neonatal infections in nulliparous women undergoing induction of labour by Foley catheter. Methods: This clinical retrospective study of 432 nulliparous women with singleton pregnancy and intact amniotic membranes at or beyond 37 gestational weeks scheduled for induction of labour by Foley catheter was conducted over the course of one year, between January 2012 and January 2013, in Helsinki University Hospital. The main outcome measures were caesarean section rate and maternal and neonatal infections. Univariate and multivariate logistic regressions were used to estimate relative risks by odds ratios with 95 % confidence intervals. Results: The caesarean section rate was 39.1 % (n = 169). In multivariate regression analysis, the factors associated with caesarean section were the need for oxytocin for labour induction [OR 2.9 (95 % CI 1.8-4.5) p

The aim of our study was to introduce outpatient induction of labor by Foley catheter, and to compare outcomes and preferences between in-patients and outpatients. This clinical cohort study was conducted in Helsinki University Hospital between January 2011 and January 2012. A total of 485 women scheduled for induction of labor by Foley catheter were included. The main outcome measures were cesarean delivery rate, and maternal and neonatal infectious morbidity. Maternal satisfaction of outpatients was measured after delivery. Two hundred and four (42.1%) women were managed as outpatients and 281 (57.9%) women as in-patients. The rates of cesarean delivery, and maternal or neonatal infections did not differ between outpatients and in-patients. Of the outpatients, 85.3% were satisfied. Induction of labor by Foley catheter appears suitable for outpatients, and resulted in no differences in cesarean delivery or infection rates compared with in-patients. Most women were satisfied with the outpatient induction.

Background: Preeclampsia and preterm labor often underlie preterm birth, and are associated with maternal inflammation. In preterm infants, respiratory distress syndrome (RDS) and mechanical ventilation are associated with systemic inflammation. Objective: We aimed to study whether early-onset preeclampsia or preterm labor modulate the systemic inflammation affecting preterm infants with RDS. Methods: We recruited mechanically ventilated infants with gestational ages Results: As compared with infants born after preterm labor, infants born after early-onset preeclampsia had higher CD11b expression on days 1–6 on both neutrophils and monocytes. In addition, infants born after early-onset preeclampsia had higher CRP concentrations on days 2–6 (all p < 0.05). Conclusions: As compared with infants born after preterm labor to mothers without preeclampsia, infants born after early-onset preeclampsia presented with a stronger postnatal systemic inflammatory reaction. Antenatal exposure to preeclampsia may induce fetal leukocyte priming and regulation of inflammation, and thereby modify postnatal inflammatory reactions and morbidity.

Phagocyte activation was studied in 48 preterm infants, gestational age 27.3 +/- 0.3 wk, birthweight 968 +/- 40 g, during the first postnatal week. Human neutrophil lipocalin as a marker of neutrophil activation was measured in plasma and tracheal aspirate fractions; and lysozyme, as a marker of monocyte and macrophage activation, in plasma. The concentration of plasma human neutrophil lipocalin was 69 (46-126) microg/l (median and quartiles), tracheal aspirate fraction fluid 213 (71-433) microg/l and plasma lysozyme 1337 (923-1764) microg/l. Infants born to mothers with premature rupture of the membranes or clinical chorioamnionitis (group A, n = 20) had significantly higher plasma [73 (58-151) vs 53 (38-108) microg/l; p=0.027], and tracheal aspirate fraction human neutrophil lipocalin [319 (129-540) vs 190 (57-324) microg/l; p = 0.019], and plasma lysozyme [1739 (1356-2021) vs 1140 (739-1557)microg/l; p=0.0001] than did infants whose mothers had intact membranes and who had no suspicion of infection (Group B, n = 28). In infants born to mothers receiving corticosteroids ante partum, correlations existed between time from treatment to delivery and plasma (r =0.322, p = 0.0256) and tracheal aspirate fraction human neutrophil lipocalin (r = 0.314, p = 0.0096).

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.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 β-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.• Mitochondrial disorders as a group are an important etiology for fetal cardiomyopathies including human trifunctional protein (TFP) disorders and several other mitochondrial diseases.• We report a fetal case with fatal outcome having a novel mitochondrial trifunctional protein mutation (c.1109+243_1438-703del in the HADHB gene).

Late-onset hospital-acquired sepsis is common in extremely low birth-weight (1000 g) (ELBW) infants. The diagnosis is difficult since, at early stages of sepsis, routine laboratory tests are neither specific nor sensitive. In term infants with sepsis neutrophil surface expression of CD11b/CD18, a beta2-integrin, is significantly increased. Here we studied whether increased CD11b/CD18 density on blood neutrophils and monocytes serves as an early sepsis marker in ELBW infants. Blood samples were obtained from 30 ELBW infants on a daily basis for 3-4 postnatal weeks, and neutrophil and monocyte CD11b/CD18 expression was determined by flow-cytometry. Patients were assigned one of 3 groups: 1) an infected group, comprised of infants who had blood culture-positive sepsis and/or necrotizing enterocolitis, 2) a non-infected group, and 3) a potentially infected group, comprised of infants in whom infection was suspected but could not be confirmed microbiologically. One patient had blood culture contamination and was excluded from the analysis. In the infected group, CD11b expression gradually increased during the three days preceding sampling for blood culture. At the day of sampling, median expression of CD11b in neutrophils and monocytes was higher in the infected group than in the control group. For neutrophils the sensitivity and specificity were 1.00 and 0.56, respectively, and for monocytes, 0.86 and 0.94, respectively. From these data, we conclude that determination of CD11b/CD18 density on neutrophils and monocytes may improve diagnosis of late-onset sepsis in ELBW infants.

Objective. To study neutrophil activation in circulation as a sign of systemic inflammation in preterm infants with respiratory distress syndrome.Methods. The study comprised very low birth weight preterm infants who had respiratory distress syndrome and required intubation and mechanical ventilation (n = 51), 1-day-old preterm infants who had no need for mechanical ventilation (n = 12), term infants (n = 47), and adult volunteers (n = 25). Neutrophil surface expression of CD11b was quantified with flow cytometry.Results. In preterm infants with respiratory distress syndrome, neutrophil CD11b expression during the first day of life was higher than in cord blood (mean: 165 relative fluorescence units [RFU] [standard deviation [SD]: 53], n = 29 vs 83 RFU [SD: 21], n = 11; 95% confidence interval [CI] for difference: 59–106) or in preterm infants without mechanical ventilation (106 RFU [SD: 33], n = 12; 95% CI for difference: 17–90). CD11b expression decreased by age of 10 days. CD11b expression was lower in preterm cord than in term cord blood (95% CI for difference: 5–53). However, in preterm infants with respiratory distress syndrome aged 2 to 5 days, it was higher than in term infants of that age.Conclusions. The observations demonstrate an early transient postnatal neutrophil activation indicative of systemic inflammation that may contribute to the tissue injury in preterm infants with respiratory distress syndrome.

Upon activation, polymorphonuclear leucocytes (PMN) release bactericidal/permeability-increasing protein, (BPI) from their azurophil granules. BPI selectively binds to the lipopolysaccharide (LPS) on gram-negative bacteria and induces their death. This study examined plasma BPI concentration levels in healthy newborns and in newborns with clinical sepsis, and the ability of PMN from preterm and term infants to release BPI. We also studied the release of myeloperoxidase (MPO), and the surface expression of adhesion molecule CD11b on PMN. In infants with clinical sepsis, plasma BPI concentration was higher, 27.8 microg/L [8.6-883; median (range)] (n = 11), than in healthy term infants 8.9 microg/L (3.9-179) (n = 17), and in adults 7.3 microg/L (0.7 -18.4) (n = 15); p = 0.014, Kruskal-Wallis. In preterm infants (n = 8), the ability of PMN to release BPI in vitro after stimulation with PMA was 8.8, in term infants it was 15.9 (n = 29; p > 0.05 vs. preterm infants) and in adults 23.4 ng/10(6) PMN (n = 15; p = 0.024 and p > 0.05 vs. preterm and term infants, respectively). The corresponding values of MPO were 20.0 ng/10(6) (11.3-46.7) in preterms, 19.0 ng/10(6) (2.2-223.7) in terms, and 27.8 ng/10(6) (9.1-80.7) in adults; p = 0.67 between groups. In infants with clinical sepsis, CD11b level was higher, 292 RFU (234-403) than the basal CD11b expression levels in healthy newborn infants, 116 RFU (76-145); P = 0.0001. FMLP-stimulated PMN CD11b expressions in preterm cord blood, 1071 RFU (552-1286) and in term cord blood, 918 (567-1472) were on the same level, but lower than that in adult blood, 1592 (973-1946); p < 0.001, ANOVA. Our findings suggest that in preterm infants the ability to release BPI is lower than in adults and term infants. These findings suggest that premature neonates have an impaired ability to mobilize BPI, possibly contributing to their marked susceptibility to infections with Gram-negative bacteria.

Objective Outcome after intrauterine transfusions due to severe hemolytic disease of the fetus and newborn. Design Nationwide population-based retrospective cohort study. Setting All women treated with intrauterine transfusions for hemolytic disease of the fetus and newborn in Finland in 2003–2012. Population 339 intrauterine transfusions, performed in 104 pregnancies of 84 women. Methods Information on antenatal screening of red cell antibodies and red cell units issued for intrauterine transfusion was obtained from the Finnish Red Cross Blood Service database, and obstetric and neonatal data from hospital records. Main outcome measures Procedure-related complications, perinatal mortality, neonatal morbidity. Results Overall survival was 94.2% (95% confidence interval 89.7–98.7). There were four fetal and two neonatal deaths. Procedure-related fetal loss rate was 1.2% (95% confidence interval 0.04–2.4) per procedure and 3.8% (95% confidence interval 0.1–7.5) per pregnancy. Of the four procedure-related losses, three were due to technically difficult intrauterine transfusions causing infection and preterm birth. Of the live born infants, 19% (95% confidence interval 11.3–26.7) were born before 32 weeks' gestation. The incidence of severe neonatal morbidity (respiratory distress syndrome, severe cerebral injury, sepsis) was 22.2% (95% confidence interval 13.4–30.2). Poor outcome (death, severe neonatal morbidity) was negatively associated with gestational age at first transfusion (p = 0.001) and at birth (p = 0.00006). Follow-up of the infants was too incomplete to assess the neurodevelopmental outcome. Conclusions Although overall survival is comparable with previous studies, our concern is procedure-related infections and preterm births. Close collaboration between the university hospitals is needed to ensure timely treatment, operator skills and systematic follow-up of the children.

Immaturity of the immune system renders newborns susceptible to infections. We searched for aberrations in leucocyte signalling profiles, using phospho-specific whole-blood flow cytometry, in cord blood of nine preterm (two born before 32nd gestational week) and nine full-term infants, born by caesarean section. Thirteen adults served as reference subjects. Monocyte NF-κB phosphorylation following tumour necrosis factor (TNF) or bacterial stimulation was higher in preterm neonates than in full-term neonates or adults, p38 phosphorylation following bacterial stimulation was higher in both preterm and full-term neonates than in adults, while STAT1 phosphorylation by IFN-γ or IL-6, STAT3 phosphorylation by IL-6 and STAT5 phosphorylation by GM-CSF were lower in both full-term and preterm neonates than in adults. Neutrophil STAT1 and STAT3 phosphorylation following IFN-γ stimulation and STAT5 phosphorylation following GM-CSF stimulation were lower in newborn neonates than in adults. In both CD3(+) CD4(+) and CD3(+) CD8(+) lymphocytes, NF-κB phosphorylation by TNF was higher and STAT5 phosphorylation by IL-2 was lower in preterm and full-term newborns than in adults. STAT6 phosphorylation by IL-4 was comparable in monocytes and lymphocytes of newborns and adults. The results suggest that innate immune signalling pathways responding to inflammatory stimuli are strongly functional in leucocytes of preterm neonates, which may render these neonates susceptible to inappropriate tissue injury. In leucocytes of both preterm and full-term newborns, responses needed against intracellular pathogens, and regulatory functions show immaturities, possibly contributing to worse control of infections.

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.

OBJECTIVE. In preterm infants with respiratory distress syndrome (RDS), circulating neutrophils are activated. Kinetics and effects of surfactant therapy on this activation are unknown. Therefore, we studied activation of circulating neutrophils and monocytes in newborn preterm infants with and without RDS.PATIENTS AND METHODS. Preterm infants with RDS who were mechanically ventilated and received surfactant (“ventilated infants”: n = 38; mean gestational age ± SD: 28.3 ± 2.2 weeks; mean birth weight ± SD: 1086 ± 353 g) and preterm infants who received nasal continuous positive airway pressure (n = 8) or no ventilatory support (n = 17) (“control infants”: mean gestational age ± SD: 32.1 ± 1.2 weeks; mean birth weight ± SD: 1787 ± 457 g) were recruited. Blood samples were taken from ventilated infants at birth, before surfactant treatment, at 1 and 2 hours after surfactant, and at 12 to 24 hours of age. Blood samples were taken from control infants at birth, at 2 to 6 hours, and at 12 to 24 hours of age. Phagocyte CD11b expression was analyzed by flow cytometry.RESULTS. In ventilated infants, phagocyte CD11b expression increased from birth to the first postnatal samples. It increased further by 12 to 24 hours of age. Control infants with or without nasal continuous positive airway pressure showed no significant increase after birth. At 12 to 24 hours of age, phagocyte CD11b expression was higher in ventilated infants than in control infants. In ventilated infants, neutrophil CD11b expression at 1 and 2 hours after surfactant correlated positively with gestational age.CONCLUSIONS. In preterm infants with RDS, significant activation of circulating phagocytes occurs within 1 to 3 hours of the onset of mechanical ventilation, independent of surfactant administration, which indicates that mechanical ventilation may be the inducer of this systemic inflammatory response.

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.

Pathophysiology of sepsis is characterised by a whole body inflammatory reaction and concurrent activation of the host's anti-inflammatory mechanisms. The balance between pro- and anti-inflammatory reactions is critical for the outcome of the patient. Strongly activated phagocytes and high levels of proinflammatory cytokines occur in patients who are at risk of developing circulatory shock and multiple organ dysfunction. Extensive anti-inflammatory reaction, which is characterised by the presence of high levels of circulating anti-inflammatory cytokines and impaired innate and adaptive immune functions, renders critically ill patients prone to secondary infections. Evaluation of the immune-inflammatory status on admission to the hospital may be helpful in the early identification of patients who are bound to develop organ dysfunction. Such patients could possibly benefit from a mode of therapy aimed at modifying the course of inflammatory response. The use of inflammatory markers may also improve diagnosis of severe infection. The present review summarises the studies on markers of inflammation and immune suppression used, first, as predictors of organ dysfunction in patients with systemic inflammation, and, second, as indicators of infection in adults and neonates.

AIM To investigate the effects of early dexamethasone administration on activation of circulating neutrophils and monocytes in preterm infants with respiratory distress syndrome requiring treatment with surfactant. METHODS Neonates (n = 30) with respiratory distress were randomized to receive dexamethasone (DEX group, 29.1 +/- 1.2 wk, 1223 +/- 156 g, n = 15) from the first postnatal day, or to serve as controls (control group, 29.2 +/- 1.4 wk, 1250 +/- 148 g, n = 15). Dexamethasone was given as a 4 d course (0.5 mg kg(-1) on postnatal days 1 and 2, and 0.25 mg kg(-1) on days 3 and 4). Polymorphonuclear leucocyte (PMN) and monocyte surface expression of CD11b, L-selectin and CD14 was quantified with flow cytometry, and plasma macrophage-inflammatory protein-1alpha (MIP-1alpha) with an enzyme-linked immunosorbent assay. Blood samples were collected on days 1, 2-3 and 5-7. RESULTS In the DEX group 1/15, and in the control group 7/15 developed bronchopulmonary dysplasia (p < 0.04). PMN CD11b (median 100, range 70-190 vs 154, 96-213, p=0.01), monocyte CD14 (235, 102-433 vs 355, 219-533, p=0.01) and plasma MIP-1alpha (20 ng l(-1), 20-32 vs 37 ng l(-1), 20-70, p = 0.005) were lower in the DEX group at days 2-3. All adhesion molecule expression and plasma MIP-1alpha levels were comparable at days 5-7, with the exception of monocyte L-selectin expression levels, which remained lower in the DEX group. CONCLUSION In preterm infants with respiratory distress syndrome, early dexamethasone causes downregulation of PMN and monocyte activation. This may attenuate pulmonary inflammation and improve pulmonary outcome.

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, χ2, 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.

Respiratory distress syndrome (RDS) and development of bronchopulmonary dysplasia (BPD) are characterized by endothelial cell damage. Persistent pulmonary hypertension of the newborn (PPHN) is a disorder that alters the pulmonary microvasculature. Immunohistochemistry for VEGFA(165), an endothelial cell mitogen, and its receptor Flt-1, was performed on lung tissues from autopsies from four fetuses, three preterm infants, four term infants without primary lung disease, four infants with BPD, and four infants with PPHN. VEGF was measured in tracheal aspirates from 31 preterm infants, 5 intubated term infants without primary lung injury, and 12 infants with PPHN during the first 10 postnatal days, and from 8 infants with BPD. Immunohistochemistry for VEGF and Flt-1 was similar in fetuses, preterm infants, and term infants: for VEGF mostly in bronchial epithelium and alveolar macrophages, and for Flt-1 mostly in vascular endothelial cells and bronchial epithelial cells. In patients with BPD, and PPHN, staining for VEGF and Flt-1 appeared also in Type II pneumocytes. Preterm infants with more severe RDS had lower VEGF than those who recovered. The persistent expression of VEGF and Flt-1 during the fetal and neonatal period supports a physiological role for VEGF in human lung development. The lower pulmonary VEGF in preterm infants with more severe RDS may contribute to the pathophysiology of the acute lung injury. In BPD, the expression of VEGF in alveolar epithelium may represent a compensatory increase after the acute phase of the lung disease. In PPHN, that more cell types express VEGF and Flt-1, and the tendency toward a higher concentration of pulmonary VEGF may represent enhanced production of VEGF in response to impaired endothelial function.

Background: In preterm infants with respiratory distress syndrome (RDS), early activation of circulating phagocytes is present as a sign of systemic inflammation. Phagocytes interact closely with lymphocytes. The role of lymphocytes in the pathogenesis in RDS is unclear. The aim of this study was to evaluate lymphocyte subsets and their activation during the first postnatal week in preterm infants with and without RDS.

Background: Majority of peripheral blood T-cells express the aâT-cell receptor (TCRaâ), which recognizes specific MHC-bound antigens. In the adult, 5–10% of blood T-cells express the TCRaa-receptor. TCRaa-cells recognize antigens in a non-MHC-restricted manner and are part of innate immunity. They are thought to act in defence against microbial pathogens and may play a role in controlling inflammation and preventing chronic inflammatory reactions. Newborn infants, especially those born very preterm, are susceptible to infections. In preterm infants inflammation may play a role in the development of chronic complications. However, little is known about the T-cell subsets in the perinatal period in newborn infants. The aim of this study was to evaluate the TCR aâ and aa -subsets in the peripheral blood in newborn preterm and term infants in comparision with adults.

Objective.To assess neutrophil CD11b and circulating interleukin 8 (IL-8) as markers of early-onset infection in neonates.Methods.The study comprised 39 neonates, with a gestational age of 29 to 41 weeks, suspected of infection within 48 hours of life. Neutrophil surface expression of CD11b was quantified with flow cytometry and plasma IL-8 with an enzyme-linked immunosorbent assay. Both data were available from 35 of 39 neonates. Serum C-reactive protein was determined at initial evaluation and, later, on the basis of the clinical picture. Neonates were allocated retrospectively into 2 groups. In the sepsis group (N = 22), 4 had culture-proven sepsis, and 14 had an antenatal risk factor for infection. In the possible-infection group (N = 13), each neonate had a noninfective disorder, but co-occurring infection remained a possibility. Twelve healthy term infants served as controls.Results.CD11b expression and IL-8 levels both increased in order of sepsis > possible infection > healthy. Sensitivity and specificity by the CD11b test for sepsis were equal, at 1.00, and those by the IL-8 test 0.91 and 1.00, respectively; 6 (17.1%) of the 35 neonates had CD11b and IL-8 below cutoff levels.Conclusions.Measuring neutrophil CD11b expression and circulating IL-8 provides a means to identify early-onset neonatal sepsis. The findings may be helpful in planning strategies to safely reduce the use of antimicrobials in neonates.

Cord Blood Neutrophils have Higher Adherence than Adult Neutrophils to Cultured Endothelial Cells (HUVEC) 790