Maternal and fetal safety outcomes after in utero stem cell injection: A systematic review.

OBJECTIVE: To investigate the maternal and fetal safety of In utero stem cell transplantation (IUSCT). METHODS: Medline®, Embase and Cochrane library (1967-2023) search for publications reporting IUSCT in humans. Two reviewers independently screened abstracts and full-text papers. RESULTS: Sixty six transplantation procedures in 52 fetuses were performed for haemoglobinopathies (n = 14), red cell/bleeding disorders (n = 4), immunodeficiencies (n = 15), storage disorders (n = 7), osteogenesis imperfecta (n = 2) and healthy fetuses (n = 10). The average gestational age was 18.9 weeks; of procedures reporting the injection route, cells were delivered by intraperitoneal (n = 37), intravenous (n = 19), or intracardiac (n = 4) injection or a combination (n = 3); most fetuses received one injection (n = 41). Haematopoietic (n = 40) or mesenchymal (n = 12) stem cells were delivered. The cell dose was inconsistently reported (range 1.8-3.3 × 109 cells total (n = 27); 2.7-5.0 × 109 /kg estimated fetal weight (n = 17)). The acute fetal procedural complication rate was 4.5% (3/66); the acute fetal mortality rate was 3.0% (2/66). Neonatal survival was 69.2% (36/52). Immediate maternal and pregnancy outcomes were reported in only 30.8% (16/52) and 44.2% (23/52) of cases respectively. Four fetal/pregnancy outcomes would also classify as ≥ Grade 2 maternal adverse events. CONCLUSIONS: Short-, medium-, and long-term maternal and fetal adverse events should be reported in all IUSCT studies.

Development of standard definitions and grading for Maternal and Fetal Adverse Event Terminology.

OBJECTIVE: Adverse event (AE) monitoring is central to assessing therapeutic safety. The lack of a comprehensive framework to define and grade maternal and fetal AEs in pregnancy trials severely limits understanding risks in pregnant women. We created AE terminology to improve safety monitoring for developing pregnancy drugs, devices and interventions. METHOD: Existing severity grading for pregnant AEs and definitions/indicators of 'severe' and 'life-threatening' conditions relevant to maternal and fetal clinical trials were identified through a literature search. An international multidisciplinary group identified and filled gaps in definitions and severity grading using Medical Dictionary for Regulatory Activities (MedDRA) terms and severity grading criteria based on Common Terminology Criteria for Adverse Event (CTCAE) generic structure. The draft criteria underwent two rounds of a modified Delphi process with international fetal therapy, obstetric, neonatal, industry experts, patients and patient representatives. RESULTS: Fetal AEs were defined as being diagnosable in utero with potential to harm the fetus, and were integrated into MedDRA. AE severity was graded independently for the pregnant woman and her fetus. Maternal (n = 12) and fetal (n = 19) AE definitions and severity grading criteria were developed and ratified by consensus. CONCLUSIONS: This Maternal and Fetal AE Terminology version 1.0 allows systematic consistent AE assessment in pregnancy trials to improve safety.

Traction force profile in children with severe perinatal outcomes delivered with a digital vacuum extraction handle: A case-control study.

INTRODUCTION: During the second stage of labor, vacuum-assisted delivery is an alternative to forceps delivery and emergency cesarean section. Extensive research concerning perinatal outcomes has indicated that the risk of complications, although rare, is higher than with a spontaneous vaginal delivery. An important factor related to perinatal outcomes is the traction force applied. Our research group previously developed a digital extraction handle, the Vacuum Intelligent Handle-3 (VIH3), that measures and records traction force. The objective of this study was to compare traction force profiles in children with and without severe perinatal outcomes delivered with the digital handle. A secondary aim was to establish a safe force limit. MATERIAL AND METHODS: This was an observational case-control study at the delivery ward at Karolinska University Hospital, Sweden. In total, 573 children delivered with the digital handle between 2012 and 2018 were included. Cases were defined as a composite of severe perinatal outcomes, including subgaleal hematoma, intracranial hemorrhage, hypoxic ischemic encephalopathy 1-3, seizures or death. The cases in the cohort were matched 1:3 based on five matching variables. Traction profiles were analyzed using the MATLAB® software and conditional logistic regression. RESULTS: The incidence of severe perinatal outcomes was 2.3%. The 13 cases were matched with three controls each (n = 39). A statistically significant increased odds for higher total traction forces was seen in the case group (odds ratio [OR] 1.004; 95% confidence interval [CI] 1.001-1.007) and for the peak force (OR 1.022; 95% CI 1.004-1.041). Several procedure-related parameters were significantly increased in the case group. As expected, some neonatal characteristics also differed significantly. An upper force limit of 343 Newton minutes (Nmin) revealed an 86% reduction in severe perinatal outcomes (adjusted OR 0.14; 95% CI 0.04-0.5). CONCLUSIONS: Children with severe perinatal outcomes had traction force profiles with significantly higher forces. The odds for severe perinatal outcomes increased for every increase in Nmin and Newton used during the extraction procedure. A calculated total force level of 343 Nmin is suggested as an upper safety limit, but this must be tested prospectively to provide validity.

Perinatal outcome after vacuum assisted delivery with digital feedback on traction force; a randomised controlled study.

BACKGROUND: Low and mid station vacuum assisted deliveries (VAD) are delicate manual procedures that entail a high degree of subjectivity from the operator and are associated with adverse neonatal outcome. Little has been done to improve the procedure, including the technical development, traction force and the possibility of objective documentation. We aimed to explore if a digital handle with instant haptic feedback on traction force would reduce the neonatal risk during low or mid station VAD. METHODS: A two centre, randomised superiority trial at Karolinska University Hospital, Sweden, 2016-2018. Cases were randomised bedside to either a conventional or a digital handle attached to a Bird metal cup (50 mm, 80 kPa). The digital handle measured applied force including an instant notification by vibration when high levels of traction force were predicted according to a predefined algorithm. Primary outcome was a composite of hypoxic ischaemic encephalopathy, intracranial haemorrhage, seizures, death and/or subgaleal hematoma. Three hundred eighty low and mid VAD in each group were estimated to decrease primary outcome from six to 2 %. RESULTS: After 2 years, an interim analyse was undertaken. Meeting the inclusion criteria, 567 vacuum extractions were randomized to the use of a digital handle (n = 296) or a conventional handle (n = 271). Primary outcome did not differ between the two groups: (2.7% digital handle vs 2.6% conventional handle). The incidence of primary outcome differed significantly between the two delivery wards (4% vs 0.9%, p < 0.05). A recalculation of power revealed that 800 cases would be needed in each group to show a decrease in primary outcome from three to 1 %. This was not feasible, and the study therefore closed. CONCLUSIONS: The incidence of primary outcome was lower than estimated and the study was underpowered. However, the difference between the two delivery wards might reflect varying degree of experience of the technical equipment. An objective documentation of the extraction procedure is an attractive alternative in respect to safety and clinical training. To demonstrate improved safety, a multicentre study is required to reach an adequate cohort. This was beyond the scope of the study. TRIAL REGISTRATION: ClinicalTrials.gov NCT03071783 , March 1, 2017, retrospectively registered.

Mesenchymal Stem Cell Therapy for Osteogenesis Imperfecta.

The aim of this study was to provide a brief overview on the background and rationale on treating fetuses and children suffering from osteogenesis imperfecta (OI) with mesenchymal stem cells (MSCs). MSCs ability to migrate, engraft, and differentiate into bone cells and to act via paracrine effects on the recipient's tissues makes these cells promising candidates as a clinical therapy for OI. Animal work and limited clinical studies in humans support the use of MSC in treating OI. Off-the-shelf MSC have a good safety profile and exhibit multilineage differentiation potential and a low immunogenic profile and thereby may enable this potential therapy to become widely available. MSC transplantation before and after birth to treat OI is an experimental therapy that is currently tested in the international multicentre phase I/II clinical trial BOOSTB4 that aims to assess the safety and efficacy of fetal MSC transplantation for the treatment of severe types of OI.

Association of traction force and adverse neonatal outcome in vacuum-assisted vaginal delivery: A prospective cohort study.

INTRODUCTION: Traction force is a possible risk factor for adverse neonatal outcome in vacuum extraction delivery, but the knowledge is scarce and further investigation is needed. Our hypothesis was that high-level traction force increases the risk of admission to the neonatal intensive care unit. MATERIAL AND METHODS: The study was a hospital-based prospective cohort study on low- and mid-vacuum extractions at the labor and delivery ward, Karolinska University Hospital, Huddinge, Sweden. Traction forces were measured in 331 women. An electronical handle was used to measure and register traction force. The main exposure variable was high-level traction force (≥75th percentile) during the first three pulls and the primary outcome was admission to the neonatal intensive care unit. Logistic regression was used to estimate the adjusted risk. RESULTS: Among the exposed, 14/84 (16.7%) were admitted to neonatal intensive care, and among the unexposed 10/247 (4%). The crude odds ratio (OR) of admission to the neonatal intensive care unit when exposed to high-level traction force was 4.7, and the adjusted (birthweight, gestational length, cup detachment, number of pulls, duration, duration >15 minutes, mid-cavity fetal head station, failed extraction, indication and parity) OR was 2.85 (95% confidence interval [CI] 1.09-7.48). No significant effect was seen in Apgar scores <7 at 5 minutes or pH <7.1. CONCLUSIONS: High-level traction force may be a risk factor for neonatal complications. Although these results do not mandate any alterations in clinical guidelines, perioperative feedback on traction force may be useful to alert the obstetrician to a timely conversion to cesarean section. To study plausible traction force specific outcomes such as head traumas, a larger sample size is required.

Is obesity in pregnancy associated with signs of chronic fetal hypoxia?

INTRODUCTION: The prevalence of obesity in pregnancy is increasing worldwide. Maternal obesity increases risks of severe fetal and neonatal complications. The underlying pathophysiological mechanisms are unclear. One possible contributing factor could be chronic fetal hypoxia. The aim of this study was to compare placentas from women with and without obesity with respect to placental lesions, which could reflect compensatory mechanisms in response to chronic fetal hypoxia as well as lesions possibly leading to chronic fetal hypoxia. In addition, levels of erythropoietin in cord blood were compared between offspring of lean and obese women. MATERIAL AND METHODS: This cohort study included 180 women with uneventful, full-term, singleton pregnancies, out of which 91 lean women had a body mass index (BMI) of 18.5-24.9 kg/m2 and 89 women had obesity (BMI ≥30 kg/m2 ). Women were recruited at Södersjukhuset between 16 October 2018 and 2 December 2019. Placentas were investigated by two senior perinatal pathologists, who were blinded for maternal BMI. Cord blood was analyzed for levels of erythropoietin. RESULTS: Levels of erythropoietin in cord blood increased with maternal BMI (P = .01, ß = 0.97, 95% CI 0.27-1.68). There was no difference between placentas of obese and lean women in number of placental lesions reflecting chronic fetal hypoxia or in lesions that could possibly lead to chronic fetal hypoxia. CONCLUSIONS: This study of term and uneventful pregnancies demonstrated a positive association between maternal obesity and concentrations of erythropoietin in cord blood at birth. This finding supports the hypothesis of chronic fetal hypoxia as a risk factor for complications in the pregnancies of obese women. There were no differences in lesions associated with hypoxia between placentas of obese and lean women.

A new microdialysis probe for continuous lactate measurement during fetal monitoring: Proof of concept in an animal model.

INTRODUCTION: Cardiotocography (CTG) is currently the most commonly used method for intrapartum fetal monitoring during labor. However, a high false-positive rate of fetal acidosis indicated by CTG leads to an increase in obstetric interventions. We developed a microdialysis probe that is integrated into a fetal scalp electrode allowing continuous measurement of lactate subcutaneously, thus giving instant information about the oxygenation status of the fetus. Our aim was to establish proof of concept in an animal model using a microdialysis probe to monitor lactate subcutaneously. MATERIAL AND METHODS: We performed an in vivo study in adult male wild-type Wistar rats. We modified electrodes used for CTG monitoring in human fetuses to incorporate a microdialysis membrane. Optimum flow rates for microdialysis were determined in vitro. For the in vivo experiment, a microdialysis probe was inserted into the skin on the back of the animal. De-oxygenation and acidosis were induced by lowering the inspiratory oxygen pressure. Oxygenation and heart rate were monitored. A jugular vein cannula was inserted to draw blood samples for analysis of lactate, pH, pco2 , and saturation. Lactate levels in dialysate were compared with plasma lactate levels. RESULTS: Baseline blood lactate levels were around 1 mmol/L. Upon de-oxygenation, oxygen saturation fell to below 40% for 1 h and blood lactate levels increased 2.5-fold. Correlation of dialysate lactate levels with plasma lactate levels was 0.89 resulting in an R2 of .78 in the corresponding linear regression. CONCLUSIONS: In this animal model, lactate levels in subcutaneous fluid collected by microdialysis closely reflected blood lactate levels upon transient de-oxygenation, indicating that our device is suitable for subcutaneous measurement of lactate. Microdialysis probe technology allows the measurement of multiple compounds in the dialysate, such as glucose, albumin, or inflammatory mediators, so this technique may offer the unique possibility to shed light on fetal physiology during the intrapartum period.

Fetal cardiac function at intrauterine transfusion assessed by automated analysis of color tissue Doppler recordings.

BACKGROUND: Fetal anemia is associated with a hyperdynamic circulation and cardiac remodeling. Rapid intrauterine transfusion (IUT) of blood with high hematocrit and viscosity into the umbilical vein used to treat this condition can temporarily further affect fetal heart function. The aim of this study was to evaluate the short-term changes in fetal myocardial function caused by IUT using automated analysis of cine-loops of the fetal heart obtained by color tissue Doppler imaging (cTDI). METHODS: Fetal echocardiography was performed before and after IUT. cTDI recordings were obtained in a four-chamber view and regions of interest were placed at the atrioventricular plane in the left ventricular (LV), right ventricular (RV) and septal walls. Myocardial velocities were analyzed by an automated analysis software to obtain peak myocardial velocities during atrial contraction (Am), ventricular ejection (Sm), rapid ventricular filling (Em) and Em/Am ratio was calculated. Myocardial velocities were converted to z-scores using published reference ranges. Delta z-scores (after minus before IUT) were calculated. Correlations were assessed between variables and hemoglobin before IUT. RESULTS: Thirty-two fetuses underwent 70 IUTs. Fourteen were first time transfusions. In the LV and septal walls, all myocardial velocities were significantly increased compared to normal values, whereas in the RV only Sm was increased before IUT (z-scores 0.26-0.52). In first time IUTs, there was a negative correlation between LV Em (rho = - 0.61, p = 0.036) and LV Em/Am (rho = - 0.82, p = 0.001) z-scores and hemoglobin before IUT. The peak myocardial velocities that were increased before IUT decreased, whereas LV Em/Am increased significantly after IUT. CONCLUSIONS: This study showed that peak myocardial velocities assessed by cTDI are increased in fetuses before IUT reflecting the physiology of hyperdynamic circulation. In these fetuses, the fetal heart is able to adapt and efficiently handle the volume load caused by IUT by altering its myocardial function.

Long-Term Follow-Up of a Pilot Study Using Placenta-Derived Decidua Stromal Cells for Severe Acute Graft-versus-Host Disease.

There is a need for effective therapy with few side effects for severe acute graft-versus-host disease (GVHD). The placenta protects the fetus from the mother's haploidentical immune system during pregnancy. We found that maternal stromal cells from the fetal membrane, so-called decidua stromal cells (DSCs), are more immunosuppressive than other sources of stromal cells. We prospectively treated 21 patients (median age, 49 years; range, 1.6 to 72 years) for grade II-IV acute GVHD. All 21 patients had biopsy-proven gastrointestinal GVHD. The majority of patients were either steroid-refractory or had progressive GVHD, 11 patients after >7 days or with progression after 3 days, and 10 were refractory to steroids after >3 days. We used an improved protocol in which DSCs were thawed and infused in a buffer with 5% human albumin. DSCs were given at a median dose of 1.2 (range, 0.9 to 2.9) × 106 cells/kg body weight with a median of 2 (range, 1 to 6) doses, given 1 week apart. The median viability of thawed DSCs was 93% (range, 69% to 100%), and the median cell passage number was 4 (range, 2 to 4). Complete resolution of GVHD was seen in 11 patients, with a partial response in the other 10. The cumulative incidence of chronic GVHD was 52%. GVHD was mild in 6 patients, moderate in 4 patients, and severe in 1 patient based on National Institutes of Health chronic GVHD severity scoring. Nine patients died, including 3 from relapse and 1 each from acute GVHD and septicemia, Zygomycetes infection, liver insufficiency, cerebral hemorrhage, multiple organ failure, and chronic GVHD with obstructive bronchiolitis. Four-year transplantation-related mortality was 28.6%, and overall survival was 57%. Survival was similar (P = .33) to that for all 293 patients who underwent allogeneic hematopoietic cell transplantation during the same period (2012 to 2015), with 66% overall survival. DSC infusion is a novel therapy for acute GVHD grade II-IV, and a randomized trial is currently underway (ClinicalTrials.gov NCT02172937).

Occupational exposure to organic particles and combustion products during pregnancy and birth outcome in a nationwide cohort study in Sweden.

OBJECTIVE: To study if children of women exposed to organic particles and combustion products at work during pregnancy, have an increased risk of low birth weight, preterm birth or small for gestational age. METHODS: A nationwide cohort of all occupationally active mothers and their children from single births during 1994 to the end of 2012 (1 182 138 observations) was formed. Information on birth outcome was obtained from the medical birth register. Information on absence from work, education, occupation, age, nationality and smoking habits was obtained from national registers. A job exposure matrix (FINJEM) was used to assess the exposure. RESULTS: Pregnant women with low absence from work and high (>50th percentile) exposure to organic particles had an increased risk of giving birth to children with low birth weight (OR=1.19; 95% CI: 1.07 to 1.32), small for gestational age (OR=1.22; 95% CI: 1.07 to 1.38) or preterm birth (OR=1.17; 95% CI: 1.08 to 1.27). Subgroup analyses showed an increased risk of small for gestational age in association with exposure to oil mist. Exposure to oil mist and cooking fumes was associated with low birth weight. Paper and other organic dust was associated with preterm birth. Exposure to combustion products showed an increased risk of small for gestational age (OR=1.40; 95% CI: 1.15 to 1.71). CONCLUSIONS: The results indicate that occupational exposure to organic particles or combustion products during pregnancy is associated with restriction of fetal growth and preterm birth. More studies are needed to confirm a casual association.

Genetic Analysis of Copy Number Variation in Large Chorangiomas.

INTRODUCTION: Chorangioma (CA) is the most common nontrophoblastic, vascular tumor-like lesion of the placenta with a reported incidence of 0.5% to 1% in all examined placentas. The underlying molecular mechanisms of CAs are still poorly elucidated, and a systematic investigation of the genetic background of CAs has not previously been done. MATERIALS AND METHODS: Tissue biopsies from 8 large (>40 mm) histologically confirmed CAs and 8 unaffected matched placenta controls, along with standard control DNA samples were analyzed for large genomic deletions and duplications using array comparative genomic hybridization (array-CGH) method. RESULTS: Array-CGH analysis revealed no rare or novel copy number variants in the CA samples compared with either standard control DNA or unaffected placenta DNA from the same individual. DISCUSSION: In this study, a systematic genetic investigation of 8 large CAs failed to demonstrate any large-scale pathogenic genetic changes. This lack of association might support a nongenetic, nontumorous origin of these lesions; however, additional genetic studies focusing on smaller genomic alterations are required to fully assess any possible genetic contribution.

Prediction of large-for-gestational-age infants in pregnancies complicated by obesity: A population-based cohort study.

INTRODUCTION: Infants born large for gestational age (LGA) have increased risks of adverse perinatal outcomes. Maternal obesity, defined as body mass index (BMI) ≥30 kg/m2 , is one of the most prevalent risk factors for LGA and the proportion of pregnancies complicated by obesity is increasing. Early identification of women with BMI ≥30 kg/m2 at increased risk of giving birth to an LGA infant may open possibilities for prevention, aiming at decreasing the incidence of LGA. MATERIAL AND METHODS: A population-based cohort study using information from the first-trimester screening database, which was cross-linked with the Swedish Medical Birth Register. The database included 139 277 full-term singletons without fetal anomalies born between 2006 and 2015 to mothers without prepregnancy diabetes. Of these, 9.1% (n = 12 704) were infants of mothers with BMI ≥30 kg/m2 . For all women with BMI ≥30 kg/m2 , a prediction model for LGA to be used in early pregnancy was constructed based on information on biochemical markers and maternal characteristics. A similar model, as well as a prepregnancy prediction model, were constructed for parous women with BMI ≥30 kg/m2 . In parous women, data from the previous pregnancy were also used. Receiver operating characteristic curve and area under curve (AUC) were calculated. RESULTS: The predictive models for LGA in parous women with BMI ≥30 kg/m2 prepregnancy and in early pregnancy had AUCs of 0.80 (95% CI 0.78-0.82) and 0.81 (95% CI 0.79-0.82), respectively. For all women with BMI ≥30 kg/m2 , the prediction of LGA in early pregnancy had an AUC of 0.66 (95% CI 0.64-0.67). CONCLUSIONS: Performance of the prepregnancy and early pregnancy prediction models for LGA in parous women with BMI ≥30 kg/m2 was good. The predictive capacity was largely driven by previous child's birthweight. First-trimester measurements of fetal size did not improve the predictive capacity in parous women. Predictions of LGA in all women with BMI ≥30 kg/m2 in early pregnancy, without taking previous child's birthweight into account, remain difficult.

Effect of team training and monitoring on the rate of failed mid and low cavity vacuum extraction: a hospital based intervention study.

BACKGROUND: Clinical team training has been advocated as a means to improve delivery care, and failed extractions is a suggested variable for clinical audit in instrumental vaginal delivery. Other activities may also have intended or unintended effects on care processes or outcomes. METHODS: We retrospectively observed 1074 mid and low vacuum extraction deliveries during three time periods (prevalence periods): Baseline (period 0), implemented team training (period 1 and 2) and monitoring of traction force during vacuum extraction (period 2). Our primary outcome was failed extraction followed by emergency cesarean section or obstetric forceps delivery. RESULTS: The prevalence proportion (relative risk) of failed extraction decreased significantly after implementation of team training, from 19% (period 0) to 8 % (period 1), corresponding to a relative risk of 0.48 [0.26-0.87]. The secondary procedural outcome complicated delivery (duration > 15 min or number of pulls > 6, or cup detachment > 1) was decreased in period 2 compared to period 1, RR 0.42 [0.23-0.76]. Secondary clinical (neonatal) outcome were not affected. CONCLUSION: Clinically based educational efforts and increased monitoring improved procedural outcome without improving neonatal outcome. The study design has inherent limitations in making causal inference.

Composition and functionality of the intrahepatic innate lymphoid cell-compartment in human nonfibrotic and fibrotic livers.

Human innate lymphoid cells have been described to exist in different organs, with functional deregulation of these cells contributing to several disease states. Here, we performed the first detailed characterization of the phenotype, tissue-residency properties, and functionality of ILC1s, ILC2s, and ILC3s in the human adult and fetal liver. In addition, we investigated changes in the ILC compartment in liver fibrosis. A unique composition of tissue-resident ILCs was observed in nonfibrotic livers as compared with that in mucosal tissues, with NKp44- ILC3s accounting for the majority of total intrahepatic ILCs. The frequency of ILC2s, representing a small fraction of ILCs in nonfibrotic livers, increased in liver fibrosis and correlated directly with the severity of the disease. Notably, intrahepatic ILC2s secreted the profibrotic cytokine IL-13 when exposed to IL-33 and thymic stromal lymphopoetin (TSLP); these cytokines were produced by hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells in response to TLR-3 stimulation. In summary, the present results provide the first detailed characterization of intrahepatic ILCs in human adult and fetal liver. The results indicate a role for ILC2s in human liver fibrosis, implying that targeting ILC2s might be a novel therapeutic strategy for its treatment.

Intracranial hemorrhages in neonates born from 32 weeks of gestation-low frequency of associated fetal and neonatal alloimmune thrombocytopenia: a register-based study.

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare condition, with an estimated incidence of one in 1000 to 2000 live births. Predominantly, FNAIT is due to maternal alloantibodies that target paternally derived human platelet antigen (HPA) 1a. The most feared complication is an intracranial hemorrhage (ICH). The aim of this study was to determine the frequency of associated maternal platelet (PLT) alloimmunization in a population of neonates born from 32 weeks of gestation and diagnosed with an ICH. STUDY DESIGN AND METHODS: The Swedish Neonatal Quality (SNQ) register was used to identify neonates diagnosed with an ICH born between 2003 and 2012. Mothers were invited to donate peripheral blood, to investigate their HPA-1a antigen status, and test for anti-HPA and anti-HLA Class I alloantibodies. Clinical data for the neonates were retrieved from the SNQ register and available clinical records. RESULTS: Of 286 registered neonates, 278 mothers were contacted. Of 105 analyzed maternal samples, two (1.9%) were HPA-1a antigen negative. Antibody analyses revealed in total three (2.9%) mothers with anti-HPA: one mother (0.94%) with anti-HPA-1a and two mothers (1.9%) with anti-HPA-5b, of whom one had concurrent anti-HPA-15a. Twenty-four percent tested positive for anti-HLA Class I antibodies. A total of 8.5% of neonates (5/59) with PLT counts available in clinical records were severely thrombocytopenic, with PLT counts of less than 50 × 109 /L. CONCLUSIONS: This retrospective cohort revealed a wide range of factors associated with ICH in neonates born from 32 weeks of gestation and suggests PLT alloimmunization to be a less common contributor than anticipated.

Fetal CD103+ IL-17-Producing Group 3 Innate Lymphoid Cells Represent the Dominant Lymphocyte Subset in Human Amniotic Fluid.

Amniotic fluid (AF) surrounds the growing fetus, and cells derived from AF are commonly used for diagnosis of genetic diseases. Intra-amniotic infections are strongly linked to preterm birth, which is the leading cause of perinatal mortality worldwide. Surprisingly little is known, however, about mature hematopoietic cells in AF, which could potentially be involved in immune responses during pregnancy. In this study, we show that the dominating population of viable CD45+ cells in AF is represented by a subset of fetal CD103+ group 3 innate lymphoid cells (ILCs) producing high levels of IL-17 and TNF. Fetal CD103+ ILC3s could also be detected at high frequency in second-trimester mucosal tissues (e.g., the intestine and lung). Taken together, our data indicate that CD103+ ILC3s accumulate with gestation in the fetal intestine and subsequently egress to the AF. The dominance of ILC3s producing IL-17 and TNF in AF suggests that they could be involved in controlling intra-amniotic infections and inflammation and as such could be important players in regulating subsequent premature birth.

Antenatal corticosteroid treatment and placental pathology, with a focus on villous maturation.

INTRODUCTION: Mothers at risk of preterm birth are treated with antenatal corticosteroids, which have advantageous effects for prematurely born infants. Accelerated villous maturation in the placenta is also associated with improved perinatal outcome. The primary aim of this study was to examine the association between antenatal corticosteroids and accelerated villous maturation. The secondary aim was to study associations with other placental pathologies. MATERIAL AND METHODS: A retrospective cohort study including 105 women who had (n = 75) or had not (n = 30) been treated with antenatal corticosteroids. The women gave birth between 22+0 and 26+6  weeks of gestation in Stockholm County between 1 April 2004 and 31 March 2007. A pathologist blinded to all clinical data except gestational age examined the placental slides to identify pathology parameters. The outcomes were correlated with antenatal corticosteroid treatment, and confounding factors were adjusted using logistic regression. RESULTS: Accelerated villous maturation was significantly higher in the group treated with corticosteroids (odds ratio 16, 95% CI 2.4-690, p = 0.0005). After adjustment for gestational age and preeclampsia, the difference remained significant (odds ratio 8.9, 95% CI 1.2-389, p = 0.021). No significant associations were found regarding the secondary outcome variables, after adjusting for possible confounders. CONCLUSIONS: Antenatal corticosteroid treatment before preterm birth is associated with accelerated villous maturation. This could be one of the pathways by which corticosteroids are beneficial for preterm infants.

Comprehensive RNA sequencing of healthy human endometrium at two time points of the menstrual cycle.

Endometrial receptivity is crucial for implantation and establishment of a normal pregnancy. The shift from proliferative to receptive endometrium is still far from being understood. In this paper, we comprehensively present the transcriptome of the human endometrium by comparing endometrial biopsies from proliferative phase with consecutive biopsies 7-9 days after ovulation. The results show a clear difference in expression between the two time points using both total and small RNA sequencing. A total of 3,297 messenger RNAs (mRNAs), 516 long noncoding RNAs (lncRNAs), and 102 small noncoding RNAs were identified as statistically differentially expressed between the two time points. We show a thorough description of the change in mRNA between the two time points and display lncRNAs, small nucleolar RNAs, and small nuclear RNAs not previously reported in the healthy human endometrium. In conclusion, this paper reports in detail the shift in RNA expression from the proliferative to receptive endometrium.

Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells.

Although NK cells are considered innate, recent studies in mice revealed the existence of a unique lineage of hepatic CD49a(+)DX5(-) NK cells with adaptive-like features. Development of this NK cell lineage is, in contrast to conventional NK cells, dependent on T-bet but not Eomes. In this study, we describe the identification of a T-bet(+)Eomes(-)CD49a(+) NK cell subset readily detectable in the human liver, but not in afferent or efferent hepatic venous or peripheral blood. Human intrahepatic CD49a(+) NK cells express killer cell Ig-like receptor and NKG2C, indicative of having undergone clonal-like expansion, are CD56(bright), and express low levels of CD16, CD57, and perforin. After stimulation, CD49a(+) NK cells express high levels of inflammatory cytokines but degranulate poorly. CD49a(+) NK cells retain their phenotype after expansion in long-term in vitro cultures. These results demonstrate the presence of a likely human counterpart of mouse intrahepatic NK cells with adaptive-like features.